(Nsaids) in Neat Organic Solvents and Organic Solvent Mixtures William E

Home , Alclofenac, Dexibuprofen, Fentiazac, Lornoxicam

IUPAC-NIST Solubility Data Series. 102. Solubility of Nonsteroidal Anti-inflammatory Drugs (NSAIDs) in Neat Organic Solvents and Organic Solvent Mixtures William E. Acree Jr.

Citation: Journal of Physical and Chemical Reference Data 43, 023102 (2014); doi: 10.1063/1.4869683 View online: http://dx.doi.org/10.1063/1.4869683 View Table of Contents: http://scitation.aip.org/content/aip/journal/jpcrd/43/2?ver=pdfcov Published by the AIP Publishing

This article is copyrighted as indicated in the article. Reuse of AIP content is subject to the terms at: http://scitation.aip.org/termsconditions. Downloaded to IP: 129.120.138.243 On: Fri, 25 Apr 2014 17:01:34 IUPAC-NIST Solubility Data Series. 102. Solubility of Nonsteroidal Anti-inﬂammatory Drugs (NSAIDs) in Neat Organic Solvents and Organic Solvent Mixtures

William E. Acree, Jr. a) Department of Chemistry, University of North Texas, Denton, Texas 76203, USA

(Received 3 March 2014; accepted 4 March 2014; published online 25 April 2014)

Solubility data are compiled and reviewed for 33 nonsteroidal anti-inﬂammatory drugs dissolved in neat organic solvents and in well-deﬁned binary and ternary organic solvents. The compiled solubility data were retrieved primarily from the chemical and pharmaceutical literature covering the period from 1980 to the beginning of 2014. Ó 2014 AIP Publishing LLC. [http://dx.doi.org/10.1063/1.4869683]

Key words: mixtures; NSAIDs; organic solvents; solubility.

CONTENTS 5.2. Dexibuprofen solubility data in saturated hydrocarbons (including cycloalkanes) . . . . 23 5.3. Dexibuprofen solubility data in esters . . . . . 23 1. Preface ...... 5 5.4. Dexibuprofen solubility data in alcohols. . . 24 1.1. Scope of this volume ...... 5 6. Solubility of Diclofenac in Organic Solvents ... 27 1.2. Concentration units for nonelectrolyte 6.1. Critical evaluation of experimental solubility solutions ...... 6 data...... 27 1.3. Procedures used in critical evaluation of 6.2. Diclofenac solubility data in saturated published solubility data ...... 6 hydrocarbons (including cycloalkanes) . . . . 27 2. Solubility of Alclofenac in Organic Solvents ... 12 6.3. Diclofenac solubility data in aromatic 2.1. Critical evaluation of experimental solubility hydrocarbons...... 28 data...... 12 6.4. Diclofenac solubility data in esters ...... 29 2.2. Alclofenac solubility data in alcohols . . . . . 12 6.5. Diclofenac solubility data in ethers...... 29 3. Solubility of Aspirin in Organic Solvents ...... 12 6.6. Diclofenac solubility data in haloalkanes, 3.1. Critical evaluation of experimental solubility haloalkenes, and haloaromatic hydrocarbons 30 data...... 12 6.7. Diclofenac solubility data in alcohols . . . . . 31 3.2. Aspirin solubility data in miscellaneous 6.8. Diclofenac solubility data in ketones ...... 35 organic solvents ...... 13 6.9. Diclofenac solubility data in miscellaneous 4. Solubility of Celecoxib in Organic Solvents.... 13 organic solvents ...... 35 4.1. Critical evaluation of experimental solubility 7. Solubility of Diflunisal in Organic Solvents .... 39 data...... 13 7.1. Critical evaluation of experimental solubility 4.2. Celecoxib solubility data in saturated data...... 39 hydrocarbons (including cycloalkanes) . . . . 14 7.2. Diflunisal solubility data in saturated 4.3. Celecoxib solubility data in esters...... 14 hydrocarbons (including cycloalkanes) . . . . 40 4.4. Celecoxib solubility data in ethers ...... 15 7.3. Diflunisal solubility data in aromatic 4.5. Celecoxib solubility data in haloalkanes, hydrocarbons...... 40 haloalkenes, and haloaromatic hydrocarbons 15 7.4. Diflunisal solubility data in alcohols ...... 41 4.6. Celecoxib solubility data in alcohols ...... 16 7.5. Diflunisal solubility data in miscellaneous 4.7. Celecoxib solubility data in miscellaneous organic solvents ...... 43 organic solvents ...... 21 8. Solubility of Etoricoxib Organic Solvents...... 44 4.8. Celecoxib solubility data in binary organic 8.1. Critical evaluation of experimental solubility solvent mixtures...... 22 data...... 44 5. Solubility of Dexibuprofen in Organic Solvents. 22 8.2. Etoricoxib solubility data in alcohols...... 45 5.1. Critical evaluation of experimental solubility 8.3. Etoricoxib solubility data in miscellaneous data...... 22 organic solvents ...... 45 9. Solubility of Fenbufen in Organic Solvents .... 45 a)Electronic mail: [email protected]. 9.1. Critical evaluation of experimental solubility Ó 2014 AIP Publishing LLC. data...... 45

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9.2. Fenbufen solubility data in saturated 14.4. Indomethacin solubility data in alcohols . 106 hydrocarbons (including cycloalkanes) . . . . 46 14.5. Indomethacin solubility data in ketones . . 109 9.3. Fenbufen solubility data in alcohols...... 46 14.6. Indomethacin solubility data in binary 9.4. Fenbufen solubility data in miscellaneous organic solvent mixtures...... 109 organic solvents ...... 47 15. Solubility of Ketoprofen in Organic Solvents.. 113 10. Solubility of Fentiazac in Organic Solvents ... 47 15.1. Critical evaluation of experimental 10.1. Critical evaluation of experimental solubility data...... 113 solubility data...... 47 15.2. Ketoprofen solubility data in saturated 10.2. Fentiazac solubility data in alcohols . . . . . 47 hydrocarbons (including cycloalkanes) . . . 114 11. Solubility of Flufenamic Acid in Organic 15.3. Ketoprofen solubility data in aromatic Solvents ...... 48 hydrocarbons ...... 115 11.1. Critical evaluation of experimental 15.4. Ketoprofen solubility data in esters ...... 116 solubility data...... 48 15.5. Ketoprofen solubility data in ethers ...... 117 11.2. Flufenamic acid solubility data in saturated 15.6. Ketoprofen solubility data in haloalkanes, hydrocarbons (including cycloalkanes) . . . 48 haloalkenes, and haloaromatic 11.3. Flufenamic acid solubility data in aromatic hydrocarbons ...... 118 hydrocarbons ...... 49 15.7. Ketoprofen solubility data in alcohols. . . . 118 11.4. Flufenamic acid solubility data in alcohols 50 15.8. Ketoprofen solubility data in ketones . . . . 127 11.5. Flufenamic acid solubility data in 15.9. Ketoprofen solubility data in miscellaneous miscellaneous organic solvents ...... 51 organic solvents...... 128 12. Solubility of Flurbiprofen in Organic Solvents. 52 16. Solubility of Ketorolac in Organic Solvents ... 130 12.1. Critical evaluation of experimental 16.1. Critical evaluation of experimental solubility data...... 52 solubility data...... 130 12.2. Flurbiprofen solubility data in saturated 16.2. Ketorolac solubility data in alcohols . . . . . 131 hydrocarbons (including cycloalkanes) . . . 53 17. Solubility of Lornoxicam in Organic Solvents . 131 12.3. Flurbiprofen solubility data in aromatic 17.1. Critical evaluation of experimental hydrocarbons ...... 54 solubility data...... 131 12.4. Flurbiprofen solubility data in esters . . . . . 55 17.2. Lornoxicam solubility data in saturated 12.5. Flurbiprofen solubility data in ethers. . . . . 55 hydrocarbons (including cycloalkanes) . . . 131 12.6. Flurbiprofen solubility data in alcohols. . . 55 17.3. Lornoxicam solubility data in aromatic 12.7. Flurbiprofen solubility data in ketones . . . 59 hydrocarbons ...... 132 12.8. Flurbiprofen solubility data in 17.4. Lornoxicam solubility data in esters . . . . . 133 miscellaneous organic solvents ...... 59 17.5. Lornoxicam solubility data in ethers . . . . . 134 13. Solubility of Ibuprofen in Organic Solvents ... 60 17.6. Lornoxicam solubility data in haloalkanes, 13.1. Critical evaluation of experimental haloalkenes, and haloaromatic solubility data...... 60 hydrocarbons ...... 134 13.2. Ibuprofen solubility data in saturated 17.7. Lornoxicam solubility data in alcohols . . . 135 hydrocarbons (including cycloalkanes) . . . 63 17.8. Lornoxicam solubility data in ketones. . . . 140 13.3. Ibuprofen solubility data in aromatic 17.9. Lornoxicam solubility data in miscellaneous hydrocarbons ...... 65 organic solvents...... 140 13.4. Ibuprofen solubility data in esters...... 65 18. Solubility of Mefenamic Acid in Organic 13.5. Ibuprofen solubility data in ethers ...... 69 Solvents ...... 142 13.6. Ibuprofen solubility data in haloalkanes, 18.1. Critical evaluation of experimental haloalkenes, and haloaromatic solubility data...... 142 hydrocarbons ...... 69 18.2. Mefenamic acid solubility data in saturated 13.7. Ibuprofen solubility data in alcohols . . . . . 71 hydrocarbons (including cycloalkanes) . . . 143 13.8. Ibuprofen solubility data in ketones ...... 91 18.3. Mefenamic acid solubility data in aromatic 13.9. Ibuprofen solubility data in miscellaneous hydrocarbons ...... 144 organic solvents...... 94 18.4. Mefenamic acid solubility data in esters . 145 13.10. Ibuprofen solubility data in binary organic 18.5. Mefenamic acid solubility data in alcohols 145 solvent mixtures ...... 102 18.6. Mefenamic acid solubility data in ketones 147 14. Solubility of Indomethacin in Organic Solvents 103 18.7. Mefenamic acid solubility data in 14.1. Critical evaluation of experimental miscellaneous organic solvents ...... 148 solubility data...... 103 19. Solubility of Meloxicam in Organic Solvents.. 149 14.2. Indomethacin solubility data in esters . . . . 103 19.1. Critical evaluation of experimental 14.3. Indomethacin solubility data in haloalkanes, solubility data...... 149 haloalkenes, and haloaromatic 19.2. Meloxicam solubility data in saturated hydrocarbons ...... 105 hydrocarbons (including cycloalkanes) . . . 150

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19.3. Meloxicam solubility data in aromatic 23.1. Critical evaluation of experimental hydrocarbons ...... 150 solubility data...... 206 19.4. Meloxicam solubility data in esters ...... 151 23.2. Nimesulide solubility data in alcohols. . . . 206 19.5. Meloxicam solubility data in ethers ...... 152 23.3. Nimesulide solubility data in miscellaneous 19.6. Meloxicam solubility data in haloalkanes, organic solvents...... 208 haloalkenes, and haloaromatic 23.4. Nimesulide solubility data in binary organic hydrocarbons ...... 152 solvent mixtures ...... 209 19.7. Meloxicam solubility data in alcohols. . . . 153 24. Solubility of Phenylbutazone in Organic Solvents 209 19.8. Meloxicam solubility data in ketones . . . . 160 24.1. Critical evaluation of experimental 19.9. Meloxicam solubility data in miscellaneous solubility data...... 209 organic solvents...... 161 24.2. Phenylbutazone solubility data in ethers. . 210 19.10. Meloxicam solubility data in binary 24.3. Phenylbutazone solubility data in alcohols 210 organic solvent mixtures ...... 162 24.4. Phenylbutazone solubility data in ketones 211 20. Solubility of Nabumetone in Organic Solvents. 164 24.5. Phenylbutazone solubility data in 20.1. Critical evaluation of experimental miscellaneous organic solvents ...... 212 solubility data...... 164 25. Solubility of Piroxicam in Organic Solvents... 212 20.2. Nabumetone solubility data in ethers. . . . . 164 25.1. Critical evaluation of experimental 20.3. Nabumetone solubility data in solubility data...... 212 miscellaneous organic solvents ...... 165 25.2. Piroxicam solubility data in saturated 21. Solubility of Naproxen in Organic Solvents ... 165 hydrocarbons (including cycloalkanes) . . . 213 21.1. Critical evaluation of experimental 25.3. Piroxicam solubility data in aromatic solubility data...... 165 hydrocarbons ...... 213 21.2. Naproxen solubility data in saturated 25.4. Piroxicam solubility data in esters ...... 214 hydrocarbons (including cycloalkanes) . . . 167 25.5. Piroxicam solubility data in ethers ...... 214 21.3. Naproxen solubility data in aromatic 25.6. Piroxicam solubility data in haloalkanes, hydrocarbons ...... 168 haloalkenes, and haloaromatic 21.4. Naproxen solubility data in esters...... 169 hydrocarbons ...... 215 21.5. Naproxen solubility data in ethers ...... 173 25.7. Piroxicam solubility data in alcohols. . . . . 216 21.6. Naproxen solubility data in haloalkanes, 25.8. Piroxicam solubility data in ketones . . . . . 219 haloalkenes, and haloaromatic 25.9. Piroxicam solubility data in miscellaneous hydrocarbons ...... 175 organic solvents...... 220 21.7. Naproxen solubility data in alcohols . . . . . 177 26. Solubility of Rofecoxib in Organic Solvents... 222 21.8. Naproxen solubility data in ketones ...... 189 26.1. Critical evaluation of experimental 21.9. Naproxen solubility data in miscellaneous solubility data...... 222 organic solvents...... 191 26.2. Rofecoxib solubility data in alcohols. . . . . 223 21.10. Naproxen solubility data in binary organic 26.3. Rofecoxib solubility data in miscellaneous solvent mixtures ...... 193 organic solvents...... 227 22. Solubility of Niflumic Acid in Organic Solvents 194 26.4. Rofecoxib solubility data in binary organic 22.1. Critical evaluation of experimental solvent mixtures ...... 228 solubility data...... 194 27. Solubility of Salicylic Acid in Organic Solvents 229 22.2. Niflumic acid solubility data in saturated 27.1. Critical evaluation of experimental hydrocarbons (including cycloalkanes) . . . 194 solubility data...... 229 22.3. Niflumic acid solubility data in aromatic 27.2. Salicylic acid solubility data in alcohols . 229 hydrocarbons ...... 196 27.3. Salicylic acid solubility data in 22.4. Niflumic acid solubility data in esters . . . . 196 miscellaneous organic solvents ...... 230 22.5. Niflumic acid solubility data in ethers. . . . 197 28. Solubility of Sodium Diclofenac in Organic 22.6. Niflumic acid solubility data in haloalkanes, Solvents ...... 231 haloalkenes, and haloaromatic 28.1. Critical evaluation of experimental hydrocarbons ...... 197 solubility data...... 231 22.7. Niflumic acid solubility data in alcohols . 199 28.2. Sodium diclofenac solubility data in 22.8. Niflumic acid solubility data in ketones . . 203 saturated hydrocarbons (including 22.9. Niflumic acid solubility data in cycloalkanes) ...... 231 miscellaneous organic solvents ...... 204 28.3. Sodium diclofenac solubility data in 22.10. Niflumic acid solubility data in binary aromatic hydrocarbons ...... 232 organic solvent mixtures ...... 205 28.4. Sodium diclofenac solubility data in esters 233 23. Solubility of Nimesulide in Organic Solvents.. 206 28.5. Sodium diclofenac solubility data in ethers 235

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28.6. Sodium diclofenac solubility data in 32.6. Tenoxicam acid solubility data in ketones 268 haloalkanes, haloalkenes, and haloaromatic 32.7. Tenoxicam solubility data in miscellaneous hydrocarbons ...... 235 organic solvents...... 268 28.7. Sodium diclofenac solubility data in 33. Solubility of Tolfenamic Acid in Organic alcohols...... 236 Solvents ...... 270 28.8. Sodium diclofenac solubility data in ketones 241 33.1. Critical evaluation of experimental 28.9. Sodium diclofenac solubility data in solubility data...... 270 miscellaneous organic solvents ...... 242 33.2. Tolfenamic acid solubility data in saturated 29. Solubility of Sodium Ibuprofen in Organic hydrocarbons (including cycloalkanes) . . . 270 Solvents ...... 246 33.3. Tolfenamic acid solubility data in alcohols 271 29.1. Critical evaluation of experimental 34. Solubility of Valdecoxib in Organic Solvents.. 271 solubility data...... 246 34.1. Critical evaluation of experimental 29.2. Sodium ibuprofen solubility data in solubility data...... 271 saturated hydrocarbons (including 34.2. Valdecoxib solubility data in alcohols. . . . 271 cycloalkanes) ...... 246 34.3. Valdecoxib solubility data in miscellaneous 29.3. Sodium ibuprofen solubility data in organic solvents...... 273 aromatic hydrocarbons ...... 247 35. References ...... 274 29.4. Sodium ibuprofen solubility data in esters 247 29.5. Sodium ibuprofen solubility data in ethers 248 29.6. Sodium ibuprofen solubility data in haloalkanes, haloalkenes, and haloaromatic List of Tables hydrocarbons ...... 248 29.7. Sodium ibuprofen solubility data in alcohols 249 1. Abraham model equation coefficients describing 29.8. Sodium ibuprofen solubility data in ketones 252 solute transfer to an organic solvent from water, 29.9. Sodium ibuprofen solubility data in Eq. (10) ...... 7 miscellaneous organic solvents ...... 253 2. Abraham model equation coefficients describing 30. Solubility of Sodium Naproxen in Organic solute transfer to an organic solvent from gas Solvents ...... 255 phase, Eq. (11)...... 9 30.1. Critical evaluation of experimental 3. Parameters of the Modified Apelblat equation for solubility data...... 255 describing the solubility of dexibuprofen in var- 30.2. Sodium naproxen solubility data in alcohols 255 ious organic solvents...... 23 31. Solubility of Sodium Salicylate in Organic 4. Parameters of the Modified Apelblat equation for Solvents ...... 256 describing the solubility of flufenamic acid in 31.1. Critical evaluation of experimental organic solvents...... 48 solubility data...... 256 5. Parameters of the Modified Apelblat equation for 31.2. Sodium salicylate solubility data in describing the solubility of flurbiprofen in organic saturated hydrocarbons (including solvents ...... 52 cycloalkanes) ...... 257 6. Comparison between observed and predicted 31.3. Sodium salicylate solubility data in aromatic molar solubilities of ibuprofen based on the Abra- hydrocarbons ...... 257 ham model, Eqs. (28) and (29) ...... 62 31.4. Sodium salicylate solubility data in esters 258 7. Parameters of the Modified Apelblat equation for 31.5. Sodium salicylate solubility data in ethers 258 describing the solubility of ibuprofen in organic 31.6. Sodium salicylate solubility data in solvents ...... 63 haloalkanes, haloalkenes, and haloaromatic 8. Parameters of the Modified Apelblat equation for hydrocarbons ...... 259 describing the solubility of indomethacin in etha- 31.7. Sodium salicylate solubility data in alcohols 260 nol and 1,2-propanediol ...... 103 31.8. Sodium salicylate solubility data in ketones 262 9. Comparison between observed and predicted 31.9. Sodium salicylate solubility data in molar solubilities of ketoprofen based on the miscellaneous organic solvents ...... 263 Abraham model, Eq. (28) ...... 114 32. Solubility of Tenoxicam in Organic Solvents .. 264 10. Parameters of the Modified Apelblat equation for 32.1. Critical evaluation of experimental describing the solubility of ketoprofen in organic solubility data...... 264 solvents ...... 114 32.2. Tenoxicam solubility data in esters ...... 265 11. Parameters of the Modified Apelblat equation for 32.3. Tenoxicam solubility data in haloalkanes, describing the solubility of mefenamic acid in haloalkenes, and haloaromatic organic solvents...... 143 hydrocarbons ...... 265 12. Comparison between observed and predicted 32.4. Tenoxicam solubility data in alcohols. . . . 266 molar solubilities of naproxen based on the Abra- 32.5. Tenoxicam solubility data in alkoxyalcohols 267 ham model, Eqs. (28) and (29) ...... 166

13. Parameters of the Modified Apelblat equation for Nonsteroidal anti-inflammatory drugs represent a diverse describing the solubility of naproxen in organic class of drugs and are among the most commonly used solvents ...... 167 analgesics for the management of pain and/or inflammation 14. Parameters of the Modified Apelblat equation for associated with rheumatoid arthritis and osteoarthritis, muscle describing the solubility of niflumic acid in stiffness, and pain due to Parkinson’s disease, muscle injury organic solvents...... 194 (tendinitis and bursitis), acute gout, dysmenorrhea (menstrual 15. Parameters of the Modified Apelblat equation for pain), dental pain, migraine, and headache. Medical research is describing the solubility of phenylbutazone in still ongoing regarding the potential of NSAIDs for the pre- ethanol and 1-octanol ...... 210 vention of colorectal cancer. Clinical trials suggested that celecoxib is very effective in reducing polyp recurrence in individuals who have undergone colorectal polypectomy.4,5 An estimated more than 30 106 people worldwide use NSAIDs on a daily basis.6 Sales of diclofenac and ibuprofen 1. Preface account for more than half of the global sales of NSAIDs for osteoarthritis, and in the United States NSAID sales represent a 1.1. Scope of this volume significant fraction of the nonprescription, over-the-counter This volume reviews experimentally determined solubility analgesic market. Side effects associated with chronic, long- data for 33 nonsteroidal anti-inflammatory drugs (NSAIDs) term use of NSAIDs include direct and indirect irritation of the dissolved in neat organic solvents and well-defined binary and gastrointestinal tract (e.g., peptic ulcer disease, stomach bleed- ternary organic solvent mixtures retrieved from the published ing, perforation, and obstruction),7–10 increased risk of cardi- chemical and pharmaceutical literature covering the period from ovascular adverse effects (e.g., myocardial infarction and 1980 to the beginning of 2014. Except for aspirin (2-acetoxy- stroke, and hypertension),11–13 renal failure (e.g., kidney fail- benzoic acid) and salicylic acid (2-hydroxybenzoic acid), very ure), and erectile dysfunction.14 Rofecoxib and valdecoxib little physical and chemical property data are available in the have been withdrawn from the world market because of their published literature for NSAIDs prior to 1980. Solubility data are association with cardiovascular risk. Valdecoxib was also compiled and critically reviewed for aclofenac, celecoxib, dex- withdrawn because of an unexpectedly high number of serious ibuprofen, diclofenac, diflunisal, etoricoxib, fenbufen, fentiazac, dermatological side effects such as Stevens-Johnson syn- flufenamic acid, flurbiprofen, ibuprofen, indomethacin, ketopro- drome, which is a potentially deadly skin disease that usually fen, ketorolac, lornoxicam, mefenamic acid, meloxiam, nabu- results from a drug reaction.15 metone, naproxen, niflumic acid, nimesulide, phenylbutazone, Nonsteroidal anti-inflammatory drugs are classified as piroxicam, rofecoxib, sodium diclofenac, sodium ibuprofen, either nonselective inhibitors or as selective COX-2 inhibitors sodium naproxen, sodium salicylate,tenoxicam, tolfenamic acid, according to their mode of action. NSAIDs relieve pain by and valdecoxib. Aqueous systems and inorganic systems blocking the effects of prostaglandins. Prostaglandins are (namely, supercritical carbon dioxide) are not included in this substances synthesized from arachidonic acid, a fatty acid volume. Readers wishing solubility data for aqueous and inor- associated with cell membranes. The synthesis of prostaglan- ganic systems are referred to Vol. 90 (Refs. 1 and 2)inthe dins from arachidonic acid is catalyzed by the cyclooxygenase IUPAC-NIST Solubility Data Series, which dealt with the or “COX” enzyme. Nonselective NSAIDs such as ibuprofen, solubility of hydroxybenzoic acid derivatives in binary, ternary, indomethacin, ketoprofen, and naproxen inhibit both the and multicomponent systems. There one will find solubility data cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) for 2-hydroxybenzoic acid (salicylic acid), 3-hydroxybenzoic enzymes throughout the body, while selective NSAIDs inhibit acid, and 4-hydroxybenzoic acid, as well as solubility data for only the COX-2 enzyme. Selective NSAIDs inhibit COX-2, an several 4-hydroxybenzoate alkyl esters (parabens) and hydro- enzyme found at sites of inflammation, more than the type that xybenzoic acid salts. Volume 90 also contains solubility data for is normally found in the stomach, blood platelets, and blood the three hydroxybenzoic acids in organic solvents. Solubility vessels (COX-1). Inhibition of the COX-1 enzyme can pro- data for aspirin (2-acetoxybenzoic acid) and salicylic acid (2- duce potential life-threatening complications, particularly in hydroxybenzoic acid) can be found in Vol. 99 (Ref. 3)inthe the gastrointestinal tract, as prostaglandins have an important IUPAC-NIST Solubility Data Series, which was devoted to the function in protecting the mucus lining of structures and solubility of benzoic acid and substituted benzoic acids in both organs such as the esophagus, stomach, and intestine. When neat organic solvents and binary organic solvent mixtures. The such protection is lost, the individual has an increased risk of a solubility data reported in Vol. 99 for salicylic acid in neat potentially life-threatening gastrointestinal bleeding and/or organic solvents is slightly more extensive than what is contained perforation. Selective NSAIDs are often prescribed/recom- in Vol. 90, and includes references that were either published mended by physicians for individuals who have had a peptic after or overlooked in the preparation of the earlier volume. ulcer, gastrointestinal bleeding, or gastrointestinal upset when Experimental solubility data for aspirin and salicylic acid taking nonselective NSAIDs. Currently, celecoxib is the only reported in Vols. 90 and 99 will not be repeated in this volume; selective NSAID available in the United States. Other selec- however, there will be a brief listing of organic solvents that are tive NSAIDs that can be found elsewhere in the world include included in the two earlier volumes for these two NSAIDs. etoricoxib and lumiracoxib.

1.2. Concentration units for nonelectrolyte ments on new mixtures as opposed to repeating measurements solutions on already studied mixtures, even if measured at different temperatures. Composition of a liquid nonelectrolyte solution can be Published solubility data may be found for a given solute- expressed in a variety of ways, as (1) the ratio of the number solvent system measured at several different temperatures. of moles of one component to the number of moles of a second The temperature variation can be critically evaluated using component, n /n , etc., (2) molar concentration 1 2 standard thermodynamic relationships based on the ideal mole ideal soly n fraction solubility of a solid solute, x in a liquid c ¼½i¼ i SI base units : mol dm 3 ð1Þ 1 i V solvent16 fus (3) mole fraction DH T DC ; T T ln x ideal soly ¼ 1 1 þ p 1 mp 1 RT T R T ¼ ni ð Þ mp xi þ þ ::::: þ þ :::: 2 n1 n2 ni DC ; T þ p 1 ln mp ; ð6Þ or (4) volume fraction R T Δ fus n V where H1 is the standard molar enthalpy of fusion of the f ¼ i i : ð3Þ i solute at its normal melting point temperature, T , ΔCp is the n1 V1 þ n2 V2 þ ::::: þ ni Vi þ :::: mp ,1 difference in the molar heat capacities of the liquid and Strictly speaking, the true volume of a real solution is not crystalline forms of the solute (ΔCp,1 ¼ Cp,liquid – Cp,solid), equal to the sum of the volumes of the individual components and R is the universal gas constant. Through suitable algebraic but is the fraction sum of partial volumes, which for a ternary manipulations, Eq. (6) can be rearranged to give solution is V ¼ x1V1 þ x2 V2 þ x3V3. For purposes of this D fus D study, volume fractions are defined in terms of the molar ideal soly H1 Cp;1 ln x1 ¼ þ ð1 þ ln TmpÞ volumes of the pure unmixed components, Vm,i (molar mass of RTmp R component i divided by density of component i) fus DH DC ; T 1 DC ; 1 þ p 1 mp þ p 1 ln T; ð7Þ ’ ¼ niVm;i ; ð Þ R R T R i 4 n V ; þ n V ; þ ::::: þ n V ; þ :::: 1 m 1 2 m 2 i m i which has the generalized mathematical form of as this quantity serves as an input parameter in expressions for B estimating solubilities in mixed solvents since it requires no a ln x1 ¼ A þ þ C ln T: ð8Þ priori knowledge concerning volumetric behavior. Solute T solubilities can be found in the chemical literature in terms Though derived for an ideal solution, Eq. (8) has been used of any of the aforementioned concentration variables, or as successfully to describe solute solubility in many nonideal molality, mi, which is the number of moles of solute i divided solutions. The equation is commonly referred to as the Mod- by the mass of the solvent ified Apelblat equation in the published literature. The λh model, developed by Buchowski et al.,17,18 is ni 1 mi ¼ SI base units : mol kg ; ð5Þ nsolventMsolvent λð1 x Þ 1 1 ln 1 þ 1 ¼ λh ; ð9Þ x T T where Msolvent is the molar mass of the solvent. 1 mp a second popular mathematical representation for describing how the mole fraction solubility varies with solution temperature. In Eq. (9), T and T refer to the solution temperature and 1.3. Procedures used in critical evaluation of mp melting-point temperature of the solute, respectively. The two published solubility data model parameters, λ and h, are determined by least-squares Procedures used in the critical evaluation of published analyses using the measured mole-fraction solubilities. solubility data for crystalline nonelectrolytes dissolved in Experimental solubility data are considered to be internally organic monosolvents and organic solvent mixtures depend consistent if the measured xi values can be accurately to a large extent on the quantity and type of data to be described by either Eq. (8) and/or Eq. (9). evaluated. In those instances where independent experimental Solution models have been used with success to rationalize measurements exist, one can compute the mean value and the solubility behavior of a given solute molecule in a series of standard deviation for each set of replicate values (or set of organic solvents. Of the models developed in recent years, the values) differing from the rest. This type of analysis will be general solvation parameter developed by Abraham and co- limited primarily to the neat mono-solvents, as published data workers19–27 is probably the most widely used approach in for binary and ternary solvent mixtures is relatively scarce correlating the solubilities of crystalline organic compounds. compared to solubility data for solutes in single-solvent sys- The model is based on two linear free energy relationships tems. Given the scarcity of binary solvent and ternary solvent describing solute transfer between two immiscible phases. The solubility data, researchers have tended to perform measure- first expression quantifies solute transfer between two

condensed phases: Abraham model correlations have been developed for predicting the solubility of crystalline nonelectrolytes in more than 70 ð Þ¼ þ þ þ 28–35 log10 SR or P cp ep E sp S ap A different organic solvents, for predicting the water-to- ð Þ þ bp B þ vp V 10 organic solvent and gas-to-organic solvent partition coefficient for more than 70 different biphasic systems,28–37 and for and the second expression involves solute transfer from the gas predicting the partition coefficients of organic vapors and phase: gaseous solutes into aqueous micellar solvent media,38,39 into humic acid,40 and into various body tissues and fluids.41–47 log ðGSR or KÞ¼c þ e E þ s S þ a A 10 k k k k Each of the aforementioned predictions requires a priori ð Þ þ bk B þ lk L; 11 knowledge of the compound’s solute descriptors as input parameters. where P is the water-to-organic solvent partition coefficient or Equation (10) correlates experimental partition coefficients nonpolar organic solvent-to-polar organic solvent partition and/or solubility ratios, and for select organic solvents both coefficient, and K is the gas-to-organic solvent partition “dry” and “wet” equation coefficients have been reported. For coefficient. For solubility predictions, the Abraham model solvents that are partially miscible with water, such as 1- uses the solubility ratio which is given by the ratio of the pentanol and butyl ethanoate, solubility ratios calculated as the sat molar solubilities of the solute in the organic solvent, c1;S, and molar solute solubility in the organic solvent divided by the sat ¼ sat = sat in water, c1;W (i.e., SR c1;S c1;W). The gas-phase solubility solute’s aqueous molar solubility are not the same as those ratio is similarly calculated as the molar solubility in the obtained from direct partition between water (saturated with organic solvent divided by the solute gas-phase concentration the organic solvent) and organic solvent (saturated with ¼ sat / (i.e., GSR c1;S c1,G), the latter value calculable from the water). Care must be taken not to confuse the two sets of solute vapor pressure above the solid at the solution transfer process. There should be no confusion in the case of temperature. solvents that are fully miscible with water, such as ethanol. The dependent variables in Eqs. (10) and (11) are solute Only one set of equation coefficients has been published, and descriptors as follows: E is the solute excess molar refraction the dependent variable is the logarithm of the solubility ratio. (in units of cm3 mol1/10), S refers to the solute dipolarity/ And for solvents that are “almost” completely immiscible with polarizability, A and B represent the overall solute hydrogen water, such as alkylbenzenes (benzene, toluene, etc.) and bond acidity and basicity, V denotes the solute’s McGowan chloroalkanes (1,2-dichloroethane, chloroform), there should characteristic molecular volume (in units of cm3 mol1/100) be no confusion because the solubility ratio [see Eq. (3)] will and L is the logarithm of the gas-to-hexadecane partition be nearly identical to the practical partition coefficient. coefficient measured at 298 K. The lower-case regression Applicability of the Abraham solvation parameter model is fairly straightforward. One starts with the set of equations that coefficients and constants (cp, ep, sp, ap, bp, vp, ck, ek, sk, ak, have been obtained for the ratio of the molar solubilities of the bk, and lk)inEqs.(10) and (11) are obtained by multiple linear ¼ sat = sat regression analysis of experimental partition coefficient data solute in the organic solvent and in water (i.e., SR c1;S c1;W). and solubility ratios for a specific biphasic system. To date, Table 1 lists the coefficients in Eq. (10) for transfer processes

TABLE 1. Abraham model equation coefﬁcients describing solute transfer to an organic solvent from water, Eq. (10)

Organic solvent cp ep sp ap bp vp Dichloromethane 0.319 0.102 0.187 3.058 4.090 4.324 Trichloromethane 0.191 0.105 0.403 3.112 3.514 4.395 Tetrachloromethane 0.199 0.523 1.159 3.560 4.594 4.618 1,2-Dichloroethane 0.183 0.294 0.134 2.801 4.291 4.180 1-Chlorobutane 0.222 0.273 0.569 2.918 4.883 4.456 Hexane 0.333 0.560 1.710 3.578 4.939 4.463 Heptane 0.297 0.634 1.755 3.571 4.946 4.488 Octane 0.241 0.690 1.769 3.545 5.011 4.511 Decane 0.172 0.726 1.750 3.446 4.496 4.489 Undecane 0.058 0.603 1.661 3.421 5.120 4.619 Dodecane 0.114 0.668 1.644 3.545 5.006 4.459 Hexadecane 0.087 0.667 1.617 3.587 4.869 4.433 Cyclohexane 0.159 0.784 1.678 3.740 4.929 4.577 Methylcyclohexane 0.246 0.782 1.982 3.517 4.293 4.528 2,2,4-Trimethylpentane 0.318 0.555 1.737 3.677 4.864 4.417 Benzene 0.142 0.464 0.588 3.099 4.625 4.491 Toluene 0.125 0.431 0.644 3.002 4.748 4.524 Ethylbenzene 0.093 0.467 0.723 3.001 4.844 5.514 1,2-Dimethylbenzene 0.083 0.518 0.813 2.884 4.821 4.559

TABLE 1. Abraham model equation coefﬁcients describing solute transfer to an organic solvent from water, Eq. (10)—Continued

Organic solvent cp ep sp ap bp vp 1,3-Dimethylbenzene 0.122 0.377 0.603 2.981 4.961 4.535 1,4-Dimethylbenzene 0.166 0.477 0.812 2.939 4.874 4.532 Fluorobenzene 0.139 0.152 0.374 3.030 4.601 4.540 Chlorobenzene 0.065 0.381 0.521 3.183 4.700 4.614 Bromobenzene 0.017 0.436 0.424 3.174 4.558 4.445 Iodobenzene 0.192 0.298 0.308 3.213 4.653 4.588 Nitrobenzene 0.152 0.525 0.081 2.332 4.494 4.187 Benzonitrile 0.097 0.285 0.059 1.605 4.562 4.028 Olive oil 0.035 0.574 0.798 1.422 4.984 4.210 Carbon disulﬁde 0.047 0.686 0.943 3.603 5.818 4.921 Isopropyl myristate 0.605 0.930 1.153 1.682 4.093 4.249 Triolein 0.385 0.983 2.083 2.007 3.452 4.072 Methanol 0.276 0.334 0.714 0.243 3.320 3.549 Ethanol 0.222 0.471 1.035 0.326 3.596 3.857 Propan-1-ol 0.139 0.405 1.029 0.247 3.767 3.986 Butan-1-ol 0.165 0.401 1.011 0.056 3.958 4.044 Pentan-1-ol 0.150 0.536 1.229 0.141 3.864 4.077 Hexan-1-ol 0.115 0.492 1.164 0.054 3.978 4.131 Heptan-1-ol 0.035 0.398 1.063 0.002 4.342 4.317 Octan-1-ol 0.034 0.489 1.044 0.024 4.235 4.218 Decan-1-ol 0.058 0.616 1.319 0.026 4.153 4.279 Propan-2-ol 0.102 0.315 1.020 0.532 3.865 4.023 2-Methylpropan-1-ol 0.161 0.310 1.069 0.183 3.774 4.040 2-Butanol 0.194 0.383 0.956 0.134 3.606 3.829 2-Methylpropan-2-ol 0.197 0.136 0.916 0.318 4.031 4.112 3-Methylbutan-1-ol 0.123 0.370 1.243 0.074 3.781 4.208 2-Pentanol 0.115 0.455 1.331 0.206 3.745 4.201 Ethylene glycol 0.270 0.578 0.511 0.715 2.619 2.729 2,2,2-Triﬂuoroethanol 0.395 0.094 0.594 1.280 1.274 3.088 1,1′-Oxybisethane 0.330 0.401 0.814 0.457 4.959 4.320 Tetrahydrofuran 0.207 0.372 0.392 0.236 4.934 4.447 Dioxane 0.098 0.350 0.083 0.556 4.826 4.172 1,1′-Oxybisbutane 0.203 0.369 0.954 1.488 5.426 4.508 2-Methoxy-2-methylpropane 0.376 0.264 0.788 1.078 5.030 4.410 Methyl ethanoate 0.351 0.223 0.150 1.035 4.527 3.972 Ethyl ethanoate 0.328 0.369 0.446 0.700 4.904 4.150 Propyl ethanoate 0.288 0.363 0.474 0.784 4.939 4.216 Butyl ethanoate 0.248 0.356 0.501 0.867 4.973 4.281 Propanone 0.313 0.312 0.121 0.608 4.753 3.942 Butanone 0.246 0.256 0.080 0.767 4.855 4.148 Cyclohexanone 0.038 0.225 0.058 0.976 4.842 4.315 Propylene carbonate 0.004 0.168 0.504 1.283 4.407 3.421 Dimethylformamide 0.305 0.058 0.343 0.358 4.865 4.486 Dimethylacetamide 0.271 0.084 0.209 0.915 5.003 4.557 Diethylacetamide 0.213 0.034 0.089 1.342 5.084 4.088 Dibutylformamide 0.332 0.302 0.436 0.358 4.902 3.952 N-Methylpyrolidinone 0.147 0.532 0.225 0.840 4.794 3.674 N-Methyl-2-piperidone 0.056 0.332 0.257 1.556 5.035 3.983 N-Formylmorpholine 0.032 0.696 0.062 0.014 4.092 3.405 N-Methylformamide 0.114 0.407 0.287 0.542 4.085 3.471 N-Ethylformamide 0.220 0.034 0.166 0.935 4.589 3.730 N-Methylacetamide 0.090 0.205 0.172 1.305 4.589 3.833 N-Ethylacetamide 0.284 0.128 0.442 1.180 4.728 3.856 Formamide 0.171 0.070 0.308 0.589 3.152 2.432 Acetonitrile 0.413 0.077 0.326 1.566 4.391 3.364 Nitromethane 0.023 0.091 0.793 1.463 4.364 3.460 Dimethylsulfoxide 0.194 0.327 0.791 1.260 4.540 3.361 Sulfolane (303 K) 0.000 0.147 0.601 0.318 4.541 3.290 Tributylphosphate 0.327 0.570 0.837 1.069 4.333 3.919 Gas-water 0.994 0.577 2.549 3.813 4.841 0.869

considered in the present volume. It is noted that coefficients solute at 298.15 K, VP°, is known. VP° is transformed into the are periodically revised when additional experimental data solute’s gas-phase molar concentration, c1,G, which is then sat becomes available. Thus, if c1;W is known, predicted log10SR used to calculate the respective gas-to-water and gas-to-sol- values based upon Eq. (10) will lead to predicted molar vent partition coefficients, GSRW and GSRS: solubilities in organic solvents through SR ¼ csat =csat . 1;S 1;W ¼ sat = sat GSRW c1;W c1;G or Solubilities in organic solvents can also be predicted and ð12Þ ¼ sat correlated with Eq. (11). Listed in Table 2 are the equation log10GSRW log10c1;W log10c1;G coefficients that have been previously determined for the gas- ¼ sat / phase solubility ratio, GSR c1;S c1,G. Predicted log10GSR sat GSRS ¼ c ; =c1;G or values can also be converted to saturation molar solubilities, 1 S ð13Þ ¼ sat provided that the saturated vapor pressure above the crystalline log10GSRS log10c1;S log10c1;G

TABLE 2. Abraham model equation coefﬁcients describing solute transfer to an organic solvent from gas phase, Eq. (11)

Organic Solvent ck ek sk ak bk lk Oleyl alcohol 0.268 0.392 0.800 3.117 0.978 0.918 Dichloromethane 0.192 0.572 1.492 0.460 0.847 0.965 Trichloromethane 0.157 0.560 1.259 0.374 1.333 0.976 Tetrachloromethane 0.217 0.435 0.554 0.000 0.000 1.069 1,2-Dichloroethane 0.017 0.337 1.600 0.774 0.637 0.921 1-Chlorobutane 0.130 0.581 1.114 0.724 0.000 1.016 Hexane 0.320 0.000 0.000 0.000 0.000 0.945 Heptane 0.284 0.000 0.000 0.000 0.000 0.950 Octane 0.219 0.000 0.000 0.000 0.000 0.960 Decane 0.159 0.000 0.000 0.000 0.000 0.972 Undecane 0.113 0.000 0.000 0.000 0.000 0.971 Dodecane 0.053 0.000 0.000 0.000 0.000 0.986 Hexadecane 0.000 0.000 0.000 0.000 0.000 1.000 Cyclohexane 0.163 0.110 0.000 0.000 0.000 1.013 Methylcyclohexane 0.318 0.215 0.000 0.000 0.000 1.012 2,2,4-Trimethylpentane 0.264 0.230 0.000 0.000 0.000 0.975 Benzene 0.107 0.313 1.053 0.457 0.169 1.020 Toluene 0.085 0.400 1.060 0.501 0.154 1.011 Ethylbenzene 0.059 0.295 0.924 0.537 0.098 1.010 1,2-Dimethylbenzene 0.064 0.296 0.934 0.647 0.000 1.010 1,3-Dimethylbenzene 0.071 0.423 1.068 0.552 0.000 1.014 1,4-Dimethylbenzene 0.113 0.302 0.826 0.651 0.000 1.011 Fluorobenzene 0.181 0.621 1.432 0.647 0.000 0.986 Chlorobenzene 0.064 0.399 1.151 0.313 0.171 1.032 Bromobenzene 0.064 0.326 1.261 0.323 0.292 1.002 Iodobenzene 0.171 0.192 1.197 0.245 0.245 1.002 Nitrobenzene 0.295 0.121 1.682 1.247 0.370 0.915 Benzonitrile 0.075 0.341 1.798 2.030 0.291 0.880 Olive oil 0.159 0.277 0.904 1.695 0.090 0.876 Carbon disulﬁde 0.101 0.251 0.177 0.027 0.095 1.068 Triolein 0.147 0.254 0.246 1.520 1.473 0.918 Methanol 0.039 0.338 1.317 3.826 1.396 0.773 Ethanol 0.017 0.232 0.867 3.894 1.192 0.846 Propan-1-ol 0.042 0.246 0.749 3.888 1.076 0.874 Butan-1-ol 0.004 0.285 0.768 3.705 0.879 0.890 Pentan-1-ol 0.002 0.161 0.535 3.778 0.960 0.900 Hexan-1-ol 0.014 0.205 0.583 3.621 0.891 0.913 Heptan-1-ol 0.056 0.216 0.554 3.596 0.803 0.933 Octan-1-ol 0.147 0.214 0.561 3.507 0.749 0.943 Decan-1-ol 0.139 0.090 0.356 3.547 0.727 0.958 Propan-2-ol 0.062 0.327 0.707 4.024 1.072 0.886 2-Methylpropan-1-ol 0.012 0.407 0.670 3.645 1.283 0.895 Butan-2-ol 0.017 0.376 0.852 3.740 1.161 0.867 2-Methylpropan-2-ol 0.071 0.538 0.818 3.951 0.823 0.905 3-Methylbutan-1-ol 0.014 0.341 0.525 3.666 1.096 0.925 2-Pentanol 0.031 0.325 0.496 3.792 1.024 0.934 Ethylene glycol 0.887 0.132 1.657 4.457 2.325 0.565 2,2,2-Triﬂuoroethanol 0.092 0.547 1.339 2.213 3.807 0.645 1,1′-Oxybisethane 0.288 0.347 0.775 2.985 0.000 0.973 Tetrahydrofuran 0.189 0.347 1.238 3.289 0.000 0.982

TABLE 2. Abraham model equation coefﬁcients describing solute transfer to an organic solvent from gas phase, Eq. (11)—Continued

Organic Solvent ck ek sk ak bk lk Dioxane 0.034 0.354 1.674 3.021 0.000 0.919 1,1′-Oxybisbutane 0.165 0.421 0.760 2.102 0.664 1.002 2-Methoxy-2-methylpropane 0.278 0.489 0.801 2.495 0.000 0.993 Methyl ethanoate 0.129 0.447 1.675 2.625 0.213 0.874 Ethyl ethanoate 0.182 0.352 1.316 2.891 0.000 0.916 Propyl ethanoate 0.165 0.383 1.264 2.757 0.000 0.954 Butyl ethanoate 0.147 0.414 1.212 2.623 0.000 0.954 Propanone 0.127 0.387 1.733 3.060 0.000 0.866 Butanone 0.112 0.474 1.671 2.878 0.000 0.916 Cyclohexanone 0.086 0.441 1.725 2.786 0.000 0.957 Propylene carbonate 0.356 0.413 2.587 2.207 0.455 0.719 Dimethylformamide 0.391 0.869 2.107 3.774 0.000 1.011 Dimethylacetamide 0.308 0.736 1.802 4.361 0.000 1.028 Diethylacetamide 0.075 0.434 1.911 4.801 0.000 0.899 Dibutylformamide 0.002 0.239 1.402 4.029 0.000 0.900 N-Methylpyrrolidinone 0.128 0.029 2.217 4.429 0.000 0.777 N-Methyl-2-piperidone 0.264 0.171 2.086 5.056 0.000 0.883 N-Formylmorpholine 0.437 0.024 2.631 4.318 0.000 0.712 N-Methylformamide 0.249 0.142 1.661 4.147 0.817 0.739 N-Ethylformamide 0.220 0.302 1.743 4.498 0.480 0.824 N-Methylacetamide 0.197 0.175 1.608 4.867 0.375 0.837 N-Ethylacetamide 0.018 0.157 1.352 4.588 0.357 0.824 Formamide 0.800 0.310 2.292 4.130 1.933 0.442 Acetonitrile 0.007 0.595 2.461 2.085 0.418 0.738 Nitromethane 0.340 0.297 2.689 2.193 0.514 0.728 Dimethylsulfoxide 0.556 0.223 2.903 5.036 0.000 0.719 Sulfolane (303 K) 0.414 0.084 2.396 3.144 0.420 0.684 Tributylphosphate 0.097 0.098 1.103 2.411 0.588 0.844 Gas-water 1.271 0.822 2.743 3.904 4.814 0.213

An estimated value of c1,G can be assumed in the pre- solvents to within overall standard deviations of 0.124 and 35 liminary calculations if an experimental vapor pressure cannot 0.109 log10 units, respectively. Standard deviations for be located in the published literature for the solute at 298.15 K. aspirin dissolved in 13 alcohols, 4 ethers, and ethyl ethanoate 25 48 25 The value can be adjusted if necessary in order to reduce the were 0.123 and 0.138 log10 units. Benzil and aspirin log10GSR deviations, and to make the log10SR and log10GSR exhibited solubilities exceeding 1 molar in several of the computations internally consistent as discussed in several organic solvents studied. In the case of aspirin it could be previous publications. argued that the model’s success relates back to when the Three specific conditions must be met in order to use the equation coefficients were originally calculated for the dry Abraham solvation parameter model to predict saturation solvents. The databases used in the regression analyses con- solubilities. First, the same solid phase must be in equilibrium tained very few carboxylic acid solutes (benzoic acid, 2- with the saturated solutions in the organic solvent and in water hydroxybenzoic acid, and 4-hydroxybenzoic acid). Most of (i.e., there should be no solvate or hydrate formation). Second, the experimental data for carboxylic acids and other very the secondary medium activity coefficient of the solid in the acidic solutes were in the form of saturation solubilities, which saturated solutions must be unity (or near unity). This condi- were also in the 1–3 molar range. Such arguments do not tion generally restricts the method to those solutes that are explain why Eqs. (10) and (11) described the measured benzil sparingly soluble in water and nonaqueous solvents. Finally, solubility data. The benzil solubilities were measured after for solutes that are ionized in aqueous solution, cA,water refers most of the equation coefficients were first determined. to the solubility of the neutral monomeric form. In the cases of Numerical values of solute descriptors exist for more than aspirin, ibuprofen, ketoprofen and naproxen (and other 5000 different organic and organometallic compounds, and if NSAIDs with a COOH functional group), this will limit the not readily available are easily calculable from measured model to solvents such as alcohols, short alkyl chain ethers, partition coefficient and solubility data.20,28,40,49,50 The alkyl alkanoates and propylene carbonate. Carboxylic acids McGowan volume solute descriptor, V, is calculated from the are known to dimerize in alkane and nonpolar aromatic molecular formula and the number of chemical bonds in the solvents. The second restriction may not be as important as solute as follows:51 initially believed. The Abraham solvation parameter model has shown remarkable success in correlating the solubility of atomsX several very soluble crystalline solutes. For example, Eqs. (10) V ¼ niAVi 6:56nbonds; ð14Þ and (11) described the molar solubility of benzil in 24 organic i

where ni and AVi denote the number of atoms and atomic The dependence of solubility upon solvent composition is volume of element i in the solute molecule, respectively, generally evaluated using semi-theoretical solution models. and nbonds is the number of chemical bonds. The bond During the past 50 years, more than 100 solution models have contribution is 6.56 cm3 mol1 for each bond, no matter been developed for describing variation of solubility with whether single, double, or triple, to be subtracted. In other solvent composition based on different assumptions regarding words, double and triple bonds count as one bond. Numer- how molecules interact in solution. Predictive expressions ical values of AVi for elements present in NSAIDs are: AVC derived from several of the proposed solution models have 3 1 3 1 ¼ 16.35 cm mol ; AVH ¼ 8.71 cm mol ; AVN served as mathematical representations for isothermal solu- 3 1 3 1 ¼ 14.39 cm mol ; AVO ¼ 12.43 cm mol ; AVF ¼ bility data in binary and ternary solvent mixtures, and for 3 1 3 1 10.48 cm mol ; AVCl ¼ 20.95 cm mol ; AVBr identifying experimental data points in need of redetermina- 3 1 3 1 ¼ 26.21 cm mol ; AVI ¼ 34.53 cm mol ; AVS ¼ tion. The Combined Nearly Ideal Binary Solvent (NIBS)/ 3 1 3 1 55,56 22.91 cm mol ;andAVP ¼ 24.87 cm mol . Redlich-Kister equation is The numerical value of the excess molar refraction solute sat ¼ ðsÞ ð satÞ þ ðsÞ sat descriptor, E, is also fairly easy to calculate. It is deﬁned as the ln x1 x2 ln x1 2 x3 ln x1 3 molar refraction of the solute using McGowan’s volume, MR , X Xr ðsÞ ðsÞ ðsÞ ðsÞ j minus the molar refraction of an alkane having the same þ x x S ; x x ; ð17Þ 20 2 3 23 j 2 3 McGowan volume. The molar refraction is given by j¼0 ðh2 1Þ likely the most popular of the proposed mathematical MR ¼ 10 V; ð15Þ X ðh2 þ Þ ðsÞ 2 representations. In Eq. (17), xi ’s refer to the initial mole η fraction solvent composition of component i calculated as if where is the refractive index of the solute as a pure liquid at sat the solute were not present, and ðx Þ denotes the measured 293 K, and V is in units of (cm3 mol 1)/100. For compounds A i solute solubility in pure solvent i. The summation in the last that are solid at 293 K, a refractive index for the liquid at 293 term on the right-hand side of Eq. (17) includesasmany K can be calculated by commercial software;52 or alterna- curve-ﬁt S parameters as are needed to accurately describe tively E can be computed by summing fragment groups in the 23,i the observed solubility data. Generally, no more than three molecule53 or by using the PharmaAlgorithm commercial parameters will be needed in a given mathematical repre- software.54 The molar refraction is one of the few properties sentation. The S parameters are determined by regression that is the same for a given molecule in both the gaseous and 23,i analysis. liquidus state, even for associated liquid molecules such as The popularity of the Combined NIBS/Redlich-Kister model water. The numerical value of molar refraction of the alkane results from the fact that the computed S parameters can be molecule needed in the computation of E is given by20 IJ,i used to predict solute solubility in ternary solvent systems:

ðMRXÞ ¼ 2:83195V 0:52553; ð16Þ ð Þ ð Þ alkane ln xsat ¼ x s ln xsat þ x s ln xsat 1 2 1 2 3 1 3 where V is the characteristic McGowan volume described ð Þ þ x s ln xsat above. The remaining four solute descriptors, S, A, B,andL, 4 1 4 Xr are calculated by solving a series of simultaneous log10P and ðsÞ ðsÞ ðsÞ ðsÞ j þ x x S ; x x log K equations for which both experimental partition 2 3 23 j 2 3 10 j¼0 coefﬁcient data and solvent equation coefﬁcients (cp, ep, sp, Xs ðsÞ ðsÞ ðsÞ ðsÞ k a , b , vp, c , e , s , a , b ,andl ) are known. The computa- þ p p k k k k k k x2 x4 S24;k x2 x4 tion method is illustrated in several published papers and will k¼0 not be repeated here. Xt þ ðsÞ ðsÞ ðsÞ ðsÞ l ð Þ The Abraham general solvation parameter model has been x3 x4 S34;l x3 x4 18 used successfully to correlate the solubility behavior of several l¼0 NSAIDs (aspirin, ibuprofen, ketoprofen, naproxen, and sal- and in higher-order multicomponent solvent systems: icylic acid) dissolved in a series of alcohols, dialkyl ethers, and "# SolventsX SolventX s Xn alkyl alkanoates. Equations (10) and (11) described the experi- sat ðsÞ ðsÞ ðsÞ ðsÞ k x ¼ x x S ; x x : ð Þ mental solubility data to within a standard deviation of 0.15 ln 1 I J IJ k I J 19 I J>I k¼0 log10 units. Past experience in using various solution models has been that the better solution will generally give predicted Equation (18) is referred to as the Combined Nearly Ideal values that fall with 40% or so (about 0.15 log10 units) of Ternary Solvent (NITS)/Redlich-Kister model. To date, Eq. (18) the observed solute solubilities. The Abraham model will be has been shown to provide very accurate predictions for the used to assess the experimental solubility data for a few select solubility of anthracene and/or pyrene in 114 different ternary NSAIDs, and to identify possible values that need to be solvent mixtures including several alcohol + hydrocarbon + remeasured. More detailed information concerning the model hydrocarbon, alcohol + alcohol + hydrocarbon, alkoxyalcohol will be given later in the volume when actual experimental + alcohol + hydrocarbon, alkoxyalcohol + alcohol + alcohol, and solubility data are being evaluated. alkyl ether + alcohol + hydrocarbon solvent systems.57–59

2. Solubility of Alclofenac in Organic 3. Solubility of Aspirin in Organic Solvents Solvents 3.1. Critical evaluation of experimental solubility 2.1. Critical evaluation of experimental solubility data data Volume 99 (Ref. 3) in the IUPAC-NIST Solubility Data Alclofenac (more formally named 3-chloro-4-(2-propen-1- Series contained experimental solubility data for aspirin (more yloxy)benzeneacetic acid) is a nonsteroidal anti-inﬂammatory formally named 2-acetoxybenzoic acid) dissolved in two drug administered orally to provide systematic relief and aromatic hydrocarbons (benzene and methylbenzene), in four reduce pain in indidivudals suffering with rheumatoid arithri- alkyl alkanoates (ethyl ethanoate, butyl ethanoate, pentyl tis and osteoarthritis. There has been only a single publication ethanoate, and methyl butanoate), in four dialkyl ethers reporting the solubility of alclofenac in organic solvents. Fini (1,1-oxybisethane, 2,2′-oxybispropane, 1,1-oxybisbutane, and et al.60 determined the molar solubility of alclofenac in 1- 2-methoxy-2-methylpropane), and two cyclic ethers (tetrahy- octanol at only three temperatures from 278 to 310 K. It is not drofuran and 1,4-dioxane), in one haloalkane (trichloro- possible to perform a critical evaluation of the experimental methane), in 22 alcohols (methanol, ethanol, 1-propanol, 2- data as measurements were made at too few temperatures to propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2- permit a meaningful linear regression analysis, and there are methyl-2-propanol, 1-pentanol, 2-pentanol, 2-methyl-1-buta- no independent experimental solubility data for alclofenac in nol, 3-methyl-1-butanol, 2-methyl-2-butanol, 1-hexanol, 2- 1-octanol. methyl-1-pentanol, 4-methyl-2-pentanol, 1-heptanol, 1-octa- The experimental solubility data for alclofenac in organic nol, 2-ethyl-1-hexanol, 1-decanol, 3,7-dimethyl-1-octanol, solvents are given in Sec. 2.2. and 1,2-propanediol), in one alkanone (propanone), and in two miscellaneous organic solvents (propylene carbonate and ethanenitrile). Except for a few select systems, the majority of 2.2. Alclofenac solubility data in alcohols the compiled solubility data was measured at 298.15 K. Maia and Giulietti61 determined the solubility of 2-acetoxybenzoic acid in ethanol (from 276 to 336 K), 2-propanol (from 282 to Components: Original Measurements: 330 K), 1,2-propanediol (from 295 to 334 K), and propanone (1) 3-Chloro-4-(2-propen-1-yloxy)- 60A. Fini, M. Laus, I. Orienti, and benzeneacetic acid (Alclofenac); V. Zecchi, J. Pharm. Sci. 75,23 (from 282 to 326 K) as a function of temperature using a

C11H11ClO3; [22131-79-9] (1986). dynamic solubility method that recorded the temperature at [ ] (2) 1-Octanol; C8H18O; 111-87-5 which the last crystal of aspirin dissolved in the respective 62 Variables: Prepared by: solvent. McLoughlin et al. reported the solubility of aspirin 63 Temperature W. E. Acree, Jr. in ethanol at both 293 and 333 K, while Lindenberg et al. performed solubility measurements of aspirin in ethanol at 298, 308, and 323 K. The authors compared the experimental Experimental Values values determined using an in situ ATR-FTIR spectroscopic method to measured values based on a gravimetric method. a T/K c1 The compiled solubility data were correlated with the Abra- 278.2 0.303 ham solvation parameter model. 298.2 0.610 Solubility data contained in Vol. 99 will not be republished 310.2 1.303 here. The listing above is provided so that readers will know a 3 c1: molar solubility of the solute in units of mol dm . what solubility data are available in the earlier volume for aspirin. There were two additional solubility measurements Auxiliary Information found in the published pharmaceutical literature for aspirin. 64 Method/Apparatus/Procedure: Wenkers and Lippold reported solubility data for ten Constant-temperature bath, analytical balance, and an UV/visible NSAIDs (aspirin, diclofenac, diflunisal, flufenamic acid, ibu- spectrophotometer. profen, ketoprofen, nabumetone, naproxen, piroxicam, and Excess solute and solvent were placed in a sealed container and allowed to tenoxicam) in light mineral oil at 305 K. Rytting et al.65 equilibrate with stirring at constant temperature. An aliquot of the saturated solution was removed, filtered through a 0.22 μm pore membrane, and diluted determined the solubility of aspirin in polyethylene glycol quantitatively for spectroscopic analysis. 400 (PEG 400) at ambient room temperature. These experimental solubility data for aspirin in organic Source and Purity of Chemicals: solvents are given in Sec. 3.2. (1) Purity not given, chemical source not specified, was recrystallized from suitable solvent before use. (2) Purity not given, chemical source not specified, no purification details were provided in the paper.

Estimated Error: Temperature: 0.2 K (estimated by compiler).

c1: 3% (relative error).

3.2. Aspirin solubility data in miscellaneous organic Source and Purity of Chemicals: (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, solvents USA, no puriﬁcation details were provided. (2) Purity not given, J. T. Baker Chemical Company, Phillipsburg, New Jersey, USA, no puriﬁcation details were provided. Components: Original Measurements: (1) 2-Acetoxybenzoic acid (Aspirin); 64B. P. Wenkers and B. C. Estimated Error: C9H8O4; [50-78-2] Lippold, J. Pharm. Sci. 88, 1326 Temperature: 2 K (estimated by compiler). % (2) Mineral oil (1999). c1: 10 (relative error, estimated by compiler). Variables: Prepared by: T/K ¼ 305.15 W. E. Acree, Jr. 4. Solubility of Celecoxib in Organic Experimental Values Solvents

The measured solubility was reported to be c1 ¼ 0.000173 4.1. Critical evaluation of experimental solubility mol dm 3. data

Auxiliary Information Celecoxib (more formally named 4-[5-(4-methylphenyl)-3- ] Method/Apparatus/Procedure: (trifluoromethyl)-1H-pyrazol-1-yl benzenesulfonamide) is a Constant-temperature bath and an UV/visible spectrophotometer. NSAID (selective COX-2 inhibitor) used in the treatment of Excess solute and solvent were placed in sealed bottles and allowed to osteoarthritis, rheumatoid arthritis, and to reduce numbers of equilibrate at a constant temperature with rotation for 24 h. Aliquots of colon and rectum polyps in individuals who have undergone μ saturated solutions were removed, filtered through a 0.45 m cellulose acetate colorectal polypectomy. There have been two studies invol- membrane filter, and diluted quantitatively for spectroscopic analysis. Reported values represent the average of three experimental measurements. ving the solubility of celecoxib in organic solvents at 298 K. Most notably, Thimmasetty et al.66 measured the mole-frac- Source and Purity of Chemicals: tion solubility of celecoxib in 17 different organic solvents, (1) Purity not given, Merck Chemical Company, Darmstadt, Germany, no including two saturated hydrocarbons (hexane and cyclohex- purification details were provided. ane), one cyclic ether (1,4-dioxane), one chloroalkane (2) Purity not given, Parafluid Mineralolgesellschaft, Hamburg, Germany, no purification details were provided. (tetrachloromethane), and 11 alcohols (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 1-pentanol, 1-hexanol, 1- Estimated Error: heptanol, 1-octanol, 1,2-propanediol, and 1,2,3-propanetriol), Temperature: 0.5 K (estimated by compiler). as well as in the binary aqueous-dioxane solvent system at six % c1: 10 (relative error). different mixture compositions. The experimental data were used to calculate the solubility parameter of celecoxib. Seed- her and Bhatia67 published molar solubility data for celecoxib Components: Original Measurements: in six alcohols (methanol, ethanol, 1-butanol, 1-octanol, 1,2- (1) 2-Acetoxybenzoic acid (Aspirin); 65E. Rytting, K. A. Lentz, X.-Q. ethanediol, and 1,2-propanediol), in polyethylene glycol 400

C9H8O4; [50-78-2] Chen, F. Qian, and S. Venkatesh, (PEG 400), and in binary solvent mixtures containing ethanol (2) Polyethylene glycol 400 AAPS J. 7, E78 (2005). and PEG 400. It is not possible to perform a critical evaluation (PEG 400) as all measurements were performed at only a single tempera- Variables: Prepared by: ture, and there are at most only two independent experimental T/K ¼ 296 W. E. Acree, Jr. values for the common solvents studied by both research groups. There are noticeable differences between the two ¼ Experimental Values independent experimental determinations: c1 0.273 mol 3 ¼ dm (Ref. 66 mole-fraction solubility converted to molar The measured solubility was reported to be c1 0.738 ¼ 3 3 solubility) versus c1 0.166 mol dm (Ref. 67) for ethanol; mol dm . 3 c1 ¼ 0.141 mol dm (Ref. 66 mole-fraction solubility con- 3 verted to molar solubility) versus c1 ¼ 0.0761 mol dm Auxiliary Information 3 (Ref. 67) for 1-butanol; c1 ¼ 0.0325 mol dm (Ref. 66 Method/Apparatus/Procedure: mole-fraction solubility converted to molar solubility) versus Centrifuge and a high-performance liquid chromatograph equipped with a 3 c1 ¼ 0.0206 mol dm (Ref. 67) for 1-octanol. Polymorphism photo-diode array detector. Excess solute and solvent were placed in sealed vials and shaken at ambient could explain fairly large differences in solubilities in a given room temperature for at least 24 h. The vials were then centrifuged for 15 min solvent; however, in the case of celecoxib a differential 68 to separate the saturated solution from the excess solute. The supernatant was scanning calorimetric study failed to show a signiﬁcant then ﬁltered and the concentration of the dissolved solute determined by high- difference in the enthalpy of fusion data for celecoxib samples performance liquid chromatographic analysis. recrystallized from methanol, ethanol, and propanone. The experimental solubility data for celecoxib in organic solvents are given in Secs. 4.2–4.8.

4.2. Celecoxib solubility data in saturated Auxiliary Information hydrocarbons (including cycloalkanes) Method/Apparatus/Procedure: Constant-temperature reciprocating shaker bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were Components: Original Measurements: allowed to equilibrate in a constant-temperature reciprocating shaker bath for (1) 4-[5-(4-Methylphenyl)-3- 66J. Thimmasetty, C. V. S. at least three days. An aliquot of the saturated solution was removed and (trifluoromethyl)-1H-pyrazol-1-yl] Subrahmanyam, B. A. filtered (0.22 μm pore size). Solubility of the dissolved solute was determined benzenesulfonamide (Celecoxib); Vishwanath, and P. R. S. Babu, by spectrophotometric measurements at 251 nm. C17H14F3N3O2S; [169590-42-5] Asian J. Res. Chem. 2, 188 (2009). (2) Hexane; C H ; [110-54-3] 6 14 Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no T/K ¼ 298.15 W. E. Acree, Jr. purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values Estimated Error: Temperature: 1K. a b x2 x1 x1: 4% (relative error, estimated by compiler). 0.9999 0.0000228 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. 4.3. Celecoxib solubility data in esters

Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: Constant-temperature reciprocating shaker bath and an UV/visible (1) 4-[5-(4-Methylphenyl)-3- 66J. Thimmasetty, C. V. S. spectrophotometer. (trifluoromethyl)-1H-pyrazol-1-yl] Subrahmanyam, B. A. Very few experimental details were provided. Excess solute and solvent were benzenesulfonamide (Celecoxib); Vishwanath, and P. R. S. Babu, allowed to equilibrate in a constant-temperature reciprocating shaker bath for C17H14F3N3O2S; [169590-42-5] Asian J. Res. Chem. 2, 188 (2009). at least three days. An aliquot of the saturated solution was removed and (2) Ethyl ethanoate; C4H8O2; filtered (0.22 μm pore size). Solubility of the dissolved solute was determined [141-78-6] by spectrophotometric measurements at 251 nm. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. Experimental Values (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. x a x b Estimated Error: 2 1 Temperature: 1K. 0.828 0.172 % a x1: 4 (relative error, estimated by compiler). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: Auxiliary Information 66 (1) 4-[5-(4-Methylphenyl)-3- J. Thimmasetty, C. V. S. Method/Apparatus/Procedure: (triﬂuoromethyl)-1H-pyrazol-1-yl] Subrahmanyam, B. A. Constant-temperature reciprocating shaker bath and an UV/visible benzenesulfonamide (Celecoxib); Vishwanath, and P. R. S. Babu, spectrophotometer. [ ] C17H14F3N3O2S; 169590-42-5 Asian J. Res. Chem. 2, 188 (2009). Very few experimental details were provided. Excess solute and solvent were [ ] (2) Cyclohexane; C6H12; 110-82-7 allowed to equilibrate in a constant-temperature reciprocating shaker bath for Variables: Prepared by: at least three days. An aliquot of the saturated solution was removed and μ T/K ¼ 298.15 W. E. Acree, Jr. ﬁltered (0.22 m pore size). Solubility of the dissolved solute was determined by spectrophotometric measurements at 251 nm.

Experimental Values Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. a b (2) Purity not given, Analytical Reagent grade, chemical source not specified, x2 x1 no purification details were provided. 0.9999 0.00000924 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 1K. x1: 4% (relative error, estimated by compiler).

Auxiliary Information Components: Original Measurements: (1) 4-[5-(4-Methylphenyl)-3- 66J. Thimmasetty, C. V. S. Method/Apparatus/Procedure: (trifluoromethyl)-1H-pyrazol-1-yl] Subrahmanyam, B. A. Constant-temperature reciprocating shaker bath and an UV/visible benzenesulfonamide (Celecoxib); Vishwanath, and P. R. S. Babu, spectrophotometer. C17H14F3N3O2S; [169590-42-5] Asian J. Res. Chem. 2, 188 (2009). Very few experimental details were provided. Excess solute and solvent were (2) Butyl ethanoate; C6H12O2; allowed to equilibrate in a constant-temperature reciprocating shaker bath for [123-86-4] at least three days. An aliquot of the saturated solution was removed and filtered (0.22 μm pore size). Solubility of the dissolved solute was determined Variables: Prepared by: by spectrophotometric measurements at 251 nm. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: Experimental Values (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, a b no purification details were provided. x2 x1 0.9920 0.00802 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. Temperature: 1K. b % x1: mole fraction solubility of the solute. x1: 4 (relative error, estimated by compiler).

Auxiliary Information Method/Apparatus/Procedure: 4.5. Celecoxib solubility data in haloalkanes, Constant-temperature reciprocating shaker bath and an UV/visible haloalkenes, and haloaromatic hydrocarbons spectrophotometer. Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate in a constant-temperature reciprocating shaker bath for Components: Original Measurements: at least three days. An aliquot of the saturated solution was removed and (1) 4-[5-(4-Methylphenyl)-3- 66J. Thimmasetty, C. V. S. filtered (0.22 μm pore size). Solubility of the dissolved solute was determined (trifluoromethyl)-1H-pyrazol-1-yl] Subrahmanyam, B. A. by spectrophotometric measurements at 251 nm. benzenesulfonamide (Celecoxib); Vishwanath, and P. R. S. Babu, C H F N O S; [169590-42-5] Asian J. Res. Chem. 2, 188 (2009). Source and Purity of Chemicals: 17 14 3 3 2 (2) Tetrachloromethane; CCl ; (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no 4 [56-23-5] purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, Variables: Prepared by: no purification details were provided. T/K ¼ 298.15 W. E. Acree, Jr.

Estimated Error: Temperature: 1K. Experimental Values x1: 4% (relative error, estimated by compiler).

a b x2 x1 0.9999 0.0000554 4.4. Celecoxib solubility data in ethers a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: (1) 4-[5-(4-Methylphenyl)-3- 66J. Thimmasetty, C. V. S. Auxiliary Information ] (trifluoromethyl)-1H-pyrazol-1-yl Subrahmanyam, B. A. Method/Apparatus/Procedure: benzenesulfonamide (Celecoxib); Vishwanath, and P. R. S. Babu, Constant-temperature reciprocating shaker bath and an UV/visible [ ] C17H14F3N3O2S; 169590-42-5 Asian J. Res. Chem. 2, 188 (2009). spectrophotometer. [ ] (2) 1,4-Dioxane; C4H8O2; 123-91-1 Very few experimental details were provided. Excess solute and solvent were Variables: Prepared by: allowed to equilibrate in a constant-temperature reciprocating shaker bath for T/K ¼ 298.15 W. E. Acree, Jr. at least three days. An aliquot of the saturated solution was removed and filtered (0.22 μm pore size). Solubility of the dissolved solute was determined by spectrophotometric measurements at 251 nm. Experimental Values Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no a b purification details were provided. x2 x1 (2) Purity not given, Analytical Reagent grade, chemical source not specified, 0.8057 0.1943 no purification details were provided. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: Temperature: 1K.

x1: 4% (relative error, estimated by compiler).

4.6. Celecoxib solubility data in alcohols Auxiliary Information Method/Apparatus/Procedure: Vortex mixer, constant-temperature bath, and an ultraviolet/visible Components: Original Measurements: spectrophotometer. (1) 4-[5-(4-Methylphenyl)-3- 66J. Thimmasetty, C. V. S. Excess solute and solvent were placed in sealed containers and equilibrated at a (trifluoromethyl)-1H-pyrazol-1-yl] Subrahmanyam, B. A. constant temperature for 24 h. During this time the tubes were shaken benzenesulfonamide (Celecoxib); Vishwanath, and P. R. S. Babu, occasionally on a vortex mixer. Aliquots of saturated solutions were removed, centrifuged, filtered through a sintered glass crucible (grade 4), and diluted C17H14F3N3O2S; [169590-42-5] Asian J. Res. Chem. 2, 188 (2009). quantitatively with 20% aqueous acetonitrile for spectroscopic analyses. (2) Methanol; CH4O; [67-56-1] Concentration of the dissolved solute was determined from the measured Variables: Prepared by: absorbance at 252 nm. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no Experimental Values purification details were provided. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, Ltd., Mumbai, India, no purification details were provided. a b x2 x1 0.9956 0.00446 Estimated Error: a Temperature: No information given in the paper. x2: mole fraction of component 2 in the saturated solution. b c1: 5% (relative error, estimated by compiler). x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 4-[5-(4-Methylphenyl)-3- 67N. Seedher and S. Bhatia, AAPS Constant-temperature reciprocating shaker bath and an UV/visible (triﬂuoromethyl)-1H-pyrazol-1-yl] PharmSciTech 4,33/1 (2003). spectrophotometer. benzenesulfonamide (Celecoxib); Very few experimental details were provided. Excess solute and solvent were C H F N O S; [169590-42-5] allowed to equilibrate in a constant-temperature reciprocating shaker bath for 17 14 3 3 2 (2) Ethanol; C H O; [64-17-5] at least three days. An aliquot of the saturated solution was removed and 2 6 ﬁltered (0.22 μm pore size). Solubility of the dissolved solute was determined Variables: Prepared by: by spectrophotometric measurements at 251 nm. T/K ¼ 298.15 W. E. Acree, Jr.

Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no Experimental Values purification details were provided. The measured solubility was reported to be c1 ¼ 0.1661 (2) Purity not given, Analytical Reagent grade, chemical source not specified, 3 no purification details were provided. mol dm .

Estimated Error: Auxiliary Information Temperature: 1K. Method/Apparatus/Procedure: x1: 4% (relative error, estimated by compiler). Vortex mixer, constant-temperature bath, and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in sealed containers and equilibrated at a constant temperature for 24 h. During this time the tubes were shaken Components: Original Measurements: occasionally on a vortex mixer. Aliquots of saturated solutions were removed, [ 67 (1) 4- 5-(4-Methylphenyl)-3- N. Seedher and S. Bhatia, AAPS centrifuged, filtered through a sintered glass crucible (grade 4), and diluted ] / (trifluoromethyl)-1H-pyrazol-1-yl PharmSciTech 4,331 (2003). quantitatively with 20% aqueous acetonitrile for spectroscopic analyses. benzenesulfonamide (Celecoxib); Concentration of the dissolved solute was determined from the measured [ ] C17H14F3N3O2S; 169590-42-5 absorbance at 252 nm. (2) Methanol; CH4O; [67-56-1] Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 298.15 W. E. Acree, Jr. (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, Experimental Values Ltd., Mumbai, India, no purification details were provided. ¼ The measured solubility was reported to be c1 0.2988 Estimated Error: 3 mol dm . Temperature: No information given in the paper.

c1: 5% (relative error, estimated by compiler).

Source and Purity of Chemicals: Experimental Values (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, x a x b 2 1 no purification details were provided. 0.9840 0.0160 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 1K. x1: 4% (relative error, estimated by compiler).

Auxiliary Information Method/Apparatus/Procedure: Constant-temperature reciprocating shaker bath and an UV/visible Components: Original Measurements: 66 spectrophotometer. (1) 4-[5-(4-Methylphenyl)-3- J. Thimmasetty, C. V. S. Very few experimental details were provided. Excess solute and solvent were (trifluoromethyl)-1H-pyrazol-1-yl] Subrahmanyam, B. A. allowed to equilibrate in a constant-temperature reciprocating shaker bath for benzenesulfonamide (Celecoxib); Vishwanath, and P. R. S. Babu, [ ] at least three days. An aliquot of the saturated solution was removed and C17H14F3N3O2S; 169590-42-5 Asian J. Res. Chem. 2, 188 (2009). [ ] filtered (0.22 μm pore size). Solubility of the dissolved solute was determined (2) 2-Propanol; C3H8O; 67-63-0 by spectrophotometric measurements at 251 nm. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. Experimental Values (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. a b x2 x1 Estimated Error: Temperature: 1K. 0.9912 0.00875 a x1: 4% (relative error, estimated by compiler). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, x a x b 2 1 no purification details were provided. 0.9833 0.0167 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 1K. x1: 4% (relative error, estimated by compiler).

Auxiliary Information Components: Original Measurements: (1) 4-[5-(4-Methylphenyl)-3- 66J. Thimmasetty, C. V. S. Method/Apparatus/Procedure: (trifluoromethyl)-1H-pyrazol-1-yl] Subrahmanyam, B. A. Vortex mixer, constant-temperature bath, and an ultraviolet/visible benzenesulfonamide (Celecoxib); Vishwanath, and P. R. S. Babu, spectrophotometer. C17H14F3N3O2S; [169590-42-5] Asian J. Res. Chem. 2, 188 (2009). Excess solute and solvent were placed in sealed containers and equilibrated at a (2) 1-Butanol; C4H10O; [71-36-3] constant temperature for 24 h. During this time the tubes were shaken occasionally on a vortex mixer. Aliquots of saturated solutions were removed, Variables: Prepared by: centrifuged, filtered through a sintered glass crucible (grade 4), and diluted T/K ¼ 298.15 W. E. Acree, Jr. quantitatively with 20% aqueous acetonitrile for spectroscopic analyses. Concentration of the dissolved solute was determined from the measured Experimental Values absorbance at 252 nm. Source and Purity of Chemicals: (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no x a x b 2 1 purification details were provided. 0.9867 0.0133 (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, a x2: mole fraction of component 2 in the saturated solution. Ltd., Mumbai, India, no purification details were provided. b x1: mole fraction solubility of the solute. Estimated Error: Temperature: No information given in the paper.

Auxiliary Information c1: 5% (relative error, estimated by compiler). Method/Apparatus/Procedure: Constant-temperature reciprocating shaker bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were Components: Original Measurements: 66 allowed to equilibrate in a constant-temperature reciprocating shaker bath for (1) 4-[5-(4-Methylphenyl)-3- J. Thimmasetty, C. V. S. at least three days. An aliquot of the saturated solution was removed and (trifluoromethyl)-1H-pyrazol-1-yl] Subrahmanyam, B. A. filtered (0.22 μm pore size). Solubility of the dissolved solute was determined benzenesulfonamide (Celecoxib); Vishwanath, and P. R. S. Babu, [ ] by spectrophotometric measurements at 251 nm. C17H14F3N3O2S; 169590-42-5 Asian J. Res. Chem. 2, 188 (2009). (2) 1-Pentanol; C5H12O; [71-41-0] Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no T/K ¼ 298.15 W. E. Acree, Jr. purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values

Estimated Error: Temperature: 1K. a b x2 x1 x : 4% (relative error, estimated by compiler). 1 0.9866 0.0134 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Components: Original Measurements: (1) 4-[5-(4-Methylphenyl)-3- 67N. Seedher and S. Bhatia, AAPS Auxiliary Information (triﬂuoromethyl)-1H-pyrazol-1-yl] PharmSciTech 4,33/1 (2003). benzenesulfonamide (Celecoxib); Method/Apparatus/Procedure: C17H14F3N3O2S; [169590-42-5] Constant-temperature reciprocating shaker bath and an UV/visible (2) 1-Butanol; C4H10O; [71-36-3] spectrophotometer. Very few experimental details were provided. Excess solute and solvent were Variables: Prepared by: allowed to equilibrate in a constant-temperature reciprocating shaker bath for T/K ¼ 298.15 W. E. Acree, Jr. at least three days. An aliquot of the saturated solution was removed and ﬁltered (0.22 μm pore size). Solubility of the dissolved solute was determined Experimental Values by spectrophotometric measurements at 251 nm.

The measured solubility was reported to be c1 ¼ 0.0761 Source and Purity of Chemicals: mol dm 3. (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided.

Estimated Error: Temperature: 1K.

x1: 4% (relative error, estimated by compiler).

Source and Purity of Chemicals: Experimental Values (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, x a x b 2 1 no purification details were provided. 0.9932 0.00683 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 1K. x1: 4% (relative error, estimated by compiler).

Auxiliary Information Method/Apparatus/Procedure: Constant-temperature reciprocating shaker bath and an UV/visible Components: Original Measurements: 66 spectrophotometer. (1) 4-[5-(4-Methylphenyl)-3- J. Thimmasetty, C. V. S. Very few experimental details were provided. Excess solute and solvent were (trifluoromethyl)-1H-pyrazol-1-yl] Subrahmanyam, B. A. allowed to equilibrate in a constant-temperature reciprocating shaker bath for benzenesulfonamide (Celecoxib); Vishwanath, and P. R. S. Babu, [ ] at least three days. An aliquot of the saturated solution was removed and C17H14F3N3O2S; 169590-42-5 Asian J. Res. Chem. 2, 188 (2009). [ ] filtered (0.22 μm pore size). Solubility of the dissolved solute was determined (2) 1-Octanol; C8H18O; 111-87-5 by spectrophotometric measurements at 251 nm. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. Experimental Values (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. x a x b Estimated Error: 2 1 Temperature: 1K. 0.9949 0.00514 % a x1: 4 (relative error, estimated by compiler). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: Auxiliary Information 66 (1) 4-[5-(4-Methylphenyl)-3- J. Thimmasetty, C. V. S. Method/Apparatus/Procedure: (triﬂuoromethyl)-1H-pyrazol-1-yl] Subrahmanyam, B. A. Constant-temperature reciprocating shaker bath and an UV/visible benzenesulfonamide (Celecoxib); Vishwanath, and P. R. S. Babu, spectrophotometer. [ ] C17H14F3N3O2S; 169590-42-5 Asian J. Res. Chem. 2, 188 (2009). Very few experimental details were provided. Excess solute and solvent were [ ] (2) 1-Heptanol; C7H16O; 111-70-6 allowed to equilibrate in a constant-temperature reciprocating shaker bath for Variables: Prepared by: at least three days. An aliquot of the saturated solution was removed and μ T/K ¼ 298.15 W. E. Acree, Jr. ﬁltered (0.22 m pore size). Solubility of the dissolved solute was determined by spectrophotometric measurements at 251 nm.

Experimental Values Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. a b (2) Purity not given, Analytical Reagent grade, chemical source not specified, x2 x1 no purification details were provided. 0.9924 0.00761 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 1K. x1: 4% (relative error, estimated by compiler).

Source and Purity of Chemicals: Components: Original Measurements: (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no [ 67 (1) 4- 5-(4-Methylphenyl)-3- N. Seedher and S. Bhatia, AAPS purification details were provided. ] / (trifluoromethyl)-1H-pyrazol-1-yl PharmSciTech 4,331 (2003). (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, benzenesulfonamide (Celecoxib); Ltd., Mumbai, India, no purification details were provided. C17H14F3N3O2S; [169590-42-5] [ ] (2) 1-Octanol; C8H18O; 111-87-5 Estimated Error: Variables: Prepared by: Temperature: No information given in the paper. % T/K ¼ 298.15 W. E. Acree, Jr. c1: 5 (relative error, estimated by compiler).

Experimental Values Components: Original Measurements: The measured solubility was reported to be c1 ¼ 0.0206 [ 67 mol dm 3. (1) 4- 5-(4-Methylphenyl)-3- N. Seedher and S. Bhatia, AAPS (triﬂuoromethyl)-1H-pyrazol-1-yl] PharmSciTech 4,33/1 (2003). benzenesulfonamide (Celecoxib);

Auxiliary Information C17H14F3N3O2S; [169590-42-5] Method/Apparatus/Procedure: (2) 1,2-Propanediol; C3H8O2; [ ] Vortex mixer, constant-temperature bath, and an ultraviolet/visible 57-55-6 spectrophotometer. Variables: Prepared by: Excess solute and solvent were placed in sealed containers and equilibrated at a T/K ¼ 298.15 W. E. Acree, Jr. constant temperature for 24 h. During this time the tubes were shaken occasionally on a vortex mixer. Aliquots of saturated solutions were removed, centrifuged, ﬁltered through a sintered glass crucible (grade 4), and diluted Experimental Values quantitatively with 20% aqueous acetonitrile for spectroscopic analyses. The measured solubility was reported to be c1 ¼ 0.0787 Concentration of the dissolved solute was determined from the measured 3 absorbance at 252 nm. mol dm .

Source and Purity of Chemicals: Auxiliary Information (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no / / purification details were provided. Method Apparatus Procedure: / (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, Vortex mixer, constant-temperature bath, and an ultraviolet visible Ltd., Mumbai, India, no purification details were provided. spectrophotometer. Excess solute and solvent were placed in sealed containers and equilibrated at a Estimated Error: constant temperature for 24 h. During this time the tubes were shaken Temperature: No information given in the paper. occasionally on a vortex mixer. Aliquots of saturated solutions were removed, centrifuged, filtered through a sintered glass crucible (grade 4), and diluted c1: 5% (relative error, estimated by compiler). quantitatively with 20% aqueous acetonitrile for spectroscopic analyses. Concentration of the dissolved solute was determined from the measured absorbance at 252 nm.

Components: Original Measurements: Source and Purity of Chemicals: [ 67 (1) 4- 5-(4-Methylphenyl)-3- N. Seedher and S. Bhatia, AAPS (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no ] / (trifluoromethyl)-1H-pyrazol-1-yl PharmSciTech 4,331 (2003). purification details were provided. benzenesulfonamide (Celecoxib); (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, [ ] C17H14F3N3O2S; 169590-42-5 Ltd., Mumbai, India, no purification details were provided. (2) 1,2-Ethanediol; C2H6O2; [ ] 107-21-1 Estimated Error: Variables: Prepared by: Temperature: No information given in the paper. % T/K ¼ 298.15 W. E. Acree, Jr. c1: 5 (relative error, estimated by compiler).

Experimental Values Components: Original Measurements: The measured solubility was reported to be c1 ¼ 0.0101 [ 66 mol dm 3. (1) 4- 5-(4-Methylphenyl)-3- J. Thimmasetty, C. V. S. (triﬂuoromethyl)-1H-pyrazol-1-yl] Subrahmanyam, B. A. benzenesulfonamide (Celecoxib); Vishwanath, and P. R. S. Babu,

Auxiliary Information C17H14F3N3O2S; [169590-42-5] Asian J. Res. Chem. 2, 188 (2009). Method/Apparatus/Procedure: (2) 1,2-Propanediol; C3H8O2; [ ] Vortex mixer, constant-temperature bath, and an ultraviolet/visible 57-55-6 spectrophotometer. Variables: Prepared by: Excess solute and solvent were placed in sealed containers and equilibrated at a T/K ¼ 298.15 W. E. Acree, Jr. constant temperature for 24 h. During this time the tubes were shaken occasionally on a vortex mixer. Aliquots of saturated solutions were removed, centrifuged, ﬁltered through a sintered glass crucible (grade 4), and diluted quantitatively with 20% aqueous acetonitrile for spectroscopic analyses. Concentration of the dissolved solute was determined from the measured absorbance at 252 nm.

Experimental Values Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. a b (2) Purity not given, Analytical Reagent grade, chemical source not specified, x2 x1 no purification details were provided. 0.9977 0.00227 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 1K. x1: 4% (relative error, estimated by compiler).

Auxiliary Information Method/Apparatus/Procedure: Constant-temperature reciprocating shaker bath and an UV/visible 4.7. Celecoxib solubility data in miscellaneous spectrophotometer. organic solvents Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate in a constant-temperature reciprocating shaker bath for at least three days. An aliquot of the saturated solution was removed and filtered (0.22 μm pore size). Solubility of the dissolved solute was determined Components: Original Measurements: [ 67 by spectrophotometric measurements at 251 nm. (1) 4- 5-(4-Methylphenyl)-3- N. Seedher and S. Bhatia, AAPS (trifluoromethyl)-1H-pyrazol-1-yl] PharmSciTech 4,33/1 (2003). Source and Purity of Chemicals: benzenesulfonamide (Celecoxib); [ ] (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no C17H14F3N3O2S; 169590-42-5 purification details were provided. (2) Polyethylene glycol 400 (2) Purity not given, Analytical Reagent grade, chemical source not specified, (PEG 400) no purification details were provided. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Estimated Error: Temperature: 1K. % x1: 4 (relative error, estimated by compiler). Experimental Values

The measured solubility was reported to be c1 ¼ 1.088 mol dm3. Components: Original Measurements: (1) 4-[5-(4-Methylphenyl)-3- 66J. Thimmasetty, C. V. S. Auxiliary Information (triﬂuoromethyl)-1H-pyrazol-1-yl] Subrahmanyam, B. A. Method/Apparatus/Procedure: benzenesulfonamide (Celecoxib); Vishwanath, and P. R. S. Babu, Vortex mixer, constant-temperature bath, and an ultraviolet/visible C H F N O S; [169590-42-5] Asian J. Res. Chem. 2, 188 (2009). 17 14 3 3 2 spectrophotometer. (2) 1,2,3-Propanetriol (Glycerol); Excess solute and solvent were placed in sealed containers and equilibrated at a C H O ; [56-81-5] 3 8 3 constant temperature for 24 h. During this time the tubes were shaken Variables: Prepared by: occasionally on a vortex mixer. Aliquots of saturated solutions were removed, T/K ¼ 298.15 W. E. Acree, Jr. centrifuged, ﬁltered through a sintered glass crucible (grade 4), and diluted quantitatively with 20% aqueous acetonitrile for spectroscopic analyses. Concentration of the dissolved solute was determined from the measured Experimental Values absorbance at 252 nm.

Source and Purity of Chemicals: a b x2 x1 (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no 0.9999 0.0000630 purification details were provided. a (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, x2: mole fraction of component 2 in the saturated solution. b Ltd., Mumbai, India, no purification details were provided. x1: mole fraction solubility of the solute. Estimated Error: Temperature: No information given in the paper. Auxiliary Information c1: 5% (relative error, estimated by compiler). Method/Apparatus/Procedure: Constant-temperature reciprocating shaker bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate in a constant-temperature reciprocating shaker bath for at least three days. An aliquot of the saturated solution was removed and filtered (0.22 μm pore size). Solubility of the dissolved solute was determined by spectrophotometric measurements at 251 nm.

4.8. Celecoxib solubility data in binary organic 5. Solubility of Dexibuprofen in Organic solvent mixtures Solvents 5.1. Critical evaluation of experimental solubility Components: Original Measurements: data (1) 4-[5-(4-Methylphenyl)-3- 67N. Seedher and S. Bhatia, AAPS (trifluoromethyl)-1H-pyrazol-1-yl] PharmSciTech 4,33/1 (2003). Dexibuprofen [(S)-ibuprofen, more formally named (+)-α- benzenesulfonamide (Celecoxib); methyl-4-(2-methylpropyl)benzeneacetic acid] is the more [ ] C17H14F3N3O2S; 169590-42-5 biologically active isomer of the dextrorotatory enantiomer [ ] (2) Ethanol; C2H6O; 64-17-5 of ibuprofen.69–71 The majority of ibuprofen formulations on (3) Polyethylene glycol 400 (PEG 400) the market contain a racemic mixture of dexibuprofen [(+)-ibuprofen] and ()-ibuprofen. Studies have shown that Variables: Prepared by: R-()-ibuprofen can be converted to S-(+)-ibuprofen in the T/K ¼ 298; Solvent composition W. E. Acree, Jr. body after oral administration.72,73 Chiral inversion of (R)- to (S)-ibuprofen (S-IB) does not occur in the case of topical Experimental Values administration, however,74 and the therapeutic anti-inflammatory effect is significantly reduced to about half of the admi-

ð Þ nistered dose. v s a c b 2 1 There have been two experimental studies examining the 0.00 1.088 solubility of dexibuprofen as a function of temperature. Zhang 0.10 1.027 75 0.20 0.962 et al. measured the solubility of dexibuprofen in hexane, 0.40 0.860 ethanol, 1-propanol, 2-propanol, and ethyl ethanoate at several 76 0.60 0.660 temperatures in the range of about 263 to 293 K. Wang et al. 0.80 0.450 determined dexibuprofen solubilities in five alcohol solvents 1.00 0.166 (methanol, 1-butanol, 2-methyl-1-propanol, 1-pentanol, and a ðsÞ v2 : volume fraction of component 2 in the initial binary solvent mixture 1-octanol) in the temperature range of 263–293 K at atmo- calculated as if the dissolved solute were not present. spheric pressure. The internal consistency of each individual b 3 c1: molar solubility of the solute in units of mol dm . dataset was assessed by curve-fitting the measured mole- fraction solubility data to Eq. (8). The values of the equation Auxiliary Information coefficients (A, B, and C) are given in Table 3, along with the root-mean-square deviation (RMSD) calculated according to Method/Apparatus/Procedure: vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi Vortex mixer, constant-temperature bath, and an ultraviolet/visible u spectrophotometer. u 1 XN ¼ t calc exp 2; ð Þ Binary solvent mixtures were prepared by volume. Excess solute and solvent RMSD x1 x1 20 were placed in sealed containers and equilibrated at a constant temperature for N 1 i¼1 24 h. During this time the tubes were shaken occasionally on a vortex mixer. Aliquots of saturated solutions were removed, centrifuged, filtered through a where N is the number of experimental solubility measure- sintered glass crucible (grade 4), and diluted quantitatively with 20% aqueous ments in an individual solute-solvent data set. Examination of acetonitrile for spectroscopic analyses. Concentration of the dissolved solute the entries in the last column of Table 3 reveals that the largest was determined from the measured absorbance at 252 nm. RMSD between the back-calculated values based on Eq. (8) Source and Purity of Chemicals: and experimental data is 0.003597, which translates to a (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no relative deviation of approximately 3.5%. Results of the purification details were provided. mathematical representation analyses indicate that the experi- (2) Purity not given, Analytical Reagent grade, chemical source not specified, mental data for all ten dexibuprofen–organic solvent systems no purification details were provided. (3) Purity not given, Analytical Reagent grade, Merck Chemical Company, are internally consistent. Ltd., Mumbai, India, no purification details were provided. The experimental solubility data for dexibuprofen in organic solvents are given in Secs. 5.2–5.4. Estimated Error: Temperature: No information given in the paper. ðsÞ v2 : 0.01. c1: 5.0% (relative error, estimated by compiler).

TABLE 3. Parameters of the Modiﬁed Apelblat equation for describing the solubility of dexibuprofen in various organic solvents Solvent T/K ABCRMSD Hexanea 263–293 237.371 5511.749 38.2053 0.003046 Methanol 263–293 20.7782 115.6012 3.2054 0.001028 Ethanola 263–293 70.7086 2183.865 10.8241 0.002169 1-Propanola 263–293 131.5510 6439.273 19.6005 0.001304 2-Propanola 263–293 180.4262 8721.97 26.7981 0.002220 1-Butanol 263–293 32.6572 115.3111 5.4097 0.002014 2-Methyl-1-propanol 263–293 33.6524 115.2922 5.5811 0.001837 1-Pentanol 263–293 32.0357 115.3343 5.3212 0.003597 1-Octanol 263–293 29.5625 115.3966 4.9375 0.002879 Ethyl ethanoatea 263–293 199.6839 9523.07 29.6784 0.002612 aNumerical values of the coefﬁcients and root-mean-square deviation were taken from Zhang et al.75

5.2. Dexibuprofen solubility data in saturated 5.3. Dexibuprofen solubility data in esters hydrocarbons (including cycloalkanes)

Components: Original Measurements: 75 Components: Original Measurements: (1) (+)-α-Methyl-4-(2-methylpropyl)- J. Zhang, L. Wang, D. Wang, J. (1) (+)-α-Methyl-4-(2-methylpropyl)- 75J. Zhang, L. Wang, D. Wang, J. benzeneacetic acid ((S)-Ibuprofen; Gong, W. Li, and J. Wang, J. benzeneacetic acid ((S)-Ibuprofen; Gong, W. Li, and J. Wang, J. Dexibuprofen); C13H18O2; Chem. Eng. Data 56, 671 (2011). [51146-56-6] Dexibuprofen); C13H18O2; Chem. Eng. Data 56, 671 (2011). [51146-56-6] (2) Ethyl ethanoate; C4H8O2; [141-78-6] (2) Hexane; C6H14; [110-54-3] Variables: Prepared by: Variables: Prepared by: Temperature W. E. Acree, Jr. Temperature W. E. Acree, Jr.

Experimental Values Experimental Values

a b T/K x a x b T/K x2 x1 2 1 263.15 0.9697 0.0303 263.15 0.8493 0.1507 268.15 0.9594 0.0406 268.15 0.8313 0.1687 273.15 0.9453 0.0547 273.15 0.8117 0.1883 278.15 0.9197 0.0803 278.15 0.7986 0.2014 283.15 0.8841 0.1159 283.15 0.7798 0.2202 288.15 0.8464 0.1556 288.15 0.7601 0.2399 293.15 0.7896 0.2104 293.15 0.7548 0.2452 a ax : mole fraction of component 2 in the saturated solution. x2: mole fraction of component 2 in the saturated solution. 2 b bx : mole fraction solubility of the solute. x1: mole fraction solubility of the solute. 1

Auxiliary Information Auxiliary Information Method/Apparatus/Procedure: Method/Apparatus/Procedure: Constant-temperature bath, analytical balance, and an UV/visible Constant-temperature bath, analytical balance, and an UV/visible spectrophotometer. spectrophotometer. Excess solute and solvent were placed in a three-necked bottle and allowed to Excess solute and solvent were placed in a three-necked bottle and allowed to equilibrate with stirring at constant temperature. An aliquot of the saturated equilibrate with stirring at constant temperature. An aliquot of the saturated solution was removed and diluted quantitatively. The molar solubility of the solution was removed and diluted quantitatively. The molar solubility of the drug was determined by spectrophotometric analysis. The reported values drug was determined by spectrophotometric analysis. The reported values represent the average of at least ﬁve determinations. represent the average of at least ﬁve determinations.

Source and Purity of Chemicals: Source and Purity of Chemicals: (1) 99%, Hubei Baike Hengdi Company, China, recrystallized twice from (1) 99%, Hubei Baike Hengdi Company, China, recrystallized twice from ethanol before use. ethanol before use. (2) 99%, Tianjin Guangfu Chemical Reagent Company, China, no puriﬁcation (2) 99%, Tianjin Guangfu Chemical Reagent Company, China, no puriﬁcation details were given in the paper. details were given in the paper.

Estimated Error: Estimated Error: Temperature: 0.05 K. Temperature: 0.05 K. x : 2% (relative error). x1: 2% (relative error). 1

5.4. Dexibuprofen solubility data in alcohols Experimental Values

a b T/K x2 x1 Components: Original Measurements: (1) (+)-α-Methyl-4-(2-methylpropyl)- 76B. Wang, L. Wang, J. Zhang, W. 263.15 0.8758 0.1242 benzeneacetic acid ((S)-Ibuprofen; Li, and J. Wang, Thermochim. 268.15 0.8713 0.1287 273.15 0.8609 0.1391 Dexibuprofen); C13H18O2; Acta 540, 91 (2012). [51146-56-6] 278.15 0.8596 0.1404 283.15 0.8459 0.1541 (2) Methanol; CH4O; [67-56-1] 288.15 0.8378 0.1622 Variables: Prepared by: 293.15 0.8309 0.1691 Temperature W. E. Acree, Jr. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Experimental Values Auxiliary Information a b / / T/K x2 x1 Method Apparatus Procedure: / 263.15 0.9162 0.0838 Constant-temperature bath, analytical balance, and an UV visible 268.15 0.9107 0.0893 spectrophotometer. 273.15 0.9070 0.0930 Excess solute and solvent were placed in a three-necked bottle and allowed to 278.15 0.9034 0.0966 equilibrate with stirring at constant temperature. An aliquot of the saturated 283.15 0.8952 0.1048 solution was removed and diluted quantitatively. The molar solubility of the 288.15 0.8915 0.1085 drug was determined by spectrophotometric analysis. The reported values 293.15 0.8871 0.1129 represent the average of at least five determinations. a x2: mole fraction of component 2 in the saturated solution. b Source and Purity of Chemicals: x1: mole fraction solubility of the solute. (1) 99%, Hubei Baike Hengdi Company, China, recrystallized twice from ethanol before use. (2) 99%, Tianjin Guangfu Chemical Reagent Company, China, no purification Auxiliary Information details were given in the paper. Method/Apparatus/Procedure: Constant-temperature bath, analytical balance, and an UV/visible Estimated Error: spectrophotometer. Temperature: 0.05 K. % Excess solute and solvent were placed in a three-necked bottle and allowed to x1: 2 (relative error). equilibrate with stirring at constant temperature. An aliquot of the saturated solution was removed and diluted quantitatively. The molar solubility of the drug was determined by spectrophotometric analysis. The reported values represent the average of at least five determinations. Components: Original Measurements: (1) (+)-α-Methyl-4-(2-methylpropyl)- 75J. Zhang, L. Wang, D. Wang, J. Source and Purity of Chemicals: benzeneacetic acid ((S)-Ibuprofen; Gong, W. Li, and J. Wang, J. (1) 99%, Hubei Baike Hengdi Company, China, recrystallized twice from Dexibuprofen); C13H18O2; Chem. Eng. Data 56, 671 (2011). ethanol before use. [51146-56-6] (2) 99%, Tianjin Guangfu Chemical Reagent Company, China, no purification (2) 1-Propanol; C3H8O; [71-23-8] details were given in the paper. Variables: Prepared by: Estimated Error: Temperature W. E. Acree, Jr. Temperature: 0.05 K.

x1: 2% (relative error). Experimental Values

a b T/K x2 x1 Components: Original Measurements: (1) (+)-α-Methyl-4-(2-methylpropyl)- 75J. Zhang, L. Wang, D. Wang, J. 263.15 0.8839 0.1161 benzeneacetic acid ((S)-Ibuprofen; Gong, W. Li, and J. Wang, J. 268.15 0.8712 0.1288 273.15 0.8620 0.1380 Dexibuprofen); C13H18O2; Chem. Eng. Data 56, 671 (2011). [51146-56-6] 278.15 0.8548 0.1452 283.15 0.8319 0.1681 (2) Ethanol; C2H6O; [64-17-5] 288.15 0.8358 0.1642 Variables: Prepared by: 293.15 0.8276 0.1724 Temperature W. E. Acree, Jr. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) (+)-α-Methyl-4-(2-methylpropyl)- 76B. Wang, L. Wang, J. Zhang, W. Constant-temperature bath, analytical balance, and an UV/visible benzeneacetic acid ((S)-Ibuprofen; Li, and J. Wang, Thermochim. spectrophotometer. Dexibuprofen); C13H18O2; Acta 540, 91 (2012). Excess solute and solvent were placed in a three-necked bottle and allowed to [51146-56-6] equilibrate with stirring at constant temperature. An aliquot of the saturated (2) 1-Butanol; C4H10O; [71-36-3] solution was removed and diluted quantitatively. The molar solubility of the Variables: Prepared by: drug was determined by spectrophotometric analysis. The reported values Temperature W. E. Acree, Jr. represent the average of at least ﬁve determinations.

Source and Purity of Chemicals: Experimental Values (1) 99%, Hubei Baike Hengdi Company, China, recrystallized twice from ethanol before use. (2) 99%, Tianjin Guangfu Chemical Reagent Company, China, no puriﬁcation T/K x a x b details were given in the paper. 2 1 263.15 0.8745 0.1255 Estimated Error: 268.15 0.8627 0.1373 Temperature: 0.05 K. 273.15 0.8456 0.1544 278.15 0.8366 0.1634 x1: 2% (relative error). 283.15 0.8164 0.1836 288.15 0.8012 0.1988 293.15 0.7860 0.2140 a Components: Original Measurements: x2: mole fraction of component 2 in the saturated solution. b (1) (+)-α-Methyl-4-(2-methylpropyl)- 75J. Zhang, L. Wang, D. Wang, J. x1: mole fraction solubility of the solute. benzeneacetic acid ((S)-Ibuprofen; Gong, W. Li, and J. Wang, J.

Dexibuprofen); C13H18O2; Chem. Eng. Data 56, 671 (2011). [51146-56-6] Auxiliary Information [ ] (2) 2-Propanol; C3H8O; 67-63-0 Method/Apparatus/Procedure: / Variables: Prepared by: Constant-temperature bath, analytical balance, and an UV visible Temperature W. E. Acree, Jr. spectrophotometer. Excess solute and solvent were placed in a three-necked bottle and allowed to equilibrate with stirring at constant temperature. An aliquot of the saturated Experimental Values solution was removed and diluted quantitatively. The molar solubility of the drug was determined by spectrophotometric analysis. The reported values represent the average of at least ﬁve determinations. a b T/K x2 x1 Source and Purity of Chemicals: 263.15 0.8721 0.1279 (1) 99%, Hubei Baike Hengdi Company, China, recrystallized twice from 268.15 0.8559 0.1441 ethanol before use. 273.15 0.8419 0.1581 (2) 99%, Tianjin Guangfu Chemical Reagent Company, China, no puriﬁcation 278.15 0.8306 0.1694 details were given in the paper. 283.15 0.8103 0.1897 288.15 0.7988 0.2012 Estimated Error: 293.15 0.7912 0.2088 Temperature: 0.05 K. a x2: mole fraction of component 2 in the saturated solution. x1: 2% (relative error). b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) (+)-α-Methyl-4-(2-methylpropyl)- 76B. Wang, L. Wang, J. Zhang, W. Constant-temperature bath, analytical balance, and an UV/visible benzeneacetic acid ((S)-Ibuprofen; Li, and J. Wang, Thermochim. spectrophotometer. Dexibuprofen); C13H18O2; Acta 540, 91 (2012). Excess solute and solvent were placed in a three-necked bottle and allowed to [51146-56-6] equilibrate with stirring at constant temperature. An aliquot of the saturated (2) 2-Methyl-1-propanol; C4H10O; solution was removed and diluted quantitatively. The molar solubility of the [78-83-1] drug was determined by spectrophotometric analysis. The reported values Variables: Prepared by: represent the average of at least ﬁve determinations. Temperature W. E. Acree, Jr. Source and Purity of Chemicals: (1) 99%, Hubei Baike Hengdi Company, China, recrystallized twice from ethanol before use. (2) 99%, Tianjin Guangfu Chemical Reagent Company, China, no puriﬁcation details were given in the paper.

Estimated Error: Temperature: 0.05 K.

x1: 2% (relative error).

Experimental Values Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath, analytical balance, and an UV/visible T/K x a x b 2 1 spectrophotometer. 263.15 0.8783 0.1217 Excess solute and solvent were placed in a three-necked bottle and allowed to 268.15 0.8668 0.1332 equilibrate with stirring at constant temperature. An aliquot of the saturated 273.15 0.8554 0.1446 solution was removed and diluted quantitatively. The molar solubility of the 278.15 0.8400 0.1600 drug was determined by spectrophotometric analysis. The reported values 283.15 0.8198 0.1802 represent the average of at least five determinations. 288.15 0.8075 0.1925 293.15 0.7895 0.2105 Source and Purity of Chemicals: a (1) 99%, Hubei Baike Hengdi Company, China, recrystallized twice from x2: mole fraction of component 2 in the saturated solution. b ethanol before use. x1: mole fraction solubility of the solute. (2) 99%, Tianjin Guangfu Chemical Reagent Company, China, no purification details were given in the paper. Auxiliary Information Estimated Error: / / Method Apparatus Procedure: Temperature: 0.05 K. Constant-temperature bath, analytical balance, and an UV/visible x1: 2% (relative error). spectrophotometer. Excess solute and solvent were placed in a three-necked bottle and allowed to equilibrate with stirring at constant temperature. An aliquot of the saturated solution was removed and diluted quantitatively. The molar solubility of the drug was determined by spectrophotometric analysis. The reported values Components: Original Measurements: + α 76 represent the average of at least five determinations. (1) ( )- -Methyl-4-(2-methylpropyl)- B. Wang, L. Wang, J. Zhang, W. benzeneacetic acid ((S)-Ibuprofen; Li, and J. Wang, Thermochim. Source and Purity of Chemicals: Dexibuprofen); C13H18O2; Acta 540, 91 (2012). [ ] (1) 99%, Hubei Baike Hengdi Company, China, recrystallized twice from 51146-56-6 [ ] ethanol before use. (2) 1-Octanol; C8H18O; 111-87-5 (2) 99%, Tianjin Guangfu Chemical Reagent Company, China, no purification Variables: Prepared by: details were given in the paper. Temperature W. E. Acree, Jr.

Estimated Error: Temperature: 0.05 K. Experimental Values x1: 2% (relative error).

a b T/K x2 x1 263.15 0.7988 0.2012 Components: Original Measurements: 268.15 0.7828 0.2172 (1) (+)-α-Methyl-4-(2-methylpropyl)- 76B. Wang, L. Wang, J. Zhang, W. 273.15 0.7650 0.2350 benzeneacetic acid ((S)-Ibuprofen; Li, and J. Wang, Thermochim. 278.15 0.7425 0.2565 Dexibuprofen); C13H18O2; Acta 540, 91 (2012). 283.15 0.7212 0.2788 [51146-56-6] 288.15 0.6929 0.3071 (2) 1-Pentanol; C5H12O; [71-41-0] 293.15 0.6777 0.3223 a Variables: Prepared by: x2: mole fraction of component 2 in the saturated solution. b Temperature W. E. Acree, Jr. x1: mole fraction solubility of the solute.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: Constant-temperature bath, analytical balance, and an UV/visible a b T/K x2 x1 spectrophotometer. Excess solute and solvent were placed in a three-necked bottle and allowed to 263.15 0.8535 0.1465 equilibrate with stirring at constant temperature. An aliquot of the saturated 268.15 0.8438 0.1562 solution was removed and diluted quantitatively. The molar solubility of the 273.15 0.8312 0.1688 drug was determined by spectrophotometric analysis. The reported values 278.15 0.8176 0.1824 represent the average of at least ﬁve determinations. 283.15 0.7928 0.2072 288.15 0.7719 0.2281 Source and Purity of Chemicals: 293.15 0.7576 0.2424 (1) 99%, Hubei Baike Hengdi Company, China, recrystallized twice from a x2: mole fraction of component 2 in the saturated solution. ethanol before use. b x1: mole fraction solubility of the solute. (2) 95%, Tianjin Guangfu Chemical Reagent Company, China, no puriﬁcation details were given in the paper.

Estimated Error: Temperature: 0.05 K.

x1: 2% (relative error).

6. Solubility of Diclofenac in Organic experimental data and back-calculated values based on Solvents Eqs. (21)and(22) of 1.4% and 0.6% are less than the experimental uncertainty associated with the measured 6.1. Critical evaluation of experimental solubility values. The mean absolute relative deviation (MARD) is data defined by Eq. (23): Diclofenac (more formally named 2-[(2,6-dichlorophenyl) X exp calc 100 x1 x1 amino]benzeneacetic acid) may be administered also as the MARDð%Þ¼ ; ð23Þ N x exp sodium or potassium salt, and is used to treat painful con- 1 ditions such as arthritis, dental pain, gout, migraine, and where N denotes the number of experimental solubility exp muscle strains. There have been several published stu- measurements in an individual solute-solvent data set, x1 60,64,77–82 calc dies involving the solubility of diclofenac in organic is the experimental mole-fraction solubility, and x1 refers 77 solvents. Barra et al. measured the solubility of diclofenac to the back-calculated mole-fraction solubility. in two saturated hydrocarbons (heptane and cyclohexane), Examination of the published solubility data reveals that 1- one aromatic hydrocarbon (benzene), one dialkyl ether octanol is the only solvent for which three or more independent (1,1′-oxybisethane) and one cyclic ether (1,4-dioxane), one sets of solubility measurements at 298 K exist. The mole 80 alkyl alkanoate (ethyl ethanoate), two chloroalkanes (trichlor- fraction solubility reported by Perlovich et al., x1 ¼ 0.0101, 77 omethane and 1,2-dichloroethane) and one chlorinated aro- and by Barra et al., x1 ¼ 0.01505, can be converted to molar matic hydrocarbon (chlorobenzene), seven alcohols solubilities by dividing the value by the molar volume of 1- 1 (methanol, ethanol, 1-pentanol, 1-octanol, 1,2-ethanediol, octanol, Vsolvent ¼ 0.15830 l mol . The calculated molar 3 1,2-propanediol, and 1,2,3-propanetriol), one alkanone (pro- solubilities of c1 ¼ 0.0638 mol dm and c1 ¼ 0.0951 mol panone) and one aromatic ketone (acetophenone), and four dm3 differ fairly substantially from each other, and differ also 78 miscellaneous organic solvents (ethanoic acid, propanoic from the published values of both Wang and Fang, c1 ¼ 3 60 3 acid, formamide, and N,N-dimethylformamide) at 298 K and 0.0835 mol dm , and Fini et al., c1 ¼ 0.078 mol dm . atmospheric pressure. The experimental results were com- Given the large variation among the four published values, no bined with measured solubility data for sodium diclofenac recommended value is given. and two other carboxylic acid/sodium carboxylate pairs (e.g., The experimental solubility data for diclofenac in organic 4-aminobenzoic acid/sodium 4-aminobenzoate and salicylic solvents are in Secs. 6.2–6.9. acid/sodium salicylate) in developing a group contribution method for calculating partial solubility parameters of sodium salts. Wang and Fang78 reported the molar solubility of 6.2. Diclofenac solubility data in saturated diclofenac in 1-octanol, and Fini et al.60 determined the hydrocarbons (including cycloalkanes) molar solubility of diclofenac in 1-octanol at only three temperatures from 278 to 310 K. Wenkers and Lippold64 published solubility data for ten NSAIDs (aspirin, diclofenac, Components: Original Measurements: (1) 2-[(2,6-Dichlorophenyl)amino]- 80G. L. Perlovich, A. O. Surov, L. diflunisal, flufenamic acid, ibuprofen, ketoprofen, nabume- benzeneacetic acid (Diclofenac); Kr. Hansen, and A. Bauer-Brandl,

tone, naproxen, piroxicam, and tenoxicam) in light mineral C14H11Cl2NO2; [15307-86-5] J. Pharm. Sci. 96, 1031 (2007). 79 [ ] oil at 305 K. Ahuja et al. measured the solubility of (2) Hexane; C6H14; 110-54-3 diclofenac in eight refined food-grade vegetable oils (arachis Variables: Prepared by: oil, mustard oil, soybean oil, castor oil, olive oil, sesame oil, Temperature W. E. Acree, Jr. safflower oil, and sunflower oil) at 277 K as part of a study examining the in vitro corneal permeation of diclofenac from Experimental Values oil drops using freshly excised goat cornea. Perlovich et al.80 determined the solubility of diclofenac in a b both hexane and 1-octanol at five temperatures from 293 to T/K x2 x1 315 K using a spectrophotometric method of analysis. The 293.2 0.9999 0.0000081 internal consistency of the two datasets was assessed by 298.2 0.9999 0.0000125 curve-fitting the measured mole-fraction solubility data to 303.2 0.9999 0.0000185 the Modified Apelblat model [see Eq. (8)] to yield the 310.2 0.9999 0.0000310 315.2 0.9999 0.0000446 following representations: a x2: mole fraction of component 2 in the saturated solution. b 112:55 x1: mole fraction solubility of the solute. ln x ¼147:424 þ þ 23:824 ln T; ð21Þ 1 T

114:25 ln x ¼72:984 þ þ 11:937 ln T; ð22Þ 1 T for solubilities in hexane and 1-octanol, respectively. The mean absolute relative deviations between the observed

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-[(2,6-Dichlorophenyl)amino]- 77J. Barra, M.-A. Peña, and P. Constant-temperature bath, analytical balance, and an UV/visible benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. spectrophotometer. C14H11Cl2NO2; [15307-86-5] 10, 153 (2000). Excess solute and solvent were placed in a glass ampoule and allowed to (2) Cyclohexane; C6H12; [110-82-7] equilibrate with rotation at constant temperature. An aliquot of the saturated Variables: Prepared by: solution was removed with isothermal filtration (Acrodisc CR syringe filter, T/K ¼ 298.15 W. E. Acree, Jr. PTFE, 0.2 μm pore size), and diluted quantitatively. The molar solubility of the drug was determined by spectrophotometric analysis. The reported values represent the average of at least five determinations. Experimental Values Source and Purity of Chemicals: (1) Purity not given, Alchemie, USA, no purification details were given in the x a x b,c paper. 2 1 (2) Purity not given, Analytical Reagent grade, Solvents Documentation 0.9999 0.0000615 a Syntheses (SDS), Peypin, France, no purification details were given in the x2: mole fraction of component 2 in the saturated solution. b paper. x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Estimated Error: Temperature: 0.1 K.

x1: 2.5% (relative error). Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with Components: Original Measurements: shaking for five days at constant temperature. Aliquots of saturated solutions 77 (1) 2-[(2,6-Dichlorophenyl)amino]- J. Barra, M.-A. Peña, and P. were removed and diluted with 96% ethanol (v/v). Concentrations were benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. determined by spectrophotometric measurements. The reported solubility [ ] C14H11Cl2NO2; 15307-86-5 10, 153 (2000). represents the average of at least three independent determinations. (2) Heptane; C7H16; [142-82-5] Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 298.15 W. E. Acree, Jr. (1) Purity not given, Unique Pharmaceutical Laboratories, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Experimental Values source not specified, no purification details were provided.

Estimated Error: a b,c Temperature: 0.2 K. x2 x1 x : 2% (relative error). 0.9999 0.0000599 1 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. 6.3. Diclofenac solubility data in aromatic hydrocarbons Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Components: Original Measurements: [ ] 77 ñ Excess solute and solvent were placed in flasks and allowed to equilibrate with (1) 2- (2,6-Dichlorophenyl)amino - J. Barra, M.-A. Pe a, and P. shaking for five days at constant temperature. Aliquots of saturated solutions benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. [ ] were removed and diluted with 96% ethanol (v/v). Concentrations were C14H11Cl2NO2; 15307-86-5 10, 153 (2000). [ ] determined by spectrophotometric measurements. The reported solubility (2) Benzene; C6H6; 71-43-2 represents the average of at least three independent determinations. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Unique Pharmaceutical Laboratories, no purification details were provided. Experimental Values (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. a b,c x2 x1 Estimated Error: 0.9973 0.00272 Temperature: 0.2 K. a x1: 2% (relative error). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-[(2,6-Dichlorophenyl)amino]- 81M. A. H. M. Kamal, N. Imura, T. Constant-temperature bath and an ultraviolet/visible spectrophotometer. benzeneacetic acid (Diclofenac); Nabekura, and S. Kitagawa, Excess solute and solvent were placed in flasks and allowed to equilibrate with C14H11Cl2NO2; [15307-86-5] Chem. Pharm. Bull. 55, 368 shaking for five days at constant temperature. Aliquots of saturated solutions (2) 1-Methylethyl tetradecanoate; (2007). % / were removed and diluted with 96 ethanol (v v). Concentrations were C17H34O2; [110-27-0] determined by spectrophotometric measurements. The reported solubility Variables: Prepared by: represents the average of at least three independent determinations. T/K ¼ 310 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Unique Pharmaceutical Laboratories, no purification Experimental Values details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical The measured solubility was reported to be c1 ¼ 0.020 source not specified, no purification details were provided. mol dm3.

Estimated Error: Temperature: 0.2 K. Auxiliary Information % x1: 2 (relative error). Method/Apparatus/Procedure: Very few experimental details were given in the paper. Excess solute and solvent were allowed to equilibrate at 310 K for a period of 24 h. An aliquot of the solution was removed and quickly centrifuged for 2 min. The concentration 6.4. Diclofenac solubility data in esters of the dissolved solute in the supernatant was determined by high-performance liquid chromatographic analysis.

Source and Purity of Chemicals: Components: Original Measurements: (1) Purity not given, Wako Pure Chemical Industries, Osaka, Japan, purchased 77 (1) 2-[(2,6-Dichlorophenyl)amino]- J. Barra, M.-A. Peña, and P. as the sodium salt and converted to the acidic form by addition of hydrochloric benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. acid. [ ] C14H11Cl2NO2; 15307-86-5 10, 153 (2000). (2) Purity not given, Nascalai Tesque, Kyoto, Japan, no puriﬁcation details (2) Ethyl ethanoate; C4H8O2; were provided in the paper. [141-78-6] Variables: Prepared by: Estimated Error: T/K ¼ 298.15 W. E. Acree, Jr. Temperature: Insufﬁcient information given in the paper to estimate. c1: 10% (relative error, estimated by compiler).

Experimental Values

6.5. Diclofenac solubility data in ethers a b,c x2 x1 0.9771 0.0229 a x2: mole fraction of component 2 in the saturated solution. Components: Original Measurements: b 77 x1: mole fraction solubility of the solute. (1) 2-[(2,6-Dichlorophenyl)amino]- J. Barra, M.-A. Peña, and P. c Experimental value was reported in the paper as ln x1. benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. C14H11Cl2NO2; [15307-86-5] 10, 153 (2000). (2) 1,1′-Oxybisethane; C4H10O; Auxiliary Information [60-29-7] Method/Apparatus/Procedure: Variables: Prepared by: Constant-temperature bath and an ultraviolet/visible spectrophotometer. T/K ¼ 298.15 W. E. Acree, Jr. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Experimental Values determined by spectrophotometric measurements. The reported solubility represents the average of at least three independent determinations. a b,c x2 x1 Source and Purity of Chemicals: 0.9979 0.00211 (1) Purity not given, Unique Pharmaceutical Laboratories, no purification a x2: mole fraction of component 2 in the saturated solution. details were provided. b x1: mole fraction solubility of the solute. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical c source not specified, no purification details were provided. Experimental value was reported in the paper as ln x1.

Estimated Error: Temperature: 0.2 K.

x1: 2% (relative error).

Auxiliary Information 6.6. Diclofenac solubility data in haloalkanes, Method/Apparatus/Procedure: haloalkenes, and haloaromatic hydrocarbons Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions Components: Original Measurements: were removed and the solvent evaporated. The residual solid was then (1) 2-[(2,6-Dichlorophenyl)amino]- 77J. Barra, M.-A. Peña, and P. dissolved and diluted with 96% ethanol (v/v). Concentrations were determined benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. by spectrophotometric measurements. The reported solubility represents the C H Cl NO ; [15307-86-5] 10, 153 (2000). average of at least three independent determinations. 14 11 2 2 (2) Trichloromethane; CHCl3; [67-66-3] Source and Purity of Chemicals: (1) Purity not given, Unique Pharmaceutical Laboratories, no purification Variables: Prepared by: details were provided. T/K ¼ 298.15 W. E. Acree, Jr. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values Estimated Error: Temperature: 0.2 K. a b,c x1: 2% (relative error). x2 x1 0.9906 0.00939 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Components: Original Measurements: c Experimental value was reported in the paper as ln x1. (1) 2-[(2,6-Dichlorophenyl)amino]- 77J. Barra, M.-A. Peña, and P. benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. [ ] C14H11Cl2NO2; 15307-86-5 10, 153 (2000). Auxiliary Information (2) 1,4-Dioxane; C4H8O2; [123-91-1] Method/Apparatus/Procedure: Variables: Prepared by: Constant-temperature bath and an ultraviolet/visible spectrophotometer. T/K ¼ 298.15 W. E. Acree, Jr. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Experimental Values determined by spectrophotometric measurements. The reported solubility represents the average of at least three independent determinations.

a b,c x2 x1 Source and Purity of Chemicals: 0.8945 0.1055 (1) Purity not given, Unique Pharmaceutical Laboratories, no purification a details were provided. x2: mole fraction of component 2 in the saturated solution. b (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x1: mole fraction solubility of the solute. c source not specified, no purification details were provided. Experimental value was reported in the paper as ln x1. Estimated Error: Temperature: 0.2 K. Auxiliary Information x1: 2% (relative error). Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions Components: Original Measurements: were removed and diluted with 96% ethanol (v/v). Concentrations were (1) 2-[(2,6-Dichlorophenyl)amino]- 77J. Barra, M.-A. Peña, and P. determined by spectrophotometric measurements. The reported solubility benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. represents the average of at least three independent determinations. C14H11Cl2NO2; [15307-86-5] 10, 153 (2000). (2) 1,2-Dichloroethane; C H Cl ; Source and Purity of Chemicals: 2 4 2 [107-06-2] (1) Purity not given, Unique Pharmaceutical Laboratories, no purification details were provided. Variables: Prepared by: (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical T/K ¼ 298.15 W. E. Acree, Jr. source not specified, no purification details were provided.

Estimated Error: Experimental Values Temperature: 0.2 K.

x1: 2% (relative error). a b,c x2 x1 0.9960 0.00403 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information 6.7. Diclofenac solubility data in alcohols Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with Components: Original Measurements: shaking for ﬁve days at constant temperature. Aliquots of saturated solutions (1) 2-[(2,6-Dichlorophenyl)amino]- 77J. Barra, M.-A. Peña, and P. % / were removed and diluted with 96 ethanol (v v). Concentrations were benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. determined by spectrophotometric measurements. The reported solubility C14H11Cl2NO2; [15307-86-5] 10, 153 (2000). represents the average of at least three independent determinations. (2) Methanol; CH4O; [67-56-1]

Source and Purity of Chemicals: Variables: Prepared by: / ¼ (1) Purity not given, Unique Pharmaceutical Laboratories, no purification T K 298.15 W. E. Acree, Jr. details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values

Estimated Error: a b,c Temperature: 0.2 K. x2 x1

x1: 2% (relative error). 0.9941 0.00587 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Components: Original Measurements: (1) 2-[(2,6-Dichlorophenyl)amino]- 77J. Barra, M.-A. Peña, and P. benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. Auxiliary Information C H Cl NO ; [15307-86-5] 10, 153 (2000). 14 11 2 2 Method/Apparatus/Procedure: (2) Chlorobenzene; C H Cl; 6 5 Constant-temperature bath and an ultraviolet/visible spectrophotometer. [108-90-7] Excess solute and solvent were placed in flasks and allowed to equilibrate with Variables: Prepared by: shaking for five days at constant temperature. Aliquots of saturated solutions T/K ¼ 298.15 W. E. Acree, Jr. were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements. The reported solubility represents the average of at least three independent determinations. Experimental Values Source and Purity of Chemicals: (1) Purity not given, Unique Pharmaceutical Laboratories, no purification a b,c x2 x1 details were provided. 0.9963 0.00368 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a source not specified, no purification details were provided. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Estimated Error: Experimental value was reported in the paper as ln x1. Temperature: 0.2 K.

x1: 2% (relative error). Auxiliary Information Method/Apparatus/Procedure: / Constant-temperature bath and an ultraviolet visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in flasks and allowed to equilibrate with (1) 2-[(2,6-Dichlorophenyl)amino]- 77J. Barra, M.-A. Peña, and P. shaking for five days at constant temperature. Aliquots of saturated solutions benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. were removed and diluted with 96% ethanol (v/v). Concentrations were C14H11Cl2NO2; [15307-86-5] 10, 153 (2000). determined by spectrophotometric measurements. The reported solubility (2) Ethanol; C2H6O; [64-17-5] represents the average of at least three independent determinations. Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 298.15 W. E. Acree, Jr. (1) Purity not given, Unique Pharmaceutical Laboratories, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Experimental Values source not specified, no purification details were provided.

a b,c Estimated Error: x2 x1 Temperature: 0.2 K. 0.9913 0.00873 x1: 2% (relative error). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-[(2,6-Dichlorophenyl)amino]- 77J. Barra, M.-A. Peña, and P. Constant-temperature bath and an ultraviolet/visible spectrophotometer. benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with C14H11Cl2NO2; [15307-86-5] 10, 153 (2000). shaking for ﬁve days at constant temperature. Aliquots of saturated solutions (2) 1-Octanol; C8H18O; [111-87-5] were removed and diluted with 96% ethanol (v/v). Concentrations were Variables: Prepared by: determined by spectrophotometric measurements. The reported solubility T/K ¼ 298.15 W. E. Acree, Jr. represents the average of at least three independent determinations.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Unique Pharmaceutical Laboratories, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x a x b,c source not specified, no purification details were provided. 2 1 0.9849 0.01505 a Estimated Error: x2: mole fraction of component 2 in the saturated solution. b Temperature: 0.2 K. x1: mole fraction solubility of the solute. % c x1: 2 (relative error). Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: 77 (1) 2-[(2,6-Dichlorophenyl)amino]- J. Barra, M.-A. Peña, and P. Constant-temperature bath and an ultraviolet/visible spectrophotometer. benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with [ ] C14H11Cl2NO2; 15307-86-5 10, 153 (2000). shaking for ﬁve days at constant temperature. Aliquots of saturated solutions [ ] (2) 1-Pentanol; C5H12O; 71-41-0 were removed and diluted with 96% ethanol (v/v). Concentrations were Variables: Prepared by: determined by spectrophotometric measurements. The reported solubility T/K ¼ 298.15 W. E. Acree, Jr. represents the average of at least three independent determinations.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Unique Pharmaceutical Laboratories, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a b,c source not specified, no purification details were provided. x2 x1 0.9871 0.01287 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. Temperature: 0.2 K. b x1: mole fraction solubility of the solute. x1: 2% (relative error). c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-[(2,6-Dichlorophenyl)amino]- 80G. L. Perlovich, A. O. Surov, L. Constant-temperature bath and an ultraviolet/visible spectrophotometer. benzeneacetic acid (Diclofenac); Kr. Hansen, and A. Bauer-Brandl, Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with C14H11Cl2NO2; [15307-86-5] J. Pharm. Sci. 96, 1031 (2007). shaking for ﬁve days at constant temperature. Aliquots of saturated solutions (2) 1-Octanol; C8H18O; [111-87-5] were removed and diluted with 96% ethanol (v/v). Concentrations were Variables: Prepared by: determined by spectrophotometric measurements. The reported solubility Temperature W. E. Acree, Jr. represents the average of at least three independent determinations.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Unique Pharmaceutical Laboratories, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical T/K x a x b source not specified, no purification details were provided. 2 1 293.2 0.9916 0.0084 Estimated Error: 298.2 0.9899 0.0101 Temperature: 0.2 K. 303.2 0.9877 0.0123 310.2 0.9838 0.0162 x1: 2% (relative error). 315.2 0.9808 0.0192 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-[(2,6-Dichlorophenyl)amino]- 78M. Wang and L. Fang, Asian J. Constant-temperature bath, analytical balance, and an UV/visible benzeneacetic acid (Diclofenac); Pharm. Sci. 3, 131 (2008). spectrophotometer. C14H11Cl2NO2; [15307-86-5] Excess solute and solvent were placed in a glass ampoule and allowed to (2) 1-Octanol; C8H18O; [111-87-5] equilibrate with rotation at constant temperature. An aliquot of the saturated Variables: Prepared by: solution was removed with isothermal filtration (Acrodisc CR syringe filter, T/K ¼ 298.15 W. E. Acree, Jr. PTFE, 0.2 μm pore size), and diluted quantitatively. The molar solubility of the drug was determined by spectrophotometric analysis. The reported values represent the average of at least five determinations. Experimental Values

Source and Purity of Chemicals: The measured solubility was reported to be c1 ¼ 0.0835 (1) Purity not given, Alchemie, USA, no puriﬁcation details were given in the mol dm 3. paper. (2) Purity not given, Analytical Reagent Grade, Sigma Chemical Company, St. Auxiliary Information Louis, Missouri, USA, no puriﬁcation details were given in the paper. Method/Apparatus/Procedure: Estimated Error: No experimental details were given in the paper. Temperature: 0.1 K.

x1: 2.5% (relative error). Source and Purity of Chemicals: (1) Purity not given, Tieling Tiande Pharmaceutic Company, Ltd., China, no purification details were provided. (2) Purity not given, chemical source not specified, no purification details were Components: Original Measurements: provided. (1) 2-[(2,6-Dichlorophenyl)amino]- 60A. Fini, M. Laus, I. Orienti, and benzeneacetic acid (Diclofenac); V. Zecchi, J. Pharm. Sci. 75,23 Estimated Error: Temperature: 0.5 K (estimated by compiler). C14H11Cl2NO2; [15307-86-5] (1986). c1: 10% (relative error, estimated by compiler). (2) 1-Octanol; C8H18O; [111-87-5] Variables: Prepared by: Temperature W. E. Acree, Jr. Components: Original Measurements: [ ] 77 ñ Experimental Values (1) 2- (2,6-Dichlorophenyl)amino - J. Barra, M.-A. Pe a, and P. benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci.

C14H11Cl2NO2; [15307-86-5] 10, 153 (2000). (2) 1,2-Ethanediol; C H O ; T/K c a 2 6 2 1 [107-21-1] 278.2 0.064 298.2 0.078 Variables: Prepared by: 310.2 0.089 T/K ¼ 298.15 W. E. Acree, Jr. a 3 c1: molar solubility of the solute in units of mol dm . Experimental Values Auxiliary Information a b,c Method/Apparatus/Procedure: x2 x1 Constant-temperature bath, analytical balance, and an UV/visible 0.9983 0.00170 spectrophotometer. ax : mole fraction of component 2 in the saturated solution. Excess solute and solvent were placed in a sealed container and allowed to 2 bx : mole fraction solubility of the solute. equilibrate with stirring at constant temperature. An aliquot of the saturated 1 cExperimental value was reported in the paper as ln x . solution was removed, filtered through a 0.22 μm pore membrane, and diluted 1 quantitatively for spectroscopic analysis. Auxiliary Information Source and Purity of Chemicals: (1) Purity not given, chemical source not specified, was recrystallized from Method/Apparatus/Procedure: suitable solvent before use. Constant-temperature bath and an ultraviolet/visible spectrophotometer. (2) Purity not given, chemical source not specified, no purification details were Excess solute and solvent were placed in flasks and allowed to equilibrate with provided in the paper. shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Estimated Error: determined by spectrophotometric measurements. The reported solubility Temperature: 0.2 K (estimated by compiler). represents the average of at least three independent determinations. c1: 3% (relative error).

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Unique Pharmaceutical Laboratories, no purification ¼ details were provided. The measured solubility was reported to be c1 0.0562 3 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical mol dm . source not specified, no purification details were provided. Auxiliary Information Estimated Error: Method/Apparatus/Procedure: Temperature: 0.2 K. Constant-temperature shaker bath and a high-performance liquid % x1: 2 (relative error). chromatograph with uv detection. Excess solute and solvent were placed in flasks and then immersed in a constant-temperature shaker bath for 24 h. Aliquots of saturated solutions were removed and filtered through a Minisart RC 4 filter of 0.45 μm pore size. Components: Original Measurements: Concentrations were determined by high-performance liquid chromatographic (1) 2-[(2,6-Dichlorophenyl)amino]- 77J. Barra, M.-A. Peña, and P. measurements at 275 nm after suitable dilution with methanol. benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci.

C14H11Cl2NO2; [15307-86-5] 10, 153 (2000). Source and Purity of Chemicals: (2) 1,2-Propanediol; C3H8O2; (1) Purity not given, Ahn-Gook Pharmaceutical Company, Seoul, South [57-55-6] Korea, purchased as the sodium salt and converted to the free-base form by adjusting the pH and collecting the precipitate. Variables: Prepared by: (2) Purity not given, HPLC grade, Merck Chemical Company, Darmstadt, / ¼ T K 298.15 W. E. Acree, Jr. Germany, no puriﬁcation details were provided in the paper.

Estimated Error: Experimental Values Temperature: Insufﬁcient information given in the paper to estimate.

c1: 12% (relative error).

a b,c x2 x1 0.9951 0.00491 a x2: mole fraction of component 2 in the saturated solution. Components: Original Measurements: b 77 x1: mole fraction solubility of the solute. (1) 2-[(2,6-Dichlorophenyl)amino]- J. Barra, M.-A. Peña, and P. c Experimental value was reported in the paper as ln x1. benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci.

C14H11Cl2NO2; [15307-86-5] 10, 153 (2000). (2) 1,2,3-Propanetriol (Glycerol); Auxiliary Information C3H8O3; [56-81-5] Method/Apparatus/Procedure: Variables: Prepared by: Constant-temperature bath and an ultraviolet/visible spectrophotometer. T/K ¼ 298.15 W. E. Acree, Jr. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Experimental Values determined by spectrophotometric measurements. The reported solubility represents the average of at least three independent determinations. a b,c x2 x1 Source and Purity of Chemicals: 0.9997 0.000308 (1) Purity not given, Unique Pharmaceutical Laboratories, no purification a details were provided. x2: mole fraction of component 2 in the saturated solution. b (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x1: mole fraction solubility of the solute. c source not specified, no purification details were provided. Experimental value was reported in the paper as ln x1.

Estimated Error: Auxiliary Information Temperature: 0.2 K. Method/Apparatus/Procedure: x1: 2% (relative error). Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Components: Original Measurements: determined by spectrophotometric measurements. The reported solubility [ ] 82 (1) 2- (2,6-Dichlorophenyl)amino - M.-J. Kim, H.-J. Doh, M.-K. represents the average of at least three independent determinations. benzeneacetic acid (Diclofenac); Choi, S.-J. Chung, C.-K. Shim, D.- [ ] C14H11Cl2NO2; 15307-86-5 D. Kim, J. S. Kim, S.-S. Yong, and Source and Purity of Chemicals: H.-G. Choi, Drug Delivery 15, 373 (2) 1,2-Propanediol; C3H8O2; (1) Purity not given, Unique Pharmaceutical Laboratories, no purification [57-55-6] (2008). details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Variables: Prepared by: source not specified, no purification details were provided. T/K ¼ 310 W. E. Acree, Jr. Estimated Error: Temperature: 0.2 K.

x1: 2% (relative error).

6.8. Diclofenac solubility data in ketones Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in flasks and allowed to equilibrate with (1) 2-[(2,6-Dichlorophenyl)amino]- 77J. Barra, M.-A. Peña, and P. shaking for five days at constant temperature. Aliquots of saturated solutions benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. were removed and the solvent evaporated. The residual solid was then dissolved and diluted with 96% ethanol (v/v). Concentrations were determined C14H11Cl2NO2; [15307-86-5] 10, 153 (2000). by spectrophotometric measurements. The reported solubility represents the (2) Propanone; C3H6O; [67-64-1] average of at least three independent determinations. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Unique Pharmaceutical Laboratories, no purification details were provided. Experimental Values (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided.

a b,c x2 x1 Estimated Error: 0.9698 0.03020 Temperature: 0.2 K. a x1: 2% (relative error). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

6.9. Diclofenac solubility data in miscellaneous Auxiliary Information organic solvents Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with Components: Original Measurements: shaking for ﬁve days at constant temperature. Aliquots of saturated solutions (1) 2-[(2,6-Dichlorophenyl)amino]- 77J. Barra, M.-A. Peña, and P. % / were removed and diluted with 96 ethanol (v v). Concentrations were benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. determined by spectrophotometric measurements. The reported solubility C14H11Cl2NO2; [15307-86-5] 10, 153 (2000). represents the average of at least three independent determinations. (2) Ethanoic acid; C2H4O2; [64-19-7]

Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Unique Pharmaceutical Laboratories, no purification T/K ¼ 298.15 W. E. Acree, Jr. details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values

Estimated Error: a b,c Temperature: 0.2 K. x2 x1 x1: 2% (relative error). 0.9943 0.00565 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Components: Original Measurements: (1) 2-[(2,6-Dichlorophenyl)amino]- 77J. Barra, M.-A. Peña, and P. benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. Auxiliary Information C H Cl NO ; [15307-86-5] 10, 153 (2000). 14 11 2 2 Method/Apparatus/Procedure: (2) Acetophenone; C H O; [98-86-2] 8 8 Constant-temperature bath and an ultraviolet/visible spectrophotometer. Variables: Prepared by: Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with T/K ¼ 298.15 W. E. Acree, Jr. shaking for ﬁve days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements. The reported solubility Experimental Values represents the average of at least three independent determinations.

Source and Purity of Chemicals: a b,c x2 x1 (1) Purity not given, Unique Pharmaceutical Laboratories, no purification 0.9553 0.04473 details were provided. a (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x2: mole fraction of component 2 in the saturated solution. b source not specified, no purification details were provided. x1: mole fraction solubility of the solute. c x Experimental value was reported in the paper as ln 1. Estimated Error: Temperature: 0.2 K.

x1: 2% (relative error).

Auxiliary Information Components: Original Measurements: (1) 2-[(2,6-Dichlorophenyl)amino]- 77J. Barra, M.-A. Peña, and P. Method/Apparatus/Procedure: benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. Constant-temperature bath and an ultraviolet/visible spectrophotometer. C14H11Cl2NO2; [15307-86-5] 10, 153 (2000). Excess solute and solvent were placed in flasks and allowed to equilibrate with (2) Propanoic acid; C3H6O2; shaking for five days at constant temperature. Aliquots of saturated solutions [79-09-4] were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements. The reported solubility Variables: Prepared by: represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: Experimental Values (1) Purity not given, Unique Pharmaceutical Laboratories, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a b,c source not specified, no purification details were provided. x2 x1 0.9902 0.00980 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. Temperature: 0.2 K. b % x1: mole fraction solubility of the solute. x1: 2 (relative error). c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: 77 Method/Apparatus/Procedure: (1) 2-[(2,6-Dichlorophenyl)amino]- J. Barra, M.-A. Peña, and P. Constant-temperature bath and an ultraviolet/visible spectrophotometer. benzeneacetic acid (Diclofenac); Bustamante, Eur. J. Pharm. Sci. [ ] Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with C14H11Cl2NO2; 15307-86-5 10, 153 (2000). shaking for ﬁve days at constant temperature. Aliquots of saturated solutions (2) N,N-Dimethylformamide; [ ] were removed and diluted with 96% ethanol (v/v). Concentrations were C3H7NO; 64-19-7 determined by spectrophotometric measurements. The reported solubility Variables: Prepared by: represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr.

Source and Purity of Chemicals: (1) Purity not given, Unique Pharmaceutical Laboratories, no purification Experimental Values details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. a b,c x2 x1 Estimated Error: 0.7795 0.2205 a Temperature: 0.2 K. x2: mole fraction of component 2 in the saturated solution. b x1: 2% (relative error). x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Unique Pharmaceutical Laboratories, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x a x b,c 2 1 source not specified, no purification details were provided. 0.9982 0.00176 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 0.2 K. c % Experimental value was reported in the paper as ln x1. x1: 2 (relative error).

Estimated Error: Components: Original Measurements: Temperature: 0.5 K (estimated by compiler). (1) 2-[(2,6-Dichlorophenyl)amino]- 64B. P. Wenkers and B. C. s1: 1.5% (relative error). benzeneacetic acid (Diclofenac); Lippold, J. Pharm. Sci. 88, 1326

C14H11Cl2NO2; [15307-86-5] (1999). (2) Mineral oil

Variables: Prepared by: Components: Original Measurements: T/K ¼ 305.15 W. E. Acree, Jr. (1) 2-[(2,6-Dichlorophenyl)amino]- 79M. Ahuja, S. K. Sharma, and D. benzeneacetic acid (Diclofenac); K. Majumdar, Yakugaku Zasshi

C14H11Cl2NO2; [15307-86-5] 127, 1739 (2007). Experimental Values (2) Castor oil ¼ The measured solubility was reported to be c1 0.0000956 Variables: Prepared by: 3 mol dm . T/K ¼ 277 W. E. Acree, Jr.

Auxiliary Information Method/Apparatus/Procedure: Experimental Values / Constant-temperature bath and an UV visible spectrophotometer. The measured solubility was reported to be s1 ¼ 1.633 Excess solute and solvent were placed in sealed bottles and allowed to (mass/volume percent). equilibrate at a constant temperature with rotation for 24 h. Aliquots of saturated solutions were removed, filtered through a 0.45 μm cellulose acetate membrane filter, and diluted quantitatively for spectroscopic analysis. Auxiliary Information Reported values represent the average of three experimental measurements. Method/Apparatus/Procedure: Centrifuge and high-performance liquid chromatograph. Source and Purity of Chemicals: Excess solute and solvent were placed in sealed bottles and allowed to pre- (1) Purity not given, Merck Chemical Company, Darmstadt, Germany, no equilibrate at 323 K for an unspecified period of time. The solution was then purification details were provided. cooled to 277 K and left overnight to equilibrate. The solution was (2) Purity not given, Parafluid Mineralolgesellschaft, Hamburg, Germany, no subsequently centrifuged at 5000 rpm to separate the clear solution and solid purification details were provided. material. An aliquot of the clear supernatant was dissolved in acetone and the concentration of the dissolved solute determined by high-performance liquid Estimated Error: chromatographic analysis at 276 nm. Temperature: 0.5 K (estimated by compiler). % c1: 10 (relative error). Source and Purity of Chemicals: (1) Purity not given, prepared by the authors by acidifying sodium diclofenac (98.58%, Dabur Research Foundation, Ghaziabad, India) with dilute hydrochloric acid solution. Components: Original Measurements: (2) Purity not given, S. D. Fine Chemical Ltd., Mumbai, India, was used as (1) 2-[(2,6-Dichlorophenyl)amino]- 79M. Ahuja, S. K. Sharma, and D. received. benzeneacetic acid (Diclofenac); K. Majumdar, Yakugaku Zasshi

C14H11Cl2NO2; [15307-86-5] 127, 1739 (2007). Estimated Error: (2) Arachis oil Temperature: 0.5 K (estimated by compiler). s : 4.0% (relative error). Variables: Prepared by: 1 T/K ¼ 277 W. E. Acree, Jr.

Experimental Values Components: Original Measurements: [ ] 79 ¼ (1) 2- (2,6-Dichlorophenyl)amino - M. Ahuja, S. K. Sharma, and D. The measured solubility was reported to be s1 0.720 benzeneacetic acid (Diclofenac); K. Majumdar, Yakugaku Zasshi / (mass volume percent). C14H11Cl2NO2; [15307-86-5] 127, 1739 (2007). (2) Mustard oil Auxiliary Information Variables: Prepared by: / ¼ Method/Apparatus/Procedure: T K 277 W. E. Acree, Jr. Centrifuge and high-performance liquid chromatograph. Excess solute and solvent were placed in sealed bottles and allowed to pre- equilibrate at 323 K for an unspeciﬁed period of time. The solution was then Experimental Values cooled to 277 K and left overnight to equilibrate. The solution was The measured solubility was reported to be s1 ¼ 0.252 subsequently centrifuged at 5000 rpm to separate the clear solution and solid (mass/volume percent). material. An aliquot of the clear supernatant was dissolved in acetone and the concentration of the dissolved solute determined by high-performance liquid chromatographic analysis at 276 nm.

Source and Purity of Chemicals: (1) Purity not given, prepared by the authors by acidifying sodium diclofenac (98.58%, Dabur Research Foundation, Ghaziabad, India) with dilute hydrochloric acid solution. (2) Purity not given, Amrit Banaspati Company, Ltd., Punjab, India, was used as received.

Auxiliary Information Variables: Prepared by: T/K ¼ 277 W. E. Acree, Jr. Method/Apparatus/Procedure: Centrifuge and high-performance liquid chromatograph. Excess solute and solvent were placed in sealed bottles and allowed to pre- Experimental Values equilibrate at 323 K for an unspeciﬁed period of time. The solution was then ¼ cooled to 277 K and left overnight to equilibrate. The solution was The measured solubility was reported to be s1 0.383 subsequently centrifuged at 5000 rpm to separate the clear solution and solid (mass/volume percent). material. An aliquot of the clear supernatant was dissolved in acetone and the concentration of the dissolved solute determined by high-performance liquid Auxiliary Information chromatographic analysis at 276 nm. Method/Apparatus/Procedure: Source and Purity of Chemicals: Centrifuge and high-performance liquid chromatograph. (1) Purity not given, prepared by the authors by acidifying sodium diclofenac Excess solute and solvent were placed in sealed bottles and allowed to pre- (98.58%, Dabur Research Foundation, Ghaziabad, India) with dilute equilibrate at 323 K for an unspeciﬁed period of time. The solution was then hydrochloric acid solution. cooled to 277 K and left overnight to equilibrate. The solution was (2) Purity not given, National Diary Development Board, Gujarat, India, was subsequently centrifuged at 5000 rpm to separate the clear solution and solid used as received. material. An aliquot of the clear supernatant was dissolved in acetone and the concentration of the dissolved solute determined by high-performance liquid Estimated Error: chromatographic analysis at 276 nm. Temperature: 0.5 K (estimated by compiler).

s1: 16% (relative error). Source and Purity of Chemicals: (1) Purity not given, prepared by the authors by acidifying sodium diclofenac (98.58%, Dabur Research Foundation, Ghaziabad, India) with dilute hydrochloric acid solution. (2) Purity not given, Marico Ltd., Mumbai, India, was used as received. Components: Original Measurements: (1) 2-[(2,6-Dichlorophenyl)amino]- 79M. Ahuja, S. K. Sharma, and D. Estimated Error: benzeneacetic acid (Diclofenac); K. Majumdar, Yakugaku Zasshi Temperature: 0.5 K (estimated by compiler). C H Cl NO ; [15307-86-5] 127, 1739 (2007). 14 11 2 2 s : 10% (relative error). (2) Olive oil 1 Variables: Prepared by: T/K ¼ 277 W. E. Acree, Jr. Components: Original Measurements: (1) 2-[(2,6-Dichlorophenyl)amino]- 79M. Ahuja, S. K. Sharma, and D. Experimental Values benzeneacetic acid (Diclofenac); K. Majumdar, Yakugaku Zasshi [ ] The measured solubility was reported to be s1 ¼ 0.291 C14H11Cl2NO2; 15307-86-5 127, 1739 (2007). (mass/volume percent). (2) Sesame oil Variables: Prepared by: Auxiliary Information T/K ¼ 277 W. E. Acree, Jr. Method/Apparatus/Procedure: Centrifuge and high-performance liquid chromatograph. Experimental Values Excess solute and solvent were placed in sealed bottles and allowed to pre- ¼ equilibrate at 323 K for an unspeciﬁed period of time. The solution was then The measured solubility was reported to be s1 0.325 cooled to 277 K and left overnight to equilibrate. The solution was (mass/volume percent). subsequently centrifuged at 5000 rpm to separate the clear solution and solid material. An aliquot of the clear supernatant was dissolved in acetone and the Auxiliary Information concentration of the dissolved solute determined by high-performance liquid chromatographic analysis at 276 nm. Method/Apparatus/Procedure: Centrifuge and high-performance liquid chromatograph. Source and Purity of Chemicals: Excess solute and solvent were placed in sealed bottles and allowed to pre- (1) Purity not given, prepared by the authors by acidifying sodium diclofenac equilibrate at 323 K for an unspeciﬁed period of time. The solution was then (98.58%, Dabur Research Foundation, Ghaziabad, India) with dilute cooled to 277 K and left overnight to equilibrate. The solution was hydrochloric acid solution. subsequently centrifuged at 5000 rpm to separate the clear solution and solid (2) Purity not given, SOS Cuetara, Madrid, Spain, was used as received. material. An aliquot of the clear supernatant was dissolved in acetone and the concentration of the dissolved solute determined by high-performance liquid Estimated Error: chromatographic analysis at 276 nm. Temperature: 0.5 K (estimated by compiler).

s1: 10% (relative error). Source and Purity of Chemicals: (1) Purity not given, prepared by the authors by acidifying sodium diclofenac (98.58%, Dabur Research Foundation, Ghaziabad, India) with dilute hydrochloric acid solution. (2) Purity not given, Shankar Udyog, Kanpur, India, was used as received. Components: Original Measurements: (1) 2-[(2,6-Dichlorophenyl)amino]- 79M. Ahuja, S. K. Sharma, and D. Estimated Error: benzeneacetic acid (Diclofenac); K. Majumdar, Yakugaku Zasshi Temperature: 0.5 K (estimated by compiler). C H Cl NO ; [15307-86-5] 127, 1739 (2007). 14 11 2 2 s : 10% (relative error). (2) Safﬂower oil 1

Source and Purity of Chemicals: Components: Original Measurements: (1) Purity not given, prepared by the authors by acidifying sodium diclofenac [ ] 79 (1) 2- (2,6-Dichlorophenyl)amino - M. Ahuja, S. K. Sharma, and D. (98.58%, Dabur Research Foundation, Ghaziabad, India) with dilute benzeneacetic acid (Diclofenac); K. Majumdar, Yakugaku Zasshi hydrochloric acid solution. [ ] C14H11Cl2NO2; 15307-86-5 127, 1739 (2007). (2) Purity not given, Amrit Banaspati Company, Ltd., Punjab, India, was used (2) Soybean oil as received. Variables: Prepared by: T/K ¼ 277 W. E. Acree, Jr. Estimated Error: Temperature: 0.5 K (estimated by compiler).

s1: 6% (relative error). Experimental Values

The measured solubility was reported to be s1 ¼ 0.327 / (mass volume percent). 7. Solubility of Diﬂunisal in Organic

Auxiliary Information Solvents Method/Apparatus/Procedure: 7.1. Critical evaluation of experimental solubility Centrifuge and high-performance liquid chromatograph. data Excess solute and solvent were placed in sealed bottles and allowed to pre- equilibrate at 323 K for an unspecified period of time. The solution was then Diflunisal (more formally named 2′,4′-difluoro-4-hydroxy- cooled to 277 K and left overnight to equilibrate. The solution was 1,1′-biphenyl-3-carboxylic acid) is a NSAID used in the subsequently centrifuged at 5000 rpm to separate the clear solution and solid treatment of mild to moderate pain from dental surgery (wis- material. An aliquot of the clear supernatant was dissolved in acetone and the concentration of the dissolved solute determined by high-performance liquid dom teeth removal) and from muscle aches and pains, and to chromatographic analysis at 276 nm. treat symptoms of rheumatoid arthritis and osteoarthritis. There have been only four studies64,65,83,84 involving the Source and Purity of Chemicals: solubility of diflunisal in organic solvents. Perlovich et al.84 (1) Purity not given, prepared by the authors by acidifying sodium diclofenac determined the solubility of diflunisal in two aromatic hydro- (98.58%, Dabur Research Foundation, Ghaziabad, India) with dilute hydrochloric acid solution. carbons (benzene, methylbenzene), in eight linear 1-alkanols (2) Purity not given, Adani Wilmar Limited, Gugarat, India, was used as (methanol through 1-octanol), and in ethanenitrile at 298 K received. and atmospheric pressure. Wenkers and Lippold64 reported solubility data for ten NSAIDs (aspirin, diclofenac, diflunisal, Estimated Error: flufenamic acid, ibuprofen, ketoprofen, nabumetone, Temperature: 0.5 K (estimated by compiler). naproxen, piroxicam, and tenoxicam) in light mineral oil at s1: 10% (relative error). 305 K. Rytting et al.65 determined the solubility of diflunisal in polyethylene glycol 400 (PEG 400) at ambient room temperature. Components: Original Measurements: Kurkov and Perlovich83 determined the solubility of diflu- (1) 2-[(2,6-Dichlorophenyl)amino]- 79M. Ahuja, S. K. Sharma, and D. nisal in both hexane and 1-octanol at five temperatures from benzeneacetic acid (Diclofenac); K. Majumdar, Yakugaku Zasshi 293 to 315 K using a spectrophotometric method of analysis. C14H11Cl2NO2; [15307-86-5] 127, 1739 (2007). (2) Sunflower oil The internal consistency of the two datasets was assessed by curve-fitting the measured mole fraction solubility data to the Variables: Prepared by: Modified Apelblat model [Eq. (8)] to yield the following T/K ¼ 277 W. E. Acree, Jr. representations: 113:934 Experimental Values ln x ¼86:483 þ þ 13:111 ln T; ð24Þ 1 T The measured solubility was reported to be s1 ¼ 0.549 (mass/volume percent). 115:363 ln x1 ¼23:689 þ þ 3:498 ln T; ð25Þ Auxiliary Information T Method/Apparatus/Procedure: for solubilities in hexane and 1-octanol, respectively. The Centrifuge and high-performance liquid chromatograph. mean absolute relative deviations between the observed Excess solute and solvent were placed in sealed bottles and allowed to pre- experimental data and back-calculated values based on equilibrate at 323 K for an unspecified period of time. The solution was then ¼ % ¼ % cooled to 277 K and left overnight to equilibrate. The solution was Eqs. (24) and (25) of MARD 1.2 and MARD 1.9 subsequently centrifuged at 5000 rpm to separate the clear solution and solid are less than the experimental uncertainty associated with the material. An aliquot of the clear supernatant was dissolved in acetone and the measured values. concentration of the dissolved solute determined by high-performance liquid The experimental solubility data for diflunisal in organic chromatographic analysis at 276 nm. solvents are in Secs. 7.2–7.5.

7.2. Diﬂunisal solubility data in saturated Experimental Values hydrocarbons (including cycloalkanes)

a b x2 x1 0.9995 0.000471 Components: Original Measurements: 83 a (1) 2′,4′-Diﬂuoro-4-hydroxy-1, S. V. Kurkov and G. L. x2: mole fraction of component 2 in the saturated solution. b 1′-biphenyl-3-carboxylic acid Perlovich, Int. J. Pharm. 357, 100 x1: mole fraction solubility of the solute.

(Diﬂunisal); C13H8F2O3; (2008). [22494-42-4] Auxiliary Information (2) Hexane; C6H14; [110-54-3] Method/Apparatus/Procedure: Variables: Prepared by: Constant-temperature bath and an analytical balance. Temperature W. E. Acree, Jr. Very few experimental details were provided. The solubility was determined with a gravimetric method that involved transferring a weighed aliquot of the saturated solution to a tared container. The solvent was evaporated and the Experimental Values solubility determined from the mass of the solid residue.

Source and Purity of Chemicals: T/K x a x b 2 1 (1) Purity not given, ICN Biomedicals, Aurora, Ohio, USA, no puriﬁcation 293.2 0.9999 0.00000900 details were provided. 298.2 0.9999 0.00001115 (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, 303.2 0.9999 0.00001434 Germany, no puriﬁcation details were provided. 310.2 0.9999 0.00001858 315.2 0.9999 0.00002247 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. Temperature: 0.1 K. b % x1: mole fraction solubility of the solute. x1: 3.0 (relative error).

Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: ′ ′ 84 Constant-temperature bath, centrifuge, and an UV/visible spectrophotometer. (1) 2 ,4 -Difluoro-4-hydroxy-1, G. L. Perlovich, S. V. Kurkov, ′ Excess solute and solvent were placed in a glass ampoule and allowed to 1 -biphenyl-3-carboxylic acid and A. Bauer-Brandl, Eur. J. equilibrate with rotation at constant temperature. An aliquot of the saturated (Diflunisal); C13H8F2O3; Pharm. Sci. 19, 423 (2003). [ ] solution was removed, centrifuged to remove suspended particulate material, 22494-42-4 [ ] and diluted quantitatively for spectroscopic analyses. The reported values (2) Methylbenzene; C7H8; 108-88-3 represent the average of at least four determinations. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, ICN Biomedicals, Aurora, Ohio, USA, no purification details were given in the paper. Experimental Values (2) Purity not given, Analytical Reagent grade, Solvents Documentation Syntheses (SDS), Peypin, France, no purification details were given in the paper. a b x2 x1 0.9994 0.000568 Estimated Error: a Temperature: 0.1 K. x2: mole fraction of component 2 in the saturated solution. b x1: 2.5% (relative error). x1: mole fraction solubility of the solute.

Auxiliary Information / / 7.3. Diﬂunisal solubility data in aromatic Method Apparatus Procedure: Constant-temperature bath and an analytical balance. hydrocarbons Very few experimental details were provided. The solubility was determined with a gravimetric method that involved transferring a weighed aliquot of the saturated solution to a tared container. The solvent was evaporated and the Components: Original Measurements: solubility determined from the mass of the solid residue. (1) 2′,4′-Diﬂuoro-4-hydroxy-1, 84G. L. Perlovich, S. V. Kurkov, 1′-biphenyl-3-carboxylic acid and A. Bauer-Brandl, Eur. J. Source and Purity of Chemicals:

(Diﬂunisal); C13H8F2O3; Pharm. Sci. 19, 423 (2003). (1) Purity not given, ICN Biomedicals, Aurora, Ohio, USA, no puriﬁcation [22494-42-4] details were provided.

(2) Benzene; C6H6; [71-43-2] (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, Germany, no puriﬁcation details were provided. Variables: Prepared by: / ¼ T K 298.15 W. E. Acree, Jr. Estimated Error: Temperature: 0.1 K.

x1: 3.0% (relative error).

7.4. Diﬂunisal solubility data in alcohols Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Components: Original Measurements: Very few experimental details were provided. Excess solute and solvent were (1) 2′,4′-Diﬂuoro-4-hydroxy-1, 84G. L. Perlovich, S. V. Kurkov, allowed to equilibrate at constant temperature. Solubility of the dissolved 1′-biphenyl-3-carboxylic acid and A. Bauer-Brandl, Eur. J. solute was determined by spectrophotometric measurements.

(Diflunisal); C13H8F2O3; Pharm. Sci. 19, 423 (2003). [22494-42-4] Source and Purity of Chemicals: (1) Purity not given, ICN Biomedicals, Aurora, Ohio, USA, no purification (2) Methanol; CH4O; [67-56-1] details were provided. Variables: Prepared by: (2) 99.6%, chemical source not specified, no purification details were / ¼ T K 298.15 W. E. Acree, Jr. provided.

Estimated Error: Experimental Values Temperature: 0.1 K.

x1: 2.5% (relative error).

a b x2 x1 0.9849 0.0151 a x2: mole fraction of component 2 in the saturated solution. Components: Original Measurements: b 84 x1: mole fraction solubility of the solute. (1) 2′,4′-Diﬂuoro-4-hydroxy-1, G. L. Perlovich, S. V. Kurkov, 1′-biphenyl-3-carboxylic acid and A. Bauer-Brandl, Eur. J.

(Diflunisal); C13H8F2O3; Pharm. Sci. 19, 423 (2003). Auxiliary Information [22494-42-4] (2) 1-Propanol; C H O; [71-23-8] Method/Apparatus/Procedure: 3 8 Constant-temperature bath and an UV/visible spectrophotometer. Variables: Prepared by: Very few experimental details were provided. Excess solute and solvent were T/K ¼ 298.15 W. E. Acree, Jr. allowed to equilibrate at constant temperature. Solubility of the dissolved solute was determined by spectrophotometric measurements. Experimental Values Source and Purity of Chemicals: (1) Purity not given, ICN Biomedicals, Aurora, Ohio, USA, no purification a b details were provided. x2 x1 (2) Purity not given, HPLC grade, Merck Chemical Company, Germany, no 0.9764 0.0236 purification details were provided. a x2: mole fraction of component 2 in the saturated solution. b Estimated Error: x1: mole fraction solubility of the solute. Temperature: 0.1 K. % x1: 2.5 (relative error). Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were Components: Original Measurements: allowed to equilibrate at constant temperature. Solubility of the dissolved (1) 2′,4′-Difluoro-4-hydroxy-1, 84G. L. Perlovich, S. V. Kurkov, solute was determined by spectrophotometric measurements. 1′-biphenyl-3-carboxylic acid and A. Bauer-Brandl, Eur. J. (Diflunisal); C H F O ; Pharm. Sci. 19, 423 (2003). 13 8 2 3 Source and Purity of Chemicals: [22494-42-4] (1) Purity not given, ICN Biomedicals, Aurora, Ohio, USA, no purification (2) Ethanol; C H O; [64-17-5] 2 6 details were provided. Variables: Prepared by: (2) Purity not given, HPLC grade, Aldrich Chemical Company, Germany, no T/K ¼ 298.15 W. E. Acree, Jr. purification details were provided.

Estimated Error: Experimental Values Temperature: 0.1 K.

x1: 2.5% (relative error).

a b x2 x1 0.9809 0.0191 ax : mole fraction of component 2 in the saturated solution. Components: Original Measurements: 2 84 b (1) 2′,4′-Diﬂuoro-4-hydroxy-1, G. L. Perlovich, S. V. Kurkov, x1: mole fraction solubility of the solute. 1′-biphenyl-3-carboxylic acid and A. Bauer-Brandl, Eur. J.

(Diﬂunisal); C13H8F2O3; Pharm. Sci. 19, 423 (2003). [22494-42-4]

(2) 1-Butanol; C4H10O; [71-36-3] Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

Experimental Values Components: Original Measurements: (1) 2′,4′-Diﬂuoro-4-hydroxy-1, 84G. L. Perlovich, S. V. Kurkov, ′ a b 1 -biphenyl-3-carboxylic acid and A. Bauer-Brandl, Eur. J. x2 x1 (Diﬂunisal); C13H8F2O3; Pharm. Sci. 19, 423 (2003). 0.9734 0.0266 [22494-42-4]

a (2) 1-Hexanol; C6H14O; [111-27-3] x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

Auxiliary Information Method/Apparatus/Procedure: Experimental Values Constant-temperature bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were a b allowed to equilibrate at constant temperature. Solubility of the dissolved x2 x1 solute was determined by spectrophotometric measurements. 0.9669 0.0331 a x2: mole fraction of component 2 in the saturated solution. Source and Purity of Chemicals: b x1: mole fraction solubility of the solute. (1) Purity not given, ICN Biomedicals, Aurora, Ohio, USA, no puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, Auxiliary Information Germany, no puriﬁcation details were provided. Method/Apparatus/Procedure: Estimated Error: Constant-temperature bath and an UV/visible spectrophotometer. Temperature: 0.1 K. Very few experimental details were provided. Excess solute and solvent were

x1: 2.5% (relative error). allowed to equilibrate at constant temperature. Solubility of the dissolved solute was determined by spectrophotometric measurements.

Source and Purity of Chemicals: (1) Purity not given, ICN Biomedicals, Aurora, Ohio, USA, no purification Components: Original Measurements: details were provided. (1) 2′,4′-Difluoro-4-hydroxy-1, 84G. L. Perlovich, S. V. Kurkov, (2) Purity not given, Analytical Reagent grade, Aldrich Chemical Company, 1′-biphenyl-3-carboxylic acid and A. Bauer-Brandl, Eur. J. Germany, no purification details were provided. (Diflunisal); C13H8F2O3; Pharm. Sci. 19, 423 (2003). [22494-42-4] Estimated Error: (2) 1-Pentanol; C H O; [71-41-0] 5 12 Temperature: 0.1 K.

Variables: Prepared by: x1: 2.5% (relative error). T/K ¼ 298.15 W. E. Acree, Jr.

a (2) 1-Heptanol; C7H16O; [111-70-6] x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

Auxiliary Information Method/Apparatus/Procedure: Experimental Values Constant-temperature bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were a b allowed to equilibrate at constant temperature. Solubility of the dissolved x2 x1 solute was determined by spectrophotometric measurements. 0.9617 0.0383 a x2: mole fraction of component 2 in the saturated solution. Source and Purity of Chemicals: b x1: mole fraction solubility of the solute. (1) Purity not given, ICN Biomedicals, Aurora, Ohio, USA, no puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, Aldrich Chemical Company, Germany, no puriﬁcation details were provided.

Estimated Error: Temperature: 0.1 K.

x1: 2.5% (relative error).

Auxiliary Information Experimental Values Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. T/K x a x b Very few experimental details were provided. Excess solute and solvent were 2 1 allowed to equilibrate at constant temperature. Solubility of the dissolved 293.2 0.9667 0.0333 solute was determined by spectrophotometric measurements. 298.2 0.9657 0.0343 303.2 0.9645 0.0355 Source and Purity of Chemicals: 310.2 0.9620 0.0380 (1) Purity not given, ICN Biomedicals, Aurora, Ohio, USA, no puriﬁcation 315.2 0.9579 0.0421 details were provided. a x2: mole fraction of component 2 in the saturated solution. (2) Purity not given, Analytical Reagent grade, Sigma Chemical Company, St. b x1: mole fraction solubility of the solute. Louis, Missouri, USA, no puriﬁcation details were provided.

Estimated Error: Auxiliary Information Temperature: 0.1 K. Method/Apparatus/Procedure: x1: 2.5% (relative error). Constant-temperature bath, centrifuge, and an UV/visible spectrophotometer. Excess solute and solvent were placed in a glass ampoule and allowed to equilibrate with rotation at constant temperature. An aliquot of the saturated solution was removed, centrifuged to remove suspended particulate material, Components: Original Measurements: and diluted quantitatively for spectroscopic analyses. The reported values ′ ′ 84 (1) 2 ,4 -Difluoro-4-hydroxy-1, G. L. Perlovich, S. V. Kurkov, represent the average of at least four determinations. 1′-biphenyl-3-carboxylic acid and A. Bauer-Brandl, Eur. J. (Diflunisal); C13H8F2O3; Pharm. Sci. 19, 423 (2003). Source and Purity of Chemicals: [ ] 22494-42-4 (1) Purity not given, ICN Biomedicals, Aurora, Ohio, USA, no purification [ ] (2) 1-Octanol; C8H18O; 111-87-5 details were given in the paper. Variables: Prepared by: (2) Purity not given, Analytical Reagent grade, Sigma Chemical Company, St. T/K ¼ 298.15 W. E. Acree, Jr. Louis, Missouri, USA, no purification details were given in the paper.

Estimated Error: Experimental Values Temperature: 0.1 K. x1: 2.5% (relative error).

a b x2 x1 0.9648 0.0352 a 7.5. Diﬂunisal solubility data in miscellaneous x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. organic solvents

Auxiliary Information Components: Original Measurements: 84 Method/Apparatus/Procedure: (1) 2′,4′-Difluoro-4-hydroxy-1, G. L. Perlovich, S. V. Kurkov, Constant-temperature bath and an UV/visible spectrophotometer. 1′-biphenyl-3-carboxylic acid and A. Bauer-Brandl, Eur. J. Very few experimental details were provided. Excess solute and solvent were (Diflunisal); C13H8F2O3; Pharm. Sci. 19, 423 (2003). allowed to equilibrate at constant temperature. Solubility of the dissolved [22494-42-4] [ ] solute was determined by spectrophotometric measurements. (2) Ethanenitrile; C2H3N; 75-05-8 Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 298.15 W. E. Acree, Jr. (1) Purity not given, ICN Biomedicals, Aurora, Ohio, USA, no purification details were provided. (2) Purity not given, Analytical Reagent grade, Sigma Chemical Company, St. Experimental Values Louis, Missouri, USA, no purification details were provided.

Estimated Error: a b x2 x1 Temperature: 0.1 K. 0.9964 0.00355 x1: 2.5% (relative error). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: (1) 2′,4′-Diﬂuoro-4-hydroxy-1, 83S. V. Kurkov and G. L. 1′-biphenyl-3-carboxylic acid Perlovich, Int. J. Pharm. 357, 100

(Diﬂunisal); C13H8F2O3; (2008). [22494-42-4]

(2) 1-Octanol; C8H18O; [111-87-5] Variables: Prepared by: Temperature W. E. Acree, Jr.

Auxiliary Information Experimental Values / / Method Apparatus Procedure: The measured solubility was reported to be c1 ¼ 0.0466 Constant-temperature bath and an analytical balance. mol dm3. Very few experimental details were provided. The solubility was determined with a gravimetric method that involved transferring a weighed aliquot of the saturated solution to a tared container. The solvent was evaporated and the Auxiliary Information solubility determined from the mass of the solid residue. Method/Apparatus/Procedure: Centrifuge and a high-performance liquid chromatograph equipped with a Source and Purity of Chemicals: photo-diode array detector. (1) Purity not given, ICN Biomedicals, Aurora, Ohio, USA, no purification Excess solute and solvent were placed in sealed vials and shaken at ambient details were provided. room temperature for at least 24 h. The vials were then centrifuged for 15 min (2) Purity not given, HPLC grade, Merck Chemical Company, Germany, no to separate the saturated solution from the excess solute. The supernatant was purification details were provided. then filtered and the concentration of the dissolved solute determined by high- performance liquid chromatographic analysis. Estimated Error: Temperature: 0.1 K. Source and Purity of Chemicals: % x1: 2.0 (relative error). (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, USA, no purification details were provided. (2) Purity not given, J. T. Baker Chemical Company, Phillipsburg, New Jersey, USA, no purification details were provided. Components: Original Measurements: (1) 2′,4′-Difluoro-4-hydroxy-1, 64B. P. Wenkers and B. C. Estimated Error: 1′-biphenyl-3-carboxylic acid Lippold, J. Pharm. Sci. 88, 1326 Temperature: 2 K (estimated by compiler). c % (Diflunisal); C13H8F2O3; (1999). 1: 10 (relative error, estimated by compiler). [22494-42-4] (2) Mineral oil Variables: Prepared by: T/K ¼ 305.15 W. E. Acree, Jr. 8. Solubility of Etoricoxib Organic Solvents 8.1. Critical evaluation of experimental solubility Experimental Values data ¼ The measured solubility was reported to be c1 0.0000675 Etoricoxib (more formally named 5-chloro-6′-methyl-3-[4- 3 mol dm . (methylsulfonyl)phenyl]-2,3′-bipyridine) is a highly selective COX-2 inhibitor. The NSAID is used in the treatment of Auxiliary Information osteoarthritis and rheumatoid arthritis, chronic back pain, and Method/Apparatus/Procedure: acute gout. There has been only one publication reporting Constant-temperature bath and an UV/visible spectrophotometer. the solubility of etoricoxib in organic solvents. Nayak and Excess solute and solvent were placed in sealed bottles and allowed to Panigrahi85 examined the solubility enhancement of etori- equilibrate at a constant temperature with rotation for 24 h. Aliquots of coxib using the cosolvency method. The very low aqueous saturated solutions were removed, filtered through a 0.45 μm cellulose acetate membrane filter, and diluted quantitatively for spectroscopic analysis. solubility of etoricoxib can cause problems in preparing drug Reported values represent the average of three experimental measurements. formulations, and can limit the drug’s effectiveness by delay- ing the rate of absorption and onset of therapeutic action. Source and Purity of Chemicals: Solubilities of etoricoxib were measured in binary water + 1,2- (1) Purity not given, MSD, Rahway, New Jersey, USA, no purification details propanediol, water + 1,2,3-propanetriol and water + polyethy- were provided. (2) Purity not given, Parafluid Mineralolgesellschaft, Hamburg, Germany, no lene glycol 400 (PEG 400) mixtures covering the entire range purification details were provided. of solvent composition at ambient room temperature, including the three neat organic solvents. The authors found that the Estimated Error: solubility was significantly increased by the addition of 1,2- Temperature: 0.5 K (estimated by compiler). propanediol, 1,2,3-propanetriol and PEG 400 as cosolvents. It c : 10% (relative error). 1 is not possible to perform a critical evaluation of the experimental data as measurements were made at only one temperature and there are no independent experimental solubility data Components: Original Measurements: for etoricoxib in these three organic solvents. (1) 2′,4′-Difluoro-4-hydroxy-1, 65E. Rytting, K. A. Lentz, X.-Q. The experimental solubility data for etoricoxib in organic 1′-biphenyl-3-carboxylic acid Chen, F. Qian, and S. Venkatesh, solvents are given in Secs. 8.2 and 8.3. (Diflunisal); C13H8F2O3; AAPS J. 7, E78 (2005). [22494-42-4] (2) Polyethylene glycol 400 (PEG 400) Variables: Prepared by: T/K ¼ 296 W. E. Acree, Jr.

8.2. Etoricoxib solubility data in alcohols Source and Purity of Chemicals: (1) Purity not given, Zydus Health Care Ltd., India, no puriﬁcation details were provided. (2) Purity not given, Qualigen Fine Chemicals, India, no puriﬁcation details Components: Original Measurements: were provided. (1) 5-Chloro-6′-methyl-3- 85A. K. Nayak and P. P. Panigrahi, [4-(methylsulfonyl)phenyl]-2, ISRN Phys. Chem. 2012, 820653. Estimated Error: 3′-bipyridine (Etoricoxib); Temperature: 1 K (estimated by compiler). [ ] C18H15ClN2O2S; 202409-33-4 c1: 5% (relative error, estimated by compiler). (2) 1,2-Propanediol; C3H8O2; [57-55-6] Variables: Prepared by: T/K ¼ 298 (room temperature) W. E. Acree, Jr. 8.3. Etoricoxib solubility data in miscellaneous organic solvents

Experimental Values ¼ The measured solubility was reported to be c1 0.00464 Components: Original Measurements: 3 mol dm . (1) 5-Chloro-6′-methyl-3- 85A. K. Nayak and P. P. Panigrahi, [4-(methylsulfonyl)phenyl]-2, ISRN Phys. Chem. 2012, 820653. Auxiliary Information 3′-bipyridine (Etoricoxib); [ ] Method/Apparatus/Procedure: C18H15ClN2O2S; 202409-33-4 Shaker and an UV/visible spectrophotometer. (2) Polyethylene glycol 400 Excess solute and solvent were placed in sealed screw cap amber color glass (PEG 400) bottles and allowed to equilibrate at room temperature with shaking for 24 h. Variables: Prepared by: μ Aliquots of saturated solutions were removed, filtered through a 0.22 m T/K ¼ 298 (room temperature) W. E. Acree, Jr. membrane filter, and diluted quantitatively for spectroscopic analysis at 284 nm. Reported values represent the average of three experimental measurements. Experimental Values ¼ Source and Purity of Chemicals: The measured solubility was reported to be c1 0.00611 3 (1) Purity not given, Zydus Health Care Ltd., India, no purification details were mol dm . provided. (2) Purity not given, Qualigen Fine Chemicals, India, no purification details Auxiliary Information were provided. Method/Apparatus/Procedure: Estimated Error: Shaker and an UV/visible spectrophotometer. Temperature: 1 K (estimated by compiler). Excess solute and solvent were placed in sealed screw cap amber color glass

c1: 5% (relative error, estimated by compiler). bottles and allowed to equilibrate at room temperature with shaking for 24 h. Aliquots of saturated solutions were removed, filtered through a 0.22 μm membrane filter, and diluted quantitatively for spectroscopic analysis at 284 nm. Reported values represent the average of three experimental measurements. Components: Original Measurements: (1) 5-Chloro-6′-methyl-3- 85A. K. Nayak and P. P. Panigrahi, Source and Purity of Chemicals: [4-(methylsulfonyl)phenyl]-2, ISRN Phys. Chem. 2012, 820653. (1) Purity not given, Zydus Health Care Ltd., India, no purification details were 3′-bipyridine (Etoricoxib); provided. C H ClN O S; [202409-33-4] 18 15 2 2 (2) Purity not given, Qualigen Fine Chemicals, India, no purification details (2) 1,2,3-Propanetriol (Glycerol); were provided. C3H8O3; [56-81-5] Variables: Prepared by: Estimated Error: T/K ¼ 298 (room temperature) W. E. Acree, Jr. Temperature: 1 K (estimated by compiler). c1: 5% (relative error, estimated by compiler).

Experimental Values

The measured solubility was reported to be c1 ¼ 0.00237 mol dm3. 9. Solubility of Fenbufen in Organic Solvents Auxiliary Information Method/Apparatus/Procedure: 9.1. Critical evaluation of experimental solubility Shaker and an UV/visible spectrophotometer. data Excess solute and solvent were placed in sealed screw cap amber color glass [ bottles and allowed to equilibrate at room temperature with shaking for 24 h. Fenbufen more formally named 3-(4-biphenylcarbonyl)- Aliquots of saturated solutions were removed, filtered through a 0.22 μm propionic acid] is a nonselective NSAID and has been used to membrane filter, and diluted quantitatively for spectroscopic analysis at treat pain and inflammation associated with musculoskeletal 284 nm. Reported values represent the average of three experimental and joint disorders. Fenbufen has been used successfully to measurements. alleviate symptoms in individuals suffering with tendinitis and

periarthritis of the shoulder, acute gout, and fibrositis (inflam- Auxiliary Information mation of fibrous tissue). There have been three publica- Method/Apparatus/Procedure: tions60,65,83 reporting the solubility of fenbufen in organic Constant-temperature bath, centrifuge, and an UV/visible spectrophotometer. solvents. Fini et al.60 determined the molar solubility of Excess solute and solvent were placed in a glass ampoule and allowed to fenbufen in 1-octanol at only three temperatures from 278 to equilibrate with rotation at constant temperature. An aliquot of the saturated 83 solution was removed, centrifuged to remove suspended particulate material, 310 K. Kurkov and Perlovich measured the mole fraction and diluted quantitatively for spectroscopic analyses. The reported values solubility of fenbufen in hexane as a function of temperature represent the average of at least four determinations. from 303 to 315 K, and in 1-octanol from 293 to 315 K. Rytting et al.65 reported the molar solubility of fenbufen in polyethy- Source and Purity of Chemicals: lene glycol 400 (PEG 400) at ambient room temperature. The (1) Purity not given, Sigma-Aldrich Chemical Company, Oslo, Norway, no purification details were given in the paper. internal consistency of the Ref. 83 datasets was assessed by (2) Purity not given, Analytical Reagent grade, Solvents Documentation curve-fitting the measured mole-fraction solubility data to the Syntheses (SDS), Peypin, France, no purification details were given in the Modified Apelblat model [see Eq. (8)] to yield the following paper. representations: Estimated Error: 110:88 Temperature: 0.1 K. ln x ¼143:936 þ þ 22:718 ln T; ð26Þ x : 2.5% (relative error). 1 T 1

111:83 ln x ¼102:395 þ þ 16:746 ln T; ð27Þ 1 T 9.3. Fenbufen solubility data in alcohols for solubilities in hexane and 1-octanol, respectively. The mean absolute relative deviations between the observed Components: Original Measurements: experimental data and back-calculated values based on (1) 3-(4-Biphenylcarbonyl)propionic 83S. V. Kurkov and G. L. ¼ % ¼ % Eqs. (26) and (27) of MARD 2.3 and MARD 2.4 acid (Fenbufen); C16H14O3; Perlovich, Int. J. Pharm. 357, 100 are comparable in magnitude to the experimental uncertainty [36330-85-5] (2008). [ ] associated with the measured values. (2) 1-Octanol; C8H18O; 111-87-5 The experimental solubility data for fenbufen in organic Variables: Prepared by: solvents are given in Secs. 9.2–9.4. Temperature W. E. Acree, Jr.

9.2. Fenbufen solubility data in saturated Experimental Values hydrocarbons (including cycloalkanes)

a b T/K x2 x1 293.2 0.9989 0.00106 Components: Original Measurements: 298.2 0.9987 0.00129 (1) 3-(4-Biphenylcarbonyl)propionic 83S. V. Kurkov and G. L. 303.2 0.9982 0.00178 acid (Fenbufen); C H O ; Perlovich, Int. J. Pharm. 357, 100 16 14 3 310.2 0.9973 0.00266 [36330-85-5] (2008). 315.2 0.9967 0.00332 (2) Hexane; C6H14; [110-54-3] a x2: mole fraction of component 2 in the saturated solution. Variables: Prepared by: b x1: mole fraction solubility of the solute. Temperature W. E. Acree, Jr.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: Constant-temperature bath, centrifuge, and an UV/visible spectrophotometer. Excess solute and solvent were placed in a glass ampoule and allowed to T/K x a x b 2 1 equilibrate with rotation at constant temperature. An aliquot of the saturated 303.2 0.9999 0.00000104 solution was removed, centrifuged to remove suspended particulate material, 305.2 0.9999 0.00000126 and diluted quantitatively for spectroscopic analyses. The reported values 308.2 0.9999 0.00000153 represent the average of at least four determinations. 310.2 0.9999 0.00000185 313.2 0.9999 0.00000224 Source and Purity of Chemicals: 315.2 0.9999 0.00000246 (1) Purity not given, Sigma-Aldrich Chemical Company, Oslo, Norway, no a x2: mole fraction of component 2 in the saturated solution. puriﬁcation details were given in the paper. b x1: mole fraction solubility of the solute. (2) Purity not given, Analytical Reagent grade, Sigma Chemical Company, USA, no puriﬁcation details were given in the paper.

Estimated Error: Temperature: 0.1 K.

x1: 2.5% (relative error).

Components: Original Measurements: Auxiliary Information (1) 3-(4-Biphenylcarbonyl)propionic 60A. Fini, M. Laus, I. Orienti, and Method/Apparatus/Procedure: acid (Fenbufen); C16H14O3; V. Zecchi, J. Pharm. Sci. 75,23 Centrifuge and a high-performance liquid chromatograph equipped with a [36330-85-5] (1986). photo-diode array detector. (2) 1-Octanol; C8H18O; [111-87-5] Excess solute and solvent were placed in sealed vials and shaken at ambient room temperature for at least 24 h. The vials were then centrifuged for 15 min Variables: Prepared by: to separate the saturated solution from the excess solute. The supernatant was Temperature W. E. Acree, Jr. then filtered and the concentration of the dissolved solute determined by high- performance liquid chromatographic analysis. Experimental Values Source and Purity of Chemicals: (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, USA, no purification details were provided. T/K c a 1 (2) Purity not given, J. T. Baker Chemical Company, Phillipsburg, New Jersey, 278.2 0.005 USA, no purification details were provided. 298.2 0.012 310.2 0.019 Estimated Error: a 3 c1: molar solubility of the solute in units of mol dm . Temperature: 2 K (estimated by compiler). c1: 10% (relative error, estimated by compiler).

Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath, analytical balance, and an UV/visible 10. Solubility of Fentiazac in Organic spectrophotometer. Solvents Excess solute and solvent were placed in a sealed container and allowed to equilibrate with stirring at constant temperature. An aliquot of the saturated 10.1. Critical evaluation of experimental solubility μ solution was removed, filtered through a 0.22 m pore membrane, and diluted data quantitatively for spectroscopic analysis. Fentiazac [more formally named 4-(4-chlorophenyl)-2-phe- Source and Purity of Chemicals: nyl-5-thiazoleacetic acid] is a NSAID that exhibits analgesic (1) Purity not given, chemical source not specified, was recrystallized from suitable solvent before use. and anti-inflammatory properties in controlling disease activ- (2) Purity not given, chemical source not specified, no purification details were ity associated with rheumatoid arthritis. There has been only a provided in the paper. single publication reporting the solubility of fentiazac in organic solvents. Fini et al.60 determined the molar solubility Estimated Error: of fentiazac in 1-octanol at only three temperatures from 278 to Temperature: 0.2 K (estimated by compiler). 310 K. It is not possible to perform a critical evaluation of the c1: 3% (relative error). experimental data as measurements were made at too few temperatures to permit a meaningful linear regression analysis, and there are no independent experimental solubility data for 9.4. Fenbufen solubility data in miscellaneous fentiazac in 1-octanol. organic solvents The experimental solubility data for fentiazac in 1-octanol are given in Sec. 10.2.

Components: Original Measurements: (1) 3-(4-Biphenylcarbonyl)propionic 65E. Rytting, K. A. Lentz, X.-Q. 10.2. Fentiazac solubility data in alcohols

acid (Fenbufen); C16H14O3; Chen, F. Qian, and S. Venkatesh, [36330-85-5] AAPS J. 7, E78 (2005). (2) Polyethylene glycol 400 Components: Original Measurements: (PEG 400) (1) 4-(4-Chlorophenyl)-2-phenyl- 60A. Fini, M. Laus, I. Orienti, and 5-thiazoleacetic acid (Fentiazac); V. Zecchi, J. Pharm. Sci. 75,23 Variables: Prepared by: C H ClNO S; [18046-21-4] (1986). T/K ¼ 296 W. E. Acree, Jr. 17 12 2 (2) 1-Octanol; C8H18O; [111-87-5] Variables: Prepared by: Experimental Values Temperature W. E. Acree, Jr.

The measured solubility was reported to be c1 ¼ 0.0986 3 mol dm . Experimental Values

a T/K c1 278.2 0.113 298.2 0.170 310.2 0.223 a 3 c1: molar solubility of the solute in units of mol dm .

Auxiliary Information TABLE 4. Parameters of the Modified Apelblat equation for describing the solubility of flufenamic acid in organic solvents Method/Apparatus/Procedure: Constant-temperature bath, analytical balance, and an UV/visible Solvent T/K ABCMARD (%) spectrophotometer. Hexanea 293–315 113.190 113.325 18.517 0.5 Excess solute and solvent were placed in a sealed container and allowed to Hexaneb 293–315 113.295 113.325 17.915 1.2 equilibrate with stirring at constant temperature. An aliquot of the saturated Ethanolc 299–322 53.857 114.658 8.905 2.0 solution was removed, filtered through a 0.22 μm pore membrane, and diluted 1-Octanola 293–315 53.992 18.719 9.043 1.6 quantitatively for spectroscopic analysis. 1-Octanolb 293–315 53.752 18.719 9.001 1.0 1-Octanolc 287–347 46.094 18.887 7.651 1.6 Source and Purity of Chemicals: aData set from Surov et al.86 (1) Purity not given, chemical source not specified, was recrystallized from bData set from Perlovich et al.87 suitable solvent before use. cData set from Domanska et al.89 (2) Purity not given, chemical source not specified, no purification details were provided in the paper.

Estimated Error: The experimental solubility data for ﬂufenamic acid in Temperature: 0.2 K (estimated by compiler). organic solvents are given in Secs. 11.2–11.5. c1: 3% (relative error).

11.2. Flufenamic acid solubility data in saturated hydrocarbons (including cycloalkanes) 11. Solubility of Flufenamic Acid in Organic Solvents Components: Original Measurements: 11.1. Critical evaluation of experimental solubility (1) 2-[[3-(Trifluoromethyl)phenyl]- 86A. O. Surov, P. Szterner, W. data amino]benzoic acid (Flufenamic Zielenkiewicz, and G. L. acid); C H F NO ; [530-78-9] Perlovich, J. Pharm. Biomed. Flufenamic acid (more formally named 2-[[3-(trifluoro- 14 10 3 2 (2) Hexane; C6H14; [110-54-3] Anal. 50, 831 (2009). methyl)phenyl]amino]benzoic acid) is a NSAID that is administered both orally and topically in the treatment of pain and Variables: Prepared by: Temperature W. E. Acree, Jr. inflammation associated with musculoskeletal and joint disorders. There have been several publications64,65,86–89 reporting the solubility of flufenamic acid in organic solvents. Lee Experimental Values et al.88 determined the solubility of flufenamic acid in cyclohexane, methylbenzene, and ethanol at 298 K and atmospheric T/K x a x b pressure using a high-performance liquid chromatographic 2 1 293.2 0.9995 0.000492 method of analysis. The measurements were performed as 298.2 0.9993 0.000674 part of a larger study that examined the effect that a cosolute 303.2 0.9991 0.000910 had on the solubility of the main solute. In this particular study, 310.2 0.9986 0.001385 flufenamic acid served as the cosolute and mefenamic acid was 315.2 0.9982 0.001824 64 a the main drug solute. Wenkers and Lippold reported solu- x2: mole fraction of component 2 in the saturated solution. b bility data for ten NSAIDs (aspirin, diclofenac, diflunisal, x1: mole fraction solubility of the solute. flufenamic acid, ibuprofen, ketoprofen, nabumetone, naproxen, piroxicam, and tenoxicam) in light mineral oil at Auxiliary Information 305 K. Rytting et al.65 determined the solubility of flufenamic / / acid in polyethylene glycol 400 (PEG 400) at ambient room Method Apparatus Procedure: Air thermostat, analytical balance, and an UV/visible spectrophotometer. temperature. Excess solute and solvent were placed in a glass ampoule and allowed to There have been three experimental studies reporting how equilibrate with rotation at constant temperature in an air thermostat for 24 h. the solubility of flufenamic acid varied with temperature. An aliquot of the saturated solution was removed with isothermal filtration Surov et al.86 and Perlovich et al.87 both examined the (Acrodisc CR syringe filter, PTFE, 0.2 μm pore size), and diluted solubility of flufenamic acid in hexane and 1-octanol. quantitatively. The molar solubility of the drug was determined by 89 spectrophotometric analysis. The solubility determination was repeated three Domanska et al. measured flufenamic acid solubilities in times. ethanol and 1-octanol using a dynamic method that recorded the temperature at which the last crystals of the solid solute Source and Purity of Chemicals: disappeared. The internal consistency of the six datasets was (1) 99.8+%, Sigma Chemical Company, St. Louis, Missouri, USA, was used as assessed by curve-fitting the measured mole fraction solubility received. (2) Purity not given, Analytical Reagent Grade, Solvents Documentation data to Eq. (8). The values of the equation coefficients (A, B, Syntheses (SDS), Peypin, France, no purification details were given in the and C) are given in Table 4, along with the mean absolute paper. relative deviation. Each of the six data sets is considered internally consistent as evidenced by the small MARD values. Estimated Error: Temperature: 0.1 K.

x1: 2.5% (relative error).

Auxiliary Information Components: Original Measurements: 87 / / (1) 2-[[3-(Trifluoromethyl)phenyl]- G. L. Perlovich, A. O. Surov, Method Apparatus Procedure: amino]benzoic acid (Flufenamic and A. Bauer-Brandl, J. Pharm. Constant-temperature refrigerated water bath and a high-performance liquid chromatograph equipped with a photodiode array detector. acid); C14H10F3NO2; [530-78-9] Biomed. Anal. 45, 679 (2007). Excess solute and solvent were dissolved in glass vials and placed in jacketed (2) Hexane; C6H14; [110-54-3] beakers connected to a refrigerated water bath. Solutions were stirred using Variables: Prepared by: magnetic stirrers for a minimum of 24 h. The saturated solutions were filtered Temperature W. E. Acree, Jr. (0.20 μm pore size) and diluted to a concentration suitable for high- performance liquid chromatographic analysis. Samples were analyzed at a wavelength of 280 nm. Experimental Values Source and Purity of Chemicals: (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, / a b T K x2 x1 USA, no purification details were provided. 293.2 0.9999 0.0000145 (2) Purity not given, Sigma-Aldrich Chemical Company, no purification 298.2 0.9999 0.0000198 details were provided. 303.2 0.9999 0.0000259 310.2 0.9999 0.0000399 Estimated Error: 315.2 0.9999 0.0000512 Temperature: 0.2 K (estimated by compiler). a x1: 2.5% (relative error, estimated by compiler). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Auxiliary Information 11.3. Flufenamic acid solubility data in aromatic Method/Apparatus/Procedure: hydrocarbons Air thermostat, analytical balance, and an UV/visible spectrophotometer. Excess solute and solvent were placed in a glass ampoule and allowed to equilibrate with rotation at constant temperature in an air thermostat for 24 h. Components: Original Measurements: An aliquot of the saturated solution was removed with isothermal filtration (1) 2-[[3-(Trifluoromethyl)phenyl]- 88E. H. Lee, S. R. Byrn, and R. μ (Acrodisc CR syringe filter, PTFE, 0.2 m pore size), and diluted amino]benzoic acid (Flufenamic Pinal, J. Pharm. Sci. 101, 4529 quantitatively. The molar solubility of the drug was determined by acid); C14H10F3NO2; [530-78-9] (2012). spectrophotometric analysis. The solubility determination was repeated three (2) Methylbenzene; C7H8; [108-88-3] times. Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 298.15 W. E. Acree, Jr. (1) 99.8+%, Sigma Chemical Company, St. Louis, Missouri, USA, was used as received. (2) Purity not given, Analytical Reagent Grade, Solvents Documentation Experimental Values Syntheses (SDS), Peypin, France, no purification details were given in the paper. a b x2 x1 Estimated Error: 0.9713 0.0287 Temperature: 0.1 K. a x2: mole fraction of component 2 in the saturated solution. x1: 2.5% (relative error). b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-[[3-(Trifluoromethyl)phenyl]- 88E. H. Lee, S. R. Byrn, and R. Constant-temperature refrigerated water bath and a high-performance liquid amino]benzoic acid; (Flufenamic Pinal, J. Pharm. Sci. 101, 4529 chromatograph equipped with a photodiode array detector. acid); C H F NO ; [530-78-9] (2012). 14 10 3 2 Excess solute and solvent were dissolved in glass vials and placed in jacketed (2) Cyclohexane; C H ; [110-82-7] 6 12 beakers connected to a refrigerated water bath. Solutions were stirred using Variables: Prepared by: magnetic stirrers for a minimum of 24 h. The saturated solutions were filtered T/K ¼ 298.15 W. E. Acree, Jr. (0.20 μm pore size) and diluted to a concentration suitable for high- performance liquid chromatographic analysis. Samples were analyzed at a wavelength of 280 nm. Experimental Values Source and Purity of Chemicals: (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, a b x2 x1 USA, no purification details were provided. 0.9987 0.001265 (2) Purity not given, HPLC grade, Mallinckrodt Baker, Inc., Phillipsburg, New a Jersey, USA, no purification details were provided. x2: mole fraction of component 2 in the saturated solution. bx 1: mole fraction solubility of the solute. Estimated Error: Temperature: 0.2 K (estimated by compiler).

x1: 2.5% (relative error, estimated by compiler).

11.4. Flufenamic acid solubility data in alcohols a b T/K x2 x1 314.3 0.8958 0.1042 318.4 0.8846 0.1154 Components: Original Measurements: 322.3 0.8750 0.1250 88 (1) 2-[[3-(Trifluoromethyl)phenyl]- E. H. Lee, S. R. Byrn, and R. a x2: mole fraction of component 2 in the saturated solution. amino]benzoic acid (Flufenamic Pinal, J. Pharm. Sci. 101, 4529 b x1: mole fraction solubility of the solute. acid); C14H10F3NO2; [530-78-9] (2012). (2) Ethanol; C2H6O; [64-17-5] Variables: Prepared by: Auxiliary Information T/K ¼ 298.15 W. E. Acree, Jr. Method/Apparatus/Procedure: Thermostated water bath, analytical balance, stirrer, and electronic thermometer. Experimental Values Solubilities were determined using a dynamic method. Known amounts of solute and solvent were placed inside a Pyrex glass equilibrium cell, which was then placed in a thermostated water bath. The sample was slowly heated x a x b 2 1 (approximately 5 K/ h) with continuous stirring. Temperature at which the last 0.9507 0.0493 crystals disappeared was taken as the temperature of the solution-crystal a equilibrium. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Source and Purity of Chemicals: (1) 99+%, Sigma-Aldrich Chemical Company, St. Louis, Missouri, USA, was Auxiliary Information used as received. (2) 99.8+%, Sigma-Aldrich Chemical Company, was stored over freshly active / / Method Apparatus Procedure: molecular sieves of type 4 A˚ . Constant-temperature refrigerated water bath and a high-performance liquid chromatograph equipped with a photodiode array detector. Estimated Error: Excess solute and solvent were dissolved in glass vials and placed in jacketed Temperature: 0.1 K. beakers connected to a refrigerated water bath. Solutions were stirred using x1: 3% (relative error, estimated by compiler). magnetic stirrers for a minimum of 24 h. The saturated solutions were filtered (0.20 μm pore size) and diluted to a concentration suitable for high- performance liquid chromatographic analysis. Samples were analyzed at a wavelength of 280 nm. Components: Original Measurements: [[ ] 89 Source and Purity of Chemicals: (1) 2- 3-(Trifluoromethyl)phenyl - U. Domanska, A. Pobudkowska, ] (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, amino benzoic acid (Flufenamic and A. Pelczarska, J. Phys. Chem. [ ] USA, no purification details were provided. acid); C14H10F3NO2; 530-78-9 B 115, 2547 (2011). [ ] (2) Purity not given, Pharmco, Brookfield, Connecticut, USA, no purification (2) 1-Octanol; C8H18O; 111-87-5 details were provided. Variables: Prepared by: Temperature W. E. Acree, Jr. Estimated Error: Temperature: 0.2 K (estimated by compiler). % x1: 2.5 (relative error, estimated by compiler). Experimental Values

a b T/K x2 x1 Components: Original Measurements: 287.4 0.9325 0.0675 (1) 2-[[3-(Triﬂuoromethyl)phenyl]- 89U. Domanska, A. Pobudkowska, 295.4 0.9178 0.0822 amino]benzoic acid (Flufenamic and A. Pelczarska, J. Phys. Chem. 303.4 0.9040 0.0960 acid); C14H10F3NO2; [530-78-9] B 115, 2547 (2011). 307.7 0.8927 0.1073 (2) Ethanol; C2H6O; [64-17-5] 310.7 0.8806 0.1194 314.6 0.8679 0.1321 Variables: Prepared by: 318.9 0.8539 0.1461 Temperature W. E. Acree, Jr. 322.1 0.8387 0.1613 328.9 0.8174 0.1826 Experimental Values 329.5 0.8117 0.1883 340.7 0.7683 0.2317 347.5 0.7404 0.2596 a b a T/K x2 x1 x2: mole fraction of component 2 in the saturated solution. b 298.8 0.9313 0.0687 x1: mole fraction solubility of the solute. 301.2 0.9298 0.0702 303.0 0.9256 0.0744 306.9 0.9232 0.0768 309.1 0.9125 0.0875 311.4 0.9064 0.0936

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-[[3-(Triﬂuoromethyl)phenyl]- 86A. O. Surov, P. Szterner, W. Thermostated water bath, analytical balance, stirrer, and electronic amino]benzoic acid (Flufenamic Zielenkiewicz, and G. L. thermometer. acid); C14H10F3NO2; [530-78-9] Perlovich, J. Pharm. Biomed.

Solubilities were determined using a dynamic method. Known amounts of (2) 1-Octanol; C8H18O; [111-87-5] Anal. 50, 831 (2009). solute and solvent were placed inside a Pyrex glass equilibrium cell, which was Variables: Prepared by: then placed in a thermostated water bath. The sample was slowly heated Temperature W. E. Acree, Jr. (approximately 5 K/h) with continuous stirring. Temperature at which the last crystals disappeared was taken as the temperature of the solution-crystal equilibrium. Experimental Values Source and Purity of Chemicals: (1) 99+%, Sigma-Aldrich Chemical Company, St. Louis, Missouri, USA, was T/K x a x b used as received. 2 1 (2) 99.8+%, Sigma-Aldrich Chemical Company, was stored over freshly active 293.2 0.9238 0.0762 molecular sieves of type 4 A˚ . 298.2 0.9067 0.0933 303.2 0.8969 0.1031 Estimated Error: 310.2 0.8727 0.1273 Temperature: 0.1 K. 315.2 0.8509 0.1491 x % a 1: 3 (relative error, estimated by compiler). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: Auxiliary Information [[ ] 87 (1) 2- 3-(Trifluoromethyl)phenyl - G. L. Perlovich, A. O. Surov, Method/Apparatus/Procedure: ] amino benzoic acid (Flufenamic and A. Bauer-Brandl, J. Pharm. Air thermostat, analytical balance, and an UV/visible spectrophotometer. [ ] acid); C14H10F3NO2; 530-78-9 Biomed. Anal. 45, 679 (2007). Excess solute and solvent were placed in a glass ampoule and allowed to [ ] (2) 1-Octanol; C8H18O; 111-87-5 equilibrate with rotation at constant temperature in an air thermostat for 24 h. Variables: Prepared by: An aliquot of the saturated solution was removed with isothermal filtration μ Temperature W. E. Acree, Jr. (Acrodisc CR syringe filter, PTFE, 0.2 m pore size), and diluted quantitatively. The molar solubility of the drug was determined by spectrophotometric analysis. The solubility determination was repeated three Experimental Values times.

Source and Purity of Chemicals: a b (1) 99.8+%, Sigma Chemical Company, St. Louis, Missouri, USA, was used as T/K x2 x1 received. 293.2 0.9228 0.0772 (2) Purity not given, Analytical Reagent Grade, Sigma Chemical Company, no 298.2 0.9080 0.0920 puriﬁcation details were given in the paper. 303.2 0.8970 0.1030 310.2 0.8720 0.1280 Estimated Error: 315.2 0.8510 0.1490 Temperature: 0.1 K. a x2: mole fraction of component 2 in the saturated solution. x1: 2.5% (relative error). b x1: mole fraction solubility of the solute.

Auxiliary Information 11.5. Flufenamic acid solubility data in Method/Apparatus/Procedure: miscellaneous organic solvents Air thermostat, analytical balance, and an UV/visible spectrophotometer. Excess solute and solvent were placed in a glass ampoule and allowed to equilibrate with rotation at constant temperature in an air thermostat for 24 h. An aliquot of the saturated solution was removed with isothermal filtration Components: Original Measurements: 64 (Acrodisc CR syringe filter, PTFE, 0.2 μm pore size), and diluted (1) 2-[[3-(Trifluoromethyl)phenyl]- B. P. Wenkers and B. C. quantitatively. The molar solubility of the drug was determined by amino]benzoic acid (Flufenamic Lippold, J. Pharm. Sci. 88, 1326 [ ] spectrophotometric analysis. The solubility determination was repeated three acid); C14H10F3NO2; 530-78-9 (1999). times. (2) Mineral oil Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 305.15 W. E. Acree, Jr. (1) 99.8+%, Sigma Chemical Company, St. Louis, Missouri, USA, was used as received. (2) Purity not given, Analytical Reagent Grade, Sigma Chemical Company, no Experimental Values purification details were given in the paper. The measured solubility was reported to be c1 ¼ 0.00338 3 Estimated Error: mol dm . Temperature: 0.1 K.

x1: 2.5% (relative error).

Auxiliary Information 12. Solubility of Flurbiprofen in Organic Method/Apparatus/Procedure: Solvents Constant-temperature bath and an UV/visible spectrophotometer Excess solute and solvent were placed in sealed bottles and allowed to 12.1. Critical evaluation of experimental solubility equilibrate at a constant temperature with rotation for 24 h. Aliquots of data saturated solutions were removed, filtered through a 0.45 μm cellulose acetate membrane filter, and diluted quantitatively for spectroscopic analysis. Flurbiprofen (more formally named 2-(2-fluoro-4-biphe- Reported values represent the average of three experimental measurements. nyl)propionic acid) is a NSAID currently used in pain treat- Source and Purity of Chemicals: ment therapies for individuals suffering with arthritis. The (1) Purity not given, Sankyo, Pfaffenhofen, Germany, no purification details drug is administered as a racemic mixture; however, the (S)- were provided. enantiomer exhibits by far the higher anti-inflammatory activ- (2) Purity not given, Parafluid Mineralolgesellschaft, Hamburg, Germany, no ity, which is reported to be 30 times larger than the activity of purification details were provided. the racemic mixture.90 There are several published stu- 60,65,83,84,91,92 Estimated Error: dies involving the solubility of flurbiprofen in 84 Temperature: 0.5 K (estimated by compiler). organic solvents. Most notably, Perlovich et al. measured the % c1: 10 (relative error). mole-fraction solubility of flurbiprofen dissolved in 22 different organic solvents, including four saturated hydrocarbons (pentane, hexane, heptane and octane), two aromatic hydrocarbons (benzene and methylbenzene), one alkyl alkanoate Components: Original Measurements: (ethyl ethanoate), one cyclic ether (1,4-dioxane), eight pri- (1) 2-[[3-(Trifluoromethyl)phenyl]- 65E. Rytting, K. A. Lentz, X.-Q. amino]benzoic acid (Flufenamic Chen, F. Qian, and S. Venkatesh, mary alcohols (methanol, ethanol, 1-propanol, 1-butanol, 1-

acid); C14H10F3NO2; [530-78-9] AAPS J. 7, E78 (2005). pentanol, 1-hexanol, 1-heptanol, and 1-octanol), one alkanone (2) Polyethylene glycol 400 (propanone), and one miscellaneous organic solvent (ethane- (PEG 400) nitrile) at 298 K and atmospheric pressure. Larsen et al.92 Variables: Prepared by: determined the solubility of flurbiprofen in castor oil at 310 K, T/K ¼ 296 W. E. Acree, Jr. while Rytting et al.65 measured the solubility in polyethylene glycol 400 (PEG 400) at ambient room temperature. 60,83,91 Experimental Values There have been three studies reporting the solubility of flurbiprofen as a function of temperature. Fini et al.60 The measured solubility was reported to be c ¼ 0.0843 1 determined the molar solubility of flurbiprofen in 1-octanol mol dm3. at only three temperatures from 278 to 310 K. Kurkov and Perlovich83 examined the solubility of flurbiprofen in both Auxiliary Information hexane and 1-octanol between 293 and 315 K using a spectro- Method/Apparatus/Procedure: photometric method. Domanska et al.91 measured the mole- Centrifuge and a high-performance liquid chromatograph equipped with a fraction solubility of flurbiprofen in ethanol and 1-octanol by photo-diode array detector. Excess solute and solvent were placed in sealed vials and shaken at ambient slowly increasing the solution temperature until the last crystal room temperature for at least 24 h. The vials were then centrifuged for 15 min dissolved. The internal consistency of the latter four datasets to separate the saturated solution from the excess solute. The supernatant was was assessed by curve-fitting the measured mole-fraction then filtered and the concentration of the dissolved solute determined by high- solubility data to Eq. (8). The values of the equation coeffi- performance liquid chromatographic analysis. cients (A, B, and C) are given in Table 5, along with the mean Source and Purity of Chemicals: absolute relative deviation. Each of the four data sets is (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, considered internally consistent as evidenced by the small USA, no purification details were provided. MARD values. There were insufficient experimental measure- (2) Purity not given, J. T. Baker Chemical Company, Phillipsburg, New Jersey, ments in the Fini et al.60 dataset to obtain a meaningful USA, no purification details were provided. regression analysis. Estimated Error: The experimental solubility data for flurbiprofen in organic Temperature: 2 K (estimated by compiler). solvents are given in Secs. 12.2–12.8.

c1: 10% (relative error, estimated by compiler).

TABLE 5. Parameters of the Modiﬁed Apelblat equation for describing the solubility of ﬂurbiprofen in organic solvents Solvent T/K ABCMARD (%) Hexanea 293–315 138.581 112.751 2.907 3.8 Ethanolb 299–322 69.962 114.290 11.772 3.3 1-Octanola 291–303 41.740 114.963 6.795 0.9 1-Octanolb 300–336 65.387 114.447 10.968 2.1 aData set of Kurkov and Perlovich.83 bData set of Domanska et al.91

12.2. Flurbiprofen solubility data in saturated Auxiliary Information hydrocarbons (including cycloalkanes) Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate at constant temperature. Solubility of the dissolved Components: Original Measurements: solute was determined by spectrophotometric measurements. (1) 2-(2-Fluoro-4-biphenyl)propionic 84G. L. Perlovich, S. V. Kurkov, acid (() Flurbiprofen); C H FO ; and A. Bauer-Brandl, Eur. J. 15 13 2 Source and Purity of Chemicals: [5104-49-4] Pharm. Sci. 19, 423 (2003). (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no (2) Pentane; C H ; [109-66-0] 5 12 puriﬁcation details were provided. Variables: Prepared by: (2) Purity not given, Analytical Reagent grade, Solvents Documentation T/K ¼ 298.15 W. E. Acree, Jr. Syntheses (SDS), Peypin, France, no puriﬁcation details were provided.

Estimated Error: Experimental Values Temperature: 0.1 K.

x1: 2.5% (relative error).

a b x2 x1 0.9996 0.000350 a Components: Original Measurements: x2: mole fraction of component 2 in the saturated solution. b 83 x1: mole fraction solubility of the solute. (1) 2-(2-Fluoro-4-biphenyl)propionic S. V. Kurkov and G. L. acid (() Flurbiprofen); C15H13FO2; Perlovich, Int. J. Pharm. 357, 100 [5104-49-4] (2008). [ ] Auxiliary Information (2) Hexane; C6H14; 110-54-3 Method/Apparatus/Procedure: Variables: Prepared by: Constant-temperature bath and an UV/visible spectrophotometer. Temperature W. E. Acree, Jr. Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate at constant temperature. Solubility of the dissolved solute was determined by spectrophotometric measurements. Experimental Values

Source and Purity of Chemicals: / a b (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no T K x2 x1 puriﬁcation details were provided. 293.2 0.9997 0.000328 (2) Purity not given, Analytical Reagent grade, Solvents Documentation 298.2 0.9996 0.000443 Syntheses (SDS), Peypin, France, no puriﬁcation details were provided. 303.2 0.9993 0.000666 310.2 0.9989 0.001059 Estimated Error: 315.2 0.9983 0.001691 Temperature: 0.1 K. a x2: mole fraction of component 2 in the saturated solution. x1: 2.5% (relative error). b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-(2-Fluoro-4-biphenyl)propionic 84G. L. Perlovich, S. V. Kurkov, Constant-temperature bath, centrifuge, and an UV/visible spectrophotometer. acid (() Flurbiprofen); C H FO ; and A. Bauer-Brandl, Eur. J. 15 13 2 Excess solute and solvent were placed in a glass ampoule and allowed to [5104-49-4] Pharm. Sci. 19, 423 (2003). equilibrate with rotation at constant temperature. An aliquot of the saturated (2) Hexane; C H ; [110-54-3] 6 14 solution was removed, centrifuged to remove suspended particulate material, Variables: Prepared by: and diluted quantitatively for spectroscopic analyses. The reported values T/K ¼ 298.15 W. E. Acree, Jr. represent the average of at least four determinations.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were given in the paper. (2) Purity not given, Analytical Reagent grade, Solvents Documentation a b x2 x1 Syntheses (SDS), Peypin, France, no puriﬁcation details were provided. 0.9995 0.000494 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. Temperature: 0.1 K. b x1: mole fraction solubility of the solute. x1: 2.5% (relative error).

Source and Purity of Chemicals: Components: Original Measurements: 84 (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no (1) 2-(2-Fluoro-4-biphenyl)propionic G. L. Perlovich, S. V. Kurkov, puriﬁcation details were provided. acid (( ) Flurbiprofen); C15H13FO2; and A. Bauer-Brandl, Eur. J. (2) Purity not given, Analytical Reagent grade, Sigma Chemical Company, no [ ] 5104-49-4 Pharm. Sci. 19, 423 (2003). puriﬁcation details were provided. (2) Heptane; C7H16; [142-82-5] Variables: Prepared by: Estimated Error: T/K ¼ 298.15 W. E. Acree, Jr. Temperature: 0.1 K. x1: 2.5% (relative error).

Experimental Values

a b 12.3. Flurbiprofen solubility data in aromatic x2 x1 hydrocarbons 0.9994 0.000631 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Components: Original Measurements: (1) 2-(2-Fluoro-4-biphenyl)propionic 84G. L. Perlovich, S. V. Kurkov, acid (() Flurbiprofen); C H FO ; and A. Bauer-Brandl, Eur. J. Auxiliary Information 15 13 2 [5104-49-4] Pharm. Sci. 19, 423 (2003). Method/Apparatus/Procedure: (2) Benzene; C6H6; [71-43-2] Constant-temperature bath and an UV/visible spectrophotometer. Variables: Prepared by: Very few experimental details were provided. Excess solute and solvent were T/K ¼ 298.15 W. E. Acree, Jr. allowed to equilibrate at constant temperature. Solubility of the dissolved solute was determined by spectrophotometric measurements. Experimental Values Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. x a x b (2) Purity not given, Analytical Reagent grade, Solvents Documentation 2 1 Syntheses (SDS), Peypin, France, no puriﬁcation details were provided. 0.9318 0.0682 a x2: mole fraction of component 2 in the saturated solution. b Estimated Error: x1: mole fraction solubility of the solute. Temperature: 0.1 K.

x1: 2.5% (relative error). Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Components: Original Measurements: Very few experimental details were provided. Excess solute and solvent were 84 (1) 2-(2-Fluoro-4-biphenyl)propionic G. L. Perlovich, S. V. Kurkov, allowed to equilibrate at constant temperature. Solubility of the dissolved acid (( ) Flurbiprofen); C15H13FO2; and A. Bauer-Brandl, Eur. J. solute was determined by spectrophotometric measurements. [5104-49-4] Pharm. Sci. 19, 423 (2003). [ ] (2) Octane; C8H18; 111-65-9 Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no T/K ¼ 298.15 W. E. Acree, Jr. puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, Germany, no puriﬁcation details were provided. Experimental Values Estimated Error: Temperature: 0.1 K.

a b x1: 2.5% (relative error). x2 x1 0.9994 0.000616 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Components: Original Measurements: (1) 2-(2-Fluoro-4-biphenyl)propionic 84G. L. Perlovich, S. V. Kurkov, acid (() Flurbiprofen); C H FO ; and A. Bauer-Brandl, Eur. J. Auxiliary Information 15 13 2 [5104-49-4] Pharm. Sci. 19, 423 (2003). [ ] Method/Apparatus/Procedure: (2) Methylbenzene; C7H8; 108-88-3 Constant-temperature bath and an UV/visible spectrophotometer. Variables: Prepared by: Very few experimental details were provided. Excess solute and solvent were T/K ¼ 298.15 W. E. Acree, Jr. allowed to equilibrate at constant temperature. Solubility of the dissolved solute was determined by spectrophotometric measurements.

Experimental Values Estimated Error: Temperature: 0.1 K.

x1: 3.0% (relative error). a b x2 x1 0.9233 0.0767 a x2: mole fraction of component 2 in the saturated solution. b 12.5. Flurbiprofen solubility data in ethers x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: (1) 2-(2-Fluoro-4-biphenyl)propionic 84G. L. Perlovich, S. V. Kurkov, Method/Apparatus/Procedure: acid (() Flurbiprofen); C H FO ; and A. Bauer-Brandl, Eur. J. Constant-temperature bath and an UV/visible spectrophotometer. 15 13 2 [5104-49-4] Pharm. Sci. 19, 423 (2003). Very few experimental details were provided. Excess solute and solvent were (2) 1,4-Dioxane; C H O ; [123-91-1] allowed to equilibrate at constant temperature. Solubility of the dissolved 4 8 2 solute was determined by spectrophotometric measurements. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. Experimental Values (2) Purity not given, Analytical Reagent grade, Germany Chemical Company, Germany, no puriﬁcation details were provided. a b x2 x1 Estimated Error: 0.8250 0.1750 Temperature: 0.1 K. a x : 2.5% (relative error). x2: mole fraction of component 2 in the saturated solution. 1 b x1: mole fraction solubility of the solute.

Auxiliary Information 12.4. Flurbiprofen solubility data in esters Method/Apparatus/Procedure: Constant-temperature bath and an analytical balance. Very few experimental details were provided. The solubility was determined Components: Original Measurements: with a gravimetric method that involved transferring a weighed aliquot of the 84 (1) 2-(2-Fluoro-4-biphenyl)propionic G. L. Perlovich, S. V. Kurkov, saturated solution to a tared container. The solvent was evaporated and the acid (( ) Flurbiprofen); C15H13FO2; and A. Bauer-Brandl, Eur. J. solubility determined from the mass of the solid residue. [5104-49-4] Pharm. Sci. 19, 423 (2003). (2) Ethyl ethanoate; C4H8O2; Source and Purity of Chemicals: [141-78-6] (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Variables: Prepared by: puriﬁcation details were provided. T/K ¼ 298.15 W. E. Acree, Jr. (2) Purity not given, Analytical Reagent grade, Sigma Chemical Company, no puriﬁcation details were provided.

Experimental Values Estimated Error: Temperature: 0.1 K.

x1: 3.0% (relative error). a b x2 x1 0.8890 0.1110 a x2: mole fraction of component 2 in the saturated solution. b 12.6. Flurbiprofen solubility data in alcohols x1: mole fraction solubility of the solute.

Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, Germany, no puriﬁcation details were provided.

Experimental Values Components: Original Measurements: (1) 2-(2-Fluoro-4-biphenyl)propionic 91U. Domanska, A. Pobudkowska, a b acid (( ) Flurbiprofen); C15H13FO2; A. Pelczarska, and P. Gierycz, J. x2 x1 [5104-49-4] Phys. Chem. B 113, 8941 (2009).

0.9522 0.0478 (2) Ethanol; C2H6O; [64-17-5] a x2: mole fraction of component 2 in the saturated solution. Variables: Prepared by: b x1: mole fraction solubility of the solute. Temperature W. E. Acree, Jr.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. / a b Very few experimental details were provided. Excess solute and solvent were T K x2 x1 allowed to equilibrate at constant temperature. Solubility of the dissolved 299.1 0.9216 0.0784 solute was determined by spectrophotometric measurements. 301.2 0.9100 0.0900 303.9 0.8952 0.1048 Source and Purity of Chemicals: 306.7 0.8863 0.1137 (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no 308.4 0.8752 0.1248 puriﬁcation details were provided. 311.3 0.8633 0.1367 (2) Purity not given, HPLC grade, Merck Chemical Company, Germany, no 313.7 0.8495 0.1505 puriﬁcation details were provided. 316.1 0.8403 0.1597 319.8 0.8246 0.1754 Estimated Error: 322.1 0.8125 0.1875 Temperature: 0.1 K. a x2: mole fraction of component 2 in the saturated solution. x1: 2.5% (relative error). b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-(2-Fluoro-4-biphenyl)propionic 84G. L. Perlovich, S. V. Kurkov, Thermostated water bath and an analytical balance. acid (() Flurbiprofen); C H FO ; and A. Bauer-Brandl, Eur. J. 15 13 2 Solubility was measured using a dynamic synthetic method. Known amounts [5104-49-4] Pharm. Sci. 19, 423 (2003). of solute and solvent were placed in Pyrex glass containers and allowed to (2) Ethanol; C H O; [64-17-5] 2 6 equilibrate in a thermostated water bath. The temperature of the bath was Variables: Prepared by: slowly increased and the temperature at which the last crystal disappeared was T/K ¼ 298.15 W. E. Acree, Jr. recorded as the solid-liquid equilibrium temperature.

Source and Purity of Chemicals: Experimental Values (1) 99%, Sigma-Aldrich Chemical Company, USA, was used as received. (2) 99.8+%, Sigma-Aldrich Chemical Company, USA, stored over freshly activated molecular sieves before use. a b x2 x1 0.9388 0.0612 Estimated Error: Temperature: 0.1 K. a x2: mole fraction of component 2 in the saturated solution. x : 2% (relative error, estimated by compiler). b 1 x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-(2-Fluoro-4-biphenyl)propionic 84G. L. Perlovich, S. V. Kurkov, Constant-temperature bath and an UV/visible spectrophotometer. acid (() Flurbiprofen); C15H13FO2; and A. Bauer-Brandl, Eur. J. Very few experimental details were provided. Excess solute and solvent were [5104-49-4] Pharm. Sci. 19, 423 (2003). allowed to equilibrate at constant temperature. Solubility of the dissolved (2) 1-Propanol; C3H8O; [71-23-8] solute was determined by spectrophotometric measurements. Variables: Prepared by: / ¼ Source and Purity of Chemicals: T K 298.15 W. E. Acree, Jr. (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. (2) 99.6%, chemical source not specified, no purification details were Experimental Values provided.

a b Estimated Error: x2 x1 Temperature: 0.1 K. 0.9332 0.0668

x1: 2.5% (relative error). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. x a x b Very few experimental details were provided. Excess solute and solvent were 2 1 allowed to equilibrate at constant temperature. Solubility of the dissolved 0.9284 0.0716 solute was determined by spectrophotometric measurements. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. Auxiliary Information (2) Purity not given, HPLC grade, Aldrich Chemical Company, Germany, no / / puriﬁcation details were provided. Method Apparatus Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Estimated Error: Very few experimental details were provided. Excess solute and solvent were Temperature: 0.1 K. allowed to equilibrate at constant temperature. Solubility of the dissolved solute was determined by spectrophotometric measurements. x1: 2.5% (relative error).

Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. Components: Original Measurements: 84 (2) Purity not given, Analytical Reagent grade, Aldrich Chemical Company, (1) 2-(2-Fluoro-4-biphenyl)propionic G. L. Perlovich, S. V. Kurkov, Germany, no puriﬁcation details were provided. acid (() Flurbiprofen); C15H13FO2; and A. Bauer-Brandl, Eur. J. [ ] 5104-49-4 Pharm. Sci. 19, 423 (2003). Estimated Error: [ ] (2) 1-Butanol; C4H10O; 71-36-3 Temperature: 0.1 K. % Variables: Prepared by: x1: 2.5 (relative error). T/K ¼ 298.15 W. E. Acree, Jr.

Experimental Values Components: Original Measurements: (1) 2-(2-Fluoro-4-biphenyl)propionic 84G. L. Perlovich, S. V. Kurkov,

acid (() Flurbiprofen); C15H13FO2; and A. Bauer-Brandl, Eur. J. a b x2 x1 [5104-49-4] Pharm. Sci. 19, 423 (2003).

0.9333 0.0667 (2) 1-Hexanol; C6H14O; [111-27-3] a x2: mole fraction of component 2 in the saturated solution. Variables: Prepared by: b x1: mole fraction solubility of the solute. T/K ¼ 298.15 W. E. Acree, Jr.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. x a x b Very few experimental details were provided. Excess solute and solvent were 2 1 allowed to equilibrate at constant temperature. Solubility of the dissolved 0.9284 0.0716 solute was determined by spectrophotometric measurements. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. Auxiliary Information (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, / / Germany, no puriﬁcation details were provided. Method Apparatus Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Estimated Error: Very few experimental details were provided. Excess solute and solvent were Temperature: 0.1 K. allowed to equilibrate at constant temperature. Solubility of the dissolved solute was determined by spectrophotometric measurements. x1: 2.5% (relative error).

Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. Components: Original Measurements: 84 (2) Purity not given, Analytical Reagent grade, Aldrich Chemical Company, (1) 2-(2-Fluoro-4-biphenyl)propionic G. L. Perlovich, S. V. Kurkov, Germany, no puriﬁcation details were provided. acid (() Flurbiprofen); C15H13FO2; and A. Bauer-Brandl, Eur. J. [ ] 5104-49-4 Pharm. Sci. 19, 423 (2003). Estimated Error: [ ] (2) 1-Pentanol; C5H12O; 71-41-0 Temperature: 0.1 K. % Variables: Prepared by: x1: 2.5 (relative error). T/K ¼ 298.15 W. E. Acree, Jr.

Source and Purity of Chemicals: Components: Original Measurements: 84 (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no (1) 2-(2-Fluoro-4-biphenyl)propionic G. L. Perlovich, S. V. Kurkov, puriﬁcation details were provided. acid (( ) Flurbiprofen); C15H13FO2; and A. Bauer-Brandl, Eur. J. (2) Purity not given, Analytical Reagent grade, Sigma Chemical Company, no [ ] 5104-49-4 Pharm. Sci. 19, 423 (2003). puriﬁcation details were provided. (2) 1-Heptanol; C7H16O; [111-70-6] Variables: Prepared by: Estimated Error: T/K ¼ 298.15 W. E. Acree, Jr. Temperature: 0.1 K. x1: 2.5% (relative error).

Experimental Values

Components: Original Measurements: a b x2 x1 (1) 2-(2-Fluoro-4-biphenyl)propionic 83S. V. Kurkov and G. L.

0.9240 0.0760 acid (() Flurbiprofen); C15H13FO2; Perlovich, Int. J. Pharm. 357, 100 a [5104-49-4] (2008). x2: mole fraction of component 2 in the saturated solution. b (2) 1-Octanol; C8H18O; [111-87-5] x1: mole fraction solubility of the solute. Variables: Prepared by: Temperature W. E. Acree, Jr. Auxiliary Information Method/Apparatus/Procedure: Experimental Values Constant-temperature bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate at constant temperature. Solubility of the dissolved / a b solute was determined by spectrophotometric measurements. T K x2 x1 291.2 0.9392 0.0608 Source and Purity of Chemicals: 293.2 0.9350 0.0650 (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no 298.2 0.9294 0.0706 puriﬁcation details were provided. 303.2 0.9204 0.0796 (2) Purity not given, Analytical Reagent grade, Sigma Chemical Company, no a x2: mole fraction of component 2 in the saturated solution. puriﬁcation details were provided. b x1: mole fraction solubility of the solute.

Estimated Error: Temperature: 0.1 K. Auxiliary Information x1: 2.5% (relative error). Method/Apparatus/Procedure: Constant-temperature bath, centrifuge, and an UV/visible spectrophotometer. Excess solute and solvent were placed in a glass ampoule and allowed to equilibrate with rotation at constant temperature. An aliquot of the saturated Components: Original Measurements: 84 solution was removed, centrifuged to remove suspended particulate material, (1) 2-(2-Fluoro-4-biphenyl)propionic G. L. Perlovich, S. V. Kurkov, and diluted quantitatively for spectroscopic analyses. The reported values acid (( ) Flurbiprofen); C15H13FO2; and A. Bauer-Brandl, Eur. J. represent the average of at least four determinations. [5104-49-4] Pharm. Sci. 19, 423 (2003). [ ] (2) 1-Octanol; C8H18O; 111-87-5 Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no T/K ¼ 298.15 W. E. Acree, Jr. puriﬁcation details were given in the paper. (2) Purity not given, Analytical Reagent grade, Sigma Chemical Company, USA, no puriﬁcation details were given in the paper. Experimental Values Estimated Error: Temperature: 0.1 K. a b % x2 x1 x1: 2.5 (relative error). 0.9183 0.0817 a x2: mole fraction of component 2 in the saturated solution. bx : mole fraction solubility of the solute. 1 Components: Original Measurements: (1) 2-(2-Fluoro-4-biphenyl)propionic 60A. Fini, M. Laus, I. Orienti, and Auxiliary Information acid (( ) Flurbiprofen); C15H13FO2; V. Zecchi, J. Pharm. Sci. 75,23 [5104-49-4] (1986). / / Method Apparatus Procedure: (2) 1-Octanol; C8H18O; [111-87-5] Constant-temperature bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were Variables: Prepared by: allowed to equilibrate at constant temperature. Solubility of the dissolved Temperature W. E. Acree, Jr. solute was determined by spectrophotometric measurements.

Experimental Values Source and Purity of Chemicals: (1) 99%, Sigma-Aldrich Chemical Company, USA, was used as received. (2) 99.8+%, Sigma-Aldrich Chemical Company, USA, stored over freshly a activated molecular sieves before use. T/K c1 278.2 0.232 Estimated Error: 298.2 0.286 Temperature: 0.1 K. 310.2 0.332 x1: 2% (relative error, estimated by compiler). a 3 c1: molar solubility of the solute in units of mol dm .

Auxiliary Information 12.7. Flurbiprofen solubility data in ketones Method/Apparatus/Procedure: Constant-temperature bath, analytical balance, and an UV/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in a sealed container and allowed to (1) 2-(2-Fluoro-4-biphenyl)propionic 84G. L. Perlovich, S. V. Kurkov, equilibrate with stirring at constant temperature. An aliquot of the saturated acid (() Flurbiprofen); C H FO ; and A. Bauer-Brandl, Eur. J. solution was removed, filtered through a 0.22 μm pore membrane, and diluted 15 13 2 [5104-49-4] Pharm. Sci. 19, 423 (2003). quantitatively for spectroscopic analysis. (2) Propanone; C3H6O; [67-64-1] Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, chemical source not specified, was recrystallized from T/K ¼ 298.15 W. E. Acree, Jr. suitable solvent before use. (2) Purity not given, chemical source not specified, no purification details were provided in the paper. Experimental Values

Estimated Error: a b Temperature: 0.2 K (estimated by compiler). x2 x1 % c1: 3 (relative error). 0.876 0.124 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: 91 (1) 2-(2-Fluoro-4-biphenyl)propionic U. Domanska, A. Pobudkowska, Auxiliary Information acid (() Flurbiprofen); C15H13FO2; A. Pelczarska, and P. Gierycz, J. [5104-49-4] Phys. Chem. B 113, 8941 (2009). Method/Apparatus/Procedure: Constant-temperature bath and an analytical balance. (2) 1-Octanol; C8H18O; [111-87-5] Very few experimental details were provided. The solubility was determined Variables: Prepared by: with a gravimetric method that involved transferring a weighed aliquot of the Temperature W. E. Acree, Jr. saturated solution to a tared container. The solvent was evaporated and the solubility determined from the mass of the solid residue.

Experimental Values Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. / a b T K x2 x1 (2) Purity not given, Analytical Reagent grade, Solvents Documentation 300.4 0.9165 0.0835 Syntheses (SDS), Peypin, France, no puriﬁcation details were provided. 305.6 0.8928 0.1072 311.3 0.8662 0.1338 Estimated Error: 317.4 0.8398 0.1602 Temperature: 0.1 K.

322.8 0.8097 0.1903 x1: 3.0% (relative error). 327.9 0.7766 0.2234 332.5 0.7452 0.2548 336.4 0.7132 0.2868 a x2: mole fraction of component 2 in the saturated solution. 12.8. Flurbiprofen solubility data in miscellaneous b x1: mole fraction solubility of the solute. organic solvents

Auxiliary Information Components: Original Measurements: / / Method Apparatus Procedure: (1) 2-(2-Fluoro-4-biphenyl)propionic 84G. L. Perlovich, S. V. Kurkov, Thermostated water bath and an analytical balance. acid (() Flurbiprofen); C15H13FO2; and A. Bauer-Brandl, Eur. J. Solubility was measured using a dynamic synthetic method. Known amounts [5104-49-4] Pharm. Sci. 19, 423 (2003). of solute and solvent were placed in Pyrex glass containers and allowed to (2) Ethanenitrile; C2H3N; [75-05-8] equilibrate in a thermostated water bath. The temperature of the bath was slowly increased and the temperature at which the last crystal disappeared was Variables: Prepared by: recorded as the solid-liquid equilibrium temperature. T/K ¼ 298.15 W. E. Acree, Jr.

Experimental Values Components: Original Measurements: (1) 2-(2-Fluoro-4-biphenyl)propionic 65E. Rytting, K. A. Lentz, X.-Q. a b acid (( ) Flurbiprofen); C15H13FO2; Chen, F. Qian, and S. Venkatesh, x2 x1 [5104-49-4] AAPS J. 7, E78 (2005). 0.9692 0.0308 (2) Polyethylene glycol 400 a (PEG 400) x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Variables: Prepared by: T/K ¼ 296 W. E. Acree, Jr.

Auxiliary Information Method/Apparatus/Procedure: Experimental Values / Constant-temperature bath and an UV visible spectrophotometer. The measured solubility was reported to be c1 ¼ 1.265 Very few experimental details were provided. Excess solute and solvent were mol dm3. allowed to equilibrate at constant temperature. Solubility of the dissolved solute was determined by spectrophotometric measurements. Auxiliary Information Source and Purity of Chemicals: Method/Apparatus/Procedure: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Centrifuge and a high-performance liquid chromatograph equipped with a purification details were provided. photo-diode array detector. (2) Purity not given, HPLC grade, Merck Chemical Company, Germany, no Excess solute and solvent were placed in sealed vials and shaken at ambient purification details were provided. room temperature for at least 24 h. The vials were then centrifuged for 15 min to separate the saturated solution from the excess solute. The supernatant was Estimated Error: then filtered and the concentration of the dissolved solute determined by high- Temperature: 0.1 K. performance liquid chromatographic analysis. x1: 2.5% (relative error). Source and Purity of Chemicals: (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, USA, no purification details were provided. Components: Original Measurements: (2) Purity not given, J. T. Baker Chemical Company, Phillipsburg, New Jersey, (1) 2-(2-Fluoro-4-biphenyl)propionic 92D. B. Larsen, H. Parshad, K. USA, no purification details were provided.

acid (() Flurbiprofen); C15H13FO2; Fredholt, and C. Larsen, Int. J. [5104-49-4] Pharm. 232, 107 (2002). Estimated Error: (2) Castor oil Temperature: 2 K (estimated by compiler). c : 10% (relative error, estimated by compiler). Variables: Prepared by: 1 T/K ¼ 310.15 W. E. Acree, Jr.

Experimental Values 13. Solubility of Ibuprofen in Organic

The measured molar solubility was reported to be c1 ¼ 0.400 Solvents mol dm3. 13.1. Critical evaluation of experimental solubility data Auxiliary Information α Method/Apparatus/Procedure: Ibuprofen (more formally named -methyl-4-(2-methyl- Constant-temperature bath and an UV/visible spectrophotometer. propyl)benzeneacetic acid) is a popular NSAID used for Excess solute and solvent were placed in a screw-capped test tube and allowed fever reduction and to treat inflammation and pain caused by to equilibrate at a constant temperature with rotation for 24 h. Aliquots of arthritis, headache, toothache, and minor injury. There are saturated solutions were removed, centrifuged at 15 000 rpm for 10 min, and several published studies60,65,93–117 involving the solubility diluted quantitatively with ethanol for spectroscopic analysis. of ibuprofen in organic solvents. Most notably, Bustamante 93 Source and Purity of Chemicals: et al. examined the solubility of ibuprofen in two saturated (1) Purity not given, chemical source not specified, no purification details were hydrocarbons (heptane and cyclohexane), in one aromatic provided. hydrocarbon (benzene), in one alkyl alkanoate (ethyl (2) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no ethanoate), in one dialkyl ether (1,1′-oxybisethane) and one purification details were provided. cyclic ether (1,4-dioxane), in two chloroalkanes (trichlor- Estimated Error: omethane and 1,2-dichloroethane) and one chlorinated aro- Temperature: 0.5 K. matic hydrocarbon (chlorobenzene), in seven alcohols % c1: 10 (relative error, estimated by compiler). (methanol, ethanol, 1-pentanol, 1-octanol, 1,2-ethanediol, 1,2-propanediol, and 1,2,3-propanetriol), in one alkanone (propanone) and one aromatic ketone (acetophenone), and in

four miscellaneous organic solvents (ethanoic acid, propa- partition coefficient data, to calculate the Abraham solute noic acid, formamide, and N,N-dimethylformamide) at 298 descriptors of ibuprofen. The authors were able to assemble 102 K and atmospheric pressure. Perlovich et al. determined a total of 50 log10(SR or P) and log10(GSR or K) equations for the solubility of ibuprofen in eight 1-alkanols (methanol which experimental partition coefficient data, solubility ratios, through 1-octanol) based on spectrophotometric measure- chromatographic retention times, Abraham Model equation ments. Stovall et al.103 also used spectroscopic methods to coefficients, and aqueous molar solubility were available. The measure the solubility of ibuprofen in six primary linear logarithm of the aqueous molar solubility of ibuprofen is 118,119 alcohols (methanol, ethanol, 1-propanol, 1-pentanol, 1-octa- log10c1,W ¼ –3.76. The McGowan volume of ibuprofen, nol, and 1-decanol), in two secondary alcohols (2-propanol V ¼ 1.7771, was calculated from the number of chemical and 2-butanol), and in one branched primary alcohol (2- bonds in the molecule and the individual atomic group methyl-1-propanol) at 298 K and atmospheric pressure. volumes, AVi, given in Sec. 1.3. The excess molar refraction GarzońandMartínez,94 Aragoń et al.,101 Wang et al.,97 solute descriptor was estimated as E ¼ 0.730. This left four Soltanpour and Jouyban,109,110 Jouyban et al.,108 Wang solute descriptors (S, A, B, and L) still to be determined. The 50 et al.,105 Manrique and Martínez,107 and Manrique equations were then solved using the Microsoft “SOLVER” et al.111 have also performed ibuprofen solubility measure- program to yield values of the remaining four solute descrip- ments at 298K.Takahashiet al.100 measured the solubility of tors, S ¼ 0.695, A ¼ 0.565, B ¼ 0.790, and L ¼ 7.184, that best ibuprofen in diethyl butanedioate, diethyl hexanedioate, described the log10(SR or P) and log10(GSR or K) values. The diisopropyl hexanedioate, and diethyl decanedioate at 305 computation treated log10c1,G as a floating parameter to be K in their study concerning the use of fatty diesters as a determined as part of the regression analyses. The data ana- means to enhance NSAID permeation through skin. lyses returned a value of log10c1,G ¼ –9.460 for the logarithm The Abraham solvation parameter model can provide an of the gas-phase solute concentration that made the log10(SR or indication of the quality of experimental solubility data for P) and log10(GSR or K) predictions internally consistent. The ibuprofen dissolved in a series of organic solvents of varying calculated molecular solute descriptors reproduced the polarity and hydrogen bonding character. As discussed in log10(SR or P) and log10(GSR or K) values to within an average Sec. 1.3, the evaluation will be restricted to those solvents standard deviation of 0.109 and 0.114 log10 units, respectively. where dimerization is not likely to occur and to solvents where Table 6 compares the experimental log10c1 values to cal- ibuprofen does not form a solid solvate. Expressions based on culated values based on Eqs. (28) and (29) of the Abraham the Abraham model have been shown to provide reasonably model. For comparison purposes, the measured mole fraction 103 accurate mathematical correlations for the solubility behavior solubilities of ibuprofen, x1, determined by Stovall et al. of numerous crystalline nonelectrolyte solutes, with devia- were converted into molar solubilities by dividing x1 by the sat tions between observed and calculated values on the order of ideal molar volume of the saturated solution (i.e., c1 ¼ x1/ 0.15 log10 units or less. The Abraham model is based on two [x1V1 + (1 – x1)Vsolvent]. The molar volume of the hypothetical 3 1 linear free energy relationships that describe solute transfer to subcooled liquid ibuprofen is Vsolute ¼ 208.0 cm mol . organic solvents from water and from the gas phase. Expressed Examination of the numerical entries in Table 6 reveals that in terms of molar solubility, the linear free energy relationships the Abraham model provides a reasonably accurate mathe- take the following forms: matical description for much of the observed solubility. Solution models, like the Abraham solvation parameter sat sat ¼ þ þ þ log10 c1;S c1;W cp ep E sp S ap A model, prove useful in screening datasets for obvious outliers,

þ bp B þ vp V; ð28Þ particularly in cases where there are only one or two experimental data points for a given solute-solvent system. Such models are only able to identify those outliers, however, which sat = ¼ þ þ þ log10 c1;S c1;G ck ek E sk S ak A fall outside of the model’s expected predictive applicability. þ bk B þ lk L; ð29Þ One does need to carefully look at the individual replicate measurements as examinations can provide useful informa- sat sat where c1;S and c1;W are the molar solubilities of the solute in the tion. The numerical entries in Table 6 further show that there is organic solvent and in water, respectively, and c1,G is the molar considerable variation in the experimental solubility of ibu- concentration of the solute in the gas phase. The molar profen determined by independent research groups for several concentrations are expressed in units of mol dm 3. For nota- organic solvents. Part of the variation may be due to differ- tional simplicity, the “sat” superscript will be dropped in ences in chemical purities and to the different experimental subsequent discussions, and the quantities simply denoted as methodologies employed by the various researchers. Pub- 120–122 c1 and c1,W. The Abraham model solvent equation coefficients lished studies have reported the existence of two poly- that are given in Tables 1 and 2 pertain to 298 K unless morphic forms of racemic ibuprofen. The first discovered otherwise noted. For a given solute–solvent system, Eqs. (28) polymorph (Form I) has a melting-point temperature of and (29) give calculated c1 values that differ from one another 349 K, and the crystal structure was first reported by McCon- by only a few hundredths of a logarithmic unit. nell in 1974.120 The second polymorph (Form II) was dis- Stovall et al.103 used their measured solubility data for covered through differential scanning calorimetry (DSC) ibuprofen in ethyl ethanoate, 1,1′-oxybisethane, and nine experiments121 where a molten racemic ibuprofen sample was alcohol solvents, combined with published solubility and quenched rapidly to 143 K, and then held at this temperature

TABLE 6. Comparison between observed and predicted molar solubilities of ibuprofen based on the Abraham model, Eqs. (28) and (29)

calc calc log10c1 ; log10c1 ; exp exp exp Solvent Eq. (28) Eq. (29) log10c1 log10c1 log10c1 Methanol 0.071 0.061 0.070a Ethanol 0.285 0.166 0.070a 0.069b 0.250c 0.343d 0.360e 0.359f 1-Propanol 0.259 0.165 0.180a 0.179b 0.311d 2-Propanol 0.258 0.215 0.330b 0.321d 1-Butanol 0.176 0.309 0.160a 0.165b 0.272d 2-Butanol 0.080 0.105 0.246a 2-Methyl-1-propanol 0.206 0.222 0.239a 0.237d 2-Methyl-2-propanol 0.180 0.243 1-Pentanol 0.308 0.267 0.160a 0.079b 0.216c 0.230d 2-Pentanol 0.386 0.278 3-Methyl-1-butanol 0.357 0.147 0.219d 1-Hexanol 0.218 0.127 0.190b 1-Heptanol 0.280 0.246 0.160b 1-Octanol 0.025 0.019 0.070a 0.071b 0.114c 0.291g 1.041h 1-Decanol 0.175 0.086 0.045a aExperimental value from Stovall et al.103 bExperimental value from Perlovich et al.102 cExperimental value from Bustamante et al.93 dExperimental value from Wang et al.97 eExperimental value from Manríque and Martínez.107 fExperimental value from Soltanpour and Jouyban.109 gExperimental value from Garzo´n and Martínez.94 hExperimental value from Fini et al.60

for a period of time, followed by annealing at 258 K. Form II tetrahydrofuran. There was no information given in the paper has a much lower melting-point temperature of 290 K, and its concerning the reproducibility of an individual solvent value. crystal structure is indeed different than that of Form I.122 A In general the solubility would increase with decreased percent metastable amorphous form of racemic ibuprofen is also crystallinity. The authors further noted that ibuprofen did not known, with a glass-transition temperature of 228 K.123 Poly- crystallize from supersaturated solutions of benzenemethanol, morphism could explain some of the observed differences; dimethylbenzene, acetone or dimethyl sulfoxide. Csoka125 had however, the experimental conditions employed in normal earlier reported that ibuprofen recrystallized from various solubility measurements are far removed from the low-tem- solvents showed different solubilities in water. perature quenching conditions used in producing Form II. It is There have been several studies60,91,94,96,101,104,107,111 noted that the samples of ibuprofen used in the solubility reporting the solubility of ibuprofen as a function of tempera- studies did come from different chemical suppliers, and there ture. Fini et al.60 determined the molar solubility of ibuprofen is no way of knowing how the various samples were synthe- in 1-octanol at only three temperatures from 278 to 310 K. sized and purified prior to use. Garzoń and Martínez94 measured the solubility of ibuprofen in While polymorphism cannot be definitively ruled out, a cyclohexane, 1-methylethyl tetradecanoate, trichloromethane more likely explanation for the large variation in the measured and 1-octanol at several temperatures from 293 to 313 K. solubilities of ibuprofen in a given solvent might be differ- Aragoń et al.101 examined the solubility of ibuprofen in ences in crystallinity. Lee et al.124 performed calorimetric dichloromethane and propanone in the temperature range of studies on acetaminophen and ibuprofen samples recrystal- 293–313 K. Manrique and co-workers107,111 reported solubi- lized from different solvent media. The authors calculated the lity data for ibuprofen in ethanol and 1,2-propanediol at percent crystallinity as several temperatures between 293 and 313 K. Gracin and Rasmuson96 employed a gravimetric method to study the Area of sample melting peak %Crystallinity ¼ ; ð30Þ solubility of ibuprofen in methylbenzene, ethyl ethanoate, Area of standard melting peak methanol, ethanol, 2-propanol, propanone, and 4-methyl-2- 91 which is the ratio of the area of the sample melting peak pentanone. Domanska et al. determined the solubility of divided by the area of a standard ibuprofen sample having a ibuprofen in ethanol and 1-octanol at as a function of tem- high degree of crystallinity. The percent crystallinity varied perature using a dynamic method that involved placing known with recrystallization solvent, from a value of 100% for a amounts of solute and solvent in sealed containers and slowly increasing the temperature until the last crystal disappeared. sample recrystallized from N,N-dimethylformamide to a low 97 value of 14.3% crystallinity for a sample crystallized from Finally, Wang et al. studied the solubility of ibuprofen in nine organic solvents (ethyl ethanoate, ethanol, 1-propanol,

TABLE 7. Parameters of the Modified Apelblat equation for describing the solubility of ibuprofen in organic solvents Solvent T/K ABCMARD (%) Cyclohexanea 298–313 17.730 5943.49 6.0 Methylbenzeneb 283–308 72.791 1.602 12.496 1.9 Ethyl ethanoateb 283–308 66.983 1.463 11.494 0.4 Ethyl ethanoatec 283–318 136.171 8863.89 18.940 0.2 2-Methylethyl tetradecanoatea 298–313 12.253 4167.98 1.6 Dichloromethaned 293–313 36.543 0.761 6.190 0.7 Trichloromethanea 298–313 10.618 3461.35 0.2 Methanolb 283–308 71.638 1.574 12.278 5.5 Ethanolb 283–308 68.545 1.496 11.759 4.5 Ethanolc 283–318 0.2894 2605.96 1.1978 0.6 Ethanole 297–330 58.237 4.902 9.919 1.3 Ethanolf 293–313 53.740 1.147 9.183 1.9 1-Propanolc 283–318 15.748 1913.22 3.6161 0.4 2-Propanolb 283–308 63.612 114.474 10.835 1.9 2-Propanolc 283–318 105.804 7348.47 14.508 0.6 1-Butanolc 283–318 53.514 158.355 9.2210 0.7 2-Methyl-1-propanolc 283–318 67.904 5987.66 8.6743 0.4 1-Pentanolc 283–318 31.136 1205.96 5.9119 0.4 3-Methyl-1-butanolc 283–318 87.427 6682.55 11.682 0.2 1-Octanola 298–313 13.752 4418.37 0.6 1-Octanole 297–339 54.166 4.816 9.240 1.2 1,2-Propanediolg 293–313 98.356 2.156 16.862 4.4 Propanoneb 283–308 59.341 114.577 10.093 0.4 Propanonec 283–318 91.530 6480.52 12.505 0.5 Propanoned 293–313 46.665 0.971 7.961 0.8 4-Methyl-2-pentanoneb 283–308 62.727 114.506 10.681 0.4 aData set of Garzoń and Martínez.94 bData set of Gracin and Rasmuson.96 cValues of the equation coefficients were taken from Wang et al.97 dData set of Aragoń, Rosas and Martínez.101 eData set of Domanska et al.91 fData set of Manrique and Martínez.107 gData set of Manrique et al.111

2-propanol, 1-butanol, 2-methyl-1-propanol, 1-pentanol, Experimental Values 3-methyl-1-butanol, and propanone) by incrementally small amounts of the solute until no further solid dissolved. The x a x b,c dissolution of the solid was observed using laser monitoring. 2 1 0.9440 0.05598 The internal consistency of the 26 datasets was assessed by a x2: mole fraction of component 2 in the saturated solution. curve-fitting the measured mole fraction solubility data to b x1: mole fraction solubility of the solute. Eq. (8). The values of the equation coefficients (A, B, and C) c Experimental value was reported in the paper as ln x1. are given in Table 7, along with the mean absolute relative deviation. Each of the data sets is considered internally consistent as evidenced by the small MARD values. There were Auxiliary Information insufficient experimental measurements in the Fini et al.60 Method/Apparatus/Procedure: dataset to obtain a meaningful regression analysis. Constant-temperature bath and an ultraviolet/visible spectrophotometer. The experimental solubility data for ibuprofen in organic Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions solvents are given in Secs. 13.2–13.10. were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 289 nm. The reported solubility represents the average of at least three independent determinations. 13.2. Ibuprofen solubility data in saturated hydrocarbons (including cycloalkanes) Source and Purity of Chemicals: (1) Purity not given, Laboratories UPSA, Agen, France, no purification details were provided. Components: Original Measurements: (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and source not specified, no purification details were provided. benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 Estimated Error: C13H18O2; [15687-27-1] (2000). Temperature: 0.2 K. (2) Heptane; C7H16; [142-82-5] x1: 2% (relative error). Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

Estimated Error: Auxiliary Information Temperature: 0.1 K. x : 3% (relative error). Method/Apparatus/Procedure: 1 Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and the solvent evaporated. The solid residue was then dissolved Components: Original Measurements: 95 and diluted with 96% ethanol (v/v). Concentrations were determined by (1) α-Methyl-4-(2-methylpropyl)- M. A. Filippa and E. I. Gasull, spectrophotometric measurements at 289 nm. The reported solubility benzeneacetic acid (Ibuprofen); Fluid Phase Equilib. 354, 185 [ ] represents the average of at least three independent determinations. C13H18O2; 15687-27-1 (2013). (2) Cyclohexane; C6H12; [110-82-7] Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Laboratories UPSA, Agen, France, no purification details T/K ¼ 300.15 W. E. Acree, Jr. were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values ¼ Estimated Error: The measured solubility was reported to be c1 0.689 mol 3 Temperature: 0.2 K. dm . x1: 2% (relative error). Auxiliary Information Method/Apparatus/Procedure: An UV/visible spectrophotometer. Components: Original Measurements: Very few experimental details were given in the paper. Excess solute and (1) α-Methyl-4-(2-methylpropyl)- 94L. C. Garzoń and F. Martínez, J. solvent were placed in closed containers and allowed to equilibrate with benzeneacetic acid (Ibuprofen); Solution Chem. 33, 1379 (2004). continuous agitation at constant temperature for 48 h. Aliquots of saturated C H O ; [15687-27-1] 13 18 2 solutions were removed and diluted quantitatively for spectroscopic analysis at (2) Cyclohexane; C H ; [110-82-7] 6 12 220 nm. Variables: Prepared by: Temperature W. E. Acree, Jr. Source and Purity of Chemicals: (1) 99%, Sigma-Aldrich Chemical Company, was used as received. (2) Purity not given, Spectroscopic grade, from either Merck Chemical Experimental Values Company or Sigma-Aldrich Chemical Company, was used as received.

Estimated Error: a b T/K x2 x1 Temperature: 1 K (estimated by compiler). % 298.15 0.8878 0.1122 c1: 3 (relative error, estimated by compiler). 303.15 0.8440 0.1560 308.15 0.8072 0.1928 313.15 0.6975 0.3025 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

13.3. Ibuprofen solubility data in aromatic Experimental Values hydrocarbons

a b T/K x2 x1 283.15 0.8966 0.1034 Components: Original Measurements: 288.15 0.8671 0.1329 (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and 293.15 0.8304 0.1696 benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 303.15 0.7491 0.2509 C H O ; [15687-27-1] (2000). 13 18 2 308.15 0.7006 0.2994 (2) Benzene; C6H6; [71-43-2] a x2: mole fraction of component 2 in the saturated solution. Variables: Prepared by: bx : mole fraction solubility of the solute. The solubility was reported in the / ¼ 1 T K 298.15 W. E. Acree, Jr. paper as the grams of solute that dissolved per kilogram of solvent. Mole fraction solubility calculated by the compiler.

Experimental Values Auxiliary Information

a b,c Method/Apparatus/Procedure: x2 x1 Thermostated water bath, analytical balance, magnetic stirrer, and vacuum 0.9153 0.08472 drying oven. a x2: mole fraction of component 2 in the saturated solution. Solubility was determined by the gravimetric method. Excess solute and b x1: mole fraction solubility of the solute. solvent were placed in Erlenmeyer flasks and allowed to equilibrate for 72 h in c Experimental value was reported in the paper as ln x1. a thermostatic water bath sitting on a multiple position magnetic stirrer. The solutions were stirred during the equilibration period. The stirring was then stopped for 4 h to allow the suspended solid to settle to the bottom of the flask. Auxiliary Information A sample of the clear saturated solution was transferred with a heated syringe Method/Apparatus/Procedure: into a previously weighed sample vial. The vial containing the saturated Constant-temperature bath and an ultraviolet/visible spectrophotometer. solution was then weighed, and the solvent was allowed to evaporate in a Excess solute and solvent were placed in flasks and allowed to equilibrate with vacuum oven at 293 K for approximately one week until a constant weight was shaking for five days at constant temperature. Aliquots of saturated solutions obtained. The solubility was calculated from the mass of the solid residue and were removed and diluted with 96% ethanol (v/v). Concentrations were mass of the saturated solution analyzed. determined by spectrophotometric measurements at 289 nm. The reported solubility represents the average of at least three independent determinations. Source and Purity of Chemicals: (1) 99.4%, AstraZeneca AB, no purification details were given in the paper. Source and Purity of Chemicals: (2) Purity not given, Pro Analyse grade, Merck Chemical Company, Germany, (1) Purity not given, Laboratories UPSA, Agen, France, no purification details no purification details were given in the paper. were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Estimated Error: source not specified, no purification details were provided. Temperature: 0.1 K. x1: 1% (relative error). Estimated Error: Temperature: 0.2 K.

x1: 2% (relative error). 13.4. Ibuprofen solubility data in esters

Components: Original Measurements: Components: Original Measurements: α 96 93 (1) -Methyl-4-(2-methylpropyl)- S. Gracin and A. C. Rasmuson, (1) α-Methyl-4-(2-methylpropyl)- P. Bustamante, M. A. Peña, and benzeneacetic acid (Ibuprofen); J. Chem. Eng. Data 47, 1379 benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 C H O ; [15687-27-1] (2002). 13 18 2 C13H18O2; [15687-27-1] (2000). (2) Toluene; C H ; [108-88-3] 7 8 (2) Ethyl ethanoate; C4H8O2; [ ] Variables: Prepared by: 141-78-6 Temperature W. E. Acree, Jr. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

Experimental Values

a b,c x2 x1 0.6652 0.3348 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information Estimated Error: Temperature: 0.1 K. Method/Apparatus/Procedure: x1: 1% (relative error). Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 289 nm. The reported Components: Original Measurements: α 97 solubility represents the average of at least three independent determinations. (1) -Methyl-4-(2-methylpropyl)- S. Wang, Z. Song, J. Wang, Y. benzeneacetic acid (Ibuprofen); Dong, and M. Wu, J. Chem. Eng. [ ] Source and Purity of Chemicals: C13H18O2; 15687-27-1 Data 55, 5283 (2010). (1) Purity not given, Laboratories UPSA, Agen, France, no purification details (2) Ethyl ethanoate; C4H8O2; [ ] were provided. 141-78-6 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Variables: Prepared by: source not specified, no purification details were provided. Temperature W. E. Acree, Jr.

Estimated Error: Temperature: 0.2 K. Experimental Values x1: 2% (relative error).

a b T/K x2 x1 283.17 0.8733 0.1267 Components: Original Measurements: 288.47 0.8416 0.1584 (1) α-Methyl-4-(2-methylpropyl)- 96S. Gracin and A. C. Rasmuson, 293.57 0.8065 0.1935 benzeneacetic acid (Ibuprofen); J. Chem. Eng. Data 47, 1379 297.69 0.7746 0.2254 C13H18O2; [15687-27-1] (2002). 302.75 0.7287 0.2713 (2) Ethyl ethanoate; C4H8O2; 307.83 0.6805 0.3195 [141-78-6] 313.07 0.6238 0.3762 318.45 0.5612 0.4388 Variables: Prepared by: a Temperature W. E. Acree, Jr. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Experimental Values Auxiliary Information Method/Apparatus/Procedure: T/K x a x b 2 1 Equilibrium jacketed glass vessel, thermostated circulating water bath, 283.15 0.8774 0.1226 electromagnetic stirrer, analytical balance, laser monitoring system. 288.15 0.8495 0.1505 Experimental solubilities were determined by a synthetic method. Preweighed 293.15 0.8150 0.1850 amounts of solute and solvent and were placed in an equilibrium vessel, which 303.15 0.7322 0.2678 was connected to a circulating constant-temperature water bath. The solution 308.15 0.6738 0.3262 was stirred and small amounts of solute were incrementally added until no a further solid dissolved. The dissolution of the solid was determined using laser x2: mole fraction of component 2 in the saturated solution. b monitoring. The total amount of solute dissolved was recorded. Experimental x1: mole fraction solubility of the solute. The solubility was reported in the paper as the grams of solute that dissolved per kilogram of solvent. Mole measurement was repeated three times. fraction solubility calculated by the compiler. Source and Purity of Chemicals: (1) 99.4%, JiangXi GuoXing Fine Chemical Industry, Co., Ltd., recrystallized Auxiliary Information twice from ethanol before use. (2) 99.7+%, Analytical Reagent grade, Beijing Chemical Reagent Company, / / Method Apparatus Procedure: China, no purification information was given in the paper. Thermostated water bath, analytical balance, magnetic stirrer, and vacuum drying oven. Estimated Error: Solubility was determined by the gravimetric method. Excess solute and Temperature: 0.1 K. solvent were placed in Erlenmeyer flasks and allowed to equilibrate for 72 h in x1: 2% (relative error). a thermostatic water bath sitting on a multiple position magnetic stirrer. The solutions were stirred during the equilibration period. The stirring was then stopped for 4 h to allow the suspended solid to settle to the bottom of the flask. A sample of the clear saturated solution was transferred with a heated syringe into a previously weighed sample vial. The vial containing the saturated Components: Original Measurements: α 98 solution was then weighed, and the solvent was allowed to evaporate in a (1) -Methyl-4-(2-methylpropyl)- K. H.-Y. Hsi, K. Chadwick, A. vacuum oven at 293 K for approximately one week until a constant weight was benzeneacetic acid (Ibuprofen); Fried, M. Kenny, and A. S. [ ] obtained. The solubility was calculated from the mass of the solid residue and C13H18O2; 15687-27-1 Myerson, Cryst. Eng. Comm. 14, mass of the saturated solution analyzed. (2) Ethyl ethanoate; C4H8O2; 2386 (2012). [141-78-6] Source and Purity of Chemicals: Variables: Prepared by: % (1) 99.4 , AstraZeneca AB, no purification details were given in the paper. T/K ¼ 293 W. E. Acree, Jr. (2) Purity not given, Pro Analyse grade, Merck Chemical Company, Germany, no purification details were given in the paper.

Experimental Values Excess solute and solvent were placed in a stoppered glass flask and stirred in a mechanical shaker for 1 h. The flasks were then transferred to a constant- The authors studied the separation of impurities from solu- temperature bath where the solution equilibrated for at least three days. An tion by selective co-crystal formation. Solubilities of ibupro- aliquot of the saturated solution was removed, isothermally filtered, and fen and the ibuprofen-4,4′-bipyridine co-crystal. Ethyl diluted quantitatively for spectrophotometric analysis. The reported values ethanoate was chosen because both ibuprofen (IBU) and represent the average of at least three determinations. The densities of the saturated solutions were measured in order to convert the molar solubilities 4,4′-bipyridine were both moderately soluble in the organic 3 given in mol dm to mole fractions. solvent. The statement in the paper regarding the solubility of ibuprofen was “the solubility of IBU was reduced by a factor of Source and Purity of Chemicals: 8 from 478.6 mg g1 to 57.6 mg g1 by forming the BIPY (1) Purity not given, UPS, Mallinckrodt, USA, no purification details were 1 given in the paper. cocrystal”. The reported solubility is s1 ¼ 478.6 mg g ; however the authors did not specify whether the solubility (2) Purity not given, F.S. grade, Merck Chemical Company, Germany, no purification details were given in the paper. was per gram of organic solvent or per gram of saturated solution. Estimated Error: Temperature: 0.1 K. % Auxiliary Information x1: 3 (relative error). Method/Apparatus/Procedure: Very few experimental details were provided in the paper. The authors state that the solubility was determined using a Thermofisher Clarity solubility Components: Original Measurements: station, and reference a published paper by [Y. Yi, D. Hatziavramidis, and A. S. (1) α-Methyl-4-(2-methylpropyl)- 99B. S. Makhmalzadeh, S. Torabi, Myerson, Ind. Eng. Chem. Res. 44, 5427 (2005)]. benzeneacetic acid (Ibuprofen); and A. Azarpanah, Iranian J. C H O ; [15687-27-1] Pharm. Res. 11, 47 (2010). Source and Purity of Chemicals: 13 18 2 (2) 1-Methylethyl tetradecanoate; (1) Purity not given, chemical source not specified, no purification details were C H O ; [110-27-0] provided in the paper. 17 34 2 (2) Purity not given, chemical source not specified, no purification details were Variables: Prepared by: provided in the paper. T/K ¼ ambient room temperature W. E. Acree, Jr.

Estimated Error: Temperature: Insufﬁcient information given in the paper. Experimental Values

s1: Insufﬁcient information given in the paper. The measured solubility was reported to be c1 ¼ 0.950 mol dm3.

Components: Original Measurements: Auxiliary Information 94 (1) α-Methyl-4-(2-methylpropyl)- L. C. Garzoń and F. Martıńez, Method/Apparatus/Procedure: benzeneacetic acid (Ibuprofen); J. Solution Chem. 33, 1379 Centrifuge and a high-performance liquid chromatograph. [ ] C13H18O2; 15687-27-1 (2004). Excess solute and solvent were placed in a screw-capped test tube and allowed (2) 1-Methylethyl tetradecanoate; to equilibrate at ambient room temperature for 24 h. Aliquots of saturated [ ] C17H34O2; 110-27-0 solutions were removed, centrifuged at 3000 rpm for 10 min, filtered, and then Variables: Prepared by: diluted quantitatively for high-performance liquid chromatographic analysis. Temperature W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Caspian Tamin, Rashat, Iran, no purification details were Experimental Values provided. (2) Purity not given, Panreac, Spain, no purification details were provided.

a b Estimated Error: T/K x2 x1 Temperature: Insufﬁcient information given in the paper to estimate. 298.15 0.8251 0.1749 c : 15% (relative error, estimated by compiler). 303.15 0.7718 0.2282 1 308.15 0.7160 0.2840 313.15 0.6581 0.3419 ax : mole fraction of component 2 in the saturated solution. 2 Components: Original Measurements: bx : mole fraction solubility of the solute. 1 (1) α-Methyl-4-(2-methylpropyl)- 100K. Takahashi, H. Sakano, N. benzeneacetic acid (Ibuprofen); Numata, S. Kuroda, and N. C H O ; [15687-27-1] Mizuno, Drug Develop. Ind. Auxiliary Information 13 18 2 (2) Diethyl butanedioate; C8H14O4; Pharm. 28, 1285 (2002). Method/Apparatus/Procedure: [123-25-1] Mechanical shaker, constant-temperature water bath, and an UV/visible Variables: Prepared by: spectrophotometer. T/K ¼ 305.15 W. E. Acree, Jr.

Experimental Values Variables: Prepared by: T/K ¼ 305.15 W. E. Acree, Jr. The measured solubility was reported to be c1 ¼ 1.453 mol dm3. Experimental Values

Auxiliary Information The measured solubility was reported to be c1 ¼ 1.223 3 Method/Apparatus/Procedure: mol dm . Constant-temperature bath and a high-performance liquid chromatograph. Excess solute and solvent were allowed to equilibrate with agitation for 24 h at Auxiliary Information constant temperature. The saturated solution was removed and filtered through / / a 0.45 μm membrane filter. The concentration of the dissolved solute was Method Apparatus Procedure: determined by high-performance liquid chromatographic analysis. Constant-temperature bath and a high-performance liquid chromatograph. Excess solute and solvent were allowed to equilibrate with agitation for 24 h at Source and Purity of Chemicals: constant temperature. The saturated solution was removed and filtered through μ (1) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, a 0.45 m membrane filter. The concentration of the dissolved solute was Japan, no purification details were provided in the paper. determined by high-performance liquid chromatographic analysis. (2) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Japan, no purification details were provided in the paper. Source and Purity of Chemicals: (1) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Estimated Error: Japan, no purification details were provided in the paper. Temperature: 0.2 K (estimated by compiler). (2) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Japan, no purification details were provided in the paper. c1: 5% (relative error, estimated by compiler). Estimated Error: Temperature: 0.2 K (estimated by compiler).

c1: 5% (relative error, estimated by compiler). Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 100K. Takahashi, H. Sakano, N. benzeneacetic acid (Ibuprofen); Numata, S. Kuroda, and N.

C13H18O2; [15687-27-1] Mizuno, Drug Develop. Ind. Components: Original Measurements: (2) Diethyl hexanedioate; C H O ; Pharm. 28, 1285 (2002). 10 18 4 (1) α-Methyl-4-(2-methylpropyl)- 100K. Takahashi, H. Sakano, N. [141-28-6] benzeneacetic acid (Ibuprofen); Numata, S. Kuroda, and N.

Variables: Prepared by: C13H18O2; [15687-27-1] Mizuno, Drug Develop. Ind. / ¼ T K 305.15 W. E. Acree, Jr. (2) Diethyl decanedioate; C14H26O4; Pharm. 28, 1285 (2002). [110-40-7]

Experimental Values Variables: Prepared by: T/K ¼ 305.15 W. E. Acree, Jr. The measured solubility was reported to be c1 ¼ 1.453 mol dm3. Experimental Values

Auxiliary Information The measured solubility was reported to be c1 ¼ 1.389 3 Method/Apparatus/Procedure: mol dm . Constant-temperature bath and a high-performance liquid chromatograph. Excess solute and solvent were allowed to equilibrate with agitation for 24 h at Auxiliary Information constant temperature. The saturated solution was removed and filtered through / / a 0.45 μm membrane filter. The concentration of the dissolved solute was Method Apparatus Procedure: determined by high-performance liquid chromatographic analysis. Constant-temperature bath and a high-performance liquid chromatograph. Excess solute and solvent were allowed to equilibrate with agitation for 24 h at Source and Purity of Chemicals: constant temperature. The saturated solution was removed and filtered through μ (1) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, a 0.45 m membrane filter. The concentration of the dissolved solute was Japan, no purification details were provided in the paper. determined by high-performance liquid chromatographic analysis. (2) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Japan, no purification details were provided in the paper. Source and Purity of Chemicals: (1) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Estimated Error: Japan, no purification details were provided in the paper. Temperature: 0.2 K (estimated by compiler). (2) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Japan, no purification details were provided in the paper. c1: 5% (relative error, estimated by compiler).

Estimated Error: Temperature: 0.2 K (estimated by compiler).

C13H18O2; [15687-27-1] Mizuno, Drug Develop. Ind. (2) Diisopropyl hexanedioate; Pharm. 28, 1285 (2002).

C12H22O4; [6938-94-9]

13.5. Ibuprofen solubility data in ethers Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in flasks and allowed to equilibrate with (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and shaking for five days at constant temperature. Aliquots of saturated solutions % / benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 were removed and diluted with 96 ethanol (v v). Concentrations were determined by spectrophotometric measurements at 289 nm. The reported C13H18O2; [15687-27-1] (2000). ′ solubility represents the average of at least three independent determinations. (2) 1,1 -Oxybisethane; C4H10O; [60-29-7] Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Laboratories UPSA, Agen, France, no purification details / ¼ T K 298.15 W. E. Acree, Jr. were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values Estimated Error: Temperature: 0.2 K. x a x b,c 2 1 x1: 2% (relative error). 0.9778 0.02223 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. 13.6. Ibuprofen solubility data in haloalkanes, haloalkenes, and haloaromatic hydrocarbons

Auxiliary Information / / Method Apparatus Procedure: Components: Original Measurements: / Constant-temperature bath and an ultraviolet visible spectrophotometer. (1) α-Methyl-4-(2-methylpropyl)- 101D. M. Aragoń, J. E. Rosas, and Excess solute and solvent were placed in flasks and allowed to equilibrate with benzeneacetic acid (Ibuprofen); F. Martínez, Brazil. J. Pharm. Sci. shaking for five days at constant temperature. Aliquots of saturated solutions C13H18O2; [15687-27-1] 46, 227 (2010). were removed and diluted with 96% ethanol (v/v). Concentrations were (2) Dichloromethane; CH2Cl2; determined by spectrophotometric measurements at 289 nm. The reported [75-09-2] solubility represents the average of at least three independent determinations. Variables: Prepared by: Source and Purity of Chemicals: Temperature W. E. Acree, Jr. (1) Purity not given, Laboratories UPSA, Agen, France, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Experimental Values source not specified, no purification details were provided.

/ a b Estimated Error: T K x2 x1 Temperature: 0.2 K. 293.15 0.7238 0.2762 x1: 2% (relative error). 298.15 0.6979 0.3021 303.15 0.6617 0.3383 308.15 0.6207 0.3793 313.15 0.5893 0.4107 a Components: Original Measurements: x2: mole fraction of component 2 in the saturated solution. α 93 ñ b (1) -Methyl-4-(2-methylpropyl)- P. Bustamante, M. A. Pe a, and x1: mole fraction solubility of the solute. benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117

C13H18O2; [15687-27-1] (2000). (2) 1,4-Dioxane; C4H8O2; [123-91-1] Auxiliary Information Variables: Prepared by: Method/Apparatus/Procedure: T/K ¼ 298.15 W. E. Acree, Jr. Thermostatic mechanical shaker and an analytical balance. Excess solute and solvent were placed in stoppered glass flasks and allowed to equilibrate in a thermostatic mechanical shaker at 313.15 K for at least three Experimental Values days. Once equilibrium had been attained, an aliquot of the saturated solution was removed and filtered in order to remove insoluble particles. The concentration of the dissolved drug was determined by weighing an aliquot of a b,c x2 x1 the saturated filtered solution, and then allowing the solvent to evaporate. The 0.9628 0.03719 mole fraction solubility was calculated from the mass of the solid residue and the mass of the sample taken for analysis. Once the solubility was determined ax : mole fraction of component 2 in the saturated solution. 2 at 313.15 K, the temperature was decreased by 5 K and stabilized at 308.15 K bx : mole fraction solubility of the solute. 1 for two days to allow the excess dissolved drug to precipitate at this lower cExperimental value was reported in the paper as ln x . 1 temperature. An aliquot of the new saturated solution was removed, filtered, and the solvent evaporated as before. The procedure was repeated by decreasing the temperature in 5 K increments to reach 293.15 K. The reported mole fraction solubilities represent the average of three experimental measurements.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, USP, no puriﬁcation details were provided in the paper. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, no puriﬁcation details were given in the paper. a b T/K x2 x1 298.15 0.629 0.371 Estimated Error: 303.15 0.550 0.450 Temperature: 0.1 K (estimated by compiler). 308.15 0.461 0.539 x : 1.0% (relative error). 1 313.15 0.352 0.648 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and Auxiliary Information benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117

C13H18O2; [15687-27-1] (2000). Method/Apparatus/Procedure: (2) Trichloromethane; CHCl3; Mechanical shaker, constant-temperature water bath, and an UV/visible [67-66-3] spectrophotometer. Excess solute and solvent were placed in a stoppered glass flask and stirred in a Variables: Prepared by: mechanical shaker for 1 h. The flasks were then transferred to a constant- T/K ¼ 298.15 W. E. Acree, Jr. temperature bath where the solution equilibrated for at least three days. An aliquot of the saturated solution was removed, isothermally filtered, and diluted quantitatively for spectrophotometric analysis. The reported values Experimental Values represent the average of at least three determinations. The densities of the saturated solutions were measured in order to convert the molar solubilities 3 a b,c given in mol dm to mole fractions. x2 x1 0.7462 0.2538 Source and Purity of Chemicals: a x2: mole fraction of component 2 in the saturated solution. (1) Purity not given, UPS, Mallinckrodt, USA, no purification details were b x1: mole fraction solubility of the solute. given in the paper. c Experimental value was reported in the paper as ln x1. (2) Purity not given, Analytical Reagent grade, Mallinckrodt, no purification details were given in the paper.

Auxiliary Information Estimated Error: Temperature: 0.1 K. Method/Apparatus/Procedure: x1: 3% (relative error). Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 289 nm. The reported Components: Original Measurements: 96 solubility represents the average of at least three independent determinations. (1) α-Methyl-4-(2-methylpropyl)- S. Gracin and A. C. Rasmuson, benzeneacetic acid (Ibuprofen); J. Chem. Eng. Data 47, 1379 [ ] Source and Purity of Chemicals: C13H18O2; 15687-27-1 (2002). (1) Purity not given, Laboratories UPSA, Agen, France, no purification details (2) Trichloromethane; CHCl3; were provided. [67-66-3] (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Variables: Prepared by: source not specified, no purification details were provided. Temperature W. E. Acree, Jr.

Estimated Error: Temperature: 0.2 K. Experimental Values x1: 2% (relative error).

a b T/K x2 x1 283.15 0.7907 0.2093 Components: Original Measurements: 288.15 0.7571 0.2429 94 (1) α-Methyl-4-(2-methylpropyl)- L. C. Garzo´n and F. Martínez, J. 293.15 0.7283 0.2717 benzeneacetic acid (Ibuprofen); Solution Chem. 33, 1379 (2004). ax : mole fraction of component 2 in the saturated solution. C H O ; [15687-27-1] 2 13 18 2 bx : mole fraction solubility of the solute. The solubility was reported in the (2) Trichloromethane; CHCl ; 1 3 paper as the grams of solute that dissolved per kilogram of solvent. Mole [67-66-3] fraction solubility calculated by the compiler. Variables: Prepared by: Temperature W. E. Acree, Jr.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and Thermostated water bath, analytical balance, magnetic stirrer, and vacuum benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 drying oven. C13H18O2; [15687-27-1] (2000). Solubility was determined by the gravimetric method. Excess solute and (2) Chlorobenzene; C6H5Cl; solvent were placed in Erlenmeyer flasks and allowed to equilibrate for 72 h in [108-90-7] a thermostatic water bath sitting on a multiple position magnetic stirrer. The Variables: Prepared by: solutions were stirred during the equilibration period. The stirring was then T/K ¼ 298.15 W. E. Acree, Jr. stopped for 4 h to allow the suspended solid to settle to the bottom of the flask. A sample of the clear saturated solution was transferred with a heated syringe into a previously weighed sample vial. The vial containing the saturated Experimental Values solution was then weighed, and the solvent was allowed to evaporate in a vacuum oven at 293 K for approximately one week until a constant weight was obtained. The solubility was calculated from the mass of the solid residue and x a x b,c mass of the saturated solution analyzed. 2 1 0.9799 0.02013 a Source and Purity of Chemicals: x2: mole fraction of component 2 in the saturated solution. % b (1) 99.4 , AstraZeneca AB, no purification details were given in the paper. x1: mole fraction solubility of the solute. c (2) Purity not given, Pro Analyse grade, Merck Chemical Company, Germany, Experimental value was reported in the paper as ln x1. no purification details were given in the paper.

Estimated Error: Auxiliary Information Temperature: 0.1 K. Method/Apparatus/Procedure: x : 1.5% (relative error). 1 Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Components: Original Measurements: determined by spectrophotometric measurements at 289 nm. The reported 93 (1) α-Methyl-4-(2-methylpropyl)- P. Bustamante, M. A. Peña, and solubility represents the average of at least three independent determinations. benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 [ ] C13H18O2; 15687-27-1 (2000). Source and Purity of Chemicals: (2) 1,2-Dichloroethane; C2H4Cl2; (1) Purity not given, Laboratories UPSA, Agen, France, no purification details [107-06-2] were provided. Variables: Prepared by: (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical T/K ¼ 298.15 W. E. Acree, Jr. source not specified, no purification details were provided.

Estimated Error: Experimental Values Temperature: 0.2 K. x1: 2% (relative error).

a b,c x2 x1 0.9141 0.08587 a 13.7. Ibuprofen solubility data in alcohols x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and Auxiliary Information benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 C H O ; [15687-27-1] (2000). Method/Apparatus/Procedure: 13 18 2 (2) Methanol; CH O; [67-56-1] Constant-temperature bath and an ultraviolet/visible spectrophotometer. 4 Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with Variables: Prepared by: shaking for ﬁve days at constant temperature. Aliquots of saturated solutions T/K ¼ 298.15 W. E. Acree, Jr. were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 289 nm. The reported solubility represents the average of at least three independent determinations. Experimental Values

Source and Purity of Chemicals: a b,c (1) Purity not given, Laboratories UPSA, Agen, France, no purification details x2 x1 were provided. 0.9753 0.02468 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a x2: mole fraction of component 2 in the saturated solution. source not specified, no purification details were provided. b x1: mole fraction solubility of the solute. c Estimated Error: Experimental value was reported in the paper as ln x1. Temperature: 0.2 K.

x1: 2% (relative error).

Auxiliary Information Experimental Values / / Method Apparatus Procedure: a b Constant-temperature bath and an ultraviolet/visible spectrophotometer. x2 x1 Excess solute and solvent were placed in flasks and allowed to equilibrate with 0.9395 0.06053 shaking for five days at constant temperature. Aliquots of saturated solutions a x2: mole fraction of component 2 in the saturated solution. were removed and diluted with 96% ethanol (v/v). Concentrations were b x1: mole fraction solubility of the solute. determined by spectrophotometric measurements at 289 nm. The reported solubility represents the average of at least three independent determinations. Auxiliary Information Source and Purity of Chemicals: (1) Purity not given, Laboratories UPSA, Agen, France, no purification details Method/Apparatus/Procedure: were provided. Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical visible spectrophotometer. source not specified, no purification details were provided. Excess solute and solvent were placed in amber glass bottles and allowed to equilibrate for several days at constant temperature. Attainment of equilibrium Estimated Error: was verified by several repetitive measurements and by approaching Temperature: 0.2 K. equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse filter into tared volumetric flasks, weighed, and x1: 2% (relative error). diluted with methanol. Concentrations were determined by spectrophotometric measurements at 264 nm.

Source and Purity of Chemicals: Components: Original Measurements: (1) 98+%, Sigma-Aldrich, St. Louis, Missouri, USA, was dried for several α 102 (1) -Methyl-4-(2-methylpropyl)- G. L. Perlovich, S. V. Kurkov, hours at 333 K before use. The purity of the commercial sample was 99.7% as benzeneacetic acid (Ibuprofen); A. N. Kinchin, and A. Bauer- determined by nonaqueous titration with freshly standardized sodium [ ] / C13H18O2; 15687-27-1 Brandl, APPS Pharm. Sci. 6,31 methoxide to the thymol blue endpoint according to the method of [J. S. Fritz [ ] (2004). (2) Methanol; CH4O; 67-56-1 and N. M. Lisicki, Anal. Chem. 23, 589 (1951)], except that methylbenzene Variables: Prepared by: was substituted for benzene in the titration solvent. % T/K ¼ 298.15 W. E. Acree, Jr. (2) 99.8 , anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use.

Experimental Values Estimated Error: Temperature: 0.1 K.

x1: 2.0% (relative error). a b x2 x1 0.9399 0.0601 ax : mole fraction of component 2 in the saturated solution. 2 Components: Original Measurements: bx : mole fraction solubility of the solute. 1 (1) α-Methyl-4-(2-methylpropyl)- 104I. Khalifeh, Ph.D. dissertation, benzeneacetic acid (Ibuprofen); Purdue University, 2000. [ ] Auxiliary Information C13H18O2; 15687-27-1 (2) Methanol; CH4O; [67-56-1] Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Variables: Prepared by: Very few experimental details were provided. Excess solute and solvent were Temperature W. E. Acree, Jr. allowed to equilibrate at constant temperature. Solubility of the dissolved solute was determined by spectrophotometric measurements. Experimental Values Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no / a puriﬁcation details were provided. T K s1 (2) Purity not given, HPLC grade, Merck Chemical Company, Germany, no 288.15 0.9943 puriﬁcation details were provided. 290.65 1.0208 293.15 1.1172 Estimated Error: 295.65 1.2905 Temperature: 0.1 K. 298.15 1.4206 x1: 2.5% (relative error). a s1: solubility of the solute expressed as grams of dissolved solute per gram. The author did not specify whether it was per gram of solvent or per gram of solution, but it is probably per gram of solvent.

Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 103D. M. Stovall, C. Givens, S. benzeneacetic acid (Ibuprofen); Keown, K. R. Hoover, E.

C13H18O2; [15687-27-1] Rodriguez, W. E. Acree, Jr., and

(2) Methanol; CH4O; [67-56-1] M. H. Abraham, Phys. Chem. Liq. 43, 261 (2005). Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

Auxiliary Information Estimated Error: Temperature: 0.1 K. Method/Apparatus/Procedure: x1: 1% (relative error). Constant-temperature water bath, high-precision thermometer, and an UV/ visible spectrophotometer. Excess solute and solvent were allowed to equilibrate with stirring in a constant-temperature water bath for 24 h. An aliquot of the saturated solution was removed, filtered through a 0.10 μm membrane filter, and then diluted for Components: Original Measurements: α 105 spectrophotometric analysis at 264 nm. (1) -Methyl-4-(2-methylpropyl)- X. Wang, C. S. Ponder, and benzeneacetic acid (Ibuprofen); D. J. Kirwan, Cryst. Growth Des. [ ] Source and Purity of Chemicals: C13H18O2; 15687-27-1 5, 85 (2005). [ ] (1) Purity not given, Pharmacia Upjohn, Kalamazoo, Michigan, USA, no (2) Methanol; CH4O; 67-56-1 purification details were provided in the paper. Variables: Prepared by: (2) Purity not given, HPLC grade, Mallinckrodt, St. Louis, Missouri, USA, no T/K ¼ 298.15 W. E. Acree, Jr. purification details were given in the paper.

Estimated Error: Experimental Values Temperature: 0.1 K.

s1: 2.0% (relative error, estimated by compiler). a b x2 x1 0.9170 0.08303 ax : mole fraction of component 2 in the saturated solution. Components: Original Measurements: 2 bx : mole fraction solubility of the solute. (1) α-Methyl-4-(2-methylpropyl)- 96S. Gracin and A. C. Rasmuson, 1 benzeneacetic acid (Ibuprofen); J. Chem. Eng. Data 47, 1379 C H O ; [15687-27-1] (2002). 13 18 2 Auxiliary Information (2) Methanol; CH4O; [67-56-1] Method/Apparatus/Procedure: Variables: Prepared by: Thermostated constant-temperature water bath and an UV/visible Temperature W. E. Acree, Jr. spectrophotometer. Excess solute and solvent were placed in a sealed container and allowed to equilibrate with agitation for 24 h to 72 h in a constant-temperature Experimental Values thermostated water bath. Aliquots of saturated solutions were removed and ﬁltered through a membrane ﬁlter of 0.22 μm pore size. Concentrations were

a b determined by spectrophotometric analysis at 304 nm. T/K x2 x1 283.15 0.8987 0.1013 Source and Purity of Chemicals: 288.15 0.8747 0.1253 (1) Purity not given, Sigma-Aldrich Chemical Company, no purification 293.15 0.8615 0.1385 details were provided. 303.15 0.7861 0.2139 (2) Purity not given, chemical source not specified, no purification details were 308.15 0.7022 0.2978 provided. a x2: mole fraction of component 2 in the saturated solution. b Estimated Error: x1: mole fraction solubility of the solute. The solubility was reported in the paper as the grams of solute that dissolved per kilogram of solvent. Mole Temperature: 0.2 K (estimated by compiler). % fraction solubility calculated by the compiler. x1: 4 (relative error, estimated by compiler).

Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: α 95 Thermostated water bath, analytical balance, magnetic stirrer, and vacuum (1) -Methyl-4-(2-methylpropyl)- M. A. Filippa and E. I. Gasull, drying oven. benzeneacetic acid (Ibuprofen); Fluid Phase Equilib. 354, 185 [ ] Solubility was determined by the gravimetric method. Excess solute and C13H18O2; 15687-27-1 (2013). [ ] solvent were placed in Erlenmeyer ﬂasks and allowed to equilibrate for 72 h in (2) Methanol; CH4O; 67-56-1 a thermostatic water bath sitting on a multiple position magnetic stirrer. The Variables: Prepared by: solutions were stirred during the equilibration period. The stirring was then T/K ¼ 300.15 W. E. Acree, Jr. stopped for 4 h to allow the suspended solid to settle to the bottom of the ﬂask. A sample of the clear saturated solution was transferred with a heated syringe into a previously weighed sample vial. The vial containing the saturated Experimental Values solution was then weighed, and the solvent was allowed to evaporate in a ¼ vacuum oven at 293 K for approximately one week until a constant weight was The measured solubility was reported to be c1 2.377 3 obtained. The solubility was calculated from the mass of the solid residue and mol dm . mass of the saturated solution analyzed.

Source and Purity of Chemicals: (1) 99.4%, AstraZeneca AB, no puriﬁcation details were given in the paper. (2) Purity not given, Pro Analyse grade, Merck Chemical Company, Germany, no puriﬁcation details were given in the paper.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: An UV/visible spectrophotometer. T/K x a x b Very few experimental details were given in the paper. Excess solute and 2 1 solvent were placed in closed containers and allowed to equilibrate with 283.15 0.8831 0.1169 continuous agitation at constant temperature for 48 h. Aliquots of saturated 288.15 0.8540 0.1460 solutions were removed and diluted quantitatively for spectroscopic analysis at 293.15 0.8347 0.1653 220 nm. 303.15 0.7592 0.2408 308.15 0.6675 0.3325 Source and Purity of Chemicals: a x2: mole fraction of component 2 in the saturated solution. (1) 99%, Sigma-Aldrich Chemical Company, was used as received. b x1: mole fraction solubility of the solute. The solubility was reported in the (2) Purity not given, Spectroscopic grade, from either Merck Chemical paper as the grams of solute that dissolved per kilogram of solvent. Mole Company or Sigma-Aldrich Chemical Company, was used as received. fraction solubility calculated by the compiler.

Estimated Error: Temperature: 1 K (estimated by compiler). Auxiliary Information c1: 3% (relative error, estimated by compiler). Method/Apparatus/Procedure: Thermostated water bath, analytical balance, magnetic stirrer, and vacuum drying oven. Solubility was determined by the gravimetric method. Excess solute and Components: Original Measurements: solvent were placed in Erlenmeyer flasks and allowed to equilibrate for 72 h in α 95 (1) -Methyl-4-(2-methylpropyl)- M. A. Filippa and E. I. Gasull, a thermostatic water bath sitting on a multiple position magnetic stirrer. The benzeneacetic acid (Ibuprofen); Fluid Phase Equilib. 354, 185 solutions were stirred during the equilibration period. The stirring was then [ ] C13H18O2; 15687-27-1 (2013). stopped for 4 h to allow the suspended solid to settle to the bottom of the flask. [ ] (2) Ethanol; C2H6O; 64-17-5 A sample of the clear saturated solution was transferred with a heated syringe Variables: Prepared by: into a previously weighed sample vial. The vial containing the saturated T/K ¼ 300.15 W. E. Acree, Jr. solution was then weighed, and the solvent was allowed to evaporate in a vacuum oven at 293 K for approximately one week until a constant weight was obtained. The solubility was calculated from the mass of the solid residue and Experimental Values mass of the saturated solution analyzed. ¼ The measured solubility was reported to be c1 2.606 Source and Purity of Chemicals: 3 mol dm . (1) 99.4%, AstraZeneca AB, no purification details were given in the paper. (2) 99.5%, Kemetyl AB, Sweden, no purification details were given in the Auxiliary Information paper.

Method/Apparatus/Procedure: Estimated Error: An UV/visible spectrophotometer. Temperature: 0.1 K. Very few experimental details were given in the paper. Excess solute and x1: 1% (relative error). solvent were placed in closed containers and allowed to equilibrate with continuous agitation at constant temperature for 48 h. Aliquots of saturated solutions were removed and diluted quantitatively for spectroscopic analysis at 220 nm. Components: Original Measurements: α 93 ñ Source and Purity of Chemicals: (1) -Methyl-4-(2-methylpropyl)- P. Bustamante, M. A. Pe a, and 194 (1) 99%, Sigma-Aldrich Chemical Company, was used as received. benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. , 117 [ ] (2) Purity not given, Spectroscopic grade, from either Merck Chemical C13H18O2; 15687-27-1 (2000). [ ] Company or Sigma-Aldrich Chemical Company, was used as received. (2) Ethanol; C2H6O; 64-17-5 Variables: Prepared by: Estimated Error: T/K ¼ 298.15 W. E. Acree, Jr. Temperature: 1 K (estimated by compiler).

c1: 3% (relative error, estimated by compiler). Experimental Values

a b,c Components: Original Measurements: x2 x1 (1) α-Methyl-4-(2-methylpropyl)- 96S. Gracin and A. C. Rasmuson, 0.8578 0.1422 benzeneacetic acid (Ibuprofen); J. Chem. Eng. Data 47, 1379 a x2: mole fraction of component 2 in the saturated solution. C13H18O2; [15687-27-1] (2002). b x1: mole fraction solubility of the solute. (2) Ethanol; C2H6O; [64-17-5] c Experimental value was reported in the paper as ln x1. Variables: Prepared by: Temperature W. E. Acree, Jr.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) α-Methyl-4-(2-methylpropyl)- 102G. L. Perlovich, S. V. Kurkov, Constant-temperature bath and an ultraviolet/visible spectrophotometer. benzeneacetic acid (Ibuprofen); A. N. Kinchin, and A. Bauer- Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with C13H18O2; [15687-27-1] Brandl, APPS Pharm. Sci. 6,3/1

shaking for ﬁve days at constant temperature. Aliquots of saturated solutions (2) Ethanol; C2H6O; [64-17-5] (2004). were removed and diluted with 96% ethanol (v/v). Concentrations were Variables: Prepared by: determined by spectrophotometric measurements at 289 nm. The reported T/K ¼ 298.15 W. E. Acree, Jr. solubility represents the average of at least three independent determinations.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Laboratories UPSA, Agen, France, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x a x b source not specified, no purification details were provided. 2 1 0.9167 0.0833 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. b Temperature: 0.2 K. x1: mole fraction solubility of the solute. x1: 2% (relative error).

Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: Constant-temperature bath and an UV/visible spectrophotometer. α 103 (1) -Methyl-4-(2-methylpropyl)- D. M. Stovall, C. Givens, S. Very few experimental details were provided. Excess solute and solvent were benzeneacetic acid (Ibuprofen); Keown, K. R. Hoover, E. allowed to equilibrate at constant temperature. Solubility of the dissolved [ ] C13H18O2; 15687-27-1 Rodriguez, W. E. Acree, Jr., and solute was determined by spectrophotometric measurements. M. H. Abraham, Phys. Chem. Liq. (2) Ethanol; C2H6O; [64-17-5] 43, 261 (2005). Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no T/K ¼ 298.15 W. E. Acree, Jr. puriﬁcation details were provided. (2) 99.6%, Arcus AB, Oslo, Norway, no puriﬁcation details were provided.

Experimental Values Estimated Error: Temperature: 0.1 K.

x1: 2.5% (relative error). a b x2 x1 0.9161 0.08392 ax : mole fraction of component 2 in the saturated solution. 2 Components: Original Measurements: bx : mole fraction solubility of the solute. 1 (1) α-Methyl-4-(2-methylpropyl)- 97S. Wang, Z. Song, J. Wang, Y. benzeneacetic acid (Ibuprofen); Dong, and M. Wu, J. Chem. Eng. C H O ; [15687-27-1] Data 55, 5283 (2010). Auxiliary Information 13 18 2 (2) Ethanol; C2H6O; [64-17-5] Method/Apparatus/Procedure: Variables: Prepared by: Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ Temperature W. E. Acree, Jr. visible spectrophotometer. Excess solute and solvent were placed in amber glass bottles and allowed to equilibrate for several days at constant temperature. Attainment of equilibrium Experimental Values was verified by several repetitive measurements and by approaching equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse filter into tared volumetric flasks, weighed, and T/K x a x b diluted with methanol. Concentrations were determined by 2 1 spectrophotometric measurements at 264 nm. 285.05 0.8768 0.1232 288.65 0.8555 0.1445 Source and Purity of Chemicals: 293.33 0.8331 0.1669 (1) 98+%, Sigma-Aldrich, St. Louis, Missouri, USA, was dried for several 298.47 0.8021 0.1979 hours at 333 K before use. The purity of the commercial sample was 99.7% as 303.39 0.7681 0.2319 determined by nonaqueous titration with freshly standardized sodium 307.87 0.7302 0.2698 methoxide to the thymol blue endpoint according to the method of [J. S. Fritz 312.93 0.6842 0.3158 and N. M. Lisicki, Anal. Chem. 23, 589 (1951)], except that methylbenzene 317.95 0.6343 0.3657 a was substituted for benzene in the titration solvent. x2: mole fraction of component 2 in the saturated solution. b (2) Absolute, Aaper Alcohol and Chemical Company, Milwaukee, Wisconsin, x1: mole fraction solubility of the solute. USA, stored over molecular sieves and distilled shortly before use.

Estimated Error: Temperature: 0.1 K.

x1: 2.0% (relative error).

Auxiliary Information Estimated Error: Temperature: 0.1 K. Method/Apparatus/Procedure: x1: 2% (relative error, estimated by compiler). Equilibrium jacketed glass vessel, thermostated circulating water bath, electromagnetic stirrer, analytical balance, laser monitoring system. Experimental solubilities were determined by a synthetic method. Preweighed amounts of solute and solvent and were placed in an equilibrium vessel, which was connected to a circulating constant-temperature water bath. The solution Components: Original Measurements: α 107 í was stirred and small amounts of solute were incrementally added until no (1) -Methyl-4-(2-methylpropyl)- J. Manrique and F. Mart nez, further solid dissolved. The dissolution of the solid was determined using laser benzeneacetic acid (Ibuprofen); Braz. Latin Am. Acta Farm. [ ] monitoring. The total amount of solute dissolved was recorded. Experimental C13H18O2; 15687-27-1 Bonaerense 26, 344 (2007). [ ] measurement was repeated three times. (2) Ethanol; C2H6O; 64-17-5 Variables: Prepared by: Source and Purity of Chemicals: Temperature W. E. Acree, Jr. (1) 99.4%, JiangXi GuoXing Fine Chemical Industry, Co., Ltd., recrystallized twice from ethanol before use. (2) 99.7+%, Analytical Reagent grade, Beijing Chemical Reagent Company, Experimental Values China, no puriﬁcation information was given in the paper.

Estimated Error: a b T/K x2 x1 Temperature: 0.1 K. 293.15 0.7955 0.2045 x : 2% (relative error). 1 298.15 0.7590 0.2410 303.15 0.7160 0.2840 308.15 0.6602 0.3398 313.15 0.6329 0.3671 Components: Original Measurements: ax : mole fraction of component 2 in the saturated solution. (1) α-Methyl-4-(2-methylpropyl)- 91U. Domanska, A. Pobudkowska, 2 bx : mole fraction solubility of the solute. benzeneacetic acid (Ibuprofen); A. Pelczarska, and P. Gierycz, J. 1

C13H18O2; [15687-27-1] Phys. Chem. B 113, 8941 (2009). (2) Ethanol; C H O; [64-17-5] 2 6 Auxiliary Information Variables: Prepared by: Method/Apparatus/Procedure: Temperature W. E. Acree, Jr. Constant-temperature water bath and an UV/visible spectrophotometer. Excess solute and solvent were placed in stoppered glass flasks and allowed to equilibrate in a constant-temperature water bath at 313.15 K for at least five Experimental Values days. Once equilibrium had been attained, an aliquot of the saturated solution was removed and filtered in order to remove insoluble particles. The concentration of the dissolved drug was determined by spectrophotometric T/K x a x b 2 1 analysis. Once the solubility was determined at 313.15 K, the temperature was 297.7 0.8207 0.1793 decreased by 5 K and stabilized at 308.15 K for two days to allow the excess 301.2 0.8046 0.1954 dissolved drug to precipitate at this lower temperature. An aliquot of the new 305.2 0.7864 0.2136 saturated solution was removed, filtered, and the solvent evaporated as before. 308.2 0.7587 0.2413 The procedure was repeated by decreasing the temperature in 5 K increments 311.1 0.7306 0.2694 to reach 293.15 K. The reported mole fraction solubilities represent the average 314.2 0.7016 0.2984 of three experimental measurements. 318.2 0.6636 0.3364 321.6 0.6239 0.3761 Source and Purity of Chemicals: 324.7 0.5959 0.4041 (1) Purity not given, USP, no purification details were provided in the paper. 327.9 0.5432 0.4568 (2) Absolute, Analytical Reagent grade, Merck Chemical Company, no 330.3 0.5077 0.4923 purification details were given in the paper. a x2: mole fraction of component 2 in the saturated solution. b Estimated Error: x1: mole fraction solubility of the solute. Temperature: 0.1 K (estimated by compiler).

x1: 1.0% (relative error). Auxiliary Information Method/Apparatus/Procedure: Thermostated water bath and an analytical balance. Solubility was measured using a dynamic synthetic method. Known amounts Components: Original Measurements: α 104 of solute and solvent were placed in Pyrex glass containers and allowed to (1) -Methyl-4-(2-methylpropyl)- I. Khalifeh, Ph.D. dissertation, equilibrate in a thermostated water bath. The temperature of the bath was benzeneacetic acid (Ibuprofen); Purdue University, 2000. [ ] slowly increased and the temperature at which the last crystal disappeared was C13H18O2; 15687-27-1 [ ] recorded as the solid-liquid equilibrium temperature. (2) Ethanol; C2H6O; 64-17-5 Variables: Prepared by: Source and Purity of Chemicals: Temperature W. E. Acree, Jr. (1) 98+%, Sigma-Aldrich Chemical Company, USA, was used as received. (2) 99.8+%, Sigma-Aldrich Chemical Company, USA, stored over freshly activated molecular sieves before use.

Experimental Values Source and Purity of Chemicals: (1) Purity not given, Sobhan Pharmaceutical Company, Iran, no purification details were provided. a (2) 99.5%, Merck Chemical Company, Germany, no purification details were T/K s1 provided. 288.15 0.8881 290.65 0.9466 Estimated Error: 293.15 1.0219 Temperature: 0.2 K. 295.65 1.0953 c : 3.4% (relative error). 298.15 1.1327 1 a s1: solubility of the solute expressed as grams of dissolved solute per gram. The author did not specify whether it was per gram of solvent or per gram of solution, but it is probably per gram of solvent. Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 106R. M. Watkinson, C. Herkenne, benzeneacetic acid (Ibuprofen); R. H. Guy, J. Hadgraft, G. Auxiliary Information C13H18O2; [15687-27-1] Oliveira, and M. E. Lane, Skin / / Pharmacol. Physiol. 22,15 Method Apparatus Procedure: (2) Ethanol; C2H6O; [64-17-5] Constant-temperature water bath, high-precision thermometer, and an UV/ (2009). visible spectrophotometer. Variables: Prepared by: Excess solute and solvent were allowed to equilibrate with stirring in a T/K ¼ 305.15 W. E. Acree, Jr. constant-temperature water bath for 24 h. An aliquot of the saturated solution was removed, filtered through a 0.10 μm membrane filter, and then diluted for spectrophotometric analysis at 264 nm. Experimental Values

Source and Purity of Chemicals: The measured solubility was reported to be c1 ¼ 2.424 mol (1) Purity not given, Pharmacia Upjohn, Kalamazoo, Michigan, USA, was dm 3. used as received. (2) 200 Proof, Pharmaco Products, Brookﬁeld, Connecticut, USA, was used as Auxiliary Information received. Method/Apparatus/Procedure: Estimated Error: Constant-temperature water bath, magnetic stirrer, centrifuge, high- Temperature: 0.1 K. performance liquid chromatograph, and an UV/visible spectrophotometer. s1: 2.0% (relative error, estimated by compiler). Excess solute and solvent were placed in sealed containers and allowed to equilibrate with continuous stirring in a constant-temperature water bath for 48 h. The sample was then centrifuged for 15 min, and an aliquot of the clear supernatant was removed and diluted. The concentration of the dissolved Components: Original Measurements: solute was determined either by high-performance liquid chromatographic or (1) α-Methyl-4-(2-methylpropyl)- 108A. Jouyban, S. Soltanpour, and spectrophotometric analysis. The reported value represents the average of benzeneacetic acid (Ibuprofen); W. E. Acree, Jr., J. Chem. Eng. three experimental measurements.

C13H18O2; [15687-27-1] Data 55, 5252 (2010). 109 Source and Purity of Chemicals: (2) Ethanol; C2H6O; [64-17-5] S. Soltanpour and A. Jouyban, Chem. Pharm. Bull. 58, 219 (1) Purity not given, Wyeth Consumer Health Care, United Kingdom, no (2010). puriﬁcation details were provided in the paper. (2) Purity not given, Reagent grade, VWR, United Kingdom, no puriﬁcation Variables: Prepared by: details were provided in the paper. T/K ¼ 298.15 W. E. Acree, Jr. Estimated Error: Temperature: 0.2 K (estimated by compiler). Experimental Values c1: 1% (relative error). The measured solubility was reported to be c1 ¼ 2.2882 mol dm3.

Auxiliary Information Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 102G. L. Perlovich, S. V. Kurkov, Method/Apparatus/Procedure: benzeneacetic acid (Ibuprofen); A. N. Kinchin, and A. Bauer-

Shaker, incubator equipped with a constant temperature controlling system C13H18O2; [15687-27-1] Brandl, APPS Pharm. Sci. 6,3/1 and an ultraviolet/visible spectrophotometer. (2) 1-Propanol; C3H8O; [71-23-8] (2004). Excess solute and solvent were placed in sealed containers and equilibrated using a shaker placed in an incubator equipped with a constant temperature Variables: Prepared by: controlling system for at least 98 h. Aliquots of saturated solutions were T/K ¼ 298.15 W. E. Acree, Jr. removed and diluted quantitatively with methanol for spectroscopic analyses. Concentration of the dissolved solute was determined from the measured absorbance at 222 nm. The reported solubility represents the average of at least three independent determinations.

Experimental Values Source and Purity of Chemicals: (1) 98+%, Sigma-Aldrich, St. Louis, Missouri, USA, was dried for several hours at 333 K before use. The purity of the commercial sample was 99.7% as a b determined by nonaqueous titration with freshly standardized sodium x2 x1 methoxide to the thymol blue endpoint according to the method of [J. S. Fritz 0.858 0.142 and N. M. Lisicki, Anal. Chem. 23, 589 (1951)], except that methylbenzene a x2: mole fraction of component 2 in the saturated solution. was substituted for benzene in the titration solvent. b x1: mole fraction solubility of the solute. (2) 99+%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use.

Auxiliary Information Estimated Error: Temperature: 0.1 K. Method/Apparatus/Procedure: x : 2.0% (relative error). Constant-temperature bath and an UV/visible spectrophotometer. 1 Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate at constant temperature. Solubility of the dissolved solute was determined by spectrophotometric measurements. Components: Original Measurements: Source and Purity of Chemicals: (1) α-Methyl-4-(2-methylpropyl)- 97S. Wang, Z. Song, J. Wang, Y. (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no benzeneacetic acid (Ibuprofen); Dong, and M. Wu, J. Chem. Eng. puriﬁcation details were provided. C13H18O2; [15687-27-1] Data 55, 5283 (2010). (2) Purity not given, HPLC grade, Aldrich Chemical Company, Taufkirchen, (2) 1-Propanol; C3H8O; [71-23-8] Germany, no puriﬁcation details were provided. Variables: Prepared by: Temperature W. E. Acree, Jr. Estimated Error: Temperature: 0.1 K. x : 2.5% (relative error). 1 Experimental Values

a b T/K x2 x1 Components: Original Measurements: 284.17 0.8721 0.1279 α 103 (1) -Methyl-4-(2-methylpropyl)- D. M. Stovall, C. Givens, S. 288.63 0.8478 0.1522 benzeneacetic acid (Ibuprofen); Keown, K. R. Hoover, E. 293.35 0.8226 0.1774 [ ] C13H18O2; 15687-27-1 Rodriguez, W. E. Acree, Jr., and 298.25 0.7888 0.2112 [ ] (2) 1-Propanol; C3H8O; 71-23-8 M. H. Abraham, Phys. Chem. Liq. 303.41 0.7516 0.2484 43, 261 (2005). 307.89 0.7113 0.2887 Variables: Prepared by: 313.01 0.6614 0.3386 T/K ¼ 298.15 W. E. Acree, Jr. 318.27 0.6008 0.3992 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Experimental Values

Auxiliary Information a b x2 x1 Method/Apparatus/Procedure: 0.8583 0.1417 Equilibrium jacketed glass vessel, thermostated circulating water bath, a x2: mole fraction of component 2 in the saturated solution. electromagnetic stirrer, analytical balance, laser monitoring system. b x1: mole fraction solubility of the solute. Experimental solubilities were determined by a synthetic method. Preweighed amounts of solute and solvent and were placed in an equilibrium vessel, which was connected to a circulating constant-temperature water bath. The solution Auxiliary Information was stirred and small amounts of solute were incrementally added until no further solid dissolved. The dissolution of the solid was determined using laser Method/Apparatus/Procedure: monitoring. The total amount of solute dissolved was recorded. Experimental Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ measurement was repeated three times. visible spectrophotometer. Excess solute and solvent were placed in amber glass bottles and allowed to Source and Purity of Chemicals: equilibrate for several days at constant temperature. Attainment of equilibrium (1) 99.4%, JiangXi GuoXing Fine Chemical Industry, Co., Ltd., recrystallized was verified by several repetitive measurements and by approaching twice from ethanol before use. equilibrium from supersaturation. Aliquots of saturated solutions were (2) 99.7+%, Analytical Reagent grade, Beijing Chemical Reagent Company, transferred through a coarse filter into tared volumetric flasks, weighed, and China, no purification information was given in the paper. diluted with methanol. Concentrations were determined by spectrophotometric measurements at 264 nm. Estimated Error: Temperature: 0.1 K.

x1: 2% (relative error).

Source and Purity of Chemicals: Components: Original Measurements: (1) 99%, Sigma-Aldrich Chemical Company, was used as received. α 104 (1) -Methyl-4-(2-methylpropyl)- I. Khalifeh, Ph.D. dissertation, (2) Purity not given, Spectroscopic grade, from either Merck Chemical benzeneacetic acid (Ibuprofen); Purdue University, 2000. Company or Sigma-Aldrich Chemical Company, was used as received. C13H18O2; [15687-27-1] [ ] (2) 1-Propanol; C3H8O; 71-23-8 Estimated Error: Variables: Prepared by: Temperature: 1 K (estimated by compiler). % Temperature W. E. Acree, Jr. c1: 3 (relative error, estimated by compiler).

Experimental Values Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 95M. A. Filippa and E. I. Gasull, a benzeneacetic acid (Ibuprofen); Fluid Phase Equilib. 354, 185 T/K s1 C13H18O2; [15687-27-1] (2013). 288.15 0.7009 (2) 2-Propanol; C3H8O; [67-63-0] 290.65 0.7786 293.15 0.8372 Variables: Prepared by: 295.65 0.8742 T/K ¼ 300.15 W. E. Acree, Jr. 298.15 0.9322 as : solubility of the solute expressed as grams of dissolved solute per gram. 1 Experimental Values The author did not specify whether it was per gram of solvent or per gram of solution, but it is probably per gram of solvent. The measured solubility was reported to be c1 ¼ 2.099 mol dm3.

Auxiliary Information Auxiliary Information Method/Apparatus/Procedure: Method/Apparatus/Procedure: Constant-temperature water bath, high-precision thermometer, and an UV/ An UV/visible spectrophotometer. visible spectrophotometer. Very few experimental details were given in the paper. Excess solute and Excess solute and solvent were allowed to equilibrate with stirring in a solvent were placed in closed containers and allowed to equilibrate with constant-temperature water bath for 24 h. An aliquot of the saturated solution continuous agitation at constant temperature for 48 h. Aliquots of saturated was removed, ﬁltered through a 0.10 μm membrane ﬁlter, and then diluted for solutions were removed and diluted quantitatively for spectroscopic analysis at spectrophotometric analysis at 264 nm. 220 nm.

Source and Purity of Chemicals: Source and Purity of Chemicals: (1) Purity not given, Pharmacia Upjohn, Kalamazoo, Michigan, USA, was (1) 99%, Sigma-Aldrich Chemical Company, was used as received. used as received. (2) Purity not given, Spectroscopic grade, from either Merck Chemical (2) Purity not given, HPLC grade, Mallinckrodt, St. Louis, Missouri, USA, was Company or Sigma-Aldrich Chemical Company, was used as received. used as received. Estimated Error: Estimated Error: Temperature: 1 K (estimated by compiler). Temperature: 0.1 K. c1: 3% (relative error, estimated by compiler). s1: 2.0% (relative error, estimated by compiler).

Components: Original Measurements: Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 96S. Gracin and A. C. Rasmuson, (1) α-Methyl-4-(2-methylpropyl)- 95M. A. Filippa and E. I. Gasull, benzeneacetic acid (Ibuprofen); J. Chem. Eng. Data 47, 1379

benzeneacetic acid (Ibuprofen); Fluid Phase Equilib. 354, 185 C13H18O2; [15687-27-1] (2002). [ ] C13H18O2; 15687-27-1 (2013). (2) 2-Propanol; C3H8O; [67-63-0] (2) 1-Propanol; C H O; [71-23-8] 3 8 Variables: Prepared by: Variables: Prepared by: Temperature W. E. Acree, Jr. T/K ¼ 300.15 W. E. Acree, Jr.

Experimental Values Experimental Values The measured solubility was reported to be c ¼ 2.028 1 T/K x a x b mol dm3. 2 1 283.15 0.8717 0.1283 288.15 0.8390 0.1610 Auxiliary Information 293.15 0.8122 0.1878 Method/Apparatus/Procedure: 303.15 0.7258 0.2742 An UV/visible spectrophotometer. 308.15 0.6903 0.3097 a Very few experimental details were given in the paper. Excess solute and x2: mole fraction of component 2 in the saturated solution. b solvent were placed in closed containers and allowed to equilibrate with x1: mole fraction solubility of the solute. The solubility was reported in the continuous agitation at constant temperature for 48 h. Aliquots of saturated paper as the grams of solute that dissolved per kilogram of solvent. Mole solutions were removed and diluted quantitatively for spectroscopic analysis at fraction solubility calculated by the compiler. 220 nm.

Auxiliary Information Estimated Error: Temperature: 0.1 K. Method/Apparatus/Procedure: s1: 2.0% (relative error, estimated by compiler). Thermostated water bath, analytical balance, magnetic stirrer, and vacuum drying oven. Solubility was determined by the gravimetric method. Excess solute and solvent were placed in Erlenmeyer ﬂasks and allowed to equilibrate for 72 h in a thermostatic water bath sitting on a multiple position magnetic stirrer. The Components: Original Measurements: 103 solutions were stirred during the equilibration period. The stirring was then (1) α-Methyl-4-(2-methylpropyl)- D. M. Stovall, C. Givens, S. stopped for 4 h to allow the suspended solid to settle to the bottom of the ﬂask. benzeneacetic acid (Ibuprofen); Keown, K. R. Hoover, E. [ ] A sample of the clear saturated solution was transferred with a heated syringe C13H18O2; 15687-27-1 Rodriguez, W. E. Acree, Jr., and M. H. Abraham, Phys. Chem. Liq. into a previously weighed sample vial. The vial containing the saturated (2) 2-Propanol; C3H8O; [67-63-0] solution was then weighed, and the solvent was allowed to evaporate in a 43, 261 (2005). vacuum oven at 293 K for approximately one week until a constant weight was Variables: Prepared by: obtained. The solubility was calculated from the mass of the solid residue and T/K ¼ 298.15 W. E. Acree, Jr. mass of the saturated solution analyzed.

Source and Purity of Chemicals: Experimental Values (1) 99.4%, AstraZeneca AB, no puriﬁcation details were given in the paper. (2) Purity not given, Pro Analyse grade, Merck Chemical Company, Germany, no puriﬁcation details were given in the paper. a b x2 x1 0.7666 0.2334 Estimated Error: a Temperature: 0.1 K. x2: mole fraction of component 2 in the saturated solution. b x1: 2% (relative error). x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) α-Methyl-4-(2-methylpropyl)- 104I. Khalifeh, Ph.D. dissertation, Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ benzeneacetic acid (Ibuprofen); Purdue University, 2000. visible spectrophotometer. C13H18O2; [15687-27-1] Excess solute and solvent were placed in amber glass bottles and allowed to (2) 2-Propanol; C3H8O; [67-63-0] equilibrate for several days at constant temperature. Attainment of equilibrium was verified by several repetitive measurements and by approaching Variables: Prepared by: equilibrium from supersaturation. Aliquots of saturated solutions were Temperature W. E. Acree, Jr. transferred through a coarse filter into tared volumetric flasks, weighed, and diluted with methanol. Concentrations were determined by spectrophotometric measurements at 264 nm. Experimental Values Source and Purity of Chemicals: (1) 98+%, Sigma-Aldrich, St. Louis, Missouri, USA, was dried for several T/K s a 1 hours at 333 K before use. The purity of the commercial sample was 99.7% as 288.15 0.8099 determined by nonaqueous titration with freshly standardized sodium 290.65 0.8630 methoxide to the thymol blue endpoint according to the method of [J. S. Fritz 293.15 0.8764 and N. M. Lisicki, Anal. Chem. 23, 589 (1951)], except that methylbenzene 295.65 0.9445 was substituted for benzene in the titration solvent. 298.15 1.0062 (2) 99+%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, a s1: solubility of the solute expressed as grams of dissolved solute per gram. USA, stored over molecular sieves and distilled shortly before use. The author did not specify whether it was per gram of solvent or per gram of solution, but it is probably per gram of solvent. Estimated Error: Temperature: 0.1 K. x : 2.0% (relative error). Auxiliary Information 1 Method/Apparatus/Procedure: Constant-temperature water bath, high-precision thermometer, and an UV/ visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were allowed to equilibrate with stirring in a (1) α-Methyl-4-(2-methylpropyl)- 97S. Wang, Z. Song, J. Wang, Y. constant-temperature water bath for 24 h. An aliquot of the saturated solution benzeneacetic acid (Ibuprofen); Dong, and M. Wu, J. Chem. Eng. was removed, filtered through a 0.10 μm membrane filter, and then diluted for C13H18O2; [15687-27-1] Data 55, 5283 (2010). spectrophotometric analysis at 264 nm. (2) 2-Propanol; C3H8O; [67-63-0] Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Pharmacia Upjohn, Kalamazoo, Michigan, USA, was Temperature W. E. Acree, Jr. used as received. (2) Purity not given, HPLC grade, Mallinckrodt, St. Louis, Missouri, USA, was used as received.

Experimental Values Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. a b (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, T/K x2 x1 Germany, no puriﬁcation details were provided. 282.97 0.8727 0.1273 288.07 0.8472 0.1528 Estimated Error: 293.43 0.8124 0.1876 Temperature: 0.1 K. 298.21 0.7781 0.2219 x : 2.5% (relative error). 303.57 0.7355 0.2645 1 307.57 0.6949 0.3051 312.75 0.6495 0.3505 318.17 0.5949 0.4051 Components: Original Measurements: ax : mole fraction of component 2 in the saturated solution. 2 (1) α-Methyl-4-(2-methylpropyl)- 97S. Wang, Z. Song, J. Wang, Y. bx : mole fraction solubility of the solute. 1 benzeneacetic acid (Ibuprofen); Dong, and M. Wu, J. Chem. Eng.

C13H18O2; [15687-27-1] Data 55, 5283 (2010). (2) 1-Butanol; C H O; [71-36-3] Auxiliary Information 4 10 Variables: Prepared by: Method/Apparatus/Procedure: Temperature W. E. Acree, Jr. Equilibrium jacketed glass vessel, thermostated circulating water bath, electromagnetic stirrer, analytical balance, laser monitoring system. Experimental solubilities were determined by a synthetic method. Preweighed Experimental Values amounts of solute and solvent and were placed in an equilibrium vessel, which was connected to a circulating constant-temperature water bath. The solution was stirred and small amounts of solute were incrementally added until no T/K x a x b further solid dissolved. The dissolution of the solid was determined using laser 2 1 monitoring. The total amount of solute dissolved was recorded. Experimental 283.97 0.8606 0.1394 measurement was repeated three times. 288.25 0.8438 0.1562 293.77 0.8088 0.1912 Source and Purity of Chemicals: 298.73 0.7749 0.2251 (1) 99.4%, JiangXi GuoXing Fine Chemical Industry, Co., Ltd., recrystallized 303.43 0.7348 0.2652 twice from ethanol before use. 308.67 0.6886 0.3114 (2) 99.7+%, Analytical Reagent grade, Beijing Chemical Reagent Company, 313.47 0.6393 0.3607 China, no puriﬁcation information was given in the paper. 318.23 0.5845 0.4155 a x2: mole fraction of component 2 in the saturated solution. b Estimated Error: x1: mole fraction solubility of the solute. Temperature: 0.1 K.

x1: 2% (relative error). Auxiliary Information Method/Apparatus/Procedure: Equilibrium jacketed glass vessel, thermostated circulating water bath, Components: Original Measurements: electromagnetic stirrer, analytical balance, laser monitoring system. 102 (1) α-Methyl-4-(2-methylpropyl)- G. L. Perlovich, S. V. Kurkov, Experimental solubilities were determined by a synthetic method. Preweighed benzeneacetic acid (Ibuprofen); A. N. Kinchin, and A. Bauer- amounts of solute and solvent and were placed in an equilibrium vessel, which [ ] / C13H18O2; 15687-27-1 Brandl, APPS Pharm. Sci. 6,31 was connected to a circulating constant-temperature water bath. The solution [ ] (2) 1-Butanol; C4H10O; 71-36-3 (2004). was stirred and small amounts of solute were incrementally added until no further solid dissolved. The dissolution of the solid was determined using laser Variables: Prepared by: monitoring. The total amount of solute dissolved was recorded. Experimental T/K ¼ 298.15 W. E. Acree, Jr. measurement was repeated three times.

Experimental Values Source and Purity of Chemicals: (1) 99.4%, JiangXi GuoXing Fine Chemical Industry, Co., Ltd., recrystallized twice from ethanol before use. +% x a x b (2) 99.7 , Analytical Reagent grade, Beijing Chemical Reagent Company, 2 1 China, no puriﬁcation information was given in the paper. 0.838 0.162 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 0.1 K. x1: 2% (relative error).

Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate at constant temperature. Solubility of the dissolved solute was determined by spectrophotometric measurements.

Source and Purity of Chemicals: Components: Original Measurements: (1) 98+%, Sigma-Aldrich, St. Louis, Missouri, USA, was dried for several α 95 (1) -Methyl-4-(2-methylpropyl)- M. A. Filippa and E. I. Gasull, hours at 333 K before use. The purity of the commercial sample was 99.7% as benzeneacetic acid (Ibuprofen); Fluid Phase Equilib. 354, 185 determined by nonaqueous titration with freshly standardized sodium [ ] C13H18O2; 15687-27-1 (2013). methoxide to the thymol blue endpoint according to the method of [J. S. Fritz [ ] (2) 1-Butanol; C4H10O; 71-36-3 and N. M. Lisicki, Anal. Chem. 23, 589 (1951)], except that methylbenzene Variables: Prepared by: was substituted for benzene in the titration solvent. T/K ¼ 300.15 W. E. Acree, Jr. (2) 99+%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use.

Experimental Values Estimated Error: Temperature: 0.1 K. The measured solubility was reported to be c1 ¼ 1.365 x1: 2.0% (relative error). mol dm3.

Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: α 103 An UV/visible spectrophotometer. (1) -Methyl-4-(2-methylpropyl)- D. M. Stovall, C. Givens, S. Very few experimental details were given in the paper. Excess solute and benzeneacetic acid (Ibuprofen); Keown, K. R. Hoover, E. [ ] solvent were placed in closed containers and allowed to equilibrate with C13H18O2; 15687-27-1 Rodriguez, W. E. Acree, Jr., and M. H. Abraham, Phys. Chem. Liq. continuous agitation at constant temperature for 48 h. Aliquots of saturated (2) 2-Methyl-1-propanol; C4H10O; [ ] solutions were removed and diluted quantitatively for spectroscopic analysis at 78-83-1 43, 261 (2005). 220 nm. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) 99%, Sigma-Aldrich Chemical Company, was used as received. (2) Purity not given, Spectroscopic grade, from either Merck Chemical Experimental Values Company or Sigma-Aldrich Chemical Company, was used as received.

Estimated Error: a b x2 x1 Temperature: 1 K (estimated by compiler). 0.7989 0.2011 c1: 3% (relative error, estimated by compiler). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: Auxiliary Information (1) α-Methyl-4-(2-methylpropyl)- 103D. M. Stovall, C. Givens, S. benzeneacetic acid (Ibuprofen); Keown, K. R. Hoover, E. Method/Apparatus/Procedure: / C13H18O2; [15687-27-1] Rodriguez, W. E. Acree, Jr., and Constant-temperature bath, calorimetric thermometer, and an ultraviolet

(2) 2-Butanol; C4H10O; [78-92-2] M. H. Abraham, Phys. Chem. Liq. visible spectrophotometer. 43, 261 (2005). Excess solute and solvent were placed in amber glass bottles and allowed to equilibrate for several days at constant temperature. Attainment of equilibrium Variables: Prepared by: was verified by several repetitive measurements and by approaching T/K ¼ 298.15 W. E. Acree, Jr. equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse filter into tared volumetric flasks, weighed, and diluted with methanol. Concentrations were determined by Experimental Values spectrophotometric measurements at 264 nm.

Source and Purity of Chemicals: x a x b 2 1 (1) 98+%, Sigma-Aldrich, St. Louis, Missouri, USA, was dried for several 0.7960 0.2040 hours at 333 K before use. The purity of the commercial sample was 99.7% as a x2: mole fraction of component 2 in the saturated solution. determined by nonaqueous titration with freshly standardized sodium b [ x1: mole fraction solubility of the solute. methoxide to the thymol blue endpoint according to the method of J. S. Fritz and N. M. Lisicki, Anal. Chem. 23, 589 (1951)], except that methylbenzene was substituted for benzene in the titration solvent. Auxiliary Information (2) 99+%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use. Method/Apparatus/Procedure: / Constant-temperature bath, calorimetric thermometer, and an ultraviolet Estimated Error: visible spectrophotometer. Temperature: 0.1 K. Excess solute and solvent were placed in amber glass bottles and allowed to x1: 2.0% (relative error). equilibrate for several days at constant temperature. Attainment of equilibrium was verified by several repetitive measurements and by approaching equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse filter into tared volumetric flasks, weighed, and diluted with methanol. Concentrations were determined by spectrophotometric measurements at 264 nm.

Auxiliary Information Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 97S. Wang, Z. Song, J. Wang, Y. Method/Apparatus/Procedure: benzeneacetic acid (Ibuprofen); Dong, and M. Wu, J. Chem. Eng. An UV/visible spectrophotometer. C13H18O2; [15687-27-1] Data 55, 5283 (2010). Very few experimental details were given in the paper. Excess solute and (2) 2-Methyl-1-propanol; C4H10O; solvent were placed in closed containers and allowed to equilibrate with [78-83-1] continuous agitation at constant temperature for 48 h. Aliquots of saturated solutions were removed and diluted quantitatively for spectroscopic analysis at Variables: Prepared by: 220 nm. Temperature W. E. Acree, Jr. Source and Purity of Chemicals: % Experimental Values (1) 99 , Sigma-Aldrich Chemical Company, was used as received. (2) Purity not given, ACS grade, Sintorgan, was used as received.

Estimated Error: T/K x a x b 2 1 Temperature: 1 K (estimated by compiler). 282.89 0.8925 0.1075 c1: 3% (relative error, estimated by compiler). 288.09 0.8657 0.1343 293.07 0.8340 0.1660 298.07 0.7978 0.2022 303.23 0.7590 0.2410 308.17 0.7082 0.2918 Components: Original Measurements: α 93 ñ 313.55 0.6517 0.3483 (1) -Methyl-4-(2-methylpropyl)- P. Bustamante, M. A. Pe a, and 317.85 0.5973 0.4027 benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 C H O ; [15687-27-1] (2000). a 13 18 2 x2: mole fraction of component 2 in the saturated solution. (2) 1-Pentanol; C H O; [71-41-0] b 5 12 x1: mole fraction solubility of the solute. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Auxiliary Information / / Method Apparatus Procedure: Experimental Values Equilibrium jacketed glass vessel, thermostated circulating water bath, electromagnetic stirrer, analytical balance, laser monitoring system. Experimental solubilities were determined by a synthetic method. Preweighed a b,c x2 x1 amounts of solute and solvent and were placed in an equilibrium vessel, which was connected to a circulating constant-temperature water bath. The solution 0.7864 0.2136 a was stirred and small amounts of solute were incrementally added until no x2: mole fraction of component 2 in the saturated solution. b further solid dissolved. The dissolution of the solid was determined using laser x1: mole fraction solubility of the solute. c monitoring. The total amount of solute dissolved was recorded. Experimental Experimental value was reported in the paper as ln x1. measurement was repeated three times.

Source and Purity of Chemicals: Auxiliary Information (1) 99.4%, JiangXi GuoXing Fine Chemical Industry, Co., Ltd., recrystallized Method/Apparatus/Procedure: twice from ethanol before use. Constant-temperature bath and an ultraviolet/visible spectrophotometer. (2) 99.7+%, Analytical Reagent grade, Beijing Chemical Reagent Company, Excess solute and solvent were placed in flasks and allowed to equilibrate with China, no purification information was given in the paper. shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Estimated Error: determined by spectrophotometric measurements at 289 nm. The reported Temperature: 0.1 K. solubility represents the average of at least three independent determinations. x1: 2% (relative error). Source and Purity of Chemicals: (1) Purity not given, Laboratories UPSA, Agen, France, no purification details were provided. Components: Original Measurements: (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical (1) α-Methyl-4-(2-methylpropyl)- 95M. A. Filippa and E. I. Gasull, source not specified, no purification details were provided. benzeneacetic acid (Ibuprofen); Fluid Phase Equilib. 354, 185

C13H18O2; [15687-27-1] (2013). Estimated Error: (2) 2-Methyl-1-propanol; C4H10O; Temperature: 0.2 K. [ ] 78-83-1 x1: 2% (relative error). Variables: Prepared by: T/K ¼ 300.15 W. E. Acree, Jr.

Experimental Values

The measured solubility was reported to be c1 ¼ 1.297 mol dm3.

Auxiliary Information Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 103D. M. Stovall, C. Givens, S. Method/Apparatus/Procedure: benzeneacetic acid (Ibuprofen); Keown, K. R. Hoover, E. Constant-temperature bath and an UV/visible spectrophotometer. C13H18O2; [15687-27-1] Rodriguez, W. E. Acree, Jr., and Very few experimental details were provided. Excess solute and solvent were M. H. Abraham, Phys. Chem. Liq. (2) 1-Pentanol; C5H12O; [71-41-0] allowed to equilibrate at constant temperature. Solubility of the dissolved 43, 261 (2005). solute was determined by spectrophotometric measurements. Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 298.15 W. E. Acree, Jr. (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. Experimental Values (2) Purity not given, Analytical Reagent grade, Aldrich Chemical Company, Taufkirchen, Germany, no puriﬁcation details were provided.

Estimated Error: x a x b 2 1 Temperature: 0.1 K. 0.8167 0.1833 x1: 2.5% (relative error). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: Auxiliary Information (1) α-Methyl-4-(2-methylpropyl)- 97S. Wang, Z. Song, J. Wang, Y. Method/Apparatus/Procedure: benzeneacetic acid (Ibuprofen); Dong, and M. Wu, J. Chem. Eng. [ ] Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ C13H18O2; 15687-27-1 Data 55, 5283 (2010). [ ] visible spectrophotometer. (2) 1-Pentanol; C5H12O; 71-41-0 Excess solute and solvent were placed in amber glass bottles and allowed to Variables: Prepared by: equilibrate for several days at constant temperature. Attainment of equilibrium Temperature W. E. Acree, Jr. was verified by several repetitive measurements and by approaching equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse filter into tared volumetric flasks, weighed, and Experimental Values diluted with methanol. Concentrations were determined by spectrophotometric measurements at 264 nm. a b T/K x2 x1 Source and Purity of Chemicals: (1) 98+%, Sigma-Aldrich, St. Louis, Missouri, USA, was dried for several 283.15 0.8664 0.1336 288.05 0.8421 0.1579 hours at 333 K before use. The purity of the commercial sample was 99.7% as determined by nonaqueous titration with freshly standardized sodium 293.37 0.8098 0.1902 methoxide to the thymol blue endpoint according to the method of [J. S. Fritz 298.03 0.7781 0.2219 and N. M. Lisicki, Anal. Chem. 23, 589 (1951)], except that methylbenzene 303.13 0.7364 0.2636 307.91 0.6897 0.3103 was substituted for benzene in the titration solvent. (2) 99+%, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored 312.57 0.6422 0.3578 over molecular sieves and distilled shortly before use. 318.15 0.5783 0.4217 a x2: mole fraction of component 2 in the saturated solution. b Estimated Error: x1: mole fraction solubility of the solute. Temperature: 0.1 K.

x1: 2.0% (relative error). Auxiliary Information Method/Apparatus/Procedure: Equilibrium jacketed glass vessel, thermostated circulating water bath, Components: Original Measurements: electromagnetic stirrer, analytical balance, laser monitoring system. (1) α-Methyl-4-(2-methylpropyl)- 102G. L. Perlovich, S. V. Kurkov, Experimental solubilities were determined by a synthetic method. Preweighed benzeneacetic acid (Ibuprofen); A. N. Kinchin, and A. Bauer- amounts of solute and solvent and were placed in an equilibrium vessel, which C13H18O2; [15687-27-1] Brandl, APPS Pharm. Sci. 6,3/1 was connected to a circulating constant-temperature water bath. The solution

(2) 1-Pentanol; C5H12O; [71-41-0] (2004). was stirred and small amounts of solute were incrementally added until no further solid dissolved. The dissolution of the solid was determined using laser Variables: Prepared by: monitoring. The total amount of solute dissolved was recorded. Experimental T/K ¼ 298.15 W. E. Acree, Jr. measurement was repeated three times.

Source and Purity of Chemicals: Experimental Values (1) 99.4%, JiangXi GuoXing Fine Chemical Industry, Co., Ltd., recrystallized twice from ethanol before use. (2) 99.7+%, Analytical Reagent grade, Beijing Chemical Reagent Company, x a x b 2 1 China, no puriﬁcation information was given in the paper. 0.852 0.148 a Estimated Error: x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Temperature: 0.1 K. x1: 2% (relative error).

C13H18O2; [15687-27-1] Data 55, 5283 (2010). Very few experimental details were provided. Excess solute and solvent were (2) 3-Methyl-1-butanol; C5H12O; allowed to equilibrate at constant temperature. Solubility of the dissolved [123-51-3] solute was determined by spectrophotometric measurements. Variables: Prepared by: Source and Purity of Chemicals: Temperature W. E. Acree, Jr. (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, Aldrich Chemical Company, Experimental Values Taufkirchen, Germany, no puriﬁcation details were provided.

Estimated Error: T/K x a x b 2 1 Temperature: 0.1 K.

283.57 0.8794 0.1206 x1: 2.5% (relative error). 288.61 0.8520 0.1480 293.71 0.8179 0.1821 297.95 0.7887 0.2113 303.13 0.7473 0.2527 Components: Original Measurements: 308.17 0.7010 0.2990 (1) α-Methyl-4-(2-methylpropyl)- 102G. L. Perlovich, S. V. Kurkov, 313.31 0.6475 0.3525 benzeneacetic acid (Ibuprofen); A. N. Kinchin, and A. Bauer- 318.83 0.5831 0.4169 C13H18O2; [15687-27-1] Brandl, APPS Pharm. Sci. 6,3/1 a x2: mole fraction of component 2 in the saturated solution. (2) 1-Heptanol; C H O; [111-70-6] (2004). b 7 16 x1: mole fraction solubility of the solute. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Auxiliary Information Method/Apparatus/Procedure: Equilibrium jacketed glass vessel, thermostated circulating water bath, Experimental Values electromagnetic stirrer, analytical balance, laser monitoring system. Experimental solubilities were determined by a synthetic method. Preweighed a b amounts of solute and solvent and were placed in an equilibrium vessel, which x2 x1 was connected to a circulating constant-temperature water bath. The solution 0.774 0.226 was stirred and small amounts of solute were incrementally added until no ax : mole fraction of component 2 in the saturated solution. further solid dissolved. The dissolution of the solid was determined using laser 2 bx : mole fraction solubility of the solute. monitoring. The total amount of solute dissolved was recorded. Experimental 1 measurement was repeated three times. Auxiliary Information Source and Purity of Chemicals: (1) 99.4%, JiangXi GuoXing Fine Chemical Industry, Co., Ltd., recrystallized Method/Apparatus/Procedure: twice from ethanol before use. Constant-temperature bath and an UV/visible spectrophotometer. (2) 99.7+%, Analytical Reagent grade, Beijing Chemical Reagent Company, Very few experimental details were provided. Excess solute and solvent were China, no purification information was given in the paper. allowed to equilibrate at constant temperature. Solubility of the dissolved solute was determined by spectrophotometric measurements. Estimated Error: Temperature: 0.1 K. Source and Purity of Chemicals: x1: 2% (relative error). (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. (2) Purity not given, Analytical Reagent grade, Sigma Chemical Company, no purification details were provided. Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 102G. L. Perlovich, S. V. Kurkov, Estimated Error: benzeneacetic acid (Ibuprofen); A. N. Kinchin, and A. Bauer- Temperature: 0.1 K. x1: 2.5% (relative error). C13H18O2; [15687-27-1] Brandl, APPS Pharm. Sci. 6,3/1

(2) 1-Hexanol; C6H14O; [111-27-3] (2004). Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 Experimental Values C13H18O2; [15687-27-1] (2000). (2) 1-Octanol; C8H18O; [111-87-5]

a b x2 x1 Variables: Prepared by: / ¼ 0.779 0.221 T K 298.15 W. E. Acree, Jr. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Experimental Values Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 103D. M. Stovall, C. Givens, S.

a b,c benzeneacetic acid (Ibuprofen); Keown, K. R. Hoover, E. x2 x1 C13H18O2; [15687-27-1] Rodriguez, W. E. Acree, Jr., and

0.7798 0.2202 (2) 1-Octanol; C8H18O; [111-87-5] M. H. Abraham, Phys. Chem. Liq. a 43, 261 (2005). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Variables: Prepared by: c Experimental value was reported in the paper as ln x1. T/K ¼ 298.15 W. E. Acree, Jr.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. a b Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with x2 x1 shaking for ﬁve days at constant temperature. Aliquots of saturated solutions 0.8007 0.1993 were removed and diluted with 96% ethanol (v/v). Concentrations were a x2: mole fraction of component 2 in the saturated solution. determined by spectrophotometric measurements at 289 nm. The reported b x1: mole fraction solubility of the solute. solubility represents the average of at least three independent determinations.

Source and Purity of Chemicals: Auxiliary Information (1) Purity not given, Laboratories UPSA, Agen, France, no purification details were provided. Method/Apparatus/Procedure: (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ source not specified, no purification details were provided. visible spectrophotometer. Excess solute and solvent were placed in amber glass bottles and allowed to Estimated Error: equilibrate for several days at constant temperature. Attainment of equilibrium Temperature: 0.2 K. was verified by several repetitive measurements and by approaching

x1: 2% (relative error). equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse ﬁlter into tared volumetric ﬂasks, weighed, and diluted with methanol. Concentrations were determined by spectrophotometric measurements at 264 nm. Components: Original Measurements: Source and Purity of Chemicals: (1) α-Methyl-4-(2-methylpropyl)- 102G. L. Perlovich, S. V. Kurkov, (1) 98+%, Sigma-Aldrich, St. Louis, Missouri, USA, was dried for several benzeneacetic acid (Ibuprofen); A. N. Kinchin, and A. Bauer- hours at 333 K before use. The purity of the commercial sample was 99.7% as C H O ; [15687-27-1] Brandl, APPS Pharm. Sci. 6,3/1 13 18 2 determined by nonaqueous titration with freshly standardized sodium [ ] (2004). (2) 1-Octanol; C8H18O; 111-87-5 methoxide to the thymol blue endpoint according to the method of [J. S. Fritz Variables: Prepared by: and N. M. Lisicki, Anal. Chem. 23, 589 (1951)], except that methylbenzene T/K ¼ 298.15 W. E. Acree, Jr. was substituted for benzene in the titration solvent. (2) 99+%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use. Experimental Values Estimated Error: Temperature: 0.1 K. a b % x2 x1 x1: 2.0 (relative error). 0.802 0.198 a x2: mole fraction of component 2 in the saturated solution. bx : mole fraction solubility of the solute. 1 Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 60A. Fini, M. Laus, I. Orienti, and Auxiliary Information benzeneacetic acid (Ibuprofen); V. Zecchi, J. Pharm. Sci. 75,23 [ ] Method/Apparatus/Procedure: C13H18O2; 15687-27-1 (1986). [ ] Constant-temperature bath and an UV/visible spectrophotometer. (2) 1-Octanol; C8H18O; 111-87-5 Very few experimental details were provided. Excess solute and solvent were Variables: Prepared by: allowed to equilibrate at constant temperature. Solubility of the dissolved Temperature W. E. Acree, Jr. solute was determined by spectrophotometric measurements.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, Sigma Chemical Company, no a T/K c1 puriﬁcation details were provided. 278.2 0.059 298.2 0.091 Estimated Error: 310.2 0.122 Temperature: 0.1 K. a 3 x1: 2.5% (relative error). c1: molar solubility of the solute in units of mol dm .

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) α-Methyl-4-(2-methylpropyl)- 94L. C. Garzo´n and F. Martínez, J. Constant-temperature bath, analytical balance, and an UV/visible benzeneacetic acid (Ibuprofen); Solution Chem. 33, 1379 (2004). spectrophotometer. C13H18O2; [15687-27-1] Excess solute and solvent were placed in a sealed container and allowed to (2) 1-Octanol; C8H18O; [111-87-5] equilibrate with stirring at constant temperature. An aliquot of the saturated Variables: Prepared by: solution was removed, ﬁltered through a 0.22 μm pore membrane, and diluted Temperature W. E. Acree, Jr. quantitatively for spectroscopic analysis.

Source and Purity of Chemicals: (1) Purity not given, chemical source not specified, was recrystallized from Experimental Values suitable solvent before use. (2) Purity not given, chemical source not specified, no purification details were / a b provided in the paper. T K x2 x1 298.15 0.6570 0.3430 Estimated Error: 303.15 0.5576 0.4424 Temperature: 0.2 K (estimated by compiler). 308.15 0.4490 0.5510 % c1: 3 (relative error). 313.15 0.2985 0.7015 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: α 91 (1) -Methyl-4-(2-methylpropyl)- U. Domanska, A. Pobudkowska, Auxiliary Information benzeneacetic acid (Ibuprofen); A. Pelczarska, and P. Gierycz, J. Method/Apparatus/Procedure: C13H18O2; [15687-27-1] Phys. Chem. B 113, 8941 (2009). Mechanical shaker, constant-temperature water bath, and an UV/visible (2) 1-Octanol; C8H18O; [111-87-5] spectrophotometer. Variables: Prepared by: Excess solute and solvent were placed in a stoppered glass flask and stirred in a Temperature W. E. Acree, Jr. mechanical shaker for 1 h. The flasks were then transferred to a constant- temperature bath where the solution equilibrated for at least three days. An aliquot of the saturated solution was removed, isothermally filtered, and Experimental Values diluted quantitatively for spectrophotometric analysis. The reported values represent the average of at least three determinations. The densities of the saturated solutions were measured in order to convert the molar solubilities / a b T K x2 x1 given in mol dm 3 to mole fractions. 296.7 0.7938 0.2062 303.2 0.7491 0.2509 Source and Purity of Chemicals: 307.8 0.7103 0.2897 (1) Purity not given, UPS, Mallinckrodt, USA, no purification details were 311.1 0.6687 0.3313 given in the paper. 315.9 0.6359 0.3641 (2) Purity not given, Extra pure grade, Merck Chemical Company, Germany, 320.0 0.5915 0.4085 no purification details were given in the paper. 323.7 0.5532 0.4468 326.3 0.5095 0.4905 Estimated Error: 329.1 0.4675 0.5325 Temperature: 0.1 K.

332.4 0.4125 0.5875 x1: 3% (relative error). 334.4 0.3776 0.6224 336.9 0.3251 0.6749 338.7 0.2825 0.7175 a x2: mole fraction of component 2 in the saturated solution. Components: Original Measurements: b 95 x1: mole fraction solubility of the solute. (1) α-Methyl-4-(2-methylpropyl)- M. A. Filippa and E. I. Gasull, benzeneacetic acid (Ibuprofen); Fluid Phase Equilib. 354, 185 [ ] Auxiliary Information C13H18O2; 15687-27-1 (2013). (2) 1-Octanol; C8H18O; [111-87-5] Method/Apparatus/Procedure: Thermostated water bath and an analytical balance. Variables: Prepared by: / ¼ Solubility was measured using a dynamic synthetic method. Known amounts T K 300.15 W. E. Acree, Jr. of solute and solvent were placed in Pyrex glass containers and allowed to equilibrate in a thermostated water bath. The temperature of the bath was Experimental Values slowly increased and the temperature at which the last crystal disappeared was recorded as the solid-liquid equilibrium temperature. The measured solubility was reported to be c1 ¼ 1.054 3 Source and Purity of Chemicals: mol dm . (1) 98+%, Sigma-Aldrich Chemical Company, USA, was used as received. (2) 99.8+%, Sigma-Aldrich Chemical Company, USA, stored over freshly activated molecular sieves before use. Estimated Error: Temperature: 0.1 K.

x1: 2% (relative error, estimated by compiler).

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and An UV/visible spectrophotometer. benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 Very few experimental details were given in the paper. Excess solute and C13H18O2; [15687-27-1] (2000). solvent were placed in closed containers and allowed to equilibrate with (2) 1,2-Ethanediol; C2H6O2; continuous agitation at constant temperature for 48 h. Aliquots of saturated [107-21-1] solutions were removed and diluted quantitatively for spectroscopic analysis at Variables: Prepared by: 220 nm. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: % (1) 99 , Sigma-Aldrich Chemical Company, was used as received. Experimental Values (2) Purity not given, Spectroscopic grade, from either Merck Chemical Company or Sigma-Aldrich Chemical Company, was used as received. x a x b,c Estimated Error: 2 1 Temperature: 1 K (estimated by compiler). 0.9810 0.01904 % a c1: 3 (relative error, estimated by compiler). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 103D. M. Stovall, C. Givens, S. Auxiliary Information benzeneacetic acid (Ibuprofen); Keown, K. R. Hoover, E. Method/Apparatus/Procedure: [ ] C13H18O2; 15687-27-1 Rodriguez, W. E. Acree, Jr., and Constant-temperature bath and an ultraviolet/visible spectrophotometer. (2) 1-Decanol; C10H22O; [112-30-1] M. H. Abraham, Phys. Chem. Liq. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with 43, 261 (2005). shaking for ﬁve days at constant temperature. Aliquots of saturated solutions % / Variables: Prepared by: were removed and diluted with 96 ethanol (v v). Concentrations were T/K ¼ 298.15 W. E. Acree, Jr. determined by spectrophotometric measurements at 289 nm. The reported solubility represents the average of at least three independent determinations.

Experimental Values Source and Purity of Chemicals: (1) Purity not given, Laboratories UPSA, Agen, France, no purification details were provided. a b (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x2 x1 source not specified, no purification details were provided. 0.7834 0.2166 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 0.2 K. x1: 2% (relative error).

Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ Components: Original Measurements: visible spectrophotometer. (1) α-Methyl-4-(2-methylpropyl)- 95M. A. Filippa and E. I. Gasull, Excess solute and solvent were placed in amber glass bottles and allowed to benzeneacetic acid (Ibuprofen); Fluid Phase Equilib. 354, 185 equilibrate for several days at constant temperature. Attainment of equilibrium C13H18O2; [15687-27-1] (2013). was verified by several repetitive measurements and by approaching (2) 1,2-Ethanediol; C2H6O2; equilibrium from supersaturation. Aliquots of saturated solutions were [107-21-1] transferred through a coarse filter into tared volumetric flasks, weighed, and Variables: Prepared by: diluted with methanol. Concentrations were determined by T/K ¼ 300.15 W. E. Acree, Jr. spectrophotometric measurements at 264 nm.

Source and Purity of Chemicals: Experimental Values (1) 98+%, Sigma-Aldrich, St. Louis, Missouri, USA, was dried for several hours at 333 K before use. The purity of the commercial sample was 99.7% as The measured solubility was reported to be c1 ¼ 0.1858 determined by nonaqueous titration with freshly standardized sodium mol dm 3. methoxide to the thymol blue endpoint according to the method of [J. S. Fritz and N. M. Lisicki, Anal. Chem. 23, 589 (1951)], except that methylbenzene was substituted for benzene in the titration solvent. (2) 99+%, Alfa Aesar, USA, stored over molecular sieves and distilled shortly before use.

Estimated Error: Temperature: 0.1 K.

x1: 2.0% (relative error).

Auxiliary Information Experimental Values Method/Apparatus/Procedure: An UV/visible spectrophotometer. x a x b,c Very few experimental details were given in the paper. Excess solute and 2 1 solvent were placed in closed containers and allowed to equilibrate with 0.9141 0.08589 continuous agitation at constant temperature for 48 h. Aliquots of saturated a x2: mole fraction of component 2 in the saturated solution. solutions were removed and diluted quantitatively for spectroscopic analysis at b x1: mole fraction solubility of the solute. 220 nm. c Experimental value was reported in the paper as ln x1.

Source and Purity of Chemicals: Auxiliary Information (1) 99%, Sigma-Aldrich Chemical Company, was used as received. (2) Purity not given, ACS grade, Sintorgan, was used as received. Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Estimated Error: Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with Temperature: 1 K (estimated by compiler). shaking for ﬁve days at constant temperature. Aliquots of saturated solutions % c1: 3 (relative error, estimated by compiler). were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 289 nm. The reported solubility represents the average of at least three independent determinations.

Components: Original Measurements: Source and Purity of Chemicals: (1) α-Methyl-4-(2-methylpropyl)- 95M. A. Filippa and E. I. Gasull, (1) Purity not given, Laboratories UPSA, Agen, France, no purification details benzeneacetic acid (Ibuprofen); Fluid Phase Equilib. 354, 185 were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical C13H18O2; [15687-27-1] (2013). source not specified, no purification details were provided. (2) 1,2-Propanediol; C3H8O2; [57-55-6] Estimated Error: Variables: Prepared by: Temperature: 0.2 K. T/K ¼ 300.15 W. E. Acree, Jr. x1: 2% (relative error).

Experimental Values ¼ Components: Original Measurements: The measured solubility was reported to be c1 0.9036 (1) α-Methyl-4-(2-methylpropyl)- 110S. Soltanpour and A. Jouyban, 3 mol dm . benzeneacetic acid (Ibuprofen); J. Mol. Liq. 155, 80 (2010).

C13H18O2; [15687-27-1] Auxiliary Information (2) 1,2-Propanediol; C3H8O2; [57-55-6] Method/Apparatus/Procedure: An UV/visible spectrophotometer. Variables: Prepared by: / ¼ Very few experimental details were given in the paper. Excess solute and T K 298.15 W. E. Acree, Jr. solvent were placed in closed containers and allowed to equilibrate with continuous agitation at constant temperature for 48 h. Aliquots of saturated Experimental Values solutions were removed and diluted quantitatively for spectroscopic analysis at 220 nm. The measured solubility was reported to be c1 ¼ 0.9376 mol dm3. Source and Purity of Chemicals: (1) 99%, Sigma-Aldrich Chemical Company, was used as received. Auxiliary Information (2) Purity not given, ACS grade, Sintorgan, was used as received. Method/Apparatus/Procedure: Estimated Error: Shaker, incubator equipped with a constant temperature controlling system Temperature: 1 K (estimated by compiler). and an ultraviolet/visible spectrophotometer.

c1: 3% (relative error, estimated by compiler). Excess solute and solvent were placed in sealed containers and equilibrated using a shaker placed in an incubator equipped with a constant temperature controlling system for at least 98 h. Aliquots of saturated solutions were removed and diluted quantitatively with methanol for spectroscopic analyses. Concentration of the dissolved solute was determined from the measured Components: Original Measurements: absorbance at 222 nm. The reported solubility represents the average of at least (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and three independent determinations. benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 C H O ; [15687-27-1] (2000). 13 18 2 Source and Purity of Chemicals: (2) 1,2-Propanediol; C H O ; 3 8 2 (1) Purity not given, Daana Pharmaceutical Company, Iran, no puriﬁcation [57-55-6] details were provided. Variables: Prepared by: (2) Purity not given, Merck Chemical Company, Germany, no puriﬁcation T/K ¼ 298.15 W. E. Acree, Jr. details were provided.

Estimated Error: Temperature: 0.2 K.

c1: 3.4% (relative error).

Components: Original Measurements: Experimental Values (1) α-Methyl-4-(2-methylpropyl)- 111Y. J. Manrique, D. P. Pacheco, í benzeneacetic acid (Ibuprofen); and F. Mart nez, J. Solution a T/K s1 C13H18O2; [15687-27-1] Chem. 37, 165 (2008). (2) 1,2-Propanediol; C3H8O2; 288.15 0.1324 [57-55-6] 290.65 0.1585 293.15 0.1729 Variables: Prepared by: 295.65 0.1966 Temperature W. E. Acree, Jr. 298.15 0.2252 a s1: solubility of the solute expressed as grams of dissolved solute per gram. Experimental Values The author did not specify whether it was per gram of solvent or per gram of solution, but it is probably per gram of solvent.

a b Auxiliary Information T/K x2 x1 293.15 0.9253 0.0747 Method/Apparatus/Procedure: 298.15 0.9015 0.0985 Constant-temperature water bath, high-precision thermometer, and an UV/ 303.15 0.8590 0.1410 visible spectrophotometer. 308.15 0.8120 0.1880 Excess solute and solvent were allowed to equilibrate with stirring in a 313.15 0.7830 0.2170 constant-temperature water bath for 24 h. An aliquot of the saturated solution # a was removed, filtered through Whatman 1 filter paper, and then diluted for x2: mole fraction of component 2 in the saturated solution. b spectrophotometric analysis at 264 nm. x1: mole fraction solubility of the solute. Source and Purity of Chemicals: (1) Purity not given, Pharmacia Upjohn, Kalamazoo, Michigan, USA, was Auxiliary Information used as received. Method/Apparatus/Procedure: (2) Purity not given, Aldrich Chemical Company, Milwaukee, Wisconsin, Constant-temperature water bath and an UV/visible spectrophotometer. USA, was used as received. Excess solute and solvent were placed in stoppered glass flasks and allowed to equilibrate at 313.15 K in a constant-temperature water bath for at least five Estimated Error: days. Once equilibrium had been attained, an aliquot of the saturated solution Temperature: 0.1 K. was removed and filtered in order to remove insoluble particles. The s1: 2.0% (relative error, estimated by compiler). concentration of the dissolved drug was determined by spectrophotometric analysis. The temperature of the water bath was then reduced by 5 K, and the samples re-equilibrated at 308.15 K for an additional two days to allow Components: Original Measurements: precipitation of the excess drug. The amount of dissolved drug at the lower (1) α-Methyl-4-(2-methylpropyl)- 112P. V. Chuahan, H. K. Patel, B. temperature was determined by spectroscopic analysis as described above. The benzeneacetic acid (Ibuprofen); A. Patel, K. N. Patel, and P. A. procedure was repeated until 293.15 K was reached. The densities of the C13H18O2; [15687-27-1] Patel, Int. J. Pharm. Res. Scholars saturated solutions were measured in order to convert the measured (2) 1,2-Propanediol; C H O ; 1, 268 (2012). concentrations in mol dm3 to mole fraction solubilities. The reported mole 3 8 2 [57-55-6] fraction solubilities represent the average of three experimental measurements. Variables: Prepared by: T/K ¼ Not given, assumed to be W. E. Acree, Jr. Source and Purity of Chemicals: ambient room temperature by (1) Purity not given, USP, no purification details were provided in the paper. compiler (2) Purity not given, USP, no purification details were given in the paper.

Estimated Error: Experimental Values Temperature: 0.05 K (estimated by compiler). The measured solubility was reported to be c1 ¼ 0.282 mol % x1: 2.0 (relative error). dm 3. Note: The compiler believes that 24 h is not sufﬁcient time for saturation to be reached.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) α-Methyl-4-(2-methylpropyl)- 104I. Khalifeh, Ph.D. dissertation, Very few experimental details were provided in the paper. Excess solute and benzeneacetic acid (Ibuprofen); Purdue University, 2000. solvent were stirred, sonicated for a half hour and then allowed to equilibrate C H O ; [15687-27-1] 13 18 2 for 24 h. An aliquot of the solution was removed, filtered, and diluted with (2) 1,2-Propanediol; C H O ; 3 8 2 methanol for spectrophotometric analysis at 222 nm. [57-55-6] Variables: Prepared by: Source and Purity of Chemicals: Temperature W. E. Acree, Jr. (1) Purity not given, ACS Chemicals, no purification details were provided. (2) Purity not given, chemical source not specified, no purification details were provided.

Estimated Error: Temperature: Insufﬁcient information given to estimate.

c1: Insufﬁcient information to estimate.

Source and Purity of Chemicals: Components: Original Measurements: (1) Purity not given, ACS Chemicals, no purification details were provided. α 93 ñ (1) -Methyl-4-(2-methylpropyl)- P. Bustamante, M. A. Pe a, and (2) Purity not given, chemical source not specified, no purification details were benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 provided. C13H18O2; [15687-27-1] (2000). (2) 1,2,3-Propanetriol (Glycerol); Estimated Error: [ ] C3H8O3; 56-81-5 Temperature: Insufficient information given to estimate. Variables: Prepared by: c1: Insufficient information to estimate. T/K ¼ 298.15 W. E. Acree, Jr.

Experimental Values 13.8. Ibuprofen solubility data in ketones

a b,c x2 x1 Components: Original Measurements: 0.9972 0.00276 (1) α-Methyl-4-(2-methylpropyl)- 101D. M. Aragoń, J. E. Rosas, and a x2: mole fraction of component 2 in the saturated solution. benzeneacetic acid (Ibuprofen); F. Martínez, Braz. J. Pharm. Sci. bx 1: mole fraction solubility of the solute. C13H18O2; [15687-27-1] 46, 227 (2010). cExperimental value was reported in the paper as ln x . 1 (2) Propanone; C3H6O; [67-64-1] Variables: Prepared by: Auxiliary Information Temperature W. E. Acree, Jr. Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Experimental Values Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were a b T/K x2 x1 determined by spectrophotometric measurements at 289 nm. The reported 293.15 0.7667 0.2333 solubility represents the average of at least three independent determinations. 298.15 0.7311 0.2689 303.15 0.6879 0.3121 Source and Purity of Chemicals: 308.15 0.6480 0.3520 (1) Purity not given, Laboratories UPSA, Agen, France, no purification details 313.15 0.6068 0.3932 were provided. a (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x2: mole fraction of component 2 in the saturated solution. b source not specified, no purification details were provided. x1: mole fraction solubility of the solute.

Estimated Error: Temperature: 0.2 K. Auxiliary Information % x1: 2 (relative error). Method/Apparatus/Procedure: Thermostatic mechanical shaker and an analytical balance. Excess solute and solvent were placed in stoppered glass ﬂasks and allowed to equilibrate in a thermostatic mechanical shaker at 313.15 K for at least three Components: Original Measurements: days. Once equilibrium had been attained, an aliquot of the saturated solution (1) α-Methyl-4-(2-methylpropyl)- 112P. V. Chuahan, H. K. Patel, B. was removed and ﬁltered in order to remove insoluble particles. The benzeneacetic acid (Ibuprofen); A. Patel, K. N. Patel, and P. A. concentration of the dissolved drug was determined by weighing an aliquot of

C13H18O2; [15687-27-1] Patel, Int. J. Pharm. Res. Scholars the saturated ﬁltered solution, and then allowing the solvent to evaporate. The (2) 1,2,3-Propanetriol (Glycerol); 1, 268 (2012). mole fraction solubility was calculated from the mass of the solid residue and

C3H8O3; [56-81-5] the mass of the sample taken for analysis. Once the solubility was determined at 313.15 K, the temperature was decreased by 5 K and stabilized at 308.15 K Variables: Prepared by: for two days to allow the excess dissolved drug to precipitate at this lower / ¼ T K Not given, assumed to be W. E. Acree, Jr. temperature. An aliquot of the new saturated solution was removed, ﬁltered, ambient room temperature by and the solvent evaporated as before. The procedure was repeated by compiler decreasing the temperature in 5 K increments to reach 293.15 K. The reported mole fraction solubilities represent the average of three experimental measurements. Experimental Values

The measured solubility was reported to be c1 ¼ 0.408 mol Source and Purity of Chemicals: dm3. Note: The compiler believes that 24 h is not sufficient (1) Purity not given, USP, no purification details were provided in the paper. time for saturation to be reached. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, no purification details were given in the paper.

Auxiliary Information Estimated Error: Temperature: 0.1 K (estimated by compiler). Method/Apparatus/Procedure: x : 1.0% (relative error). Very few experimental details were provided in the paper. Excess solute and 1 solvent were stirred, sonicated for a half hour and then allowed to equilibrate for 24 h. An aliquot of the solution was removed, ﬁltered, and diluted with methanol for spectrophotometric analysis at 222 nm.

Auxiliary Information Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and Method/Apparatus/Procedure: benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 Thermostated water bath, analytical balance, magnetic stirrer, and vacuum C13H18O2; [15687-27-1] (2000). drying oven. (2) Propanone; C3H6O; [67-64-1] Solubility was determined by the gravimetric method. Excess solute and solvent were placed in Erlenmeyer flasks and allowed to equilibrate for 72 h in Variables: Prepared by: a thermostatic water bath sitting on a multiple position magnetic stirrer. The T/K ¼ 298.15 W. E. Acree, Jr. solutions were stirred during the equilibration period. The stirring was then stopped for 4 h to allow the suspended solid to settle to the bottom of the flask. Experimental Values A sample of the clear saturated solution was transferred with a heated syringe into a previously weighed sample vial. The vial containing the saturated solution was then weighed, and the solvent was allowed to evaporate in a vacuum oven at 293 K for approximately one week until a constant weight was x a x b,c 2 1 obtained. The solubility was calculated from the mass of the solid residue and 0.6492 0.3508 mass of the saturated solution analyzed. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Source and Purity of Chemicals: c % Experimental value was reported in the paper as ln x1. (1) 99.4 , AstraZeneca AB, no purification details were given in the paper. (2) Purity not given, Pro Analyse grade, Merck Chemical Company, Germany, no purification details were given in the paper. Auxiliary Information Estimated Error: Method/Apparatus/Procedure: Temperature: 0.1 K. Constant-temperature bath and an ultraviolet/visible spectrophotometer. x : 1% (relative error). Excess solute and solvent were placed in flasks and allowed to equilibrate with 1 shaking for five days at constant temperature. Aliquots of saturated solutions % / were removed and diluted with 96 ethanol (v v). Concentrations were Components: Original Measurements: determined by spectrophotometric measurements at 289 nm. The reported (1) α-Methyl-4-(2-methylpropyl)- 97S. Wang, Z. Song, J. Wang, Y. solubility represents the average of at least three independent determinations. benzeneacetic acid (Ibuprofen); Dong, and M. Wu, J. Chem. Eng.

C13H18O2; [15687-27-1] Data 55, 5283 (2010). Source and Purity of Chemicals: (2) Propanone; C3H6O; [67-64-1] (1) Purity not given, Laboratories UPSA, Agen, France, no purification details were provided. Variables: Prepared by: (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Temperature W. E. Acree, Jr. source not specified, no purification details were provided.

Estimated Error: Experimental Values Temperature: 0.2 K.

x1: 2% (relative error). a b T/K x2 x1 283.57 0.8563 0.1437 288.49 0.8316 0,1684 Components: Original Measurements: 293.37 0.8004 0.1996 (1) α-Methyl-4-(2-methylpropyl)- 96S. Gracin and A. C. Rasmuson, 297.87 0.7670 0.2330 benzeneacetic acid (Ibuprofen); J. Chem. Eng. Data 47, 1379 303.07 0.7268 0.2732 308.07 0.6886 0.3114 C13H18O2; [15687-27-1] (2002). 312.65 0.6484 0.3516 (2) Propanone; C3H6O; [67-64-1] 317.99 0.5949 0.4051 Variables: Prepared by: a x2: mole fraction of component 2 in the saturated solution. Temperature W. E. Acree, Jr. b x1: mole fraction solubility of the solute.

Experimental Values Auxiliary Information Method/Apparatus/Procedure: Equilibrium jacketed glass vessel, thermostated circulating water bath, T/K x a x b 2 1 electromagnetic stirrer, analytical balance, laser monitoring system. 283.15 0.8580 0.1420 Experimental solubilities were determined by a synthetic method. Preweighed 288.15 0.8326 0.1674 amounts of solute and solvent and were placed in an equilibrium vessel, which 293.15 0.8008 0.1992 was connected to a circulating constant-temperature water bath. The solution 303.15 0.7236 0.2764 was stirred and small amounts of solute were incrementally added until no 308.15 0.6790 0.3210 further solid dissolved. The dissolution of the solid was determined using laser a x2: mole fraction of component 2 in the saturated solution. monitoring. The total amount of solute dissolved was recorded. Experimental b x1: mole fraction solubility of the solute. The solubility was reported in the measurement was repeated three times. paper as the grams of solute that dissolved per kilogram of solvent. Mole fraction solubility calculated by the compiler. Source and Purity of Chemicals: (1) 99.4%, JiangXi GuoXing Fine Chemical Industry, Co., Ltd., recrystallized twice from ethanol before use. (2) 99.7+%, Analytical Reagent grade, Beijing Chemical Reagent Company, China, no puriﬁcation information was given in the paper.

Estimated Error: Auxiliary Information Temperature: 0.1 K. Method/Apparatus/Procedure: x1: 2% (relative error). Thermostated water bath, analytical balance, magnetic stirrer, and vacuum drying oven. Solubility was determined by the gravimetric method. Excess solute and solvent were placed in Erlenmeyer flasks and allowed to equilibrate for 72 h in Components: Original Measurements: a thermostatic water bath sitting on a multiple position magnetic stirrer. The α 95 (1) -Methyl-4-(2-methylpropyl)- M. A. Filippa and E. I. Gasull, solutions were stirred during the equilibration period. The stirring was then benzeneacetic acid (Ibuprofen); Fluid Phase Equilib. 354, 185 stopped for 4 h to allow the suspended solid to settle to the bottom of the flask. [ ] C13H18O2; 15687-27-1 (2013). A sample of the clear saturated solution was transferred with a heated syringe [ ] (2) Propanone; C3H6O; 67-64-1 into a previously weighed sample vial. The vial containing the saturated Variables: Prepared by: solution was then weighed, and the solvent was allowed to evaporate in a T/K ¼ 300.15 W. E. Acree, Jr. vacuum oven at 293 K for approximately one week until a constant weight was obtained. The solubility was calculated from the mass of the solid residue and mass of the saturated solution analyzed. Experimental Values ¼ Source and Purity of Chemicals: The measured solubility was reported to be c1 2.965 (1) 99.4%, AstraZeneca AB, no purification details were given in the paper. 3 mol dm . (2) Purity not given, Pro Analyse grade, Merck Chemical Company, Germany, no purification details were given in the paper. Auxiliary Information Estimated Error: Method/Apparatus/Procedure: Temperature: 0.1 K. / An UV visible spectrophotometer. x1: 1% (relative error). Very few experimental details were given in the paper. Excess solute and solvent were placed in closed containers and allowed to equilibrate with continuous agitation at constant temperature for 48 h. Aliquots of saturated solutions were removed and diluted quantitatively for spectroscopic analysis at Components: Original Measurements: 220 nm. (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 Source and Purity of Chemicals: C H O ; [15687-27-1] (2000). (1) 99%, Sigma-Aldrich Chemical Company, was used as received. 13 18 2 (2) Acetophenone; C H O; [98-86-2] (2) Purity not given, Spectroscopic grade, from either Merck Chemical 8 8 Company or Sigma-Aldrich Chemical Company, was used as received. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Estimated Error: Temperature: 1 K (estimated by compiler).

c1: 3% (relative error, estimated by compiler). Experimental Values

a b,c x2 x1 Components: Original Measurements: 0.9969 0.00309 96 (1) α-Methyl-4-(2-methylpropyl)- S. Gracin and A. C. Rasmuson, a x2: mole fraction of component 2 in the saturated solution. benzeneacetic acid (Ibuprofen); J. Chem. Eng. Data 47, 1379 b x1: mole fraction solubility of the solute. C13H18O2; [15687-27-1] (2002). c Experimental value was reported in the paper as ln x1. (2) 4-Methyl-2-pentanone; C6H12O; [108-10-1] Variables: Prepared by: Auxiliary Information Temperature W. E. Acree, Jr. Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with Experimental Values shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 289 nm. The reported / a b T K x2 x1 solubility represents the average of at least three independent determinations. 283.15 0.8672 0.1328 288.15 0.8405 0.1595 Source and Purity of Chemicals: 293.15 0.8085 0.1915 (1) Purity not given, Laboratories UPSA, Agen, France, no purification details 303.15 0.7295 0.2705 were provided. 308.15 0.6836 0.3164 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a source not specified, no purification details were provided. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. The solubility was reported in the paper as the grams of solute that dissolved per kilogram of solvent. Mole Estimated Error: fraction solubility calculated by the compiler. Temperature: 0.2 K. x1: 2% (relative error).

13.9. Ibuprofen solubility data in miscellaneous Auxiliary Information organic solvents Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions Components: Original Measurements: were removed and diluted with 96% ethanol (v/v). Concentrations were (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and determined by spectrophotometric measurements at 289 nm. The reported benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 solubility represents the average of at least three independent determinations. C13H18O2; [15687-27-1] (2000). (2) Ethanoic acid; C H O ; [64-19-7] 2 4 2 Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Laboratories UPSA, Agen, France, no purification details T/K ¼ 298.15 W. E. Acree, Jr. were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values Estimated Error: Temperature: 0.2 K. a b,c x2 x1 x1: 2% (relative error). 0.8863 0.1137 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Components: Original Measurements: Experimental value was reported in the paper as ln x1. (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 [ ] Auxiliary Information C13H18O2; 15687-27-1 (2000). (2) Formamide; CH3NO; [75-12-7] Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Variables: Prepared by: Excess solute and solvent were placed in flasks and allowed to equilibrate with T/K ¼ 298.15 W. E. Acree, Jr. shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 289 nm. The reported Experimental Values solubility represents the average of at least three independent determinations.

a b,c Source and Purity of Chemicals: x2 x1 (1) Purity not given, Laboratories UPSA, Agen, France, no purification details 0.9986 0.00143 were provided. a x2: mole fraction of component 2 in the saturated solution. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical b x1: mole fraction solubility of the solute. source not specified, no purification details were provided. c Experimental value was reported in the paper as ln x1. Estimated Error: Temperature: 0.2 K. Auxiliary Information x1: 2% (relative error). Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions Components: Original Measurements: were removed and the solvent evaporated. The solid residue was then dissolved (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and and diluted with 96% ethanol (v/v). Concentrations were determined by benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 spectrophotometric measurements at 289 nm. The reported solubility C H O ; [15687-27-1] (2000). 13 18 2 represents the average of at least three independent determinations. (2) Propanoic acid; C3H6O2; [79-09-4] Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Laboratories UPSA, Agen, France, no purification details T/K ¼ 298.15 W. E. Acree, Jr. were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values Estimated Error: Temperature: 0.2 K. a b,c x2 x1 x1: 2% (relative error). 0.7901 0.2099 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Source and Purity of Chemicals: Components: Original Measurements: (1) 99%, Sigma-Aldrich Chemical Company, was used as received. α 93 ñ (1) -Methyl-4-(2-methylpropyl)- P. Bustamante, M. A. Pe a, and (2) Purity not given, Spectroscopic grade, from either Merck Chemical benzeneacetic acid (Ibuprofen); J. Barra, Int. J. Pharm. 194, 117 Company or Sigma-Aldrich Chemical Company, was used as received. C13H18O2; [15687-27-1] (2000). (2) N,N-Dimethylformamide; Estimated Error: [ ] C3H7NO; 64-19-7 Temperature: 1 K (estimated by compiler). % Variables: Prepared by: c1: 3 (relative error, estimated by compiler). T/K ¼ 298.15 W. E. Acree, Jr.

Experimental Values Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 113S. Soltanpour and A. Jouyban, benzeneacetic acid (Ibuprofen); J. Solution Chem. 40, 2032 x a x b,c 2 1 C13H18O2; [15687-27-1] (2011). 0.8723 0.1277 (2) N-Methyl-2-pyrrolidone; a C5H9NO; [872-50-4] x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Variables: Prepared by: c Experimental value was reported in the paper as ln x1. T/K ¼ 298.15 W. E. Acree, Jr.

Auxiliary Information Experimental Values / / Method Apparatus Procedure: The measured solubility was reported to be c1 ¼ 5.5121 Constant-temperature bath and an ultraviolet/visible spectrophotometer. mol dm3. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and the solvent evaporated. The solid residue was then dissolved Auxiliary Information and diluted with 96% ethanol (v/v). Concentrations were determined by Method/Apparatus/Procedure: spectrophotometric measurements at 289 nm. The reported solubility Shaker, incubator equipped with a constant temperature controlling system represents the average of at least three independent determinations. and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in sealed containers and equilibrated Source and Purity of Chemicals: using a shaker placed in an incubator equipped with a constant temperature (1) Purity not given, Laboratories UPSA, Agen, France, no purification details controlling system for at least 98 h. Aliquots of saturated solutions were were provided. removed and diluted quantitatively with methanol for spectroscopic analyses. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Concentration of the dissolved solute was determined from the measured source not specified, no purification details were provided. absorbance at 222 nm. The reported solubility represents the average of at least three independent determinations. Estimated Error: Temperature: 0.2 K. Source and Purity of Chemicals: % x1: 2 (relative error). (1) Purity not given, Sobhan Pharmaceutical Company, Iran, no purification details were provided. (2) Purity not given, Merck Chemical Company, Germany, no purification details were provided. Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 95M. A. Filippa and E. I. Gasull, Estimated Error: benzeneacetic acid (Ibuprofen); Fluid Phase Equilib. 354, 185 Temperature: 0.2 K. % C13H18O2; [15687-27-1] (2013). c1: 3.1 (relative error). (2) N,N-Dimethylformamide;

C3H7NO; [64-19-7] Variables: Prepared by: T/K ¼ 300.15 W. E. Acree, Jr. Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 104I. Khalifeh, Ph.D. dissertation, benzeneacetic acid (Ibuprofen); Purdue University, 2000. [ ] Experimental Values C13H18O2; 15687-27-1 ¼ (2) Dimethyl sulfoxide; C2H6OS; The measured solubility was reported to be c1 1.466 [67-68-5] mol dm3. Variables: Prepared by: Temperature W. E. Acree, Jr. Auxiliary Information Method/Apparatus/Procedure: An UV/visible spectrophotometer. Very few experimental details were given in the paper. Excess solute and solvent were placed in closed containers and allowed to equilibrate with continuous agitation at constant temperature for 48 h. Aliquots of saturated solutions were removed and diluted quantitatively for spectroscopic analysis at 220 nm.

Experimental Values Estimated Error: Temperature: 1 K (estimated by compiler).

c1: 3% (relative error, estimated by compiler). a T/K s1 288.15 2.383 290.65 2.433 293.15 2.646 Components: Original Measurements: 95 295.65 2.711 (1) α-Methyl-4-(2-methylpropyl)- M. A. Filippa and E. I. Gasull, 298.15 3.161 benzeneacetic acid (Ibuprofen); Fluid Phase Equilib. 354, 185 C H O ; [15687-27-1] (2013). as : solubility of the solute expressed as grams of dissolved solute per gram. 13 18 2 1 (2) Ethanenitrile; C H N; [75-05-8] The author did not specify whether it was per gram of solvent or per gram of 2 3 solution, but it is probably per gram of solvent. Variables: Prepared by: T/K ¼ 300.15 W. E. Acree, Jr.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: Constant-temperature water bath, high-precision thermometer, and an UV/ The measured solubility was reported to be c1 ¼ 2.061 visible spectrophotometer. mol dm 3. Excess solute and solvent were allowed to equilibrate with stirring in a constant-temperature water bath for 24 h. An aliquot of the saturated solution Auxiliary Information was removed, ﬁltered through Whatman #1 ﬁlter paper, and then diluted for spectrophotometric analysis at 264 nm. Method/Apparatus/Procedure: An UV/visible spectrophotometer. Source and Purity of Chemicals: Very few experimental details were given in the paper. Excess solute and (1) Purity not given, Pharmacia Upjohn, Kalamazoo, Michigan, USA, was solvent were placed in closed containers and allowed to equilibrate with used as received. continuous agitation at constant temperature for 48 h. Aliquots of saturated (2) Purity not given, Acros Organics, New Jersey, USA, was used as received. solutions were removed and diluted quantitatively for spectroscopic analysis at 220 nm. Estimated Error: Temperature: 0.1 K. Source and Purity of Chemicals: s1: 2.0% (relative error, estimated by compiler). (1) 99%, Sigma-Aldrich Chemical Company, used as received. (2) Purity not given, Spectroscopic grade, from either Merck Chemical Company or Sigma-Aldrich Chemical Company, used as received.

Components: Original Measurements: Estimated Error: (1) α-Methyl-4-(2-methylpropyl)- 95M. A. Filippa and E. I. Gasull, Temperature: 1 K (estimated by compiler). % benzeneacetic acid (Ibuprofen); Fluid Phase Equilib. 354, 185 c1: 3 (relative error, estimated by compiler).

C13H18O2; [15687-27-1] (2013). (2) Dimethyl sulfoxide; C2H6OS; [67-68-5] Components: Original Measurements: Variables: Prepared by: (1) α-Methyl-4-(2-methylpropyl)- 114M. A. Roni and R. Jalil, Dhaka T/K ¼ 300.15 W. E. Acree, Jr. benzeneacetic acid (Ibuprofen); Univ. J. Pharm. Sci. 10, 65 (2011).

C13H18O2; [15687-27-1] Experimental Values (2) (9Z)-Octadecenoic acid (Oleic acid); C18H34O2; [112-80-1] The measured solubility was reported to be c1 ¼ 2.799 Variables: Prepared by: mol dm 3. T/K ¼ ambient room temperature W. E. Acree, Jr.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: 3 An UV/visible spectrophotometer. The measured solubility was reported to be 311.4 g dm , 3 Very few experimental details were given in the paper. Excess solute and which corresponds to a molar solubility of c1 ¼ 1.510 mol dm . solvent were placed in closed containers and allowed to equilibrate with continuous agitation at constant temperature for 48 h. Aliquots of saturated Auxiliary Information solutions were removed and diluted quantitatively for spectroscopic analysis at 220 nm. Method/Apparatus/Procedure: Vortex mixer, centrifuge, and an UV/visible spectrophotometer. Source and Purity of Chemicals: Excess solute and solvent were placed in sealed containers, shaken in a vortex (1) 99%, Sigma-Aldrich Chemical Company, was used as received. mixer for 15 min, and allowed to equilibrate at room temperature for 24 h. The (2) Purity not given, Spectroscopic grade, from either Merck Chemical sample was then centrifuged for 5 min at 3000 rpm to separate the clear Company or Sigma-Aldrich Chemical Company, was used as received. saturated solution from the undissolved solid. The supernatant was ﬁltered through Whatman 102 ﬁlter paper and diluted with methanol for spectrophotometric analysis at 222 nm. The reported values represent the average of two experimental measurements.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Xamim Company, China, no purification details were provided in the paper. (2) Purity not given, Merck Chemical Company, Germany, no purification a T/K s1 details were provided in the paper. 288.15 0.1969 290.65 0.2096 Estimated Error: 293.15 0.2215 Temperature: Insufficient details given in the paper. 295.65 0.2422 c : 2% (relative error). 1 298.15 0.2585 a s1: solubility of the solute expressed as grams of dissolved solute per gram. The author did not specify whether it was per gram of solvent or per gram of solution, but it is probably per gram of solvent. Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 108A. Jouyban, S. Soltanpour, and benzeneacetic acid (Ibuprofen); W. E. Acree, Jr., J. Chem. Eng. Auxiliary Information C13H18O2; [15687-27-1] Data 55, 5252 (2010). (2) Polyethylene glycol 200 Method/Apparatus/Procedure: (PEG 200) Constant-temperature water bath, high-precision thermometer, and an UV/ visible spectrophotometer. Variables: Prepared by: Excess solute and solvent were allowed to equilibrate with stirring in a T/K ¼ 298.15 W. E. Acree, Jr. constant-temperature water bath for 24 h. An aliquot of the saturated solution was removed, filtered through Whatman #1 filter paper, and then diluted for spectrophotometric analysis at 264 nm. Experimental Values

The measured solubility was reported to be c1 ¼ 0.9467 Source and Purity of Chemicals: mol dm 3. (1) Purity not given, Pharmacia Upjohn, Kalamazoo, Michigan, USA, was used as received. (2) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, was Auxiliary Information used as received. Method/Apparatus/Procedure: Shaker, incubator equipped with a constant temperature controlling system Estimated Error: and an ultraviolet/visible spectrophotometer. Temperature: 0.1 K. Excess solute and solvent were placed in sealed containers and equilibrated s1: 2.0% (relative error, estimated by compiler). using a shaker placed in an incubator equipped with a constant temperature controlling system for at least 98 h. Aliquots of saturated solutions were removed and diluted quantitatively with methanol for spectroscopic analyses. Concentration of the dissolved solute was determined from the measured Components: Original Measurements: absorbance at 222 nm. The reported solubility represents the average of at least (1) α-Methyl-4-(2-methylpropyl)- 105X. Wang, C. S. Ponder, and D. three independent determinations. benzeneacetic acid (Ibuprofen); J. Kirwan, Cryst. Growth Des. 5,

C13H18O2; [15687-27-1] 85 (2005). Source and Purity of Chemicals: (2) Polyethylene glycol 300 (1) Purity not given, Sobhan Pharmaceutical Company, Iran, no puriﬁcation (PEG 300) details were provided in the paper. (2) 99.5%, Merck Chemical Company, Germany, no puriﬁcation details were Variables: Prepared by: provided in the paper. T/K ¼ 298.15 W. E. Acree, Jr.

Estimated Error: Temperature: 0.2 K. Experimental Values

c1: 3.4% (relative error).

a b,c x2 x1 0.7310 0.2690 a Components: Original Measurements: x2: mole fraction of component 2 in the saturated solution. α 104 b (1) -Methyl-4-(2-methylpropyl)- I. Khalifeh, Ph.D. dissertation, x1: mole fraction solubility of the solute. benzeneacetic acid (Ibuprofen); Purdue University, 2000. csolubility reported in the paper as 253 g of dissolved solute per kilogram of C13H18O2; [15687-27-1] solvent. Mole fraction calculated by compiler assuming a molar mass of 300 g (2) Polyethylene glycol 200 mol1 for PEG 300. (PEG 200) Variables: Prepared by: Auxiliary Information Temperature W. E. Acree, Jr. Method/Apparatus/Procedure: Thermostated constant-temperature water bath and an UV/visible spectrophotometer. Excess solute and solvent were placed in a sealed container and allowed to equilibrate with agitation for 24 h to 72 h in a constant-temperature thermostated water bath. Aliquots of saturated solutions were removed and ﬁltered through a membrane ﬁlter of 0.22 μm pore size. Concentrations were determined by spectrophotometric analysis at 304 nm.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Sigma-Aldrich Chemical Company, no purification ¼ details were provided in the paper. The measured solubility was reported to be c1 0.591 mol 3 (2) Purity not given, chemical source not specified, no purification details were dm . Note: The compiler believes that 24 h is not sufficient provided in the paper. time for saturation to be reached.

Estimated Error: Auxiliary Information Temperature: 0.2 K (estimated by compiler). x1: 4% (relative error, estimated by compiler). Method/Apparatus/Procedure: Very few experimental details were provided in the paper. Excess solute and solvent were stirred, sonicated for a half hour and then allowed to equilibrate for 24 h. An aliquot of the solution was removed, filtered, and diluted with Components: Original Measurements: methanol for spectrophotometric analysis at 222 nm. (1) α-Methyl-4-(2-methylpropyl)- 108A. Jouyban, S. Soltanpour, and benzeneacetic acid (Ibuprofen); W. E. Acree, Jr., J. Chem. Eng. Source and Purity of Chemicals: (1) Purity not given, ACS Chemicals, no purification details were provided in C13H18O2; [15687-27-1] Data 55, 5252 (2010). (2) Polyethylene glycol 400 (PEG the paper. 400) (2) Purity not given, chemical source not specified, no purification details were provided in the paper. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Estimated Error: Temperature: Insufficient information given to estimate.

c1: Insufﬁcient information to estimate. Experimental Values

The measured solubility was reported to be c1 ¼ 1.2055 mol dm3. Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 65E. Rytting, K. A. Lentz, X.-Q. Auxiliary Information benzeneacetic acid (Ibuprofen); Chen, F. Qian, and S. Venkatesh,

Method/Apparatus/Procedure: C13H18O2; [15687-27-1] AAPS J. 7, E78 (2005). Shaker, incubator equipped with a constant temperature controlling system (2) Polyethylene glycol 400 and an ultraviolet/visible spectrophotometer. (PEG 400) Excess solute and solvent were placed in sealed containers and equilibrated Variables: Prepared by: using a shaker placed in an incubator equipped with a constant temperature T/K ¼ 296 W. E. Acree, Jr. controlling system for at least 98 h. Aliquots of saturated solutions were removed and diluted quantitatively with methanol for spectroscopic analyses. Concentration of the dissolved solute was determined from the measured Experimental Values absorbance at 222 nm. The reported solubility represents the average of at least three independent determinations. The measured solubility was reported to be c1 ¼ 1.199 mol dm3. Source and Purity of Chemicals: (1) Purity not given, Sobhan Pharmaceutical Company, Iran, no purification Auxiliary Information details were provided in the paper. (2) Purity not given, Daana Pharmaceutical Company, Iran, no purification Method/Apparatus/Procedure: details were provided in the paper. Centrifuge and a high-performance liquid chromatograph equipped with a photo-diode array detector. Estimated Error: Excess solute and solvent were placed in sealed vials and shaken at ambient Temperature: 0.2 K. room temperature for at least 24 h. The vials were then centrifuged for 15 min % c1: 3.4 (relative error). to separate the saturated solution from the excess solute. The supernatant was then filtered and the concentration of the dissolved solute determined by high- performance liquid chromatographic analysis.

Components: Original Measurements: Source and Purity of Chemicals: (1) α-Methyl-4-(2-methylpropyl)- 112P. V. Chuahan, H. K. Patel, (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, benzeneacetic acid (Ibuprofen); B. A. Patel, K. N. Patel, and P. A. USA, no puriﬁcation details were provided in the paper. (2) Purity not given, J. T. Baker Chemical Company, Phillipsburg, New Jersey, C13H18O2; [15687-27-1] Patel, Int. J. Pharm. Res. Scholars (2) Polyethylene glycol 400 1, 268 (2012). USA, no puriﬁcation details were provided in the paper. (PEG 400) Estimated Error: Variables: Prepared by: Temperature: 2 K (estimated by compiler). / ¼ T K Not given, assumed to be W. E. Acree, Jr. c1: 10% (relative error, estimated by compiler). ambient room temperature by compiler

Source and Purity of Chemicals: Components: Original Measurements: (1) Purity not given, ACS Chemicals, no purification details were provided in α 110 (1) -Methyl-4-(2-methylpropyl)- S. Soltanpour and A. Jouyban, the paper. benzeneacetic acid (Ibuprofen); J. Mol. Liq. 155, 80 (2010). (2) Purity not given, chemical source not specified, no purification details were [ ] 109 C13H18O2; 15687-27-1 S. Soltanpour and A. Jouyban, provided in the paper. (2) Polyethylene glycol 600 Chem. Pharm. Bull. 58, 219 (PEG 600) (2010). Estimated Error: Variables: Prepared by: Temperature: Insufficient information given to estimate. T/K ¼ 298.15 W. E. Acree, Jr. c1: Insufficient information to estimate.

Experimental Values ¼ Components: Original Measurements: The measured solubility was reported to be c1 1.4425 64 3 (1) α-Methyl-4-(2-methylpropyl)- B. P. Wenkers and B. C. mol dm . benzeneacetic acid (Ibuprofen); Lippold, J. Pharm. Sci. 88, 1326

C13H18O2; [15687-27-1] (1999). Auxiliary Information (2) Mineral oil Method/Apparatus/Procedure: Variables: Prepared by: Shaker, incubator equipped with a constant temperature controlling system T/K ¼ 305.15 W. E. Acree, Jr. and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in sealed containers and equilibrated using a shaker placed in an incubator equipped with a constant temperature Experimental Values controlling system for at least 98 h. Aliquots of saturated solutions were The measured solubility was reported to be c1 ¼ 0.122 removed and diluted quantitatively with methanol for spectroscopic analyses. 3 Concentration of the dissolved solute was determined from the measured mol dm . absorbance at 222 nm. The reported solubility represents the average of at least three independent determinations. Auxiliary Information Method/Apparatus/Procedure: Source and Purity of Chemicals: Constant-temperature bath and an UV/visible spectrophotometer (1) Purity not given, Daana Pharmaceutical Company, Iran, no purification Excess solute and solvent were placed in sealed bottles and allowed to details were provided in the paper. equilibrate at a constant temperature with rotation for 24 h. Aliquots of (2) Purity not given, Daana Pharmaceutical Company, no purification details saturated solutions were removed, filtered through a 0.45 μm cellulose acetate were provided in the paper. membrane filter, and diluted quantitatively for spectroscopic analysis. Reported values represent the average of three experimental measurements. Estimated Error: Temperature: 0.2 K. Source and Purity of Chemicals: c : 3.4% (relative error). 1 (1) Purity not given, Sankyo, Pfaffenhofen, Germany, no purification details were provided in the paper. (2) Purity not given, Parafluid Mineralolgesellschaft, Hamburg, Germany, no purification details were provided in the paper. Components: Original Measurements: 112 (1) α-Methyl-4-(2-methylpropyl)- P. V. Chuahan, H. K. Patel, Estimated Error: benzeneacetic acid (Ibuprofen); B. A. Patel, K. N. Patel, and P. A. Temperature: 0.5 K (estimated by compiler). [ ] C13H18O2; 15687-27-1 Patel, Int. J. Pharm. Res. Scholars c1: 10% (relative error). (2) Polyethylene glycol 600 1, 268 (2012). (PEG 600) Variables: Prepared by: T/K ¼ Not given, assumed to be W. E. Acree, Jr. Components: Original Measurements: ambient room temperature by (1) α-Methyl-4-(2-methylpropyl)- 115R. M. Watkinson, R. H. Guy, G. compiler benzeneacetic acid (Ibuprofen); Oliveira, J. Hadgraft, and M. E. C13H18O2; [15687-27-1] Lane, Skin Pharmacol. Physiol. (2) Mineral oil 24, 22 (2011). Experimental Values Variables: Prepared by: The measured solubility was reported to be c1 ¼ 0.566 mol T/K ¼ 305.15 W. E. Acree, Jr. dm3. Note: The compiler believes that 24 h is not sufficient time for saturation to be reached. Experimental Values ¼ Auxiliary Information The measured solubility was reported to be c1 0.155 mol dm3. Method/Apparatus/Procedure: Very few experimental details were provided in the paper. Excess solute and solvent were stirred, sonicated for a half hour and then allowed to equilibrate for 24 h. An aliquot of the solution was removed, filtered, and diluted with methanol for spectrophotometric analysis at 222 nm.

Auxiliary Information Experimental Values / / Method Apparatus Procedure: The measured solubility was reported to be c1 ¼ 0.911 Constant-temperature bath, high-performance liquid chromatograph, and mol dm3. anUV/visible spectrophotometer. Excess solute and solvent were placed in sealed bottles and allowed to equilibrate with stirring in a constant-temperature bath for 48 h. Aliquots of Auxiliary Information saturated solutions were removed and centrifuged. Concentrations of the Method/Apparatus/Procedure: dissolved solute were determined by either spectroscopic or high-performance Constant-temperature bath and an UV/visible spectrophotometer. liquid chromatographic analysis. Excess solute and solvent were placed in a screw-capped test tube and allowed to equilibrate at a constant temperature with rotation for 24 h. Aliquots of Source and Purity of Chemicals: saturated solutions were removed, centrifuged at 15 000 rpm for 10 min, and (1) Purity not given, Wyeth Consumer Health Care, Havant, United Kingdom, diluted quantitatively with ethanol for spectroscopic analysis. no purification details were provided in the paper. (2) Purity not given, Sigma-Aldrich, United Kingdom, no purification details Source and Purity of Chemicals: were provided in the paper. (1) Purity not given, chemical source not specified, no purification details were provided in the paper. Estimated Error: (2) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Temperature: 0.5 K (estimated by compiler). purification details were provided in the paper. c1: 5% (relative error). Estimated Error: Temperature: 0.5 K.

c1: 10% (relative error, estimated by compiler). Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 114M. A. Roni and R. Jalil, Dhaka benzeneacetic acid (Ibuprofen); Univ. J. Pharm. Sci. 10, 65 (2011). [ ] C13H18O2; 15687-27-1 Components: Original Measurements: (2) Arachis oil (1) α-Methyl-4-(2-methylpropyl)- 114M. A. Roni and R. Jalil, Dhaka Variables: Prepared by: benzeneacetic acid (Ibuprofen); Univ. J. Pharm. Sci. 10, 65 (2011). [ ] T/K ¼ ambient room temperature W. E. Acree, Jr. C13H18O2; 15687-27-1 (2) Castor oil Variables: Prepared by: Experimental Values T/K ¼ ambient room temperature W. E. Acree, Jr. The measured solubility was reported to be 113.4 g dm3, which corresponds to a molar solubility of c ¼ 0.550 mol dm3. 1 Experimental Values The measured solubility was reported to be 223.7 g dm3, Auxiliary Information 3 which corresponds to a molar solubility of c1 ¼ 1.084 mol dm . Method/Apparatus/Procedure: Vortex mixer, centrifuge, and an UV/visible spectrophotometer. Excess solute and solvent were placed in sealed containers, shaken in a vortex Auxiliary Information mixer for 15 min, and allowed to equilibrate at room temperature for 24 h. The Method/Apparatus/Procedure: sample was then centrifuged for 5 min at 3000 rpm to separate the clear Vortex mixer, centrifuge, and an UV/visible spectrophotometer. saturated solution from the undissolved solid. The supernatant was filtered Excess solute and solvent were placed in sealed containers, shaken in a vortex through Whatman 102 filter paper and diluted with methanol for mixer for 15 min, and allowed to equilibrate at room temperature for 24 h. The spectrophotometric analysis at 222 nm. The reported values represent the sample was then centrifuged for 5 min at 3000 rpm to separate the clear average of two experimental measurements. saturated solution from the undissolved solid. The supernatant was filtered through Whatman 102 filter paper and diluted with methanol for Source and Purity of Chemicals: spectrophotometric analysis at 222 nm. The reported values represent the (1) Purity not given, Xamim Company, China, no purification details were average of two experimental measurements. provided in the paper. (2) Purity not given, chemical source not specified, no purification details were Source and Purity of Chemicals: provided in the paper. (1) Purity not given, Xamim Company, China, no purification details were provided in the paper. Estimated Error: (2) Purity not given, chemical source not specified, no purification details were Temperature: Insufficient details given in the paper. provided in the paper. c1: 2% (relative error). Estimated Error: Temperature: Insufficient details given in the paper. % Components: Original Measurements: c1: 2 (relative error). (1) α-Methyl-4-(2-methylpropyl)- 92D. B. Larsen, H. Parshad, K. benzeneacetic acid (Ibuprofen); Fredholt, and C. Larsen, Int. J.

C13H18O2; [15687-27-1] Pharm. 232, 107 (2002). (2) Castor oil Variables: Prepared by: T/K ¼ 310.15 W. E. Acree, Jr.

Estimated Error: Components: Original Measurements: Temperature: Insufﬁcient details given in the paper. (1) α-Methyl-4-(2-methylpropyl)- 116A. Zaghloul, A. Nada, and I. s1: 10% (relative error, estimated by compiler). benzeneacetic acid (Ibuprofen); Khattab, Int. J. Pharm. Technol. 3,

C13H18O2; [15687-27-1] 1674 (2011). (2) Corn oil

Variables: Prepared by: Components: Original Measurements: T/K ¼ 293.15 W. E. Acree, Jr. (1) α-Methyl-4-(2-methylpropyl)- 116A. Zaghloul, A. Nada, and I. benzeneacetic acid (Ibuprofen); Khattab, Int. J. Pharm. Technol. 3,

C13H18O2; [15687-27-1] 1674 (2011). Experimental Values (2) Soybean oil ¼ The measured solubility was reported to be s1 5.281 Variables: Prepared by: (% mass/volume). T/K ¼ 293.15 W. E. Acree, Jr.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: ¼ Platform shaker and a high-performance liquid chromatograph equipped with The measured solubility was reported to be s1 8.799 a photodiode array detector. (% mass/volume). Excess solute and solvent were placed a sealed container that was put on a platform shaker and allowed to equilibrate at constant temperature for 24 h. Auxiliary Information Aliquots of saturated solutions were removed and the concentration of the / / dissolved solute determined by high-performance liquid chromatographic Method Apparatus Procedure: analysis at 252 nm. Platform shaker and a high-performance liquid chromatograph equipped with a photodiode array detector. Source and Purity of Chemicals: Excess solute and solvent were placed in a sealed container that was put on a (1) Purity not given, Sigma Chemical Company, New Jersey, USA, no platform shaker and allowed to equilibrate at constant temperature for 24 h. puriﬁcation details were provided in the paper. Aliquots of saturated solutions were removed and the concentration of the (2) Purity not given, Sigma Chemical Company, no puriﬁcation details were dissolved solute determined by high-performance liquid chromatographic provided in the paper. analysis at 252 nm.

Estimated Error: Source and Purity of Chemicals: Temperature: Insufficient details given in the paper. (1) Purity not given, Sigma Chemical Company, New Jersey, USA, no purification details were provided in the paper. s1: 10% (relative error, estimated by compiler). (2) Purity not given, Sigma Chemical Company, no purification details were provided in the paper.

C13H18O2; [15687-27-1] 1674 (2011). (2) Peanut oil

Variables: Prepared by: Components: Original Measurements: T/K ¼ 293.15 W. E. Acree, Jr. (1) α-Methyl-4-(2-methylpropyl)- 114M. A. Roni and R. Jalil, Dhaka benzeneacetic acid (Ibuprofen); Univ. J. Pharm. Sci. 10, 65 (2011).

C13H18O2; [15687-27-1] Experimental Values (2) Soybean oil ¼ The measured solubility was reported to be s1 4.980 Variables: Prepared by: (% mass/volume). T/K ¼ ambient room temperature W. E. Acree, Jr.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: 3 Platform shaker and a high-performance liquid chromatograph equipped with The measured solubility was reported to be 96.3 g dm , ¼ 3 a photodiode array detector. which corresponds to a molar solubility of c1 0.467 mol dm . Excess solute and solvent were placed in a sealed container that was put on a platform shaker and allowed to equilibrate at constant temperature for 24 h. Auxiliary Information Aliquots of saturated solutions were removed and the concentration of the / / dissolved solute determined by high-performance liquid chromatographic Method Apparatus Procedure: / analysis at 252 nm. Vortex mixer, centrifuge, and an UV visible spectrophotometer. Excess solute and solvent were placed in sealed containers, shaken in a vortex Source and Purity of Chemicals: mixer for 15 min, and allowed to equilibrate at room temperature for 24 h. The (1) Purity not given, Sigma Chemical Company, New Jersey, USA, no sample was then centrifuged for 5 min at 3000 rpm to separate the clear purification details were provided in the paper. saturated solution from the undissolved solid. The supernatant was filtered (2) Purity not given, Sigma Chemical Company, no purification details were through Whatman 102 filter paper and diluted with methanol for provided in the paper. spectrophotometric analysis at 222 nm. The reported values represent the average of two experimental measurements.

Source and Purity of Chemicals: Auxiliary Information (1) Purity not given, Xamim Company, China, no purification details were / / provided in the paper. Method Apparatus Procedure: / (2) Purity not given, chemical source not specified, no purification details were Vortex mixer, centrifuge, and an UV visible spectrophotometer. provided in the paper. Excess solute and solvent were placed in sealed containers, shaken in a vortex mixer for 15 min, and allowed to equilibrate at room temperature for 24 h. The Estimated Error: sample was then centrifuged for 5 min at 3000 rpm to separate the clear Temperature: Insufficient details given in the paper. saturated solution from the undissolved solid. The supernatant was filtered through Whatman 102 filter paper and diluted with methanol for c1: 2% (relative error). spectrophotometric analysis at 222 nm. The reported values represent the average of two experimental measurements.

Source and Purity of Chemicals: Components: Original Measurements: (1) Purity not given, Xamim Company, China, no purification details were α 116 (1) -Methyl-4-(2-methylpropyl)- A. Zaghloul, A. Nada, and I. provided in the paper. benzeneacetic acid (Ibuprofen); Khattab, Int. J. Pharm. Technol. 3, (2) Purity not given, chemical source not specified, no purification details were [ ] C13H18O2; 15687-27-1 1674 (2011). provided in the paper. (2) Olive oil Variables: Prepared by: Estimated Error: T/K ¼ 293.15 W. E. Acree, Jr. Temperature: Insufficient details given in the paper. c1: 2% (relative error).

Experimental Values

The measured solubility was reported to be s1 ¼ 3.689 (% mass/volume). 13.10. Ibuprofen solubility data in binary organic solvent mixtures Auxiliary Information / / Method Apparatus Procedure: Components: Original Measurements: Platform shaker and a high-performance liquid chromatograph equipped with (1) α-Methyl-4-(2-methylpropyl)- 117D. P. Pacheco, Y. J. Manrique, a photodiode array detector. benzeneacetic acid (Ibuprofen); and F. Martinez, Fluid Phase Excess solute and solvent were placed in a sealed container that was put on a C13H18O2; [15687-27-1] Equilib. 262, 23 (2007). platform shaker and allowed to equilibrate at constant temperature for 24 h. (2) Ethanol; C2H6O; [64-17-5] Aliquots of saturated solutions were removed and the concentration of the (3) 1,2-Propanediol; C3H8O2; dissolved solute determined by high-performance liquid chromatographic [57-55-6] analysis at 252 nm. Variables: Prepared by: Source and Purity of Chemicals: Temperature; Solvent composition W. E. Acree, Jr. (1) Purity not given, Sigma Chemical Company, New Jersey, USA, no puriﬁcation details were provided in the paper. (2) Purity not given, Sigma Chemical Company, no puriﬁcation details were Experimental Values provided in the paper.

Estimated Error: / ðsÞa b T K w2 x1 Temperature: Insufﬁcient details given in the paper. 293.15 0.00 0.0747 s : 10% (relative error, estimated by compiler). 1 293.15 0.20 0.117 293.15 0.40 0.160 293.15 0.60 0.184 293.15 0.80 0.202 Components: Original Measurements: 293.15 1.00 0.205 (1) α-Methyl-4-(2-methylpropyl)- 114M. A. Roni and R. Jalil, Dhaka benzeneacetic acid (Ibuprofen); Univ. J. Pharm. Sci. 10, 65 (2011). 298.15 0.00 0.0985 C13H18O2; [15687-27-1] 298.15 0.20 0.147 (2) Olive oil 298.15 0.40 0.192 298.15 0.60 0.209 Variables: Prepared by: 298.15 0.80 0.233 T/K ¼ ambient room temperature W. E. Acree, Jr. 298.15 1.00 0.241

303.15 0.00 0.141 Experimental Values 303.15 0.20 0.183 3 The measured solubility was reported to be 153.3 g dm , 303.15 0.40 0.231 3 which corresponds to a molar solubility of c1 ¼ 0.743 mol dm . 303.15 0.60 0.250 303.15 0.80 0.268 303.15 1.00 0.284

TABLE 8. Parameters of the Modified Apelblat equation for describing the / ðsÞa b T K w2 x1 solubility of indomethacin in ethanol and 1,2-propanediol 308.15 0.00 0.188 MARD 308.15 0.20 0.230 Solvent T/K ABC(%) 308.15 0.40 0.276 a 308.15 0.60 0.290 Ethanol 293–313 74.152 18.471 12.060 1.2 b 308.15 0.80 0.316 Ethanol 293–313 100.928 19.070 16.727 0.7 b 308.15 1.00 0.340 1,2-Propanediol 293–313 107.913 19.216 17.823 2.7 1,2-Propanediolc 293–313 93.379 18.870 15.286 1.6 313.15 0.00 0.217 aData set from Ruidiaz et al.129 313.15 0.20 0.260 bData set from Cantillo et al.128 313.15 0.40 0.310 cData set from Holguín et al.130 313.15 0.60 0.337 313.15 0.80 0.363 313.15 1.00 0.367 et al.126 determined the solubility of indomethacin in ethyl a ðsÞ w2 : initial mass fraction of component 2 in the binary solvent mixture. ethanoate, methanol, and ethanol as part of a much larger study b x1: mole fraction solubility of the solute. that examined the solubility behavior and solution chemistry of indomethacin-saccharin cocrystals in organic media. Phase Auxiliary Information solubility diagrams of the cocrystals in various solvents were recorded and the transition concentration (at which the drug Method/Apparatus/Procedure: Constant-temperature water bath and an UV/visible spectrophotometer. and cocrystals are in equilibrium with the solvents) were Excess solute and solvent were placed in stoppered glass flasks and allowed to calculated from the measured solubility data. Takahashi equilibrate at 313.15 K in a constant-temperature water bath for at least five et al.100 measured the solubility of indomethacin in diethyl days. Once equilibrium had been attained, an aliquot of the saturated solution butanedioate, diethyl hexanedioate, diisopropyl hexanedioate, was removed and filtered in order to remove insoluble particles. The and diethyl decanedioate at 305 K in their study concerning the concentration of the dissolved drug was determined by spectrophotometric analysis. The temperature of the water bath was then reduced by 5 K, and the use of fatty diesters as a means to enhance NSAID permeation 127 samples re-equilibrated at 308.15 K for an additional two days to allow through skin. Hellstén et al. measured the solubility of precipitation of the excess drug. The amount of dissolved drug at the lower indomethacin in ethyl ethanoate, dichloromethane, methanol, temperature was determined by spectroscopic analysis as described above. The ethanol, and propanone at 298 K, as well as in binary methanol procedure was repeated until 293.15 K was reached. The densities of the + dichloromethane, ethanol + dichloromethane, methanol + saturated solutions were measured in order to convert the measured + + concentrations in mol dm3 to mole fraction solubilities. The reported mole propanone, ethanol propanone, methanol ethyl ethanoate, fraction solubilities represent the average of three experimental and ethanol + ethyl ethanoate solvent mixtures. The equili- measurements. The densities of the saturated solutions were measured in order brium solid phase was analyzed using a confocal Raman to convert the measured molar solubilities (in units of mol dm 3) to mole microscope equipped with a laser. In several of the solvents fraction solubilities and mixtures, the authors found evidence of a solid solvate. 128–130 Source and Purity of Chemicals: Delgado and co-workers measured the solubility of (1) Purity not given, USP, no purification details were given in the paper. indomethacin in ethanol and 1,2-propanediol as a function of (2) Absolute, Analytical Reagent grade, Merck Chemical Company, Germany, temperature using spectroscopic and gravimetric methods of no purification details were given in the paper. analyses. The internal consistency of the dataset was assessed (3) Purity not given, USP, no purification details were given in the paper. by curve-fitting the measured mole fraction solubility data to Estimated Error: Eq. (8). Each of the four data sets is considered internally Temperature: 0.05 K. consistent as evidenced by the small MARD values. The ðsÞ values of the equation coefficients (A, B, and C) are given in w2 : 0.01. x1: 3% (relative error). Table 8, along with the mean absolute relative deviation. The experimental solubility data for indomethacin in organic solvents are given in Secs. 14.2–14.6. 14. Solubility of Indomethacin in Organic Solvents 14.2. Indomethacin solubility data in esters 14.1. Critical evaluation of experimental solubility data Components: Original Measurements: (1) 1-(4-Chlorobenzoyl)-2-methyl- 126A. Alhalaweh, A. Sokolowski, Indomethacin (more formally named 1-(4-chlorobenzoyl)- 5-methoxyindole-3-acetic acid N. R. Hornedo, and S. P. Velaga, 2-methyl-5-methoxyindole-3-acetic acid) is a NSAID com- (Indomethacin); C15H16ClNO4; Cryst. Growth Des. 11, 3923 monly prescribed by physicians to treat pain and inflammation [53-86-1] (2011). in individuals suffering from gout, osteoarthritis, rheumatoid (2) Ethyl ethanoate; C4H8O2; [141-78-6] arthritis, ankylosing spondylitis, bursitis or tendinitis. There have been several published studies100,126–130 involving the Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. solubility of indomethacin in organic solvents. Alhalaweh

Experimental Values Source and Purity of Chemicals: ¼ (1) Purity not given, USP grade, Hawkins, Inc., used as received. The measured solubility was reported to be c1 0.102 (2) 99.5%, Merck Chemical Company, Germany, used as received. mol dm3. The equilibrium solid phase was the γ-form of the solute. Estimated Error: Temperature: 0.2 K (estimated by compiler). m : 3% (relative error, estimated by compiler). Auxiliary Information 1 Method/Apparatus/Procedure: Magnetic stirrer, constant-temperature bath, x-ray powder diffractometer, and a high-performance liquid chromatograph. Components: Original Measurements: Excess solute and solvent were placed in sealed glass vials and allowed to (1) 1-(4-Chlorobenzoyl)-2-methyl- 100K. Takahashi, H. Sakano, N. equilibrate at a constant temperature with stirring for 24 h. Aliquots of 5-methoxyindole-3-acetic acid Numata, S. Kuroda, and N. μ saturated solutions were removed, filtered through a 0.2 m cellulose acetate (Indomethacin); C H ClNO ; Mizuno, Drug Develop. Ind. μ 15 16 4 membrane filter or 0.45 m polypropylene membrane filter, and diluted [53-86-1] Pharm. 28, 1285 (2002). quantitatively for high-performance liquid chromatographic analyses. (2) Diethyl butanedioate; C8H14O4; Solubility measurements were repeated after an additional 72 h to ensure that [123-25-1] equilibrium had been obtained. Samples of the equilibrated solid phase were removed, filtered, dried, and analyzed by powder x-ray diffraction. Variables: Prepared by: T/K ¼ 305.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma-Aldrich Chemical Company, Stockholm, Sweden, used as received. Experimental Values (2) Purity not given, Sigma-Aldrich Chemical Company, used as received. The measured solubility was reported to be c1 ¼ 0.0874 mol dm3. Estimated Error: Temperature: 0.5 K.

c1: 5% (relative error, estimated by compiler). Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and a high-performance liquid chromatograph. Excess solute and solvent were allowed to equilibrate with agitation for 24 h at Components: Original Measurements: constant temperature. The saturated solution was removed and ﬁltered through (1) 1-(4-Chlorobenzoyl)-2-methyl- 127S. Hellstén, H. Qu, and M. a 0.45 μm membrane ﬁlter. The concentration of the dissolved solute was 5-methoxyindole-3-acetic acid Louhi-Kultanen, Chem. Eng. determined by high-performance liquid chromatographic analysis. (Indomethacin); C15H16ClNO4; Technol. 34, 1667 (2011). [53-86-1] Source and Purity of Chemicals:

(2) Ethyl ethanoate; C4H8O2; (1) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, [141-78-6] Japan, no puriﬁcation details were provided in the paper. (2) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Variables: Prepared by: Japan, no puriﬁcation details were provided in the paper. T/K ¼ 298.2 W. E. Acree, Jr. Estimated Error: Temperature: 0.2 K (estimated by compiler). Experimental Values c1: 5% (relative error, estimated by compiler). The measured molal solubility was reported to be m1 ¼ 0.127 mol/kg of solvent. The equilibrated solid phase was the α-form and γ-form of indomethacin plus a solid solvate. Components: Original Measurements: 100 Auxiliary Information (1) 1-(4-Chlorobenzoyl)-2-methyl- K. Takahashi, H. Sakano, N. 5-methoxyindole-3-acetic acid Numata, S. Kuroda, and N. / / Method Apparatus Procedure: (Indomethacin); C15H16ClNO4; Mizuno, Drug Develop. Ind. Constant-temperature bath, analytical balance, confocal Raman microscope [53-86-1] Pharm. 28, 1285 (2002).

equipped with a laser. (2) Diethyl hexanedioate; C10H18O4; Solubility was determined gravimetrically using the shake flask method. [141-28-6] Excess solute and solvent were placed in sealed flasks and allowed to equilibrate in a constant-temperature bath with stirring for 24 h. An aliquot of Variables: Prepared by: / ¼ the saturated solution was withdrawn using a syringe equipped with a 0.20 μm T K 305.15 W. E. Acree, Jr. pore size cellulose membrane filter. The sample was transferred to a tared container, weighed, and the solvent evaporated at reduced pressure at 309 K Experimental Values until constant mass was obtained. The solubility was calculated from the mass of the solid residue and the mass of the sample analyzed. The equilibrated solid The measured solubility was reported to be c1 ¼ 0.1068 phase was analyzed using a confocal Raman microscope equipped with a laser mol dm3. operating at 785 nm as the excitation source.

Auxiliary Information Experimental Values / / Method Apparatus Procedure: The measured solubility was reported to be c1 ¼ 0.0582 Constant-temperature bath and a high-performance liquid chromatograph. mol dm3. Excess solute and solvent were allowed to equilibrate with agitation for 24 h at Auxiliary Information constant temperature. The saturated solution was removed and filtered through a 0.45 μm membrane filter. The concentration of the dissolved solute was Method/Apparatus/Procedure: determined by high-performance liquid chromatographic analysis. Constant-temperature bath and a high-performance liquid chromatograph. Excess solute and solvent were allowed to equilibrate with agitation for 24 h at Source and Purity of Chemicals: constant temperature. The saturated solution was removed and filtered through (1) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, a 0.45 μm membrane filter. The concentration of the dissolved solute was Japan, no purification details were provided in the paper. determined by high-performance liquid chromatographic analysis. (2) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Japan, no purification details were provided in the paper. Source and Purity of Chemicals: (1) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Estimated Error: Japan, no purification details were provided in the paper. Temperature: 0.2 K (estimated by compiler). (2) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka,

c1: 5% (relative error, estimated by compiler). Japan, no puriﬁcation details were provided in the paper.

Estimated Error: Temperature: 0.2 K (estimated by compiler). % Components: Original Measurements: c1: 5 (relative error, estimated by compiler). (1) 1-(4-Chlorobenzoyl)-2-methyl- 100K. Takahashi, H. Sakano, N. 5-methoxyindole-3-acetic acid Numata, S. Kuroda, and N.

(Indomethacin); C15H16ClNO4; Mizuno, Drug Develop. Ind. 14.3. Indomethacin solubility data in haloalkanes, [53-86-1] Pharm. 28, 1285 (2002). haloalkenes, and haloaromatic hydrocarbons (2) Diisopropyl hexanedioate;

C12H22O4; [6938-94-9] Variables: Prepared by: Components: Original Measurements: T/K ¼ 305.15 W. E. Acree, Jr. (1) 1-(4-Chlorobenzoyl)-2-methyl- 127S. Hellstén, H. Qu, and M. 5-methoxyindole-3-acetic acid Louhi-Kultanen, Chem. Eng.

(Indomethacin); C15H16ClNO4; Technol. 34, 1667 (2011). Experimental Values [53-86-1]

(2) Dichloromethane; CH2Cl2; The measured solubility was reported to be c1 ¼ 0.0578 [75-09-2] mol dm 3. Variables: Prepared by: T/K ¼ 298.2 W. E. Acree, Jr. Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and a high-performance liquid chromatograph. Experimental Values Excess solute and solvent were allowed to equilibrate with agitation for 24 h at The measured molal solubility was reported to be m ¼ constant temperature. The saturated solution was removed and ﬁltered through 1 a 0.45 μm membrane ﬁlter. The concentration of the dissolved solute was 0.135 mol/kg of solvent. The equilibrated solid phase was the determined by high-performance liquid chromatographic analysis. α-form of indomethacin plus a solid solvate.

Source and Purity of Chemicals: Auxiliary Information (1) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Japan, no purification details were provided in the paper. Method/Apparatus/Procedure: (2) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Constant-temperature bath, analytical balance, confocal Raman microscope Japan, no purification details were provided in the paper. equipped with a laser. Solubility was determined gravimetrically using the shake flask method. Estimated Error: Excess solute and solvent were placed in sealed flasks and allowed to Temperature: 0.2 K (estimated by compiler). equilibrate in a constant-temperature bath with stirring for 24 h. An aliquot of the saturated solution was withdrawn using a syringe equipped with a 0.20 μm c1: 5% (relative error, estimated by compiler). pore size cellulose membrane filter. The sample was transferred to a tared container, weighed, and the solvent evaporated at reduced pressure at 309 K until constant mass was obtained. The solubility was calculated from the mass of the solid residue and the mass of the sample analyzed. The equilibrated solid Components: Original Measurements: 100 phase was analyzed using a confocal Raman microscope equipped with a laser (1) 1-(4-Chlorobenzoyl)-2-methyl- K. Takahashi, H. Sakano, N. operating at 785 nm as the excitation source. 5-methoxyindole-3-acetic acid Numata, S. Kuroda, and N. (Indomethacin); C15H16ClNO4; Mizuno, Drug Develop. Ind. Source and Purity of Chemicals: [ ] 28 53-86-1 Pharm. , 1285 (2002). (1) Purity not given, USP grade, Hawkins, Inc., used as received. (2) Diethyl decanedioate; C14H26O4; (2) Purity not given, stabilized with 0.5% of methanol, Orion, used as received. [110-40-7] Variables: Prepared by: Estimated Error: T/K ¼ 305.15 W. E. Acree, Jr. Temperature: 0.2 K (estimated by compiler). m1: 3% (relative error, estimated by compiler).

14.4. Indomethacin solubility data in alcohols Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath, analytical balance, confocal Raman microscope Components: Original Measurements: equipped with a laser. (1) 1-(4-Chlorobenzoyl)-2-methyl- 126A. Alhalaweh, A. Sokolowski, Solubility was determined gravimetrically using the shake flask method. 5-methoxyindole-3-acetic acid N. R. Hornedo, and S. P. Velaga, Excess solute and solvent were placed in sealed flasks and allowed to (Indomethacin); C H ClNO ; Cryst. Growth Des. 11, 3923 equilibrate in a constant-temperature bath with stirring for 24 h. An aliquot of 15 16 4 μ [53-86-1] (2011). the saturated solution was withdrawn using a syringe equipped with a 0.20 m pore size cellulose membrane filter. The sample was transferred to a tared (2) Methanol; CH4O; [67-56-1] container, weighed, and the solvent evaporated at reduced pressure at 309 K Variables: Prepared by: until constant mass was obtained. The solubility was calculated from the mass / ¼ T K 298.15 W. E. Acree, Jr. of the solid residue and the mass of the sample analyzed. The equilibrated solid phase was analyzed using a confocal Raman microscope equipped with a laser operating at 785 nm as the excitation source. Experimental Values Source and Purity of Chemicals: The measured solubility was reported to be c1 ¼ 0.047 mol dm3. The equilibrium solid phase was a methanol (1) Purity not given, USP grade, Hawkins, Inc., used as received. (2) Purity not given, LiChrosolv grade, Merck Chemical Company, Germany, solvate. used as received.

Auxiliary Information Estimated Error: Temperature: 0.2 K (estimated by compiler). Method/Apparatus/Procedure: m : 3% (relative error, estimated by compiler). Magnetic stirrer, constant-temperature bath, x-ray powder diffractometer, and 1 a high-performance liquid chromatograph. Excess solute and solvent were placed in sealed glass vials and allowed to equilibrate at a constant temperature with stirring for 24 h. Aliquots of saturated solutions were removed, filtered through a 0.2 μm cellulose acetate Components: Original Measurements: 127 membrane filter or 0.45 μm polypropylene membrane filter, and diluted (1) 1-(4-Chlorobenzoyl)-2-methyl- S. Hellstén, H. Qu, and M. quantitatively for high-performance liquid chromatographic analyses. 5-methoxyindole-3-acetic acid Louhi-Kultanen, Chem. Eng. Solubility measurements were repeated after an additional 72 h to ensure that (Indomethacin); C15H16ClNO4; Technol. 34, 1667 (2011). equilibrium had been obtained. Samples of the equilibrated solid phase were [53-86-1] [ ] removed, filtered, dried, and analyzed by powder x-ray diffraction. (2) Ethanol; C2H6O; 64-17-5 Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 298.2 W. E. Acree, Jr. (1) Purity not given, Sigma-Aldrich Chemical Company, Stockholm, Sweden, used as received. (2) Purity not given, Analytical Reagent grade, Sigma-Aldrich Chemical Experimental Values Company, used as received. The measured molal solubility was reported to be m1 ¼ Estimated Error: 0.0781 mol/kg of solvent. The equilibrated solid phase was the Temperature: 0.5 K. α-form and γ-form of indomethacin. c1: 5% (relative error, estimated by compiler). Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: Constant-temperature bath, analytical balance, confocal Raman microscope (1) 1-(4-Chlorobenzoyl)-2-methyl- 127S. Hellstén, H. Qu, and M. equipped with a laser. 5-methoxyindole-3-acetic acid Louhi-Kultanen, Chem. Eng. Solubility was determined gravimetrically using the shake flask method. Excess solute and solvent were placed in sealed flasks and allowed to (Indomethacin); C15H16ClNO4; Technol. 34, 1667 (2011). [53-86-1] equilibrate in a constant-temperature bath with stirring for 24 h. An aliquot of the saturated solution was withdrawn using a syringe equipped with a 0.20 μm (2) Methanol; CH4O; [67-56-1] pore size cellulose membrane filter. The sample was transferred to a tared Variables: Prepared by: container, weighed, and the solvent evaporated at reduced pressure at 309 K / ¼ T K 298.2 W. E. Acree, Jr. until constant mass was obtained. The solubility was calculated from the mass of the solid residue and the mass of the sample analyzed. The equilibrated solid phase was analyzed using a confocal Raman microscope equipped with a laser Experimental Values operating at 785 nm as the excitation source.

The measured molal solubility was reported to be m1 ¼ 0.0712 mol/kg of solvent. The equilibrated solid phase was the Source and Purity of Chemicals: α (1) Purity not given, USP grade, Hawkins, Inc., used as received. -form of indomethacin plus a solid solvate. (2) 99.5%, Altia Chemical Company, used as received.

Estimated Error: Temperature: 0.2 K (estimated by compiler).

m1: 3% (relative error, estimated by compiler).

Components: Original Measurements: Experimental Values (1) 1-(4-Chlorobenzoyl)-2-methyl- 128E. A. Cantillo, D. R. Delgado,

5-methoxyindole-3-acetic acid and F. Martinez, J. Mol. Liq. 181, a b T/K x2 x1 (Indomethacin); C15H16ClNO4; 62 (2013). [53-86-1] 293.15 0.9967 0.003318

(2) Ethanol; C2H6O; [64-17-5] 298.15 0.9958 0.004169 303.15 0.9951 0.004887 Variables: Prepared by: 308.15 0.9938 0.006166 Temperature W. E. Acree, Jr. 313.15 0.9926 0.007413 a x2: mole fraction of component 2 in the saturated solution. b Experimental Values x1: mole fraction solubility of the solute.

a b Auxiliary Information T/K x2 x1 293.15 0.9975 0.002530 Method/Apparatus/Procedure: 298.15 0.9966 0.003423 Constant-temperature bath and an analytical balance. 303.15 0.9955 0.004528 Excess solute and solvent were placed in a stoppered dark glass flask and 308.15 0.9941 0.005877 allowed to equilibrate with sporadic stirring in a constant-temperature bath for 313.15 0.9923 0.007711 at least three days. An aliquot of the saturated solution was removed and a isothermally filtered to remove insoluble particles. The solubility of the drug x2: mole fraction of component 2 in the saturated solution. b was determined by mass balance weighing of a specified quantity of the x1: mole fraction solubility of the solute. saturated solution and then allowing the solvent to evaporate until a constant residue mass is obtained. The solubility was calculated from the mass of the Auxiliary Information solid residue and the mass of the sample taken for analysis. The reported value represents the average of three experimental determinations. Method/Apparatus/Procedure: Thermostatic mechanical shaker bath, recirculating thermostatic bath, and an Source and Purity of Chemicals: UV/visible spectrophotometer. (1) Purity not given, meet British Pharmacopoeia quality requirements, Excess solute and solvent were placed in a stoppered dark glass flask and chemical source not specified, no purification details were provided in the allowed to equilibrate with stirring in a thermostatic mechanical shaker bath paper. (for measurements at 303.15, 308.15, and 313.15 K), or in a recirculating (2) Absolute, Analytical Reagent grade, Merck Chemical Company, dried over thermostatic bath (for measurements at 293.15 and 298.15 K) for at least three molecular sieves before use. days. An aliquot of the saturated solution was removed, isothermally filtered, and diluted quantitatively with an aqueous 0.10 molar sodium hydroxide Estimated Error: solution. The molar solubility of the drug was determined by Temperature: 0.05 K.

spectrophotometric analysis at 281 nm. The reported values represent the x1: 6% (relative error). average of at least three determinations. The densities of the saturated solutions were measured in order to convert the measured molar solubilities (in units of mol dm3) to mole fraction solubilities. Components: Original Measurements: Source and Purity of Chemicals: (1) 1-(4-Chlorobenzoyl)-2-methyl- 126A. Alhalaweh, A. Sokolowski, (1) Purity not given, Sigma-Aldrich Chemical Company, USA, no puriﬁcation 5-methoxyindole-3-acetic acid N. R. Hornedo, and S. P. Velaga, details were given in the paper. (Indomethacin); C H ClNO ; Cryst. Growth Des. 11, 3923 (2) Absolute, Analytical Reagent grade, Merck Chemical Company, Germany, 15 16 4 [53-86-1] (2011). no puriﬁcation details were given in the paper. (2) Ethanol; C2H6O; [64-17-5] Estimated Error: Variables: Prepared by: Temperature: 0.05 K. T/K ¼ 298.15 W. E. Acree, Jr. x1: 3% (relative error).

Experimental Values

The measured solubility was reported to be c1 ¼ 0.054 Components: Original Measurements: 3 γ 129 mol dm . The equilibrium solid phase was the -form of the (1) 1-(4-Chlorobenzoyl)-2-methyl- M. A. Ruidiaz, D. R. Delgado, solute. 5-methoxyindole-3-acetic acid and F. Martinez, Rev. Acad.

(Indomethacin); C15H16ClNO4; Colomb. Cienc. 35, 329 (2011). [53-86-1]

(2) Ethanol; C2H6O; [64-17-5] Variables: Prepared by: Temperature W. E. Acree, Jr.

Auxiliary Information Source and Purity of Chemicals: (1) Purity not given, Sigma-Aldrich Chemical Company, USA, no purification / / Method Apparatus Procedure: details were given in the paper. Magnetic stirrer, constant-temperature bath, x-ray powder diffractometer, and (2) Purity not given, Dow Chemical Company, USA, no purification details a high-performance liquid chromatograph. were given in the paper. Excess solute and solvent were placed in sealed glass vials and allowed to equilibrate at a constant temperature with stirring for 24 h. Aliquots of Estimated Error: μ saturated solutions were removed, filtered through a 0.2 m cellulose acetate Temperature: 0.05 K. membrane filter or 0.45 μm polypropylene membrane filter, and diluted x1: 3% (relative error). quantitatively for high-performance liquid chromatographic analyses. Solubility measurements were repeated after an additional 72 h to ensure that equilibrium had been obtained. Samples of the equilibrated solid phase were removed, filtered, dried, and analyzed by powder x-ray diffraction. Components: Original Measurements: 130 í Source and Purity of Chemicals: (1) 1-(4-Chlorobenzoyl)-2-methyl- A. R. Holgu n, G. A. í (1) Purity not given, Sigma-Aldrich Chemical Company, Stockholm, Sweden, 5-methoxyindole-3-acetic acid Rodr guez, D. M. Cristancho, D. í used as received. (Indomethacin); C15H16ClNO4; R. Delgado, and F. Mart nez, [ ] (2) 99.5%, Kemetyl, Sweden, used as received. 53-86-1 Fluid Phase. Equil. 314, 134 (2) 1,2-Propanediol; C3H8O2; (2012). Estimated Error: [57-55-6] Temperature: 0.5 K. Variables: Prepared by: % c1: 5 (relative error, estimated by compiler). Temperature W. E. Acree, Jr.

Experimental Values Components: Original Measurements: (1) 1-(4-Chlorobenzoyl)-2-methyl- 128E. A. Cantillo, D. R. Delgado, a b 5-methoxyindole-3-acetic acid and F. Martinez, J. Mol. Liq. 181, T/K x2 x1 (Indomethacin); C15H16ClNO4; 62 (2013). 293.15 0.9986 0.001372 [53-86-1] 298.15 0.9983 0.001690 (2) 1,2-Propanediol; C3H8O2; 303.15 0.9977 0.002267 [57-55-6] 308.15 0.9970 0.002950 Variables: Prepared by: 313.15 0.9963 0.003683 a Temperature W. E. Acree, Jr. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Experimental Values Auxiliary Information Method/Apparatus/Procedure: T/K x a x b 2 1 Thermostatic mechanical shaker bath, recirculating thermostatic bath, and an 293.15 0.9988 0.001186 UV/visible spectrophotometer. 298.15 0.9984 0.001588 Excess solute and solvent were placed in a stoppered dark glass flask and 303.15 0.9978 0.002204 allowed to equilibrate with stirring in a thermostatic mechanical shaker bath 308.15 0.9969 0.003082 (for measurements at 303.15, 308.15, and 313.15 K), or in a recirculating 313.15 0.9963 0.003719 thermostatic bath (for measurements at 293.15 and 298.15 K) for at least three a x2: mole fraction of component 2 in the saturated solution. days. An aliquot of the saturated solution was removed, isothermally filtered, b x1: mole fraction solubility of the solute. and diluted quantitatively for spectrophotometric analyses. The reported values represent the average of at least three determinations. The densities of the saturated solutions were measured in order to convert the measured molar Auxiliary Information solubilities (in units of mol dm 3) to mole fraction solubilities. / / Method Apparatus Procedure: Source and Purity of Chemicals: Thermostatic mechanical shaker bath, recirculating thermostatic bath, and an (1) 99.8%, chemical source not specified, no purification details were given in / UV visible spectrophotometer. the paper. Excess solute and solvent were placed in a stoppered dark glass flask and (2) 99.8%, chemical source not specified, no purification details were given in allowed to equilibrate with stirring in a thermostatic mechanical shaker bath the paper. (for measurements at 303.15, 308.15, and 313.15 K), or in a recirculating thermostatic bath (for measurements at 293.15 and 298.15 K) for at least three Estimated Error: days. An aliquot of the saturated solution was removed, isothermally filtered, Temperature: 0.05 K. and diluted quantitatively with an aqueous 0.10 molar sodium hydroxide x1: 2% (relative error). solution. The molar solubility of the drug was determined by spectrophotometric analysis at 281 nm. The reported values represent the average of at least three determinations. The densities of the saturated solutions were measured in order to convert the measured molar solubilities (in units of mol dm3) to mole fraction solubilities.

14.5. Indomethacin solubility data in ketones Experimental Values

ð Þ T/ w s a x b Components: Original Measurements: K 2 1 (1) 1-(4-Chlorobenzoyl)-2-methyl- 127S. Hellstén, H. Qu, and M. 293.15 0.00 0.001186 5-methoxyindole-3-acetic acid Louhi-Kultanen, Chem. Eng. 293.15 0.10 0.001201

(Indomethacin); C15H16ClNO4; Technol. 34, 1667 (2011). 293.15 0.20 0.001246 [53-86-1] 293.15 0.30 0.001291

(2) Propanone; C3H6O; [67-64-1] 293.15 0.40 0.001430 293.15 0.50 0.001509 Variables: Prepared by: 293.15 0.60 0.001696 / ¼ T K 298.2 W. E. Acree, Jr. 293.15 0.70 0.001854 293.15 0.80 0.002109 293.15 0.90 0.002303 Experimental Values 293.15 1.00 0.002530 The measured molal solubility was reported to be m1 ¼ 0.358 mol/kg of solvent. The equilibrated solid phase was the 298.15 0.00 0.001588 α-form of indomethacin plus solvate. 298.15 0.10 0.001626 298.15 0.20 0.001696 298.15 0.30 0.001820 Auxiliary Information 298.15 0.40 0.001988 298.15 0.50 0.002181 Method/Apparatus/Procedure: 298.15 0.60 0.002403 Constant-temperature bath, analytical balance, confocal Raman microscope 298.15 0.70 0.002542 equipped with a laser. 298.15 0.80 0.002824 Solubility was determined gravimetrically using the shake flask method. 298.15 0.90 0.003258 Excess solute and solvent were placed in sealed flasks and allowed to 298.15 1.00 0.003423 equilibrate in a constant-temperature bath with stirring for 24 h. An aliquot of the saturated solution was withdrawn using a syringe equipped with a 0.20 μm 303.15 0.00 0.002204 pore size cellulose membrane filter. The sample was transferred to a tared 303.15 0.10 0.002250 container, weighed, and the solvent evaporated at reduced pressure at 309 K 303.15 0.20 0.002284 until constant mass was obtained. The solubility was calculated from the mass 303.15 0.30 0.002442 of the solid residue and the mass of the sample analyzed. The equilibrated solid 303.15 0.40 0.002675 phase was analyzed using a confocal Raman microscope equipped with a laser 303.15 0.50 0.002960 operating at 785 nm as the excitation source. 303.15 0.60 0.003310 303.15 0.70 0.003569 Source and Purity of Chemicals: 303.15 0.80 0.003861 (1) Purity not given, USP grade, Hawkins, Inc., used as received. 303.15 0.90 0.004369 (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, 303.15 1.00 0.004528 used as received. 308.15 0.00 0.003082 Estimated Error: 308.15 0.10 0.003107 Temperature: 0.2 K (estimated by compiler). 308.15 0.20 0.003148 m : 3% (relative error, estimated by compiler). 1 308.15 0.30 0.003258 308.15 0.40 0.003657 308.15 0.50 0.003980 308.15 0.60 0.004528 14.6. Indomethacin solubility data in binary organic 308.15 0.70 0.004902 solvent mixtures 308.15 0.80 0.005406 308.15 0.90 0.005807 308.15 1.00 0.005877

Components: Original Measurements: 128 313.15 0.00 0.003719 (1) 1-(4-Chlorobenzoyl)-2-methyl- E. A. Cantillo, D. R. Delgado, 313.15 0.10 0.003807 5-methoxyindole-3-acetic acid and F. Martinez, J. Mol. Liq. 181, 313.15 0.20 0.004031 (Indomethacin); C15H16ClNO4; 62 (2013). 313.15 0.30 0.004309 [ ] 53-86-1 313.15 0.40 0.004809 [ ] (2) Ethanol; C2H6O; 64-17-5 313.15 0.50 0.005289 (3) 1,2-Propanediol; C3H8O2; 313.15 0.60 0.006103 [ ] 57-55-6 313.15 0.70 0.006701 Variables: Prepared by: 313.15 0.80 0.007509 Temperature; Solvent composition W. E. Acree, Jr. 313.15 0.90 0.007650 313.15 1.00 0.007711

a ðsÞ w2 : initial mass fraction of component 2 in the binary solvent mixture. b x1: mole fraction solubility of the solute.

Auxiliary Information Auxiliary Information Method/Apparatus/Procedure: Method/Apparatus/Procedure: Thermostatic mechanical shaker bath, recirculating thermostatic bath, and an Constant-temperature bath, analytical balance, confocal Raman microscope UV/visible spectrophotometer. equipped with a laser. Excess solute and solvent were placed in a stoppered dark glass flask and Solubility was determined gravimetrically using the shake flask method. allowed to equilibrate with stirring in a thermostatic mechanical shaker bath Excess solute and solvent were placed in sealed flasks and allowed to (for measurements at 303.15, 308.15, and 313.15 K), or in a recirculating equilibrate in a constant-temperature bath with stirring for 24 h. An aliquot of thermostatic bath (for measurements at 293.15 and 298.15 K) for at least three the saturated solution was withdrawn using a syringe equipped with a 0.20 μm days. An aliquot of the saturated solution was removed, isothermally filtered, pore size cellulose membrane filter. The sample was transferred to a tared and diluted quantitatively with an aqueous 0.10 molar sodium hydroxide container, weighed, and the solvent evaporated at reduced pressure at 309 K solution. The molar solubility of the drug was determined by until constant mass was obtained. The solubility was calculated from the mass spectrophotometric analysis at 281 nm. The reported values represent the of the solid residue and the mass of the sample analyzed. The equilibrated solid average of at least three determinations. The densities of the saturated solutions phase was analyzed using a confocal Raman microscope equipped with a laser were measured in order to convert the measured molar solubilities (in units of operating at 785 nm as the excitation source. mol dm3) to mole fraction solubilities. Source and Purity of Chemicals: Source and Purity of Chemicals: (1) Purity not given, USP grade, Hawkins, Inc., used as received. (1) Purity not given, Sigma-Aldrich Chemical Company, USA, no purification (2) Purity not given, LiChrosolv, Merck Chemical Company, used as received. details were given in the paper. (3) Purity not given, stabilized with 0.5% of methanol, Orion, used as received. (2) Absolute, Analytical Reagent grade, Merck Chemical Company, Germany, no purification details were given in the paper. Estimated Error: (3) Purity not given, Dow Chemical Company, USA, no purification details Temperature: 0.2 K. (s) were given in the paper. x2 : 0.001. m1: 3% (relative error). Estimated Error: Temperature: 0.01 K. ðsÞ w2 : 0.01. % x1: 3 (relative error). Components: Original Measurements: (1) 1-(4-Chlorobenzoyl)-2-methyl- 127S. Hellstén, H. Qu, and M. 5-methoxyindole-3-acetic acid Louhi-Kultanen, Chem. Eng.

(Indomethacin); C15H16ClNO4; Technol. 34, 1667 (2011). [ ] Components: Original Measurements: 53-86-1 [ ] (1) 1-(4-Chlorobenzoyl)-2-methyl- 127S. Hellstén, H. Qu, and M. (2) Ethanol; C2H6O; 64-17-5 5-methoxyindole-3-acetic acid Louhi-Kultanen, Chem. Eng. (3) Dichloromethane; CH2Cl2; [75-09-2] (Indomethacin); C15H16ClNO4; Technol. 34, 1667 (2011). [ ] 53-86-1 Variables: Prepared by: [ ] (2) Methanol; CH4O; 67-56-1 T/K ¼ 298.2; Solvent composition W. E. Acree, Jr. (3) Dichloromethane; CH2Cl2; [75-09-2] Variables: Prepared by: Experimental Values T/K ¼ 298.2; Solvent composition W. E. Acree, Jr.

(s)a b c x2 m1 Equilibrated solid phase Experimental Values 0.000 0.135 α-form + solvate 0.170 0.653 Solvate 0.245 0.672 Solvate (s)a b c x2 m1 Equilibrated solid phase 0.315 0.710 Solvate 0.000 0.135 α-form + solvate 0.316 0.498 Solvate α + γ 0.227 0.783 α-form + solvate 0.381 0.468 -form -form 0.397 0.969 α-form + solvate 0.442 0.766 Solvate 0.399 0.930 α-form + solvate 0.443 0.787 Solvate γ + 0.532 0.885 α-form + solvate 0.549 0.610 -form solvate α 0.534 0.862 Solvate 0.552 0.469 -form α + γ 0.638 0.731 Solvate 0.646 0.476 -form -form γ 0.640 0.696 Solvate 0.729 0.335 -form α + γ 0.799 0.336 Solvate 1.000 0.078 -form -form α + a (s) 1.000 0.0712 -form solvate x2 : initial mole fraction of component 2 in the binary solvent mixture. a (s) bm : molal solubility of the solute given as moles of dissolved solute per x2 : initial mole fraction of component 2 in the binary solvent mixture. 1 bm : molal solubility of the solute given as moles of dissolved solute per kilogram of solvent. 1 c α γ kilogram of solvent. Possible phases: -form of indomethacin, -form of indomethacin, and solid cPossible phases: α-form of indomethacin, γ-form of indomethacin, and solid solvate. solvate.

Auxiliary Information Auxiliary Information Method/Apparatus/Procedure: Method/Apparatus/Procedure: Constant-temperature bath, analytical balance, confocal Raman microscope Constant-temperature bath, analytical balance, confocal Raman microscope equipped with a laser. equipped with a laser. Solubility was determined gravimetrically using the shake flask method. Solubility was determined gravimetrically using the shake flask method. Excess solute and solvent were placed in sealed flasks and allowed to Excess solute and solvent were placed in sealed flasks and allowed to equilibrate in a constant-temperature bath with stirring for 24 h. An aliquot of equilibrate in a constant-temperature bath with stirring for 24 h. An aliquot of the saturated solution was withdrawn using a syringe equipped with a 0.20 μm the saturated solution was withdrawn using a syringe equipped with a 0.20 μm pore size cellulose membrane filter. The sample was transferred to a tared pore size cellulose membrane filter. The sample was transferred to a tared container, weighed, and the solvent evaporated at reduced pressure at 309 K container, weighed, and the solvent evaporated at reduced pressure at 309 K until constant mass was obtained. The solubility was calculated from the mass until constant mass was obtained. The solubility was calculated from the mass of the solid residue and the mass of the sample analyzed. The equilibrated solid of the solid residue and the mass of the sample analyzed. The equilibrated solid phase was analyzed using a confocal Raman microscope equipped with a laser phase was analyzed using a confocal Raman microscope equipped with a laser operating at 785 nm as the excitation source. operating at 785 nm as the excitation source.

Source and Purity of Chemicals: Source and Purity of Chemicals: (1) Purity not given, USP grade, Hawkins, Inc., used as received. (1) Purity not given, USP grade, Hawkins, Inc., used as received. (2) 99.5%, Altia Chemical Company, used as received. (2) Purity not given, LiChrosolv, Merck Chemical Company, used as received. (3) Purity not given, stabilized with 0.5% of methanol, Orion, used as received. (3) Purity not give, Analytical Reagent grade, Merck Chemical Company, used as received. Estimated Error: Temperature: 0.2 K. Estimated Error: (s) x2 : 0.001. Temperature: 0.2 K. (s) m1: 3% (relative error). x2 : 0.001. m1: 3% (relative error).

Components: Original Measurements: (1) 1-(4-Chlorobenzoyl)-2-methyl- 127S. Hellstén, H. Qu, and M. Components: Original Measurements: 5-methoxyindole-3-acetic acid Louhi-Kultanen, Chem. Eng. (1) 1-(4-Chlorobenzoyl)-2-methyl- 127S. Hellstén, H. Qu, and M.

(Indomethacin); C15H16ClNO4; Technol. 34, 1667 (2011). 5-methoxyindole-3-acetic acid Louhi-Kultanen, Chem. Eng. [53-86-1] (Indomethacin); C15H16ClNO4; Technol. 34, 1667 (2011). (2) Methanol; CH4O; [67-56-1] [53-86-1] (3) Propanone; C3H6O; [67-64-1] (2) Ethanol; C2H6O; [64-17-5] (3) Propanone; C H O; [67-64-1] Variables: Prepared by: 3 6 T/K ¼ 298.2; Solvent composition W. E. Acree, Jr. Variables: Prepared by: T/K ¼ 298.2; Solvent composition W. E. Acree, Jr.

Experimental Values Experimental Values

(s)a b c x2 m1 Equilibrated solid phase (s)a b c 0.000 0.358 α-form + solvate x2 m1 Equilibrated solid phase 0.233 0.339 Solvate 0.000 0.358 α-form + solvate 0.234 0.585 Solvate 0.175 0.501 Solvate 0.407 0.634 γ-form + solvate 0.255 0.558 γ-form + solvate 0.408 0.621 α-form 0.323 0.589 γ-form + solvate 0.477 0.635 γ-form 0.324 0.609 α-form + solvate 0.478 0.673 Solvate 0.450 0.593 α-form + γ-form + solvate 0.540 0.612 γ-form 0.451 0.601 α-form + γ-form 0.541 0.640 γ-form + solvate 0.560 0.568 α-form + γ-form + solvate 0.646 0.579 α-form + solvate 0.562 0.573 α-form + γ-form 0.647 0.576 α-form + γ-form 0.657 0.505 α-form + γ-form 0.804 0.385 α-form + γ-form 0.741 0.423 α-form + γ-form 0.805 0.395 γ-form + solvate 0.741 0.421 α-form 1.000 0.071 α-form + solvate 1.000 0.078 α-form + solvate a (s) a (s) x2 : initial mole fraction of component 2 in the binary solvent mixture. x2 : initial mole fraction of component 2 in the binary solvent mixture. b b m1: molal solubility of the solute given as moles of dissolved solute per m1: molal solubility of the solute given as moles of dissolved solute per kilogram of solvent. kilogram of solvent. cPossible phases: α-form of indomethacin, γ-form of indomethacin, and solid cPossible phases: α-form of indomethacin, γ-form of indomethacin, and solid solvate. solvate.

Source and Purity of Chemicals: Source and Purity of Chemicals: (1) Purity not given, USP grade, Hawkins, Inc., used as received. (1) Purity not given, USP grade, Hawkins, Inc., used as received. (2) 99.5%, Altia Chemical Company, was used as received. (2) Purity not given, LiChrosolv, Merck Chemical Company, used as received. (3) Purity not given, Analytical Reagent grade, Merck Chemical Company, (3) 99.5%, Merck Chemical Company, Germany, used as received. used as received. Estimated Error: Estimated Error: Temperature: 0.2 K. (s) Temperature: 0.2 K. x2 : 0.001. (s) x2 : 0.001. m1: 3% (relative error). m1: 3% (relative error).

Components: Original Measurements: Components: Original Measurements: (1) 1-(4-Chlorobenzoyl)-2-methyl- 127S. Hellstén, H. Qu, and M. (1) 1-(4-Chlorobenzoyl)-2-methyl- 127S. Hellstén, H. Qu, and M. 5-methoxyindole-3-acetic acid Louhi-Kultanen, Chem. Eng.

5-methoxyindole-3-acetic acid Louhi-Kultanen, Chem. Eng. (Indomethacin); C15H16ClNO4; Technol. 34, 1667 (2011). (Indomethacin); C15H16ClNO4; Technol. 34, 1667 (2011). [53-86-1] [53-86-1] (2) Ethanol; C2H6O; [64-17-5] (2) Methanol; CH4O; [67-56-1] (3) Ethyl ethanoate; C4H8O2; (3) Ethyl ethanoate; C4H8O2; [141-78-6] [141-78-6] Variables: Prepared by: Variables: Prepared by: T/K ¼ 298.2; Solvent composition W. E. Acree, Jr. T/K ¼ 298.2; Solvent composition W. E. Acree, Jr.

Experimental Values Experimental Values

(s)a b c x2 m1 Equilibrated solid phase (s)a b c x2 m1 Equilibrated solid phase 0.000 0.127 α-form + γ-form + solvate 0.000 0.127 α-form + γ-form + solvate 0.328 0.349 α-form 0.234 0.297 α-form + γ-form 0.451 0.377 α-form + γ-form 0.407 0.406 α-form + γ-form 0.481 0.374 α-form 0.409 0.393 γ-form 0.512 0.387 α-form 0.437 0.425 α-form 0.559 0.366 α-form 0.478 0.418 α-form 0.561 0.367 α-form 0.539 0.430 α-form 0.610 0.358 α-form + solvate 0.541 0.416 α-form + γ-form 0.656 0.329 α-form + γ-form 0.597 0.418 α-form + γ-form 0.656 0.331 α-form + γ-form 0.647 0.402 α-form + γ-form 0.700 0.303 α-form + γ-form 0.650 0.406 γ-form 0.742 0.275 γ-form 0.733 0.359 α-form + γ-form + solvate 0.816 0.222 γ-form 0.805 0.268 α-form + solvate 0.818 0.219 α-form 1.000 0.071 α-form + solvate 1.000 0.078 α-form + γ-form a (s) a (s) x2 : initial mole fraction of component 2 in the binary solvent mixture. x2 : initial mole fraction of component 2 in the binary solvent mixture. b b m1: molal solubility of the solute given as moles of dissolved solute per m1: molal solubility of the solute given as moles of dissolved solute per kilogram of solvent. kilogram of solvent. cPossible phases: α-form of indomethacin, γ-form of indomethacin, and solid cPossible phases: α-form of indomethacin, γ-form of indomethacin, and solid solvate. solvate.

Auxiliary Information entire solvent composition range. They reported the experi- Method/Apparatus/Procedure: mental solubility in 1,2-propanediol as 369.1 mg/ml of satu- Constant-temperature bath, analytical balance, confocal Raman microscope rated solution. Solubility data for the binary mixtures were equipped with a laser. given only in graphical form as the milligrams of dissolved Solubility was determined gravimetrically using the shake flask method. solute per milliliter of saturated solution versus the initial Excess solute and solvent were placed in sealed flasks and allowed to equilibrate in a constant-temperature bath with stirring for 24 h. An aliquot of volume percent composition of the organic cosolvent calcu- the saturated solution was withdrawn using a syringe equipped with a 0.20 μm lated as if the solute were not present. pore size cellulose membrane filter. The sample was transferred to a tared Daniels et al.134 used their measured solubility data for container, weighed, and the solvent evaporated at reduced pressure at 309 K ketoprofen in ethyl ethanoate, 1,1′-oxybisethane, and seven until constant mass was obtained. The solubility was calculated from the mass alcohol solvents, combined with published solubility and of the solid residue and the mass of the sample analyzed. The equilibrated solid phase was analyzed using a confocal Raman microscope equipped with a laser partition coefficient data, to calculate the Abraham solute operating at 785 nm as the excitation source. descriptors of ketoprofen. The authors were able to assemble a total of 19 log10(SR or P) equations for which experimental Source and Purity of Chemicals: partition coefficient data, solubility ratios, Abraham Model (1) Purity not given, USP grade, Hawkins, Inc., used as received. equation coefficients, and aqueous molar solubility were (2) 99.5%, Altia Chemical Company, was used as received. (3) 99.5%, Merck Chemical Company, Germany, used as received. available. The logarithm of the aqueous molar solubility of 118,144,145 ketoprofen is log10c1,W ¼ –3.16. Other numerical Estimated Error: values for the molar solubility of ketoprofen in water are Temperature: 0.2 K. log c ¼ –3.29,146 log c ¼ –3.25,60 log c ¼ (s) 10 1,W 10 1,W 10 1,W x2 : 0.001. –3.33,147 and log c ¼ –3.43.148 The McGowan volume m : 3% (relative error). 10 1,W 1 of ketoprofen, V ¼ 1.9779, was calculated from the number of chemical bonds in the molecule and the individual atomic group volumes, AVi, given in Sec. 1.3. The excess molar refraction solute descriptor was estimated as E ¼ 1.650. This 15. Solubility of Ketoprofen in Organic left three solute descriptors (S, A, and B) still to be determined. Solvents The 19 equations were then solved using the Microsoft “SOLVER” program to yield numerical values of the remain- 15.1. Critical evaluation of experimental solubility ing solute descriptors, S ¼ 2.260, A ¼ 0.550, and B ¼ 0.890, data that best described the log10(SR or P) values. The calculated α Ketoprofen (more formally named 3-benzoyl- -methylben- molecular solute descriptors reproduced the log10(SR or P) zeneacetic acid) is a NSAID which is available in both values to within an average standard deviation of 0.123 log10 nonprescription and prescription formulations. Nonprescrip- units. tion ketoprofen is used to relieve minor headaches, toothaches, Table 9 compares the experimental log10c1 values to cal- muscle and backaches, and the common cold. Physicians culated values based on Eq. (28) of the Abraham model. For prescribe ketoprofen to individuals suffering with osteoarthri- comparison purposes, the measured mole-fraction solubilities 134 tis and rheumatoid arthritis to manage pain and inflammation. of ketoprofen, x1, determined by Daniels et al. were con- 60,64,65,100,131–143 There have been several published studies verted into molar solubilities by dividing x1 by the ideal molar sat involving the solubility of ketoprofen in organic solvents at volume of the saturated solution (i.e., c1 ¼ x1/[x1V1 + (1 – x1) 136 298 K. Most notably, Perlovich et al. determined the mole- Vsolvent]. The molar volume of the hypothetical subcooled 3 1 fraction solubility of ketoprofen in eight primary alcohols liquid ketoprofen is Vsolute ¼ 185.75 cm mol . Examination (methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-hex- of the numerical entries in Table 9 reveals that the Abraham anol, 1-heptanol, and 1-octanol). Daniels et al.134 later model provides a reasonably accurate mathematical descrip- reported the solubility behavior of ketoprofen in ethyl ethano- tion of the observed solubility data for many of the organic ate, 1,1′-oxybisethane, methanol, ethanol, 1-propanol, 2-pro- solvents. panol, 2-methyl-1-propanol, 1-pentanol, and 1-decanol. There is considerable variation in the independent sets of Bustamante and Selles,133 Gantiva and Martínez,139 Ribeiro ketoprofen solubility data for both methanol and ethanol at et al.,137 and Fini et al.60 also performed ketoprofen solubility 298 K. In the case of ethanol, the molar solubility data 100 134 measurements at 298 K. Takahashi et al. measured the determined by Daniels et al. (log10c1 ¼0.040) is in very solubility of ketoprofen in diethyl butanedioate, diethyl hex- good agreement with the value reported by Perlovich et al.136 anedioate, diisopropyl hexanedioate, and diethyl decanedioate (log10c1 ¼0.069). Both sets of values differ significantly 137 at 305 K in their study concerning the use of fatty diesters as a from the value of log10c1 ¼ 0.0429 that Ribeiro et al. means to enhance NSAID permeation through skin. Wenkers published. For ethanol, there have been five published experi- and Lippold64 reported solubility data for ten NSAIDs (aspirin, mental values for the molar solubility of ketoprofen, and the diclofenac, diflunisal, flufenamic acid, ibuprofen, ketoprofen, values differ fairly significantly, ranging from c1 ¼ 0.685 mol 3 3 nabumetone, naproxen, piroxicam, and tenoxicam) in light dm to c1 ¼ 2.685 mol dm . Given the large variation in the mineral oil at 305 K. Kumprakob et al.141 determined the observed values, it is not possible to list a recommended value. solubility of ketoprofen in binary water + 1,2-propanediol and More detailed studies are needed to identify the reason for the water + 1,2,3-propanetriol solvent mixtures at 310 K over the large differences in published values. Future studies need to

TABLE 9. Comparison between observed and predicted molar solubilities of ketoprofen based on the Abraham model, Eq. (28)

calc log10c1 ; exp exp exp exp Solvent Eq. (28) log10c1 log10c1 log10c1 log10c1 Methanol 0.120 0.040a 0.069b 0.391c Ethanol 0.183 0.016a 0.019b 0.164d 0.242c 0.429e 1-Propanol 0.042 0.000a 0.000b 2-Propanol 0.002 0.146a 1-Butanol 0.228 0.062b 2-Butanol 0.012 0.144a 2-Methyl-1-propanol 0.162 0.004a 1-Pentanol 0.186 0.169a 0.168b 1-Hexanol 0.107 0.203b 1-Heptanol 0.165 0.333b 1-Octanol 0.188 0.366b 0.349f 1-Decanol 0.361 0.362a 1,1′-Oxybisethane 0.124 0.010a Ethyl ethanoate 0.167 0.136a aExperimental value from Daniels et al.134 bExperimental value from Perlovich et al.136 cExperimental value from Ribeiro et al.137 dExperimental value from Gantiva and Martínez.139 eExperimental value from Gantiva et al.138 fExperimental value from Fini et al.60

examine the equilibrated solid phase in greater detail to The experimental solubility data for ketoprofen in organic determine if ketoprofen exhibits polymorphism and whether solvents are given in Secs. 15.2–15.9. the phase is crystalline. For the other solvents listed in Table 9, there are at most only two independent measurements. 15.2. Ketoprofen solubility data in saturated There have been four experimental studies60,138,139,142 hydrocarbons (including cycloalkanes) reporting the solubility of ketoprofen as a function of temperature. Fini et al.60 determined the molar solubility of ketoprofen in 1-octanol at only three temperatures from 278 138,139 Components: Original Measurements: to 310 K. Gantiva et al. measured the solubility of (1) 3-Benzoyl- 131N. A. Abd-El Gawad, Bull. Fac. ketoprofen in cyclohexane, ethanol, and 1,2-propanediol at α-methylbenzeneacetic acid Pharm. Cairo Univ. 35, 137 several temperatures from 293 to 313 K using a spectrophoto- (( )-Ketoprofen); C16H14O3; (1997). metric method of analysis. Espitalier et al.142 reported solu- [22071-15-4] [ ] bility data for ketoprofen in propanone at several temperatures (2) Hexane; C6H14; 110-54-3 between 283 and 322 K. The authors used an hplc to quantify Variables: Prepared by: the concentration of the dissolved solute. The internal con- T/K ¼ 298.15 W. E. Acree, Jr. sistency of the latter four datasets was assessed by curve-fitting the measured mole fraction solubility data to Eq. (8). The Experimental Values values of the equation coefficients (A, B, and C) are given in Table 10, along with the mean absolute relative deviation. a b Each of the four data sets is considered internally consistent as x2 x1 evidenced by the small MARD values. There were insufficient 0.9989 0.0011 60 a experimental measurements in the Fini et al. dataset to x2: mole fraction of component 2 in the saturated solution. b obtain a meaningful regression analysis. x1: mole fraction solubility of the solute.

Auxiliary Information TABLE 10. Parameters of the Modified Apelblat equation for describing the solubility of ketoprofen in organic solvents Method/Apparatus/Procedure: / MARD Oscillating thermostatically controlled water bath and an ultraviolet visible Solvent T/K ABC(%) spectrophotometer. Excess solute and solvent were placed in a screw-capped vial, and allowed to a Cyclohexane 293–313 140.622 113.960 22.896 4.4 equilibrate with shaking for 24 h in a constant-temperature bath. At the end of b Ethanol 293–313 43.246 116.185 7.271 0.1 the shaking period, the sample was allowed to stand unagitated for another a 1,2-Propanediol 293–313 44.702 116.160 7.026 0.4 hour to allow the undissolved solid to the settle to the bottom of the container. c Propanone 283–322 50.372 116.031 8.463 0.9 Aliquots of saturated solution were withdrawn and rapidly filtered through a aData set of Gantiva and Martínez.139 0.45 μm membrane filter. Concentrations were determined by bData set of Gantiva et al.138 spectrophotometric measurements at 260 nm. cData set of Espitalier et al.142

Source and Purity of Chemicals: 15.3. Ketoprofen solubility data in aromatic (1) Purity not given, Alexandria Pharmaceutical Company, Egypt, no purification details were provided in the paper. hydrocarbons (2) Purity not given, chemical source not specified, no purification details were provided in the paper. Components: Original Measurements: Estimated Error: (1) 3-Benzoyl- 133P. Bustamante and E. Selles, Temperature: 1K. α-methylbenzeneacetic acid Ciencia Ind. Farm. 2, 403 (1983). % x1: 5 (relative error, estimated by compiler). (()-Ketoprofen); C16H14O3; [22071-15-4]

(2) Benzene; C6H6; [71-43-2] Variables: Prepared by: Components: Original Measurements: T/K ¼ 298.15 W. E. Acree, Jr. (1) 3-Benzoyl- 132M. Gantiva and F. Martínez, α-methylbenzeneacetic acid Fluid Phase Equilib. 293, 242 (( )-Ketoprofen); C16H14O3; (2010). Experimental Values [22071-15-4] The measured mole fraction solubility was reported to be x (2) Cyclohexane; C6H12; [110-82-7] 1 ¼ 0.0334. Variables: Prepared by: Temperature W. E. Acree, Jr. Auxiliary Information Method/Apparatus/Procedure: Experimental Values This is a secondary reference. The authors reference the experimental data to a presentation that they made in 1982. Source and Purity of Chemicals: / a b T K x2 x1 (1) Purity not given, chemical source not specified, no purification details were 293.15 0.9999 0.0000366 provided. 298.15 0.9999 0.0000598 (2) Purity not given, chemical source not specified, no purification details were 303.15 0.9999 0.0000807 provided. 308.15 0.9999 0.0001240 313.15 0.9998 0.0001620 Estimated Error: a Temperature: No information given in the paper. x2: mole fraction of component 2 in the saturated solution. % b x1: 5 (relative error, estimated by compiler). x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: / / Method Apparatus Procedure: (1) 3-Benzoyl- 133P. Bustamante and E. Selles, / Thermostatic mechanical shaker and an UV visible spectrophotometer. α-methylbenzeneacetic acid Ciencia Ind. Farm. 2, 403 (1983). Excess solute and solvent were placed in stoppered glass flasks and allowed to (()-Ketoprofen); C16H14O3; equilibrate in a thermostatic mechanical shaker at 313.15 K for at least five [22071-15-4] days. Once equilibrium had been attained, an aliquot of the saturated solution (2) Methylbenzene; C7H8; [108-88-3] was removed and filtered in order to remove insoluble particles. The concentration of the dissolved drug was determined by weighing an aliquot of Variables: Prepared by: the saturated filtered solution, which was then diluted for spectrophotometric T/K ¼ 298.15 W. E. Acree, Jr. analysis. The concentration of the dissolved drug was determined from the measured absorbance. Once the solubility was determined at 313.15 K, the temperature was decreased by 5 K and stabilized at 308.15 K for two days to Experimental Values allow the excess dissolved drug to precipitate at this lower temperature. An The measured mole fraction solubility was reported to be x1 aliquot of the new saturated solution was removed, filtered, and the solvent ¼ 0.0207. evaporated as before. The procedure was repeated by decreasing the temperature in 5 K increments to reach 293.15 K. The reported mole fraction Auxiliary Information solubilities represent the average of three experimental measurements. The densities of the saturated solutions were measured in order to convert the Method/Apparatus/Procedure: measured concentrations in mol dm3 to mole fraction solubilities. This is a secondary reference. The authors reference the experimental data to a presentation that they made in 1982. Source and Purity of Chemicals: (1) Purity not given, chemical source not specified, authors stated that the Source and Purity of Chemicals: sample met requirements indicated in the American Pharmacopeia, USP. (1) Purity not given, chemical source not specified, no purification details were (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, no provided. purification details were given in the paper. (2) Purity not given, chemical source not specified, no purification details were provided. Estimated Error: Temperature: 0.05 K. Estimated Error:

x1: 3.0% (relative error, estimated by compiler). Temperature: No information given in the paper. x1: 5% (relative error, estimated by compiler).

15.4. Ketoprofen solubility data in esters Experimental Values

The measured molar solubility was reported to be c1 ¼ 0.05899 mol dm3. Components: Original Measurements: (1) 3-Benzoyl- 134C. R. Daniels, A. K. Charlton, Auxiliary Information α-methylbenzeneacetic acid W. E. Acree, Jr., and M. H. / / (()-Ketoprofen); C16H14O3; Abraham, Phys. Chem. Liq. 42, Method Apparatus Procedure: [22071-15-4] 305 (2004). Magnetic stirrer and a high-performance liquid chromatograph.

(2) Ethyl ethanoate; C4H8O2; Excess solute and solvent were placed in a screw-capped vial. The contents [141-78-6] were stirred by an externally driven teflon-coated magnetic bar at ambient room temperature until equilibrium was obtained. An aliquot of the saturated Variables: Prepared by: solution was removed and filtered through 0.45 μm membrane filter (Millipore, T/K ¼ 298.15 W. E. Acree, Jr. Bedford, Massachusetts, USA). The concentration of the dissolved solute was determined by high-performance liquid chromatographic analysis after suitable dilution. Experimental Values Source and Purity of Chemicals: (1) Purity not given, Jeil Pharmaceutical Company, Seoul, South Korea, no x a x b 2 1 purification details were provided. 0.8470 0.1530 (2) Purity not given, Reagent grade, chemical source not specified, was used as a x2: mole fraction of component 2 in the saturated solution. received. b x1: mole fraction solubility of the solute. Estimated Error: Temperature: No information given in the paper. % Auxiliary Information c1: 2.7 (relative error, estimated by compiler). Method/Apparatus/Procedure: Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ visible spectrophotometer. Excess solute and solvent were placed in amber glass bottles and allowed to Components: Original Measurements: 100 equilibrate for several days at constant temperature. Attainment of equilibrium (1) 3-Benzoyl- K. Takahashi, H. Sakano, N. α was verified by several repetitive measurements and by approaching -methylbenzeneacetic acid Numata, S. Kuroda, and N. equilibrium from supersaturation. Aliquots of saturated solutions were (( )-Ketoprofen); C16H14O3; Mizuno, Drug Develop. Ind. [ ] transferred through a coarse filter into tared volumetric flasks, weighed, and 22071-15-4 Pharm. 28, 1285 (2002). diluted with methanol. Concentrations were determined by (2) Diethyl butanedioate; C8H14O4; [ ] spectrophotometric measurements at 280 nm. 123-25-1 Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 305.15 W. E. Acree, Jr. (1) 99+%, Sigma-Aldrich, St. Louis, Missouri, USA, and 99%, TCI America, Portland, Oregon, USA, was used as received. The purity of the commercial sample was 99.7% as determined by nonaqueous titration with freshly Experimental Values standardized sodium methoxide to the thymol blue endpoint according to the ¼ method of [J. S. Fritz and N. M. Lisicki, Anal. Chem. 23, 589 (1951)], except The measured solubility was reported to be c1 0.7947 3 that methylbenzene was substituted for benzene in the titration solvent. mol dm . (2) 99.9%, HPLC grade, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use. Auxiliary Information

Estimated Error: Method/Apparatus/Procedure: Temperature: 0.1 K. Constant-temperature bath and a high-performance liquid chromatograph.

x1: 1.5% (relative error). Excess solute and solvent were allowed to equilibrate with agitation for 24 h at constant temperature. The saturated solution was removed and filtered through a 0.45 μm membrane filter. The concentration of the dissolved solute was determined by high-performance liquid chromatographic analysis. Components: Original Measurements: Source and Purity of Chemicals: (1) 3-Benzoyl- 135Y.-J. Cho and H.-K. Choi, Int. (1) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, α-methylbenzeneacetic acid J. Pharm. 169, 95 (1998). Japan, no purification details were provided in the paper. (()-Ketoprofen); C H O ; 16 14 3 (2) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, [22071-15-4] Japan, no purification details were provided in the paper. (2) 1-Methylethyl tetradecanoate; C H O ; [110-27-0] 17 34 2 Estimated Error: Variables: Prepared by: Temperature: 0.2 K (estimated by compiler). T/K ¼ ambient room temperature W. E. Acree, Jr. c1: 5% (relative error, estimated by compiler).

Estimated Error: Components: Original Measurements: Temperature: 0.2 K (estimated by compiler). (1) 3-Benzoyl- 100K. Takahashi, H. Sakano, N. c1: 5% (relative error, estimated by compiler). α-methylbenzeneacetic acid Numata, S. Kuroda, and N.

(()-Ketoprofen); C16H14O3; Mizuno, Drug Develop. Ind. [22071-15-4] Pharm. 28, 1285 (2002).

(2) Diethyl hexanedioate; C10H18O4; [141-28-6] Components: Original Measurements: (1) 3-Benzoyl- 100K. Takahashi, H. Sakano, N. Variables: Prepared by: α-methylbenzeneacetic acid Numata, S. Kuroda, and N. T/K ¼ 305.15 W. E. Acree, Jr. (()-Ketoprofen); C16H14O3; Mizuno, Drug Develop. Ind. [22071-15-4] Pharm. 28, 1285 (2002).

(2) Diethyl decanedioate; C14H26O4; Experimental Values [110-40-7] ¼ The measured solubility was reported to be c1 0.7947 Variables: Prepared by: 3 mol dm . T/K ¼ 305.15 W. E. Acree, Jr.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: The measured solubility was reported to be c1 ¼ 0.4557 Constant-temperature bath and a high-performance liquid chromatograph. 3 Excess solute and solvent were allowed to equilibrate with agitation for 24 h at mol dm . constant temperature. The saturated solution was removed and filtered through a 0.45 μm membrane filter. The concentration of the dissolved solute was Auxiliary Information determined by high-performance liquid chromatographic analysis. Method/Apparatus/Procedure: Source and Purity of Chemicals: Constant-temperature bath and a high-performance liquid chromatograph. (1) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Excess solute and solvent were allowed to equilibrate with agitation for 24 h at Japan, no purification details were provided in the paper. constant temperature. The saturated solution was removed and filtered through μ (2) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, a 0.45 m membrane filter. The concentration of the dissolved solute was Japan, no purification details were provided in the paper. determined by high-performance liquid chromatographic analysis.

Estimated Error: Source and Purity of Chemicals: Temperature: 0.2 K (estimated by compiler). (1) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Japan, no puriﬁcation details were provided in the paper. c1: 5% (relative error, estimated by compiler). (2) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Japan, no puriﬁcation details were provided in the paper.

(()-Ketoprofen); C16H14O3; Mizuno, Drug Develop. Ind. [22071-15-4] Pharm. 28, 1285 (2002). (2) Diisopropyl hexanedioate;

C12H22O4; [6938-94-9] 15.5. Ketoprofen solubility data in ethers Variables: Prepared by: T/K ¼ 305.15 W. E. Acree, Jr. Components: Original Measurements: (1) 3-Benzoyl- 134C. R. Daniels, A. K. Charlton, Experimental Values α-methylbenzeneacetic acid W. E. Acree, Jr., and M. H. ¼ (( )-Ketoprofen); C16H14O3; Abraham, Phys. Chem. Liq. 42, The measured solubility was reported to be c1 0.4619 [22071-15-4] 305 (2004). 3 mol dm . (2) 1,1′-Oxybisethane; C4H10O; [60-29-7] Auxiliary Information Variables: Prepared by: / ¼ Method/Apparatus/Procedure: T K 298.15 W. E. Acree, Jr. Constant-temperature bath and a high-performance liquid chromatograph. Excess solute and solvent were allowed to equilibrate with agitation for 24 h at constant temperature. The saturated solution was removed and filtered through Experimental Values a 0.45 μm membrane filter. The concentration of the dissolved solute was determined by high-performance liquid chromatographic analysis. a b x2 x1 Source and Purity of Chemicals: 0.8888 0.1112 (1) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, a x2: mole fraction of component 2 in the saturated solution. Japan, no purification details were provided in the paper. b x1: mole fraction solubility of the solute. (2) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Japan, no purification details were provided in the paper.

Auxiliary Information 15.7. Ketoprofen solubility data in alcohols Method/Apparatus/Procedure: Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in amber glass bottles and allowed to (1) 3-Benzoyl- 136G. L. Perlovich, S. V. Kurkov, equilibrate for several days at constant temperature. Attainment of equilibrium α-methylbenzeneacetic acid A. N. Kinchin, and A. Bauer- was verified by several repetitive measurements and by approaching (()-Ketoprofen); C16H14O3; Brandl, J. Pharm. Sci. 92, 2502 equilibrium from supersaturation. Aliquots of saturated solutions were [22071-15-4] (2003). transferred through a coarse filter into tared volumetric flasks, weighed, and (2) Methanol; CH4O; [67-56-1] diluted with methanol. Concentrations were determined by spectrophotometric measurements at 280 nm. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) 99+%, Sigma-Aldrich, St. Louis, Missouri, USA, and 99%, TCI America, Portland, Oregon, USA, was used as received. The purity of the commercial Experimental Values sample was 99.7% as determined by nonaqueous titration with freshly standardized sodium methoxide to the thymol blue endpoint according to the a b method of [J. S. Fritz and N. M. Lisicki, Anal. Chem. 23, 589 (1951)], except x2 x1 that methylbenzene was substituted for benzene in the titration solvent. 0.9604 0.0396 (2) 99+%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, a x2: mole fraction of component 2 in the saturated solution. USA, stored over molecular sieves and distilled shortly before use. b x1: mole fraction solubility of the solute. Estimated Error: Temperature: 0.1 K. Auxiliary Information x1: 1.5% (relative error). Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate at constant temperature. Solubility of the dissolved 15.6. Ketoprofen solubility data in haloalkanes, solute was determined by spectrophotometric measurements. haloalkenes, and haloaromatic hydrocarbons Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Components: Original Measurements: purification details were provided. (1) 3-Benzoyl- 133P. Bustamante and E. Selles, (2) Purity not given, HPLC grade, Merck Chemical Company, Germany, no α-methylbenzeneacetic acid Ciencia Ind. Farm. 2, 403 (1983). purification details were provided.

(()-Ketoprofen); C16H14O3; [22071-15-4] Estimated Error: (2) Trichloromethane; CHCl ; Temperature: 0.1 K. 3 % [67-66-3] x1: 2.5 (relative error). Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Components: Original Measurements: 134 Experimental Values (1) 3-Benzoyl- C. R. Daniels, A. K. Charlton, α-methylbenzeneacetic acid W. E. Acree, Jr., and M. H.

The measured mole fraction solubility was reported to be x1 (()-Ketoprofen); C16H14O3; Abraham, Phys. Chem. Liq. 42, ¼ 0.1419. [22071-15-4] 305 (2004). (2) Methanol; CH4O; [67-56-1] Auxiliary Information Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Method/Apparatus/Procedure: This is a secondary reference. The authors reference the experimental data to a presentation that they made in 1982. Experimental Values Source and Purity of Chemicals: (1) Purity not given, chemical source not specified, no purification details were x a x b provided. 2 1 (2) Purity not given, chemical source not specified, no purification details were 0.9572 0.0428 a provided. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: Temperature: No information given in the paper.

x1: 5% (relative error, estimated by compiler).

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 3-Benzoyl- 136G. L. Perlovich, S. V. Kurkov, Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ α-methylbenzeneacetic acid A. N. Kinchin, and A. Bauer- visible spectrophotometer. (()-Ketoprofen); C16H14O3; Brandl, J. Pharm. Sci. 92, 2502 Excess solute and solvent were placed in amber glass bottles and allowed to [22071-15-4] (2003). equilibrate for several days at constant temperature. Attainment of equilibrium (2) Ethanol; C2H6O; [64-17-5] was verified by several repetitive measurements and by approaching Variables: Prepared by: equilibrium from supersaturation. Aliquots of saturated solutions were T/K ¼ 298.15 W. E. Acree, Jr. transferred through a coarse filter into tared volumetric flasks, weighed, and diluted with methanol. Concentrations were determined by spectrophotometric measurements at 280 nm. Experimental Values Source and Purity of Chemicals: (1) 99+%, Sigma-Aldrich, St. Louis, Missouri, USA, and 99%, TCI America, x a x b Portland, Oregon, USA, was used as received. The purity of the commercial 2 1 sample was 99.7% as determined by nonaqueous titration with freshly 0.9360 0.0640 a standardized sodium methoxide to the thymol blue endpoint according to the x2: mole fraction of component 2 in the saturated solution. [ ] b method of J. S. Fritz and N. M. Lisicki, Anal. Chem. 23, 589 (1951) , except x1: mole fraction solubility of the solute. that methylbenzene was substituted for benzene in the titration solvent. (2) 99.8%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use. Auxiliary Information Method/Apparatus/Procedure: Estimated Error: Constant-temperature bath and an UV/visible spectrophotometer. Temperature: 0.1 K. x : 1.5% (relative error). Very few experimental details were provided. Excess solute and solvent were 1 allowed to equilibrate at constant temperature. Solubility of the dissolved solute was determined by spectrophotometric measurements.

Source and Purity of Chemicals: Components: Original Measurements: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no 137 (1) 3-Benzoyl- A. E. Ribeiro, N. S. Graca, L. S. purification details were provided. α-methylbenzeneacetic acid Pais, and A. E. Rodrigues, Sep. (2) 99.6%, chemical source not specified, no purification details were (( )-Ketoprofen); C16H14O3; Purif. Technol. 61, 375 (2008). provided. [22071-15-4] [ ] (2) Methanol; CH4O; 67-56-1 Estimated Error: Variables: Prepared by: Temperature: 0.1 K. % T/K ¼ 298.15 W. E. Acree, Jr. x1: 2.5 (relative error).

Experimental Values Components: Original Measurements: (1) 3-Benzoyl- 134C. R. Daniels, A. K. Charlton, a b x2 x1 α-methylbenzeneacetic acid W. E. Acree, Jr., and M. H. 0.8444 0.1556 (( )-Ketoprofen); C16H14O3; Abraham, Phys. Chem. Liq. 42, [ ] a 22071-15-4 305 (2004). x2: mole fraction of component 2 in the saturated solution. [ ] b (2) Ethanol; C2H6O; 64-17-5 x1: mole fraction solubility of the solute. Variables: Prepared by: / ¼ Auxiliary Information T K 298.15 W. E. Acree, Jr. Method/Apparatus/Procedure: Constant-temperature bath and an analytical balance. Experimental Values Excess solute and solvent were placed in sealed containers and allowed to equilibrate in a constant-temperature bath. After equilibrium was reached, an a b aliquot of the clear saturated solution was transferred to a previously weighed x2 x1 glass vial. The mass of the vial plus the saturated solution was recorded. The 0.9299 0.0701 vial was then placed in oven at 303 K for solvent evaporation until a constant a mass was obtained. The solubility of the solute was calculated based on the x2: mole fraction of component 2 in the saturated solution. b mass of the solid residue and mass of the sample analyzed. x1: mole fraction solubility of the solute.

Source and Purity of Chemicals: (1) Purity not given, chemical source not specified, no purification details were provided. (2) Purity not given, chemical source not specified, no purification details were provided.

Estimated Error: Temperature: 0.2 K (estimated by compiler).

x1: 5% (relative error, estimated by compiler).

Auxiliary Information Auxiliary Information Method/Apparatus/Procedure: Method/Apparatus/Procedure: Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ Thermostatic mechanical shaker and an UV/visible spectrophotometer. visible spectrophotometer. Excess solute and solvent were placed in stoppered glass flasks and allowed to Excess solute and solvent were placed in amber glass bottles and allowed to equilibrate in a thermostatic mechanical shaker at 313.15 K for at least five equilibrate for several days at constant temperature. Attainment of equilibrium days. Once equilibrium had been attained, an aliquot of the saturated solution was verified by several repetitive measurements and by approaching was removed and filtered in order to remove insoluble particles. The equilibrium from supersaturation. Aliquots of saturated solutions were concentration of the dissolved drug was determined by weighing an aliquot of transferred through a coarse filter into tared volumetric flasks, weighed, and the saturated filtered solution, which was then diluted for spectrophotometric diluted with methanol. Concentrations were determined by analysis. The concentration of the dissolved drug was determined from the spectrophotometric measurements at 280 nm. measured absorbance. Once the solubility was determined at 313.15 K, the temperature was decreased by 5 K and stabilized at 308.15 K for two days to Source and Purity of Chemicals: allow the excess dissolved drug to precipitate at this lower temperature. An (1) 99+%, Sigma-Aldrich, St. Louis, Missouri, USA, and 99%, TCI America, aliquot of the new saturated solution was removed, filtered, and the solvent Portland, Oregon, USA, was used as received. The purity of the commercial evaporated as before. The procedure was repeated by decreasing the sample was 99.7% as determined by nonaqueous titration with freshly temperature in 5 K increments to reach 293.15 K. The reported mole fraction standardized sodium methoxide to the thymol blue endpoint according to the solubilities represent the average of three experimental measurements. The method of [J. S. Fritz and N. M. Lisicki, Anal. Chem. 23, 589 (1951)], except densities of the saturated solutions were measured in order to convert the that methylbenzene was substituted for benzene in the titration solvent. measured concentrations in mol dm3 to mole fraction solubilities. (2) Absolute, Aaper Alcohol and Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use. Source and Purity of Chemicals: (1) Purity not given, chemical source not specified, authors stated that the Estimated Error: sample met requirements indicated in the American Pharmacopeia, USP. Temperature: 0.1 K. (2) Absolute, Analytical Reagent grade, Merck Chemical Company, no

x1: 1.5% (relative error). puriﬁcation details were given in the paper.

Estimated Error: Temperature: 0.05 K. x % Components: Original Measurements: 1: 3.0 (relative error, estimated by compiler). (1) 3-Benzoyl- 138M. Gantiva, A. Yurquina, and α-methylbenzeneacetic acid F. Martínez, J. Chem. Eng. Data (()-Ketoprofen); C16H14O3; 55, 113 (2010). Components: Original Measurements: [22071-15-4] (1) 3-Benzoyl- 135Y.-J. Cho and H.-K. Choi, Int. (2) Ethanol; C2H6O; [64-17-5] α-methylbenzeneacetic acid J. Pharm. 169, 95 (1998). (()-Ketoprofen); C H O ; Variables: Prepared by: 16 14 3 [22071-15-4] Temperature W. E. Acree, Jr. (2) Ethanol; C2H6O; [64-17-5] Variables: Prepared by: Experimental Values T/K ¼ ambient room temperature W. E. Acree, Jr.

a b T/K x2 x1 Experimental Values 293.15 0.7871 0.2129 The measured molar solubility was reported to be c1 ¼ 1.805 298.15 0.7608 0.2392 mol dm3. 303.15 0.7318 0.2682 308.15 0.6999 0.3001 Auxiliary Information 313.15 0.6647 0.3353 Method/Apparatus/Procedure: ax : mole fraction of component 2 in the saturated solution. 2 Magnetic stirrer and a high-performance liquid chromatograph. bx : mole fraction solubility of the solute. 1 Excess solute and solvent were placed in a screw-capped vial. The contents were stirred by an externally driven teflon-coated magnetic bar at ambient room temperature until equilibrium was obtained. An aliquot of the saturated solution was removed, filtered through 0.45 μm membrane filter (Millipore, Bedford, Massachusetts, USA). The concentration of the dissolved solute was determined by high-performance liquid chromatographic analysis after suitable dilution.

Source and Purity of Chemicals: (1) Purity not given, Jeil Pharmaceutical Company, Seoul, South Korea, no puriﬁcation details were provided. (2) Purity not given, Reagent grade, chemical source not speciﬁed, was used as received.

Estimated Error: Temperature: No information given in the paper.

c1: 6% (relative error, estimated by compiler).

Auxiliary Information Components: Original Measurements: (1) 3-Benzoyl-α-methylbenzeneacetic 139M. Gantiva and F. Martínez, Method/Apparatus/Procedure: acid (()-Ketoprofen); C16H14O3; Quim. Nova 33, 370 (2010). Constant-temperature bath and an analytical balance. [22071-15-4] Excess solute and solvent were placed in sealed containers and allowed to (2) Ethanol; C2H6O; [64-17-5] equilibrate in a constant-temperature bath. After equilibrium was reached an aliquot of the clear saturated solution was transferred to a previously weighed Variables: Prepared by: glass vial. The mass of the vial plus the saturated solution was recorded. The T/K ¼ 298.15 W. E. Acree, Jr. vial was then placed in oven at 303 K for solvent evaporation until a constant mass was obtained. The solubility of the solute was calculated based on the Experimental Values mass of the solid residue and mass of the sample analyzed. Source and Purity of Chemicals: (1) Purity not given, chemical source not specified, no purification details were x a x b 2 1 provided. 0.9559 0.0441 (2) Purity not given, chemical source not specified, no purification details were a x2: mole fraction of component 2 in the saturated solution. provided. b x1: mole fraction solubility of the solute. Estimated Error: Temperature: 0.2 K (estimated by compiler).

Auxiliary Information x1: 5% (relative error, estimated by compiler). Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Excess solute and solvent were placed in glass bottles and then saturated in a constant-temperature bath for ﬁve days at 313.15 K. The samples were allowed Components: Original Measurements: 136 to equilibrate in a constant temperature at 298.15 K for an additional two days (1) 3-Benzoyl- G. L. Perlovich, S. V. Kurkov, to allow the precipitation of the excess dissolved drug. An aliquot of the α-methylbenzeneacetic acid A. N. Kinchin, and A. Bauer- saturated solution was then removed, ﬁltered, and diluted quantitatively with (( )-Ketoprofen); C16H14O3; Brandl, J. Pharm. Sci. 92, 2502 alcohol for spectroscopic analysis. The reported value represents the average [22071-15-4] (2003). [ ] of at least three experimental determinations. The densities of the saturated (2) 1-Propanol; C3H8O; 71-23-8 solutions were measured in order to convert the measured concentrations in 3 Variables: Prepared by: mol dm to mole fraction solubilities. T/K ¼ 298.15 W. E. Acree, Jr.

Source and Purity of Chemicals: (1) Purity not given, USP, no puriﬁcation details were provided. Experimental Values (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, Germany, no puriﬁcation details were provided. a b x2 x1 Estimated Error: 0.9155 0.0845 Temperature: 0.05 K. a x1: 2.5% (relative error). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: (1) 3-Benzoyl- 137A. E. Ribeiro, N. S. Graca, L. S. Method/Apparatus/Procedure: α-methylbenzeneacetic acid Pais, and A. E. Rodrigues, Sep. Constant-temperature bath and an UV/visible spectrophotometer. (()-Ketoprofen); C16H14O3; Purif. Technol. 61, 375 (2008). Very few experimental details were provided. Excess solute and solvent were [22071-15-4] allowed to equilibrate at constant temperature. Solubility of the dissolved (2) Ethanol; C2H6O; [64-17-5] solute was determined by spectrophotometric measurements. Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 298.15 W. E. Acree, Jr. (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. Experimental Values (2) Purity not given, HPLC grade, Aldrich Chemical Company, Germany, no puriﬁcation details were provided.

Estimated Error: x a x b 2 1 Temperature: 0.1 K. 0.8683 0.1317 x1: 2.5% (relative error). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: (1) 3-Benzoyl- 134C. R. Daniels, A. K. Charlton, Method/Apparatus/Procedure: α-methylbenzeneacetic acid W. E. Acree, Jr., and M. H. Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ (()-Ketoprofen); C16H14O3; Abraham, Phys. Chem. Liq. 42, visible spectrophotometer. [22071-15-4] 305 (2004). Excess solute and solvent were placed in amber glass bottles and allowed to (2) 1-Propanol; C3H8O; [71-23-8] equilibrate for several days at constant temperature. Attainment of equilibrium was verified by several repetitive measurements and by approaching Variables: Prepared by: equilibrium from supersaturation. Aliquots of saturated solutions were T/K ¼ 298.15 W. E. Acree, Jr. transferred through a coarse filter into tared volumetric flasks, weighed, and diluted with methanol. Concentrations were determined by Experimental Values spectrophotometric measurements at 280 nm. Source and Purity of Chemicals: (1) 99+%, Sigma-Aldrich, St. Louis, Missouri, USA, and 99%, TCI America, x a x b 2 1 Portland, Oregon, USA, was used as received. The purity of the commercial 0.9152 0.0848 sample was 99.7% as determined by nonaqueous titration with freshly a x2: mole fraction of component 2 in the saturated solution. standardized sodium methoxide to the thymol blue endpoint according to the b [ ] x1: mole fraction solubility of the solute. method of J. S. Fritz and N. M. Lisicki, Anal. Chem. 23, 589 (1951) , except that methylbenzene was substituted for benzene in the titration solvent. (2) 99+%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, Auxiliary Information USA, stored over molecular sieves and distilled shortly before use. Method/Apparatus/Procedure: Estimated Error: Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ Temperature: 0.1 K. visible spectrophotometer. x : 1.5% (relative error). Excess solute and solvent were placed in amber glass bottles and allowed to 1 equilibrate for several days at constant temperature. Attainment of equilibrium was verified by several repetitive measurements and by approaching equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse filter into tared volumetric flasks, weighed, and Components: Original Measurements: 136 diluted with methanol. Concentrations were determined by (1) 3-Benzoyl- G. L. Perlovich, S. V. Kurkov, spectrophotometric measurements at 280 nm. α-methylbenzeneacetic acid A. N. Kinchin, and A. Bauer- (()-Ketoprofen); C16H14O3; Brandl, J. Pharm. Sci. 92, 2502 Source and Purity of Chemicals: [22071-15-4] (2003). [ ] (1) 99+%, Sigma-Aldrich, St. Louis, Missouri, USA, and 99%, TCI America, (2) 1-Butanol; C4H10O; 71-36-3 Portland, Oregon, USA, was used as received. The purity of the commercial Variables: Prepared by: % sample was 99.7 as determined by nonaqueous titration with freshly T/K ¼ 298.15 W. E. Acree, Jr. standardized sodium methoxide to the thymol blue endpoint according to the method of [J. S. Fritz and N. M. Lisicki, Anal. Chem. 23, 589 (1951)], except that methylbenzene was substituted for benzene in the titration solvent. Experimental Values (2) 99+%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use. a b x2 x1 Estimated Error: Temperature: 0.1 K. 0.9132 0.0868 a x1: 1.5% (relative error). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Estimated Error: x a x b 2 1 Temperature: 0.1 K. 0.8731 0.1269 x1: 2.5% (relative error). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Excess solute and solvent were placed in amber glass bottles and allowed to x1: 1.5% (relative error). equilibrate for several days at constant temperature. Attainment of equilibrium was verified by several repetitive measurements and by approaching equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse filter into tared volumetric flasks, weighed, and Components: Original Measurements: diluted with methanol. Concentrations were determined by (1) 3-Benzoyl- 136G. L. Perlovich, S. V. Kurkov, spectrophotometric measurements at 280 nm. α-methylbenzeneacetic acid A. N. Kinchin, and A. Bauer- (()-Ketoprofen); C H O ; Brandl, J. Pharm. Sci. 92, 2502 Source and Purity of Chemicals: 16 14 3 [22071-15-4] (2003). +% % (1) 99 , Sigma-Aldrich, St. Louis, Missouri, USA, and 99 , TCI America, (2) 1-Pentanol; C H O; [71-41-0] Portland, Oregon, USA, was used as received. The purity of the commercial 5 12 sample was 99.7% as determined by nonaqueous titration with freshly Variables: Prepared by: standardized sodium methoxide to the thymol blue endpoint according to the T/K ¼ 298.15 W. E. Acree, Jr. method of [J. S. Fritz and N. M. Lisicki, Anal. Chem. 23, 589 (1951)], except that methylbenzene was substituted for benzene in the titration solvent. (2) 99+%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, Experimental Values USA, stored over molecular sieves and distilled shortly before use.

a b Estimated Error: x2 x1 Temperature: 0.1 K. 0.9222 0.0778 % x1: 1.5 (relative error). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: Auxiliary Information (1) 3-Benzoyl- 134C. R. Daniels, A. K. Charlton, / / α-methylbenzeneacetic acid W. E. Acree, Jr., and M. H. Method Apparatus Procedure: Constant-temperature bath and an UV/visible spectrophotometer. (()-Ketoprofen); C16H14O3; Abraham, Phys. Chem. Liq. 42, [22071-15-4] 305 (2004). Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate at constant temperature. Solubility of the dissolved (2) 2-Methyl-1-propanol; C4H10O; [78-83-1] solute was determined by spectrophotometric measurements.

Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 298.15 W. E. Acree, Jr. (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, Aldrich Chemical Company, Experimental Values Germany, no puriﬁcation details were provided.

Estimated Error: a b x2 x1 Temperature: 0.1 K. % 0.8991 0.1009 x1: 2.5 (relative error). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Estimated Error: x a x b 2 1 Temperature: 0.1 K. 0.9224 0.0776 x1: 2.5% (relative error). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: Auxiliary Information (1) 3-Benzoyl- 136G. L. Perlovich, S. V. Kurkov, Method/Apparatus/Procedure: α-methylbenzeneacetic acid A. N. Kinchin, and A. Bauer- Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ (( )-Ketoprofen); C16H14O3; Brandl, J. Pharm. Sci. 92, 2502 visible spectrophotometer. [22071-15-4] (2003). [ ] Excess solute and solvent were placed in amber glass bottles and allowed to (2) 1-Heptanol; C7H16O; 111-70-6 equilibrate for several days at constant temperature. Attainment of equilibrium Variables: Prepared by: was verified by several repetitive measurements and by approaching T/K ¼ 298.15 W. E. Acree, Jr. equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse filter into tared volumetric flasks, weighed, and diluted with methanol. Concentrations were determined by Experimental Values spectrophotometric measurements at 280 nm.

Source and Purity of Chemicals: a b x2 x1 (1) 99+%, Sigma-Aldrich, St. Louis, Missouri, USA, and 99%, TCI America, 0.9326 0.0674 Portland, Oregon, USA, was used as received. The purity of the commercial a sample was 99.7% as determined by nonaqueous titration with freshly x2: mole fraction of component 2 in the saturated solution. b standardized sodium methoxide to the thymol blue endpoint according to the x1: mole fraction solubility of the solute. method of [J. S. Fritz and N. M. Lisicki, Anal. Chem. 23, 589 (1951)], except that methylbenzene was substituted for benzene in the titration solvent. Auxiliary Information (2) 99+%, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use. Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Estimated Error: Very few experimental details were provided. Excess solute and solvent were Temperature: 0.1 K. allowed to equilibrate at constant temperature. Solubility of the dissolved

x1: 2.0% (relative error). solute was determined by spectrophotometric measurements.

Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. Components: Original Measurements: (2) Purity not given, Analytical Reagent grade, Aldrich Chemical Company, (1) 3-Benzoyl- 136G. L. Perlovich, S. V. Kurkov, Germany, no puriﬁcation details were provided. α-methylbenzeneacetic acid A. N. Kinchin, and A. Bauer- (()-Ketoprofen); C H O ; Brandl, J. Pharm. Sci. 92, 2502 16 14 3 Estimated Error: [22071-15-4] (2003). Temperature: 0.1 K. (2) 1-Hexanol; C6H14O; [111-27-3] x1: 2.5% (relative error). Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

Components: Original Measurements: Experimental Values 136 (1) 3-Benzoyl- G. L. Perlovich, S. V. Kurkov, α-methylbenzeneacetic acid A. N. Kinchin, and A. Bauer- a b (( )-Ketoprofen); C16H14O3; Brandl, J. Pharm. Sci. 92, 2502 x2 x1 [22071-15-4] (2003).

0.9186 0.0814 (2) 1-Octanol; C8H18O; [111-87-5] a x2: mole fraction of component 2 in the saturated solution. Variables: Prepared by: b x1: mole fraction solubility of the solute. T/K ¼ 298.15 W. E. Acree, Jr.

Experimental Values Components: Original Measurements: (1) 3-Benzoyl- 60A. Fini, M. Laus, I. Orienti, and α a b -methylbenzeneacetic acid V. Zecchi, J. Pharm. Sci. 75,23 x2 x1 (()-Ketoprofen); C16H14O3; (1986). 0.9309 0.0691 [22071-15-4]

a (2) 1-Octanol; C8H18O; [111-87-5] x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Variables: Prepared by: Temperature W. E. Acree, Jr.

Auxiliary Information Method/Apparatus/Procedure: Experimental Values Constant-temperature bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were / a allowed to equilibrate at constant temperature. Solubility of the dissolved T K c1 solute was determined by spectrophotometric measurements. 278.2 0.227 298.2 0.448 Source and Purity of Chemicals: 310.2 0.667 (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no a 3 c1: molar solubility of the solute in units of mol dm . puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, Aldrich Chemical Company, Germany, no puriﬁcation details were provided. Auxiliary Information

Estimated Error: Method/Apparatus/Procedure: Temperature: 0.1 K. Constant-temperature bath, analytical balance, and an UV/visible

x1: 2.5% (relative error). spectrophotometer. Excess solute and solvent were placed in a sealed container and allowed to equilibrate with stirring at constant temperature. An aliquot of the saturated solution was removed, filtered through a 0.22 μm pore membrane, and diluted quantitatively for spectroscopic analysis. Components: Original Measurements: (1) 3-Benzoyl- 135Y.-J. Cho and H.-K. Choi, Int. Source and Purity of Chemicals: α-methylbenzeneacetic acid J. Pharm. 169, 95 (1998). (1) Purity not given, chemical source not specified, was recrystallized from (()-Ketoprofen); C H O ; 16 14 3 suitable solvent before use. [22071-15-4] (2) Purity not given, chemical source not specified, no purification details were (2) 1-Octanol; C H O; [111-87-5] 8 18 provided in the paper. Variables: Prepared by: T/K ¼ ambient room temperature W. E. Acree, Jr. Estimated Error: Temperature: 0.2 K (estimated by compiler).

c1: 3% (relative error). Experimental Values

The measured molar solubility was reported to be c1 ¼ 0.5466 mol dm3. Components: Original Measurements: (1) 3-Benzoyl- 134C. R. Daniels, A. K. Charlton, Auxiliary Information α-methylbenzeneacetic acid W. E. Acree, Jr., and M. H. Method/Apparatus/Procedure: (( )-Ketoprofen); C16H14O3; Abraham, Phys. Chem. Liq. 42, [ ] Magnetic stirrer and a high-performance liquid chromatograph. 22071-15-4 305 (2004). [ ] Excess solute and solvent were placed in a screw-capped vial. The contents (2) 1-Decanol; C10H22O; 112-30-1 were stirred by an externally driven teflon-coated magnetic bar at ambient Variables: Prepared by: room temperature until equilibrium was obtained. An aliquot of the saturated T/K ¼ 298.15 W. E. Acree, Jr. solution was removed, filtered through 0.45 μm membrane filter (Millipore, Bedford, Massachusetts, USA). The concentration of the dissolved solute was determined by high-performance liquid chromatographic analysis after Experimental Values suitable dilution.

Source and Purity of Chemicals: a b x2 x1 (1) Purity not given, Jeil Pharmaceutical Company, Seoul, South Korea, no 0.9169 0.0831 puriﬁcation details were provided. a (2) Purity not given, Reagent grade, chemical source not speciﬁed, was used as x2: mole fraction of component 2 in the saturated solution. b received. x1: mole fraction solubility of the solute.

Estimated Error: Temperature: No information given in the paper.

c1: 5% (relative error, estimated by compiler).

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 3-Benzoyl- 140G. V. Vittal, R. Deveswaran, Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ α-methylbenzeneacetic acid S. Bharath, B. V. Basavaraj, and visible spectrophotometer. (()-Ketoprofen); C16H14O3; V. Madhavan, Int. J. Pharm. Excess solute and solvent were placed in amber glass bottles and allowed to [22071-15-4] Invest. 2, 150 (2012). equilibrate for several days at constant temperature. Attainment of equilibrium (2) 1,2-Propanediol; C3H8O2; was verified by several repetitive measurements and by approaching [57-55-6] equilibrium from supersaturation. Aliquots of saturated solutions were Variables: Prepared by: transferred through a coarse filter into tared volumetric flasks, weighed, and T/K ¼ ambient room temperature W. E. Acree, Jr. diluted with methanol. Concentrations were determined by spectrophotometric measurements at 280 nm. Experimental Values Source and Purity of Chemicals: (1) 99+%, Sigma-Aldrich, St. Louis, Missouri, USA, and 99%, TCI America, The measured solubility was reported to be s1 ¼ 1000 mg Portland, Oregon, USA, was used as received. The purity of the commercial cm 3. Note: It is not apparent from reading the paper whether sample was 99.7% as determined by nonaqueous titration with freshly the amount dissolved is per cm3 of saturated solution or per standardized sodium methoxide to the thymol blue endpoint according to the cm3 of solvent. method of [J. S. Fritz and N. M. Lisicki, Anal. Chem. 23, 589 (1951)], except that methylbenzene was substituted for benzene in the titration solvent. (2) 99+%, Alfa Aesar, USA, stored over molecular sieves and distilled shortly Auxiliary Information before use. Method/Apparatus/Procedure: Magnetic stirrer and a high-performance liquid chromatograph. Estimated Error: Excess solute and solvent were placed in volumetric flask and then allowed to Temperature: 0.1 K. equilibrate at ambient room temperature in a water shaker bath for 48 h under x : 1.5% (relative error). 1 continued vibration. An aliquot of the saturated solution was removed, filtered through 0.45 μm membrane filter (Millipore, Bedford, Massachusetts, USA), and diluted for spectrophotometric analysis at 260 nm. The reported value represents the average of three experimental determinations. Components: Original Measurements: (1) 3-Benzoyl- 135Y.-J. Cho and H.-K. Choi, Int. Source and Purity of Chemicals: α-methylbenzeneacetic acid J. Pharm. 169, 95 (1998). (1) Purity not given, Yarrow Chem Products, Mumbai, India, no purification (()-Ketoprofen); C16H14O3; details were provided. [22071-15-4] (2) Purity not given, Ranbaxy Fine Chemicals Ltd., New Delhi, India, no (2) 1,2-Propanediol; C3H8O2; purification details were provided. [57-55-6] Estimated Error: Variables: Prepared by: Temperature: No information given in the paper. T/K ¼ ambient room temperature W. E. Acree, Jr. s1: 12% (relative error, estimated by compiler).

Experimental Values

The measured molar solubility was reported to be c1 ¼ 3 Components: Original Measurements: 0.7826 mol dm . (1) 3-Benzoyl- 141U. Kumprakob, J. Kawakami, α-methylbenzeneacetic acid and I. Adachi, Biol. Pharm. Bull. Auxiliary Information (( )-Ketoprofen); C16H14O3; 28, 1684 (2005). [22071-15-4] Method/Apparatus/Procedure: (2) 1,2-Propanediol; C3H8O2; Magnetic stirrer and a high-performance liquid chromatograph. [57-55-6] Excess solute and solvent were placed in a screw-capped vial. The contents were stirred by an externally driven teflon-coated magnetic bar at ambient Variables: Prepared by: room temperature until equilibrium was obtained. An aliquot of the saturated T/K ¼ 310.15 W. E. Acree, Jr. solution was removed, filtered through 0.45 μm membrane filter (Millipore, Bedford, Massachusetts, USA). The concentration of the dissolved solute was determined by high-performance liquid chromatographic analysis after Experimental Values suitable dilution. The measured solubility was reported to be s1 ¼ 369.1 mg 3 cm , which corresponds to a molar solubility of c1 ¼ 1.452 Source and Purity of Chemicals: 3 (1) Purity not given, Jeil Pharmaceutical Company, Seoul, South Korea, no mol dm . purification details were provided. (2) Purity not given, Reagent grade, chemical source not specified, was used as received.

Estimated Error: Temperature: No information given in the paper.

c1: 12% (relative error, estimated by compiler).

Auxiliary Information Source and Purity of Chemicals: (1) Purity not given, chemical source not speciﬁed, authors stated that the / / Method Apparatus Procedure: sample met requirements indicated in the American Pharmacopeia, USP. Magnetic stirrer and a high-performance liquid chromatograph equipped with (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, no an UV absorbance detector. puriﬁcation details were given in the paper. Excess solute and solvent were placed in sealed containers and then allowed to equilibrate with stirring in a water bath for 24 h. The sample was then Estimated Error: centrifuged and an aliquot of the clear supernatant was removed. The Temperature: 0.05 K. concentration of the dissolved solute was determined by high-performance x1: 3.0% (relative error, estimated by compiler). liquid chromatographic analysis at 254 nm.

Source and Purity of Chemicals: (1) Purity not given, Wako Pure Chemical Industries, Ltd., Japan, no puriﬁcation details were provided. Components: Original Measurements: 135 (2) Purity not given, Analytical Reagent grade, Nacalai Tesque, Inc., Japan, no (1) 3-Benzoyl- Y.-J. Cho and H.-K. Choi, Int. α puriﬁcation details were provided. -methylbenzeneacetic acid J. Pharm. 169, 95 (1998). (()-Ketoprofen); C16H14O3; [ ] Estimated Error: 22071-15-4 Temperature: 0.2 (estimated by compiler). (2) (Z)-Octadec-9-en-1-ol (Oleyl alcohol); C18H36O; [143-28-2] s1: 5% (relative error, estimated by compiler). Variables: Prepared by: T/K ¼ ambient room temperature W. E. Acree, Jr.

Components: Original Measurements: (1) 3-Benzoyl- 132M. Gantiva and F. Martínez, Experimental Values α-methylbenzeneacetic acid Fluid Phase Equilib. 293, 242 The measured molar solubility was reported to be c1 ¼ (( )-Ketoprofen); C16H14O3; (2010). 0.1888 mol dm 3. [22071-15-4]

(2) 1,2-Propanediol; C3H8O2; [57-55-6] Auxiliary Information Variables: Prepared by: Method/Apparatus/Procedure: Temperature W. E. Acree, Jr. Magnetic stirrer and a high-performance liquid chromatograph. Excess solute and solvent were placed in a screw-capped vial. The contents were stirred by an externally driven teflon-coated magnetic bar at ambient Experimental Values room temperature until equilibrium was obtained. An aliquot of the saturated solution was removed, filtered through 0.45 μm membrane filter (Millipore, Bedford, Massachusetts, USA). The concentration of the dissolved solute was a b T/K x2 x1 determined by high-performance liquid chromatographic analysis after 293.15 0.9876 0.01236 suitable dilution. 298.15 0.9862 0.01383 303.15 0.9845 0.01550 Source and Purity of Chemicals: 308.15 0.9826 0.01740 (1) Purity not given, Jeil Pharmaceutical Company, Seoul, South Korea, no 313.15 0.9809 0.01905 purification details were provided. (2) Purity not given, Reagent grade, chemical source not specified, was used as a x2: mole fraction of component 2 in the saturated solution. received. b x1: mole fraction solubility of the solute. Estimated Error: Temperature: No information given in the paper. Auxiliary Information c1: 13% (relative error, estimated by compiler). Method/Apparatus/Procedure: Thermostatic mechanical shaker and an UV/visible spectrophotometer. Excess solute and solvent were placed in stoppered glass flasks and allowed to equilibrate in a thermostatic mechanical shaker at 313.15 K for at least five 15.8. Ketoprofen solubility data in ketones days. Once equilibrium had been attained, an aliquot of the saturated solution was removed and filtered in order to remove insoluble particles. The concentration of the dissolved drug was determined by weighing an aliquot of the saturated filtered solution, which was then diluted for spectrophotometric Components: Original Measurements: 142 analysis. The concentration of the dissolved drug was determined from the (1) 3-Benzoyl- P. Espitalier, B. Biscans, and α é measured absorbance. Once the solubility was determined at 313.15 K, the -methylbenzeneacetic acid C. Lagu rie, J. Chem. Eng. Data temperature was decreased by 5 K and stabilized at 308.15 K for two days to (( )-Ketoprofen); C16H14O3; 40, 1222 (1995). [ ] allow the excess dissolved drug to precipitate at this lower temperature. An 22071-15-4 [ ] aliquot of the new saturated solution was removed, filtered, and the solvent (2) Propanone; C3H6O; 67-64-1 evaporated as before. The procedure was repeated by decreasing the Variables: Prepared by: temperature in 5 K increments to reach 293.15 K. The reported mole fraction Temperature W. E. Acree, Jr. solubilities represent the average of three experimental measurements. The densities of the saturated solutions were measured in order to convert the measured concentrations in mol dm3 to mole fraction solubilities.

Experimental Values Auxiliary Information Method/Apparatus/Procedure: Magnetic stirrer and a high-performance liquid chromatograph. T/K x a x b,c 2 1 Excess solute and solvent were placed in a screw-capped vial. The contents 283.0 0.8861 0.1139 were stirred by an externally driven teflon-coated magnetic bar at ambient 293.0 0.8525 0.1475 room temperature until equilibrium was obtained. An aliquot of the saturated 303.1 0.8061 0.1939 solution was removed, filtered through 0.45 μm membrane filter (Millipore, 314.3 0.7343 0.2657 Bedford, Massachusetts, USA). The concentration of the dissolved solute was 322.5 0.6763 0.3237 determined by high-performance liquid chromatographic analysis after a suitable dilution. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. csolubility data reported in the paper as mass fractions. The tabulated mole Source and Purity of Chemicals: fraction solubilities were calculated by the compiler. (1) Purity not given, Jeil Pharmaceutical Company, Seoul, South Korea, no purification details were provided. (2) Purity not given, Reagent grade, chemical source not specified, was used as Auxiliary Information received. / / Method Apparatus Procedure: Estimated Error: Constant-temperature bath, analytical balance, and high-performance liquid Temperature: No information given in the paper. chromatographic analysis with UV detection. c1: 17% (relative error, estimated by compiler). Experimental method consisted of periodically dissolving small quantities of solid solute in a stirred solution of solvent maintained at constant temperature. When the solid did not appear to dissolve any more, the suspension was stirred for a few additional days to ensure saturation. During this time the solution was μ Components: Original Measurements: withdrawn by syringe, filtered at ambient room temperature through a 0.45 m 135 porosity membrane filter, and analyzed by high-performance liquid (1) 3-Benzoyl- Y.-J. Cho and H.-K. Choi, Int. α chromatography at 280 nm. -methylbenzeneacetic acid J. Pharm. 169, 95 (1998). (()-Ketoprofen); C16H14O3; [ ] Source and Purity of Chemicals: 22071-15-4 (1) 99.9%, Rhone-Poulenc Rorer Company, France, was used as received. (2) Mineral oil (2) 99.7%, Synthesis grade, Siciete de Distribution de Service et de Recherche, Variables: Prepared by: France, was used as received. T/K ¼ ambient room temperature W. E. Acree, Jr.

Estimated Error: Temperature: 0.1 K. Experimental Values x1: 3.5% between 283.15 K and 293.15; 12% at 303.15 K (relative error). The measured molar solubility was reported to be c1 ¼ 0.000747 mol dm3.

15.9. Ketoprofen solubility data in miscellaneous Auxiliary Information organic solvents Method/Apparatus/Procedure: Magnetic stirrer and a high-performance liquid chromatograph. Excess solute and solvent were placed in a screw-capped vial. The contents Components: Original Measurements: were stirred by an externally driven teflon-coated magnetic bar at ambient (1) 3-Benzoyl- 135Y.-J. Cho and H.-K. Choi, Int. room temperature until equilibrium was obtained. An aliquot of the saturated μ α-methylbenzeneacetic acid J. Pharm. 169, 95 (1998). solution was removed and filtered through 0.45 m membrane filter (Millipore, Bedford, Massachusetts, USA). The concentration of the dissolved solute was (()-Ketoprofen); C16H14O3; [22071-15-4] determined by high-performance liquid chromatographic analysis after (2) (9Z)-Octadecenoic acid suitable dilution. (Oleic acid); C H O ; [112-80-1] 18 34 2 Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Jeil Pharmaceutical Company, Seoul, South Korea, no T/K ¼ ambient room temperature W. E. Acree, Jr. purification details were provided. (2) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. Experimental Values Estimated Error: The measured molar solubility was reported to be c1 ¼ Temperature: No information given in the paper. 0.0944 mol dm 3. c1: 50% (relative error, estimated by compiler).

Estimated Error: Components: Original Measurements: Temperature: Insufﬁcient details given in the paper. (1) 3-Benzoyl- 64B. P. Wenkers and B. C. c1: 10% (relative error, estimated by compiler). α-methylbenzeneacetic acid Lippold, J. Pharm. Sci. 88, 1326

(()-Ketoprofen); C16H14O3; (1999). [22071-15-4] (2) Mineral oil Components: Original Measurements: Variables: Prepared by: (1) 3-Benzoyl- 135Y.-J. Cho and H.-K. Choi, Int. T/K ¼ 305.15 W. E. Acree, Jr. α-methylbenzeneacetic acid J. Pharm. 169, 95 (1998).

(()-Ketoprofen); C16H14O3; [22071-15-4] Experimental Values (2) Peanut oil ¼ The measured solubility was reported to be c1 0.000503 Variables: Prepared by: 3 mol dm . T/K ¼ ambient room temperature W. E. Acree, Jr.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: ¼ / The measured molar solubility was reported to be c1 Constant-temperature bath and an UV visible spectrophotometer. 3 Excess solute and solvent were placed in sealed bottles and allowed to 0.0307 mol dm . equilibrate at a constant temperature with rotation for 24 h. Aliquots of saturated solutions were removed, filtered through a 0.45 μm cellulose acetate Auxiliary Information membrane filter, and diluted quantitatively for spectroscopic analysis. / / Reported values represent the average of three experimental measurements. Method Apparatus Procedure: Magnetic stirrer and a high-performance liquid chromatograph. Source and Purity of Chemicals: Excess solute and solvent were placed in a screw-capped vial. The contents (1) Purity not given, Sankyo, Pfaffenhofen, Germany, no purification details were stirred by an externally driven teflon-coated magnetic bar at ambient were provided. room temperature until equilibrium was obtained. An aliquot of the saturated μ (2) Purity not given, Bayer Leverkusen and Rhone Poulenc Rorer, Cologne, solution was removed, filtered through 0.45 m membrane filter (Millipore, Germany, no purification details were provided. Bedford, Massachusetts, USA). The concentration of the dissolved solute was determined by high-performance liquid chromatographic analysis after Estimated Error: suitable dilution. Temperature: 0.5 K (estimated by compiler). Source and Purity of Chemicals: c1: 10% (relative error). (1) Purity not given, Jeil Pharmaceutical Company, Seoul, South Korea, no purification details were provided. (2) Purity not given, Croda, Parsippany, New Jersey, USA, no purification details were provided. Components: Original Measurements: 143 (1) 3-Benzoyl- M. T. J. Garcia, C. H. Tomich Estimated Error: α -methylbenzeneacetic acid de Paula da Silva, D. C. R. de Temperature: No information given in the paper. (()-Ketoprofen); C16H14O3; Oliveira, E. C. A. Braga, J. A. x1: 26% (relative error, estimated by compiler). [22071-15-4] Thomazini, and M. V. L. B. (2) Mineral oil Gently, Pharm. Res. 23, 1776 (2006).

Variables: Prepared by: Components: Original Measurements: T/K ¼ ambient room temperature W. E. Acree, Jr. (1) 3-Benzoyl- 92D. B. Larsen, H. Parshad, K. α-methylbenzeneacetic acid Fredholt, and C. Larsen, Int. J.

(()-Ketoprofen); C16H14O3; Pharm. 232, 107 (2002). Experimental Values [22071-15-4] (2) Castor oil The measured solubility was reported to be c1 ¼ 0.000465 3 mol dm . Variables: Prepared by: T/K ¼ 310.15 W. E. Acree, Jr. Auxiliary Information Method/Apparatus/Procedure: Centrifuge and a high-performance liquid chromatograph. Experimental Values Excess solute and solvent were placed in sealed bottles and allowed to The measured solubility was reported to be c1 ¼ 0.377 equilibrate at ambient room temperature with constant stirring for 24 h. The mol dm3. suspension was then centrifuged for 10 min, and an aliquot of the supernatant was removed for analysis. The concentration of the dissolved solute was determined by high-performance liquid chromatographic analysis. Auxiliary Information Method/Apparatus/Procedure: Source and Purity of Chemicals: Constant-temperature bath and an UV/visible spectrophotometer. (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Excess solute and solvent were placed in a screw-capped test tube and allowed puriﬁcation details were provided. to equilibrate at a constant temperature with rotation for 24 h. Aliquots of (2) Purity not given, Analytical Reagent or HPLC grade, Merck Chemical saturated solutions were removed, centrifuged at 15 000 rpm for 10 min, and Company, Darmstadt, Germany, no puriﬁcation details were provided. diluted quantitatively with ethanol for spectroscopic analysis.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, chemical source not specified, no purification details were ¼ provided. The measured solubility was reported to be c1 0.955 3 (2) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no mol dm . purification details were provided. Auxiliary Information Estimated Error: Temperature: 0.5 K. Method/Apparatus/Procedure:

c1: 10% (relative error, estimated by compiler). Centrifuge and a high-performance liquid chromatograph equipped with a photo-diode array detector. Excess solute and solvent were placed in sealed vials and shaken at ambient room temperature for at least 24 h. The vials were then centrifuged for 15 min to separate the saturated solution from the excess solute. The supernatant was Components: Original Measurements: then filtered and the concentration of the dissolved solute determined by high- (1) 3-Benzoyl- 140G. V. Vittal, R. Deveswaran, S. performance liquid chromatographic analysis. α-methylbenzeneacetic acid Bharath, B. V. Basavaraj, and V. (()-Ketoprofen); C H O ; Madhavan, Int. J. Pharm. Invest. 16 14 3 Source and Purity of Chemicals: [22071-15-4] 2, 150 (2012). (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, (2) Polyethylene glycol 400 USA, no purification details were provided. (PEG 400) (2) Purity not given, J. T. Baker Chemical Company, Phillipsburg, New Jersey, Variables: Prepared by: USA, no purification details were provided. T/K ¼ ambient room temperature W. E. Acree, Jr. Estimated Error: Temperature: 2 K (estimated by compiler).

Experimental Values c1: 10% (relative error, estimated by compiler).

The measured solubility was reported to be s1 ¼ 3000 mg cm3. Note: It is not apparent from reading the paper whether 3 the amount dissolved is per cm of saturated solution or per 16. Solubility of Ketorolac in Organic cm3 of solvent. Solvents Auxiliary Information 16.1. Critical evaluation of experimental solubility Method/Apparatus/Procedure: data Magnetic stirrer and a high-performance liquid chromatograph. Excess solute and solvent were placed in volumetric flask and then allowed to Ketorolac (more formally named 5-benzoyl-2,3-dihydro- equilibrate at ambient room temperature in a water shaker bath for 48 h under 1H-pyrrolizine-1-carboxylic acid) is a member of the pyrrolo- continued vibration. An aliquot of the saturated solution was removed, filtered pyrrole class of NSAIDs. The drug is available in several μ through 0.45 m membrane filter (Millipore, Bedford, Massachusetts, USA), different formulations (oral, intravenous, and intramuscular) and diluted for spectrophotometric analysis at 260 nm. The reported value represents the average of three experimental determinations. and has been used effectively in pain management therapies. New formulations are continually being investigated. Intra- Source and Purity of Chemicals: nasal ketorolac has been shown to provide short-term relief for (1) Purity not given, Yarrow Chem Products, Mumbai, India, no purification individuals suffering from postoperative pain. Ophthalmic details were provided. solutions have been used to reduce ocular pain and inflamma- (2) Purity not given, E. Merck Chemical Company Ltd., Mumbai, India, no 149,150 purification details were provided. tion. There have been two publications reporting the solubility of ketorolac in organic solvents. Doh et al.149 Estimated Error: determined the molar solubility of ketorolac and seven alkyl Temperature: No information given in the paper. ester prodrugs (methyl, ethyl, propyl, isopropyl, butyl, iso- % s1: 12 (relative error, estimated by compiler). butyl, pentyl ester) in water, 1,2-propanediol, and isotonic phosphate buffer at 310 K as part of an experimental study involving transdermal delivery and rat skin permeation. The Components: Original Measurements: authors found that the skin permeation rate of the alkyl ester (1) 3-Benzoyl- 65E. Rytting, K. A. Lentz, X.-Q. prodrugs was significantly higher with a shorter lag time than 150 α-methylbenzeneacetic acid Chen, F. Qian, and S. Venkatesh, that of ketorolac. A followup study performed by Kim et al. (( )-Ketoprofen); C16H14O3; AAPS J. 7, E78 (2005). examined the transdermal ketorolac amide prodrugs. The [ ] 22071-15-4 solubility of ketorolac in 1,2-propanediol was reported again (2) Polyethylene glycol 400 (PEG 400) in this second study. It is not possible to perform a critical evaluation of the experimental data as measurements were Variables: Prepared by: made at one temperature and there are no independent experi- T/K ¼ 296 W. E. Acree, Jr. mental solubility data for ketorolac in 1,2-propanediol. The experimental solubility data for ketorolac dissolved in 1,2-propanediol are given in Sec. 16.2.

16.2. Ketorolac solubility data in alcohols alkyl alkanoates (ethyl ethanoate and butyl ethanoate), in one cyclic ether (1,4-dioxane), in two chloroalkanes (trichloromethane and tetrachloromethane) and one chlorinated aro- Components: Original Measurements: matic hydrocarbon (chlorobenzene), in nine alcohols 149 (1) 5-Benzoyl-2,3-dihydro- H.-J. Doh, W.-J. Cho, C.-S. (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2- 1H-pyrrolizine-1-carboxylic acid Yong, H.-G. Choi, J. S. Kim, C.-C. methyl-1-propanol, 1-pentanol, 1-octanol, 1,2-propanediol, (()-Ketorolac); C15H13NO3; Lee, and D. D. Kim, J. Pharm. Sci. [74103-06-3] 92, 1008 (2003). and 1,2,3-propanetriol), in one alkanone (propanone) and one 150 (2) 1,2-Propanediol; C3H8O2; B.-Y. Kim, H.-J. Doh, T. N. Le, aromatic ketone (acetophenone), and in three miscellaneous [57-55-6] W.-J. Cho, C.-S. Yong, H.-G. organic solvents (dimethyl sulfoxide, N,N-dimethylforma- Choi, J. S. Kim, C.-H. Lee, and mide, and benzenamine) at 298 K and atmospheric pressure. D.-D. Kim, Int. J. Pharm. 293, 193 Lee and Chun153 investigated the effects of various vehicles (2005). and fatty acids on the in vitro transdermal permeation of Variables: Prepared by: T/K ¼ 310.15 W. E. Acree, Jr. lornoxicam using hairless dorsal skin and human cadaver full skin. As part of their investigation, they determined the solubility in ethanol, propylene glycol, polyethylene glycol Experimental Values 400, dimethyl sulfoxide, isopropyl myristate, and N-methyl-

The measured solubility was reported to be c1 ¼ 0.05285 pyrrolidone at 305 K. It is not possible to perform a critical mol dm3. evaluation of the experimental data as there are not sufficient independent experimental solubility data for lornoxicam in the Auxiliary Information aforementioned solvents. Method/Apparatus/Procedure: The experimental solubility data for lornoxicam in organic Constant-temperature water bath and a high-performance liquid solvents are given in Secs. 17.2–17.9. chromatograph. Very few experimental details were provided. Excess solute was added to 1cm3 of 1,2-propanediol. The solution was placed in a constant-temperature 17.2. Lornoxicam solubility data in saturated water bath and stirred for 24 h to reach equilibrium. The sample was withdrawn hydrocarbons (including cycloalkanes) and filtered through a Minisart RC 4 filter (0.45 μm, from Satorius, Germany). The filtrate was diluted with methanol. The concentration of the dissolved solute was determined by high-performance liquid chromatographic (HPLC) Components: Original Measurements: analysis. (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. Source and Purity of Chemicals: 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 (1) Purity not given, chemical source not specified, no purification details were 1-dioxide (Lornoxicam); (2013). provided. C H ClN O S ; [70374-39-9] (2) Purity not given, chemical source not specified, no purification details were 13 10 3 4 2 (2) Hexane; C H ; [110-54-3] provided. 6 14 Variables: Prepared by: Estimated Error: T/K ¼ 298.15 W. E. Acree, Jr. Temperature: No information was given.

c1: 0.00595. Experimental Values

a b 17. Solubility of Lornoxicam in Organic x2 x1 Solvents 0.9999 0.000000223 a x2: mole fraction of component 2 in the saturated solution. b 17.1. Critical evaluation of experimental solubility x1: mole fraction solubility of the solute. data Lornoxicam (more formally named 6-chloro-4-hydroxy-2- Auxiliary Information methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-car- Method/Apparatus/Procedure: boxamide-1,1-dioxide) is a NSAID drug possessing potent Constant-temperature orbital shaker bath and an UV/visible analgesic and anti-inflammatory properties. The drug is pre- spectrophotometer. scribed in the treatment of pain resulting from osteoarthritis, Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate in a constant-temperature reciprocating shaker bath for sciatica, and inflammatory diseases of the joints. There have at least three days. An aliquot of the saturated solution was removed, filtered, 151–153 been three publications reporting the solubility of lor- and then diluted with a 0.05 molar sodium chloride solution. Solubility of the noxicam in organic solvents. Kharwade et al.152 determined dissolved solute was determined by spectrophotometric measurements at the molar solubility of lornoxicam in ethanol at 288 K. 376 nm. Reference 151 examined the solubility of lornoxicam in two saturated hydrocarbons (hexane and cyclohexane), in two aromatic hydrocarbons (benzene and methylbenzene), in two

Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no T/K ¼ 298.15 W. E. Acree, Jr. puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., Mumbai, India, no puriﬁcation details were provided. Experimental Values

Estimated Error: a b Temperature: 0.05 K. x2 x1 % x1: 4 (relative error, estimated by compiler). 0.9999 0.0000905 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: 151 (1) 6-Chloro-4-hydroxy-2-methyl- M. Kharwade, C. V. S. Auxiliary Information N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. / / 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 Method Apparatus Procedure: / 1-dioxide (Lornoxicam); (2013). Constant-temperature orbital shaker bath and an UV visible spectrophotometer. C13H10ClN3O4S2; [70374-39-9] Very few experimental details were provided. Excess solute and solvent were (2) Cyclohexane; C6H12; [110-82-7] allowed to equilibrate in a constant-temperature reciprocating shaker bath for Variables: Prepared by: at least three days. An aliquot of the saturated solution was removed, filtered, T/K ¼ 298.15 W. E. Acree, Jr. and then diluted with a 0.05 molar sodium chloride solution. Solubility of the dissolved solute was determined by spectrophotometric measurements at 376 nm. Experimental Values Source and Purity of Chemicals: (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no a b x2 x1 purification details were provided. 0.9999 0.0000640 (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., a Mumbai, India, no purification details were provided. x2: mole fraction of component 2 in the saturated solution. bx : mole fraction solubility of the solute. 1 Estimated Error: Temperature: 0.05 K. % Auxiliary Information x1: 4 (relative error, estimated by compiler). Method/Apparatus/Procedure: Constant-temperature orbital shaker bath and an UV/visible spectrophotometer. Components: Original Measurements: Very few experimental details were provided. Excess solute and solvent were (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. allowed to equilibrate in a constant-temperature reciprocating shaker bath for N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. at least three days. An aliquot of the saturated solution was removed, filtered, 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 and then diluted with a 0.05 molar sodium chloride solution. Solubility of the 1-dioxide (Lornoxicam); (2013). dissolved solute was determined by spectrophotometric measurements at C H ClN O S ; [70374-39-9] 376 nm. 13 10 3 4 2 (2) Methylbenzene; C7H8; [108-88-3] Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no T/K ¼ 298.15 W. E. Acree, Jr. purification details were provided. (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., Mumbai, India, no purification details were provided. Experimental Values

Estimated Error: a b Temperature: 0.05 K. x2 x1 % x1: 4 (relative error, estimated by compiler). 0.9999 0.0000392 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. 17.3. Lornoxicam solubility data in aromatic hydrocarbons Auxiliary Information Method/Apparatus/Procedure: Constant-temperature orbital shaker bath and an UV/visible Components: Original Measurements: spectrophotometer. (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. Very few experimental details were provided. Excess solute and solvent were N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. allowed to equilibrate in a constant-temperature reciprocating shaker bath for 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 at least three days. An aliquot of the saturated solution was removed, ﬁltered, 1-dioxide (Lornoxicam); (2013). and then diluted with a 0.05 molar sodium chloride solution. Solubility of the

C13H10ClN3O4S2; [70374-39-9] dissolved solute was determined by spectrophotometric measurements at (2) Benzene; C6H6; [71-43-2] 376 nm.

Source and Purity of Chemicals: Components: Original Measurements: (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no 151 puriﬁcation details were provided. (1) 6-Chloro-4-hydroxy-2-methyl- M. Kharwade, C. V. S. [ ] (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., N-2-pyridinyl-2H-thieno 2,3-e -1, Subrahmanyam, and P. R. S. Mumbai, India, no puriﬁcation details were provided. 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 1-dioxide (Lornoxicam); (2013). [ ] Estimated Error: C13H10ClN3O4S2; 70374-39-9 Temperature: 0.05 K. (2) Butyl ethanoate; C6H12O2; [123-86-4] x1: 4% (relative error, estimated by compiler). Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

17.4. Lornoxicam solubility data in esters Experimental Values

a b Components: Original Measurements: x2 x1 (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. 0.9999 0.0000943 N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. a 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 x2: mole fraction of component 2 in the saturated solution. b 1-dioxide (Lornoxicam); (2013). x1: mole fraction solubility of the solute.

C13H10ClN3O4S2; [70374-39-9] (2) Ethyl ethanoate; C4H8O2; [141-78-6] Auxiliary Information Variables: Prepared by: Method/Apparatus/Procedure: T/K ¼ 298.15 W. E. Acree, Jr. Constant-temperature orbital shaker bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were Experimental Values allowed to equilibrate in a constant-temperature reciprocating shaker bath for at least three days. An aliquot of the saturated solution was removed, filtered, and then diluted with a 0.05 molar sodium chloride solution. Solubility of the a b dissolved solute was determined by spectrophotometric measurements at x2 x1 376 nm. 0.9999 0.000109 a x2: mole fraction of component 2 in the saturated solution. Source and Purity of Chemicals: b x1: mole fraction solubility of the solute. (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., Auxiliary Information Mumbai, India, no purification details were provided. Method/Apparatus/Procedure: Constant-temperature orbital shaker bath and an UV/visible Estimated Error: spectrophotometer. Temperature: 0.05 K. % Very few experimental details were provided. Excess solute and solvent were x1: 4 (relative error, estimated by compiler). allowed to equilibrate in a constant-temperature reciprocating shaker bath for at least three days. An aliquot of the saturated solution was removed, filtered, and then diluted with a 0.05 molar sodium chloride solution. Solubility of the dissolved solute was determined by spectrophotometric measurements at Components: Original Measurements: 376 nm. (1) 6-Chloro-4-hydroxy-2-methyl- 153J. H. Lee and I. K. Chun, J. N-2-pyridinyl-2H-thieno[2,3-e]-1, Pharm. Invest. 42, 235 (2012). Source and Purity of Chemicals: 2-thiazine-3-carboxamide-1, (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no 1-dioxide (Lornoxicam);

puriﬁcation details were provided. C13H10ClN3O4S2; [70374-39-9] (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., (2) 1-Methylethyl tetradecanoate;

Mumbai, India, no puriﬁcation details were provided. C17H34O2; [110-27-0] Variables: Prepared by: Estimated Error: T/K ¼ 305.15 W. E. Acree, Jr. Temperature: 0.05 K.

x1: 4% (relative error, estimated by compiler). Experimental Values

The measured solubility was reported to be c1 ¼ 0.00011 mol dm3.

Auxiliary Information 17.6. Lornoxicam solubility data in haloalkanes, Method/Apparatus/Procedure: haloalkenes, and haloaromatic hydrocarbons High-performance liquid chromatograph. Excess solute and solvent were allowed to equilibrate at constant temperature with shaking for 48 h. The saturated solution was removed and quickly filtered Components: Original Measurements: (0.45 μm filter). The concentration of the dissolved drug was determined by (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. high-performance liquid chromatographic analysis after appropriate dilution N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. with an aqueous methanol solution. 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 1-dioxide (Lornoxicam); (2013). Source and Purity of Chemicals: C H ClN O S ; [70374-39-9] (1) Purity not given, Hyundai Pharmaceutical Company, Seoul, South Korea, 13 10 3 4 2 (2) Trichloromethane; CHCl ; no purification details were provided. 3 [67-66-3] (2) Analytical Reagent grade, Chemical source not provided, no purification details were provided. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Estimated Error: Temperature: No information given in the paper.

c1: 5% (relative error, estimated by compiler). Experimental Values

a b x2 x1 17.5. Lornoxicam solubility data in ethers 0.9993 0.000660 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Components: Original Measurements: (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. Auxiliary Information N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 Method/Apparatus/Procedure: 1-dioxide (Lornoxicam); (2013). Constant-temperature orbital shaker bath and an UV/visible C13H10ClN3O4S2; [70374-39-9] spectrophotometer. (2) 1,4-Dioxane; C4H8O2; [123-91-1] Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate in a constant-temperature reciprocating shaker bath for Variables: Prepared by: at least three days. An aliquot of the saturated solution was removed, ﬁltered T/K ¼ 298.15 W. E. Acree, Jr. and then diluted with a 0.05 molar sodium chloride solution. Solubility of the dissolved solute was determined by spectrophotometric measurements at Experimental Values 376 nm.

Source and Purity of Chemicals: a b (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no x x 2 1 puriﬁcation details were provided. 0.9998 0.000191 (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., a x2: mole fraction of component 2 in the saturated solution. Mumbai, India, no puriﬁcation details were provided. b x1: mole fraction solubility of the solute. Estimated Error: Temperature: 0.05 K.

Auxiliary Information x1: 4% (relative error, estimated by compiler). Method/Apparatus/Procedure: Constant-temperature orbital shaker bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were Components: Original Measurements: 151 allowed to equilibrate in a constant-temperature reciprocating shaker bath for (1) 6-Chloro-4-hydroxy-2-methyl- M. Kharwade, C. V. S. at least three days. An aliquot of the saturated solution was removed, filtered, N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. and then diluted with a 0.05 molar sodium chloride solution. Solubility of the 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 dissolved solute was determined by spectrophotometric measurements at 1-dioxide (Lornoxicam); (2013). [ ] 376 nm. C13H10ClN3O4S2; 70374-39-9 (2) Tetrachloromethane; CCl4; Source and Purity of Chemicals: [56-23-5] (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no Variables: Prepared by: purification details were provided. T/K ¼ 298.15 W. E. Acree, Jr. (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., Mumbai, India, no purification details were provided.

Estimated Error: Temperature: 0.05 K.

x1: 4% (relative error, estimated by compiler).

Experimental Values Source and Purity of Chemicals: (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no puriﬁcation details were provided. a b (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., x2 x1 Mumbai, India, no puriﬁcation details were provided. 0.9999 0.0000277 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 0.05 K. x1: 4% (relative error, estimated by compiler).

Auxiliary Information Method/Apparatus/Procedure: Constant-temperature orbital shaker bath and an UV/visible 17.7. Lornoxicam solubility data in alcohols spectrophotometer. Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate in a constant-temperature reciprocating shaker bath for Components: Original Measurements: at least three days. An aliquot of the saturated solution was removed, filtered, (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. and then diluted with a 0.05 molar sodium chloride solution. Solubility of the N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. dissolved solute was determined by spectrophotometric measurements at 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 376 nm. 1-dioxide (Lornoxicam); (2013). C H ClN O S ; [70374-39-9] Source and Purity of Chemicals: 13 10 3 4 2 (2) Methanol; CH O; [67-56-1] (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no 4 purification details were provided. Variables: Prepared by: (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., T/K ¼ 298.15 W. E. Acree, Jr. Mumbai, India, no purification details were provided.

Estimated Error: Experimental Values Temperature: 0.05 K.

x1: 4% (relative error, estimated by compiler). a b x2 x1 0.9999 0.0000126 a x2: mole fraction of component 2 in the saturated solution. Components: Original Measurements: b x1: mole fraction solubility of the solute. (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 Auxiliary Information 1-dioxide (Lornoxicam); (2013). Method/Apparatus/Procedure: C13H10ClN3O4S2; [70374-39-9] Constant-temperature orbital shaker bath and an UV/visible (2) Chlorobenzene; C6H5Cl; [108-90-7] spectrophotometer. Very few experimental details were provided. Excess solute and solvent were Variables: Prepared by: allowed to equilibrate in a constant-temperature reciprocating shaker bath for / ¼ T K 298.15 W. E. Acree, Jr. at least three days. An aliquot of the saturated solution was removed, ﬁltered, and then diluted with a 0.05 molar sodium chloride solution. Solubility of the dissolved solute was determined by spectrophotometric measurements at Experimental Values 376 nm.

Source and Purity of Chemicals: a b x2 x1 (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no 0.9999 0.000142 purification details were provided. a (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., x2: mole fraction of component 2 in the saturated solution. b Mumbai, India, no purification details were provided. x1: mole fraction solubility of the solute. Estimated Error: Auxiliary Information Temperature: 0.05 K. x1: 4% (relative error, estimated by compiler). Method/Apparatus/Procedure: Constant-temperature orbital shaker bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate in a constant-temperature reciprocating shaker bath for at least three days. An aliquot of the saturated solution was removed, filtered, and then diluted with a 0.05 molar sodium chloride solution. Solubility of the dissolved solute was determined by spectrophotometric measurements at 376 nm.

Auxiliary Information Components: Original Measurements: (1) 6-Chloro-4-hydroxy-2-methyl- 152M. Kharwade, G. Archyuto, C. Method/Apparatus/Procedure: N-2-pyridinyl-2H-thieno[2,3-e]-1, V. S. Subrahmanyam, and P. R. S. Constant-temperature orbital shaker bath and an UV/visible 2-thiazine-3-carboxamide-1, Babu, J. Solution Chem. 41, 1364 spectrophotometer. 1-dioxide (Lornoxicam); (2012). Very few experimental details were provided. Excess solute and solvent were C13H10ClN3O4S2; [70374-39-9] allowed to equilibrate in a constant-temperature reciprocating shaker bath for (2) Ethanol; C2H6O; [64-17-5] at least three days. An aliquot of the saturated solution was removed, ﬁltered and then diluted with a 0.05 molar sodium chloride solution. Solubility of the Variables: Prepared by: dissolved solute was determined by spectrophotometric measurements at T/K ¼ 298.15 W. E. Acree, Jr. 376 nm.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., x a x b 2 1 Mumbai, India, no puriﬁcation details were provided. 0.9999 0.000013 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 0.05 K. x1: 4% (relative error, estimated by compiler).

Auxiliary Information Method/Apparatus/Procedure: Orbital shaking incubator and an ultraviolet/visible spectrophotometer. Components: Original Measurements: 153 Excess solute and solvent were placed in stoppered flasks and allowed to (1) 6-Chloro-4-hydroxy-2-methyl- J. H. Lee and I. K. Chun, J. equilibrate for three days at constant temperature in an orbital shaking N-2-pyridinyl-2H-thieno[2,3-e]-1, Pharm. Invest. 42, 235 (2012). incubator. Aliquots of saturated solutions were filtered to remove the 2-thiazine-3-carboxamide-1, undissolved solute, and then diluted with 0.05 mol dm3 for spectroscopic 1-dioxide (Lornoxicam); [ ] analysis. Concentration was determined by spectrophotometric measurements C13H10ClN3O4S2; 70374-39-9 [ ] at 264 nm. Solubility measurement was conducted in triplicate. (2) Ethanol; C2H6O; 64-17-5 Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 305.15 W. E. Acree, Jr. (1) Purity not given, Hetero Drugs, Hyderabad, India, no purification details were provided. (2) Purity not given, chemical source not specified, no purification details were Experimental Values provided. The measured solubility was reported to be c1 ¼ 0.000377 3 Estimated Error: mol dm . Temperature: 1K. x % 1: 2.0 (relative error). Auxiliary Information Method/Apparatus/Procedure: High-performance liquid chromatograph. Excess solute and solvent were allowed to equilibrate at constant temperature Components: Original Measurements: with shaking for 48 h. The saturated solution was removed and quickly filtered (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. (0.45 μm filter). The concentration of the dissolved drug was determined by N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. high-performance liquid chromatographic analysis after appropriate dilution 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 with an aqueous methanol solution. 1-dioxide (Lornoxicam); (2013). C H ClN O S ; [70374-39-9] 13 10 3 4 2 Source and Purity of Chemicals: (2) Ethanol; C H O; [64-17-5] 2 6 (1) Purity not given, Hyundai Pharmaceutical Company, Seoul, South Korea, Variables: Prepared by: no purification details were provided. T/K ¼ 298.15 W. E. Acree, Jr. (2) Analytical Reagent grade, Chemical source not provided, no purification details were provided.

Experimental Values Estimated Error: Temperature: No information given in the paper.

c1: 5% (relative error, estimated by compiler). a b x2 x1 0.9999 0.0000133 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., x a x b 2 1 Mumbai, India, no puriﬁcation details were provided. 0.9999 0.0000225 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 0.05 K. x1: 4% (relative error, estimated by compiler).

Auxiliary Information Method/Apparatus/Procedure: Constant-temperature orbital shaker bath and an UV/visible Components: Original Measurements: 151 spectrophotometer. (1) 6-Chloro-4-hydroxy-2-methyl- M. Kharwade, C. V. S. Very few experimental details were provided. Excess solute and solvent were N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. allowed to equilibrate in a constant-temperature reciprocating shaker bath for 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 at least three days. An aliquot of the saturated solution was removed, filtered, 1-dioxide (Lornoxicam); (2013). [ ] and then diluted with a 0.05 molar sodium chloride solution. Solubility of the C13H10ClN3O4S2; 70374-39-9 [ ] dissolved solute was determined by spectrophotometric measurements at (2) 1-Butanol; C4H10O; 71-36-3 376 nm. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no purification details were provided. Experimental Values (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., Mumbai, India, no purification details were provided. a b x2 x1 Estimated Error: Temperature: 0.05 K. 0.9999 0.0000139 a x1: 4% (relative error, estimated by compiler). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., x a x b 2 1 Mumbai, India, no puriﬁcation details were provided. 0.9999 0.0000121 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 0.05 K. x1: 4% (relative error, estimated by compiler).

Auxiliary Information Components: Original Measurements: (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. Method/Apparatus/Procedure: N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. Constant-temperature orbital shaker bath and an UV/visible 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 spectrophotometer. 1-dioxide (Lornoxicam); (2013). Very few experimental details were provided. Excess solute and solvent were C13H10ClN3O4S2; [70374-39-9] allowed to equilibrate in a constant-temperature reciprocating shaker bath for (2) 2-Methyl-1-propanol; C4H10O; at least three days. An aliquot of the saturated solution was removed, filtered, [78-83-1] and then diluted with a 0.05 molar sodium chloride solution. Solubility of the dissolved solute was determined by spectrophotometric measurements at Variables: Prepared by: 376 nm. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: Experimental Values (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., a b Mumbai, India, no purification details were provided. x2 x1 0.9999 0.0000119 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. Temperature: 0.05 K. b % x1: mole fraction solubility of the solute. x1: 4 (relative error, estimated by compiler).

Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: 151 Constant-temperature orbital shaker bath and an UV/visible (1) 6-Chloro-4-hydroxy-2-methyl- M. Kharwade, C. V. S. spectrophotometer. N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. Very few experimental details were provided. Excess solute and solvent were 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 allowed to equilibrate in a constant-temperature reciprocating shaker bath for 1-dioxide (Lornoxicam); (2013). [ ] at least three days. An aliquot of the saturated solution was removed, ﬁltered, C13H10ClN3O4S2; 70374-39-9 [ ] and then diluted with a 0.05 molar sodium chloride solution. Solubility of the (2) 1-Octanol; C8H18O; 111-87-5 dissolved solute was determined by spectrophotometric measurements at Variables: Prepared by: 376 nm. T/K ¼ 298.15 W. E. Acree, Jr.

Source and Purity of Chemicals: (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no Experimental Values puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., Mumbai, India, no puriﬁcation details were provided. a b x2 x1 Estimated Error: 0.9998 0.000212 a Temperature: 0.05 K. x2: mole fraction of component 2 in the saturated solution. b x1: 4% (relative error, estimated by compiler). x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. Constant-temperature orbital shaker bath and an UV/visible N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. spectrophotometer. 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 Very few experimental details were provided. Excess solute and solvent were 1-dioxide (Lornoxicam); (2013). allowed to equilibrate in a constant-temperature reciprocating shaker bath for C13H10ClN3O4S2; [70374-39-9] at least three days. An aliquot of the saturated solution was removed, filtered, (2) 1-Pentanol; C5H12O; [71-41-0] and then diluted with a 0.05 molar sodium chloride solution. Solubility of the dissolved solute was determined by spectrophotometric measurements at Variables: Prepared by: 376 nm. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: Experimental Values (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., a b Mumbai, India, no purification details were provided. x2 x1 0.9999 0.0000385 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. Temperature: 0.05 K. b % x1: mole fraction solubility of the solute. x1: 4 (relative error, estimated by compiler).

Auxiliary Information Components: Original Measurements: (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. Method/Apparatus/Procedure: N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. High-performance liquid chromatograph. 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 Excess solute and solvent were allowed to equilibrate at constant temperature 1-dioxide (Lornoxicam); (2013). with shaking for 48 h. The saturated solution was removed and quickly filtered C13H10ClN3O4S2; [70374-39-9] (0.45 μm filter). The concentration of the dissolved drug was determined by (2) 1,2-Propanediol; C3H8O2; high-performance liquid chromatographic analysis after appropriate dilution [57-55-6] with an aqueous methanol solution. Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 298.15 W. E. Acree, Jr. (1) Purity not given, Hyundai Pharmaceutical Company, Seoul, South Korea, no purification details were provided. Experimental Values (2) Analytical Reagent grade, Chemical source not provided, no purification details were provided.

Estimated Error: x a x b 2 1 Temperature: No information given in the paper. 0.9999 0.0000304 c1: 5% (relative error, estimated by compiler). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: Auxiliary Information (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. Method/Apparatus/Procedure: N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. Constant-temperature orbital shaker bath and an UV/visible 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 spectrophotometer. 1-dioxide (Lornoxicam); (2013). [ ] Very few experimental details were provided. Excess solute and solvent were C13H10ClN3O4S2; 70374-39-9 allowed to equilibrate in a constant-temperature reciprocating shaker bath for (2) 1,2,3-Propanetriol (Glycerol); [ ] at least three days. An aliquot of the saturated solution was removed, ﬁltered, C3H8O3; 56-81-5 and then diluted with a 0.05 molar sodium chloride solution. Solubility of the Variables: Prepared by: dissolved solute was determined by spectrophotometric measurements at T/K ¼ 298.15 W. E. Acree, Jr. 376 nm.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., a b x2 x1 Mumbai, India, no puriﬁcation details were provided. 0.9999 0.00000540 a Estimated Error: x2: mole fraction of component 2 in the saturated solution. b Temperature: 0.05 K. x1: mole fraction solubility of the solute. x1: 4% (relative error, estimated by compiler).

Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: Constant-temperature orbital shaker bath and an UV/visible (1) 6-Chloro-4-hydroxy-2-methyl- 153J. H. Lee and I. K. Chun, J. spectrophotometer. N-2-pyridinyl-2H-thieno[2,3-e]-1, Pharm. Invest. 42, 235 (2012). Very few experimental details were provided. Excess solute and solvent were 2-thiazine-3-carboxamide-1, allowed to equilibrate in a constant-temperature reciprocating shaker bath for 1-dioxide (Lornoxicam); at least three days. An aliquot of the saturated solution was removed, filtered C13H10ClN3O4S2; [70374-39-9] and then diluted with a 0.05 molar sodium chloride solution. Solubility of the (2) 1,2-Propanediol; C3H8O2; dissolved solute was determined by spectrophotometric measurements at [57-55-6] 376 nm. Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 305.15 W. E. Acree, Jr. (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no purification details were provided. Experimental Values (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., Mumbai, India, no purification details were provided. The measured solubility was reported to be c1 ¼ 0.000323 mol dm 3. Estimated Error: Temperature: 0.05 K.

x1: 4% (relative error, estimated by compiler).

17.8. Lornoxicam solubility data in ketones Auxiliary Information Method/Apparatus/Procedure: Constant-temperature orbital shaker bath and an UV/visible Components: Original Measurements: spectrophotometer. (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. Very few experimental details were provided. Excess solute and solvent were N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. allowed to equilibrate in a constant-temperature reciprocating shaker bath for 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 at least three days. An aliquot of the saturated solution was removed, ﬁltered, 1-dioxide (Lornoxicam); (2013). and then diluted with a 0.05 molar sodium chloride solution. Solubility of the dissolved solute was determined by spectrophotometric measurements at C13H10ClN3O4S2; [70374-39-9] 376 nm. (2) Propanone; C3H6O; [67-64-1]

Variables: Prepared by: Source and Purity of Chemicals: / ¼ T K 298.15 W. E. Acree, Jr. (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., Experimental Values Mumbai, India, no puriﬁcation details were provided.

Estimated Error: a b x2 x1 Temperature: 0.05 K.

0.9999 0.0000813 x1: 4% (relative error, estimated by compiler). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. 17.9. Lornoxicam solubility data in miscellaneous organic solvents Auxiliary Information Method/Apparatus/Procedure: Constant-temperature orbital shaker bath and an UV/visible Components: Original Measurements: spectrophotometer. (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. Very few experimental details were provided. Excess solute and solvent were N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. allowed to equilibrate in a constant-temperature reciprocating shaker bath for 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 at least three days. An aliquot of the saturated solution was removed, ﬁltered, 1-dioxide (Lornoxicam); (2013).

and then diluted with a 0.05 molar sodium chloride solution. Solubility of the C13H10ClN3O4S2; [70374-39-9] dissolved solute was determined by spectrophotometric measurements at (2) Dimethyl sulfoxide; C2H6OS; 376 nm. [67-68-5]

Source and Purity of Chemicals: Variables: Prepared by: / ¼ (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no T K 298.15 W. E. Acree, Jr. puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., Experimental Values Mumbai, India, no puriﬁcation details were provided.

Estimated Error: a b Temperature: 0.05 K. x2 x1

x1: 4% (relative error, estimated by compiler). 0.9983 0.00173 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: Auxiliary Information (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. / / N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. Method Apparatus Procedure: / 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 Constant-temperature orbital shaker bath and an UV visible 1-dioxide (Lornoxicam); (2013). spectrophotometer. Very few experimental details were provided. Excess solute and solvent were C13H10ClN3O4S2; [70374-39-9] allowed to equilibrate in a constant-temperature reciprocating shaker bath for (2) Acetophenone; C8H8O; [98-86-2] at least three days. An aliquot of the saturated solution was removed, ﬁltered Variables: Prepared by: and then diluted with a 0.05 molar sodium chloride solution. Solubility of the T/K ¼ 298.15 W. E. Acree, Jr. dissolved solute was determined by spectrophotometric measurements at 376 nm.

Experimental Values Source and Purity of Chemicals: (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no puriﬁcation details were provided. a b x2 x1 (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., 0.9992 0.000779 Mumbai, India, no puriﬁcation details were provided. a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 0.05 K. x1: 4% (relative error, estimated by compiler).

Auxiliary Information Components: Original Measurements: (1) 6-Chloro-4-hydroxy-2-methyl- 153J. H. Lee and I. K. Chun, J. Method/Apparatus/Procedure: N-2-pyridinyl-2H-thieno[2,3-e]-1, Pharm. Invest. 42, 235 (2012). Constant-temperature orbital shaker bath and an UV/visible 2-thiazine-3-carboxamide-1, spectrophotometer. 1-dioxide (Lornoxicam); Very few experimental details were provided. Excess solute and solvent were C13H10ClN3O4S2; [70374-39-9] allowed to equilibrate in a constant-temperature reciprocating shaker bath for (2) Dimethyl sulfoxide; C2H6OS; at least three days. An aliquot of the saturated solution was removed, filtered, [67-68-5] and then diluted with a 0.05 molar sodium chloride solution. Solubility of the dissolved solute was determined by spectrophotometric measurements at Variables: Prepared by: 376 nm. T/K ¼ 305.15 W. E. Acree, Jr. Source and Purity of Chemicals: Experimental Values (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no purification details were provided. The measured solubility was reported to be c1 ¼ 0.0325 (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., mol dm 3. Mumbai, India, no purification details were provided.

Estimated Error: Auxiliary Information Temperature: 0.05 K.

Method/Apparatus/Procedure: x1: 4% (relative error, estimated by compiler). High-performance liquid chromatograph. Excess solute and solvent were allowed to equilibrate at constant temperature with shaking for 48 h. The saturated solution was removed and quickly filtered μ (0.45 m filter). The concentration of the dissolved drug was determined by Components: Original Measurements: high-performance liquid chromatographic analysis after appropriate dilution (1) 6-Chloro-4-hydroxy-2-methyl- 151M. Kharwade, C. V. S. with an aqueous methanol solution. N-2-pyridinyl-2H-thieno[2,3-e]-1, Subrahmanyam, and P. R. S. 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 Source and Purity of Chemicals: 1-dioxide (Lornoxicam); (2013). (1) Purity not given, Hyundai Pharmaceutical Company, Seoul, South Korea, C13H10ClN3O4S2; [70374-39-9] no purification details were provided. (2) Benzenamine; C6H7N; [62-53-3] (2) Analytical Reagent grade, Chemical source not provided, no purification details were provided. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Estimated Error: Temperature: No information given in the paper. Experimental Values c1: 5% (relative error, estimated by compiler).

a b x2 x1 Components: Original Measurements: 0.9974 0.00263 151 a (1) 6-Chloro-4-hydroxy-2-methyl- M. Kharwade, C. V. S. x2: mole fraction of component 2 in the saturated solution. [ ] b N-2-pyridinyl-2H-thieno 2,3-e -1, Subrahmanyam, and P. R. S. x1: mole fraction solubility of the solute. 2-thiazine-3-carboxamide-1, Babu, J. Pharm. Res. 7, 409 1-dioxide (Lornoxicam); (2013).

C13H10ClN3O4S2; [70374-39-9] Auxiliary Information (2) N,N-Dimethylformamide; Method/Apparatus/Procedure: C H NO; [64-19-7] 3 7 Constant-temperature orbital shaker bath and an UV/visible Variables: Prepared by: spectrophotometer. T/K ¼ 298.15 W. E. Acree, Jr. Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate in a constant-temperature reciprocating shaker bath for at least three days. An aliquot of the saturated solution was removed, filtered, Experimental Values and then diluted with a 0.05 molar sodium chloride solution. Solubility of the dissolved solute was determined by spectrophotometric measurements at 376 nm. a b x2 x1 0.9988 0.00115 Source and Purity of Chemicals: (1) Purity not given, gift sample from Hetero Drugs, Hyderabad, India, no ax : mole fraction of component 2 in the saturated solution. 2 purification details were provided. bx : mole fraction solubility of the solute. 1 (2) Purity not given, Analytical Reagent grade, S. D. Fine Chemicals Ltd., Mumbai, India, no purification details were provided.

Estimated Error: Temperature: 0.05 K.

x1: 4% (relative error, estimated by compiler).

Source and Purity of Chemicals: Components: Original Measurements: 153 (1) Purity not given, Hyundai Pharmaceutical Company, Seoul, South Korea, (1) 6-Chloro-4-hydroxy-2-methyl- J. H. Lee and I. K. Chun, J. no purification details were provided. [ ] N-2-pyridinyl-2H-thieno 2,3-e -1, Pharm. Invest. 42, 235 (2012). (2) Analytical Reagent grade, Chemical source not provided, no purification 2-thiazine-3-carboxamide-1, details were provided. 1-dioxide (Lornoxicam); [ ] C13H10ClN3O4S2; 70374-39-9 Estimated Error: (2) N-Methyl-2-pyrrolidone; Temperature: No information given in the paper. C5H9NO; [872-50-4] c1: 5% (relative error, estimated by compiler). Variables: Prepared by: T/K ¼ 305.15 W. E. Acree, Jr. 18. Solubility of Mefenamic Acid in Organic Experimental Values Solvents The measured solubility was reported to be c1 ¼ 0.0328 mol dm3. 18.1. Critical evaluation of experimental solubility data Auxiliary Information Mefenamic acid (more formally named 2-[(2,3-dimethyl- Method/Apparatus/Procedure: phenyl)amino]benzoic acid) is a NSAID that is prescribed for High-performance liquid chromatograph. dysmenorrhea and to treat pain and inflammation caused by Excess solute and solvent were allowed to equilibrate at constant temperature 65,88,154,155 with shaking for 48 h. The saturated solution was removed and quickly filtered arthritis. There have been four publications report- (0.45 μm filter). The concentration of the dissolved drug was determined by ing the solubility of mefenamic acid in organic solvents. Lee high-performance liquid chromatographic analysis after appropriate dilution et al.88 measured the mole fraction solubility of mefenamic with an aqueous methanol solution. acid in cyclohexane, methylbenzene, and ethanol at 298 K. The measurements were performed as part of a larger study Source and Purity of Chemicals: (1) Purity not given, Hyundai Pharmaceutical Company, Seoul, South Korea, that examined the effect that a cosolute had on the solubility of no purification details were provided. the main solute. In this particular study, flufenamic acid served (2) Analytical Reagent grade, Chemical source not provided, no purification as the cosolute and mefenamic acid was the main drug solute. details were provided. Swathi et al.154 determined the molar solubility of mefenamic acid in ethanol, 1,2-ethanediol, 1,2-propanediol, 1,2,3-propa- Estimated Error: Temperature: No information given in the paper. netriol, and polyethylene glycol 400. The five solvents are

c1: 5% (relative error, estimated by compiler). often used as vehicles and enhancers in skin penetration studies. Ethanol is the only solvent common to both studies. The solubility data were published in different concentration units. Using a value of 0.05870 l mol1 for the molar volume Components: Original Measurements: of ethanol, the measured mole fraction solubility of x1 ¼ (1) 6-Chloro-4-hydroxy-2-methyl- 153J. H. Lee and I. K. Chun, J. 88 [ ] 0.00168 of Lee et al. is converted to a molar solubility of N-2-pyridinyl-2H-thieno 2,3-e -1, Pharm. Invest. 42, 235 (2012). ¼ 3 2-thiazine-3-carboxamide-1, c1 0.0286 mol dm , which differs significantly from the 3 1-dioxide (Lornoxicam); value of c1 ¼ 0.06127 mol dm reported by Swathi et al. 65 C13H10ClN3O4S2; [70374-39-9] Rytting et al. reported the solubility of mefenamic acid in (2) Polyethylene glycol 400 polyethylene glycol 400 (PEG 400) at ambient room (PEG 400) temperature. Variables: Prepared by: Mudalip et al.155 measured the solubility of mefenamic acid T/K ¼ 305.15 W. E. Acree, Jr. in three hydrocarbons (hexane, heptane, and cyclohexane), in one alkyl alkanoate (ethyl ethanoate), in two alcohols (ethanol Experimental Values and 2-propanol), and in two miscellaneous organic solvents (N,N-dimethylformamide and N,N-dimethylacetamide) at six The measured solubility was reported to be c1 ¼ 0.00761 different temperatures from 298 to 323 K. The internal con- mol dm 3. sistency of the eight datasets was assessed by curve-fitting the measured mole fraction solubility data to Eq. (8). The values of Auxiliary Information the equation coefficients (A, B, and C) are given in Table 11, Method/Apparatus/Procedure: along with the mean absolute relative deviation. Each of the High-performance liquid chromatograph. eight data sets is considered internally consistent as evidenced Excess solute and solvent were allowed to equilibrate at constant temperature with shaking for 48 h. The saturated solution was removed and quickly filtered by the small MARD values. (0.45 μm filter). The concentration of the dissolved drug was determined by The experimental solubility data for mefenamic acid in high-performance liquid chromatographic analysis after appropriate dilution organic solvents are given in Secs. 18.2–18.7. with an aqueous methanol solution.

TABLE 11. Parameters of the Modiﬁed Apelblat equation for describing the solubility of mefenamic acid in organic solvents Solvent T/K ABCMARD (%) Hexanea 298–323 52.123 114.678 7.909 2.3 Heptanea 298–323 55.447 114.609 8.473 2.5 Cyclohexanea 298–323 52.886 114.672 7.974 3.2 Ethyl ethanoatea 298–323 73.205 114.222 11.806 2.4 Ethanola 298–323 70.431 114.292 11.184 4.7 2-Propanola 298–323 75.784 114.180 12.137 4.8 Propanonea 298–323 51.389 114.730 8.025 3.6 N,N-Dimethylformamidea 298–323 86.491 113.952 14.397 3.6 N,N-Dimethylacetamidea 298–323 35.101 115.100 5.729 1.6 aData set from Mudalip et al.155

18.2. Mefenamic acid solubility data in saturated hydrocarbons (including cycloalkanes)

Components: Original Measurements: (1) 2-[(2,3-Dimethylphenyl)amino]- 155S. K. A. Mudalip, M. R. A. Components: Original Measurements: benzoic acid (Mefenamic acid); Bakar, P. Jamal, and F. Adam, J. (1) 2-[(2,3-Dimethylphenyl)amino]- 155S. K. A. Mudalip, M. R. A. C15H15NO2; [61-68-7] Chem. Eng. Data 58, 3447 (2013). benzoic acid (Mefenamic acid); Bakar, P. Jamal, and F. Adam, J. (2) Heptane; C7H16; [142-82-5] C15H15NO2; [61-68-7] Chem. Eng. Data 58, 3447 (2013). Variables: Prepared by: (2) Hexane; C6H14; [110-54-3] Temperature W. E. Acree, Jr. Variables: Prepared by: Temperature W. E. Acree, Jr. Experimental Values

Experimental Values a b T/K x2 x1 298 0.9989 0.0011 T/K x a x b 2 1 303 0.9987 0.0013 298 0.9987 0.0013 308 0.9985 0.0015 303 0.9986 0.0014 313 0.9983 0.0017 308 0.9984 0.0016 318 0.9982 0.0018 313 0.9982 0.0018 323 0.9978 0.0022 318 0.9980 0.0020 a x2: mole fraction of component 2 in the saturated solution. 323 0.9976 0.0024 b x1: mole fraction solubility of the solute. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Auxiliary Information / / Auxiliary Information Method Apparatus Procedure: Temperature-controlled shaker bath and analytical balance. Method/Apparatus/Procedure: Excess solute and solvent were placed in sealed glass vials and allowed to Temperature-controlled shaker bath and analytical balance. equilibrate in a constant-temperature shaker bath for 24 h. An aliquot was Excess solute and solvent were placed in sealed glass vials and allowed to removed and filtered using a 0.45 μm membrane filter. The supernatant was equilibrate in a constant-temperature shaker bath for 24 h. An aliquot was transferred into a tared evaporating dish. The evaporating dish with saturated removed and filtered using a 0.45 μm membrane filter. The supernatant was solution was weighed to determine the amount of sample analyzed. The solvent transferred into a tared evaporating dish. The evaporating dish with saturated was evaporated initially for several hours at room temperature and then at solution was weighed to determine the amount of sample analyzed. The solvent 333 K. The evaporating dish with solid residue was repeatedly weighed and was evaporated initially for several hours at room temperature and then at dried until constant weight was achieved. The solubility was calculated from 333 K. The evaporating dish with solid residue was repeatedly weighed and the mass of the solid residue and the weight of the sample analyzed. dried until constant weight was achieved. The solubility was calculated from Experimental solubilities represent the average of three replicated the mass of the solid residue and the weight of the sample analyzed. measurements. Experimental solubilities represent the average of three replicated measurements. Source and Purity of Chemicals: (1) 98%, Baoji Tianxin Pharmaceutical Company, Ltd., China, was used as Source and Purity of Chemicals: received. (1) 98%, Baoji Tianxin Pharmaceutical Company, Ltd., China, was used as (2) 99%, Fisher Scientific, USA, was used as received. received. (2) 99.9%, Fisher Scientific, USA, was used as received. Estimated Error: Temperature: 1K. Estimated Error: x1: 4% (relative error, estimated by compiler). Temperature: 1K.

x1: 4% (relative error, estimated by compiler).

Auxiliary Information Components: Original Measurements: (1) 2-[(2,3-Dimethylphenyl)amino]- 155S. K. A. Mudalip, M. R. A. Method/Apparatus/Procedure: benzoic acid (Mefenamic acid); Bakar, P. Jamal, and F. Adam, J. Constant-temperature refrigerated water bath and a high-performance liquid C15H15NO2; [61-68-7] Chem. Eng. Data 58, 3447 (2013). chromatograph equipped with a photodiode array detector. (2) Cyclohexane; C6H12; [110-82-7] Excess solute and solvent were dissolved in glass vials and placed in jacketed beakers connected to a refrigerated water bath. Solutions were stirred using Variables: Prepared by: magnetic stirrers for a minimum of 24 h. The saturated solutions were filtered Temperature W. E. Acree, Jr. (0.20 μm pore size) and diluted to a concentration suitable for high- performance liquid chromatographic analysis. Samples were analyzed at a Experimental Values wavelength of 280 nm. Source and Purity of Chemicals: (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, T/K x a x b 2 1 USA, no purification details were provided. 298 0.9991 0.0009 (2) Purity not given, Sigma-Aldrich Chemical Company, no purification 303 0.9991 0.0009 details were provided. 308 0.9989 0.0011 313 0.9988 0.0012 Estimated Error: 318 0.9986 0.0014 Temperature: 0.2 K (estimated by compiler). 323 0.9984 0.0016 x1: 2.5% (relative error, estimated by compiler). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Auxiliary Information 18.3. Mefenamic acid solubility data in aromatic Method/Apparatus/Procedure: hydrocarbons Temperature-controlled shaker bath and analytical balance. Excess solute and solvent were placed in sealed glass vials and allowed to equilibrate in a constant-temperature shaker bath for 24 h. An aliquot was Components: Original Measurements: removed and ﬁltered using a 0.45 μm membrane ﬁlter. The supernatant was (1) 2-[(2,3-Dimethylphenyl)amino]- 88E. H. Lee, S. R. Byrn, and R. transferred into a tared evaporating dish. The evaporating dish with saturated benzoic acid (Mefenamic acid); Pinal, J. Pharm. Sci. 101, 4529

solution was weighed to determine the amount of sample analyzed. The solvent C15H15NO2; [61-68-7] (2012). was evaporated initially for several hours at room temperature and then at (2) Methylbenzene; C7H8; [108-88-3] 333 K. The evaporating dish with solid residue was repeatedly weighed and dried until constant weight was achieved. The solubility was calculated from Variables: Prepared by: / ¼ the mass of the solid residue and the weight of the sample analyzed. T K 298.15 W. E. Acree, Jr. Experimental solubilities represent the average of three replicated measurements. Experimental Values Source and Purity of Chemicals: (1) 98%, Baoji Tianxin Pharmaceutical Company, Ltd., China, was used as a b received. x2 x1 (2) 99%, Fisher Scientiﬁc, USA, was used as received. 0.9996 0.00037 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 1K.

x1: 4% (relative error, estimated by compiler). Auxiliary Information Method/Apparatus/Procedure: Constant-temperature refrigerated water bath and a high-performance liquid Components: Original Measurements: chromatograph equipped with a photodiode array detector. (1) 2-[(2,3-Dimethylphenyl)amino]- 88E. H. Lee, S. R. Byrn, and R. Excess solute and solvent were dissolved in glass vials and placed in jacketed benzoic acid (Mefenamic acid); Pinal, J. Pharm. Sci. 101, 4529 beakers connected to a refrigerated water bath. Solutions were stirred using C H NO ; [61-68-7] (2012). 15 15 2 magnetic stirrers for a minimum of 24 h. The saturated solutions were ﬁltered (2) Cyclohexane; C H ; [110-82-7] 6 12 (0.20 μm pore size) and diluted to a concentration suitable for high- Variables: Prepared by: performance liquid chromatographic analysis. Samples were analyzed at a T/K ¼ 298.15 W. E. Acree, Jr. wavelength of 280 nm.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. (2) Purity not given, Mallinckrodt Baker, Inc., Phillipsburg, New Jersey, USA, a b x2 x1 no puriﬁcation details were provided. 0.9999 0.000029 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. Temperature: 0.2 K (estimated by compiler). b x1: mole fraction solubility of the solute. x1: 2.5% (relative error, estimated by compiler).

18.4. Mefenamic acid solubility data in esters Experimental Values

a b x2 x1 Components: Original Measurements: (1) 2-[(2,3-Dimethylphenyl)amino]- 155S. K. A. Mudalip, M. R. A. 0.9983 0.00168 a benzoic acid (Mefenamic acid); Bakar, P. Jamal, and F. Adam, J. x2: mole fraction of component 2 in the saturated solution. b C15H15NO2; [61-68-7] Chem. Eng. Data 58, 3447 (2013). x1: mole fraction solubility of the solute. (2) Ethyl ethanoate; C4H8O2; [141-78-6] Auxiliary Information Variables: Prepared by: Temperature W. E. Acree, Jr. Method/Apparatus/Procedure: Constant-temperature refrigerated water bath and a high-performance liquid chromatograph equipped with a photodiode array detector. Experimental Values Excess solute and solvent were dissolved in glass vials and placed in jacketed beakers connected to a refrigerated water bath. Solutions were stirred using magnetic stirrers for a minimum of 24 h. The saturated solutions were filtered a b μ T/K x2 x1 (0.20 m pore size) and diluted to a concentration suitable for high- 298 0.9961 0.0039 performance liquid chromatographic analysis. Samples were analyzed at a 303 0.9955 0.0045 wavelength of 280 nm. 308 0.9945 0.0055 313 0.9929 0.0071 Source and Purity of Chemicals: 318 0.9921 0.0079 (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, 323 0.9904 0.0096 USA, no purification details were provided. a (2) Purity not given, Pharmco, Brookfield, Connecticut, USA, no purification x2: mole fraction of component 2 in the saturated solution. b details were provided. x1: mole fraction solubility of the solute. Estimated Error: Temperature: 0.2 K (estimated by compiler). Auxiliary Information x1: 2.5% (relative error, estimated by compiler). Method/Apparatus/Procedure: Temperature-controlled shaker bath and analytical balance. Excess solute and solvent were placed in sealed glass vials and allowed to equilibrate in a constant-temperature shaker bath for 24 h. An aliquot was Components: Original Measurements: μ removed and filtered using a 0.45 m membrane filter. The supernatant was (1) 2-[(2,3-Dimethylphenyl)amino]- 154C. H. Swathi, C. V. S. transferred into a tared evaporating dish. The evaporating dish with saturated benzoic acid (Mefenamic acid); Subrahmanyam, S. A. Kedarnath, solution was weighed to determine the amount of sample analyzed. The solvent C15H15NO2; [61-68-7] and P. R. S. Babu, Int. J. Pharm. was evaporated initially for several hours at room temperature and then at (2) Ethanol; C2H6O; [64-17-5] Technol. 3, 3267 (2011). 333 K. The evaporating dish with solid residue was repeatedly weighed and dried until constant weight was achieved. The solubility was calculated from Variables: Prepared by: the mass of the solid residue and the weight of the sample analyzed. T/K ¼ 298 W. E. Acree, Jr. Experimental solubilities represent the average of three replicated measurements. Experimental Values Source and Purity of Chemicals: The measured solubility was reported to be c ¼ 0.06127 % 1 (1) 98 , Baoji Tianxin Pharmaceutical Company, Ltd., China, was used as mol dm3. received. (2) 99.5%, Fisher Scientific, USA, was used as received. Auxiliary Information Estimated Error: Method/Apparatus/Procedure: Temperature: 1K. Constant-temperature shaker bath and an UV/visible spectrophotometer. x : 4% (relative error, estimated by compiler). 1 Excess solute and solvent were placed in stoppered volumetric flasks and allowed to equilibrate in a constant-temperature shaker bath for 24 h. An aliquot of the saturated solution was removed, filtered through a 0.22 μm membrane filter, and diluted with 0.1 molar aqueous hydrochloric acid solution 18.5. Mefenamic acid solubility data in alcohols for spectroscopic analysis at 333 nm. Reported values represent the average of three experimental determinations.

Source and Purity of Chemicals: Components: Original Measurements: (1) Purity not given, Wanbury Ltd., no purification details were given in the (1) 2-[(2,3-Dimethylphenyl)amino]- 88E. H. Lee, S. R. Byrn, and R. paper. benzoic acid (Mefenamic acid); Pinal, J. Pharm. Sci. 101, 4529 (2) Purity not given, chemical source not specified, no purification details were C H NO ; [61-68-7] (2012). 15 15 2 provided. (2) Ethanol; C2H6O; [64-17-5] Variables: Prepared by: Estimated Error: T/K ¼ 298.15 W. E. Acree, Jr. Temperature: 0.5 K (estimated by compiler). c1: 5% (relative error, estimated by compiler).

a b Components: Original Measurements: T/K x2 x1 [ ] 155 (1) 2- (2,3-Dimethylphenyl)amino - S. K. A. Mudalip, M. R. A. 313 0.9967 0.0033 benzoic acid (Mefenamic acid); Bakar, P. Jamal, and F. Adam, J. 318 0.9960 0.0040 [ ] C15H15NO2; 61-68-7 Chem. Eng. Data 58, 3447 (2013). 323 0.9947 0.0053 (2) Ethanol; C H O; [64-17-5] 2 6 a x2: mole fraction of component 2 in the saturated solution. Variables: Prepared by: b x1: mole fraction solubility of the solute. Temperature W. E. Acree, Jr. Auxiliary Information Experimental Values Method/Apparatus/Procedure: Temperature-controlled shaker bath and analytical balance. Excess solute and solvent were placed in sealed glass vials and allowed to / a b T K x2 x1 equilibrate in a constant-temperature shaker bath for 24 h. An aliquot was 298 0.9981 0.0019 removed and ﬁltered using a 0.45 μm membrane ﬁlter. The supernatant was 303 0.9980 0.0020 transferred into a tared evaporating dish. The evaporating dish with saturated 308 0.9976 0.0024 solution was weighed to determine the amount of sample analyzed. The solvent 313 0.9968 0.0032 was evaporated initially for several hours at room temperature and then at 318 0.9963 0.0037 333 K. The evaporating dish with solid residue was repeatedly weighed and 323 0.9958 0.0042 dried until constant weight was achieved. The solubility was calculated from the mass of the solid residue and the weight of the sample analyzed. ax : mole fraction of component 2 in the saturated solution. 2 Experimental solubilities represent the average of three replicated bx : mole fraction solubility of the solute. 1 measurements.

Auxiliary Information Source and Purity of Chemicals: (1) 98%, Baoji Tianxin Pharmaceutical Company, Ltd., China, was used as Method/Apparatus/Procedure: received. Temperature-controlled shaker bath and analytical balance. (2) 99.9+%, Fisher Scientific, USA, was used as received. Excess solute and solvent were placed in sealed glass vials and allowed to equilibrate in a constant-temperature shaker bath for 24 h. An aliquot was Estimated Error: removed and filtered using a 0.45 μm membrane filter. The supernatant was Temperature: 1K. transferred into a tared evaporating dish. The evaporating dish with saturated x : 4% (relative error, estimated by compiler). solution was weighed to determine the amount of sample analyzed. The solvent 1 was evaporated initially for several hours at room temperature and then at 333 K. The evaporating dish with solid residue was repeatedly weighed and dried until constant weight was achieved. The solubility was calculated from Components: Original Measurements: the mass of the solid residue and the weight of the sample analyzed. (1) 2-[(2,3-Dimethylphenyl)amino]- 154C. H. Swathi, C. V. S. Experimental solubilities represent the average of three replicated benzoic acid (Mefenamic acid); Subrahmanyam, S. A. Kedarnath, measurements. C15H15NO2; [61-68-7] and P. R. S. Babu, Int. J. Pharm. (2) 1,2-Ethanediol; C H O ; Technol. 3, 3267 (2011). Source and Purity of Chemicals: 2 6 2 [107-21-1] (1) 98%, Baoji Tianxin Pharmaceutical Company, Ltd., China, was used as received. Variables: Prepared by: (2) 99.9%, Fisher Scientific, USA, was used as received. T/K ¼ 298 W. E. Acree, Jr.

Estimated Error: Temperature: 1K. Experimental Values

x1: 4% (relative error, estimated by compiler). The measured solubility was reported to be c1 ¼ 0.000911 mol dm3. Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-[(2,3-Dimethylphenyl)amino]- 155S. K. A. Mudalip, M. R. A. Constant-temperature shaker bath and an UV/visible spectrophotometer. benzoic acid (Mefenamic acid); Bakar, P. Jamal, and F. Adam, J. Excess solute and solvent were placed in stoppered volumetric flasks and C15H15NO2; [61-68-7] Chem. Eng. Data 58, 3447 (2013). allowed to equilibrate in a constant-temperature shaker bath for 24 h. An (2) 2-Propanol; C3H8O; [67-63-0] aliquot of the saturated solution was removed, filtered through a 0.22 μm membrane filter, and diluted with 0.1 molar aqueous hydrochloric acid solution Variables: Prepared by: for spectroscopic analysis at 333 nm. Reported values represent the average of Temperature W. E. Acree, Jr. three experimental determinations.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Wanbury Ltd., no purification details were given in the paper. (2) Purity not given, chemical source not specified, no purification details were T/K x a x b 2 1 provided. 298 0.9980 0.0020 303 0.9976 0.0024 Estimated Error: 308 0.9974 0.0026 Temperature: 0.5 K (estimated by compiler).

c1: 5% (relative error, estimated by compiler).

Source and Purity of Chemicals: Components: Original Measurements: (1) Purity not given, Wanbury Ltd., no purification details were given in the [ ] 154 (1) 2- (2,3-Dimethylphenyl)amino - C. H. Swathi, C. V. S. paper. benzoic acid (Mefenamic acid); Subrahmanyam, S. A. Kedarnath, (2) Purity not given, chemical source not specified, no purification details were [ ] C15H15NO2; 61-68-7 and P. R. S. Babu, Int. J. Pharm. provided. (2) 1,2-Propanediol; C3H8O2; Technol. 3, 3267 (2011). [ ] 57-55-6 Estimated Error: Variables: Prepared by: Temperature: 0.5 K (estimated by compiler). % T/K ¼ 298 W. E. Acree, Jr. c1: 5 (relative error, estimated by compiler).

Experimental Values

The measured solubility was reported to be c1 ¼ 0.000907 18.6. Mefenamic acid solubility data in ketones mol dm3.

Auxiliary Information Components: Original Measurements: (1) 2-[(2,3-Dimethylphenyl)amino]- 155S. K. A. Mudalip, M. R. A. Method/Apparatus/Procedure: benzoic acid (Mefenamic acid); Bakar, P. Jamal, and F. Adam, J. / Constant-temperature shaker bath and an UV visible spectrophotometer. C15H15NO2; [61-68-7] Chem. Eng. Data 58, 3447 (2013). Excess solute and solvent were placed in stoppered volumetric flasks and (2) Propanone; C3H6O; [67-64-1] allowed to equilibrate in a constant-temperature shaker bath for 24 h. An aliquot of the saturated solution was removed, filtered through a 0.22 μm Variables: Prepared by: membrane filter, and diluted with 0.1 molar aqueous hydrochloric acid solution Temperature W. E. Acree, Jr. for spectroscopic analysis at 333 nm. Reported values represent the average of three experimental determinations. Experimental Values Source and Purity of Chemicals: (1) Purity not given, Wanbury Ltd., no purification details were given in the / a b paper. T K x2 x1 (2) Purity not given, chemical source not specified, no purification details were 298 0.9946 0.0054 provided. 303 0.9945 0.0055 308 0.9935 0.0065 Estimated Error: 313 0.9930 0.0070 Temperature: 0.5 K (estimated by compiler). 318 0.9916 0.0084

c1: 5% (relative error, estimated by compiler). 323 0.9902 0.0098 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: (1) 2-[(2,3-Dimethylphenyl)amino]- 154C. H. Swathi, C. V. S. Auxiliary Information benzoic acid (Mefenamic acid); Subrahmanyam, S. A. Kedarnath, Method/Apparatus/Procedure: [ ] C15H15NO2; 61-68-7 and P. R. S. Babu, Int. J. Pharm. Temperature-controlled shaker bath and analytical balance. (2) 1,2,3-Propanetriol (Glycerol); Technol. 3, 3267 (2011). Excess solute and solvent were placed in sealed glass vials and allowed to [ ] C3H8O3; 56-81-5 equilibrate in a constant-temperature shaker bath for 24 h. An aliquot was μ Variables: Prepared by: removed and filtered using a 0.45 m membrane filter. The supernatant was T/K ¼ 298 W. E. Acree, Jr. transferred into a tared evaporating dish. The evaporating dish with saturated solution was weighed to determine the amount of sample analyzed. The solvent was evaporated initially for several hours at room temperature and then at Experimental Values 333 K. The evaporating dish with solid residue was repeatedly weighed and ¼ dried until constant weight was achieved. The solubility was calculated from The measured solubility was reported to be c1 0.000648 the mass of the solid residue and the weight of the sample analyzed. 3 mol dm . Experimental solubilities represent the average of three replicated measurements. Auxiliary Information Source and Purity of Chemicals: Method/Apparatus/Procedure: (1) 98%, Baoji Tianxin Pharmaceutical Company, Ltd., China, was used as Constant-temperature shaker bath and an UV/visible spectrophotometer. received. Excess solute and solvent were placed in stoppered volumetric flasks and (2) 99.5%, Fisher Scientific, USA, was used as received. allowed to equilibrate in a constant-temperature shaker bath for 24 h. An aliquot of the saturated solution was removed, filtered through a 0.22 μm Estimated Error: membrane filter, and diluted with 0.1 molar aqueous hydrochloric acid solution Temperature: 1K.

for spectroscopic analysis at 333 nm. Reported values represent the average of x1: 4% (relative error, estimated by compiler). three experimental determinations.

18.7. Mefenamic acid solubility data in Experimental Values miscellaneous organic solvents

a b T/K x2 x1 298 0.8781 0.1219 Components: Original Measurements: 303 0.8623 0.1377 (1) 2-[(2,3-Dimethylphenyl)amino]- 155S. K. A. Mudalip, M. R. A. 308 0.8465 0.1535 benzoic acid (Mefenamic acid); Bakar, P. Jamal, and F. Adam, J. 313 0.8352 0.1648 C H NO ; [61-68-7] Chem. Eng. Data 58, 3447 (2013). 15 15 2 318 0.8247 0.1753 (2) N,N-Dimethylformamide; 323 0.8099 0.1901 C3H7NO; [64-19-7] a x2: mole fraction of component 2 in the saturated solution. Variables: Prepared by: b x1: mole fraction solubility of the solute. Temperature W. E. Acree, Jr.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: Temperature-controlled shaker bath and analytical balance. a b Excess solute and solvent were placed in sealed glass vials and allowed to T/K x2 x1 equilibrate in a constant-temperature shaker bath for 24 h. An aliquot was 298 0.9829 0.0171 removed and ﬁltered using a 0.45 μm membrane ﬁlter. The supernatant was 303 0.9792 0.0208 transferred into a tared evaporating dish. The evaporating dish with saturated 308 0.9725 0.0275 solution was weighed to determine the amount of sample analyzed. The solvent 313 0.9673 0.0327 was evaporated initially for several hours at room temperature and then at 318 0.9609 0.0391 333 K. The evaporating dish with solid residue was repeatedly weighed and 323 0.9449 0.0551 dried until constant weight was achieved. The solubility was calculated from a x2: mole fraction of component 2 in the saturated solution. the mass of the solid residue and the weight of the sample analyzed. b x1: mole fraction solubility of the solute. Experimental solubilities represent the average of three replicated measurements.

Auxiliary Information Source and Purity of Chemicals: % Method/Apparatus/Procedure: (1) 98 , Baoji Tianxin Pharmaceutical Company, Ltd., China, was used as Temperature-controlled shaker bath and analytical balance. received. % Excess solute and solvent were placed in sealed glass vials and allowed to (2) 99 , Fisher Scientific, USA, was used as received. equilibrate in a constant-temperature shaker bath for 24 h. An aliquot was removed and filtered using a 0.45 μm membrane filter. The supernatant was Estimated Error: transferred into a tared evaporating dish. The evaporating dish with saturated Temperature: 1K. % solution was weighed to determine the amount of sample analyzed. The solvent x1: 4 (relative error, estimated by compiler). was evaporated initially for several hours at room temperature and then at 333 K. The evaporating dish with solid residue was repeatedly weighed and dried until constant weight was achieved. The solubility was calculated from the mass of the solid residue and the weight of the sample analyzed. Components: Original Measurements: Experimental solubilities represent the average of three replicated (1) 2-[(2,3-Dimethylphenyl)amino]- 154C. H. Swathi, C. V. S. measurements. benzoic acid (Mefenamic acid); Subrahmanyam, S. A. Kedarnath,

C15H15NO2; [61-68-7] and P. R. S. Babu, Int. J. Pharm. Source and Purity of Chemicals: (2) Polyethylene glycol 400 (PEG Technol. 3, 3267 (2011). (1) 98%, Baoji Tianxin Pharmaceutical Company, Ltd., China, was used as 400) received. (2) 99%, Fisher Scientiﬁc, USA, was used as received. Variables: Prepared by: T/K ¼ 298 W. E. Acree, Jr. Estimated Error: Temperature: 1K. Experimental Values x1: 4% (relative error, estimated by compiler). The measured solubility was reported to be c1 ¼ 0.04770 mol dm3.

Components: Original Measurements: (1) 2-[(2,3-Dimethylphenyl)amino]- 155S. K. A. Mudalip, M. R. A. benzoic acid (Mefenamic acid); Bakar, P. Jamal, and F. Adam, J.

C15H15NO2; [61-68-7] Chem. Eng. Data 58, 3447 (2013). (2) N,N-Dimethylacetamide;

C4H9NO; [127-19-5] Variables: Prepared by: Temperature W. E. Acree, Jr.

Auxiliary Information 19. Solubility of Meloxicam in Organic Method/Apparatus/Procedure: Solvents Constant-temperature shaker bath and an UV/visible spectrophotometer. Excess solute and solvent were placed in stoppered volumetric flasks and 19.1. Critical evaluation of experimental solubility allowed to equilibrate in a constant-temperature shaker bath for 24 h. An data aliquot of the saturated solution was removed, filtered through a 0.22 μm membrane filter, and diluted with 0.1 molar aqueous hydrochloric acid solution Meloxicam (more formally named 4-hydroxy-2-methyl- for spectroscopic analysis at 333 nm. Reported values represent the average of N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxa- three experimental determinations. mide-1,1-dioxide) has been used to manage pain, stiffness, Source and Purity of Chemicals: swelling, and tenderness caused by osteoarthritis and rheu- (1) Purity not given, Wanbury Ltd., no purification details were given in the matoid arthritis. There have been several publications67,156– paper. 159 reporting the solubility of meloxicam in organic solvents. (2) Purity not given, chemical source not specified, no purification details were Most notably, Babu et al.156 measured the mole-fraction provided. solubility of meloxicam in 25 different organic solvents, Estimated Error: including two saturated hydrocarbons (hexane and cyclo- Temperature: 0.5 K (estimated by compiler). hexane), two aromatic hydrocarbons (benzene and methyl- % c1: 5 (relative error, estimated by compiler). benzene), two alkyl alkanoates (ethyl ethanoate and butyl ethanoate), one cyclic ether (1,4-dioxane), two chloroalkanes (trichloromethane and tetrachloromethane), 12 alcohols (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, Components: Original Measurements: (1) 2-[(2,3-Dimethylphenyl)amino]- 65E. Rytting, K. A. Lentz, X.-Q. 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, benzene- benzoic acid (Mefenamic acid); Chen, F. Qian, and S. Venkatesh, methanol, 1,2-propanediol, and 1,2,3-propanetriol), one [ ] C15H15NO2; 61-68-7 AAPS J. 7, E78 (2005). alkanone (propanone) and one aromatic ketone (acetophe- (2) Polyethylene glycol 400 none), and two miscellaneous organic solvents (dimethyl (PEG 400) sulfoxide and N,N-dimethylformamide) at 298 K and atmo- Variables: Prepared by: spheric pressure. Reference 157 also reported molar melox- T/K ¼ 296 W. E. Acree, Jr. icam solubility data in ethanol, 1,3-propanediol, polyethylene glycol 300 (PEG 300), and polyethylene glycol Experimental Values 400 (PEG 400), as well as in binary ethanol + PEG 400 and ¼ 1,2-propanediol + PEG 400 solvent mixtures. Seedher and The measured solubility was reported to be c1 0.0883 67 mol dm3. Bhatia determined the molar solubility of meloxicam in methanol, ethanol, 1-butanol, 1-octanol, 1,2-ethanediol, 1,2- propanediol, 1,2,3-propanetriol, and polyethylene glycol Auxiliary Information 400 (PEG 400) at 298 K. Meloxicam solubilities were also Method/Apparatus/Procedure: measured in binary ethanol + 1,2,3-propanetriol and ethanol Centrifuge and a high-performance liquid chromatograph equipped with a + PEG 400 solvent mixtures. photo-diode array detector. 158,159 Excess solute and solvent were placed in sealed vials and shaken at ambient There have been two studies reporting the solubility room temperature for at least 24 h. The vials were then centrifuged for 15 min of the analgesic drug meloxicam in organic solvents as a to separate the saturated solution from the excess solute. The supernatant was function of temperature. Holguín et al.159 examined the solu- then filtered and the concentration of the dissolved solute determined by high- bility behavior and preferential solvation in binary water + 1,2- performance liquid chromatographic analysis. propanediol mixtures at several temperatures from 293 to 158 Source and Purity of Chemicals: 313 K. Delgado et al. performed similar solubility measure- (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, ments in binary aqueous-ethanol solvent mixtures. In both USA, no purification details were provided. cases, the authors determined the solubility of meloxicam in (2) Purity not given, J. T. Baker Chemical Company, Phillipsburg, New Jersey, water and in the neat organic solvent. The internal consistency USA, no purification details were provided. of the two datasets was assessed by curve-fitting the measured Estimated Error: mole-fraction solubility data to the Modified Apelblat model Temperature: 2 K (estimated by compiler). [Eq. (8)] to yield the following representations: c1: 10% (relative error, estimated by compiler). 114:212 ln x ¼131:031 þ þ 21:086 ln T ð31Þ 1 T

115:550 ln x ¼73:046 þ þ 10:983 ln T ð32Þ 1 T

for solubilities in ethanol and 1,2-propanediol, respectively. Experimental Values The mean absolute relative deviations between the observed

experimental data and back-calculated values based on a b x x Eqs. (31) and (32) of MARD ¼ 2.5% and MARD ¼ 1.3% 2 1 0.9999 0.00000447 are less than the experimental uncertainty associated with the a measured values. x2: mole fraction of component 2 in the saturated solution. bx : mole fraction solubility of the solute. The experimental solubility data for meloxicam in organic 1 solvents are given in Secs. 19.2–19.10. Auxiliary Information / / 19.2. Meloxicam solubility data in saturated Method Apparatus Procedure: Constant-temperature shaker bath and an UV/visible spectrophotometer. hydrocarbons (including cycloalkanes) Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate in a constant-temperature shaker bath for at least three days. An aliquot of the saturated solution was removed and ﬁltered (0.20 μm Components: Original Measurements: pore size). Solubility of the dissolved solute was determined by (1) 4-Hydroxy-2-methyl-N- 156P. R. S. Babu, C. V. S. spectrophotometric measurements. (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, Source and Purity of Chemicals: 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no

C14H13N3O4S2; [71125-38-7] purification details were provided. (2) Hexane; C6H14; [110-54-3] (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. Variables: Prepared by: / ¼ T K 298.15 W. E. Acree, Jr. Estimated Error: Temperature: 0.5 K. x : 4% (relative error, estimated by compiler). Experimental Values 1

a b x2 x1 0.9999 0.00000770 19.3. Meloxicam solubility data in aromatic a hydrocarbons x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

allowed to equilibrate in a constant-temperature shaker bath for at least three C14H13N3O4S2; [71125-38-7] μ days. An aliquot of the saturated solution was removed and filtered (0.20 m (2) Benzene; C6H6; [71-43-2] pore size). Solubility of the dissolved solute was determined by Variables: Prepared by: spectrophotometric measurements. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no Experimental Values purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified,

no puriﬁcation details were provided. a b x2 x1 Estimated Error: 0.9998 0.000161 a Temperature: 0.5 K. x2: mole fraction of component 2 in the saturated solution. x % b 1: 4 (relative error, estimated by compiler). x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: 156 (1) 4-Hydroxy-2-methyl-N- P. R. S. Babu, C. V. S. Constant-temperature shaker bath and an UV/visible spectrophotometer. (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, Very few experimental details were provided. Excess solute and solvent were 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, allowed to equilibrate in a constant-temperature shaker bath for at least three 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). days. An aliquot of the saturated solution was removed and ﬁltered (0.20 μm [ ] C14H13N3O4S2; 71125-38-7 pore size). Solubility of the dissolved solute was determined by [ ] (2) Cyclohexane; C6H12; 110-82-7 spectrophotometric measurements. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, a b x2 x1 no purification details were provided. 0.9999 0.0000348 a Estimated Error: x2: mole fraction of component 2 in the saturated solution. b Temperature: 0.5 K. x1: mole fraction solubility of the solute. x1: 4% (relative error, estimated by compiler).

Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: Constant-temperature shaker bath and an UV/visible spectrophotometer. (1) 4-Hydroxy-2-methyl-N- 156P. R. S. Babu, C. V. S. Very few experimental details were provided. Excess solute and solvent were (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, allowed to equilibrate in a constant-temperature shaker bath for at least three 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, days. An aliquot of the saturated solution was removed and filtered (0.20 μm 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). pore size). Solubility of the dissolved solute was determined by C14H13N3O4S2; [71125-38-7] spectrophotometric measurements. (2) Methylbenzene; C7H8; [108-88-3] Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no T/K ¼ 298.15 W. E. Acree, Jr. purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values Estimated Error:

a b Temperature: 0.5 K. x2 x1 x1: 4% (relative error, estimated by compiler). 0.9998 0.000170 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Components: Original Measurements: Auxiliary Information (1) 4-Hydroxy-2-methyl-N- 156P. R. S. Babu, C. V. S. (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, / / Method Apparatus Procedure: 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, / Constant-temperature shaker bath and an UV visible spectrophotometer. 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). Very few experimental details were provided. Excess solute and solvent were C14H13N3O4S2; [71125-38-7] allowed to equilibrate in a constant-temperature shaker bath for at least three (2) Butyl ethanoate; C H O ; μ 6 12 2 days. An aliquot of the saturated solution was removed and filtered (0.20 m [123-86-4] pore size). Solubility of the dissolved solute was determined by spectrophotometric measurements. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. Experimental Values (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. a b x2 x1 Estimated Error: 0.9996 0.000396 Temperature: 0.5 K. a % x2: mole fraction of component 2 in the saturated solution. x1: 4 (relative error, estimated by compiler). b x1: mole fraction solubility of the solute.

19.4. Meloxicam solubility data in esters Auxiliary Information Method/Apparatus/Procedure: Constant-temperature shaker bath and an UV/visible spectrophotometer. Components: Original Measurements: Very few experimental details were provided. Excess solute and solvent were 156 (1) 4-Hydroxy-2-methyl-N- P. R. S. Babu, C. V. S. allowed to equilibrate in a constant-temperature shaker bath for at least three (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, days. An aliquot of the saturated solution was removed and filtered (0.20 μm 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, pore size). Solubility of the dissolved solute was determined by 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). spectrophotometric measurements. C14H13N3O4S2; [71125-38-7] (2) Ethyl ethanoate; C4H8O2; Source and Purity of Chemicals: [ ] 141-78-6 (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no Variables: Prepared by: purification details were provided. T/K ¼ 298.15 W. E. Acree, Jr. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided.

Estimated Error: Experimental Values Temperature: 0.5 K.

x1: 4% (relative error, estimated by compiler). a b x2 x1 0.9982 0.001814 a x2: mole fraction of component 2 in the saturated solution. 19.5. Meloxicam solubility data in ethers b x1: mole fraction solubility of the solute.

Components: Original Measurements: Auxiliary Information (1) 4-Hydroxy-2-methyl-N- 156P. R. S. Babu, C. V. S. Method/Apparatus/Procedure: (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, Constant-temperature shaker bath and an UV/visible spectrophotometer. 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, Very few experimental details were provided. Excess solute and solvent were 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). allowed to equilibrate in a constant-temperature shaker bath for at least three C H N O S ; [71125-38-7] 14 13 3 4 2 days. An aliquot of the saturated solution was removed and filtered (0.20 μm (2) 1,4-Dioxane; C H O ; [123-91-1] 4 8 2 pore size). Solubility of the dissolved solute was determined by Variables: Prepared by: spectrophotometric measurements. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no Experimental Values purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. a b x2 x1 0.9982 0.001796 Estimated Error: Temperature: 0.5 K. a x2: mole fraction of component 2 in the saturated solution. x : 4% (relative error, estimated by compiler). b 1 x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 4-Hydroxy-2-methyl-N- 156P. R. S. Babu, C. V. S. Constant-temperature shaker bath and an UV/visible spectrophotometer. (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, Very few experimental details were provided. Excess solute and solvent were 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, allowed to equilibrate in a constant-temperature shaker bath for at least three 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). days. An aliquot of the saturated solution was removed and ﬁltered (0.20 μm C14H13N3O4S2; [71125-38-7] pore size). Solubility of the dissolved solute was determined by (2) Tetrachloromethane; CCl4; spectrophotometric measurements. [56-23-5]

Source and Purity of Chemicals: Variables: Prepared by: / ¼ (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no T K 298.15 W. E. Acree, Jr. purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values

Estimated Error: a b Temperature: 0.5 K. x2 x1

x1: 4% (relative error, estimated by compiler). 0.9999 0.0000617 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

19.6. Meloxicam solubility data in haloalkanes, haloalkenes, and haloaromatic hydrocarbons Auxiliary Information Method/Apparatus/Procedure: Constant-temperature shaker bath and an UV/visible spectrophotometer. Components: Original Measurements: Very few experimental details were provided. Excess solute and solvent were (1) 4-Hydroxy-2-methyl-N- 156P. R. S. Babu, C. V. S. allowed to equilibrate in a constant-temperature shaker bath for at least three μ (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, days. An aliquot of the saturated solution was removed and ﬁltered (0.20 m 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, pore size). Solubility of the dissolved solute was determined by 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). spectrophotometric measurements.

C14H13N3O4S2; [71125-38-7] Source and Purity of Chemicals: (2) Trichloromethane; CHCl3; [67-66-3] (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. Variables: Prepared by: (2) Purity not given, Analytical Reagent grade, chemical source not specified, T/K ¼ 298.15 W. E. Acree, Jr. no purification details were provided.

Estimated Error: Auxiliary Information Temperature: 0.5 K. Method/Apparatus/Procedure: x1: 4% (relative error, estimated by compiler). Vortex mixer, constant-temperature bath, and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in sealed containers and equilibrated at a constant temperature for 24 h. During this time the tubes were shaken 19.7. Meloxicam solubility data in alcohols occasionally on a vortex mixer. Aliquots of saturated solutions were removed, centrifuged, filtered through a sintered glass crucible (grade 4), and diluted quantitatively with 10% aqueous N,N-dimethylformamide for spectroscopic Components: Original Measurements: analyses. Concentration of the dissolved solute was determined from the (1) 4-Hydroxy-2-methyl-N- 156P. R. S. Babu, C. V. S. measured absorbance at 363 nm. (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, Source and Purity of Chemicals: 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). (1) Purity not given, Sun Pharmaceutical Industries, Ltd., Mumbai, India, no purification details were provided. C14H13N3O4S2; [71125-38-7] (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, (2) Methanol; CH4O; [67-56-1] Ltd., Mumbai, India, no purification details were provided. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Estimated Error: Temperature: No information given in the paper.

c1: 5% (relative error, estimated by compiler). Experimental Values

x a x b 2 1 Components: Original Measurements: 0.9999 0.0000564 (1) 4-Hydroxy-2-methyl-N- 67N. Seedher and S. Bhatia, AAPS a / x2: mole fraction of component 2 in the saturated solution. (5-methyl-2-thiazolyl)-2H-1, PharmSciTech 4,331 (2003). b x1: mole fraction solubility of the solute. 2-benzothiazine-3-carboxamide-1, 1-dioxide (Meloxicam);

C14H13N3O4S2; [71125-38-7] Auxiliary Information (2) Ethanol; C2H6O; [64-17-5] Method/Apparatus/Procedure: Variables: Prepared by: Constant-temperature shaker bath and an UV/visible spectrophotometer. T/K ¼ 298.15 W. E. Acree, Jr. Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate in a constant-temperature shaker bath for at least three days. An aliquot of the saturated solution was removed and filtered (0.20 μm Experimental Values pore size). Solubility of the dissolved solute was determined by The measured solubility was reported to be c ¼ 0.00101 spectrophotometric measurements. 1 mol dm3. Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no Auxiliary Information purification details were provided. Method/Apparatus/Procedure: (2) Purity not given, Analytical Reagent grade, chemical source not specified, Vortex mixer, constant-temperature bath, and an ultraviolet/visible no purification details were provided. spectrophotometer. Excess solute and solvent were placed in sealed containers and equilibrated at a Estimated Error: constant temperature for 24 h. During this time the tubes were shaken Temperature: 0.5 K. occasionally on a vortex mixer. Aliquots of saturated solutions were removed, x : 4% (relative error, estimated by compiler). 1 centrifuged, filtered through a sintered glass crucible (grade 4), and diluted quantitatively with 10% aqueous N,N-dimethylformamide for spectroscopic analyses. Concentration of the dissolved solute was determined from the measured absorbance at 363 nm. Components: Original Measurements: 67 (1) 4-Hydroxy-2-methyl-N- N. Seedher and S. Bhatia, AAPS Source and Purity of Chemicals: (5-methyl-2-thiazolyl)-2H-1, PharmSciTech 4,33/1 (2003). (1) Purity not given, Sun Pharmaceutical Industries, Ltd., Mumbai, India, no 2-benzothiazine-3-carboxamide-1, purification details were provided. 1-dioxide (Meloxicam); (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, [ ] C14H13N3O4S2; 71125-38-7 Ltd., Mumbai, India, no purification details were provided. (2) Methanol; CH4O; [67-56-1] Variables: Prepared by: Estimated Error: T/K ¼ 298.15 W. E. Acree, Jr. Temperature: No information given in the paper. c1: 5% (relative error, estimated by compiler).

Experimental Values

The measured solubility was reported to be c1 ¼ 0.00109 mol dm3.

Source and Purity of Chemicals: Components: Original Measurements: 157 (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no (1) 4-Hydroxy-2-methyl-N- P. R. S. Babu, C. V. S. purification details were provided. (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, (2) Purity not given, Analytical Reagent grade, chemical source not specified, 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, no purification details were provided. 1-dioxide (Meloxicam); Ethiop. Pharm. J. 25, 23 (2007). [ ] C14H13N3O4S2; 71125-38-7 Estimated Error: [ ] (2) Ethanol; C2H6O; 64-17-5 Temperature: 0.5 K. % Variables: Prepared by: x1: 4 (relative error, estimated by compiler). T/K ¼ 298 W. E. Acree, Jr.

Experimental Values Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N-(5-methyl- 158D. R. Delgado, A. R. Holguín, The measured solubility was reported to be c1 ¼ 0.000698 í mol dm 3. 2-thiazolyl)-2H-1,2-benzothiazine- O. A. Almanza, F. Mart nez, and 3-carboxamide-1,1-dioxide Y. Marcus, Fluid Phase Equilib. Auxiliary Information (Meloxicam); C14H13N3O4S2; 305, 88 (2011). [71125-38-7] Method/Apparatus/Procedure: (2) Ethanol; C2H6O; [64-17-5] Constant-temperature shaker bath and an UV/visible spectrophotometer. Excess solute and solvent were placed in stoppered volumetric flasks and Variables: Prepared by: allowed to equilibrate in a constant-temperature shaker bath for 24 h. An Temperature W. E. Acree, Jr. aliquot of the saturated solution was removed, filtered through a 0.2 μm membrane filter, and diluted with 0.1 molar aqueous hydrochloric acid solution for spectroscopic analysis at 345 nm. Reported values represent the average of Experimental Values three experimental determinations.

/ a b Source and Purity of Chemicals: T K x2 x1 (1) Purity not given, Reddy Labs, Hyderabad, India, no purification details 293.15 0.9999 0.0000188 were given in the paper. 298.15 0.9999 0.0000272 (2) Purity not given, Analytical Reagent grade, chemical source not specified, 303.15 0.9999 0.0000412 no purification details were provided. 308.15 0.9999 0.0000541 313.15 0.9999 0.0000735 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. Temperature: 1.0 K (estimated by compiler). b x1: mole fraction solubility of the solute. c1: 5% (relative error, estimated by compiler).

Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: Thermostatic mechanical shaker bath, recirculating thermostatic bath, and an (1) 4-Hydroxy-2-methyl-N- 156P. R. S. Babu, C. V. S. UV/visible spectrophotometer. (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, Excess solute and solvent were placed in a stoppered dark glass ﬂask and 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, allowed to equilibrate with stirring in a thermostatic mechanical shaker bath 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). (for measurements at 303.15, 308.15, and 313.15 K), or in a recirculating C H N O S ; [71125-38-7] 14 13 3 4 2 thermostatic bath (for measurements at 293.15 and 298.15 K) for at least seven (2) Ethanol; C H O; [64-17-5] 2 6 days. An aliquot of the saturated solution was removed, isothermally ﬁltered, Variables: Prepared by: and diluted quantitatively for spectrophotometric analysis. The reported T/K ¼ 298.15 W. E. Acree, Jr. values represent the average of at least three determinations.

Source and Purity of Chemicals: Experimental Values (1) 99.8%, chemical source not specified, no purification details were given in the paper. (2) 99.8%, Absolute, Analytical Reagent grade, Merck Chemical Company, a b x2 x1 Germany, no purification details were given in the paper. 0.9999 0.0000458 a Estimated Error: x2: mole fraction of component 2 in the saturated solution. b Temperature: 0.05 K. x1: mole fraction solubility of the solute. x1: 3% (relative error).

Auxiliary Information Method/Apparatus/Procedure: Constant-temperature shaker bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate in a constant-temperature shaker bath for at least three days. An aliquot of the saturated solution was removed and ﬁltered (0.20 μm pore size). Solubility of the dissolved solute was determined by spectrophotometric measurements.

Auxiliary Information Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 156P. R. S. Babu, C. V. S. Method/Apparatus/Procedure: (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, Constant-temperature shaker bath and an UV/visible spectrophotometer. 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, Very few experimental details were provided. Excess solute and solvent were 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). allowed to equilibrate in a constant-temperature shaker bath for at least three C14H13N3O4S2; [71125-38-7] days. An aliquot of the saturated solution was removed and filtered (0.20 μm (2) 1-Propanol; C3H8O; [71-23-8] pore size). Solubility of the dissolved solute was determined by spectrophotometric measurements. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no Experimental Values purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. x a x b 2 1 Estimated Error: 0.9999 0.0000556 Temperature: 0.5 K. a % x2: mole fraction of component 2 in the saturated solution. x1: 4 (relative error, estimated by compiler). b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: 156 Method/Apparatus/Procedure: (1) 4-Hydroxy-2-methyl-N- P. R. S. Babu, C. V. S. Constant-temperature shaker bath and an UV/visible spectrophotometer. (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, Very few experimental details were provided. Excess solute and solvent were 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, allowed to equilibrate in a constant-temperature shaker bath for at least three 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). [ ] days. An aliquot of the saturated solution was removed and filtered (0.20 μm C14H13N3O4S2; 71125-38-7 [ ] pore size). Solubility of the dissolved solute was determined by (2) 1-Butanol; C4H10O; 71-36-3 spectrophotometric measurements. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. Experimental Values (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. a b x2 x1 Estimated Error: Temperature: 0.5 K. 0.9999 0.0000880 a x1: 4% (relative error, estimated by compiler). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 156P. R. S. Babu, C. V. S. Method/Apparatus/Procedure: (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, Constant-temperature shaker bath and an UV/visible spectrophotometer. 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, Very few experimental details were provided. Excess solute and solvent were 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). allowed to equilibrate in a constant-temperature shaker bath for at least three C14H13N3O4S2; [71125-38-7] days. An aliquot of the saturated solution was removed and filtered (0.20 μm (2) 2-Propanol; C3H8O; [67-63-0] pore size). Solubility of the dissolved solute was determined by spectrophotometric measurements. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no Experimental Values purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. x a x b 2 1 Estimated Error: 0.9999 0.0000393 Temperature: 0.5 K. a % x2: mole fraction of component 2 in the saturated solution. x1: 4 (relative error, estimated by compiler). b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 67N. Seedher and S. Bhatia, AAPS Method/Apparatus/Procedure: (5-methyl-2-thiazolyl)-2H-1, PharmSciTech 4,33/1 (2003). Constant-temperature shaker bath and an UV/visible spectrophotometer. 2-benzothiazine-3-carboxamide-1, Very few experimental details were provided. Excess solute and solvent were 1-dioxide (Meloxicam); allowed to equilibrate in a constant-temperature shaker bath for at least three C14H13N3O4S2; [71125-38-7] days. An aliquot of the saturated solution was removed and filtered (0.20 μm (2) 1-Butanol; C4H10O; [71-36-3] pore size). Solubility of the dissolved solute was determined by spectrophotometric measurements. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no Experimental Values purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, The measured solubility was reported to be c1 ¼ 0.000811 no purification details were provided. mol dm3. Estimated Error: Temperature: 0.5 K. Auxiliary Information x1: 4% (relative error, estimated by compiler). Method/Apparatus/Procedure: Vortex mixer, constant-temperature bath, and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in sealed containers and equilibrated at a Components: Original Measurements: constant temperature for 24 h. During this time the tubes were shaken (1) 4-Hydroxy-2-methyl-N- 156P. R. S. Babu, C. V. S. occasionally on a vortex mixer. Aliquots of saturated solutions were removed, (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, centrifuged, filtered through a sintered glass crucible (grade 4), and diluted 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, % quantitatively with 10 aqueous N,N-dimethylformamide for spectroscopic 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). analyses. Concentration of the dissolved solute was determined from the C14H13N3O4S2; [71125-38-7] measured absorbance at 363 nm. (2) 1-Hexanol; C6H14O; [111-27-3] Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Sun Pharmaceutical Industries, Ltd., Mumbai, India, no T/K ¼ 298.15 W. E. Acree, Jr. purification details were provided. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, Ltd., Mumbai, India, no purification details were provided. Experimental Values

Estimated Error: a b Temperature: No information given in the paper. x2 x1 % c1: 5 (relative error, estimated by compiler). 0.9999 0.000138 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 156P. R. S. Babu, C. V. S. Auxiliary Information (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, Method/Apparatus/Procedure: 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, Constant-temperature shaker bath and an UV/visible spectrophotometer. 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). Very few experimental details were provided. Excess solute and solvent were C H N O S ; [71125-38-7] 14 13 3 4 2 allowed to equilibrate in a constant-temperature shaker bath for at least three (2) 1-Pentanol; C H O; [71-41-0] 5 12 days. An aliquot of the saturated solution was removed and ﬁltered (0.20 μm Variables: Prepared by: pore size). Solubility of the dissolved solute was determined by T/K ¼ 298.15 W. E. Acree, Jr. spectrophotometric measurements.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, a b x2 x1 no purification details were provided. 0.9999 0.000109 a Estimated Error: x2: mole fraction of component 2 in the saturated solution. b Temperature: 0.5 K. x1: mole fraction solubility of the solute. x1: 4% (relative error, estimated by compiler).

Auxiliary Information Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 156P. R. S. Babu, C. V. S. Method/Apparatus/Procedure: (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, Vortex mixer, constant-temperature bath, and an ultraviolet/visible 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, spectrophotometer. 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). Excess solute and solvent were placed in sealed containers and equilibrated at a C14H13N3O4S2; [71125-38-7] constant temperature for 24 h. During this time the tubes were shaken (2) 1-Heptanol; C7H16O; [111-70-6] occasionally on a vortex mixer. Aliquots of saturated solutions were removed, centrifuged, filtered through a sintered glass crucible (grade 4), and diluted Variables: Prepared by: quantitatively with 10% aqueous N,N-dimethylformamide for spectroscopic T/K ¼ 298.15 W. E. Acree, Jr. analyses. Concentration of the dissolved solute was determined from the measured absorbance at 363 nm. Experimental Values Source and Purity of Chemicals: (1) Purity not given, Sun Pharmaceutical Industries, Ltd., Mumbai, India, no purification details were provided. x a x b 2 1 (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, 0.9998 0.000226 Ltd., Mumbai, India, no purification details were provided. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: Temperature: No information given in the paper.

c1: 5% (relative error, estimated by compiler). Auxiliary Information Method/Apparatus/Procedure: Constant-temperature shaker bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were Components: Original Measurements: 156 allowed to equilibrate in a constant-temperature shaker bath for at least three (1) 4-Hydroxy-2-methyl-N- P. R. S. Babu, C. V. S. days. An aliquot of the saturated solution was removed and filtered (0.20 μm (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, pore size). Solubility of the dissolved solute was determined by 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, spectrophotometric measurements. 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). C14H13N3O4S2; [71125-38-7] [ ] Source and Purity of Chemicals: (2) 1-Octanol; C8H18O; 111-87-5 (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no Variables: Prepared by: purification details were provided. T/K ¼ 298.15 W. E. Acree, Jr. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values Estimated Error: Temperature: 0.5 K.

x1: 4% (relative error, estimated by compiler). a b x2 x1 0.9997 0.000309 a x2: mole fraction of component 2 in the saturated solution. bx : mole fraction solubility of the solute. Components: Original Measurements: 1 (1) 4-Hydroxy-2-methyl-N- 67N. Seedher and S. Bhatia, AAPS (5-methyl-2-thiazolyl)-2H-1, PharmSciTech 4,33/1 (2003). Auxiliary Information 2-benzothiazine-3-carboxamide-1, 1-dioxide (Meloxicam); Method/Apparatus/Procedure: C14H13N3O4S2; [71125-38-7] Constant-temperature shaker bath and an UV/visible spectrophotometer. (2) 1-Octanol; C8H18O; [111-87-5] Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate in a constant-temperature shaker bath for at least three Variables: Prepared by: days. An aliquot of the saturated solution was removed and filtered (0.20 μm T/K ¼ 298.15 W. E. Acree, Jr. pore size). Solubility of the dissolved solute was determined by spectrophotometric measurements. Experimental Values Source and Purity of Chemicals: The measured solubility was reported to be c1 ¼ 0.000532 (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no mol dm 3. purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided.

Estimated Error: Temperature: 0.5 K.

x1: 4% (relative error, estimated by compiler).

Experimental Values Source and Purity of Chemicals: (1) Purity not given, Sun Pharmaceutical Industries, Ltd., Mumbai, India, no puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, x a x b 2 1 Ltd., Mumbai, India, no puriﬁcation details were provided. 0.9982 0.00184 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: No information given in the paper. c1: 5% (relative error, estimated by compiler).

Auxiliary Information Method/Apparatus/Procedure: Constant-temperature shaker bath and an UV/visible spectrophotometer. Components: Original Measurements: 67 Very few experimental details were provided. Excess solute and solvent were (1) 4-Hydroxy-2-methyl-N- N. Seedher and S. Bhatia, AAPS allowed to equilibrate in a constant-temperature shaker bath for at least three (5-methyl-2-thiazolyl)-2H-1, PharmSciTech 4,33/1 (2003). days. An aliquot of the saturated solution was removed and filtered (0.20 μm 2-benzothiazine-3-carboxamide-1, pore size). Solubility of the dissolved solute was determined by 1-dioxide (Meloxicam); [ ] spectrophotometric measurements. C14H13N3O4S2; 71125-38-7 (2) 1,2-Propanediol; C3H8O2; Source and Purity of Chemicals: [57-55-6] (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no Variables: Prepared by: purification details were provided. T/K ¼ 298.15 W. E. Acree, Jr. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values Estimated Error: ¼ Temperature: 0.5 K. The measured solubility was reported to be c1 0.000874 3 x1: 4% (relative error, estimated by compiler). mol dm .

Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: Vortex mixer, constant-temperature bath, and an ultraviolet/visible (1) 4-Hydroxy-2-methyl-N- 67N. Seedher and S. Bhatia, AAPS spectrophotometer. (5-methyl-2-thiazolyl)-2H-1, PharmSciTech 4,33/1 (2003). Excess solute and solvent were placed in sealed containers and equilibrated at a 2-benzothiazine-3-carboxamide-1, constant temperature for 24 h. During this time the tubes were shaken 1-dioxide (Meloxicam); occasionally on a vortex mixer. Aliquots of saturated solutions were removed, C H N O S ; [71125-38-7] 14 13 3 4 2 centrifuged, filtered through a sintered glass crucible (grade 4), and diluted (2) 1,2-Ethanediol; C H O ; 2 6 2 quantitatively with 10% aqueous N,N-dimethylformamide for spectroscopic [107-21-1] analyses. Concentration of the dissolved solute was determined from the Variables: Prepared by: measured absorbance at 363 nm. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sun Pharmaceutical Industries, Ltd., Mumbai, India, no Experimental Values purification details were provided. The measured solubility was reported to be c ¼ 0.000267 (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, 1 Ltd., Mumbai, India, no purification details were provided. mol dm3. Estimated Error: Temperature: No information given in the paper.

c1: 5% (relative error, estimated by compiler).

Auxiliary Information Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 156P. R. S. Babu, C. V. S. Method/Apparatus/Procedure: (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, Constant-temperature shaker bath and an UV/visible spectrophotometer. 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, Excess solute and solvent were placed in stoppered volumetric flasks and 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). allowed to equilibrate in a constant-temperature shaker bath for 24 h. An C14H13N3O4S2; [71125-38-7] aliquot of the saturated solution was removed, filtered through a 0.2 μm (2) 1,2-Propanediol; C3H8O2; membrane filter, and diluted with 0.1 molar aqueous hydrochloric acid solution [57-55-6] for spectroscopic analysis at 345 nm. Reported values represent the average of three experimental determinations. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Reddy Labs, Hyderabad, India, no purification details Experimental Values were given in the paper. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. x a x b 2 1 Estimated Error: 0.9999 0.0000815 Temperature: 1.0 K (estimated by compiler). a % x2: mole fraction of component 2 in the saturated solution. c1: 5 (relative error, estimated by compiler). b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 159A. R. Holguín, D. R. Delgado, Method/Apparatus/Procedure: (5-methyl-2-thiazolyl)-2H-1, F. Martínez and Y. Marcus, J. Constant-temperature shaker bath and an UV/visible spectrophotometer. 2-benzothiazine-3-carboxamide-1, Solution Chem. 40, 1987 (2011). Very few experimental details were provided. Excess solute and solvent were 1-dioxide (Meloxicam); allowed to equilibrate in a constant-temperature shaker bath for at least three C14H13N3O4S2; [71125-38-7] days. An aliquot of the saturated solution was removed and filtered (0.20 μm (2) 1,2-Propanediol; C3H8O2; pore size). Solubility of the dissolved solute was determined by [57-55-6] spectrophotometric measurements. Variables: Prepared by: Source and Purity of Chemicals: Temperature W. E. Acree, Jr. (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, Experimental Values no purification details were provided. / a b Estimated Error: T K x2 x1 Temperature: 0.5 K. 293.15 0.9999 0.0000356

x1: 4% (relative error, estimated by compiler). 298.15 0.9999 0.0000420 303.15 0.9999 0.0000484 308.15 0.9999 0.0000598 313.15 0.9999 0.0000713 a Components: Original Measurements: x2: mole fraction of component 2 in the saturated solution. 157 b (1) 4-Hydroxy-2-methyl-N- P. R. S. Babu, C. V. S. x1: mole fraction solubility of the solute. (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, Auxiliary Information 1-dioxide (Meloxicam); Ethiop. Pharm. J. 25, 23 (2007). / / C14H13N3O4S2; [71125-38-7] Method Apparatus Procedure: / (2) 1,2-Propanediol; C3H8O2; Thermostatic mechanical shaker, recirculating thermostatic bath, and an UV [57-55-6] visible spectrophotometer. Excess solute and solvent were placed in dark stoppered glass flasks and Variables: Prepared by: allowed to equilibrate in a thermostatic mechanical shaker (for 303.15, 308.15, / ¼ T K 298 W. E. Acree, Jr. and 313.15 K) or recirculating thermostatic bath (for 293.15 and 298.15 K) for at least seven days. An aliquot of the saturated solution was withdrawn and filtered to remove any particulate matter. Concentrations were determined by Experimental Values spectrophotometric measurements. Experimental determinations were The measured solubility was reported to be c1 ¼ 0.000993 performed in at least triplicate. mol dm3. Source and Purity of Chemicals: (1) 99.8%, chemical source not specified, no purification details were provided in the paper. (2) 99.8%, chemical source not specified, no purification details were given in the paper.

Estimated Error: Temperature: 0.05 K (estimated by compiler).

x1: 2.0% (relative error).

C14H13N3O4S2; [71125-38-7] constant temperature for 24 h. During this time the tubes were shaken (2) 1,2,3-Propanetriol (Glycerol); occasionally on a vortex mixer. Aliquots of saturated solutions were removed,

C3H8O3; [56-81-5] centrifuged, ﬁltered through a sintered glass crucible (grade 4), and diluted quantitatively with 10% aqueous N,N-dimethylformamide for spectroscopic Variables: Prepared by: analyses. Concentration of the dissolved solute was determined from the / ¼ T K 298.15 W. E. Acree, Jr. measured absorbance at 363 nm.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Sun Pharmaceutical Industries, Ltd., Mumbai, India, no puriﬁcation details were provided.

a b (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, x2 x1 Ltd., Mumbai, India, no puriﬁcation details were provided. 0.9999 0.00000339 a Estimated Error: x2: mole fraction of component 2 in the saturated solution. b Temperature: No information given in the paper. x1: mole fraction solubility of the solute. c1: 5% (relative error, estimated by compiler).

Auxiliary Information Method/Apparatus/Procedure: Constant-temperature shaker bath and an UV/visible spectrophotometer. 19.8. Meloxicam solubility data in ketones Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate in a constant-temperature shaker bath for at least three days. An aliquot of the saturated solution was removed and filtered (0.20 μm Components: Original Measurements: pore size). Solubility of the dissolved solute was determined by (1) 4-Hydroxy-2-methyl-N- 156P. R. S. Babu, C. V. S. spectrophotometric measurements. (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, Source and Purity of Chemicals: 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no C14H13N3O4S2; [71125-38-7] purification details were provided. (2) Propanone; C3H6O; [67-64-1] (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Estimated Error: Temperature: 0.5 K. Experimental Values x1: 4% (relative error, estimated by compiler).

a b x2 x1 0.9994 0.000606 Components: Original Measurements: 67 a (1) 4-Hydroxy-2-methyl-N- N. Seedher and S. Bhatia, AAPS x2: mole fraction of component 2 in the saturated solution. b (5-methyl-2-thiazolyl)-2H-1, PharmSciTech 4,33/1 (2003). x1: mole fraction solubility of the solute. 2-benzothiazine-3-carboxamide-1, 1-dioxide (Meloxicam); Auxiliary Information C14H13N3O4S2; [71125-38-7] (2) 1,2,3-Propanetriol (Glycerol); Method/Apparatus/Procedure: / C3H8O3; [56-81-5] Constant-temperature shaker bath and an UV visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were Variables: Prepared by: allowed to equilibrate in a constant-temperature shaker bath for at least three / ¼ T K 298.15 W. E. Acree, Jr. days. An aliquot of the saturated solution was removed and ﬁltered (0.20 μm pore size). Solubility of the dissolved solute was determined by spectrophotometric measurements. Experimental Values

The measured solubility was reported to be c1 ¼ 0.000393 Source and Purity of Chemicals: mol dm3. (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided.

Estimated Error: Temperature: 0.5 K.

x1: 4% (relative error, estimated by compiler).

Auxiliary Information Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 156P. R. S. Babu, C. V. S. Method/Apparatus/Procedure: (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, Constant-temperature shaker bath and an UV/visible spectrophotometer. 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, Very few experimental details were provided. Excess solute and solvent were 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). allowed to equilibrate in a constant-temperature shaker bath for at least three C14H13N3O4S2; [71125-38-7] days. An aliquot of the saturated solution was removed and filtered (0.20 μm (2) Acetophenone; C8H8O; [98-86-2] pore size). Solubility of the dissolved solute was determined by spectrophotometric measurements. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no Experimental Values purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. x a x b 2 1 Estimated Error: 0.9977 0.00229 Temperature: 0.5 K. a % x2: mole fraction of component 2 in the saturated solution. x1: 4 (relative error, estimated by compiler). b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: 156 Method/Apparatus/Procedure: (1) 4-Hydroxy-2-methyl-N- P. R. S. Babu, C. V. S. Constant-temperature shaker bath and an UV/visible spectrophotometer. (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, Very few experimental details were provided. Excess solute and solvent were 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, allowed to equilibrate in a constant-temperature shaker bath for at least three 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). [ ] days. An aliquot of the saturated solution was removed and filtered (0.20 μm C14H13N3O4S2; 71125-38-7 pore size). Solubility of the dissolved solute was determined by (2) N,N-Dimethylformamide; [ ] spectrophotometric measurements. C3H7NO; 64-19-7 Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 298.15 W. E. Acree, Jr. (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, Experimental Values no purification details were provided.

Estimated Error: a b x2 x1 Temperature: 0.5 K. 0.9841 0.01585 x1: 4% (relative error, estimated by compiler). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

19.9. Meloxicam solubility data in miscellaneous Auxiliary Information organic solvents Method/Apparatus/Procedure: Constant-temperature shaker bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were Components: Original Measurements: allowed to equilibrate in a constant-temperature shaker bath for at least three 156 (1) 4-Hydroxy-2-methyl-N- P. R. S. Babu, C. V. S. days. An aliquot of the saturated solution was removed and filtered (0.20 μm (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, pore size). Solubility of the dissolved solute was determined by 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, spectrophotometric measurements. 1-dioxide (Meloxicam); Pak. J. Pharm. Sci. 20, 311 (2007). [ ] C14H13N3O4S2; 71125-38-7 Source and Purity of Chemicals: (2) Dimethyl sulfoxide; C2H6OS; (1) Purity not given, gift sample from Dr. Reddy Labs., Hyderabad, India, no [ ] 67-68-5 purification details were provided. Variables: Prepared by: (2) Purity not given, Analytical Reagent grade, chemical source not specified, T/K ¼ 298.15 W. E. Acree, Jr. no purification details were provided.

Estimated Error: Experimental Values Temperature: 0.5 K. x1: 4% (relative error, estimated by compiler).

a b x2 x1 0.9945 0.00550 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Source and Purity of Chemicals: Components: Original Measurements: 157 (1) Purity not given, Reddy Labs, Hyderabad, India, no purification details (1) 4-Hydroxy-2-methyl-N- P. R. S. Babu, C. V. S. were given in the paper. (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, (2) Purity not given, Analytical Reagent grade, chemical source not specified, 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, no purification details were provided. 1-dioxide (Meloxicam); Ethiop. Pharm. J. 25, 23 (2007). [ ] C14H13N3O4S2; 71125-38-7 Estimated Error: (2) Polyethylene glycol 300 Temperature: 1.0 K (estimated by compiler). (PEG 300) c1: 5% (relative error, estimated by compiler). Variables: Prepared by: T/K ¼ 298 W. E. Acree, Jr.

Components: Original Measurements: Experimental Values (1) 4-Hydroxy-2-methyl-N- 67N. Seedher and S. Bhatia, AAPS (5-methyl-2-thiazolyl)-2H-1, PharmSciTech 4,33/1 (2003). The measured solubility was reported to be c1 ¼ 0.01816 mol dm3. 2-benzothiazine-3-carboxamide-1, 1-dioxide (Meloxicam);

C14H13N3O4S2; [71125-38-7] Auxiliary Information (2) Polyethylene glycol 400 Method/Apparatus/Procedure: (PEG 400) Constant-temperature shaker bath and an UV/visible spectrophotometer. Variables: Prepared by: Excess solute and solvent were placed in stoppered volumetric flasks and T/K ¼ 298.15 W. E. Acree, Jr. allowed to equilibrate in a constant-temperature shaker bath for 24 h. An aliquot of the saturated solution was removed, filtered through a 0.2 μm membrane filter, and diluted with 0.1 molar aqueous hydrochloric acid solution Experimental Values for spectroscopic analysis at 345 nm. Reported values represent the average of ¼ three experimental determinations. The measured solubility was reported to be c1 0.0107 mol dm3. Source and Purity of Chemicals: (1) Purity not given, Reddy Labs, Hyderabad, India, no purification details Auxiliary Information were given in the paper. / / (2) Purity not given, Analytical Reagent grade, chemical source not specified, Method Apparatus Procedure: / no purification details were provided. Vortex mixer, constant-temperature bath, and an ultraviolet visible spectrophotometer. Estimated Error: Excess solute and solvent were placed in sealed containers and equilibrated at a Temperature: 1.0 K (estimated by compiler). constant temperature for 24 h. During this time the tubes were shaken occasionally on a vortex mixer. Aliquots of saturated solutions were removed, c1: 5% (relative error, estimated by compiler). centrifuged, filtered through a sintered glass crucible (grade 4), and diluted quantitatively with 10% aqueous N,N-dimethylformamide for spectroscopic analyses. Concentration of the dissolved solute was determined from the measured absorbance at 363 nm. Components: Original Measurements: 157 (1) 4-Hydroxy-2-methyl-N- P. R. S. Babu, C. V. S. Source and Purity of Chemicals: (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, (1) Purity not given, Sun Pharmaceutical Industries, Ltd., Mumbai, India, no 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, purification details were provided. 1-dioxide (Meloxicam); Ethiop. Pharm. J. 25, 23 (2007). (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, [ ] C14H13N3O4S2; 71125-38-7 Ltd., Mumbai, India, no purification details were provided. (2) Polyethylene glycol 400 (PEG 400) Estimated Error: Variables: Prepared by: Temperature: No information given in the paper. % T/K ¼ 298 W. E. Acree, Jr. c1: 5 (relative error, estimated by compiler).

Experimental Values

The measured solubility was reported to be c1 ¼ 0.01992 19.10. Meloxicam solubility data in binary organic mol dm3. solvent mixtures

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 4-Hydroxy-2-methyl-N- 157P. R. S. Babu, C. V. S. Constant-temperature shaker bath and an UV/visible spectrophotometer. (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, Excess solute and solvent were placed in stoppered volumetric flasks and 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, allowed to equilibrate in a constant-temperature shaker bath for 24 h. An 1-dioxide (Meloxicam); Ethiop. Pharm. J. 25, 23 (2007). aliquot of the saturated solution was removed, filtered through a 0.2 μm C H N O S ; [71125-38-7] membrane filter, and diluted with 0.1 molar aqueous hydrochloric acid solution 14 13 3 4 2 (2) Polyethylene glycol 400 for spectroscopic analysis at 345 nm. Reported values represent the average of (PEG 400) three experimental determinations. (3) Ethanol; C2H6O; [64-17-5]

Variables: Prepared by: / ¼ ðsÞa b T K 298; Solvent composition W. E. Acree, Jr. v2 c1 0.60 0.00458 0.80 0.00223 Experimental Values 1.00 0.00101

a ðsÞ v2 : volume fraction of component 2 in the initial binary solvent mixture ðsÞa b calculated as if the dissolved solute were not present. v2 c1 b 3 c1: molar solubility of the solute in units of mol dm . 0.00 0.000698 0.20 0.005166 0.40 0.009117 Auxiliary Information 0.60 0.01435 Method/Apparatus/Procedure: 0.80 0.01854 Vortex mixer, constant-temperature bath, and an ultraviolet/visible 0.90 0.01947 spectrophotometer. 1.00 0.01992 Binary solvent mixtures were prepared by volume. Excess solute and solvent a ðsÞ were placed in sealed containers and equilibrated at a constant temperature for v2 : volume fraction of component 2 in the initial binary solvent mixture calculated as if the dissolved solute were not present. 24 h. During this time the tubes were shaken occasionally on a vortex mixer. b 3 Aliquots of saturated solutions were removed, centrifuged, ﬁltered through a c1: molar solubility of the solute in units of mol dm . sintered glass crucible (grade 4), and diluted quantitatively with 10% aqueous N,N-dimethylformamide for spectroscopic analyses. Concentration of the Auxiliary Information dissolved solute was determined from the measured absorbance at 363 nm.

Method/Apparatus/Procedure: Source and Purity of Chemicals: Constant-temperature shaker bath and an UV/visible spectrophotometer. (1) Purity not given, Panacea Biotec Ltd., Lalru, India, no purification details Binary solvent mixtures were prepared by volume. Excess solute and solvent were provided. were placed in stoppered volumetric flasks and allowed to equilibrate in a (2) Purity not given, Analytical Reagent grade, chemical source not specified, constant-temperature shaker bath for 24 h. An aliquot of the saturated solution no purification details were provided. was removed, filtered through a 0.2 μm membrane filter, and diluted with 0.1 (3) Purity not given, Analytical Reagent grade, Merck Chemical Company, molar aqueous hydrochloric acid solution for spectroscopic analysis at 345 nm. Ltd., Mumbai, India, no purification details were provided. Reported values represent the average of three experimental determinations. Estimated Error: Source and Purity of Chemicals: Temperature: No information given in the paper. ð Þ (1) Purity not given, Reddy Labs, Hyderabad, India, no purification details v s : 0.01. were given in the paper. 2 c : 5.0% (relative error, estimated by compiler). (2) Purity not given, Analytical Reagent grade, chemical source not specified, 1 no purification details were provided. (3) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. Components: Original Measurements: 157 Estimated Error: (1) 4-Hydroxy-2-methyl-N- P. R. S. Babu, C. V. S. Temperature: 1.0 K (estimated by compiler). (5-methyl-2-thiazolyl)-2H-1, Subrahmanyam, J. Thimmasetty, ðsÞ 2-benzothiazine-3-carboxamide-1, R. Manavalan, and K. Valliappan, v : 0.01. 2 1-dioxide (Meloxicam); Ethiop. Pharm. J. 25, 23 (2007). c1: 5.0% (relative error, estimated by compiler). C14H13N3O4S2; [71125-38-7] (2) Polyethylene glycol 400 (PEG 400)

(3) 1,2-Propanediol; C3H8O2; Components: Original Measurements: [57-55-6] (1) 4-Hydroxy-2-methyl-N- 67N. Seedher and S. Bhatia, AAPS (5-methyl-2-thiazolyl)-2H-1, PharmSciTech 4,33/1 (2003). Variables: Prepared by: / ¼ 2-benzothiazine-3-carboxamide-1, T K 298; Solvent composition W. E. Acree, Jr. 1-dioxide (Meloxicam);

C14H13N3O4S2; [71125-38-7] Experimental Values (2) Ethanol; C2H6O; [64-17-5] (3) Polyethylene glycol 400 (PEG 400) ð Þ v s a c b Variables: Prepared by: 2 1 T/K ¼ 298; Solvent composition W. E. Acree, Jr. 0.00 0.000993 0.20 0.003320 0.40 0.006840 Experimental Values 0.60 0.01037 0.80 0.01559 0.90 0.01919

ðsÞa b 1.00 0.01992 v2 c1 a ðsÞ 0.00 0.01071 v2 : volume fraction of component 2 in the initial binary solvent mixture 0.10 0.01145 calculated as if the dissolved solute were not present. b 3 0.20 0.01093 c1: molar solubility of the solute in units of mol dm . 0.40 0.00777

Auxiliary Information Source and Purity of Chemicals: (1) Purity not given, Panacea Biotec Ltd., Lalru, India, no purification details / / Method Apparatus Procedure: were provided. / Constant-temperature shaker bath and an UV visible spectrophotometer. (2) Purity not given, Analytical Reagent grade, chemical source not specified, Binary solvent mixtures were prepared by volume. Excess solute and solvent no purification details were provided. were placed in stoppered volumetric flasks and allowed to equilibrate in a (3) Purity not given, Analytical Reagent grade, Merck Chemical Company, constant-temperature shaker bath for 24 h. An aliquot of the saturated solution Ltd., Mumbai, India, no purification details were provided. was removed, filtered through a 0.2 μm membrane filter, and diluted with 0.1 molar aqueous hydrochloric acid solution for spectroscopic analysis at 345 nm. Estimated Error: Reported values represent the average of three experimental determinations. Temperature: No information given in the paper. ð Þ v s : 0.01. Source and Purity of Chemicals: 2 c : 5.0% (relative error, estimated by compiler). (1) Purity not given, Reddy Labs, Hyderabad, India, no purification details 1 were given in the paper. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. 20. Solubility of Nabumetone in Organic (3) Purity not given, Analytical Reagent grade, chemical source not specified, Solvents no purification details were provided. 20.1. Critical evaluation of experimental solubility Estimated Error: data Temperature: 1.0 K (estimated by compiler). ðsÞ v2 : 0.01. Nabumetone (more formally named 4-(6-methoxy-2- % c1: 10.0 (relative error, estimated by compiler). naphthyl)-2-butanone) is a nonacidic nonsteroidal anti-inflammatory prodrug that reduces pain and inflammation by selec- tively blocking COX-2 activity. The drug is converted in the liver to 6-methoxy-2-napthylacetic acid which is the principal Components: Original Measurements: metabolite responsible for the observed therapeutic effect.160 (1) 4-Hydroxy-2-methyl-N- 67N. Seedher and S. Bhatia, AAPS (5-methyl-2-thiazolyl)-2H-1, PharmSciTech 4,33/1 (2003). Nabumetone is used by physicians in the treatment of indivi- 2-benzothiazine-3-carboxamide-1, duals suffering from arthritis. There have been only two 1-dioxide (Meloxicam); publications64,161 reporting the solubility of nabumetone in [ ] 161 C14H13N3O4S2; 71125-38-7 organic solvents. Rathi et al. determined the mole fraction [ ] (2) Ethanol; C2H6O; 64-17-5 solubility of nabumetone in 1,4-dioxane at 298 K. Wenkers (3) 1,2,3-Propanetriol (Glycerol); and Lippold64 reported solubility data for ten NSAIDs (aspirin, C3H8O3; [56-81-5] diclofenac, diflunisal, flufenamic acid, ibuprofen, ketoprofen, Variables: Prepared by: T/K ¼ 298; Solvent composition W. E. Acree, Jr. nabumetone, naproxen, piroxicam, and tenoxicam) in light mineral oil at 305 K. It is not possible to perform a critical evaluation of the experimental data as measurements were Experimental Values made at only one temperature and there are no independent experimental solubility data for nabumetone in either 1,4-

ð Þ dioxane or mineral oil. v s a c b 2 1 The experimental solubility data for nabumetone in organic 0.00 0.000393 solvents are given in Secs. 20.2 and 20.3. 0.10 0.000848 0.20 0.001116 0.40 0.001147 20.2. Nabumetone solubility data in ethers 0.60 0.001377 0.80 0.001158 0.90 0.001059 1.00 0.001007 Components: Original Measurements: 161 ð Þ (1) 4-(6-Methoxy-2-naphthyl)-2- P. B. Rathi, K. V. Deshpande, av s : volume fraction of component 2 in the initial binary solvent mixture 2 butanone (Nabumetone); C15H16O2; P. S. Panzade, and I. Roul, Asian J. calculated as if the dissolved solute were not present. [42924-53-8] Biomed. Pharm. Sci. 3, 33 (2013). b 3 c1: molar solubility of the solute in units of mol dm . (2) 1,4-Dioxane; C4H8O2; [123-91-1] Variables: Prepared by: Auxiliary Information T/K ¼ 298.15 W. E. Acree, Jr. Method/Apparatus/Procedure: Vortex mixer, constant-temperature bath, and an ultraviolet/visible spectrophotometer. Experimental Values Binary solvent mixtures were prepared by volume. Excess solute and solvent were placed in sealed containers and equilibrated at a constant temperature for a b 24 h. During this time the tubes were shaken occasionally on a vortex mixer. x2 x1 Aliquots of saturated solutions were removed, centrifuged, ﬁltered through a 0.9947 0.00526 sintered glass crucible (grade 4), and diluted quantitatively with 10% aqueous ax : mole fraction of component 2 in the saturated solution. N,N-dimethylformamide for spectroscopic analyses. Concentration of the 2 bx : mole fraction solubility of the solute. dissolved solute was determined from the measured absorbance at 363 nm. 1

Auxiliary Information 21. Solubility of Naproxen in Organic Method/Apparatus/Procedure: Solvents Constant-temperature bath and an UV/visible spectrophotometer. Excess solute and solvent were placed in a screw-capped vials allowed to 21.1. Critical evaluation of experimental solubility equilibrate submerged with shaking at constant temperature for 24 h. An data aliquot of the saturated solution was removed and filtered through Whatman filter paper (No. 42). Solubility of the dissolved solute was determined by Naproxen (more formally named (S)-6-methoxy-α-methyl- spectrophotometric measurements at 262 nm. 2-naphthaleneacetic acid) is a nonselective NSAID and is used Source and Purity of Chemicals: to relieve pain and inflammation associated with kidney (1) Purity not given, GlaxoSmithKline Pharmaceuticals, Ltd., Nasik, India, no stones, gout, dysmenorrhea, bursitis, tendinitis, osteoarthritis, purification details were provided. psoriatic arthritis, and rheumatoid arthritis. Lejal et al.162 (2) Purity not given, Research Lab Fine Chemical Industry, Islampur, India, no found that naproxen protected Madin-Darby canine cells purification details were provided. against HqN1 and H3N2 viral strains, and that naproxen Estimated Error: decreased the viral titers in mice lungs after intranasal viral 64,65,92,111,117,163–170 Temperature: 0.2 K (estimated by compiler). infection. There have been several studies % x1: 4 (relative error, estimated by compiler). involving the solubility of naproxen in organic solvents. Perlovich et al.163 measured naproxen solubilities in hexane, benzene, methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-heptanol, and 1-octanol at 298 K based on spectroscopic 20.3. Nabumetone solubility data in miscellaneous methods. Bustamante et al.164 reported solubility data for organic solvents naproxen at 298 K in two saturated hydrocarbons (heptane and cyclohexane), in one aromatic hydrocarbon (benzene), in one alkyl alkanoate (ethyl ethanoate), in one dialkyl ether Components: Original Measurements: (1,1′-oxybisethane) and one cyclic ether (1,4-dioxane), in two (1) 4-(6-Methoxy-2-naphthyl)-2- 64B. P. Wenkers and B. C. chloroalkanes (trichloromethane and 1,2-dichloroethane) and butanone (Nabumetone); C15H16O2; Lippold, J. Pharm. Sci. 88, 1326 [42924-53-8] (1999). one chlorinated aromatic hydrocarbon (chlorobenzene), in six (2) Mineral oil alcohols (methanol, ethanol, 1-pentanol, 1-octanol, 1,2-pro- Variables: Prepared by: panediol, and 1,2,3-propanetriol), in one alkanone (propa- T/K ¼ 305.15 W. E. Acree, Jr. none) and one aromatic ketone (acetophenone), and four miscellaneous organic solvents (ethanoic acid, propanoic acid, formamide, and N,N-dimethylformamide). Daniels et al.165 Experimental Values determined the solubility of naproxen in two alkyl alkanoates ¼ The measured solubility was reported to be c1 0.0154 (methyl ethanoate and butyl ethanoate), in three dialkyl ethers 3 mol dm . (1,1-oxybisethane, 2,2′-oxybispropane, and 1,1′-oxybisbutane), and two cyclic ethers (tetrahydrofuran and 1,4-dioxane), Auxiliary Information and in 12 alcohols (1-propanol, 2-propanol, 1-butanol, 2- Method/Apparatus/Procedure: butanol, 2-methyl-1-propanol, 1-pentanol, 2-pentanol, 3- Constant-temperature bath and an UV/visible spectrophotometer methyl-1-butanol, 1-hexanol, 1-heptanol, 1-octanol, and 1- Excess solute and solvent were placed in sealed bottles and allowed to decanol) at 298 K. Manrique et al.,111 Yan et al.,168 Fini equilibrate at a constant temperature with rotation for 24 h. Aliquots of 60 í 167 170 μ et al., Mora and Mart nez, Claramonte et al., and saturated solutions were removed, filtered through a 0.45 m cellulose acetate 166,169 membrane filter, and diluted quantitatively for spectroscopic analysis. Aragoń et al. have also performed naproxen solubility 64 Reported values represent the average of three experimental measurements. measurements at 298 K. Wenkers and Lippold reported solubility data for ten NSAIDs (aspirin, diclofenac, diflunisal, Source and Purity of Chemicals: flufenamic acid, ibuprofen, ketoprofen, nabumetone, (1) Purity not given, SmithKline Beecham, Worthing, Great Britain, no purification details were provided. naproxen, piroxicam, and tenoxicam) in light mineral oil at (2) Purity not given, Bayer Leverkusen and Rhone Poulenc Rorer, Cologne, 305 K. 165 Germany, no purification details were provided. Daniels et al. used their measured solubility data for naproxen in ethyl ethanoate, 1,1′-oxybisethane, and 12 alcohol Estimated Error: solvents, combined with published solubility and partition coef- Temperature: 0.5 K (estimated by compiler). ficient data, to calculate the Abraham solute descriptors of c1: 10% (relative error). naproxen. The authors were able to assemble a total of 40 log10(SR or P) and log10(GSR or K) equations for which experimental partition coefficient data, solubility ratios, Abraham Model equation coefficients, and aqueous molar solubility were

165 available. The logarithm of the aqueous molar solubility of solubilities of naproxen, x1, determined by Daniels et al. 60 naproxen is log10c1,W ¼ –4.16 (corrected for ionization). Other were converted into molar solubilities by dividing x1 by the sat published values for the aqueous molar solubility of naproxen ideal molar volume of the saturated solution (i.e., c1 ¼ x1/ include log10c1,W ¼ –4.216 (Ref. 147)andlog10c1,W ¼ [x1V1 + (1 – x1)Vsolvent]. The molar volume of the hypothetical 118,119 3 1 –4.20. The McGowan volume of ibuprofen, V ¼ subcooled liquid naproxen is Vsolute ¼ 198.70 cm mol . 1.7821, was calculated from the number of chemical bonds in Examination of the numerical entries in Table 12 reveals that the molecule and the individual atomic group volumes, AVi, the Abraham model provides a reasonably accurate mathe- given in Sec. 1.3. The excess molar refraction solute descriptor matical description for much of the observed solubility. The was estimated as E¼ 1.510. This left four solute descriptors (S,A, comparison did identify the experimental solubility of B,andL) still to be determined. The 40 equations were then naproxen in diethyl ether determined by Bustamante solved using the Microsoft “SOLVER” program to yield numer- et al.166 as a suspected outlier value, as well as the solubility ical values of the remaining four solute descriptors, S ¼ 2.022, A of naproxen in propanone reported by Yan et al.167 Both values ¼ 0.600, B ¼ 0.673, and L ¼ 9.207, that best described the differ significantly from the predicted log10c1 value and from log10(SR or P)andlog10(GSR or K) values. The computation at least one other independently measured molar solubility for treated log10c1,G as a floating parameter to be determined as part naproxen dissolved in the respective organic solvent. of the regression analyses. The data analyses returned a value of There have been five studies60,111,166–168 reporting the log10c1,G ¼ –12.96 for the logarithm of the gas-phase solute solubility of naproxen as a function of temperature. Fini 60 concentration that made the log10(SR or P) and log10(GSR or K) et al. determined the molar solubility of naproxen in 1- predictionsinternally consistent. Thecalculatedmolecular solute octanol at only three temperatures from 278 to 310 K. Mora 167 descriptors reproduced the log10(SR or P)andlog10(GSR or K) and Martínez measured the solubility of naproxen in cyclo- values to within an average standard deviation of 0.075 and 0.071 hexane, 1-methylethyl tetradecanoate, trichloromethane, and log10 units, respectively. 1-octanol at several temperatures from 293 to 313 K. Aragoń 166 Table 12 compares the experimental log10c1 values to et al. examined the solubility behavior of naproxen in ethyl calculated values based on Eqs. (28) and (29) of the Abraham ethanoate, dichloromethane, propanone and ethanenitrile in model. For comparison purposes, the measured mole fraction the temperature range of 293–313 K. Manrique et al.111

TABLE 12. Comparison between observed and predicted molar solubilities of naproxen based on the Abraham model, Eqs. (28) and (29)

calc calc log10c1 ; log10c1 ; exp exp exp Solvent Eq. (28) Eq. (29) log10c1 log10c1 log10c1 Methanol 0.712 0.652 0.470a 0.531b 0.691c Ethanol 0.616 0.747 0.486a 0.780c 0.611d 1-Propanol 0.769 0.841 0.770e 0.798c 2-Propanol 0.744 0.774 0.770e 0.829b 1-Butanol 0.962 0.784 0.820e 0.828c 2-Butanol 0.761 0.775 0.820e 2-Methyl-1-propanol 0.951 0.919 1.030e 1-Pentanol 0.917 0.847 0.848e 0.546a 0.874c 2-Pentanol 0.959 0.915 0.867e 3-Methyl-1-butanol 0.986 0.941 0.964e 1-Hexanol 0.848 0.835 0.881e 0.882c 1-Heptanol 0.897 0.954 0.875e 0.874c 1-Octanol 0.919 0.991 0.996e 0.980a 1.037c 0.936f 0.960g 1-Decanol 1.078 1.053 1.070e 1,1′-Oxybisethane 0.778 0.880 0.730e 1.573a Tetrahydrofuran 0.277 0.223 0.200e 1,4-Dioxane 0.151 0.130 0.030e 0.238a Methyl ethanoate 0.365 0.338 0.481e Ethyl ethanoate 0.537 0.521 0.634e 0.460a 0.584h 0.582b Propyl ethanoate 0.563 0.555 Butyl ethanoate 0.625 0.630 0.758e Propanone 0.176 0.194 0.077a 0.202h 1.423b aExperimental value from Bustamante et al.164 bExperimental value from Yan et al.168 cExperimental value from Perlovich et al.163 dExperimental value from Arago´n et al.169 eExperimental value from Daniels et al.165 fExperimental value from Fini et al.60 gExperimental value from Mora and Martínez.167 hExperimental value from Arago´n, Rosas, and Martínez.166

TABLE 13. Parameters of the Modiﬁed Apelblat equation for describing the solubility of naproxen in organic solvents Solvent T/K ABCMARD (%) Cyclohexanea 293–313 142.252 112.669 23.181 3.9 Ethyl ethanoateb 293–313 42.558 114.950 6.764 0.4 Ethyl ethanoatec 278–320 56.145 114.690 9.150 0.4 1-Methylethyl tetradecanoatea 293–313 60.494 114.550 9.671 1.2 Dichloromethaneb 293–313 94.370 113.787 15.761 1.3 Trichloromethanea 293–313 64.496 114.523 10.243 1.3 Methanolc 278–320 67.824 114.824 11.069 0.8 Ethanolc 278–320 76.734 114.212 12.615 1.7 2-Propanolc 278–320 73.697 114.280 12.088 0.7 1-Octanola 293–313 73.586 114.280 12.131 1.9 1,2-Propanediold 293–313 69.694 114.326 11.302 0.9 Propanoneb 293–313 48.718 114.811 7.958 0.3 Propanonec 278–320 73.707 114.258 12.090 0.7 Ethanenitrileb 293–313 91.152 113.854 15.044 1.4 aData set of Mora and Martínez.167 bData set of Arago´n et al.166 cData set of Yan et al.168 dData set of Manrique et al.111

reported solubility data for naproxen in 1,2-propanediol at Auxiliary Information several temperatures between 293 and 313 K. Finally, Yan Method/Apparatus/Procedure: et al.168 studied the solubility of naproxen in five organic Constant-temperature bath and an UV/visible spectrophotometer. solvents (ethyl ethanoate, methanol, ethanol, 2-propanol, and Very few experimental details were provided. Excess solute and solvent were propanone) by incrementally adding small amounts of the allowed to equilibrate at constant temperature. Solubility of the dissolved solute was determined by spectrophotometric measurements. solute until no further solid dissolved. The dissolution of the solid was observed using laser monitoring. The internal con- Source and Purity of Chemicals: sistency of the latter 13 datasets was assessed by curve-fitting (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no the measured mole fraction solubility data to Eq. (8). The purification details were provided. values of the equation coefficients (A, B, and C) are given in (2) Purity not given, Analytical Reagent grade, Solvents Documentation Syntheses (SDS), Peypin, France, no purification details were provided. Table 13, along with the mean absolute relative deviation. Each of the data sets is considered internally consistent as Estimated Error: evidenced by the small MARD values. There were insufficient Temperature: 0.1 K. 60 % experimental measurements in the Fini et al. dataset to x1: 2.5 (relative error). obtain a meaningful regression analysis. The experimental solubility data for naproxen in organic solvents are found in Secs. 21.2–21.10. Components: Original Measurements: (1) (S)-6-Methoxy-α-methyl- 164P. Bustamante, M. A. Peña, and 21.2. Naproxen solubility data in saturated 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, C H O ; [22204-53-1] 975 (1998). hydrocarbons (including cycloalkanes) 14 14 3 (2) Heptane; C7H16; [142-82-5] Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Components: Original Measurements: (1) (S)-6-Methoxy-α-methyl- 163G. L. Perlovich, S. V. Kurkov, 2-naphthaleneacetic acid (Naproxen); A. N. Kinchin, and A. Bauer- Experimental Values C14H14O3; [22204-53-1] Brandl, Eur. J. Pharm. Biopharm.

(2) Hexane; C6H14; [110-54-3] 57, 411 (2004). a b,c Variables: Prepared by: x2 x1 T/K ¼ 298.15 W. E. Acree, Jr. 0.9982 0.00180 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Experimental Values c Experimental value was reported in the paper as ln x1.

a b x2 x1 0.9990 0.000957 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) (S)-6-Methoxy-α-methyl- 164P. Bustamante, M. A. Peña, and Constant-temperature bath and an ultraviolet/visible spectrophotometer. 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with C14H14O3; [22204-53-1] 975 (1998). shaking for several days at constant temperature. After equilibrium was (2) Cyclohexane; C6H12; [110-82-7] attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 μm Variables: Prepared by: pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were T/K ¼ 298.15 W. E. Acree, Jr. determined by spectrophotometric measurements at 233 nm. The reported solubility represents the average of at least three independent determinations. The density of the saturated solution was determined in order to convert the Experimental Values measured molar solubilities in units of mol dm3 to mole fractions.

Source and Purity of Chemicals: x a x b,c (1) Purity not given, USPA, France, no purification details were provided. 2 1 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 0.9999 0.000120 a source not specified, no purification details were provided. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Estimated Error: Experimental value was reported in the paper as ln x1. Temperature: 0.1 K.

x1: 2% (relative error). Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with 167 (1) (S)-6-Methoxy-α-methyl- C. P. Mora and F. Martínez, shaking for several days at constant temperature. After equilibrium was 2-naphthaleneacetic acid (Naproxen); Fluid Phase Equilib. 255,70 attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 μm [ ] C14H14O3; 22204-53-1 (2007). pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were [ ] (2) Cyclohexane; C6H12; 110-82-7 determined by spectrophotometric measurements at 233 nm. The reported Variables: Prepared by: solubility represents the average of at least three independent determinations. Temperature W. E. Acree, Jr. The density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions.

Experimental Values Source and Purity of Chemicals: (1) Purity not given, USPA, France, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a b source not specified, no purification details were provided. T/K x2 x1 293.15 0.9999 0.0000355 Estimated Error: 298.15 0.9999 0.0000587 Temperature: 0.1 K. 303.15 0.9999 0.0000840 x : 2% (relative error). 308.15 0.9999 0.0001183 1 313.15 0.9998 0.0001639 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. 21.3. Naproxen solubility data in aromatic hydrocarbons Auxiliary Information Method/Apparatus/Procedure: / Constant-temperature water bath and an UV visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in stoppered glass flasks and allowed to (1) (S)-6-Methoxy-α-methyl- 163G. L. Perlovich, S. V. Kurkov, equilibrate in a constant-temperature water bath for at least three days. Once 2-naphthaleneacetic acid (Naproxen); A. N. Kinchin, and A. Bauer- equilibrium had been attained, an aliquot of the saturated solution was C14H14O3; [22204-53-1] Brandl, Eur. J. Pharm. Biopharm. removed and filtered in order to remove insoluble particles. The concentration (2) Benzene; C H ; [71-43-2] 57, 411 (2004). of the dissolved drug was determined by spectrophotometric analysis. The 6 6 densities of the saturated solutions were measured in order to convert the Variables: Prepared by: measured concentrations in mol dm3 to mole fraction solubilities. The T/K ¼ 298.15 W. E. Acree, Jr. reported mole fraction solubilities represent the average of three experimental measurements. Experimental Values Source and Purity of Chemicals: (1) Purity not given, USP, no purification details were provided in the paper. a b (2) Purity not given, Merck Chemical Company, no purification details were x2 x1 given in the paper. 0.9963 0.00372 ax : mole fraction of component 2 in the saturated solution. Estimated Error: 2 bx : mole fraction solubility of the solute. Temperature: 0.05 K (estimated by compiler). 1

x1: 2.0% (relative error).

Auxiliary Information 21.4. Naproxen solubility data in esters Method/Apparatus/Procedure: Constant-temperature bath and an analytical balance. Very few experimental details were provided. The solubility was determined Components: Original Measurements: with a gravimetric method that involved transferring a weighed aliquot of the (1) (S)-6-Methoxy-α-methyl- 165C. R. Daniels, A. K. Charlton, saturated solution to a tared container. The solvent was evaporated and the 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. solubility determined from the mass of the solid residue. C14H14O3; [22204-53-1] Furman, A. C. Bilbrey, J. N. Love,

(2) Methyl ethanoate; C3H6O2; J. A. Garza, W. E. Acree, Jr., and Source and Purity of Chemicals: [79-20-9] M. H. Abraham, Phys. Chem. Liq. (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no 42, 481 (2004). puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, Variables: Prepared by: / ¼ Germany, no puriﬁcation details were provided. T K 298.15 W. E. Acree, Jr.

Estimated Error: Temperature: 0.1 K. Experimental Values

x1: 3% (relative error).

a b x2 x1 0.9725 0.02746 a Components: Original Measurements: x2: mole fraction of component 2 in the saturated solution. 164 b (1) (S)-6-Methoxy-α-methyl-2- P. Bustamante, M. A. Peña, and x1: mole fraction solubility of the solute. naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50,

C14H14O3; [22204-53-1] 975 (1998). (2) Benzene; C6H6; [71-43-2] Auxiliary Information Variables: Prepared by: Method/Apparatus/Procedure: T/K ¼ 298.15 W. E. Acree, Jr. Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ visible spectrophotometer. Excess solute and solvent were placed in amber glass bottles and allowed to Experimental Values equilibrate for several days at constant temperature. Attainment of equilibrium was verified by several repetitive measurements and by approaching equilibrium from supersaturation. Aliquots of saturated solutions were a b,c x2 x1 transferred through a coarse filter into tared volumetric flasks, weighed, and 0.9928 0.00724 diluted with methanol. Concentrations were determined by a spectrophotometric measurements at 320 nm. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Source and Purity of Chemicals: Experimental value was reported in the paper as ln x1. (1) 99%, TCI America, Portland, Oregon, USA, was used as received. (2) 99.5%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use. Auxiliary Information Method/Apparatus/Procedure: Estimated Error: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Temperature: 0.1 K. % Excess solute and solvent were placed in flasks and allowed to equilibrate with x1: 1.5 (relative error). shaking for several days at constant temperature. After equilibrium was attained, aliquots of saturated solutions were removed, filtered through 0.2 μm pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 233 nm. The reported Components: Original Measurements: solubility represents the average of at least three independent determinations. (1) (S)-6-Methoxy-α-methyl- 166D. M. Aragoń, J. E. Rosas, and The density of the saturated solution was determined in order to convert the 2-naphthaleneacetic acid (Naproxen); F. Martínez, Phys. Chem. Liq. 48, measured molar solubilities in units of mol dm3 to mole fractions. C14H14O3; [22204-53-1] 437 (2010). (2) Ethyl ethanoate; C4H8O2; Source and Purity of Chemicals: [141-78-6] (1) Purity not given, USPA, France, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Variables: Prepared by: source not specified, no purification details were provided. Temperature W. E. Acree, Jr.

Estimated Error: Temperature: 0.1 K.

x1: 2% (relative error).

Experimental Values a b T/K x2 x1 313.70 0.9585 0.04149 a b 318.70 0.9524 0.04756 T/K x2 x1 320.10 0.9501 0.04986 293.15 0.9763 0.02370 a 298.15 0.9737 0.02633 x2: mole fraction of component 2 in the saturated solution. b 303.15 0.9704 0.02958 x1: mole fraction solubility of the solute. 308.15 0.9677 0.03234 313.15 0.9638 0.03620 a Auxiliary Information x2: mole fraction of component 2 in the saturated solution. b / / x1: mole fraction solubility of the solute. Method Apparatus Procedure: Equilibrium jacketed glass vessel, thermostated circulating water bath, electromagnetic stirrer, analytical balance, laser monitoring system. Auxiliary Information Experimental solubilities were determined by a synthetic method. Preweighed amounts of solute and solvent and were placed in an equilibrium vessel, which Method/Apparatus/Procedure: was connected to a circulating constant-temperature water bath. The solution Thermostatic mechanical shaker and an analytical balance. was stirred and small amounts of solute were incrementally added until no Excess solute and solvent were placed in stoppered glass flasks and allowed to further solid dissolved. The dissolution of the solid was determined using laser equilibrate in a thermostatic mechanical shaker at 313.15 K for at least three monitoring. The total amount of solute dissolved was recorded. Experimental days. Once equilibrium had been attained, an aliquot of the saturated solution measurement was repeated three times. was removed and filtered in order to remove insoluble particles. The concentration of the dissolved drug was determined by weighing an aliquot of Source and Purity of Chemicals: the saturated filtered solution, and then allowing the solvent to evaporate. The (1) Purity not given, Pharmaceutical Purity grade, Zhejian Chejiu mole fraction solubility was calculated from the mass of the solid residue and Pharmaceutical Plant, China, dried in vacuo at 323 K for 24 h and stored in a the mass of the sample taken for analysis. Once the solubility was determined desiccator before use. at 313.15 K, the temperature was decreased by 5 K and stabilized at 308.15 K (2) 99.8+%, Analytical Reagent grade, Tianjin Chemical Reagent Company, for two days to allow the excess dissolved drug to precipitate at this lower China, no purification information was given in the paper. temperature. An aliquot of the new saturated solution was removed, filtered, and the solvent evaporated as before. The procedure was repeated by Estimated Error: decreasing the temperature in 5 K increments to reach 293.15 K. The reported Temperature: 0.05 K. mole fraction solubilities represent the average of three experimental x : 0.5% (relative error). measurements. 1

Source and Purity of Chemicals: (1) Purity not given, USP, no puriﬁcation details were provided in the paper. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, no Components: Original Measurements: 164 puriﬁcation details were given in the paper. (1) (S)-6-Methoxy-α-methyl- P. Bustamante, M. A. Peña, and 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, [ ] Estimated Error: C14H14O3; 22204-53-1 975 (1998). Temperature: 0.1 K (estimated by compiler). (2) Ethyl ethanoate; C4H8O2; [ ] x1: 1.0% (relative error). 141-78-6 Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

Components: Original Measurements: (1) (S)-6-Methoxy-α-methyl- 168F.-Y. Yan, L. Chen, D.-Q. Liu, Experimental Values 2-naphthaleneacetic acid (Naproxen); L.-F. SiMa, M.-J. Chen, H. Shi,

C14H14O3; [22204-53-1] and J.-X. Zhu, J. Chem. Eng. Data a b,c (2) Ethyl ethanoate; C4H8O2; 54, 1117 (2009). x2 x1 [141-78-6] 0.9645 0.0355 a Variables: Prepared by: x2: mole fraction of component 2 in the saturated solution. b Temperature W. E. Acree, Jr. x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Experimental Values Auxiliary Information Method/Apparatus/Procedure: T/K x a x b 2 1 Constant-temperature bath and an ultraviolet/visible spectrophotometer. 278.20 0.9855 0.01447 Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with 283.45 0.9828 0.01716 shaking for several days at constant temperature. After equilibrium was 288.15 0.9804 0.01964 attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 μm 293.10 0.9771 0.02294 pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were 298.50 0.9729 0.02710 determined by spectrophotometric measurements at 233 nm. The reported 303.25 0.9693 0.03065 solubility represents the average of at least three independent determinations. 308.65 0.9640 0.03603 The density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, USPA, France, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. a b T/K x2 x1 293.15 0.9943 0.00569 Estimated Error: 298.15 0.9932 0.00679 Temperature: 0.1 K. 303.15 0.9923 0.00766 x : 2% (relative error). 1 308.15 0.9908 0.00922 313.15 0.9895 0.01051 a x2: mole fraction of component 2 in the saturated solution. bx : mole fraction solubility of the solute. Components: Original Measurements: 1 (1) (S)-6-Methoxy-α-methyl- 165C. R. Daniels, A. K. Charlton, 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. Auxiliary Information C14H14O3; [22204-53-1] Furman, A. C. Bilbrey, J. N. Love, / / (2) Butyl ethanoate; C6H12O2; J. A. Garza, W. E. Acree, Jr., and Method Apparatus Procedure: [123-86-4] M. H. Abraham, Phys. Chem. Liq. Constant-temperature water bath and an UV/visible spectrophotometer. 42, 481 (2004). Excess solute and solvent were placed in stoppered glass flasks and allowed to equilibrate in a constant-temperature water bath for at least three days. Once Variables: Prepared by: equilibrium had been attained, an aliquot of the saturated solution was T/K ¼ 298.15 W. E. Acree, Jr. removed and filtered in order to remove insoluble particles. The concentration of the dissolved drug was determined by spectrophotometric analysis. The densities of the saturated solutions were measured in order to convert the Experimental Values measured concentrations in mol dm3 to mole fraction solubilities. The reported mole fraction solubilities represent the average of three experimental a b measurements. x2 x1 0.9766 0.02342 Source and Purity of Chemicals: a x2: mole fraction of component 2 in the saturated solution. (1) Purity not given, USP, no purification details were provided in the paper. b x1: mole fraction solubility of the solute. (2) Purity not given, Merck Chemical Company, no purification details were given in the paper.

Auxiliary Information Estimated Error: Temperature: 0.05 K (estimated by compiler). Method/Apparatus/Procedure: x1: 2.0% (relative error). Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ visible spectrophotometer. Excess solute and solvent were placed in amber glass bottles and allowed to equilibrate for several days at constant temperature. Attainment of equilibrium was verified by several repetitive measurements and by approaching Components: Original Measurements: 170 equilibrium from supersaturation. Aliquots of saturated solutions were (1) (S)-6-Methoxy-α-methyl- M. D. C. Claramonte, A. P. transferred through a coarse filter into tared volumetric flasks, weighed, and 2-naphthaleneacetic acid (Naproxen); Vialard, and F. G. Vilchez, Int. J. [ ] diluted with methanol. Concentrations were determined by C14H14O3; 22204-53-1 Pharm. 94, 23 (1993). spectrophotometric measurements at 320 nm. (2) 1-Methylethyl tetradecanoate; C17H34O2; [110-27-0] Source and Purity of Chemicals: Variables: Prepared by: % (1) 99 , TCI America, Portland, Oregon, USA, was used as received. T/K ¼ 298 K W. E. Acree, Jr. (2) 99.7%, HPLC grade, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use. Experimental Values Estimated Error: Temperature: 0.1 K.

x1: 1.5% (relative error). a b,c x2 x1 0.9930 0.0070 a x2: mole fraction of component 2 in the saturated solution. bx : mole fraction solubility of the solute. Components: Original Measurements: 1 cThe data were reported in the paper in graphical format, and the mole fraction (1) (S)-6-Methoxy-α-methyl- 167C. P. Mora and F. Martínez, solubility was interpolated from an enlarged copy of the ﬁgure given in the 2-naphthaleneacetic acid (Naproxen); Fluid Phase Equilib. 255,70 manuscript. C14H14O3; [22204-53-1] (2007). (2) 1-Methylethyl tetradecanoate;

C17H34O2; [110-27-0] Variables: Prepared by: Temperature W. E. Acree, Jr.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) (S)-6-Methoxy-α-methyl- 170M. D. C. Claramonte, A. P. Constant-temperature water bath and an UV/visible spectrophotometer. 2-naphthaleneacetic acid (Naproxen); Vialard, and F. G. Vilchez, Int. J. The equilibration method was similar to that described elsewhere [M. D. C14H14O3; [22204-53-1] Pharm. 94, 23 (1993). Contreras, A. Parera, and F. Girela, An. Real Acad. Farm. 58, 563 (1992)], (2) Dibutyl hexanedioate; C14H26O4; except that the solute was added to the solvent at 308 K until a precipitate [105-99-7] appeared. The samples were then sealed and mechanically shaken at 298 K. Variables: Prepared by: After equilibrium was obtained, a weighed aliquot of the saturated solution was T/K ¼ 298 K W. E. Acree, Jr. removed and diluted with ethanol for spectroscopic analysis at either 271 or 316 nm. Experimental Values Source and Purity of Chemicals: (1) Purity not given, Elmu S.A., used as received. (2) Purity not given, Glyco Iberica, used as received. a b,c x2 x1 Estimated Error: 0.9690 0.0310 a Temperature: 0.2 K (estimated by compiler). x2: mole fraction of component 2 in the saturated solution. % b x1: 5 (relative error, estimated by compiler). x1: mole fraction solubility of the solute. cThe data were reported in the paper in graphical format, and the mole fraction solubility was interpolated from an enlarged copy of the ﬁgure given in the manuscript. Components: Original Measurements: (1) (S)-6-Methoxy-α-methyl- 170M. D. C. Claramonte, A. P. 2-naphthaleneacetic acid (Naproxen); Vialard, and F. G. Vilchez, Int. J. Auxiliary Information [ ] C14H14O3; 22204-53-1 Pharm. 94, 23 (1993). Method/Apparatus/Procedure: (2) 1-Methylethyl hexadecanoate; Constant-temperature water bath and an UV/visible spectrophotometer. [ ] C19H38O2; 142-91-6 The equilibration method was similar to that described elsewhere [M. D. ] Variables: Prepared by: Contreras, A. Parera, and F. Girela, An. Real Acad. Farm. 58, 563 (1992) , T/K ¼ 298 K W. E. Acree, Jr. except that the solute was added to the solvent at 308 K until a precipitate appeared. The samples were then sealed and mechanically shaken at 298 K. After equilibrium was obtained, a weighed aliquot of the saturated solution was Experimental Values removed and diluted with ethanol for spectroscopic analysis at either 271 or 316 nm.

a b,c Source and Purity of Chemicals: x2 x1 (1) Purity not given, Elmu S.A., used as received. 0.9932 0.0068 (2) Purity not given, Henkel, used as received. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: cThe data were reported in the paper in graphical format, and the mole fraction Temperature: 0.2 K (estimated by compiler).

solubility was interpolated from an enlarged copy of the ﬁgure given in the x1: 5% (relative error, estimated by compiler). manuscript.

Auxiliary Information 21.5. Naproxen solubility data in ethers Method/Apparatus/Procedure: Constant-temperature water bath and an UV/visible spectrophotometer. [ The equilibration method was similar to that described elsewhere M. D. Components: Original Measurements: ] 165 Contreras, A. Parera, and F. Girela, An. Real Acad. Farm. 58, 563 (1992) , (1) (S)-6-Methoxy-α-methyl- C. R. Daniels, A. K. Charlton, except that the solute was added to the solvent at 308 K until a precipitate 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. appeared. The samples were then sealed and mechanically shaken at 298 K. C14H14O3; [22204-53-1] Furman, A. C. Bilbrey, J. N. Love, After equilibrium was obtained, a weighed aliquot of the saturated solution was (2) 1,1′-Oxybisethane; C4H10O; J. A. Garza, W. E. Acree, Jr., and removed and diluted with ethanol for spectroscopic analysis at either 271 or [60-29-7] M. H. Abraham, Phys. Chem. Liq. 316 nm. 42, 481 (2004).

Source and Purity of Chemicals: Variables: Prepared by: / ¼ (1) Purity not given, Elmu S.A., used as received. T K 298.15 W. E. Acree, Jr. (2) Purity not given, Aldabo-Julia, used as received.

Estimated Error: Experimental Values Temperature: 0.2 K (estimated by compiler).

x1: 5% (relative error, estimated by compiler). a b x2 x1 0.9802 0.01984 a x2: mole fraction of component 2 in the saturated solution. b Components: Original Measurements: x1: mole fraction solubility of the solute. (1) (S)-6-Methoxy-α-methyl- 170M. D. C. Claramonte, A. P. 2-naphthaleneacetic acid (Naproxen); Vialard, and F. G. Vilchez, Int. J.

C14H14O3; [22204-53-1] Pharm. 94, 23 (1993). Auxiliary Information (2) Propylene glycol dipelargonate; Method/Apparatus/Procedure: C H O ; [41395-83-9] 22 42 4 Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ Variables: Prepared by: visible spectrophotometer. T/K ¼ 298 K W. E. Acree, Jr. Excess solute and solvent were placed in amber glass bottles and allowed to equilibrate for several days at constant temperature. Attainment of equilibrium was verified by several repetitive measurements and by approaching Experimental Values equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse filter into tared volumetric flasks, weighed, and diluted with methanol. Concentrations were determined by a b,c x2 x1 spectrophotometric measurements at 320 nm. 0.9755 0.0245 a Source and Purity of Chemicals: x2: mole fraction of component 2 in the saturated solution. % b (1) 99 , TCI America, Portland, Oregon, USA, was used as received. x1: mole fraction solubility of the solute. +% c (2) 99 , anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, The data were reported in the paper in graphical format, and the mole fraction USA, stored over molecular sieves and distilled shortly before use. solubility was interpolated from an enlarged copy of the figure given in the manuscript. Estimated Error: Temperature: 0.1 K.

x1: 1.5% (relative error). Auxiliary Information Method/Apparatus/Procedure: Constant-temperature water bath and an UV/visible spectrophotometer. [ The equilibration method was similar to that described elsewhere M. D. Components: Original Measurements: ] 164 Contreras, A. Parera, and F. Girela, An. Real Acad. Farm. 58, 563 (1992) , (1) (S)-6-Methoxy-α-methyl- P. Bustamante, M. A. Peña, and except that the solute was added to the solvent at 308 K until a precipitate 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, appeared. The samples were then sealed and mechanically shaken at 298 K. C14H14O3; [22204-53-1] 975 (1998). After equilibrium was obtained, a weighed aliquot of the saturated solution was (2) 1,1′-Oxybisethane; C4H10O; removed and diluted with ethanol for spectroscopic analysis at either 271 or [60-29-7] 316 nm. Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 298.15 W. E. Acree, Jr. (1) Purity not given, Elmu S.A., used as received. (2) Purity not given, Glyco Iberica, used as received. Experimental Values Estimated Error: Temperature: 0.2 K (estimated by compiler). x a x b,c x1: 5% (relative error, estimated by compiler). 2 1 0.9970 0.00299 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) (S)-6-Methoxy-α-methyl- 165C. R. Daniels, A. K. Charlton, Constant-temperature bath and an ultraviolet/visible spectrophotometer. 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with C14H14O3; [22204-53-1] Furman, A. C. Bilbrey, J. N. Love,

shaking for several days at constant temperature. After equilibrium was (2) 1,1′-Oxybisbutane; C8H18O; J. A. Garza, W. E. Acree, Jr., and attained, aliquots of saturated solutions were removed, filtered through 0.2 μm [142-96-1] M. H. Abraham, Phys. Chem. Liq. pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were 42, 481 (2004). determined by spectrophotometric measurements at 233 nm. The reported Variables: Prepared by: solubility represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr. The density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions. Experimental Values Source and Purity of Chemicals: (1) Purity not given, USPA, France, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x a x b source not specified, no purification details were provided. 2 1 0.9951 0.00493 a Estimated Error: x2: mole fraction of component 2 in the saturated solution. b Temperature: 0.1 K. x1: mole fraction solubility of the solute. x1: 2% (relative error).

Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ 165 (1) (S)-6-Methoxy-α-methyl- C. R. Daniels, A. K. Charlton, visible spectrophotometer. 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. Excess solute and solvent were placed in amber glass bottles and allowed to [ ] C14H14O3; 22204-53-1 Furman, A. C. Bilbrey, J. N. Love, equilibrate for several days at constant temperature. Attainment of equilibrium (2) 2,2′-Oxybispropane; C6H14O; J. A. Garza, W. E. Acree, Jr., and was verified by several repetitive measurements and by approaching [108-20-3] M. H. Abraham, Phys. Chem. Liq. equilibrium from supersaturation. Aliquots of saturated solutions were 42, 481 (2004). transferred through a coarse filter into tared volumetric flasks, weighed, and Variables: Prepared by: diluted with methanol. Concentrations were determined by T/K ¼ 298.15 W. E. Acree, Jr. spectrophotometric measurements at 320 nm.

Source and Purity of Chemicals: % Experimental Values (1) 99 , TCI America, Portland, Oregon, USA, was used as received. (2) 99.3%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use. a b x2 x1 Estimated Error: 0.9941 0.00585 Temperature: 0.1 K. a x2: mole fraction of component 2 in the saturated solution. x1: 1.5% (relative error). b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) (S)-6-Methoxy-α-methyl- 165C. R. Daniels, A. K. Charlton, Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. visible spectrophotometer. C14H14O3; [22204-53-1] Furman, A. C. Bilbrey, J. N. Love,

Excess solute and solvent were placed in amber glass bottles and allowed to (2) Tetrahydrofuran; C4H8O; J. A. Garza, W. E. Acree, Jr., and equilibrate for several days at constant temperature. Attainment of equilibrium [109-99-9] M. H. Abraham, Phys. Chem. Liq. was verified by several repetitive measurements and by approaching 42, 481 (2004). equilibrium from supersaturation. Aliquots of saturated solutions were Variables: Prepared by: transferred through a coarse filter into tared volumetric flasks, weighed, and T/K ¼ 298.15 W. E. Acree, Jr. diluted with methanol. Concentrations were determined by spectrophotometric measurements at 320 nm. Experimental Values Source and Purity of Chemicals: (1) 99%, TCI America, Portland, Oregon, USA, was used as received. (2) 99%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, x a x b USA, stored over molecular sieves and distilled shortly before use. 2 1 0.8582 0.1418 a Estimated Error: x2: mole fraction of component 2 in the saturated solution. b Temperature: 0.1 K. x1: mole fraction solubility of the solute. x1: 1.5% (relative error).

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) (S)-6-Methoxy-α-methyl- 164P. Bustamante, M. A. Peña, and Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, visible spectrophotometer. C14H14O3; [22204-53-1] 975 (1998). Excess solute and solvent were placed in amber glass bottles and allowed to (2) 1,4-Dioxane; C4H8O2; [123-91-1] equilibrate for several days at constant temperature. Attainment of equilibrium Variables: Prepared by: was verified by several repetitive measurements and by approaching T/K ¼ 298.15 W. E. Acree, Jr. equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse filter into tared volumetric flasks, weighed, and diluted with methanol. Concentrations were determined by Experimental Values spectrophotometric measurements at 320 nm.

Source and Purity of Chemicals: x a x b,c (1) 99%, TCI America, Portland, Oregon, USA, was used as received. 2 1 (2) 99.9%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, 0.8157 0.1843 a USA, stored over molecular sieves and distilled shortly before use. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Estimated Error: Experimental value was reported in the paper as ln x1. Temperature: 0.1 K.

x1: 1.5% (relative error). Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in flasks and allowed to equilibrate with 165 (1) (S)-6-Methoxy-α-methyl- C. R. Daniels, A. K. Charlton, shaking for several days at constant temperature. After equilibrium was 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. attained, aliquots of saturated solutions were removed, filtered through 0.2 μm [ ] C14H14O3; 22204-53-1 Furman, A. C. Bilbrey, J. N. Love, pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were (2) 1,4-Dioxane; C4H8O2; [123-91-1] J. A. Garza, W. E. Acree, Jr., and determined by spectrophotometric measurements at 233 nm. The reported M. H. Abraham, Phys. Chem. Liq. solubility represents the average of at least three independent determinations. 42, 481 (2004). The density of the saturated solution was determined in order to convert the 3 Variables: Prepared by: measured molar solubilities in units of mol dm to mole fractions. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, USPA, France, no purification details were provided. Experimental Values (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided.

a b Estimated Error: x2 x1 Temperature: 0.1 K. 0.8960 0.1040 x1: 2% (relative error). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Auxiliary Information 21.6. Naproxen solubility data in haloalkanes, haloalkenes, and haloaromatic hydrocarbons Method/Apparatus/Procedure: Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ visible spectrophotometer. Excess solute and solvent were placed in amber glass bottles and allowed to Components: Original Measurements: α 166 equilibrate for several days at constant temperature. Attainment of equilibrium (1) (S)-6-Methoxy- -methyl- D. M. Aragoń, J. E. Rosas, and í was verified by several repetitive measurements and by approaching 2-naphthaleneacetic acid (Naproxen); F. Mart nez, Phys. Chem. Liq. 48, [ ] equilibrium from supersaturation. Aliquots of saturated solutions were C14H14O3; 22204-53-1 437 (2010). transferred through a coarse filter into tared volumetric flasks, weighed, and (2) Dichloromethane; CH2Cl2; [ ] diluted with methanol. Concentrations were determined by 75-09-2 spectrophotometric measurements at 320 nm. Variables: Prepared by: Temperature W. E. Acree, Jr. Source and Purity of Chemicals: (1) 99%, TCI America, Portland, Oregon, USA, was used as received. (2) 99.5%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use.

Estimated Error: Temperature: 0.1 K.

x1: 1.5% (relative error).

Experimental Values Auxiliary Information Method/Apparatus/Procedure: Constant-temperature water bath and an UV/visible spectrophotometer. T/K x a x b 2 1 Excess solute and solvent were placed in stoppered glass ﬂasks and allowed to 293.15 0.9885 0.01145 equilibrate in a constant-temperature water bath for at least three days. Once 298.15 0.9844 0.01564 equilibrium had been attained, an aliquot of the saturated solution was 303.15 0.9804 0.01963 removed and ﬁltered in order to remove insoluble particles. The concentration 308.15 0.9747 0.02531 of the dissolved drug was determined by spectrophotometric analysis. The 313.15 0.9680 0.03197 densities of the saturated solutions were measured in order to convert the a measured concentrations in mol dm 3 to mole fraction solubilities. The x2: mole fraction of component 2 in the saturated solution. b reported mole fraction solubilities represent the average of three experimental x1: mole fraction solubility of the solute. measurements.

Auxiliary Information Source and Purity of Chemicals: (1) Purity not given, USP, no purification details were provided in the paper. / / Method Apparatus Procedure: (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, no Thermostatic mechanical shaker and an analytical balance. purification details were given in the paper. Excess solute and solvent were placed in stoppered glass flasks and allowed to equilibrate in a thermostatic mechanical shaker at 313.15 K for at least three Estimated Error: days. Once equilibrium had been attained, an aliquot of the saturated solution Temperature: 0.05 K (estimated by compiler). was removed and filtered in order to remove insoluble particles. The x1: 2.0% (relative error). concentration of the dissolved drug was determined by weighing an aliquot of the saturated filtered solution, and then allowing the solvent to evaporate. The mole fraction solubility was calculated from the mass of the solid residue and the mass of the sample taken for analysis. Once the solubility was determined at 313.15 K, the temperature was decreased by 5 K and stabilized at 308.15 K Components: Original Measurements: α 164 ñ for two days to allow the excess dissolved drug to precipitate at this lower (1) (S)-6-Methoxy- -methyl- P. Bustamante, M. A. Pe a, and temperature. An aliquot of the new saturated solution was removed, filtered, 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, [ ] and the solvent evaporated as before. The procedure was repeated by C14H14O3; 22204-53-1 975 (1998). decreasing the temperature in 5 K increments to reach 293.15 K. The reported (2) Trichloromethane; CHCl3; [ ] mole fraction solubilities represent the average of three experimental 67-66-3 measurements. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, USP, no purification details were provided in the paper. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, no Experimental Values purification details were given in the paper.

Estimated Error: a b,c x2 x1 Temperature: 0.1 K (estimated by compiler). 0.9697 0.03029 x1: 1.0% (relative error). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Components: Original Measurements: α 167 í (1) (S)-6-Methoxy- -methyl- C. P. Mora and F. Mart nez, Auxiliary Information 2-naphthaleneacetic acid (Naproxen); Fluid Phase Equilib. 255,70 / / C14H14O3; [22204-53-1] (2007). Method Apparatus Procedure: / (2) Trichloromethane; CHCl3; Constant-temperature bath and an ultraviolet visible spectrophotometer. [67-66-3] Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for several days at constant temperature. After equilibrium was Variables: Prepared by: attained, aliquots of saturated solutions were removed, filtered through 0.2 μm Temperature W. E. Acree, Jr. pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 233 nm. The reported solubility represents the average of at least three independent determinations. Experimental Values The density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions. T/ x a x b K 2 1 Source and Purity of Chemicals: 293.15 0.9803 0.0197 (1) Purity not given, USPA, France, no purification details were provided. 298.15 0.9759 0.0241 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 303.15 0.9728 0.0272 source not specified, no purification details were provided. 308.15 0.9672 0.0328 313.15 0.9619 0.0381 Estimated Error: a Temperature: 0.1 K. x2: mole fraction of component 2 in the saturated solution. b x : 2% (relative error). x1: mole fraction solubility of the solute. 1

Auxiliary Information Components: Original Measurements: (1) (S)-6-Methoxy-α-methyl- 164P. Bustamante, M. A. Peña, and Method/Apparatus/Procedure: 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, Constant-temperature bath and an ultraviolet/visible spectrophotometer. C14H14O3; [22204-53-1] 975 (1998). Excess solute and solvent were placed in flasks and allowed to equilibrate with (2) 1,2-Dichloroethane; C2H4Cl2; shaking for several days at constant temperature. After equilibrium was [107-06-2] attained, aliquots of saturated solutions were removed, filtered through 0.2 μm pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were Variables: Prepared by: determined by spectrophotometric measurements at 233 nm. The reported T/K ¼ 298.15 W. E. Acree, Jr. solubility represents the average of at least three independent determinations. The density of the saturated solution was determined in order to convert the 3 Experimental Values measured molar solubilities in units of mol dm to mole fractions. Source and Purity of Chemicals: (1) Purity not given, USPA, France, no purification details were provided. x a x b,c 2 1 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 0.9867 0.01329 source not specified, no purification details were provided. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: c Experimental value was reported in the paper as ln x1. Temperature: 0.1 K. x1: 2% (relative error).

Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. 21.7. Naproxen solubility data in alcohols Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for several days at constant temperature. After equilibrium was μ attained, aliquots of saturated solutions were removed, filtered through 0.2 m Components: Original Measurements: % / pore size membranes, and diluted with 96 ethanol (v v). Concentrations were (1) (S)-6-Methoxy-α-methyl- 163G. L. Perlovich, S. V. Kurkov, determined by spectrophotometric measurements at 233 nm. The reported 2-naphthaleneacetic acid (Naproxen); A. N. Kinchin, and A. Bauer- solubility represents the average of at least three independent determinations. C14H14O3; [22204-53-1] Brandl, Eur. J. Pharm. Biopharm. The density of the saturated solution was determined in order to convert the (2) Methanol; CH O; [67-56-1] 57, 411 (2004). measured molar solubilities in units of mol dm 3 to mole fractions. 4 Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 298.15 W. E. Acree, Jr. (1) Purity not given, USPA, France, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values

Estimated Error: a b Temperature: 0.1 K. x2 x1 % x1: 2 (relative error). 0.9914 0.00857 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: 164 (1) (S)-6-Methoxy-α-methyl- P. Bustamante, M. A. Peña, and Auxiliary Information 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, Method/Apparatus/Procedure: C14H14O3; [22204-53-1] 975 (1998). Constant-temperature bath and an UV/visible spectrophotometer. (2) Chlorobenzene; C6H5Cl; [108-90-7] Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate at constant temperature. Solubility of the dissolved Variables: Prepared by: solute was determined by spectrophotometric measurements. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Experimental Values puriﬁcation details were provided. (2) Purity not given, HPLC grade, Merck Chemical Company, Germany, no puriﬁcation details were provided. a b,c x2 x1 0.9911 0.008891 Estimated Error: a Temperature: 0.1 K. x2: mole fraction of component 2 in the saturated solution. b x1: 2.5% (relative error). x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Components: Original Measurements: Experimental Values (1) (S)-6-Methoxy-α-methyl- 168F.-Y. Yan, L. Chen, D.-Q. Liu,

2-naphthaleneacetic acid (Naproxen); L.-F. SiMa, M.-J. Chen, H. Shi, a b,c x2 x1 C14H14O3; [22204-53-1] and J.-X. Zhu, J. Chem. Eng. Data

(2) Methanol; CH4O; [67-56-1] 54, 1117 (2009). 0.9854 0.01458 a x2: mole fraction of component 2 in the saturated solution. Variables: Prepared by: b x1: mole fraction solubility of the solute. Temperature W. E. Acree, Jr. c Experimental value was reported in the paper as ln x1.

Experimental Values Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. T/K x a x b 2 1 Excess solute and solvent were placed in flasks and allowed to equilibrate with 278.20 0.9939 0.006123 shaking for several days at constant temperature. After equilibrium was 283.60 0.9927 0.007293 attained, aliquots of saturated solutions were removed, filtered through 0.2 μm 288.15 0.9913 0.008746 pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were 293.10 0.9895 0.010490 determined by spectrophotometric measurements at 233 nm. The reported 298.15 0.9874 0.012570 solubility represents the average of at least three independent determinations. 303.90 0.9846 0.015400 The density of the saturated solution was determined in order to convert the 308.65 0.9816 0.018350 measured molar solubilities in units of mol dm3 to mole fractions. 313.40 0.9784 0.021590 318.80 0.9745 0.025490 Source and Purity of Chemicals: 320.15 0.9727 0.027340 (1) Purity not given, USPA, France, no purification details were provided. a x2: mole fraction of component 2 in the saturated solution. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical b x1: mole fraction solubility of the solute. source not specified, no purification details were provided.

Estimated Error: Auxiliary Information Temperature: 0.1 K. x : 2% (relative error). Method/Apparatus/Procedure: 1 Equilibrium jacketed glass vessel, thermostated circulating water bath, electromagnetic stirrer, analytical balance, laser monitoring system. Experimental solubilities were determined by a synthetic method. Preweighed Components: Original Measurements: amounts of solute and solvent and were placed in an equilibrium vessel, which (1) (S)-6-Methoxy-α-methyl- 163G. L. Perlovich, S. V. Kurkov, was connected to a circulating constant-temperature water bath. The solution 2-naphthaleneacetic acid (Naproxen); A. N. Kinchin, and A. Bauer- was stirred and small amounts of solute were incrementally added until no C14H14O3; [22204-53-1] Brandl, Eur. J. Pharm. Biopharm. further solid dissolved. The dissolution of the solid was determined using laser (2) Ethanol; C2H6O; [64-17-5] 57, 411 (2004). monitoring. The total amount of solute dissolved was recorded. Experimental measurement was repeated three times. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Pharmaceutical Purity grade, Zhejian Chejiu Pharmaceutical Plant, China, dried in vacuo at 323 K for 24 h and stored in a Experimental Values desiccator before use. (2) 99.8+%, Analytical Reagent grade, Tianjin Chemical Reagent Company, a b China, no puriﬁcation information was given in the paper. x2 x1 0.9893 0.0107 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. Temperature: 0.05 K. b x1: mole fraction solubility of the solute. x1: 0.5% (relative error).

Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: Constant-temperature bath and an UV/visible spectrophotometer. (1) (S)-6-Methoxy-α-methyl- 164P. Bustamante, M. A. Peña, and Very few experimental details were provided. Excess solute and solvent were 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, allowed to equilibrate at constant temperature. Solubility of the dissolved

C14H14O3; [22204-53-1] 975 (1998). solute was determined by spectrophotometric measurements. (2) Methanol; CH4O; [67-56-1] Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no T/K ¼ 298.15 W. E. Acree, Jr. purification details were provided. (2) 99.6%, chemical source not specified, no purification details were provided.

Estimated Error: Temperature: 0.1 K.

x1: 2.5% (relative error).

a b Components: Original Measurements: T/K x2 x1 α 169 ´ (1) (S)-6-Methoxy- -methyl- D. M. Aragon, D. P. Pacheco, 313.40 0.9788 0.021190 2-naphthaleneacetic acid (Naproxen); M. A. Ruidiaz, A. D. Sosnik, and 318.80 0.9754 0.024610 [ ] í C14H14O3; 22204-53-1 F. Mart nez, Vitae, Rev. Fac. 320.15 0.9721 0.027930 [ ] Quim. Farm. 15, 113 (2008). (2) Ethanol; C2H6O; 64-17-5 a x2: mole fraction of component 2 in the saturated solution. b Variables: Prepared by: x1: mole fraction solubility of the solute. T/K ¼ 298.15 W. E. Acree, Jr.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: Equilibrium jacketed glass vessel, thermostated circulating water bath, a b electromagnetic stirrer, analytical balance, laser monitoring system. x2 x1 Experimental solubilities were determined by a synthetic method. Preweighed 0.9851 0.0149 amounts of solute and solvent and were placed in an equilibrium vessel, which a x2: mole fraction of component 2 in the saturated solution. was connected to a circulating constant-temperature water bath. The solution b x1: mole fraction solubility of the solute. was stirred and small amounts of solute were incrementally added until no further solid dissolved. The dissolution of the solid was determined using laser monitoring. The total amount of solute dissolved was recorded. Experimental Auxiliary Information measurement was repeated three times. Method/Apparatus/Procedure: Source and Purity of Chemicals: Mechanical stirrer, constant-temperature bath, and an UV/visible (1) Purity not given, Pharmaceutical Purity grade, Zhejian Chejiu spectrophotometer. Pharmaceutical Plant, China, dried in vacuo at 323 K for 24 h and stored in a Excess solute and solvent were placed in glass bottles, mechanically stirred for desiccator before use. 1 h, and then saturated in a constant-temperature bath for 72 h at 313.15 K. The (2) 99.8+%, Analytical Reagent grade, Tianjin Chemical Reagent Company, samples were allowed to equilibrate in a constant temperature at 298.15 K for China, no puriﬁcation information was given in the paper. an additional 24 h to allow the precipitation of the excess dissolved drug. An aliquot of the saturated solution was then removed, ﬁltered, and diluted Estimated Error: quantitatively with alcohol for spectroscopic analysis. The reported value Temperature: 0.05 K. represents the average of at least three experimental determinations. The x : 0.5% (relative error). densities of the saturated solutions were measured in order to convert the 1 measured concentrations in mol dm3 to mole fraction solubilities.

Source and Purity of Chemicals: (1) Purity not given, USP, no puriﬁcation details were provided. Components: Original Measurements: (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, (1) (S)-6-Methoxy-α-methyl- 164P. Bustamante, M. A. Peña, and Germany, no puriﬁcation details were provided. 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, C14H14O3; [22204-53-1] 975 (1998). Estimated Error: (2) Ethanol; C2H6O; [64-17-5] Temperature: 0.05 K. Variables: Prepared by: x : 2.5% (relative error). 1 T/K ¼ 298.15 W. E. Acree, Jr.

Experimental Values Components: Original Measurements: (1) (S)-6-Methoxy-α-methyl- 168F.-Y. Yan, L. Chen, D.-Q. Liu, a b,c 2-naphthaleneacetic acid (Naproxen); L.-F. SiMa, M.-J. Chen, H. Shi, x2 x1 [ ] C14H14O3; 22204-53-1 and J.-X. Zhu, J. Chem. Eng. Data 0.9799 0.02011 [ ] (2) Ethanol; C2H6O; 64-17-5 54, 1117 (2009). a x2: mole fraction of component 2 in the saturated solution. b Variables: Prepared by: x1: mole fraction solubility of the solute. c Temperature W. E. Acree, Jr. Experimental value was reported in the paper as ln x1.

Source and Purity of Chemicals: Auxiliary Information (1) Purity not given, USPA, France, no purification details were provided. / / (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Method Apparatus Procedure: / source not specified, no purification details were provided. Constant-temperature bath, calorimetric thermometer, and an ultraviolet visible spectrophotometer. Estimated Error: Excess solute and solvent were placed in amber glass bottles and allowed to Temperature: 0.1 K. equilibrate for several days at constant temperature. Attainment of equilibrium was verified by several repetitive measurements and by approaching x1: 2% (relative error). equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse filter into tared volumetric flasks, weighed, and diluted with methanol. Concentrations were determined by spectrophotometric measurements at 320 nm. Components: Original Measurements: α 163 (1) (S)-6-Methoxy- -methyl- G. L. Perlovich, S. V. Kurkov, Source and Purity of Chemicals: 2-naphthaleneacetic acid (Naproxen); A. N. Kinchin, and A. Bauer- (1) 99%, TCI America, Portland, Oregon, USA, was used as received. [ ] C14H14O3; 22204-53-1 Brandl, Eur. J. Pharm. Biopharm. (2) 99+%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, [ ] (2) 1-Propanol; C3H8O; 71-23-8 57, 411 (2004). USA, stored over molecular sieves and distilled shortly before use. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Estimated Error: Temperature: 0.1 K.

x1: 1.5% (relative error). Experimental Values

a b x2 x1 Components: Original Measurements: 165 0.9878 0.0122 (1) (S)-6-Methoxy-α-methyl- C. R. Daniels, A. K. Charlton, a 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. x2: mole fraction of component 2 in the saturated solution. [ ] b C14H14O3; 22204-53-1 Furman, A. C. Bilbrey, J. N. Love, x1: mole fraction solubility of the solute. (2) 2-Propanol; C3H8O; [67-63-0] J. A. Garza, W. E. Acree, Jr., and M. H. Abraham, Phys. Chem. Liq. Auxiliary Information 42, 481 (2004). Method/Apparatus/Procedure: Variables: Prepared by: Constant-temperature bath and an UV/visible spectrophotometer. T/K ¼ 298.15 W. E. Acree, Jr. Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate at constant temperature. Solubility of the dissolved solute was determined by spectrophotometric measurements. Experimental Values

Source and Purity of Chemicals: a b (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no x2 x1 purification details were provided. 0.9867 0.01334 (2) Purity not given, HPLC grade, Aldrich Chemical Company, Germany, no a purification details were provided. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: Temperature: 0.1 K. Auxiliary Information x1: 2.5% (relative error). Method/Apparatus/Procedure: Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in amber glass bottles and allowed to (1) (S)-6-Methoxy-α-methyl- 165C. R. Daniels, A. K. Charlton, equilibrate for several days at constant temperature. Attainment of equilibrium 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. was verified by several repetitive measurements and by approaching C H O ; [22204-53-1] Furman, A. C. Bilbrey, J. N. Love, 14 14 3 equilibrium from supersaturation. Aliquots of saturated solutions were [ ] J. A. Garza, W. E. Acree, Jr., and (2) 1-Propanol; C3H8O; 71-23-8 transferred through a coarse filter into tared volumetric flasks, weighed, and M. H. Abraham, Phys. Chem. Liq. diluted with methanol. Concentrations were determined by 42, 481 (2004). spectrophotometric measurements at 320 nm. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) 99%, TCI America, Portland, Oregon, USA, was used as received. (2) 99+%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, Experimental Values USA, stored over molecular sieves and distilled shortly before use.

Estimated Error: a b x2 x1 Temperature: 0.1 K. % 0.9870 0.01302 x1: 1.5 (relative error). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: Experimental Values (1) (S)-6-Methoxy-α-methyl- 168F.-Y. Yan, L. Chen, D.-Q. Liu,

2-naphthaleneacetic acid (Naproxen); L.-F. SiMa, M.-J. Chen, H. Shi, a b x2 x1 C14H14O3; [22204-53-1] and J.-X. Zhu, J. Chem. Eng. Data

(2) 2-Propanol; C3H8O; [67-63-0] 54, 1117 (2009). 0.9861 0.0139 a x2: mole fraction of component 2 in the saturated solution. Variables: Prepared by: b Temperature W. E. Acree, Jr. x1: mole fraction solubility of the solute.

Experimental Values Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. / a b T K x2 x1 Very few experimental details were provided. Excess solute and solvent were 278.15 0.9948 0.005232 allowed to equilibrate at constant temperature. Solubility of the dissolved 283.60 0.9934 0.006644 solute was determined by spectrophotometric measurements. 288.35 0.9920 0.008030 293.75 0.9902 0.009750 Source and Purity of Chemicals: 298.50 0.9882 0.011810 (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no 303.25 0.9857 0.014270 puriﬁcation details were provided. 308.65 0.9823 0.017690 (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, 313.40 0.9788 0.021180 Germany, no puriﬁcation details were provided. 318.80 0.9741 0.025920 320.15 0.9728 0.027240 Estimated Error: a Temperature: 0.1 K. x2: mole fraction of component 2 in the saturated solution. b x1: 2.5% (relative error). x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) (S)-6-Methoxy-α-methyl- 165C. R. Daniels, A. K. Charlton, Equilibrium jacketed glass vessel, thermostated circulating water bath, 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. electromagnetic stirrer, analytical balance, laser monitoring system. C H O ; [22204-53-1] Furman, A. C. Bilbrey, J. N. Love, Experimental solubilities were determined by a synthetic method. Preweighed 14 14 3 (2) 1-Butanol; C H O; [71-36-3] J. A. Garza, W. E. Acree, Jr., and amounts of solute and solvent and were placed in an equilibrium vessel, which 4 10 M. H. Abraham, Phys. Chem. Liq. was connected to a circulating constant-temperature water bath. The solution 42, 481 (2004). was stirred and small amounts of solute were incrementally added until no further solid dissolved. The dissolution of the solid was determined using laser Variables: Prepared by: monitoring. The total amount of solute dissolved was recorded. Experimental T/K ¼ 298.15 W. E. Acree, Jr. measurement was repeated three times.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Pharmaceutical Purity grade, Zhejian Chejiu Pharmaceutical Plant, China, dried in vacuo at 323 K for 24 h and stored in a a b desiccator before use. x2 x1 (2) 99.8+%, Analytical Reagent grade, Tianjin Chemical Reagent Company, 0.9858 0.01416 China, no purification information was given in the paper. a x2: mole fraction of component 2 in the saturated solution. bx : mole fraction solubility of the solute. Estimated Error: 1 Temperature: 0.05 K. x : 0.5% (relative error). 1 Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ Components: Original Measurements: visible spectrophotometer. 164 Excess solute and solvent were placed in amber glass bottles and allowed to (1) (S)-6-Methoxy-α-methyl- G. L. Perlovich, S. V. Kurkov, equilibrate for several days at constant temperature. Attainment of equilibrium 2-naphthaleneacetic acid (Naproxen); A. N. Kinchin, and A. Bauer- was verified by several repetitive measurements and by approaching C H O ; [22204-53-1] Brandl, Eur. J. Pharm. Biopharm. 14 14 3 equilibrium from supersaturation. Aliquots of saturated solutions were (2) 1-Butanol; C H O; [71-36-3] 57, 411 (2004). 4 10 transferred through a coarse filter into tared volumetric flasks, weighed, and Variables: Prepared by: diluted with methanol. Concentrations were determined by T/K ¼ 298.15 W. E. Acree, Jr. spectrophotometric measurements at 320 nm.

Source and Purity of Chemicals: Experimental Values (1) 99%, TCI America, Portland, Oregon, USA, was used as received. (2) 99.8+%, HPLC grade, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use. a b x2 x1 0.9914 0.00864 Estimated Error: a Temperature: 0.1 K. x2: mole fraction of component 2 in the saturated solution. b x1: 1.5% (relative error). x1: mole fraction solubility of the solute.

Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ (1) (S)-6-Methoxy-α-methyl- 165C. R. Daniels, A. K. Charlton, visible spectrophotometer. 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. Excess solute and solvent were placed in amber glass bottles and allowed to C H O ; [22204-53-1] Furman, A. C. Bilbrey, J. N. Love, 14 14 3 equilibrate for several days at constant temperature. Attainment of equilibrium [ ] J. A. Garza, W. E. Acree, Jr., and (2) 2-Butanol; C4H10O; 78-92-2 was verified by several repetitive measurements and by approaching M. H. Abraham, Phys. Chem. Liq. equilibrium from supersaturation. Aliquots of saturated solutions were 42, 481 (2004). transferred through a coarse filter into tared volumetric flasks, weighed, and Variables: Prepared by: diluted with methanol. Concentrations were determined by T/K ¼ 298.15 W. E. Acree, Jr. spectrophotometric measurements at 320 nm.

Source and Purity of Chemicals: Experimental Values (1) 99%, TCI America, Portland, Oregon, USA, was used as received. (2) 99+%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use. a b x2 x1 0.9858 0.01418 Estimated Error: Temperature: 0.1 K. a x2: mole fraction of component 2 in the saturated solution. x : 1.5% (relative error). b 1 x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: (1) (S)-6-Methoxy-α-methyl- 163G. L. Perlovich, S. V. Kurkov, Method/Apparatus/Procedure: 2-naphthaleneacetic acid (Naproxen); A. N. Kinchin, and A. Bauer- Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ C H O ; [22204-53-1] Brandl, Eur. J. Pharm. Biopharm. visible spectrophotometer. 14 14 3 [ ] 57, 411 (2004). Excess solute and solvent were placed in amber glass bottles and allowed to (2) 1-Pentanol; C5H12O; 71-41-0 equilibrate for several days at constant temperature. Attainment of equilibrium Variables: Prepared by: was verified by several repetitive measurements and by approaching T/K ¼ 298.15 W. E. Acree, Jr. equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse filter into tared volumetric flasks, weighed, and diluted with methanol. Concentrations were determined by Experimental Values spectrophotometric measurements at 320 nm.

Source and Purity of Chemicals: a b x2 x1 (1) 99%, TCI America, Portland, Oregon, USA, was used as received. 0.9853 0.0147 (2) 99+%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, a USA, stored over molecular sieves and distilled shortly before use. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: Temperature: 0.1 K. Auxiliary Information x1: 1.5% (relative error). Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate at constant temperature. Solubility of the dissolved Components: Original Measurements: solute was determined by spectrophotometric measurements. (1) (S)-6-Methoxy-α-methyl- 165C. R. Daniels, A. K. Charlton, 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. Source and Purity of Chemicals: [ ] C14H14O3; 22204-53-1 Furman, A. C. Bilbrey, J. N. Love, (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no (2) 2-Methyl-1-propanol; C4H10O; J. A. Garza, W. E. Acree, Jr., and puriﬁcation details were provided. [ ] 78-83-1 M. H. Abraham, Phys. Chem. Liq. (2) Purity not given, Analytical Reagent grade, Aldrich Chemical Company, 42, 481 (2004). Germany, no puriﬁcation details were provided. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Estimated Error: Temperature: 0.1 K.

x1: 2.5% (relative error).

Auxiliary Information Components: Original Measurements: (1) (S)-6-Methoxy-α-methyl- 165C. R. Daniels, A. K. Charlton, Method/Apparatus/Procedure: 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. Constant-temperature bath and an ultraviolet/visible spectrophotometer. C14H14O3; [22204-53-1] Furman, A. C. Bilbrey, J. N. Love, Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with

(2) 1-Pentanol; C5H12O; [71-41-0] J. A. Garza, W. E. Acree, Jr., and shaking for several days at constant temperature. After equilibrium was M. H. Abraham, Phys. Chem. Liq. attained, aliquots of saturated solutions were removed, filtered through 0.2 μm 42, 481 (2004). pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 233 nm. The reported Variables: Prepared by: solubility represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr. The density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions. Experimental Values Source and Purity of Chemicals: (1) Purity not given, USPA, France, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x a x b 2 1 source not specified, no purification details were provided. 0.9844 0.01561 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 0.1 K. x1: 2% (relative error).

Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ Components: Original Measurements: 165 visible spectrophotometer. (1) (S)-6-Methoxy-α-methyl- C. R. Daniels, A. K. Charlton, Excess solute and solvent were placed in amber glass bottles and allowed to 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. [ ] equilibrate for several days at constant temperature. Attainment of equilibrium C14H14O3; 22204-53-1 Furman, A. C. Bilbrey, J. N. Love, was verified by several repetitive measurements and by approaching (2) 2-Pentanol; C5H12O; [6032-29-7] J. A. Garza, W. E. Acree, Jr., and equilibrium from supersaturation. Aliquots of saturated solutions were M. H. Abraham, Phys. Chem. Liq. transferred through a coarse filter into tared volumetric flasks, weighed, and 42, 481 (2004). diluted with methanol. Concentrations were determined by Variables: Prepared by: spectrophotometric measurements at 320 nm. T/K ¼ 298.15 W. E. Acree, Jr.

Source and Purity of Chemicals: % (1) 99 , TCI America, Portland, Oregon, USA, was used as received. Experimental Values (2) 99+%, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use. a b x2 x1 Estimated Error: Temperature: 0.1 K. 0.9850 0.01504 a x1: 1.5% (relative error). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: (1) (S)-6-Methoxy-α-methyl-2- 164P. Bustamante, M. A. Peña, and Method/Apparatus/Procedure: naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ C14H14O3; [22204-53-1] 975 (1998). visible spectrophotometer. (2) 1-Pentanol; C5H12O; [71-41-0] Excess solute and solvent were placed in amber glass bottles and allowed to equilibrate for several days at constant temperature. Attainment of equilibrium Variables: Prepared by: was verified by several repetitive measurements and by approaching T/K ¼ 298.15 W. E. Acree, Jr. equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse filter into tared volumetric flasks, weighed, and Experimental Values diluted with methanol. Concentrations were determined by spectrophotometric measurements at 320 nm.

Source and Purity of Chemicals: x a x b,c 2 1 (1) 99%, TCI America, Portland, Oregon, USA, was used as received. 0.9683 0.03174 (2) 99+%, Acros Organics, USA, stored over molecular sieves and distilled a x2: mole fraction of component 2 in the saturated solution. shortly before use. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Estimated Error: Temperature: 0.1 K.

x1: 1.5% (relative error).

Auxiliary Information Components: Original Measurements: (1) (S)-6-Methoxy-α-methyl- 165C. R. Daniels, A. K. Charlton, Method/Apparatus/Procedure: 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. Constant-temperature bath and an UV/visible spectrophotometer. C14H14O3; [22204-53-1] Furman, A. C. Bilbrey, J. N. Love, Very few experimental details were provided. Excess solute and solvent were

(2) 3-Methyl-1-butanol; C5H12O; J. A. Garza, W. E. Acree, Jr., and allowed to equilibrate at constant temperature. Solubility of the dissolved [123-51-3] M. H. Abraham, Phys. Chem. Liq. solute was determined by spectrophotometric measurements. 42, 481 (2004). Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no T/K ¼ 298.15 W. E. Acree, Jr. purification details were provided. (2) Purity not given, Analytical Reagent grade, Aldrich Chemical Company, Experimental Values Germany, no purification details were provided. Estimated Error: a b Temperature: 0.1 K. x2 x1 x1: 2.5% (relative error). 0.9880 0.01204 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Components: Original Measurements: (1) (S)-6-Methoxy-α-methyl- 165C. R. Daniels, A. K. Charlton, Auxiliary Information 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. [ ] Method/Apparatus/Procedure: C14H14O3; 22204-53-1 Furman, A. C. Bilbrey, J. N. Love, Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ (2) 1-Hexanol; C6H14O; [111-27-3] J. A. Garza, W. E. Acree, Jr., and visible spectrophotometer. M. H. Abraham, Phys. Chem. Liq. Excess solute and solvent were placed in amber glass bottles and allowed to 42, 481 (2004). equilibrate for several days at constant temperature. Attainment of equilibrium Variables: Prepared by: was verified by several repetitive measurements and by approaching T/K ¼ 298.15 W. E. Acree, Jr. equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse filter into tared volumetric flasks, weighed, and diluted with methanol. Concentrations were determined by Experimental Values spectrophotometric measurements at 320 nm.

Source and Purity of Chemicals: a b x2 x1 (1) 99%, TCI America, Portland, Oregon, USA, was used as received. (2) 99%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, 0.9834 0.01663 a USA, stored over molecular sieves before use. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: Temperature: 0.1 K.

x1: 1.5% (relative error). Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in amber glass bottles and allowed to (1) (S)-6-Methoxy-α-methyl- 163G. L. Perlovich, S. V. Kurkov, equilibrate for several days at constant temperature. Attainment of equilibrium 2-naphthaleneacetic acid (Naproxen); A. N. Kinchin, and A. Bauer- was veriﬁed by several repetitive measurements and by approaching C14H14O3; [22204-53-1] Brandl, Eur. J. Pharm. Biopharm. equilibrium from supersaturation. Aliquots of saturated solutions were

(2) 1-Hexanol; C6H14O; [111-27-3] 57, 411 (2004). transferred through a coarse ﬁlter into tared volumetric ﬂasks, weighed, and diluted with methanol. Concentrations were determined by Variables: Prepared by: spectrophotometric measurements at 320 nm. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) 99%, TCI America, Portland, Oregon, USA, was used as received. Experimental Values (2) 99+%, Alfa Aesar, USA, stored over molecular sieves and distilled shortly before use. x a x b 2 1 Estimated Error: 0.9834 0.0166 Temperature: 0.1 K. a x % x2: mole fraction of component 2 in the saturated solution. 1: 1.5 (relative error). b x1: mole fraction solubility of the solute.

(2) 1-Heptanol; C7H16O; [111-70-6] 57, 411 (2004). Excess solute and solvent were placed in amber glass bottles and allowed to equilibrate for several days at constant temperature. Attainment of equilibrium Variables: Prepared by: was verified by several repetitive measurements and by approaching T/K ¼ 298.15 W. E. Acree, Jr. equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse filter into tared volumetric flasks, weighed, and diluted with methanol. Concentrations were determined by Experimental Values spectrophotometric measurements at 320 nm.

Source and Purity of Chemicals: x a x b 2 1 (1) 99%, TCI America, Portland, Oregon, USA, was used as received. 0.9799 0.0201 (2) 99+%, Alfa Aesar, USA, stored over molecular sieves and distilled shortly a x2: mole fraction of component 2 in the saturated solution. before use. b x1: mole fraction solubility of the solute. Estimated Error: Temperature: 0.1 K. % Auxiliary Information x1: 1.5 (relative error). Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were allowed to equilibrate at constant temperature. Solubility of the dissolved Components: Original Measurements: α 163 solute was determined by spectrophotometric measurements. (1) (S)-6-Methoxy- -methyl- G. L. Perlovich, S. V. Kurkov, 2-naphthaleneacetic acid (Naproxen); A. N. Kinchin, and A. Bauer- [ ] Source and Purity of Chemicals: C14H14O3; 22204-53-1 Brandl, Eur. J. Pharm. Biopharm. [ ] (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no (2) 1-Octanol; C8H18O; 111-87-5 57, 411 (2004). puriﬁcation details were provided. Variables: Prepared by: (2) Purity not given, Analytical Reagent grade, Sigma Chemical Company, no T/K ¼ 298.15 W. E. Acree, Jr. puriﬁcation details were provided.

Estimated Error: Experimental Values Temperature: 0.1 K.

x1: 2.5% (relative error). a b x2 x1 0.9854 0.0146 ax : mole fraction of component 2 in the saturated solution. Components: Original Measurements: 2 bx : mole fraction solubility of the solute. (1) (S)-6-Methoxy-α-methyl- 165C. R. Daniels, A. K. Charlton, 1 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. C H O ; [22204-53-1] Furman, A. C. Bilbrey, J. N. Love, 14 14 3 Auxiliary Information (2) 1-Heptanol; C7H16O; [111-70-6] J. A. Garza, W. E. Acree, Jr., and M. H. Abraham, Phys. Chem. Liq. Method/Apparatus/Procedure: 42, 481 (2004). Constant-temperature bath and an UV/visible spectrophotometer. Very few experimental details were provided. Excess solute and solvent were Variables: Prepared by: allowed to equilibrate at constant temperature. Solubility of the dissolved T/K ¼ 298.15 W. E. Acree, Jr. solute was determined by spectrophotometric measurements.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, Sigma Chemical Company, no x a x b 2 1 puriﬁcation details were provided. 0.9809 0.01909 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 0.1 K. x1: 2.5% (relative error).

Auxiliary Information Components: Original Measurements: (1) (S)-6-Methoxy-α-methyl- 165C. R. Daniels, A. K. Charlton, Method/Apparatus/Procedure: 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N. Constant-temperature water bath and an UV/visible spectrophotometer. C14H14O3; [22204-53-1] Furman, A. C. Bilbrey, J. N. Love, Excess solute and solvent were placed in stoppered glass ﬂasks and allowed to

(2) 1-Octanol; C8H18O; [111-87-5] J. A. Garza, W. E. Acree, Jr., and equilibrate in a constant-temperature water bath for at least three days. Once M. H. Abraham, Phys. Chem. Liq. equilibrium had been attained, an aliquot of the saturated solution was 42, 481 (2004). removed and filtered in order to remove insoluble particles. The concentration of the dissolved drug was determined by spectrophotometric analysis. The Variables: Prepared by: densities of the saturated solutions were measured in order to convert the T/K ¼ 298.15 W. E. Acree, Jr. measured concentrations in mol dm3 to mole fraction solubilities. The reported mole fraction solubilities represent the average of three experimental Experimental Values measurements. Source and Purity of Chemicals: (1) Purity not given, USP, no purification details were provided in the paper. x a x b 2 1 (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, no 0.9840 0.01604 purification details were given in the paper. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: Temperature: 0.05 K (estimated by compiler).

x1: 2.0% (relative error). Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ visible spectrophotometer. Components: Original Measurements: 164 Excess solute and solvent were placed in amber glass bottles and allowed to (1) (S)-6-Methoxy-α-methyl- P. Bustamante, M. A. Peña, and equilibrate for several days at constant temperature. Attainment of equilibrium 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, [ ] was verified by several repetitive measurements and by approaching C14H14O3; 22204-53-1 975 (1998). [ ] equilibrium from supersaturation. Aliquots of saturated solutions were (2) 1-Octanol; C8H18O; 111-87-5 transferred through a coarse filter into tared volumetric flasks, weighed, and Variables: Prepared by: diluted with methanol. Concentrations were determined by T/K ¼ 298.15 W. E. Acree, Jr. spectrophotometric measurements at 320 nm.

Source and Purity of Chemicals: Experimental Values (1) 99%, TCI America, Portland, Oregon, USA, was used as received. (2) 99+%, anhydrous, Aldrich Chemical Company, Milwaukee, Wisconsin, USA, stored over molecular sieves and distilled shortly before use. a b,c x2 x1 Estimated Error: 0.9834 0.01664 a Temperature: 0.1 K. x2: mole fraction of component 2 in the saturated solution. b x1: 1.5% (relative error). x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: (1) (S)-6-Methoxy-α-methyl- 167C. P. Mora and F. Martínez, Method/Apparatus/Procedure: 2-naphthaleneacetic acid (Naproxen); Fluid Phase Equilib. 255,70 Constant-temperature bath and an ultraviolet/visible spectrophotometer. C14H14O3; [22204-53-1] (2007). Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with (2) 1-Octanol; C8H18O; [111-87-5] shaking for several days at constant temperature. After equilibrium was attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 μm Variables: Prepared by: pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were Temperature W. E. Acree, Jr. determined by spectrophotometric measurements at 233 nm. The reported solubility represents the average of at least three independent determinations. Experimental Values The density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions.

Source and Purity of Chemicals: T/K x a x b 2 1 (1) Purity not given, USPA, France, no purification details were provided. 293.15 0.9866 0.01342 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 298.15 0.9826 0.01742 source not specified, no purification details were provided. 303.15 0.9798 0.02024 308.15 0.9750 0.02499 Estimated Error: 313.15 0.9705 0.02949 Temperature: 0.1 K. a % x2: mole fraction of component 2 in the saturated solution. x1: 2 (relative error). b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: (1) (S)-6-Methoxy-α-methyl- 60A. Fini, M. Laus, I. Orienti, and Method/Apparatus/Procedure: 2-naphthaleneacetic acid (Naproxen); V. Zecchi, J. Pharm. Sci. 75,23 Constant-temperature bath, calorimetric thermometer, and an ultraviolet/ C14H14O3; [22204-53-1] (1986). visible spectrophotometer. (2) 1-Octanol; C8H18O; [111-87-5] Excess solute and solvent were placed in amber glass bottles and allowed to equilibrate for several days at constant temperature. Attainment of equilibrium Variables: Prepared by: was verified by several repetitive measurements and by approaching Temperature W. E. Acree, Jr. equilibrium from supersaturation. Aliquots of saturated solutions were transferred through a coarse filter into tared volumetric flasks, weighed, and Experimental Values diluted with methanol. Concentrations were determined by spectrophotometric measurements at 320 nm.

Source and Purity of Chemicals: T/K c a 1 (1) 99%, TCI America, Portland, Oregon, USA, was used as received. 278.2 0.061 (2) 99+%, Alfa Aesar, USA, stored over molecular sieves and distilled shortly 298.2 0.116 before use. 310.2 0.157 a 3 c1: molar solubility of the solute in units of mol dm . Estimated Error: Temperature: 0.1 K.

x1: 1.5% (relative error). Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath, analytical balance, and an UV/visible spectrophotometer. Components: Original Measurements: 170 Excess solute and solvent were placed in a sealed container and allowed to (1) (S)-6-Methoxy-α-methyl- M. D. C. Claramonte, A. P. equilibrate with stirring at constant temperature. An aliquot of the saturated 2-naphthaleneacetic acid (Naproxen); Vialard, and F. G. Vilchez, Int. J. [ ] solution was removed, filtered through a 0.22 μm pore membrane, and diluted C14H14O3; 22204-53-1 Pharm. 94, 23 (1993). quantitatively for spectroscopic analysis. (2) (Z)-Octadec-9-en-1-ol (Oleyl alcohol); C18H36O; [143-28-2] Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, chemical source not specified, was recrystallized from T/K ¼ 298 K W. E. Acree, Jr. suitable solvent before use. (2) Purity not given, chemical source not specified, no purification details were provided in the paper. Experimental Values

Estimated Error: Temperature: 0.2 K (estimated by compiler). a b,c x2 x1 c : 3% (relative error). 1 0.9797 0.0203 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. cThe data were reported in the paper in graphical format, and the mole fraction Components: Original Measurements: solubility was interpolated from an enlarged copy of the ﬁgure given in the (1) (S)-6-Methoxy-α-methyl- 165C. R. Daniels, A. K. Charlton, manuscript. 2-naphthaleneacetic acid (Naproxen); R. W. Wold, E. Pustejovsky, A. N.

C14H14O3; [22204-53-1] Furman, A. C. Bilbrey, J. N. Love, (2) 1-Decanol; C H O; [112-30-1] J. A. Garza, W. E. Acree, Jr., and 10 22 Auxiliary Information M. H. Abraham, Phys. Chem. Liq. 42, 481 (2004). Method/Apparatus/Procedure: Constant-temperature water bath and an UV/visible spectrophotometer. Variables: Prepared by: The equilibration method was similar to that described elsewhere [M. D. T/K ¼ 298.15 W. E. Acree, Jr. Contreras, A. Parera, and F. Girela, An. Real Acad. Farm. 58, 563 (1992)], except that the solute was added to the solvent at 308 K until a precipitate Experimental Values appeared. The samples were then sealed and mechanically shaken at 298 K. After equilibrium was obtained, a weighed aliquot of the saturated solution was removed and diluted with ethanol for spectroscopic analysis at either 271 or a b 316 nm. x2 x1 0.9837 0.01630 Source and Purity of Chemicals: a x2: mole fraction of component 2 in the saturated solution. (1) Purity not given, Elmu S.A., used as received. b x1: mole fraction solubility of the solute. (2) Purity not given, Henkel, used as received.

Estimated Error: Temperature: 0.2 K (estimated by compiler).

x1: 5% (relative error, estimated by compiler).

Source and Purity of Chemicals: x a x b,c 2 1 (1) Purity not given, USPA, France, no purification details were provided. 0.9962 0.003849 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a x2: mole fraction of component 2 in the saturated solution. source not specified, no purification details were provided. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Estimated Error: Temperature: 0.1 K.

x1: 2% (relative error). Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with Components: Original Measurements: 111 shaking for several days at constant temperature. After equilibrium was (1) (S)-6-Methoxy-α-methyl- Y. J. Manrique, D. P. Pacheco, attained, aliquots of saturated solutions were removed, centrifuged, ﬁltered 2-naphthaleneacetic acid (Naproxen); and F. Martínez, J. Solution [ ] through 0.2 μm pore size membranes, and then diluted with 96% ethanol (v/v). C14H14O3; 22204-53-1 Chem. 37, 165 (2008). Concentrations were determined by spectrophotometric measurements at (2) 1,2-Propanediol; C3H8O2; 233 nm. The reported solubility represents the average of at least three [57-55-6] independent determinations. The density of the saturated solution was Variables: Prepared by: determined in order to convert the measured molar solubilities in units of Temperature W. E. Acree, Jr. mol dm3 to mole fractions.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, USPA, France, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. a b T/K x2 x1 Estimated Error: 293.15 0.9939 0.00614 Temperature: 0.1 K. 298.15 0.9927 0.00726 x : 2% (relative error). 303.15 0.9914 0.00861 1 308.15 0.9894 0.01060 313.15 0.9875 0.01250 a x2: mole fraction of component 2 in the saturated solution. bx : mole fraction solubility of the solute. Components: Original Measurements: 1 (1) (S)-6-Methoxy-α-methyl- 164P. Bustamante, M. A. Peña, and 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, Auxiliary Information C14H14O3; [22204-53-1] 975 (1998). (2) 1,2-Propanediol; C3H8O2; Method/Apparatus/Procedure: [57-55-6] Constant-temperature water bath and an UV/visible spectrophotometer. Excess solute and solvent were placed in stoppered glass flasks and allowed to Variables: Prepared by: equilibrate at 313.15 K in a constant-temperature water bath for at least five T/K ¼ 298.15 W. E. Acree, Jr. days. Once equilibrium had been attained, an aliquot of the saturated solution was removed and filtered in order to remove insoluble particles. The Experimental Values concentration of the dissolved drug was determined by spectrophotometric analysis. The temperature of the water bath was then reduced by 5 K, and the samples re-equilibrated at 308.15 K for an additional two days to allow precipitation of the excess drug. The amount of dissolved drug at the lower x a x b,c 2 1 temperature was determined by spectroscopic analysis as described above. The 0.9923 0.007670 procedure was repeated until 293.15 K was reached. The densities of the a x2: mole fraction of component 2 in the saturated solution. saturated solutions were measured in order to convert the measured b 3 x1: mole fraction solubility of the solute. concentrations in mol dm to mole fraction solubilities. The reported mole c Experimental value was reported in the paper as ln x1. fraction solubilities represent the average of three experimental measurements.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, USP, no puriﬁcation details were provided in the paper. (2) Purity not given, USP, no puriﬁcation details were given in the paper. a b T/K x2 x1 Estimated Error: 293.15 0.9559 0.0441 Temperature: 0.05 K (estimated by compiler). 298.15 0.9496 0.0504 x : 2.0% (relative error). 1 303.15 0.9435 0.0565 308.15 0.9356 0.0644 313.15 0.9271 0.0729 ax : mole fraction of component 2 in the saturated solution. Components: Original Measurements: 2 bx : mole fraction solubility of the solute. (1) (S)-6-Methoxy-α-methyl- 164P. Bustamante, M. A. Peña, and 1 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, C H O ; [22204-53-1] 975 (1998). 14 14 3 Auxiliary Information (2) 1,2,3-Propanetriol (Glycerol);

C3H8O3; [56-81-5] Method/Apparatus/Procedure: Thermostatic mechanical shaker and an analytical balance. Variables: Prepared by: Excess solute and solvent were placed in stoppered glass flasks and allowed to T/K ¼ 298.15 W. E. Acree, Jr. equilibrate in a thermostatic mechanical shaker at 313.15 K for at least three days. Once equilibrium had been attained, an aliquot of the saturated solution was removed and filtered in order to remove insoluble particles. The Experimental Values concentration of the dissolved drug was determined by weighing an aliquot of the saturated filtered solution, and then allowing the solvent to evaporate. The mole fraction solubility was calculated from the mass of the solid residue and x a x b,c 2 1 the mass of the sample taken for analysis. Once the solubility was determined 0.9994 0.000558 at 313.15 K, the temperature was decreased by 5 K and stabilized at 308.15 K a x2: mole fraction of component 2 in the saturated solution. for two days to allow the excess dissolved drug to precipitate at this lower b x1: mole fraction solubility of the solute. temperature. An aliquot of the new saturated solution was removed, filtered, c Experimental value was reported in the paper as ln x1. and the solvent evaporated as before. The procedure was repeated by decreasing the temperature in 5 K increments to reach 293.15 K. The reported mole fraction solubilities represent the average of three experimental Auxiliary Information measurements. / / Method Apparatus Procedure: Source and Purity of Chemicals: / Constant-temperature bath and an ultraviolet visible spectrophotometer. (1) Purity not given, USP, no purification details were provided in the paper. Excess solute and solvent were placed in flasks and allowed to equilibrate with (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, no shaking for several days at constant temperature. After equilibrium was purification details were given in the paper. attained, aliquots of saturated solutions were removed, centrifuged, filtered μ % / through 0.2 m pore size membranes, and then diluted with 96 ethanol (v v). Estimated Error: Concentrations were determined by spectrophotometric measurements at Temperature: 0.1 K (estimated by compiler). 233 nm. The reported solubility represents the average of at least three x1: 1.0% (relative error). independent determinations. The density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions.

Source and Purity of Chemicals: Components: Original Measurements: 168 (1) Purity not given, USPA, France, no purification details were provided. (1) (S)-6-Methoxy-α-methyl- F.-Y. Yan, L. Chen, D.-Q. Liu, (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 2-naphthaleneacetic acid (Naproxen); L.-F. SiMa, M.-J. Chen, H. Shi, [ ] source not specified, no purification details were provided. C14H14O3; 22204-53-1 and J.-X. Zhu, J. Chem. Eng. Data (2) Propanone; C3H6O; [67-64-1] 54, 1117 (2009). Estimated Error: Variables: Prepared by: Temperature: 0.1 K. Temperature W. E. Acree, Jr. x1: 2% (relative error).

21.8. Naproxen solubility data in ketones

Components: Original Measurements: (1) (S)-6-Methoxy-α-methyl- 166D. M. Arago´n, J. E. Rosas, and 2-naphthaleneacetic acid (Naproxen); F. Martínez, Phys. Chem. Liq. 48,

C14H14O3; [22204-53-1] 437 (2010). (2) Propanone; C3H6O; [67-64-1] Variables: Prepared by: Temperature W. E. Acree, Jr.

Experimental Values Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. T/K x a x b 2 1 Excess solute and solvent were placed in flasks and allowed to equilibrate with 278.25 0.9991 0.000946 shaking for several days at constant temperature. After equilibrium was 283.60 0.9986 0.001374 attained, aliquots of saturated solutions were removed, filtered through 0.2 μm 288.30 0.9983 0.001645 pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were 293.05 0.9978 0.002162 determined by spectrophotometric measurements at 233 nm. The reported 298.45 0.9972 0.002811 solubility represents the average of at least three independent determinations. 303.20 0.9964 0.003617 The density of the saturated solution was determined in order to convert the 308.70 0.9954 0.004590 measured molar solubilities in units of mol dm3 to mole fractions. 313.45 0.9941 0.005919 318.10 0.9928 0.007206 Source and Purity of Chemicals: 320.15 0.9916 0.008403 (1) Purity not given, USPA, France, no purification details were provided. a (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x2: mole fraction of component 2 in the saturated solution. b source not specified, no purification details were provided. x1: mole fraction solubility of the solute.

Estimated Error: Auxiliary Information Temperature: 0.1 K. x1: 2% (relative error). Method/Apparatus/Procedure: Equilibrium jacketed glass vessel, thermostated circulating water bath, electromagnetic stirrer, analytical balance, laser monitoring system. Experimental solubilities were determined by a synthetic method. Preweighed amounts of solute and solvent and were placed in an equilibrium vessel, which Components: Original Measurements: α 164 ñ was connected to a circulating constant-temperature water bath. The solution (1) (S)-6-Methoxy- -methyl- P. Bustamante, M. A. Pe a, and was stirred and small amounts of solute were incrementally added until no 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, [ ] further solid dissolved. The dissolution of the solid was determined using laser C14H14O3; 22204-53-1 975 (1998). [ ] monitoring. The total amount of solute dissolved was recorded. Experimental (2) Acetophenone; C8H8O; 98-86-2 measurement was repeated three times. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Pharmaceutical Purity grade, Zhejian Chejiu Pharmaceutical Plant, China, dried in vacuo at 323 K for 24 h and stored in a Experimental Values desiccator before use. (2) 99.8+%, Analytical Reagent grade, Tianjin Chemical Reagent Company, a b,c China, no puriﬁcation information was given in the paper. x2 x1 0.7047 0.2953 Estimated Error: a Temperature: 0.05 K. x2: mole fraction of component 2 in the saturated solution. bx x1: 0.5% (relative error). 1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

C14H14O3; [22204-53-1] 975 (1998). Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with (2) Propanone; C3H6O; [67-64-1] shaking for several days at constant temperature. After equilibrium was attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 μm Variables: Prepared by: pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were T/ ¼ K 298.15 W. E. Acree, Jr. determined by spectrophotometric measurements at 233 nm. The reported solubility represents the average of at least three independent determinations. The density of the saturated solution was determined in order to convert the Experimental Values measured molar solubilities in units of mol dm 3 to mole fractions.

Source and Purity of Chemicals: x a x b,c 2 1 (1) Purity not given, USPA, France, no purification details were provided. 0.9308 0.06922 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a source not specified, no purification details were provided. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Estimated Error: Experimental value was reported in the paper as ln x1. Temperature: 0.1 K.

x1: 2% (relative error).

21.9. Naproxen solubility data in miscellaneous Experimental Values organic solvents

a b,c x2 x1 0.9847 0.01530 Components: Original Measurements: 166 a (1) (S)-6-Methoxy-α-methyl- D. M. Arago´n, J. E. Rosas, and x2: mole fraction of component 2 in the saturated solution. b 2-naphthaleneacetic acid (Naproxen); F. Martínez, Phys. Chem. Liq. 48, x1: mole fraction solubility of the solute. cExperimental value was reported in the paper as ln x . C14H14O3; [22204-53-1] 437 (2010). 1 (2) Ethanenitrile; C2H3N; [75-05-8]

Variables: Prepared by: Auxiliary Information Temperature W. E. Acree, Jr. Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Experimental Values Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for several days at constant temperature. After equilibrium was attained, aliquots of saturated solutions were removed, filtered through 0.2 μm a b pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were T/K x2 x1 determined by spectrophotometric measurements at 233 nm. The reported 293.15 0.9951 0.00491 solubility represents the average of at least three independent determinations. 298.15 0.9936 0.00642 The density of the saturated solution was determined in order to convert the 303.15 0.9917 0.00829 measured molar solubilities in units of mol dm 3 to mole fractions. 308.15 0.9895 0.01051 313.15 0.9871 0.01286 Source and Purity of Chemicals: a x2: mole fraction of component 2 in the saturated solution. (1) Purity not given, USPA, France, no purification details were provided. b x1: mole fraction solubility of the solute. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided.

Auxiliary Information Estimated Error: Method/Apparatus/Procedure: Temperature: 0.1 K. % Thermostatic mechanical shaker and an analytical balance. x1: 2 (relative error). Excess solute and solvent were placed in stoppered glass flasks and allowed to equilibrate in a thermostatic mechanical shaker at 313.15 K for at least three days. Once equilibrium had been attained, an aliquot of the saturated solution was removed and filtered in order to remove insoluble particles. The Components: Original Measurements: concentration of the dissolved drug was determined by weighing an aliquot of (1) (S)-6-Methoxy-α-methyl- 164P. Bustamante, M. A. Peña, and the saturated filtered solution, and then allowing the solvent to evaporate. The 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50,

mole fraction solubility was calculated from the mass of the solid residue and C14H14O3; [22204-53-1] 975 (1998). the mass of the sample taken for analysis. Once the solubility was determined (2) Propanoic acid; C3H6O2; at 313.15 K, the temperature was decreased by 5 K and stabilized at 308.15 K [79-09-4] for two days to allow the excess dissolved drug to precipitate at this lower Variables: Prepared by: temperature. An aliquot of the new saturated solution was removed, ﬁltered, T/K ¼ 298.15 W. E. Acree, Jr. and the solvent evaporated as before. The procedure was repeated by decreasing the temperature in 5 K increments to reach 293.15 K. The reported mole fraction solubilities represent the average of three experimental Experimental Values measurements.

Source and Purity of Chemicals: x a x b,c (1) Purity not given, USP, no puriﬁcation details were provided in the paper. 2 1 (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, no 0.9713 0.02871 a puriﬁcation details were given in the paper. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: c Experimental value was reported in the paper as ln x1. Temperature: 0.1 K (estimated by compiler).

x1: 1.0% (relative error). Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with α 164 ñ (1) (S)-6-Methoxy- -methyl- P. Bustamante, M. A. Pe a, and shaking for several days at constant temperature. After equilibrium was 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 μm [ ] C14H14O3; 22204-53-1 975 (1998). pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were [ ] (2) Ethanoic acid; C2H4O2; 64-19-7 determined by spectrophotometric measurements at 233 nm. The reported Variables: Prepared by: solubility represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr. The density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions.

Source and Purity of Chemicals: x a x b,c 2 1 (1) Purity not given, USPA, France, no purification details were provided. 0.9935 0.006540 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a x2: mole fraction of component 2 in the saturated solution. source not specified, no purification details were provided. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Estimated Error: Temperature: 0.1 K.

x1: 2% (relative error). Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with Components: Original Measurements: 64 shaking for several days at constant temperature. After equilibrium was (1) (S)-6-Methoxy-α-methyl- B. P. Wenkers and B. C. attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 μm 2-naphthaleneacetic acid (Naproxen); Lippold, J. Pharm. Sci. 88, 1326 [ ] pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were C14H14O3; 22204-53-1 (1999). determined by spectrophotometric measurements at 233 nm. The reported (2) Mineral oil solubility represents the average of at least three independent determinations. Variables: Prepared by: The density of the saturated solution was determined in order to convert the T/K ¼ 305.15 W. E. Acree, Jr. measured molar solubilities in units of mol dm3 to mole fractions.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, USPA, France, no purification details were provided. ¼ (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical The measured solubility was reported to be c1 0.000342 3 source not specified, no purification details were provided. mol dm .

Estimated Error: Auxiliary Information Temperature: 0.1 K. / / x1: 2% (relative error). Method Apparatus Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Excess solute and solvent were placed in sealed bottles and allowed to equilibrate at a constant temperature with rotation for 24 h. Aliquots of saturated solutions were removed, filtered through a 0.45 μm cellulose acetate Components: Original Measurements: membrane filter, and diluted quantitatively for spectroscopic analysis. (1) (S)-6-Methoxy-α-methyl- 164P. Bustamante, M. A. Peña, and Reported values represent the average of three experimental measurements. 2-naphthaleneacetic acid (Naproxen); J. Barra, J. Pharm. Pharamcol. 50, C H O ; [22204-53-1] 975 (1998). 14 14 3 Source and Purity of Chemicals: (2) N,N-Dimethylformamide; (1) Purity not given, PharmActiv, Feldkirchen-Westerham, Germany, no C H NO; [64-19-7] 3 7 purification details were provided. Variables: Prepared by: (2) Purity not given, Bayer Leverkusen and Rhone Poulenc Rorer, Cologne, T/K ¼ 298.15 W. E. Acree, Jr. Germany, no purification details were provided.

Estimated Error: Temperature: 0.5 K (estimated by compiler).

c1: 10% (relative error).

Estimated Error: Components: Original Measurements: Temperature: 2 K (estimated by compiler). (1) (S)-6-Methoxy-α-methyl- 92D. B. Larsen, H. Parshad, K. c1: 10% (relative error, estimated by compiler). 2-naphthaleneacetic acid (Naproxen); Fredholt, and C. Larsen, Int. J.

C14H14O3; [22204-53-1] Pharm. 232, 107 (2002). (2) Castor oil Variables: Prepared by: 21.10. Naproxen solubility data in binary organic / ¼ T K 310.15 W. E. Acree, Jr. solvent mixtures

Experimental Values ¼ Components: Original Measurements: The measured solubility was reported to be c1 0.125 117 3 (1) (S)-6-Methoxy-α-methyl- D. P. Pacheco, Y. J. Manrique, mol dm . 2-naphthaleneacetic acid (Naproxen); and F. Martinez, Fluid Phase

C14H14O3; [22204-53-1] Equilib. 262, 23 (2007). Auxiliary Information (2) Ethanol; C2H6O; [64-17-5] (3) 1,2-Propanediol; C H O ; Method/Apparatus/Procedure: 3 8 2 [57-55-6] Constant-temperature bath and an UV/visible spectrophotometer. Excess solute and solvent were placed in a screw-capped test tube and allowed Variables: Prepared by: to equilibrate at a constant temperature with rotation for 24 h. Aliquots of Temperature; Solvent composition W. E. Acree, Jr. saturated solutions were removed, centrifuged at 15 000 rpm for 10 min, and diluted quantitatively with ethanol for spectroscopic analysis. Experimental Values Source and Purity of Chemicals: (1) Purity not given, chemical source not specified, no purification details were provided. / ðsÞa b T K w2 x1 (2) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no 293.15 0.00 0.00614 purification details were provided. 293.15 0.20 0.00848 293.15 0.40 0.0104 Estimated Error: 293.15 0.60 0.0117 Temperature: 0.5 K. 293.15 0.80 0.0125 c : 10% (relative error, estimated by compiler). 1 293.15 1.00 0.0124 298.15 0.00 0.00726 298.15 0.20 0.00986 298.15 0.40 0.0126 Components: Original Measurements: 298.15 0.60 0.0141 (1) (S)-6-Methoxy-α-methyl-2- 65E. Rytting, K. A. Lentz, X.-Q. 298.15 0.80 0.0149 naphthaleneacetic acid (Naproxen); Chen, F. Qian, and S. Venkatesh, 298.15 1.00 0.0149 C14H14O3; [22204-53-1] AAPS J. 7, E78 (2005). 303.15 0.00 0.00861 (2) Polyethylene glycol 400 303.15 0.20 0.0125 (PEG 400) 303.15 0.40 0.0159 303.15 0.60 0.0179 Variables: Prepared by: 303.15 0.80 0.0199 T/K ¼ 296 W. E. Acree, Jr. 303.15 1.00 0.0198 308.15 0.00 0.0106 Experimental Values 308.15 0.20 0.0149 308.15 0.40 0.0187 The measured solubility was reported to be c1 ¼ 0.718 308.15 0.60 0.0207 mol dm 3. 308.15 0.80 0.0221 308.15 1.00 0.0232 313.15 0.00 0.0125 Auxiliary Information 313.15 0.20 0.0179 Method/Apparatus/Procedure: 313.15 0.40 0.0231 Centrifuge and a high-performance liquid chromatograph equipped with a 313.15 0.60 0.0271 photo-diode array detector. 313.15 0.80 0.0293 Excess solute and solvent were placed in sealed vials and shaken at ambient 313.15 1.00 0.0284 room temperature for at least 24 h. The vials were then centrifuged for 15 min ð Þ aw s : initial mass fraction of component 2 in the binary solvent mixture. to separate the saturated solution from the excess solute. The supernatant was 2 bx : mole fraction solubility of the solute. then filtered and the concentration of the dissolved solute determined by high- 1 performance liquid chromatographic analysis.

Source and Purity of Chemicals: (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, USA, no puriﬁcation details were provided. (2) Purity not given, J. T. Baker Chemical Company, Phillipsburg, New Jersey, USA, no puriﬁcation details were provided.

Auxiliary Information TABLE 14. Parameters of the Modified Apelblat equation for describing the solubility of niflumic acid in organic solvents Method/Apparatus/Procedure: Constant-temperature water bath and an UV/visible spectrophotometer. MARD Excess solute and solvent were placed in stoppered glass flasks and allowed to Solvent T/K ABC(%) equilibrate at 313.15 K in a constant-temperature water bath for at least five Hexanea 293–315 71.358 114.277 10.526 1.1 days. Once equilibrium had been attained, an aliquot of the saturated solution Ethyl ethanoateb 289–308 20.496 115.461 2.884 0.4 was removed and filtered in order to remove insoluble particles. The Ethanolb 283–308 58.915 114.603 9.549 1.7 concentration of the dissolved drug was determined by spectrophotometric Ethanolc 289–321 56.561 114.652 9.081 7.9 analysis. The temperature of the water bath was then reduced by 5 K, and the 1-Octanola 293–315 52.996 113.928 8.616 0.5 samples re-equilibrated at 308.15 K for an additional two days to allow 1-Octanolc 282–356 51.768 114.762 8.340 3.8 precipitation of the excess drug. The amount of dissolved drug at the lower aData set of both Surov et al.169 and Perlovich et al.87 temperature was determined by spectroscopic analysis as described above. The b 173 procedure was repeated until 293.15 K was reached. The densities of the Data set of Bustamante et al. c 89 saturated solutions were measured in order to convert the measured Data set of Domanska et al. concentrations in mol dm3 to mole fraction solubilities. The reported mole fraction solubilities represent the average of three experimental Performing this conversion, one finds that the molar solubi- measurements. The densities of the saturated solutions were measured in order 171 ¼ ¼ 3 lities determined by Bustamante et al. of c1 0.01580, c1 to convert the measured molar solubilities (in units of mol dm ) to mole ¼ fraction solubilities 0.1854, and c1 0.1286 for chloroform, methanol, and ethanol differ significantly from the respective values of c1 ¼ 0.00539, 172 Source and Purity of Chemicals: c1 ¼ 0.2055, and c1 ¼ 0.1063 determined by Pinvidic et al. It (1) Purity not given, USP, no purification details were given in the paper. is also noted that Bustamante et al.173 later determined the (2) Absolute, Analytical Reagent grade, Merck Chemical Company, Germany, solubility of niflumic acid in ethanol at several temperatures, no purification details were given in the paper. ¼ (3) Purity not given, USP, no purification details were given in the paper. and their later value of x1 0.0163 at 298 K differs from their earlier value of x1 ¼ 0.01442 by slightly more than 10 relative Estimated Error: percent. Large deviations are also noted in two sets of solu- Temperature: 0.05 K. ð Þ bility data determined by Bustamante et al. for niflumic acid w s : 0.01. 2 dissolved in ethyl ethanoate, x1 ¼ 0.0000910 (Ref. 171) versus x1: 3% (relative error). x1 ¼ 0.0254 (Ref. 173). Currently there are no polymorphic modifications known for niflumic acid175 that would explain the large deviations between the independent sets of experimental solubility measurements. 22. Solubility of Niflumic Acid in Organic 86,87,89,173 Solvents There have been four experimental studies reporting how the solubility of niflumic acid varied with tempera- 22.1. Critical evaluation of experimental solubility ture. Surov et al.86 and Perlovich et al.87 both examined the data solubility of niflumic acid in hexane and 1-octanol. Domanska et al.89 measured niflumic acid solubilities in ethanol and 1- Niflumic acid (more formally named 2-[[3-(trifluoro- ] ] octanol using a dynamic method that recorded the temperature methyl)phenyl amino -3-pyridinecarboxylic acid) is an at which the last crystals of the solid solute disappeared. analgesic and NSAID used in the treatment of rheumatoid Bustamante et al.173 reported niflumic acid solubilities in ethyl arthritis and arthrosis. There have been several published ethanoate and ethanol in the temperature range between 283 studies86,87,89,171–174 involving the solubility of niflumic acid 171 and 308 K. The internal consistency of the six datasets was in organic solvents. Most notably, Bustamante et al. mea- assessed by curve-fitting the measured mole-fraction solubi- sured the mole fraction solubility of niflumic acid in 22 lity data to Eq. (8). The values of the equation coefficients (A, different organic solvents, including two saturated hydrocar- B, and C) are given in Table 14, along with the mean absolute bons (heptane and cyclohexane), one aromatic hydrocarbon relative deviation. (benzene), one alkyl alkanoate (ethyl ethanoate), one dialkyl The experimental solubility data for niflumic acid in organic ′ ether (1,1 -oxybisethane) and one cyclic ether (1,4-dioxane), solvents are given in Secs. 22.2–22.10. two chloroalkanes (trichloromethane and 1,2-dichloroethane) and one chlorinated aromatic hydrocarbon (chlorobenzene), seven alcohols (methanol, ethanol, 1-pentanol, 1-octanol, 1,2- 22.2. Niflumic acid solubility data in saturated ethanediol, 1,2-propanediol, and 1,2,3-propanetriol), one alka- hydrocarbons (including cycloalkanes) none (propanone) and one aromatic ketone (acetophenone), and four miscellaneous organic solvents (ethanoic acid, propanoic acid, formamide, and N,N-dimethylformamide) at Components: Original Measurements: [[ ] 86 298 K and atmospheric pressure. Pinvidic et al.172 determined (1) 2- 3-(Trifluoromethyl)phenyl - A. O. Surov, P. Szterner, W. amino]-3-pyridinecarboxylic acid Zielenkiewicz, and G. L. the molar solubility of niflumic acid in trichloromethane, (Niflumic acid); C13H9F3N2O2; Perlovich, J. Pharm. Biomed. methanol, and ethanol at 298 K. The solubility is sufficiently [4394-00-7] Anal. 50, 831 (2009). 87 small in these three solvents that one should be able to (2) Hexane; C6H14; [110-54-3] G. L. Perlovich, A. O. Surov, reasonably convert the observed mole fractions to molarities and A. Bauer-Brandl, J. Pharm. simply by dividing by the molar volume of the solvent. Biomed. Anal. 45, 679 (2007).

Variables: Prepared by: Auxiliary Information Temperature W. E. Acree, Jr. Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Experimental Values Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were a b determined by spectrophotometric measurements at 289 nm. The reported T/K x2 x1 solubility represents the average of at least three independent determinations. 293.2 0.9999 0.0000140 298.2 0.9999 0.0000165 Source and Purity of Chemicals: 303.2 0.9999 0.0000203 (1) Purity not given, UPSA, Agen, France, no purification details were 310.2 0.9999 0.0000247 provided. Water content of the sample was determined to be 5% based on Karl 315.2 0.9999 0.0000291 Fisher analysis. a x2: mole fraction of component 2 in the saturated solution. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical b x1: mole fraction solubility of the solute. source not specified, no purification details were provided.

Estimated Error: Auxiliary Information Temperature: 0.2 K. x : 2% (relative error). Method/Apparatus/Procedure: 1 Air thermostat, analytical balance, and an UV/visible spectrophotometer. Excess solute and solvent were placed in a glass ampoule and allowed to equilibrate with rotation at constant temperature in an air thermostat for 24 h. An aliquot of the saturated solution was removed with isothermal filtration Components: Original Measurements: (Acrodisc CR syringe filter, PTFE, 0.2 μm pore size), and diluted (1) 2-[[3-(Trifluoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and quantitatively. The molar solubility of the drug was determined by amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 spectrophotometric analysis. The solubility determination was repeated three (Niflumic acid); C13H9F3N2O2; (1998). times. [4394-00-7] (2) Cyclohexane; C6H12; [110-82-7] Source and Purity of Chemicals: Variables: Prepared by: (1) 99.8+%, Sigma Chemical Company, St. Louis, Missouri, USA, was used as T/K ¼ 298.15 W. E. Acree, Jr. received. (2) Purity not given, Analytical Reagent Grade, Solvents Documentation Syntheses (SDS), Peypin, France, no purification details were given in the Experimental Values paper.

Estimated Error: x a x b,c Temperature: 0.1 K. 2 1 0.9999 0.0000162 x1: 2.5% (relative error). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Components: Original Measurements: (1) 2-[[3-(Trifluoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 Auxiliary Information (Niflumic acid); C13H9F3N2O2; (1998). Method/Apparatus/Procedure: [ ] 4394-00-7 Constant-temperature bath and an ultraviolet/visible spectrophotometer. [ ] (2) Heptane; C7H16; 142-82-5 Excess solute and solvent were placed in flasks and allowed to equilibrate with Variables: Prepared by: shaking for five days at constant temperature. Aliquots of saturated solutions % / T/K ¼ 298.15 W. E. Acree, Jr. were removed and diluted with 96 ethanol (v v). Concentrations were determined by spectrophotometric measurements at 289 nm. The reported solubility represents the average of at least three independent determinations. Experimental Values Source and Purity of Chemicals: (1) Purity not given, UPSA, Agen, France, no purification details were a b,c provided. Water content of the sample was determined to be 5% based on Karl x2 x1 Fisher analysis. 0.9928 0.00718 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a x2: mole fraction of component 2 in the saturated solution. source not specified, no purification details were provided. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Estimated Error: Temperature: 0.2 K.

x1: 2% (relative error).

22.3. Niﬂumic acid solubility data in aromatic Experimental Values hydrocarbons

a b,c x2 x1 0.9999 0.0000910 Components: Original Measurements: 171 a (1) 2-[[3-(Triﬂuoromethyl)phenyl]- P. Bustamante, M. A. Peña, and x2: mole fraction of component 2 in the saturated solution. b amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 x1: mole fraction solubility of the solute. cExperimental value was reported in the paper as ln x . (Niﬂumic acid); C13H9F3N2O2; (1998). 1 [4394-00-7]

(2) Benzene; C6H6; [71-43-2] Auxiliary Information Variables: Prepared by: / / T/K ¼ 298.15 W. E. Acree, Jr. Method Apparatus Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with Experimental Values shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 289 nm. The reported a b,c solubility represents the average of at least three independent determinations. x2 x1 0.9995 0.000470 Source and Purity of Chemicals: a x2: mole fraction of component 2 in the saturated solution. (1) Purity not given, UPSA, Agen, France, no purification details were b x1: mole fraction solubility of the solute. provided. Water content of the sample was determined to be 5% based on Karl c Experimental value was reported in the paper as ln x1. Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Auxiliary Information Method/Apparatus/Procedure: Estimated Error: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Temperature: 0.2 K. % Excess solute and solvent were placed in flasks and allowed to equilibrate with x1: 2 (relative error). shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 289 nm. The reported solubility represents the average of at least three independent determinations. Components: Original Measurements: (1) 2-[[3-(Trifluoromethyl)phenyl]- 173P. Bustamante, J. Navarro, S. Source and Purity of Chemicals: amino]-3-pyridinecarboxylic acid Romero, and B. Escalera, J.

(1) Purity not given, UPSA, Agen, France, no puriﬁcation details were (Niﬂumic acid); C13H9F3N2O2; Pharm. Sci. 91, 874 (2002). provided. Water content of the sample was determined to be 5% based on Karl [4394-00-7]

Fisher analysis. (2) Ethyl ethanoate; C4H8O2; (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical [141-78-6] source not speciﬁed, no puriﬁcation details were provided. Variables: Prepared by: Temperature W. E. Acree, Jr. Estimated Error: Temperature: 0.2 K. x : 2% (relative error). 1 Experimental Values

a b T/K x2 x1 22.4. Niflumic acid solubility data in esters 283.2 0.9778 0.0222 288.2 0.9769 0.0231 293.2 0.9756 0.0244 Components: Original Measurements: 298.2 0.9746 0.0254 (1) 2-[[3-(Trifluoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and 303.2 0.9736 0.0264 amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 308.2 0.9723 0.0273 (Niflumic acid); C H F N O ; (1998). a 13 9 3 2 2 x2: mole fraction of component 2 in the saturated solution. [4394-00-7] b x1: mole fraction solubility of the solute. (2) Ethyl ethanoate; C4H8O2; [141-78-6] Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

Auxiliary Information Estimated Error: Temperature: 0.2 K. Method/Apparatus/Procedure: x1: 2% (relative error). Temperature-controlled bath, analytical balance, and an UV/visible spectrophotometer. Excess solute and solvent were placed in sealed flasks and allowed to equilibrate at constant temperature with shaking in a temperature-controlled bath for four days. An aliquot of the saturated solution was removed, filtered Components: Original Measurements: [[ ] 171 ñ through a 0.2 μm pore size membrane filter, and diluted quantitatively with (1) 2- 3-(Trifluoromethyl)phenyl - P. Bustamante, M. A. Pe a, and ] 96% (by volume) ethanol. The molar solubility of the drug was determined by amino -3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 spectrophotometric analysis at 290 nm. The solubility determinations were (Niflumic acid); C13H9F3N2O2; (1998). [ ] repeated three times. The densities of the saturated solutions were determined 4394-00-7 [ ] in order to convert the measured molar solubilities in units of mol dm 3 to mole (2) 1,4-Dioxane; C4H8O2; 123-91-1 fraction. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided in the paper. Experimental Values (2) Purity not given, Spectrophotometric grade, Panreac, Monplet and Esteban, Barcelona, Spain, no purification details were given in the paper. a b,c x2 x1 Estimated Error: 0.9517 0.04832 Temperature: 0.1 K. a x1: 2.5% (relative error). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

22.5. Niflumic acid solubility data in ethers Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in flasks and allowed to equilibrate with [[ ] 171 ñ (1) 2- 3-(Trifluoromethyl)phenyl - P. Bustamante, M. A. Pe a, and shaking for five days at constant temperature. Aliquots of saturated solutions ] amino -3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 were removed and diluted with 96% ethanol (v/v). Concentrations were (Niflumic acid); C13H9F3N2O2; (1998). determined by spectrophotometric measurements at 289 nm. The reported [ ] 4394-00-7 solubility represents the average of at least three independent determinations. (2) 1,1′-Oxybisethane; C4H10O; [ ] 60-29-7 Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, UPSA, Agen, France, no purification details were T/K ¼ 298.15 W. E. Acree, Jr. provided. Water content of the sample was determined to be 5% based on Karl Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Experimental Values source not specified, no purification details were provided.

Estimated Error: a b,c x2 x1 Temperature: 0.2 K. x : 2% (relative error). 0.9722 0.02785 1 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. cExperimental value was reported in the paper as ln x . 1 22.6. Niflumic acid solubility data in haloalkanes, haloalkenes, and haloaromatic hydrocarbons Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in flasks and allowed to equilibrate with (1) 2-[[3-(Trifluoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and shaking for five days at constant temperature. Aliquots of saturated solutions amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 were removed and diluted with 96% ethanol (v/v). Concentrations were (Niflumic acid); C13H9F3N2O2; (1998). determined by spectrophotometric measurements at 289 nm. The reported [4394-00-7] solubility represents the average of at least three independent determinations. (2) Trichloromethane; CHCl3; [67-66-3] Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, UPSA, Agen, France, no purification details were T/K ¼ 298.15 W. E. Acree, Jr. provided. Water content of the sample was determined to be 5% based on Karl Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided.

Experimental Values Components: Original Measurements: (1) 2-[[3-(Triﬂuoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and ] a b,c amino -3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 x2 x1 (Niﬂumic acid); C13H9F3N2O2; (1998). 0.9987 0.00128 [4394-00-7]

a (2) 1,2-Dichloroethane; C2H4Cl2; x2: mole fraction of component 2 in the saturated solution. b [107-06-2] x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Auxiliary Information / / Method Apparatus Procedure: Experimental Values Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions a b,c x2 x1 were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 289 nm. The reported 0.9817 0.01832 a solubility represents the average of at least three independent determinations. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Source and Purity of Chemicals: Experimental value was reported in the paper as ln x1. (1) Purity not given, UPSA, Agen, France, no purification details were provided. Water content of the sample was determined to be 5% based on Karl Fisher analysis. Auxiliary Information (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Method/Apparatus/Procedure: source not specified, no purification details were provided. Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with Estimated Error: shaking for five days at constant temperature. Aliquots of saturated solutions Temperature: 0.2 K. were removed and diluted with 96% ethanol (v/v). Concentrations were x : 2% (relative error). 1 determined by spectrophotometric measurements at 289 nm. The reported solubility represents the average of at least three independent determinations.

Source and Purity of Chemicals: Components: Original Measurements: (1) Purity not given, UPSA, Agen, France, no purification details were (1) 2-[[3-(Trifluoromethyl)phenyl]- 172J. J. Pinvidic, A. Gonthier- provided. Water content of the sample was determined to be 5% based on Karl amino]-3-pyridinecarboxylic acid Vassal, H. Szwarc, R. Ceolin, P. Fisher analysis. (Niflumic acid); C13H9F3N2O2; Toffoli, J. M. Teulon, and C. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical [4394-00-7] Guechot, Thermochim. Acta 153, source not specified, no purification details were provided.

(2) Trichloromethane; CHCl3; 37 (1989). [67-66-3] Estimated Error: Temperature: 0.2 K. Variables: Prepared by: x : 2% (relative error). T/K ¼ 298.15 W. E. Acree, Jr. 1

Experimental Values ¼ Components: Original Measurements: The measured solubility was reported to be c1 0.00532 (1) 2-[[3-(Triﬂuoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and 3 mol dm . amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141

(Niflumic acid); C13H9F3N2O2; (1998). Auxiliary Information [4394-00-7] Method/Apparatus/Procedure: (2) Chlorobenzene; C6H5Cl; Very few details were reported in the paper. Solvent was slowly added in [108-90-7] 3 increments of 0.10 cm to a known quantity of solid solute. The solution was Variables: Prepared by: observed under transverse light against a dark background. The final T/K ¼ 298.15 W. E. Acree, Jr. concentration at which the solid traces was still visible and the first concentration at which trace solid was not visible were recorded. Solubility was calculated as the mean of the two recorded concentrations. Experimental Values

Source and Purity of Chemicals: (1) Purity not given, chemical source not specified, no purification details were a b,c x2 x1 provided in the paper. (2) Purity not given, chemical source not specified, no purification details were 0.9950 0.00502 a provided in the paper. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Estimated Error: Experimental value was reported in the paper as ln x1. Temperature: 1K.

c1: 3.5% (relative error).

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-[[3-(Trifluoromethyl)phenyl]- 172J. J. Pinvidic, A. Gonthier- Constant-temperature bath and an ultraviolet/visible spectrophotometer. amino]-3-pyridinecarboxylic acid Vassal, H. Szwarc, R. Ceolin, P. Excess solute and solvent were placed in flasks and allowed to equilibrate with (Niflumic acid); C13H9F3N2O2; Toffoli, J. M. Teulon, and C. shaking for five days at constant temperature. Aliquots of saturated solutions [4394-00-7] Guechot, Thermochim. Acta 153, were removed and diluted with 96% ethanol (v/v). Concentrations were (2) Methanol; CH4O; [67-56-1] 37 (1989). determined by spectrophotometric measurements at 289 nm. The reported Variables: Prepared by: solubility represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, UPSA, Agen, France, no purification details were Experimental Values provided. Water content of the sample was determined to be 5% based on Karl Fisher analysis. The measured solubility was reported to be c1 ¼ 0.2055 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical mol dm 3. source not specified, no purification details were provided. Auxiliary Information Estimated Error: Temperature: 0.2 K. Method/Apparatus/Procedure: x1: 2% (relative error). Very few details were reported in the paper. Solvent was slowly added in increments of 0.10 cm3 to a known quantity of solid solute. The solution was observed under transverse light against a dark background. The final concentration at which the solid traces was still visible and the first 22.7. Niflumic acid solubility data in alcohols concentration at which trace solid was not visible were recorded. Solubility was calculated as the mean of the two recorded concentrations.

Source and Purity of Chemicals: Components: Original Measurements: (1) Purity not given, chemical source not specified, no purification details were (1) 2-[[3-(Trifluoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and provided in the paper. amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 (2) Purity not given, chemical source not specified, no purification details were (Niflumic acid); C13H9F3N2O2; (1998). provided in the paper. [4394-00-7]

(2) Methanol; CH4O; [67-56-1] Estimated Error: Temperature: 1K. Variables: Prepared by: c : 4.0% (relative error). T/K ¼ 298.15 W. E. Acree, Jr. 1

Experimental Values Components: Original Measurements: (1) 2-[[3-(Triﬂuoromethyl)phenyl]- 172J. J. Pinvidic, A. Gonthier- a b,c ] x2 x1 amino -3-pyridinecarboxylic acid Vassal, H. Szwarc, R. Ceolin, P. 0.9924 0.00755 (Niﬂumic acid); C13H9F3N2O2; Toffoli, J. M. Teulon, and C. [ ] a 4394-00-7 Guechot, Thermochim. Acta 153, x2: mole fraction of component 2 in the saturated solution. [ ] b (2) Ethanol; C2H6O; 64-17-5 37 (1989). x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. The measured solubility was reported to be c1 ¼ 0.1063 Excess solute and solvent were placed in flasks and allowed to equilibrate with mol dm 3. shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Auxiliary Information determined by spectrophotometric measurements at 289 nm. The reported solubility represents the average of at least three independent determinations. Method/Apparatus/Procedure: Very few details were reported in the paper. Solvent was slowly added in Source and Purity of Chemicals: increments of 0.10 cm3 to a known quantity of solid solute. The solution was (1) Purity not given, UPSA, Agen, France, no purification details were observed under transverse light against a dark background. The final provided. Water content of the sample was determined to be 5% based on Karl concentration at which the solid traces was still visible and the first Fisher analysis. concentration at which trace solid was not visible were recorded. Solubility (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical was calculated as the mean of the two recorded concentrations. source not specified, no purification details were provided. Source and Purity of Chemicals: Estimated Error: (1) Purity not given, chemical source not specified, no purification details were Temperature: 0.2 K. provided in the paper. x1: 2% (relative error). (2) Purity not given, chemical source not specified, no purification details were provided in the paper.

Estimated Error: Experimental Values Temperature: 1K.

c1: 7.0% (relative error). a b T/K x2 x1 289.4 0.9896 0.0104 299.0 0.9889 0.0111 Components: Original Measurements: 304.6 0.9872 0.0128 171 (1) 2-[[3-(Triﬂuoromethyl)phenyl]- P. Bustamante, M. A. Peña, and 310.3 0.9838 0.0162 amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 316.7 0.9799 0.0201 (Niﬂumic acid); C13H9F3N2O2; (1998). 320.8 0.9751 0.0249 [ ] 4394-00-7 a [ ] x2: mole fraction of component 2 in the saturated solution. (2) Ethanol; C2H6O; 64-17-5 b x1: mole fraction solubility of the solute. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Auxiliary Information Method/Apparatus/Procedure: Experimental Values Thermostated water bath, analytical balance, stirrer, and electronic thermometer. Solubilities were determined using a dynamic method. Known amounts of x a x b,c 2 1 solute and solvent were placed inside a Pyrex glass equilibrium cell, which was 0.9855 0.01449 then placed in a thermostated water bath. The sample was slowly heated a x2: mole fraction of component 2 in the saturated solution. (approximately 5 K/h) with continuous stirring. Temperature at which the last b x1: mole fraction solubility of the solute. crystals disappeared was taken as the temperature of the solution-crystal c Experimental value was reported in the paper as ln x1. equilibrium.

Source and Purity of Chemicals: Auxiliary Information (1) 99+%, Sigma-Aldrich Chemical Company, St. Louis, Missouri, USA, was used as received. / / Method Apparatus Procedure: (2) 99.8+%, Sigma-Aldrich Chemical Company, was stored over freshly active / Constant-temperature bath and an ultraviolet visible spectrophotometer. molecular sieves of type 4 Å. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with shaking for ﬁve days at constant temperature. Aliquots of saturated solutions Estimated Error: % / were removed and diluted with 96 ethanol (v v). Concentrations were Temperature: 0.1 K. determined by spectrophotometric measurements at 289 nm. The reported x1: 3% (relative error, estimated by compiler). solubility represents the average of at least three independent determinations.

Source and Purity of Chemicals: (1) Purity not given, UPSA, Agen, France, no purification details were provided. Water content of the sample was determined to be 5% based on Karl Components: Original Measurements: 173 Fisher analysis. (1) 2-[[3-(Trifluoromethyl)phenyl]- P. Bustamante, J. Navarro, S. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical amino]-3-pyridinecarboxylic acid Romero, and B. Escalera, J. source not specified, no purification details were provided. (Niflumic acid); C13H9F3N2O2; Pharm. Sci. 91, 874 (2002). [4394-00-7] [ ] Estimated Error: (2) Ethanol; C2H6O; 64-17-5 Temperature: 0.2 K. Variables: Prepared by: % x1: 2 (relative error). Temperature W. E. Acree, Jr.

Experimental Values Components: Original Measurements: (1) 2-[[3-(Triﬂuoromethyl)phenyl]- 89U. Domanska, A. Pobudkowska, a b amino]-3-pyridinecarboxylic acid and A. Pelczarska, J. Phys. Chem. T/K x2 x1 (Niﬂumic acid); C13H9F3N2O2; B 115, 2547 (2011). 283.2 0.9897 0.0103 [4394-00-7] 288.2 0.9881 0.0119 [ ] (2) Ethanol; C2H6O; 64-17-5 293.2 0.9865 0.0135 Variables: Prepared by: 298.2 0.9837 0.0163 Temperature W. E. Acree, Jr. 303.2 0.9815 0.0185 308.2 0.9775 0.0225 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-[[3-(Trifluoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and Temperature-controlled bath, analytical balance, and an UV/visible amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 spectrophotometer. (Niflumic acid); C13H9F3N2O2; (1998). Excess solute and solvent were placed in sealed flasks and allowed to [4394-00-7] equilibrate at constant temperature with shaking in a temperature-controlled (2) 1-Octanol; C8H18O; [111-87-5] bath for four days. An aliquot of the saturated solution was removed, filtered Variables: Prepared by: through a 0.2 μm pore size membrane filter, and diluted quantitatively with T/K ¼ 298.15 W. E. Acree, Jr. 96% (by volume) ethanol. The molar solubility of the drug was determined by spectrophotometric analysis at 290 nm. The solubility determinations were repeated three times. The densities of the saturated solutions were determined Experimental Values in order to convert the measured molar solubilities in units of mol dm3 to mole fraction. x a x b,c Source and Purity of Chemicals: 2 1 (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no 0.9999 0.0000457 a purification details were provided in the paper. x2: mole fraction of component 2 in the saturated solution. b (2) Purity not given, Spectrophotometric grade, Panreac, Monplet and Esteban, x1: mole fraction solubility of the solute. c Barcelona, Spain, no purification details were given in the paper. Experimental value was reported in the paper as ln x1.

Estimated Error: Auxiliary Information Temperature: 0.1 K.

x1: 2.5% (relative error). Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions % / Components: Original Measurements: were removed and diluted with 96 ethanol (v v). Concentrations were 171 determined by spectrophotometric measurements at 289 nm. The reported (1) 2-[[3-(Trifluoromethyl)phenyl]- P. Bustamante, M. A. Peña, and solubility represents the average of at least three independent determinations. amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 (Niflumic acid); C13H9F3N2O2; (1998). Source and Purity of Chemicals: [ ] 4394-00-7 (1) Purity not given, UPSA, Agen, France, no purification details were [ ] (2) 1-Pentanol; C5H12O; 71-41-0 provided. Water content of the sample was determined to be 5% based on Karl Variables: Prepared by: Fisher analysis. T/K ¼ 298.15 W. E. Acree, Jr. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided.

Estimated Error: Experimental Values Temperature: 0.2 K.

x1: 2% (relative error). a b,c x2 x1 0.9816 0.01841 a Components: Original Measurements: x2: mole fraction of component 2 in the saturated solution. 89 b (1) 2-[[3-(Trifluoromethyl)phenyl]- U. Domanska, A. Pobudkowska, x1: mole fraction solubility of the solute. c amino]-3-pyridinecarboxylic acid and A. Pelczarska, J. Phys. Chem. Experimental value was reported in the paper as ln x1. (Niflumic acid); C13H9F3N2O2; B 115, 2547 (2011). [4394-00-7] [ ] Auxiliary Information (2) 1-Octanol; C8H18O; 111-87-5 Method/Apparatus/Procedure: Variables: Prepared by: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Temperature W. E. Acree, Jr. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions Experimental Values were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 289 nm. The reported

solubility represents the average of at least three independent determinations. a b T/K x2 x1 Source and Purity of Chemicals: 282.3 0.9851 0.0149 (1) Purity not given, UPSA, Agen, France, no purification details were 299.3 0.9798 0.0202 provided. Water content of the sample was determined to be 5% based on Karl 305.2 0.9759 0.0241 Fisher analysis. 313.3 0.9694 0.0306 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 321.6 0.9623 0.0377 source not specified, no purification details were provided. 329.3 0.9550 0.0450 335.3 0.9441 0.0559 Estimated Error: 346.5 0.9295 0.0705 Temperature: 0.2 K. 355.8 0.9121 0.0879

x1: 2% (relative error). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-[[3-(Triﬂuoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and Thermostated water bath, analytical balance, stirrer, and electronic amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141

thermometer. (Niﬂumic acid); C13H9F3N2O2; (1998). Solubilities were determined using a dynamic method. Known amounts of [4394-00-7]

solute and solvent were placed inside a Pyrex glass equilibrium cell, which was (2) 1,2-Ethanediol; C2H6O2; then placed in a thermostated water bath. The sample was slowly heated [107-21-1] (approximately 5 K/h) with continuous stirring. Temperature at which the last Variables: Prepared by: crystals disappeared was taken as the temperature of the solution-crystal T/K ¼ 298.15 W. E. Acree, Jr. equilibrium.

Source and Purity of Chemicals: Experimental Values (1) 99+%, Sigma-Aldrich Chemical Company, St. Louis, Missouri, USA, was used as received. (2) 99.8+%, Sigma-Aldrich Chemical Company, was stored over freshly active x a x b,c molecular sieves of type 4 Å. 2 1 0.9989 0.00106 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. b Temperature: 0.1 K. x1: mole fraction solubility of the solute. x % c 1: 3 (relative error, estimated by compiler). Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: (1) 2-[[3-(Triﬂuoromethyl)phenyl]- 86A. O. Surov, P. Szterner, W. Method/Apparatus/Procedure: amino]-3-pyridinecarboxylic acid Zielenkiewicz, and G. L. Constant-temperature bath and an ultraviolet/visible spectrophotometer.

(Niflumic acid); C13H9F3N2O2; Perlovich, J. Pharm. Biomed. Excess solute and solvent were placed in flasks and allowed to equilibrate with [4394-00-7] Anal. 50, 831 (2009). shaking for five days at constant temperature. Aliquots of saturated solutions 87 % / (2) 1-Octanol; C8H18O; [111-87-5] G. L. Perlovich, A. O. Surov, were removed and diluted with 96 ethanol (v v). Concentrations were and A. Bauer-Brandl, J. Pharm. determined by spectrophotometric measurements at 289 nm. The reported Biomed. Anal. 45, 679 (2007). solubility represents the average of at least three independent determinations. Variables: Prepared by: Source and Purity of Chemicals: Temperature W. E. Acree, Jr. (1) Purity not given, UPSA, Agen, France, no purification details were provided. Water content of the sample was determined to be 5% based on Karl Experimental Values Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. T/K x a x b 2 1 Estimated Error: 293.2 0.9741 0.0259 Temperature: 0.2 K. 298.2 0.9706 0.0294 x1: 2% (relative error). 303.2 0.9664 0.0336 310.2 0.9591 0.0409 315.2 0.9532 0.0468 a x2: mole fraction of component 2 in the saturated solution. b Components: Original Measurements: x1: mole fraction solubility of the solute. (1) 2-[[3-(Trifluoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141

Auxiliary Information (Niflumic acid); C13H9F3N2O2; (1998). [4394-00-7] Method/Apparatus/Procedure: (2) 1,2-Propanediol; C H O ; Air thermostat, analytical balance, and an UV/visible spectrophotometer. 3 8 2 [57-55-6] Excess solute and solvent were placed in a glass ampoule and allowed to equilibrate with rotation at constant temperature in an air thermostat for 24 h. Variables: Prepared by: An aliquot of the saturated solution was removed with isothermal filtration T/K ¼ 298.15 W. E. Acree, Jr. (Acrodisc CR syringe filter, PTFE, 0.2 μm pore size), and diluted quantitatively. The molar solubility of the drug was determined by spectrophotometric analysis. The solubility determination was repeated three Experimental Values times.

a b,c Source and Purity of Chemicals: x2 x1 +% (1) 99.8 , Sigma Chemical Company, St. Louis, Missouri, USA, was used as 0.9994 0.000625 received. a x2: mole fraction of component 2 in the saturated solution. (2) Purity not given, Analytical Reagent Grade, Sigma Chemical Company, no b x1: mole fraction solubility of the solute. puriﬁcation details were given in the paper. c Experimental value was reported in the paper as ln x1. Estimated Error: Temperature: 0.1 K.

x1: 2.5% (relative error).

Auxiliary Information 22.8. Niflumic acid solubility data in ketones Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with Components: Original Measurements: shaking for five days at constant temperature. Aliquots of saturated solutions (1) 2-[[3-(Trifluoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and % / were removed and diluted with 96 ethanol (v v). Concentrations were amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 determined by spectrophotometric measurements at 289 nm. The reported (Niflumic acid); C13H9F3N2O2; (1998). solubility represents the average of at least three independent determinations. [4394-00-7]

(2) Propanone; C3H6O; [67-64-1] Source and Purity of Chemicals: (1) Purity not given, UPSA, Agen, France, no purification details were Variables: Prepared by: / ¼ provided. Water content of the sample was determined to be 5% based on Karl T K 298.15 W. E. Acree, Jr. Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values

Estimated Error: a b,c Temperature: 0.2 K. x2 x1

x1: 2% (relative error). 0.9990 0.000970 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Components: Original Measurements: (1) 2-[[3-(Trifluoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 Auxiliary Information (Niflumic acid); C H F N O ; (1998). 13 9 3 2 2 Method/Apparatus/Procedure: [4394-00-7] Constant-temperature bath and an ultraviolet/visible spectrophotometer. (2) 1,2,3-Propanetriol (Glycerol); Excess solute and solvent were placed in flasks and allowed to equilibrate with C H O ; [56-81-5] 3 8 3 shaking for five days at constant temperature. Aliquots of saturated solutions Variables: Prepared by: were removed and diluted with 96% ethanol (v/v). Concentrations were T/K ¼ 298.15 W. E. Acree, Jr. determined by spectrophotometric measurements at 289 nm. The reported solubility represents the average of at least three independent determinations.

Experimental Values Source and Purity of Chemicals: (1) Purity not given, UPSA, Agen, France, no purification details were provided. Water content of the sample was determined to be 5% based on Karl a b,c x2 x1 Fisher analysis. 0.9993 0.000652 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a source not specified, no purification details were provided. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Estimated Error: Experimental value was reported in the paper as ln x1. Temperature: 0.2 K.

x1: 2% (relative error). Auxiliary Information Method/Apparatus/Procedure: / Constant-temperature bath and an ultraviolet visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in flasks and allowed to equilibrate with (1) 2-[[3-(Trifluoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and shaking for five days at constant temperature. Aliquots of saturated solutions amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 were removed and diluted with 96% ethanol (v/v). Concentrations were (Niflumic acid); C13H9F3N2O2; (1998). determined by spectrophotometric measurements at 289 nm. The reported [4394-00-7] solubility represents the average of at least three independent determinations. (2) Acetophenone; C8H8O; [98-86-2]

Source and Purity of Chemicals: Variables: Prepared by: / ¼ (1) Purity not given, UPSA, Agen, France, no purification details were T K 298.15 W. E. Acree, Jr. provided. Water content of the sample was determined to be 5% based on Karl Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Experimental Values source not specified, no purification details were provided.

a b,c Estimated Error: x2 x1 Temperature: 0.2 K. 0.9992 0.000751 x1: 2% (relative error). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-[[3-(Trifluoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and Constant-temperature bath and an ultraviolet/visible spectrophotometer. amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 Excess solute and solvent were placed in flasks and allowed to equilibrate with (Niflumic acid); C13H9F3N2O2; (1998). shaking for five days at constant temperature. Aliquots of saturated solutions [4394-00-7] were removed and the solvent was evaporated. The residual solid was then (2) N,N-Dimethylformamide; dissolved and diluted with 96% ethanol (v/v). Concentrations were determined C3H7NO; [64-19-7] by spectrophotometric measurements at 289 nm. The reported solubility Variables: Prepared by: represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, UPSA, Agen, France, no purification details were Experimental Values provided. Water content of the sample was determined to be 5% based on Karl Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x a x b,c source not specified, no purification details were provided. 2 1 0.5328 0.4672 a Estimated Error: x2: mole fraction of component 2 in the saturated solution. b Temperature: 0.2 K. x1: mole fraction solubility of the solute. % c x1: 2 (relative error). Experimental value was reported in the paper as ln x1.

22.9. Niflumic acid solubility data in miscellaneous Auxiliary Information organic solvents Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with Components: Original Measurements: shaking for five days at constant temperature. Aliquots of saturated solutions % / (1) 2-[[3-(Trifluoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and were removed and diluted with 96 ethanol (v v). Concentrations were amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 determined by spectrophotometric measurements at 289 nm. The reported solubility represents the average of at least three independent determinations. (Niflumic acid); C13H9F3N2O2; (1998). [4394-00-7] (2) Formamide; CH NO; [75-12-7] Source and Purity of Chemicals: 3 (1) Purity not given, UPSA, Agen, France, no purification details were Variables: Prepared by: provided. Water content of the sample was determined to be 5% based on Karl T/K ¼ 298.15 W. E. Acree, Jr. Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values Estimated Error: Temperature: 0.2 K. a b,c x2 x1 x1: 2% (relative error). 0.9973 0.00274 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Components: Original Measurements: (1) 2-[[3-(Trifluoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 Auxiliary Information (Niflumic acid); C13H9F3N2O2; (1998). Method/Apparatus/Procedure: [4394-00-7] Constant-temperature bath and an ultraviolet/visible spectrophotometer. (2) Ethanoic acid; C2H4O2; [64-19-7] Excess solute and solvent were placed in flasks and allowed to equilibrate with Variables: Prepared by: shaking for five days at constant temperature. Aliquots of saturated solutions T/K ¼ 298.15 W. E. Acree, Jr. were removed and the solvent was evaporated. The residual solid was then dissolved and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 289 nm. The reported solubility Experimental Values represents the average of at least three independent determinations.

Source and Purity of Chemicals: x a x b,c (1) Purity not given, UPSA, Agen, France, no purification details were 2 1 provided. Water content of the sample was determined to be 5% based on Karl 0.9921 0.00788 a Fisher analysis. x2: mole fraction of component 2 in the saturated solution. b (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x1: mole fraction solubility of the solute. c source not specified, no purification details were provided. Experimental value was reported in the paper as ln x1.

Estimated Error: Temperature: 0.2 K.

x1: 2% (relative error).

Auxiliary Information 22.10. Niflumic acid solubility data in binary organic Method/Apparatus/Procedure: solvent mixtures Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions Components: Original Measurements: were removed and diluted with 96% ethanol (v/v). Concentrations were (1) 2-[[3-(Trifluoromethyl)phenyl]- 173P. Bustamante, J. Navarro, determined by spectrophotometric measurements at 289 nm. The reported amino]-3-pyridinecarboxylic acid S. Romero, and B. Escalera, solubility represents the average of at least three independent determinations. (Niflumic acid); C13H9F3N2O2; J. Pharm. Sci. 91, 874 (2002). [4394-00-7] Source and Purity of Chemicals: (2) Ethyl ethanoate; C H O ; (1) Purity not given, UPSA, Agen, France, no purification details were 4 8 2 [141-78-6] provided. Water content of the sample was determined to be 5% based on Karl (3) Ethanol; C H O; [64-17-5] Fisher analysis. 2 6 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Variables: Prepared by: source not specified, no purification details were provided. Temperature; Solvent composition W. E. Acree, Jr.

Estimated Error: Temperature: 0.2 K. Experimental Values

x1: 2% (relative error).

/ ðsÞa b T K v2 x1 283.2 0.00 0.0103 Components: Original Measurements: 283.2 0.10 0.0149 (1) 2-[[3-(Trifluoromethyl)phenyl]- 171P. Bustamante, M. A. Peña, and 283.2 0.30 0.0237 amino]-3-pyridinecarboxylic acid J. Barra, Int. J. Pharm. 174, 141 283.2 0.50 0.0370 (Niflumic acid); C13H9F3N2O2; (1998). 283.2 0.60 0.0429 [4394-00-7] 283.2 0.70 0.0472 (2) Propanoic acid; C3H6O2; 283.2 0.80 0.0507 [79-09-4] 283.2 0.90 0.0344 283.2 1.00 0.0322 Variables: Prepared by: 288.2 0.00 0.0119 T/K ¼ 298.15 W. E. Acree, Jr. 288.2 0.10 0.0179 288.2 0.30 0.0273 Experimental Values 288.2 0.50 0.0400 288.2 0.60 0.0460 288.2 0.70 0.0500 288.2 0.80 0.0513 x a x b,c 2 1 288.2 0.90 0.0355 0.9793 0.02071 288.2 1.00 0.0231 a x2: mole fraction of component 2 in the saturated solution. 293.2 0.00 0.0135 b x1: mole fraction solubility of the solute. 293.2 0.10 0.0206 c Experimental value was reported in the paper as ln x1. 293.2 0.30 0.0312 293.2 0.50 0.0428 293.2 0.60 0.0504 Auxiliary Information 293.2 0.70 0.0527 293.2 0.80 0.0519 Method/Apparatus/Procedure: 293.2 0.90 0.0365 Constant-temperature bath and an ultraviolet/visible spectrophotometer. 293.2 1.00 0.0244 Excess solute and solvent were placed in flasks and allowed to equilibrate with 298.2 0.00 0.0163 shaking for five days at constant temperature. Aliquots of saturated solutions 298.2 0.10 0.0240 were removed and diluted with 96% ethanol (v/v). Concentrations were 298.2 0.30 0.0352 determined by spectrophotometric measurements at 289 nm. The reported 298.2 0.50 0.0482 solubility represents the average of at least three independent determinations. 298.2 0.60 0.0542 298.2 0.70 0.0550 Source and Purity of Chemicals: 298.2 0.80 0.0524 (1) Purity not given, UPSA, Agen, France, no purification details were 298.2 0.90 0.0374 provided. Water content of the sample was determined to be 5% based on Karl 298.2 1.00 0.0254 Fisher analysis. 303.2 0.00 0.0185 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 303.2 0.10 0.0266 source not specified, no purification details were provided. 303.2 0.30 0.0400 303.2 0.50 0.0510 Estimated Error: 303.2 0.60 0.0570 Temperature: 0.2 K. 303.2 0.70 0.0580 x : 2% (relative error). 1 303.2 0.80 0.0528 303.2 0.90 0.0386 303.2 1.00 0.0264

ð Þ were also measured in binary ethanol + 1,2,3-propanetriol and T/K v s a x b 2 1 ethanol + PEG 400 solvent mixtures. It is not possible to 308.2 0.00 0.0225 308.2 0.10 0.0310 perform a critical evaluation of the experimental data as there 308.2 0.30 0.0456 are no independent experimental solubility data for nimesulide 308.2 0.50 0.0558 in these eight organic solvents. 308.2 0.60 0.0607 The experimental solubility data for nimesulide in organic 308.2 0.70 0.0608 solvents are given in Secs. 23.2–23.4. 308.2 0.80 0.0533 308.2 0.90 0.0397 308.2 1.00 0.0273 23.2. Nimesulide solubility data in alcohols a ðsÞ v2 : initial volume fraction of component 2 in the binary solvent mixture. b x1: mole fraction solubility of the solute. Components: Original Measurements: (1) 2-Phenoxy-4- 67N. Seedher and S. Bhatia, AAPS Auxiliary Information nitromethanesulfonanilide PharmSciTech 4,33/1 (2003). Method/Apparatus/Procedure: (Nimesulide); C13H12N2O5S; [ ] Temperature-controlled bath, analytical balance, and an UV/visible 51803-78-2 [ ] spectrophotometer. (2) Methanol; CH4O; 67-56-1 Binary solvent mixtures were prepared by volume. Excess solute and solvent Variables: Prepared by: were placed in sealed flasks and allowed to equilibrate at constant temperature T/K ¼ 298.15 W. E. Acree, Jr. with shaking in a temperature-controlled bath for four days. An aliquot of the saturated solution was removed, filtered through a 0.2 μm pore size membrane filter, and diluted quantitatively with 96% (by volume) ethanol. The molar Experimental Values solubility of the drug was determined by spectrophotometric analysis at ¼ 290 nm. The solubility determinations were repeated three times. The densities The measured solubility was reported to be c1 0.0286 3 of the saturated solutions were determined in order to convert the measured mol dm . molar solubilities in units of mol dm3 to mole fraction. Auxiliary Information Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Method/Apparatus/Procedure: purification details were provided in the paper. Vortex mixer, constant-temperature bath, and an ultraviolet/visible (2) Purity not given, Spectrophotometric grade, Panreac, Monplet and Esteban, spectrophotometer. Barcelona, Spain, no purification details were given in the paper. Excess solute and solvent were placed in sealed containers and equilibrated at a (3) Purity not given, Spectrophotometric grade, Panreac, Monplet and Esteban, constant temperature for 24 h. During this time the tubes were shaken Barcelona, Spain, no purification details were given in the paper. occasionally on a vortex mixer. Aliquots of saturated solutions were removed, centrifuged, filtered through a sintered glass crucible (grade 4), and diluted Estimated Error: quantitatively with 20% aqueous acetonitrile for spectroscopic analyses. Temperature: 0.1 K. Concentration of the dissolved solute was determined from the measured ðsÞ absorbance at 302 nm. v2 : 0.01. x : 3% (relative error). 1 Source and Purity of Chemicals: (1) Purity not given, Panacea Biotec Ltd., Lalru, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, 23. Solubility of Nimesulide in Organic Ltd., Mumbai, India, no purification details were provided. Solvents Estimated Error: 23.1. Critical evaluation of experimental solubility Temperature: No information given in the paper. % data c1: 5 (relative error, estimated by compiler). Nimesulide (more formally named 2-phenoxy-4-nitromethanesulfonanilide) is a selective COX-2 inhibitor, and was once among the most prescribed NSAIDs for the treatment of Components: Original Measurements: 67 osteoarthritis, muscular pain, chronic inflammation, and other (1) 2-Phenoxy-4- N. Seedher and S. Bhatia, AAPS nitromethanesulfonanilide PharmSciTech 4,33/1 (2003). painful conditions. Concerns regarding harmful liver-asso- (Nimesulide); C13H12N2O5S; ciated side effects have resulted in the withdrawal of the drug [51803-78-2]

from the market in several countries, while in other countries (2) Ethanol; C2H6O; [64-17-5] the drug was never marketed or restrictions have been imposed Variables: Prepared by: 175–178 on its use. There has been only a single publication T/K ¼ 298.15 W. E. Acree, Jr. reporting the solubility of nimesulide in organic solvents. Seedher and Bhatia67 determined the molar solubility of nimesulide in methanol, ethanol, 1-butanol, 1-octanol, 1,2- Experimental Values ¼ ethanediol, 1,2-propanediol, 1,2,3-propanetriol, and polyethy- The measured solubility was reported to be c1 0.0108 3 lene glycol 400 (PEG 400) at 298 K. Nimesulide solubilities mol dm .

Source and Purity of Chemicals: The measured solubility was reported to be c1 ¼ 0.00315 (1) Purity not given, Panacea Biotec Ltd., Lalru, India, no purification details mol dm 3. were provided. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, Auxiliary Information Ltd., Mumbai, India, no purification details were provided. Method/Apparatus/Procedure: Estimated Error: Vortex mixer, constant-temperature bath, and an ultraviolet/visible Temperature: No information given in the paper. spectrophotometer. c1: 5% (relative error, estimated by compiler). Excess solute and solvent were placed in sealed containers and equilibrated at a constant temperature for 24 h. During this time the tubes were shaken occasionally on a vortex mixer. Aliquots of saturated solutions were removed, centrifuged, filtered through a sintered glass crucible (grade 4), and diluted % Components: Original Measurements: quantitatively with 20 aqueous acetonitrile for spectroscopic analyses. (1) 2-Phenoxy-4- 67N. Seedher and S. Bhatia, AAPS Concentration of the dissolved solute was determined from the measured nitromethanesulfonanilide PharmSciTech 4,33/1 (2003). absorbance at 302 nm.

(Nimesulide); C13H12N2O5S; [51803-78-2] Source and Purity of Chemicals: (1) Purity not given, Panacea Biotec Ltd., Lalru, India, no puriﬁcation details (2) 1-Butanol; C4H10O; [71-36-3] were provided. Variables: Prepared by: (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, T/K ¼ 298.15 W. E. Acree, Jr. Ltd., Mumbai, India, no puriﬁcation details were provided.

Estimated Error: Experimental Values Temperature: No information given in the paper. c : 5% (relative error, estimated by compiler). The measured solubility was reported to be c1 ¼ 0.00688 1 mol dm3.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-Phenoxy-4- 67N. Seedher and S. Bhatia, AAPS Vortex mixer, constant-temperature bath, and an ultraviolet/visible nitromethanesulfonanilide PharmSciTech 4,33/1 (2003). spectrophotometer. (Nimesulide); C13H12N2O5S; Excess solute and solvent were placed in sealed containers and equilibrated at a [51803-78-2] constant temperature for 24 h. During this time the tubes were shaken (2) 1,2-Ethanediol; C2H6O2; occasionally on a vortex mixer. Aliquots of saturated solutions were removed, [107-21-1] centrifuged, filtered through a sintered glass crucible (grade 4), and diluted Variables: Prepared by: quantitatively with 20% aqueous acetonitrile for spectroscopic analyses. T/K ¼ 298.15 W. E. Acree, Jr. Concentration of the dissolved solute was determined from the measured absorbance at 302 nm. Experimental Values Source and Purity of Chemicals: (1) Purity not given, Panacea Biotec Ltd., Lalru, India, no purification details The measured solubility was reported to be c1 ¼ 0.00165 were provided. mol dm 3. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, Ltd., Mumbai, India, no purification details were provided. Auxiliary Information Estimated Error: Method/Apparatus/Procedure: Temperature: No information given in the paper. Vortex mixer, constant-temperature bath, and an ultraviolet/visible c1: 5% (relative error, estimated by compiler). spectrophotometer. Excess solute and solvent were placed in sealed containers and equilibrated at a constant temperature for 24 h. During this time the tubes were shaken occasionally on a vortex mixer. Aliquots of saturated solutions were removed, centrifuged, filtered through a sintered glass crucible (grade 4), and diluted quantitatively with 20% aqueous acetonitrile for spectroscopic analyses. Concentration of the dissolved solute was determined from the measured absorbance at 302 nm.

Source and Purity of Chemicals: Auxiliary Information (1) Purity not given, Panacea Biotec Ltd., Lalru, India, no purification details / / were provided. Method Apparatus Procedure: / (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, Vortex mixer, constant-temperature bath, and an ultraviolet visible Ltd., Mumbai, India, no purification details were provided. spectrophotometer. Excess solute and solvent were placed in sealed containers and equilibrated at a Estimated Error: constant temperature for 24 h. During this time the tubes were shaken Temperature: No information given in the paper. occasionally on a vortex mixer. Aliquots of saturated solutions were removed, centrifuged, filtered through a sintered glass crucible (grade 4), and diluted c1: 5% (relative error, estimated by compiler). quantitatively with 20% aqueous acetonitrile for spectroscopic analyses. Concentration of the dissolved solute was determined from the measured absorbance at 302 nm.

Components: Original Measurements: Source and Purity of Chemicals: 67 (1) 2-Phenoxy-4- N. Seedher and S. Bhatia, AAPS (1) Purity not given, Panacea Biotec Ltd., Lalru, India, no puriﬁcation details / nitromethanesulfonanilide PharmSciTech 4,331 (2003). were provided. (Nimesulide); C13H12N2O5S; (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, [ ] 51803-78-2 Ltd., Mumbai, India, no puriﬁcation details were provided. (2) 1,2-Propanediol; C3H8O2; [ ] 57-55-6 Estimated Error: Variables: Prepared by: Temperature: No information given in the paper. % T/K ¼ 298.15 W. E. Acree, Jr. c1: 5 (relative error, estimated by compiler).

Experimental Values

The measured solubility was reported to be c1 ¼ 0.00571 23.3. Nimesulide solubility data in miscellaneous mol dm3. organic solvents

Auxiliary Information Components: Original Measurements: / / Method Apparatus Procedure: (1) 2-Phenoxy-4- 67N. Seedher and S. Bhatia, AAPS / Vortex mixer, constant-temperature bath, and an ultraviolet visible nitromethanesulfonanilide PharmSciTech 4,33/1 (2003). spectrophotometer. (Nimesulide); C13H12N2O5S; Excess solute and solvent were placed in sealed containers and equilibrated at a [51803-78-2] constant temperature for 24 h. During this time the tubes were shaken (2) Polyethylene glycol 400 occasionally on a vortex mixer. Aliquots of saturated solutions were removed, (PEG 400) centrifuged, ﬁltered through a sintered glass crucible (grade 4), and diluted quantitatively with 20% aqueous acetonitrile for spectroscopic analyses. Variables: Prepared by: Concentration of the dissolved solute was determined from the measured T/K ¼ 298.15 W. E. Acree, Jr. absorbance at 302 nm.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Panacea Biotec Ltd., Lalru, India, no purification details The measured solubility was reported to be c1 ¼ 0.2047 were provided. mol dm3. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, Ltd., Mumbai, India, no purification details were provided. Auxiliary Information Estimated Error: Method/Apparatus/Procedure: Temperature: No information given in the paper. Vortex mixer, constant-temperature bath, and an ultraviolet/visible c : 5% (relative error, estimated by compiler). 1 spectrophotometer. Excess solute and solvent were placed in sealed containers and equilibrated at a constant temperature for 24 h. During this time the tubes were shaken occasionally on a vortex mixer. Aliquots of saturated solutions were removed, Components: Original Measurements: centrifuged, filtered through a sintered glass crucible (grade 4), and diluted (1) 2-Phenoxy-4- 67N. Seedher and S. Bhatia, AAPS quantitatively with 20% aqueous acetonitrile for spectroscopic analyses. nitromethanesulfonanilide PharmSciTech 4,33/1 (2003). Concentration of the dissolved solute was determined from the measured (Nimesulide); C13H12N2O5S; absorbance at 302 nm. [51803-78-2] (2) 1,2,3-Propanetriol (Glycerol); Source and Purity of Chemicals: C3H8O3; [56-81-5] (1) Purity not given, Panacea Biotec Ltd., Lalru, India, no purification details were provided. Variables: Prepared by: (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, T/K ¼ 298.15 W. E. Acree, Jr. Ltd., Mumbai, India, no purification details were provided.

Experimental Values Estimated Error: Temperature: No information given in the paper. ¼ The measured solubility was reported to be c1 0.000707 c1: 5% (relative error, estimated by compiler). mol dm3.

23.4. Nimesulide solubility data in binary organic Components: Original Measurements: solvent mixtures (1) 2-Phenoxy-4- 67N. Seedher and S. Bhatia, AAPS nitromethanesulfonanilide PharmSciTech 4,33/1 (2003).

(Nimesulide); C13H12N2O5S; [51803-78-2] Components: Original Measurements: (2) Ethanol; C H O; [64-17-5] (1) 2-Phenoxy-4- 67N. Seedher and S. Bhatia, AAPS 2 6 (3) 1,2,3-Propanetriol (Glycerol); nitromethanesulfonanilide PharmSciTech 4,33/1 (2003). C3H8O3; [56-81-5] (Nimesulide); C13H12N2O5S; [51803-78-2] Variables: Prepared by: (2) Ethanol; C2H6O; [64-17-5] T/K ¼ 298; Solvent composition W. E. Acree, Jr. (3) Polyethylene glycol 400 (PEG 400) Experimental Values Variables: Prepared by: T/K ¼ 298; Solvent composition W. E. Acree, Jr.

ðsÞa b v2 c1 Experimental Values 0.00 0.000693 0.10 0.001323 0.20 0.002198 ðsÞa b 0.40 0.005386 v2 c1 0.60 0.008744 0.00 0.2008 0.80 0.01088 0.10 0.2087 0.90 0.01285 0.20 0.1798 1.00 0.01056 0.40 0.1145 a ðsÞ 0.60 0.0784 v2 : volume fraction of component 2 in the initial binary solvent mixture 0.80 0.0315 calculated as if the dissolved solute were not present. b 3 1.00 0.0106 c1: molar solubility of the solute in units of mol dm . a ðsÞ v2 : volume fraction of component 2 in the initial binary solvent mixture calculated as if the dissolved solute were not present. b 3 Auxiliary Information c1: molar solubility of the solute in units of mol dm . Method/Apparatus/Procedure: Vortex mixer, constant-temperature bath, and an ultraviolet/visible Auxiliary Information spectrophotometer. Binary solvent mixtures were prepared by volume. Excess solute and solvent Method/Apparatus/Procedure: were placed in sealed containers and equilibrated at a constant temperature for Vortex mixer, constant-temperature bath, and an ultraviolet/visible 24 h. During this time the tubes were shaken occasionally on a vortex mixer. spectrophotometer. Aliquots of saturated solutions were removed, centrifuged, filtered through a Binary solvent mixtures were prepared by volume. Excess solute and solvent sintered glass crucible (grade 4), and diluted quantitatively with 20% aqueous were placed in sealed containers and equilibrated at a constant temperature for acetonitrile for spectroscopic analyses. Concentration of the dissolved solute 24 h. During this time the tubes were shaken occasionally on a vortex mixer. was determined from the measured absorbance at 302 nm. Aliquots of saturated solutions were removed, centrifuged, filtered through a sintered glass crucible (grade 4), and diluted quantitatively with 20% aqueous Source and Purity of Chemicals: acetonitrile for spectroscopic analyses. Concentration of the dissolved solute (1) Purity not given, Panacea Biotec Ltd., Lalru, India, no purification details was determined from the measured absorbance at 302 nm. were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, Source and Purity of Chemicals: no purification details were provided. (1) Purity not given, Panacea Biotec Ltd., Lalru, India, no purification details (3) Purity not given, Analytical Reagent grade, Merck Chemical Company, were provided. Ltd., Mumbai, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. Estimated Error: (3) Purity not given, Analytical Reagent grade, Merck Chemical Company, Temperature: No information given in the paper. Ltd., Mumbai, India, no purification details were provided. ðsÞ v2 : 0.01. % Estimated Error: c1: 5.0 (relative error, estimated by compiler). Temperature: No information given in the paper. ðsÞ v2 : 0.01. c1: 5.0% (relative error, estimated by compiler). 24. Solubility of Phenylbutazone in Organic Solvents 24.1. Critical evaluation of experimental solubility data Phenylbutazone (more formally named 4-butyl-1,2-diphenyl-pyrazolidine-3,5-dione) is a NSAID and potent pain reliever used for the relief of lameness, soft-tissue injury, muscle

TABLE 15. Parameters of the Modified Apelblat equation for describing the Experimental Values solubility of phenylbutazone in ethanol and 1-octanol The measured solubility was reported to be c1 ¼ 0.000259 MARD mol dm3. The density of the saturated solution was / % Solvent T K ABC( ) 0.703 g cm 3. Ethanola 278–345 14.798 5623.65 0.118 20.0 1-Octanola 278–345 33.709 5624.73 8.246 14.7 Auxiliary Information a 180 Experimental data determined by Domanska et al. Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Excess solute and solvent were placed in sealed containers and allowed to equilibrate at a constant temperature with shaking for 72 h. Aliquots of soreness, laminitis, and bone and joint problems in horses. saturated solutions were removed, and diluted quantitatively for spectroscopic 65,179,180 There have been three published studies involving the analysis at 243 nm. Reported values represent the average of three solubility of phenylbutazone in organic solvents. Datta and experimental measurements. Grant179 determined the molar solubility of phenylbutazone in 1,1′-oxybisethane, methanol, and propanone at 305 K in their Source and Purity of Chemicals: (1) 99.9%, Sigma Chemical Company, St. Louis, Missouri, USA, no investigation of the relative nucleation rate of phenylbutazone purification details were provided. and ulfamerazine in organic solvents. The solvent’s physical (2) Purity not given, Fisher Scientific Chemicals, Fairlawn, New Jersey, USA, and chemical properties affect the crystallization rate, and play was stored over molecular sieves before use. an important role in determining particle size and morphology of the crystallized material. Rytting et al.65 reported the Estimated Error: Temperature: 0.2 K (estimated by compiler). solubility of phenylbutazone in polyethylene glycol 400 (PEG c1: 3% (relative error). 400) at ambient room temperature. Domanska et al.180 measured the solubility of phenylbutazone in ethanol and 1-octanol as a function of temperature using a dynamic method that recorded the temperature at 24.3. Phenylbutazone solubility data in alcohols which the last crystal disappeared. The internal consistency of the dataset was assessed by curve-fitting the measured mole fraction solubility data to Eq. (8). The values of the equation Components: Original Measurements: 179 coefficients (A, B, and C) are given in Table 15, along with the (1) 4-Butyl-1,2-diphenyl- S. Datta and D. J. W. Grant, mean absolute relative deviation. Readers are reminded that, in pyrazolidine-3,5-dione Cryst. Growth Des. 5, 1351 (Phenylbutazone); C19H20N2O2; (2005). assessing the derived mathematical correlations, one must take [50-33-9]

into account the size of the range of mole fraction solubilities (2) Methanol; CH4O; [67-56-1] covered in each dataset. It is very easy to describe solubility Variables: Prepared by: data that vary little with temperature. In the case of 1-octanol, T/K ¼ 305.15 W. E. Acree, Jr. the experimental phenylbutazone solubilities cover more than sat a 180-fold range in mole fraction, from approximately x1 ¼ sat Experimental Values 0.0019 at 295.0 K to x1 ¼ 0.3560 at 355.7 K. The measured ¼ phenylbutazone solubilities at both 286.6 and 290.7 K were The measured solubility was reported to be c1 0.000174 3 excluded from the regression analysis in order to lower the mol dm . The density of the saturated solution was 0.844 g 3 MARD to a reasonable value. cm . The experimental solubility data for phenylbutazone in organic solvents are given in Secs. 24.2–24.5. Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. 24.2. Phenylbutazone solubility data in ethers Excess solute and solvent were placed in sealed containers and allowed to equilibrate at a constant temperature with shaking for 72 h. Aliquots of saturated solutions were removed, and diluted quantitatively for spectroscopic Components: Original Measurements: analysis at 243 nm. Reported values represent the average of three (1) 4-Butyl-1,2-diphenyl- 179S. Datta and D. J. W. Grant, experimental measurements. pyrazolidine-3,5-dione Cryst. Growth Des. 5, 1351

(Phenylbutazone); C19H20N2O2; (2005). Source and Purity of Chemicals: [50-33-9] (1) 99.9%, Sigma Chemical Company, St. Louis, Missouri, USA, no

(2) 1,1′-Oxybisethane; C4H10O; puriﬁcation details were provided. [60-29-7] (2) Purity not given, Fisher Scientiﬁc Chemicals, Fairlawn, New Jersey, USA, was stored over molecular sieves before use. Variables: Prepared by: / ¼ T K 305.15 W. E. Acree, Jr. Estimated Error: Temperature: 0.2 K (estimated by compiler).

c1: 3% (relative error).

Components: Original Measurements: Experimental Values (1) 4-Butyl-1,2-diphenyl- 180U. Domanska, A.

pyrazolidine-3,5-dione Pobudkowska, A. Pelczarska, and a b T/K x2 x1 (Phenylbutazone); C19H20N2O2; L. Zukowski, Int. J. Pharm. 403, [50-33-9] 115 (2011). 286.6 0.9998 0.0002

(2) Ethanol; C2H6O; [64-17-5] 290.7 0.9990 0.0010 295.0 0.9981 0.0019 Variables: Prepared by: 300.5 0.9950 0.0050 Temperature W. E. Acree, Jr. 306.7 0.9911 0.0089 310.8 0.9851 0.0149 317.3 0.9767 0.0233 Experimental Values 320.7 0.9715 0.0285 325.0 0.9626 0.0374 330.0 0.9511 0.0489 T/K x a x b 2 1 335.0 0.9390 0.0610 277.5 0.9972 0.0028 337.3 0.9290 0.0710 279.2 0.9967 0.0033 341.4 0.8790 0.1210 283.3 0.9961 0.0039 346.7 0.8090 0.1910 286.7 0.9955 0.0045 351.1 0.7350 0.2650 291.5 0.9946 0.0054 355.7 0.6440 0.3560 297.0 0.9938 0.0062 ax : mole fraction of component 2 in the saturated solution. 303.1 0.9914 0.0086 2 bx : mole fraction solubility of the solute. 306.7 0.9897 0.0103 1 312.0 0.9840 0.0160 316.9 0.9788 0.0212 Auxiliary Information 320.7 0.9716 0.0284 325.9 0.9603 0.0397 Method/Apparatus/Procedure: 330.0 0.9467 0.0533 Thermostated water bath, analytical balance, stirrer, and electronic 333.0 0.9319 0.0681 thermometer. 336.3 0.9041 0.0959 Solubilities were determined using a dynamic method. Known amounts of 339.7 0.8520 0.1480 solute and solvent were placed inside a Pyrex glass equilibrium cell, which was 345.2 0.7750 0.2250 then placed in a thermostated water bath. The sample was slowly heated a (approximately 5 K/h) with continuous stirring. Temperature at which the last x2: mole fraction of component 2 in the saturated solution. b crystals disappeared was taken as the temperature of the solution-crystal x1: mole fraction solubility of the solute. equilibrium.

Auxiliary Information Source and Purity of Chemicals: +% Method/Apparatus/Procedure: (1) 99 , Sigma-Aldrich Chemical Company, St. Louis, Missouri, USA, was Thermostated water bath, analytical balance, stirrer, and electronic used as received. +% thermometer. (2) 99.8 , Sigma-Aldrich Chemical Company, was stored over freshly active Å Solubilities were determined using a dynamic method. Known amounts of molecular sieves of type 4 . solute and solvent were placed inside a Pyrex glass equilibrium cell, which was then placed in a thermostated water bath. The sample was slowly heated Estimated Error: (approximately 5 K/h) with continuous stirring. Temperature at which the last Temperature: 0.1 K. % crystals disappeared was taken as the temperature of the solution-crystal x1: 3 (relative error, estimated by compiler). equilibrium.

Source and Purity of Chemicals: (1) 99+%, Sigma-Aldrich Chemical Company, St. Louis, Missouri, USA, was 24.4. Phenylbutazone solubility data in ketones used as received. (2) 99.8+%, Sigma-Aldrich Chemical Company, was stored over freshly active molecular sieves of type 4 Å. Components: Original Measurements: 179 Estimated Error: (1) 4-Butyl-1,2-diphenyl- S. Datta and D. J. W. Grant, Temperature: 0.1 K. pyrazolidine-3,5-dione Cryst. Growth Des. 5, 1351 (Phenylbutazone); C19H20N2O2; (2005). x1: 3% (relative error, estimated by compiler). [50-33-9]

(2) Propanone; C3H6O; [67-64-1] Variables: Prepared by: Components: Original Measurements: T/K ¼ 305.15 W. E. Acree, Jr. (1) 4-Butyl-1,2-diphenyl- 180U. Domanska, A. pyrazolidine-3,5-dione Pobudkowska, A. Pelczarska, and Experimental Values (Phenylbutazone); C19H20N2O2; L. Zukowski, Int. J. Pharm. 403, [50-33-9] 115 (2011). The measured solubility was reported to be c ¼ 0.00111 [ ] 1 (2) 1-Octanol; C8H18O; 111-87-5 mol dm3. The density of the saturated solution was Variables: Prepared by: 0.900gcm3. Temperature W. E. Acree, Jr.

Auxiliary Information 25. Solubility of Piroxicam in Organic Method/Apparatus/Procedure: Solvents Constant-temperature bath and an UV/visible spectrophotometer. Excess solute and solvent were placed in sealed containers and allowed to 25.1. Critical evaluation of experimental solubility equilibrate at a constant temperature with shaking for 72 h. Aliquots of data saturated solutions were removed, and diluted quantitatively for spectroscopic analysis at 243 nm. Reported values represent the average of three Piroxicam (more formally named 4-hydroxy-2-methyl-N- experimental measurements. (2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-diox- Source and Purity of Chemicals: ide) is a NSAID used to relieve symptoms of osteoarthritis (1) 99.9%, Sigma Chemical Company, St. Louis, Missouri, USA, no and rheumatoid arthritis in humans. It has also been used in puriﬁcation details were provided. veterinary medicine to treat canines with transitional cell (2) Purity not given, Fisher Scientiﬁc Chemicals, Fairlawn, New Jersey, USA, carcinoma of the urinary bladder.181,182 There have been was stored over molecular sieves before use. several publications64,171,183–185 involving the solubility of Estimated Error: piroxicam in organic solvents. Most notably, Bustamante 171 Temperature: 0.2 K (estimated by compiler). et al. measured the mole fraction solubility of piroxicam % c1: 3 (relative error). in 22 different organic solvents, including two saturated hydrocarbons (heptane and cyclohexane), one aromatic hydrocarbon (benzene), one alkyl alkanoate (ethyl ethanoate), one dialkyl ether (1,1′-oxybisethane) and one cyclic ether (1,4- 24.5. Phenylbutazone solubility data in dioxane), two chloroalkanes (trichloromethane and 1,2- miscellaneous organic solvents dichloroethane) and one chlorinated aromatic hydrocarbon (chlorobenzene), seven alcohols (methanol, ethanol, 1-pentanol, 1-octanol, 1,2-ethanediol, 1,2-propanediol, and 1,2,3- Components: Original Measurements: propanetriol), one alkanone (propanone) and one aromatic (1) 4-Butyl-1,2-diphenyl- 65E. Rytting, K. A. Lentz, X.-Q. pyrazolidine-3,5-dione Chen, F. Qian, and S. Venkatesh, ketone (acetophenone), and four miscellaneous organic sol-

(Phenylbutazone); C19H20N2O2; AAPS J. 7, E78 (2005). vents (ethanoic acid, propanoic acid, formamide, and N,N- [50-33-9] dimethylformamide) at 298 K and atmospheric pressure. (2) Polyethylene glycol 400 Wyttenbach et al.185 investigated the solubility of piroxicam (PEG 400) in ethanol, polyethylene glycol 400, and olive oil at ambient Variables: Prepared by: room temperature using a residual solid screening assay T/K ¼ 296 W. E. Acree, Jr. method performed in 96-well multiscreen solubility filter plates. Wenkers and Lippold64 reported solubility data for ten Experimental Values NSAIDs (aspirin, diclofenac, diflunisal, flufenamic acid, ibuprofen, ketoprofen, nabumetone, naproxen, piroxicam, and The measured solubility was reported to be c1 ¼ 0.192 mol dm3. tenoxicam) in light mineral oil at 305 K. It is not possible to perform a critical evaluation in regard to these solubility data as ethanol is the only common solvent and the independent sets Auxiliary Information of measurements were performed at different temperatures Method/Apparatus/Procedure: (298 K and ambient room temperature). Centrifuge and a high-performance liquid chromatograph equipped with a There is only a single publication reporting the solubility of photo-diode array detector. 184 Excess solute and solvent were placed in sealed vials and shaken at ambient piroxicam as a function of temperature. Sotomayor et al. room temperature for at least 24 h. The vials were then centrifuged for 15 min measured the mole fraction solubility of piroxicam in ethanol to separate the saturated solution from the excess solute. The supernatant was as a function of temperature from 293 to 315 K. The internal then filtered and the concentration of the dissolved solute determined by high- consistency of the Sotomayor et al. dataset was assessed by performance liquid chromatographic analysis. curve-fitting the measured mole fraction solubility data to the Source and Purity of Chemicals: Modified Apelblat model [see Eq. (8)] to yield the following (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, representation: USA, no purification details were provided. (2) Purity not given, J. T. Baker Chemical Company, Phillipsburg, New Jersey, 115:356 ln x ¼80:938 þ þ 12:652 ln T: ð33Þ USA, no purification details were provided. 1 T Estimated Error: The mean absolute relative deviation between the observed Temperature: 2 K (estimated by compiler). experimental data and back-calculated values based on % c1: 10 (relative error, estimated by compiler). Eq. (33) of MARD ¼ 2.7% is comparable in magnitude to the experimental uncertainty associated with the measured values. The experimental solubility data for piroxicam in organic solvents are in Secs. 25.2–25.9.

25.2. Piroxicam solubility data in saturated Auxiliary Information hydrocarbons (including cycloalkanes) Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with Components: Original Measurements: shaking for ﬁve days at constant temperature. Aliquots of saturated solutions % / (1) 4-Hydroxy-2-methyl-N-(2- 171P. Bustamante, M. A. Peña, and were removed and diluted with 96 ethanol (v v). Concentrations were pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 determined by spectrophotometric measurements at 256 nm. The reported 3-carboxamide 1,1-dioxide (1998). solubility represents the average of at least three independent determinations.

(Piroxicam); C15H13N3O4S; [36322-90-4] Source and Purity of Chemicals: (1) Purity not given, UPSA, Agen, France, no purification details were (2) Heptane; C7H16; [142-82-5] provided. Water content of the sample was determined to be 5.8% based on Variables: Prepared by: Karl Fisher analysis. T/K ¼ 298.15 W. E. Acree, Jr. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided.

Experimental Values Estimated Error: Temperature: 0.2 K.

x1: 2% (relative error). a b,c x2 x1 0.9999 0.0000135 a x2: mole fraction of component 2 in the saturated solution. 25.3. Piroxicam solubility data in aromatic b x1: mole fraction solubility of the solute. hydrocarbons c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 171P. Bustamante, M. A. Peña, and Method/Apparatus/Procedure: (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 Constant-temperature bath and an ultraviolet/visible spectrophotometer. 3-carboxamide 1,1-dioxide (1998). Excess solute and solvent were placed in flasks and allowed to equilibrate with (Piroxicam); C H N O S; shaking for five days at constant temperature. Aliquots of saturated solutions 15 13 3 4 [36322-90-4] were removed and diluted with 96% ethanol (v/v). Concentrations were (2) Benzene; C H ; [71-43-2] determined by spectrophotometric measurements at 256 nm. The reported 6 6 solubility represents the average of at least three independent determinations. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, UPSA, Agen, France, no purification details were provided. Water content of the sample was determined to be 5.8% based on Experimental Values Karl Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a b,c source not specified, no purification details were provided. x2 x1 0.9999 0.0000722 Estimated Error: a Temperature: 0.2 K. x2: mole fraction of component 2 in the saturated solution. b x : 2% (relative error). x1: mole fraction solubility of the solute. 1 c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: 171 ñ (1) 4-Hydroxy-2-methyl-N- P. Bustamante, M. A. Pe a, and Constant-temperature bath and an ultraviolet/visible spectrophotometer. (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 Excess solute and solvent were placed in flasks and allowed to equilibrate with 3-carboxamide 1,1-dioxide (1998). shaking for five days at constant temperature. Aliquots of saturated solutions (Piroxicam); C15H13N3O4S; were removed and the solvent evaporated. The residual solid was then [ ] 36322-90-4 dissolved and diluted with 96% ethanol (v/v). Concentrations were determined [ ] (2) Cyclohexane; C6H12; 110-82-7 by spectrophotometric measurements at 256 nm. The reported solubility Variables: Prepared by: represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, UPSA, Agen, France, no purification details were Experimental Values provided. Water content of the sample was determined to be 5.8% based on Karl Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a b,c source not specified, no purification details were provided. x2 x1 0.9999 0.0000179 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. Temperature: 0.2 K. b x1: mole fraction solubility of the solute. x1: 2% (relative error). c Experimental value was reported in the paper as ln x1.

25.4. Piroxicam solubility data in esters Experimental Values

a b,c x2 x1 Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 171P. Bustamante, M. A. Peña, and 0.9999 0.0000505 a (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 x2: mole fraction of component 2 in the saturated solution. b 3-carboxamide 1,1-dioxide (1998). x1: mole fraction solubility of the solute. c (Piroxicam); C15H13N3O4S; Experimental value was reported in the paper as ln x1. [36322-90-4]

(2) Ethyl ethanoate; C4H8O2; [141-78-6] Auxiliary Information Variables: Prepared by: Method/Apparatus/Procedure: T/K ¼ 298.15 W. E. Acree, Jr. Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions Experimental Values were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 256 nm. The reported solubility represents the average of at least three independent determinations. a b,c x2 x1 0.9976 0.00244 Source and Purity of Chemicals: a (1) Purity not given, UPSA, Agen, France, no purification details were x2: mole fraction of component 2 in the saturated solution. % b provided. Water content of the sample was determined to be 5.8 based on x1: mole fraction solubility of the solute. c Karl Fisher analysis. Experimental value was reported in the paper as ln x1. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided.

Auxiliary Information Estimated Error: Method/Apparatus/Procedure: Temperature: 0.2 K. % Constant-temperature bath and an ultraviolet/visible spectrophotometer. x1: 2 (relative error). Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 256 nm. The reported Components: Original Measurements: solubility represents the average of at least three independent determinations. (1) 4-Hydroxy-2-methyl-N- 171P. Bustamante, M. A. Peña, and (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 Source and Purity of Chemicals: 3-carboxamide 1,1-dioxide (1998). (1) Purity not given, UPSA, Agen, France, no purification details were (Piroxicam); C H N O S; % 15 13 3 4 provided. Water content of the sample was determined to be 5.8 based on [36322-90-4] Karl Fisher analysis. (2) 1,4-Dioxane; C4H4O2; [123-91-1] (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Estimated Error: Temperature: 0.2 K. Experimental Values x1: 2% (relative error).

a b,c x2 x1 25.5. Piroxicam solubility data in ethers 0.9951 0.00494 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. cExperimental value was reported in the paper as ln x . Components: Original Measurements: 1 (1) 4-Hydroxy-2-methyl-N- 171P. Bustamante, M. A. Peña, and (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 Auxiliary Information 3-carboxamide 1,1-dioxide (1998). / / (Piroxicam); C15H13N3O4S; Method Apparatus Procedure: [36322-90-4] Constant-temperature bath and an ultraviolet/visible spectrophotometer.

(2) 1,1′-Oxybisethane; C4H10O; Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with [60-29-7] shaking for ﬁve days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Variables: Prepared by: determined by spectrophotometric measurements at 256 nm. The reported / ¼ T K 298.15 W. E. Acree, Jr. solubility represents the average of at least three independent determinations.

Source and Purity of Chemicals: (1) Purity not given, UPSA, Agen, France, no purification details were Components: Original Measurements: 171 ñ provided. Water content of the sample was determined to be 5.8% based on (1) 4-Hydroxy-2-methyl-N- P. Bustamante, M. A. Pe a, and Karl Fisher analysis. (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 3-carboxamide 1,1-dioxide (1998). source not specified, no purification details were provided. (Piroxicam); C15H13N3O4S; [36322-90-4] Estimated Error: (2) 1,2-Dichloroethane; C2H4Cl2; [ ] Temperature: 0.2 K. 107-06-2 % x1: 2 (relative error). Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

25.6. Piroxicam solubility data in haloalkanes, Experimental Values haloalkenes, and haloaromatic hydrocarbons a b,c x2 x1 0.9912 0.00884 Components: Original Measurements: a 171 x (1) 4-Hydroxy-2-methyl-N- P. Bustamante, M. A. Peña, and 2: mole fraction of component 2 in the saturated solution. bx (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 1: mole fraction solubility of the solute. c x 3-carboxamide 1,1-dioxide (1998). Experimental value was reported in the paper as ln 1.

(Piroxicam); C15H13N3O4S; [36322-90-4] Auxiliary Information (2) Trichloromethane; CHCl3; [67-66-3] Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Variables: Prepared by: Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with T/K ¼ 298.15 W. E. Acree, Jr. shaking for ﬁve days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Experimental Values determined by spectrophotometric measurements at 256 nm. The reported solubility represents the average of at least three independent determinations.

a b,c Source and Purity of Chemicals: x x 2 1 (1) Purity not given, UPSA, Agen, France, no purification details were 0.9774 0.0226 provided. Water content of the sample was determined to be 5.8% based on a x2: mole fraction of component 2 in the saturated solution. Karl Fisher analysis. b x1: mole fraction solubility of the solute. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical c Experimental value was reported in the paper as ln x1. source not specified, no purification details were provided.

Estimated Error: Auxiliary Information Temperature: 0.2 K. x : 2% (relative error). Method/Apparatus/Procedure: 1 Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Components: Original Measurements: 171 determined by spectrophotometric measurements at 256 nm. The reported (1) 4-Hydroxy-2-methyl-N- P. Bustamante, M. A. Peña, and solubility represents the average of at least three independent determinations. (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 3-carboxamide 1,1-dioxide (1998). Source and Purity of Chemicals: (Piroxicam); C15H13N3O4S; (1) Purity not given, UPSA, Agen, France, no purification details were [36322-90-4] provided. Water content of the sample was determined to be 5.8% based on (2) Chlorobenzene; C6H5Cl; Karl Fisher analysis. [108-90-7] (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Variables: Prepared by: source not specified, no purification details were provided. T/K ¼ 298.15 W. E. Acree, Jr.

Estimated Error: Temperature: 0.2 K. Experimental Values x1: 2% (relative error).

a b,c x2 x1 0.9999 0.0000704 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 4-Hydroxy-2-methyl-N- 171P. Bustamante, M. A. Peña, and Constant-temperature bath and an ultraviolet/visible spectrophotometer. (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 Excess solute and solvent were placed in flasks and allowed to equilibrate with 3-carboxamide 1,1-dioxide (1998). shaking for five days at constant temperature. Aliquots of saturated solutions (Piroxicam); C15H13N3O4S; were removed, and the solvent was evaporated. The residual solid was then [36322-90-4] dissolved and diluted with 96% ethanol (v/v). Concentrations were determined (2) Ethanol; C2H6O; [64-17-5] by spectrophotometric measurements at 256 nm. The reported solubility Variables: Prepared by: represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, UPSA, Agen, France, no purification details were Experimental Values provided. Water content of the sample was determined to be 5.8% based on Karl Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x a x b,c source not specified, no purification details were provided. 2 1 0.9999 0.000141 a Estimated Error: x2: mole fraction of component 2 in the saturated solution. b Temperature: 0.2 K. x1: mole fraction solubility of the solute. % c x1: 2 (relative error). Experimental value was reported in the paper as ln x1.

25.7. Piroxicam solubility data in alcohols Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with (1) 4-Hydroxy-2-methyl-N- 171P. Bustamante, M. A. Peña, and shaking for ﬁve days at constant temperature. Aliquots of saturated solutions (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 were removed and diluted with 96% ethanol (v/v). Concentrations were 3-carboxamide 1,1-dioxide (1998). determined by spectrophotometric measurements at 256 nm. The reported

(Piroxicam); C15H13N3O4S; solubility represents the average of at least three independent determinations. [36322-90-4] Source and Purity of Chemicals: (2) Methanol; CH4O; [67-56-1] (1) Purity not given, UPSA, Agen, France, no purification details were Variables: Prepared by: provided. Water content of the sample was determined to be 5.8% based on / ¼ T K 298.15 W. E. Acree, Jr. Karl Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values Estimated Error: Temperature: 0.2 K. a b,c x2 x1 x1: 2% (relative error). 0.9999 0.0000206 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 183R. G. Sotomayor, A. R. Auxiliary Information (2-pyridyl)-2H-1,2-benzothiazine- Holguin, D. M. Cristancho, D. R. 3-carboxamide 1,1-dioxide Delgado, and F. Martínez, J. Mol. / / Method Apparatus Procedure: (Piroxicam); C15H13N3O4S; Liq. 180, 34 (2013). Constant-temperature bath and an ultraviolet/visible spectrophotometer. [36322-90-4]

Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with (2) Ethanol; C2H6O; [64-17-5] shaking for ﬁve days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Variables: Prepared by: / ¼ determined by spectrophotometric measurements at 256 nm. The reported T K 298.15 W. E. Acree, Jr. solubility represents the average of at least three independent determinations.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, UPSA, Agen, France, no purification details were % provided. Water content of the sample was determined to be 5.8 based on a b Karl Fisher analysis. x2 x1 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 0.9998 0.000214 source not specified, no purification details were provided. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: Temperature: 0.2 K.

x1: 2% (relative error).

Auxiliary Information Estimated Error: Temperature: 0.05 K (estimated by compiler). Method/Apparatus/Procedure: x1: 2.0% (relative error). Recirculating thermostatic bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in stoppered dark glass flasks and allowed to equilibrate in a recirculating thermostatic bath for at least seven days. Aliquots of saturated solutions were removed and filtered to ensure that they were free of particulate matter. The filtrate was diluted with ethanol for Components: Original Measurements: 185 spectroscopic analysis. The reported solubility represents the average of at (1) 4-Hydroxy-2-methyl-N- N. Wyttenbach, J. Alsenz, and least three independent determinations. (2-pyridyl)-2H-1,2-benzothiazine- O. Grassmann, Pharm. Res. 24, 3-carboxamide 1,1-dioxide 888 (2007). Source and Purity of Chemicals: (Piroxicam); C15H13N3O4S; [ ] (1) 99.5%, Sinobright Pharmaceutical Company, Ltd., no purification details 36322-90-4 [ ] were provided. The authors stated that the sample used was in agreement with (2) Ethanol; C2H6O; 64-17-5 the quality requirements of the American Pharmacopeia, USP. Variables: Prepared by: (2) Absolute, Analytical Reagent grade, Merck Chemical Company, Germany, T/K ¼ ambient room temperature W. E. Acree, Jr. no purification details were provided.

Estimated Error: Experimental Values Temperature: 0.05 K. The measured solubility was reported to be c1 ¼ 0.00407 x1: 1% (relative error). mol dm3.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 4-Hydroxy-2-methyl-N- 184R. G. Sotomayor, S. R. 96-Well multiscreen solubility filter plates, centrifuge, and a ultraperformance (2-pyridyl)-2H-1,2-benzothiazine- Holguín, A. Romdhani, F. liquid chromatograph. 3-carboxamide 1,1-dioxide Martínez, and A. Jouyban, J. Solubilities were determined by the solubility and residual solid screening (Piroxicam); C H N O S; Solution Chem. 42, 358 (2013). 15 13 3 4 assay method, which was performed in 96-well multiscreen solubility filter [36322-90-4] plates. The compound was dispersed volumetrically into filter plates using a (2) Ethanol; C H O; [64-17-5] 2 6 manual powder dispenser for 96-well plates. Single-use stirring bars and 100 μl Variables: Prepared by: of the solvent were then added. Immediately after filling the plate was sealed by Temperature W. E. Acree, Jr. a septum sheet using a custom-built clamp device. The resulting solution was mixed by head-over-head rotation at 20 rpm for 24 h at ambient room temperature. The septum sheet was removed, and the liquid was separated Experimental Values from the residual solid by centrifugation for 5 min. The concentration of the dissolved solute was determined by ultraperformance liquid chromatographic analysis. Reported value represents the average of three experimental a b T/K x2 x1 measurements. 293.15 0.9998 0.000166 298.15 0.9998 0.000214 Source and Purity of Chemicals: 303.15 0.9997 0.000270 (1) Purity not given, Sigma-Aldrich Chemie GmbH, Buchs, Switzerland, no 308.15 0.9997 0.000320 purification details were provided. 313.15 0.9996 0.000373 (2) Purity not given, HPLC grade, chemical source not specified, used as received. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: Temperature: No information given in the paper.

c1: 5% (relative error, estimated by compiler). Auxiliary Information Method/Apparatus/Procedure: Thermostatic mechanical shaker, recirculating thermostatic bath, and an UV/ visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in dark stoppered glass ﬂasks and (1) 4-Hydroxy-2-methyl-N- 171P. Bustamante, M. A. Peña, and allowed to equilibrate in a thermostatic mechanical shaker (for 303.15, 308.15, (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 and 313.15 K) or recirculating thermostatic bath (for 293.15 and 298.15 K) for 3-carboxamide 1,1-dioxide (1998).

at least seven days. An aliquot of the saturated solution was withdrawn and (Piroxicam); C15H13N3O4S; ﬁltered to remove any particulate matter. Samples were diluted quantitatively [36322-90-4]

with alcohol and concentrations determined by spectrophotometric (2) 1-Pentanol; C5H12O; [71-41-0] measurements. Experimental determinations were performed in at least triplicate. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) 99.5+%, Sinobright Pharmaceutical Company, Ltd., puriﬁcation details were provided in the paper. (2) Absolute, Analytical Reagent grade, Merck Chemical Company, Germany, no puriﬁcation details were given in the paper.

Experimental Values Source and Purity of Chemicals: (1) Purity not given, UPSA, Agen, France, no purification details were provided. Water content of the sample was determined to be 5.8% based on a b,c Karl Fisher analysis. x2 x1 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 0.9998 0.000247 source not specified, no purification details were provided. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: c Experimental value was reported in the paper as ln x1. Temperature: 0.2 K. x1: 2% (relative error).

Auxiliary Information / / Method Apparatus Procedure: Components: Original Measurements: / Constant-temperature bath and an ultraviolet visible spectrophotometer. (1) 4-Hydroxy-2-methyl-N- 171P. Bustamante, M. A. Peña, and Excess solute and solvent were placed in flasks and allowed to equilibrate with (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 shaking for five days at constant temperature. Aliquots of saturated solutions 3-carboxamide 1,1-dioxide (1998). were removed and diluted with 96% ethanol (v/v). Concentrations were (Piroxicam); C15H13N3O4S; determined by spectrophotometric measurements at 256 nm. The reported [36322-90-4] solubility represents the average of at least three independent determinations. (2) 1,2-Ethanediol; C2H6O2; [107-21-1] Source and Purity of Chemicals: (1) Purity not given, UPSA, Agen, France, no purification details were Variables: Prepared by: provided. Water content of the sample was determined to be 5.8% based on T/K ¼ 298.15 W. E. Acree, Jr. Karl Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values

Estimated Error: a b,c Temperature: 0.2 K. x2 x1 % x1: 2 (relative error). 0.9999 0.000140 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 171P. Bustamante, M. A. Peña, and Auxiliary Information (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 3-carboxamide 1,1-dioxide (1998). Method/Apparatus/Procedure:

(Piroxicam); C15H13N3O4S; Constant-temperature bath and an ultraviolet/visible spectrophotometer. [36322-90-4] Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with (2) 1-Octanol; C8H18O; [111-87-5] shaking for ﬁve days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Variables: Prepared by: determined by spectrophotometric measurements at 256 nm. The reported T/K ¼ 298.15 W. E. Acree, Jr. solubility represents the average of at least three independent determinations.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, UPSA, Agen, France, no purification details were provided. Water content of the sample was determined to be 5.8% based on Karl Fisher analysis. x a x b,c 2 1 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 0.9997 0.000300 source not specified, no purification details were provided. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: c Experimental value was reported in the paper as ln x1. Temperature: 0.2 K. x1: 2% (relative error).

Auxiliary Information

Method/Apparatus/Procedure: Components: Original Measurements: Constant-temperature bath and an ultraviolet/visible spectrophotometer. (1) 4-Hydroxy-2-methyl-N- 171P. Bustamante, M. A. Peña, and Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 shaking for ﬁve days at constant temperature. Aliquots of saturated solutions 3-carboxamide 1,1-dioxide (1998). % / were removed and diluted with 96 ethanol (v v). Concentrations were (Piroxicam); C15H13N3O4S; determined by spectrophotometric measurements at 256 nm. The reported [36322-90-4]

solubility represents the average of at least three independent determinations. (2) 1,2-Propanediol; C3H8O2; [57-55-6] Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

Experimental Values Source and Purity of Chemicals: (1) Purity not given, UPSA, Agen, France, no purification details were provided. Water content of the sample was determined to be 5.8% based on a b,c Karl Fisher analysis. x2 x1 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 0.9997 0.000271 source not specified, no purification details were provided. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: c Experimental value was reported in the paper as ln x1. Temperature: 0.2 K. x1: 2% (relative error).

Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. 25.8. Piroxicam solubility data in ketones Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Components: Original Measurements: determined by spectrophotometric measurements at 256 nm. The reported (1) 4-Hydroxy-2-methyl-N- 171P. Bustamante, M. A. Peña, and solubility represents the average of at least three independent determinations. (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 3-carboxamide 1,1-dioxide (1998). Source and Purity of Chemicals: (Piroxicam); C H N O S; (1) Purity not given, UPSA, Agen, France, no purification details were 15 13 3 4 [36322-90-4] provided. Water content of the sample was determined to be 5.8% based on (2) Propanone; C H O; [67-64-1] Karl Fisher analysis. 3 6 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Variables: Prepared by: source not specified, no purification details were provided. T/K ¼ 298.15 W. E. Acree, Jr.

Estimated Error: Temperature: 0.2 K. Experimental Values

x1: 2% (relative error).

a b,c x2 x1 0.9972 0.00281 Components: Original Measurements: ax : mole fraction of component 2 in the saturated solution. 171 2 (1) 4-Hydroxy-2-methyl-N- P. Bustamante, M. A. Peña, and b x1: mole fraction solubility of the solute. (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 c Experimental value was reported in the paper as ln x1. 3-carboxamide 1,1-dioxide (1998).

(Piroxicam); C15H13N3O4S; [ ] 36322-90-4 Auxiliary Information (2) 1,2,3-Propanetriol (Glycerol); Method/Apparatus/Procedure: C3H8O3; [56-81-5] Constant-temperature bath and an ultraviolet/visible spectrophotometer. Variables: Prepared by: Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with / ¼ T K 298.15 W. E. Acree, Jr. shaking for ﬁve days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 256 nm. The reported Experimental Values solubility represents the average of at least three independent determinations.

Source and Purity of Chemicals: a b,c x2 x1 (1) Purity not given, UPSA, Agen, France, no purification details were 0.9999 0.0000283 provided. Water content of the sample was determined to be 5.8% based on a Karl Fisher analysis. x2: mole fraction of component 2 in the saturated solution. b (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x1: mole fraction solubility of the solute. c source not specified, no purification details were provided. Experimental value was reported in the paper as ln x1. Estimated Error: Auxiliary Information Temperature: 0.2 K. x1: 2% (relative error). Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 256 nm. The reported solubility represents the average of at least three independent determinations.

Auxiliary Information Components: Original Measurements: 171 / / (1) 4-Hydroxy-2-methyl-N- P. Bustamante, M. A. Peña, and Method Apparatus Procedure: / (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 Constant-temperature bath and an ultraviolet visible spectrophotometer. 3-carboxamide 1,1-dioxide (1998). Excess solute and solvent were placed in flasks and allowed to equilibrate with (Piroxicam); C H N O S; shaking for five days at constant temperature. Aliquots of saturated solutions 15 13 3 4 % / [36322-90-4] were removed and diluted with 96 ethanol (v v). Concentrations were determined by spectrophotometric measurements at 256 nm. The reported (2) Acetophenone; C8H8O; [98-86-2] solubility represents the average of at least three independent determinations. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, UPSA, Agen, France, no purification details were provided. Water content of the sample was determined to be 5.8% based on Experimental Values Karl Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. a b,c x2 x1 0.9998 0.000204 Estimated Error: a Temperature: 0.2 K. x2: mole fraction of component 2 in the saturated solution. b x1: 2% (relative error). x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

shaking for ﬁve days at constant temperature. Aliquots of saturated solutions (Piroxicam); C15H13N3O4S; were removed, and the solvent was evaporated. The residual solid was then [36322-90-4] dissolved and diluted with 96% ethanol (v/v). Concentrations were determined (2) N,N-Dimethylformamide;

by spectrophotometric measurements at 256 nm. The reported solubility C3H7NO; [68-12-2] represents the average of at least three independent determinations. Variables: Prepared by: / ¼ Source and Purity of Chemicals: T K 298.15 W. E. Acree, Jr. (1) Purity not given, UPSA, Agen, France, no puriﬁcation details were provided. Water content of the sample was determined to be 5.8% based on Experimental Values Karl Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical

source not speciﬁed, no puriﬁcation details were provided. a b,c x2 x1 Estimated Error: 0.9832 0.01676 Temperature: 0.2 K. a x2: mole fraction of component 2 in the saturated solution. x : 2% (relative error). b 1 x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

25.9. Piroxicam solubility data in miscellaneous organic solvents Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in flasks and allowed to equilibrate with 171 ñ (1) 4-Hydroxy-2-methyl-N- P. Bustamante, M. A. Pe a, and shaking for five days at constant temperature. Aliquots of saturated solutions (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 were removed and diluted with 96% ethanol (v/v). Concentrations were 3-carboxamide 1,1-dioxide (1998). determined by spectrophotometric measurements at 256 nm. The reported (Piroxicam); C15H13N3O4S; solubility represents the average of at least three independent determinations. [36322-90-4] [ ] (2) Formamide; CH3NO; 75-12-7 Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, UPSA, Agen, France, no purification details were T/K ¼ 298.15 W. E. Acree, Jr. provided. Water content of the sample was determined to be 5.8% based on Karl Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Experimental Values source not specified, no purification details were provided.

Estimated Error: a b,c x2 x1 Temperature: 0.2 K. x : 2% (relative error). 0.9995 0.000499 1 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 171P. Bustamante, M. A. Peña, and Method/Apparatus/Procedure: (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 Constant-temperature bath and an ultraviolet/visible spectrophotometer. 3-carboxamide 1,1-dioxide (1998). Excess solute and solvent were placed in flasks and allowed to equilibrate with (Piroxicam); C15H13N3O4S; shaking for five days at constant temperature. Aliquots of saturated solutions [36322-90-4] were removed and diluted with 96% ethanol (v/v). Concentrations were (2) Ethanoic acid; C2H4O2; [64-19-7] determined by spectrophotometric measurements at 256 nm. The reported solubility represents the average of at least three independent determinations. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, UPSA, Agen, France, no purification details were % Experimental Values provided. Water content of the sample was determined to be 5.8 based on Karl Fisher analysis. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a b,c source not specified, no purification details were provided. x2 x1 0.9991 0.000881 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. Temperature: 0.2 K. b % x1: mole fraction solubility of the solute. x1: 2 (relative error). c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: 185 Method/Apparatus/Procedure: (1) 4-Hydroxy-2-methyl-N- N. Wyttenbach, J. Alsenz, and Constant-temperature bath and an ultraviolet/visible spectrophotometer. (2-pyridyl)-2H-1,2-benzothiazine- O. Grassmann, Pharm. Res. 24, Excess solute and solvent were placed in flasks and allowed to equilibrate with 3-carboxamide 1,1-dioxide 888 (2007). shaking for five days at constant temperature. Aliquots of saturated solutions (Piroxicam); C15H13N3O4S; were removed and diluted with 96% ethanol (v/v). Concentrations were [36322-90-4] determined by spectrophotometric measurements at 256 nm. The reported (2) Polyethylene glycol 400 solubility represents the average of at least three independent determinations. (PEG 400) Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ ambient room temperature W. E. Acree, Jr. (1) Purity not given, UPSA, Agen, France, no purification details were provided. Water content of the sample was determined to be 5.8% based on Karl Fisher analysis. Experimental Values (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical ¼ source not specified, no purification details were provided. The measured solubility was reported to be c1 0.0606 mol dm3. Estimated Error: Temperature: 0.2 K. Auxiliary Information x1: 2% (relative error). Method/Apparatus/Procedure: 96-Well multiscreen solubility filter plates, centrifuge, and a ultraperformance liquid chromatograph. Solubilities were determined by the solubility and residual solid screening Components: Original Measurements: assay method, which was performed in 96-well multiscreen solubility filter (1) 4-Hydroxy-2-methyl-N- 171P. Bustamante, M. A. Peña, and plates. The compound was dispersed volumetrically into filter plates using a (2-pyridyl)-2H-1,2-benzothiazine- J. Barra, Int. J. Pharm. 174, 141 manual powder dispenser for 96-well plates. Single-use stirring bars and 100 μl 3-carboxamide 1,1-dioxide (1998). of the solvent were then added. Immediately after filling the plate was sealed by (Piroxicam); C H N O S; 15 13 3 4 a septum sheet using a custom-built clamp device. The resulting solution was [36322-90-4] mixed by head-over-head rotation at 20 rpm for 24 h at ambient room (2) Propanoic acid; C H O ; 3 6 2 temperature. The septum sheet was removed, and the liquid was separated [79-09-4] from the residual solid by centrifugation for 5 min. The concentration of the Variables: Prepared by: dissolved solute was determined by ultraperformance liquid chromatographic T/K ¼ 298.15 W. E. Acree, Jr. analysis. Reported value represents the average of three experimental measurements.

Experimental Values Source and Purity of Chemicals: (1) Purity not given, Sigma-Aldrich Chemie GmbH, Buchs, Switzerland, no puriﬁcation details were provided. a b,c x2 x1 (2) Purity not given, chemical source not speciﬁed, used as received. 0.9984 0.00160 a Estimated Error: x2: mole fraction of component 2 in the saturated solution. b Temperature: No information given in the paper. x1: mole fraction solubility of the solute. % c c1: 5 (relative error, estimated by compiler). Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 185N. Wyttenbach, J. Alsenz, and Method/Apparatus/Procedure: (2-pyridyl)-2H-1,2-benzothiazine- O. Grassmann, Pharm. Res. 24, Constant-temperature bath and an UV/visible spectrophotometer. 3-carboxamide 1,1-dioxide 888 (2007). Excess solute and solvent were placed in sealed bottles and allowed to (Piroxicam); C15H13N3O4S; equilibrate at a constant temperature with rotation for 24 h. Aliquots of [36322-90-4] saturated solutions were removed, filtered through a 0.45 μm cellulose acetate (2) Olive oil membrane filter, and diluted quantitatively for spectroscopic analysis. Reported values represent the average of three experimental measurements. Variables: Prepared by: T/K ¼ ambient room temperature W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Pfizer, Karlsruhe, Germany, no purification details were Experimental Values provided. (2) Purity not given, Bayer Leverkusen and Rhone Poulenc Rorer, Cologne, The measured solubility was reported to be c1 ¼ 0.00220 Germany, no purification details were provided. mol dm3. Estimated Error: Temperature: 0.5 K (estimated by compiler). Auxiliary Information c1: 10% (relative error). Method/Apparatus/Procedure: 96-Well multiscreen solubility filter plates, centrifuge, and a ultraperformance liquid chromatograph. Solubilities were determined by the solubility and residual solid screening 26. Solubility of Rofecoxib in Organic assay method, which was performed in 96-well multiscreen solubility filter plates. The compound was dispersed volumetrically into filter plates using a Solvents manual powder dispenser for 96-well plates. Single-use stirring bars and 100 μl of the solvent were then added. Immediately after filling the plate was sealed by 26.1. Critical evaluation of experimental solubility a septum sheet using a custom-built clamp device. The resulting solution was data mixed by head-over-head rotation at 20 rpm for 24 h at ambient room [ temperature. The septum sheet was removed, and the liquid was separated Rofecoxib (more formally named 3-phenyl-4- 4-(methyl- from the residual solid by centrifugation for 5 min. The concentration of the sulfonyl)phenyl]-2(5H)-furanone) is a NSAID that was once dissolved solute was determined by ultraperformance liquid chromatographic used to treat patients having arthritis and other medical con- analysis. Reported value represents the average of three experimental ditions causing acute or chronic pain. The drug was withdrawn measurements. from the market in 2004 because of concerns regarding Source and Purity of Chemicals: increased risk of adverse cardiovascular events (heart attacks 186 (1) Purity not given, Sigma-Aldrich Chemie GmbH, Buchs, Switzerland, no and strokes) due to high-dosage and long-term use. There purification details were provided. have been several studies67,187–189 involving the solubility of (2) Purity not given, chemical source not specified, used as received. rofecoxib in organic solvents. Desai and co-workers187,188 determined the molar solubility of rofecoxib in methanol, Estimated Error: Temperature: No information given in the paper. ethanol, 1,2-propanediol, and 1,2,3-propanetriol at 298, 303,

c1: 5% (relative error, estimated by compiler). and 308 K based on spectrophotometric measurements. Seed- her and Bhatia67 published molar solubility data for rofecoxib in six alcohols (methanol, ethanol, 1-butanol, 1-octanol, 1,2- ethanediol, and 1,2-propanediol), and in polyethylene glycol Components: Original Measurements: 64 400 (PEG 400). Rofecoxib solubilities were also measured in (1) 4-Hydroxy-2-methyl-N- B. P. Wenkers and B. C. binary ethanol + 1,2,3-propanetriol and ethanol + PEG solvent (2-pyridyl)-2H-1,2-benzothiazine- Lippold, J. Pharm. Sci. 88, 1326 3-carboxamide 1,1-dioxide (1999). mixtures. There are two common solvents in the independent

(Piroxicam); C15H13N3O4S; sets of experimental solubility data. The independent sets of [36322-90-4] solubility measurements differ by approximately a factor of (2) Mineral oil 1.7: c1 ¼ 0.00266 (Ref. 67) versus c1 ¼ 0.00445 (Ref. 187) for Variables: Prepared by: the solubility in methanol at 298 K; and c1 ¼ 0.00217 (Ref. 67) T/K ¼ 305.15 W. E. Acree, Jr. versus c1 ¼ 0.00126 (Ref. 188) versus c1 ¼ 0.00124 (Ref. 187) for the solubility in ethanol at 298 K. Experimental Values The experimental solubility data for rofecoxib in organic solvents are given in Secs. 26.2–26.4. The measured solubility was reported to be c1 ¼ 0.000180 mol dm3.

26.2. Rofecoxib solubility data in alcohols Auxiliary Information Method/Apparatus/Procedure: Constant-temperature water bath and an UV/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in a closed cap tube, shaken thoroughly (1) 3-Phenyl-4-[4-(methylsulfonyl)- 67N. Seedher and S. Bhatia, AAPS for 6 h at each temperature, and then allowed to stand immersed in a stirred phenyl]-2(5H)-furanone (Rofecoxib); PharmSciTech 4,33/1 (2003). circulation constant-temperature water bath until equilibrium was obtained. An aliquot of the saturated solution was removed and the concentration of the C17H14O4S; [162011-90-7] dissolved solute determined spectrophotometrically at 285 nm. (2) Methanol; CH4O; [67-56-1]

Variables: Prepared by: Source and Purity of Chemicals: / ¼ T K 298.15 W. E. Acree, Jr. (1) 99.4%, Eros Pharma, Bangalore, India, no puriﬁcation details were given in the paper. (2) Purity not given, S. D. Fine Chemicals, Mumbai, India, no puriﬁcation Experimental Values details were given in the paper.

The measured solubility was reported to be c1 ¼ 0.00266 mol dm3. Estimated Error: Temperature: 0.1 K.

c1: 2.0% (relative error). Auxiliary Information Method/Apparatus/Procedure: Vortex mixer, constant-temperature bath, and an ultraviolet/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in sealed containers and equilibrated at a (1) 3-Phenyl-4-[4-(methylsulfonyl)- 188C. Liu, K. G. H. Desai, X. Tang, constant temperature for 24 h. During this time the tubes were shaken phenyl]-2(5H)-furanone (Rofecoxib); and X. Chen, J. Chem. Eng. Data.

occasionally on a vortex mixer. Aliquots of saturated solutions were removed, C17H14O4S; [162011-90-7] 50, 2061 (2005). centrifuged, ﬁltered through a sintered glass crucible (grade 4), and diluted (2) Ethanol; C2H6O; [64-17-5] quantitatively with l0% aqueous dimethyl sulfoxide for spectroscopic Variables: Prepared by: analyses. Concentration of the dissolved solute was determined from the Temperature W. E. Acree, Jr. measured absorbance at 263 nm.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no puriﬁcation details were provided. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, T/K c a,b Ltd., Mumbai, India, no puriﬁcation details were provided. 1 298.15 0.00126 Estimated Error: 303.15 0.00162 Temperature: No information given in the paper. 308.15 0.00199 % a 3 c1: 5 (relative error, estimated by compiler). c1: molar solubility of the solute in units of mol dm . bsolubilities are reported in the paper as the micrograms of dissolved solute per milliliter of solution. Molar solubilities were calculated by the compiler.

Components: Original Measurements: (1) 3-Phenyl-4-[4-(methylsulfonyl)- 187K. G. H. Desai, A. R. Kulkarni, Auxiliary Information ] phenyl -2(5H)-furanone (Rofecoxib); and T. M. Aminabhavi, J. Chem. Method/Apparatus/Procedure: [ ] C17H14O4S; 162011-90-7 Eng. Data. 48, 942 (2003). Constant-temperature shaker bath and a high-performance liquid [ ] (2) Methanol; CH4O; 67-56-1 chromatograph with UV detection. Variables: Prepared by: Excess solute and solvent were placed in a closed cap tube and allowed to Temperature W. E. Acree, Jr. equilibrate in a constant-temperature shaker bath for 48 h. An aliquot of the saturated solution was removed, filtered through a 0.22 μm membrane filter (Millipore, USA), and diluted quantitatively. The molar solubility of the drug Experimental Values was determined by high-performance chromatographic analysis with uv detection at 254 nm. Reported values represent the average of six experimental determinations. a,b T/K c1 Source and Purity of Chemicals: 298.15 0.00445 (1) 99.2%, Cipla Ltd., Mumbai, India, no purification details were given in the 303.15 0.00624 paper. 308.15 0.00875 (2) Purity not given, Showa Chemicals Company, Tokyo, Japan, no a 3 c1: molar solubility of the solute in units of mol dm . purification details were given in the paper. bSolubilities are reported in the paper as the micrograms of dissolved solute per milliliter of solution. Molar solubilities were calculated by the compiler. Estimated Error: Temperature: 0.1 K.

c1: 1.5% (relative error).

Auxiliary Information Components: Original Measurements: (1) 3-Phenyl-4-[4-(methylsulfonyl)- 187K. G. H. Desai, A. R. Kulkarni, Method/Apparatus/Procedure: phenyl]-2(5H)-furanone (Rofecoxib); and T. M. Aminabhavi, J. Chem. Vortex mixer, constant-temperature bath, and an ultraviolet/visible C17H14O4S; [162011-90-7] Eng. Data. 48, 942 (2003). spectrophotometer. (2) Ethanol; C2H6O; [64-17-5] Excess solute and solvent were placed in sealed containers and equilibrated at a constant temperature for 24 h. During this time the tubes were shaken Variables: Prepared by: occasionally on a vortex mixer. Aliquots of saturated solutions were removed, Temperature W. E. Acree, Jr. centrifuged, ﬁltered through a sintered glass crucible (grade 4), and diluted quantitatively with l0% aqueous dimethyl sulfoxide for spectroscopic Experimental Values analyses. Concentration of the dissolved solute was determined from the measured absorbance at 263 nm.

Source and Purity of Chemicals: T/K c a,b 1 (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no 298.15 0.00124 puriﬁcation details were provided. 303.15 0.00161 (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, 308.15 0.00195 Ltd., Mumbai, India, no puriﬁcation details were provided. a 3 c1: molar solubility of the solute in units of mol dm . bSolubilities are reported in the paper as the micrograms of dissolved solute per Estimated Error: milliliter of solution. Molar solubilities were calculated by the compiler. Temperature: No information given in the paper. c1: 5% (relative error, estimated by compiler).

Auxiliary Information Method/Apparatus/Procedure: Constant-temperature water bath and an UV/visible spectrophotometer. Components: Original Measurements: 67 Excess solute and solvent were placed in a closed cap tube, shaken thoroughly (1) 3-Phenyl-4-[4-(methylsulfonyl)- N. Seedher and S. Bhatia, AAPS for 6 h at each temperature, and then allowed to stand immersed in a stirred phenyl]-2(5H)-furanone (Rofecoxib); PharmSciTech 4,33/1 (2003). [ ] circulation constant-temperature water bath until equilibrium was obtained. C17H14O4S; 162011-90-7 [ ] An aliquot of the saturated solution was removed and the concentration of the (2) 1-Butanol; C4H10O; 71-36-3 dissolved solute determined spectrophotometrically at 285 nm. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) 99.4%, Eros Pharma, Bangalore, India, no purification details were given in the paper. Experimental Values (2) Purity not given, S. D. Fine Chemicals, Mumbai, India, no purification ¼ details were given in the paper. The measured solubility was reported to be c1 0.000601 mol dm3. Estimated Error: Temperature: 0.1 K. Auxiliary Information c1: 2.0% (relative error). Method/Apparatus/Procedure: Vortex mixer, constant-temperature bath, and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in sealed containers and equilibrated at a Components: Original Measurements: constant temperature for 24 h. During this time the tubes were shaken (1) 3-Phenyl-4-[4-(methylsulfonyl)- 67N. Seedher and S. Bhatia, AAPS occasionally on a vortex mixer. Aliquots of saturated solutions were removed, phenyl]-2(5H)-furanone (Rofecoxib); PharmSciTech 4,33/1 (2003). centrifuged, filtered through a sintered glass crucible (grade 4), and diluted C H O S; [162011-90-7] 17 14 4 quantitatively with l0% aqueous dimethyl sulfoxide for spectroscopic (2) Ethanol; C H O; [64-17-5] 2 6 analyses. Concentration of the dissolved solute was determined from the Variables: Prepared by: measured absorbance at 263 nm. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no Experimental Values purification details were provided. The measured solubility was reported to be c ¼ 0.00217 (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, 1 Ltd., Mumbai, India, no purification details were provided. mol dm3. Estimated Error: Temperature: No information given in the paper.

c1: 5% (relative error, estimated by compiler).

Source and Purity of Chemicals: Components: Original Measurements: (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no [ 67 (1) 3-Phenyl-4- 4-(methylsulfonyl)- N. Seedher and S. Bhatia, AAPS puriﬁcation details were provided. ] / phenyl -2(5H)-furanone (Rofecoxib); PharmSciTech 4,331 (2003). (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, [ ] C17H14O4S; 162011-90-7 Ltd., Mumbai, India, no puriﬁcation details were provided. (2) 1-Octanol; C8H18O; [111-87-5] Variables: Prepared by: Estimated Error: T/K ¼ 298.15 W. E. Acree, Jr. Temperature: No information given in the paper. c1: 5% (relative error, estimated by compiler).

Experimental Values

The measured solubility was reported to be c1 ¼ 0.000372 mol dm3. Components: Original Measurements: (1) 3-Phenyl-4-[4-(methylsulfonyl)- 67N. Seedher and S. Bhatia, AAPS phenyl]-2(5H)-furanone (Rofecoxib); PharmSciTech 4,33/1 (2003).

Auxiliary Information C17H14O4S; [162011-90-7] Method/Apparatus/Procedure: (2) 1,2-Propanediol; C3H8O2; [ ] Vortex mixer, constant-temperature bath, and an ultraviolet/visible 57-55-6 spectrophotometer. Variables: Prepared by: Excess solute and solvent were placed in sealed containers and equilibrated at a T/K ¼ 298.15 W. E. Acree, Jr. constant temperature for 24 h. During this time the tubes were shaken occasionally on a vortex mixer. Aliquots of saturated solutions were removed, centrifuged, ﬁltered through a sintered glass crucible (grade 4), and diluted Experimental Values quantitatively with l0% aqueous dimethyl sulfoxide for spectroscopic The measured solubility was reported to be c1 ¼ 0.00366 analyses. Concentration of the dissolved solute was determined from the 3 measured absorbance at 263 nm. mol dm .

Source and Purity of Chemicals: Auxiliary Information (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no / / purification details were provided. Method Apparatus Procedure: / (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, Vortex mixer, constant-temperature bath, and an ultraviolet visible Ltd., Mumbai, India, no purification details were provided. spectrophotometer. Excess solute and solvent were placed in sealed containers and equilibrated at a Estimated Error: constant temperature for 24 h. During this time the tubes were shaken Temperature: No information given in the paper. occasionally on a vortex mixer. Aliquots of saturated solutions were removed, centrifuged, filtered through a sintered glass crucible (grade 4), and diluted c1: 5% (relative error, estimated by compiler). quantitatively with l0% aqueous dimethyl sulfoxide for spectroscopic analyses. Concentration of the dissolved solute was determined from the measured absorbance at 263 nm.

Components: Original Measurements: Source and Purity of Chemicals: [ 67 (1) 3-Phenyl-4- 4-(methylsulfonyl)- N. Seedher and S. Bhatia, AAPS (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no ] / phenyl -2(5H)-furanone (Rofecoxib); PharmSciTech 4,331 (2003). puriﬁcation details were provided. [ ] C17H14O4S; 162011-90-7 (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, (2) 1,2-Ethanediol; C2H6O2; Ltd., Mumbai, India, no puriﬁcation details were provided. [107-21-1] Variables: Prepared by: Estimated Error: T/K ¼ 298.15 W. E. Acree, Jr. Temperature: No information given in the paper. c1: 5% (relative error, estimated by compiler).

Experimental Values

The measured solubility was reported to be c1 ¼ 0.000401 mol dm3. Components: Original Measurements: (1) 3-Phenyl-4-[4-(methylsulfonyl)- 188C. Liu, K. G. H. Desai, X. Tang, phenyl]-2(5H)-furanone (Rofecoxib); and X. Chen, J. Chem. Eng. Data.

Auxiliary Information C17H14O4S; [162011-90-7] 50, 2061 (2005). Method/Apparatus/Procedure: (2) 1,2-Propanediol; C3H8O2; [ ] Vortex mixer, constant-temperature bath, and an ultraviolet/visible 57-55-6 spectrophotometer. Variables: Prepared by: Excess solute and solvent were placed in sealed containers and equilibrated at a Temperature W. E. Acree, Jr. constant temperature for 24 h. During this time the tubes were shaken occasionally on a vortex mixer. Aliquots of saturated solutions were removed, centrifuged, ﬁltered through a sintered glass crucible (grade 4), and diluted quantitatively with l0% aqueous dimethyl sulfoxide for spectroscopic analyses. Concentration of the dissolved solute was determined from the measured absorbance at 263 nm.

Experimental Values Components: Original Measurements: (1) 3-Phenyl-4-[4-(methylsulfonyl)- 188C. Liu, K. G. H. Desai, X. Tang, ] a,b phenyl -2(5H)-furanone (Rofecoxib); and X. Chen, J. Chem. Eng. Data. T/K c1 C17H14O4S; [162011-90-7] 50, 2061 (2005). 298.15 0.000544 (2) 1,2,3-Propanetriol (Glycerol);

303.15 0.000607 C3H8O3; [56-81-5] 308.15 0.000721 Variables: Prepared by: a 3 c1: molar solubility of the solute in units of mol dm . Temperature W. E. Acree, Jr. bSolubilities are reported in the paper as the micrograms of dissolved solute per milliliter of solution. Molar solubilities were calculated by the compiler. Experimental Values Auxiliary Information

Method/Apparatus/Procedure: a,b T/K c1 Constant-temperature shaker bath and a high-performance liquid chromatograph with uv detection. 298.15 0.000225 Excess solute and solvent were placed in a closed cap tube and allowed to 303.15 0.000303 equilibrate in a constant-temperature shaker bath for 48 h. An aliquot of the 308.15 0.000376 a 3 saturated solution was removed, filtered through a 0.22 μm membrane filter c1: molar solubility of the solute in units of mol dm . (Millipore, USA), and diluted quantitatively. The molar solubility of the drug bSolubilities are reported in the paper as the micrograms of dissolved solute per was determined by high-performance chromatographic analysis with uv milliliter of solution. Molar solubilities were calculated by the compiler. detection at 254 nm. Reported values represent the average of six experimental determinations. Auxiliary Information Source and Purity of Chemicals: Method/Apparatus/Procedure: (1) 99.2%, Cipla Ltd., Mumbai, India, no purification details were given in the Constant-temperature shaker bath and a high-performance liquid paper. chromatograph with uv detection. (2) 99%, Showa Chemicals Company, Tokyo, Japan, no purification details Excess solute and solvent were placed in a closed cap tube and allowed to were given in the paper. equilibrate in a constant-temperature shaker bath for 48 h. An aliquot of the saturated solution was removed, filtered through a 0.22 μm membrane filter Estimated Error: (Millipore, USA), and diluted quantitatively. The molar solubility of the drug Temperature: 0.1 K. was determined by high-performance chromatographic analysis with uv c : 1.5% (relative error). 1 detection at 254 nm. Reported values represent the average of six experimental determinations.

Components: Original Measurements: Source and Purity of Chemicals: (1) 3-Phenyl-4-[4-(methylsulfonyl)- 189K. M. El-Say, A. M. Samy, and (1) 99.2%, Cipla Ltd., Mumbai, India, no puriﬁcation details were given in the phenyl]-2(5H)-furanone (Rofecoxib); M. I. Fetouh, Int. J. Pharm. Sci. paper.

C17H14O4S; [162011-90-7] Rev. Res. 3, 135 (2010). (2) Purity not given, Showa Chemicals Company, Tokyo, Japan, no (2) 1,2-Propanediol; C3H8O2; puriﬁcation details were given in the paper. [57-55-6] Estimated Error: Variables: Prepared by: Temperature: 0.1 K. T/K ¼ 298.15 W. E. Acree, Jr. c1: 1.5% (relative error).

Experimental Values ¼ The measured solubility was reported to be s1 0.0435 Components: Original Measurements: (mass percent). (1) 3-Phenyl-4-[4-(methylsulfonyl)- 67N. Seedher and S. Bhatia, AAPS phenyl]-2(5H)-furanone (Rofecoxib); PharmSciTech 4,33/1 (2003). Auxiliary Information C17H14O4S; [162011-90-7] Method/Apparatus/Procedure: (2) 1,2,3-Propanetriol (Glycerol); [ ] Ultrasonic bath and an ultraviolet/visible spectrophotometer. C3H8O3; 56-81-5 Excess solute and solvent were placed in sealed test tubes and sonicated for 48 h. Variables: Prepared by: The sample was then cooled to 298 K. The solution was then filtered through a T/K ¼ 298.15 W. E. Acree, Jr. 0.45 μm Millipore filter, and a weighted aliquot of the filtered supernatant solution was diluted with methanol for spectrophotometric analysis at 268 nm. Experimental Values Source and Purity of Chemicals: ¼ (1) Purity not given, Egyptian International Pharmaceutical Industries The measured solubility was reported to be c1 0.000344 3 Company, Egypt, no purification details were provided. mol dm . (2) Purity not given, El-Nasr Pharmaceutical Chemicals, Egypt, no purification details were provided.

Estimated Error: Temperature: No information given in the paper.

s1: 5% (relative error, estimated by compiler).

Auxiliary Information 26.3. Rofecoxib solubility data in miscellaneous Method/Apparatus/Procedure: organic solvents Vortex mixer, constant-temperature bath, and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in sealed containers and equilibrated at a Components: Original Measurements: constant temperature for 24 h. During this time the tubes were shaken (1) 3-Phenyl-4-[4-(methylsulfonyl)- 67N. Seedher and S. Bhatia, AAPS occasionally on a vortex mixer. Aliquots of saturated solutions were removed, phenyl]-2(5H)-furanone (Rofecoxib); PharmSciTech 4,33/1 (2003). centrifuged, filtered through a sintered glass crucible (grade 4), and diluted C H O S; [162011-90-7] quantitatively with l0% aqueous dimethyl sulfoxide for spectroscopic 17 14 4 (2) Polyethylene glycol 400 analyses. Concentration of the dissolved solute was determined from the (PEG 400) measured absorbance at 263 nm. Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 298.15 W. E. Acree, Jr. (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no purification details were provided. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, Experimental Values Ltd., Mumbai, India, no purification details were provided. The measured solubility was reported to be c1 ¼ 0.0357 3 Estimated Error: mol dm . Temperature: No information given in the paper.

c1: 5% (relative error, estimated by compiler). Auxiliary Information Method/Apparatus/Procedure: Vortex mixer, constant-temperature bath, and an ultraviolet/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in sealed containers and equilibrated at a 189 (1) 3-Phenyl-4-[4-(methylsulfonyl)- K. M. El-Say, A. M. Samy, and constant temperature for 24 h. During this time the tubes were shaken phenyl]-2(5H)-furanone (Rofecoxib); M. I. Fetouh, Int. J. Pharm. Sci. occasionally on a vortex mixer. Aliquots of saturated solutions were removed, [ ] C17H14O4S; 162011-90-7 Rev. Res. 3, 135 (2010). centrifuged, filtered through a sintered glass crucible (grade 4), and diluted (2) 1,2,3-Propanetriol (Glycerol); quantitatively with l0% aqueous dimethyl sulfoxide for spectroscopic [ ] C3H8O3; 56-81-5 analyses. Concentration of the dissolved solute was determined from the Variables: Prepared by: measured absorbance at 263 nm. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no Experimental Values purification details were provided. (2) Purity not given, Analytical Reagent grade, Merck Chemical Company, ¼ The measured solubility was reported to be s1 0.2405 Ltd., Mumbai, India, no purification details were provided. (mass percent). Estimated Error: Temperature: No information given in the paper. Auxiliary Information c1: 5% (relative error, estimated by compiler). Method/Apparatus/Procedure: Ultrasonic bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in sealed test tubes and sonicated for 48 h. The sample was then cooled to 298 K. The solution was then filtered Components: Original Measurements: through a 0.45 μm Millipore filter, and a weighted aliquot of the filtered (1) 3-Phenyl-4-[4-(methylsulfonyl)- 189K. M. El-Say, A. M. Samy, and supernatant solution was diluted with methanol for spectrophotometric phenyl]-2(5H)-furanone (Rofecoxib); M. I. Fetouh, Int. J. Pharm. Sci. analysis at 268 nm. C17H14O4S; [162011-90-7] Rev. Res. 3, 135 (2010). (2) Polyethylene glycol 400 Source and Purity of Chemicals: (PEG 400) (1) Purity not given, Egyptian International Pharmaceutical Industries Company, Egypt, no purification details were provided. Variables: Prepared by: (2) Purity not given, El-Nasr Pharmaceutical Chemicals, Egypt, no purification T/K ¼ 298.15 W. E. Acree, Jr. details were provided.

Estimated Error: Experimental Values Temperature: No information given in the paper. The measured solubility was reported to be s ¼ 0.9569 s : 5% (relative error, estimated by compiler). 1 1 (mass percent).

Auxiliary Information Variables: Prepared by: T/K ¼ 298; Solvent composition W. E. Acree, Jr. Method/Apparatus/Procedure: Ultrasonic bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in sealed test tubes and sonicated for 48 h. Experimental Values The sample was then cooled to 298 K. The solution was then filtered through a 0.45 μm Millipore filter, and a weighted aliquot of the filtered supernatant solution

was diluted with methanol for spectrophotometric analysis at 268 nm. ðsÞa b v2 c1 Source and Purity of Chemicals: 0.00 0.0357 (1) Purity not given, Egyptian International Pharmaceutical Industries 0.10 0.0285 Company, Egypt, no puriﬁcation details were provided. 0.20 0.0259 (2) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no 0.40 0.0126 puriﬁcation details were provided. 0.60 0.00709 0.80 0.00320 Estimated Error: 1.00 0.00217 ð Þ Temperature: No information given in the paper. av s : volume fraction of component 2 in the initial binary solvent mixture s : 5% (relative error, estimated by compiler). 2 1 calculated as if the dissolved solute were not present. b 3 c1: molar solubility of the solute in units of mol dm .

Components: Original Measurements: Auxiliary Information (1) 3-Phenyl-4-[4-(methylsulfonyl)- 189K. M. El-Say, A. M. Samy, and Method/Apparatus/Procedure: phenyl]-2(5H)-furanone (Rofecoxib); M. I. Fetouh, Int. J. Pharm. Sci. Vortex mixer, constant-temperature bath, and an ultraviolet/visible C H O S; [162011-90-7] Rev. Res. 3, 135 (2010). 17 14 4 spectrophotometer. (2) Polyethylene glycol 600 Binary solvent mixtures were prepared by volume. Excess solute and solvent (PEG 600) were placed in sealed containers and equilibrated at a constant temperature for Variables: Prepared by: 24 h. During this time the tubes were shaken occasionally on a vortex mixer. T/K ¼ 298.15 W. E. Acree, Jr. Aliquots of saturated solutions were removed, centrifuged, filtered through a sintered glass crucible (grade 4), and diluted quantitatively with l0% aqueous dimethyl sulfoxide for spectroscopic analyses. Concentration of the dissolved Experimental Values solute was determined from the measured absorbance at 263 nm. The measured solubility was reported to be s ¼ 1.0382 1 Source and Purity of Chemicals: (mass percent). (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no purification details were provided. Auxiliary Information (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. Method/Apparatus/Procedure: (3) Purity not given, Analytical Reagent grade, Merck Chemical Company, Ultrasonic bath and an ultraviolet/visible spectrophotometer. Ltd., Mumbai, India, no purification details were provided. Excess solute and solvent were placed in sealed test tubes and sonicated for 48 h. The sample was then cooled to 298 K. The solution was then filtered through a Estimated Error: 0.45 μm Millipore filter, and a weighted aliquot of the filtered supernatant solution Temperature: No information given in the paper. was diluted with methanol for spectrophotometric analysis at 268 nm. ðsÞ v2 : 0.01. % Source and Purity of Chemicals: c1: 5.0 (relative error, estimated by compiler). (1) Purity not given, Egyptian International Pharmaceutical Industries Company, Egypt, no purification details were provided. (2) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. Components: Original Measurements: (1) 3-Phenyl-4-[4-(methylsulfonyl)- 67N. Seedher and S. Bhatia, AAPS Estimated Error: phenyl]-2(5H)-furanone (Rofecoxib); PharmSciTech 4,33/1 (2003).

Temperature: No information given in the paper. C17H14O4S; [162011-90-7] % s1: 5 (relative error, estimated by compiler). (2) Ethanol; C2H6O; [64-17-5] (3) 1,2,3-Propanetriol (Glycerol);

C3H8O3; [56-81-5] Variables: Prepared by: 26.4. Rofecoxib solubility data in binary organic T/K ¼ 298; Solvent composition W. E. Acree, Jr. solvent mixtures

Components: Original Measurements: (1) 3-Phenyl-4-[4-(methylsulfonyl)- 67N. Seedher and S. Bhatia, AAPS phenyl]-2(5H)-furanone (Rofecoxib); PharmSciTech 4,33/1 (2003).

C17H14O4S; [162011-90-7] (2) Ethanol; C2H6O; [64-17-5] (3) Polyethylene glycol 400 (PEG 400)

Experimental Values (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pen-

ð Þ tanol, 1-hexanol, 1-heptanol, 1-octanol, 1-decanol, cyclohex- v s a c b 2 1 anol, benzenemethanol, 1,2-ethanediol, 1,2-propanediol, and 0.00 0.000343 1,2,3-propanetriol), in one alkoxyalcohol (2-ethoxyethanol), 0.10 0.000394 0.20 0.000646 in four alkanones (propanone, butanone, 2-pentanone, cyclo- 0.40 0.001730 hexanone), in one aromatic ketone (acetophenone), and in 0.60 0.002179 several miscellaneous organic solvents (N-methyl-2-pyrroli- 0.80 0.002414 done, propylene carbonate, dimethyl sulfoxide, formamide, 0.90 0.002351 N-methylformamide, N,N-dimethylformamide, ethanenitrile, 1.00 0.002173 nitrobenzene, ethanoic acid, propanoic acid, 9(Z)-octadece- a ðsÞ v2 : volume fraction of component 2 in the initial binary solvent mixture noic acid (oleic acid), ethyl 2-hydroxypropanoate, 1-methyl- calculated as if the dissolved solute were not present. ethyl 2-hydroxypropanoate, and butyl 2-hydroxypropanoate). bc : molar solubility of the solute in units of mol dm3. 1 The compilations also included salicylic acid solubilities in binary ethanol + ethyl ethanoate, propanone + benzene, ethyl Auxiliary Information ethanoate + benzene, and heptane + ethanol solvent mixtures. Method/Apparatus/Procedure: While many of the measurements were performed at 298 K, / Vortex mixer, constant-temperature bath, and an ultraviolet visible there is considerable solubility data for other temperatures as spectrophotometer. Binary solvent mixtures were prepared by volume. Excess solute and solvent well. The compiled solubility data were correlated with the were placed in sealed containers and equilibrated at a constant temperature for Abraham solvation parameter model. As an informational 24 h. During this time the tubes were shaken occasionally on a vortex mixer. note, Vol. 90 (Refs. 1 and 2) also contains solubility data for Aliquots of saturated solutions were removed, centrifuged, filtered through a salicylic acid in water and in aqueous-organic solvent % sintered glass crucible (grade 4), and diluted quantitatively with l0 aqueous mixtures. dimethyl sulfoxide for spectroscopic analyses. Concentration of the dissolved solute was determined from the measured absorbance at 263 nm. Solubility data contained in Vols. 90 (Refs. 1 and 2) and 99 (Ref. 3) will not be republished here. The listing above is Source and Purity of Chemicals: provided so that readers will know what solubility data are (1) Purity not given, Ranbaxy Research Laboratories, Gurgaon, India, no available in the earlier volume for salicylic acid. There were a purification details were provided. few additional solubility measurements found in the published (2) Purity not given, Analytical Reagent grade, chemical source not specified, 65,105,190 no purification details were provided. pharmaceutical literature for salicylic acid. Wang 105 (3) Purity not given, Analytical Reagent grade, Merck Chemical Company, et al. determined the mole-fraction solubility of salicylic Ltd., Mumbai, India, no purification details were provided. acid in methanol and polyethylene glycol 300 (PEG 300) at 298 K. Matsuda et al.190 also measured the mole-fraction Estimated Error: solubility of salicylic acid in PEG 300 at 298 K. The two sets Temperature: No information given in the paper. ¼ ðsÞ for PEG 300 do differ, a mole-fraction solubility of x1 v2 : 0.01. 0.4931 in Ref. 190 versus x1 ¼ 0.3921 in Ref. 105. Rytting c1: 5.0% (relative error, estimated by compiler). et al.65 reported the molar solubility of salicylic acid in PEG 400 at ambient room temperature. The experimental solubility data for salicylic acid in organic 27. Solubility of Salicylic Acid in Organic solvents are in Secs. 27.2 and 27.3. Solvents 27.1. Critical evaluation of experimental solubility 27.2. Salicylic acid solubility data in alcohols data

Volumes 90 (Refs. 1 and 2) and 99 (Ref. 3) in the IUPAC- Components: Original Measurements: NIST Solubility Data Series contained experimental solubility (1) 2-Hydroxybenzoic acid (Salicylic 105X. Wang, C. S. Ponder, and [ ] data for salicylic acid (more formally named 2-hydroxyben- acid); C7H6O3; 69-72-7 D. J. Kirwan, Cryst. Growth Des. [ ] 5, 85 (2005). zoic acid) in seven saturated hydrocarbons (hexane, heptane, (2) Methanol; CH4O; 67-56-1 2,2,4-trimethylpentane, decane, dodecane, hexadecane, and Variables: Prepared by: cyclohexane), in three aromatic hydrocarbons (benzene, T/K ¼ 298.15 W. E. Acree, Jr. methylbenzene, and 1,3-dimethylbenzene), in three alkyl alkanoates (ethyl ethanoate, butyl ethanoate, and 1-methyl- Experimental Values ethyl tetradecanoate), in one dialkyl ether (1,1-oxybisethane) and two cyclic ethers (tetrahydrofuran and 1,4-dioxane), in a b four haloalkanes (trichloromethane, tetrachloromethane, 1,2- x2 x1 dichloroethane, 1,1,1,2,2-pentachloroethane), in two haloalk- 0.9126 0.08739 a enes (trichloroethene and tetrachloroethene), in one chlori- x2: mole fraction of component 2 in the saturated solution. b nated aromatic hydrocarbon (chlorobenzene), in 18 alcohols x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-Hydroxybenzoic acid (Salicylic 105X. Wang, C. S. Ponder, and D. / Thermostated constant-temperature water bath and an UV visible acid); C7H6O3; [69-72-7] J. Kirwan, Cryst. Growth Des. 5, spectrophotometer. (2) Polyethylene glycol 300 85 (2005). Excess solute and solvent were placed in a sealed container and allowed to (PEG 300) equilibrate with agitation for 24 to 72 h in a constant-temperature thermostated water bath. Aliquots of saturated solutions were removed and ﬁltered through a Variables: Prepared by: / ¼ membrane ﬁlter of 0.22 μm pore size. Concentrations were determined by T K 298.15 W. E. Acree, Jr. spectrophotometric analysis at 304 nm.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Sigma-Aldrich Chemical Company, no puriﬁcation

details were provided. a b,c (2) Purity not given, chemical source not speciﬁed, no puriﬁcation details were x2 x1 provided. 0.6079 0.3921 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: bx : mole fraction solubility of the solute. 1 Temperature: 0.2 K (estimated by compiler). csolubility reported in the paper as 297 g of dissolved solute per kilogram of % x1: 4 (relative error, estimated by compiler). solvent. Mole fraction calculated by compiler assuming a molar mass of 300 g mol1 for PEG 300.

27.3. Salicylic acid solubility data in miscellaneous Auxiliary Information organic solvents Method/Apparatus/Procedure: Thermostated constant-temperature water bath and an UV/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in a sealed container and allowed to (1) 2-Hydroxybenzoic acid (Salicylic 190H. Matsuda, K. Kaburagi, S. equilibrate with agitation for 24 to 72 h in a constant-temperature thermostated water bath. Aliquots of saturated solutions were removed and filtered through a acid); C7H6O3; [69-72-7] Matsumoto, K. Kurihara, K. membrane filter of 0.22 μm pore size. Concentrations were determined by (2) Polyethylene glycol 300 Tochigi, and K. Tomono, J. Chem. spectrophotometric analysis at 304 nm. (PEG 300) Eng. Data 54, 480 (2009). Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 298.15 W. E. Acree, Jr. (1) Purity not given, Sigma-Aldrich Chemical Company, no purification details were provided. (2) Purity not given, chemical source not specified, no purification details were Experimental Values provided.

Estimated Error: a b x2 x1 Temperature: 0.2 K (estimated by compiler). % 0.5069 0.4931 x1: 4 (relative error, estimated by compiler). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Components: Original Measurements: 65 Auxiliary Information (1) 2-Hydroxybenzoic acid (Salicylic E. Rytting, K. A. Lentz, X.-Q. acid); C H O ; [69-72-7] Chen, F. Qian, and S. Venkatesh, / / 7 6 3 Method Apparatus Procedure: (2) Polyethylene glycol 400 AAPS J. 7, E78 (2005). Thermostated constant-temperature water bath and high-performance liquid (PEG 400) chromatograph with uv detector. Excess solute and solvent were allowed to equilibrate for 24 h in a constant- Variables: Prepared by: temperature thermostated water bath. Aliquots of saturated solutions were T/K ¼ 296 W. E. Acree, Jr. removed and filtered through a membrane filter of 0.45 μm pore size (Millipore, USA). Concentrations were determined by high-performance liquid chromatography equipped with an UV detector (254 nm detection). Experimental Values Benzene was added to the sample as an internal standard. The measured solubility was reported to be c1 ¼ 2.301 mol dm3. Source and Purity of Chemicals: (1) 99.5%, Wako Pure Chemical Industries, Ltd., Japan, was used without further purification. (2) Purity not given, chemical source not specified, no purification details were provided.

Estimated Error: Temperature: 0.05 K.

x1: 2% (relative error).

Auxiliary Information eous-alcohol solvent mixtures at 298 K. The authors reported Method/Apparatus/Procedure: molar sodium diclofenac solubilities in the neat alcohols Centrifuge and a high-performance liquid chromatograph equipped with a (methanol, ethanol and 2-propanol) as part of their experi- photo-diode array detector. mental measurements. Excess solute and solvent were placed in sealed vials and shaken at ambient There have been three studies89,191,195 examining the solu- room temperature for at least 24 h. The vials were then centrifuged for 15 min to separate the saturated solution from the excess solute. The supernatant was bility of sodium diclofenac as a function of temperature. Zilnik 191 then filtered and the concentration of the dissolved solute determined by high- et al. determined the solubility of sodium diclofenac in ethyl performance liquid chromatographic analysis. ethanoate, propanone and dimethyl sulfoxide at several temperatures between 293 and 313 K. The experimental solid- Source and Purity of Chemicals: liquid equilibrium data were modeled using expressions based (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, USA, no purification details were provided. on the Nonrandom Two Liquid (NRTL) and UNIQUAC (2) Purity not given, J. T. Baker Chemical Company, Phillipsburg, New Jersey, models. The authors found that both solution models provided USA, no purification details were provided. a reasonably accurate mathematical description of the observed solubility behavior of sodium diclofenac in the three Estimated Error: solvents, with average relative deviations between the back- Temperature: 2 K (estimated by compiler). calculated and measured data on the order of 2% or less. c1: 10% (relative error, estimated by compiler). Nayak195 measured the solubility of sodium diclofenac in several natural oils (olive oil, castor oil, sunflower oil, soybean oil, and arachis oil) from 300 to 315 K. Domanska et al.89 28. Solubility of Sodium Diclofenac in determined the mole fraction solubility of sodium diclofenac Organic Solvents in both ethanol and 1-octanol at several temperatures using a dynamic method that recorded the temperature at which the 28.1. Critical evaluation of experimental solubility last crystal dissolved. The internal consistency of the latter two data datasets was assessed by curve-fitting the measured mole Sodium diclofenac is a NSAID agent that is widely used in fraction solubility data to the Modified Apelblat model [see long-term therapy for individuals suffering with rheumatoid Eq. (8)] to yield the following representations: arthritis. There have been several studies81,100,164,191–195 115:57 involving the solubility of sodium diclofenac in organic ln x ¼13:670 þ þ 1:514 ln T; ð34Þ 1 T solvents. Most notably, Bustamante et al.164 measured the mole fraction solubility of sodium diclofenac in 22 different 114:02 organic solvents, including two saturated hydrocarbons (hep- ln x1 ¼79:513 þ þ 13:039 ln T; ð35Þ tane and cyclohexane), one aromatic hydrocarbon (benzene), T one alkyl alkanoate (ethyl ethanoate), one dialkyl ether (1,1′- for solubilities in ethanol and 1-octanol, respectively. The oxybisethane) and one cyclic ether (1,4-dioxane), two chlor- mean absolute relative deviations between the observed oalkanes (trichloromethane and 1,2-dichloroethane) and one experimental data and back-calculated values based on chlorinated aromatic hydrocarbon (chlorobenzene), seven Eqs. (34) and (35) are MARD ¼ 1.3% and MARD ¼ 5.1%, alcohols (methanol, ethanol, 1-pentanol, 1-octanol, 1,2-etha- the latter of which is slightly more than the experimental nediol, 1,2-propanediol, and 1,2,3-propanetriol), one alkanone uncertainty associated with the measured values. (propanone) and one aromatic ketone (acetophenone), and The experimental solubility data for sodium diclofenac in four miscellaneous organic solvents (ethanoic acid, propanoic organic solvents are in Secs. 28.2–28.9. acid, formamide, and N,N-dimethylformamide) at 298 K and atmospheric pressure. The experimental results were combined with measured solubility data for diclofenac and two 28.2. Sodium diclofenac solubility data in saturated other carboxylic acid/sodium carboxylate pairs (e.g., 4-ami- hydrocarbons (including cycloalkanes) nobenzoic acid/sodium 4-aminobenzoate and salicylic acid/ sodium salicylate) in developing a group-contribution method Components: Original Measurements: for calculating partial solubility parameters of sodium salts. 164 ñ 194 (1) 2-(2,6-Dichloroanilino)- P. Bustamante, M. A. Pe a, and Minghetti et al. determined the solubility of the sodium and phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, potassium salts of diclofenac in different penetration vehicles (Sodium diclofenac); 975 (1998). [ ] (1,2-propanediol and oleic acid) at 305 K as part of a study C14H10Cl2NNaO2; 15307-79-6 [ ] examining transdermal permeation of pharmaceutical salts. (2) Heptane; C7H16; 142-82-5 100 Takahashi et al. measured the solubility of sodium diclo- Variables: Prepared by: fenac in diethyl butanedioate, diethyl hexanedioate, diisopro- T/K ¼ 298.15 W. E. Acree, Jr. pyl hexanedioate, and diethyl decanedioate at 305 K in their study concerning the use of fatty diesters as a means to enhance NSAID permeation through skin. Saei et al.192 investigated the solubility behavior of sodium diclofenac in three binary aqu-

Experimental Values Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. x a x b,c,d 2 1 Excess solute and solvent were placed in flasks and allowed to equilibrate with 0.9815 0.01850 shaking for several days at constant temperature. After equilibrium was a attained, aliquots of saturated solutions were removed, filtered through 0.2 μm x2: mole fraction of component 2 in the saturated solution. b pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were x1: mole fraction solubility of the solute. c determined by spectrophotometric measurements at 284 nm. The reported Experimental value was reported in the paper as ln x1. dThe experimental solubility in heptane is out of line with measured values for solubility represents the average of at least three independent determinations. other nonpolar solvents, like cyclohexane and benzene. The reported mole The density of the saturated solution was determined in order to convert the 3 fraction solubility of sodium diclofenac in these latter two solvents is sig- measured molar solubilities in units of mol dm to mole fractions. nificantly smaller. Source and Purity of Chemicals: (1) Purity not given, USPA, France, no purification details were provided. Auxiliary Information (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Method/Apparatus/Procedure: / Constant-temperature bath and an ultraviolet visible spectrophotometer. Estimated Error: Excess solute and solvent were placed in flasks and allowed to equilibrate with Temperature: 0.1 K. shaking for several days at constant temperature. After equilibrium was x1: 2% (relative error). attained, aliquots of saturated solutions were removed, filtered through 0.2 μm pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 284 nm. The reported 28.3. Sodium diclofenac solubility data in aromatic solubility represents the average of at least three independent determinations. The density of the saturated solution was determined in order to convert the hydrocarbons measured molar solubilities in units of mol dm3 to mole fractions.

Source and Purity of Chemicals: Components: Original Measurements: (1) Purity not given, USPA, France, no purification details were provided. (1) 2-(2,6-Dichloroanilino)- 164P. Bustamante, M. A. Peña, and (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, source not specified, no purification details were provided. (Sodium diclofenac); 975 (1998).

C14H10Cl2NNaO2; [15307-79-6] Estimated Error: (2) Benzene; C6H6; [71-43-2] Temperature: 0.1 K. Variables: Prepared by: x1: 2% (relative error). T/K ¼ 298.15 W. E. Acree, Jr.

Experimental Values Components: Original Measurements: (1) 2-(2,6-Dichloroanilino)- 164P. Bustamante, M. A. Peña, and phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, a b,c x2 x1 (Sodium diclofenac); 975 (1998). 0.9999 0.00000452 C14H10Cl2NNaO2; [15307-79-6] a (2) Cyclohexane; C6H12; [110-82-7] x2: mole fraction of component 2 in the saturated solution. bx : mole fraction solubility of the solute. Variables: Prepared by: 1 cExperimental value was reported in the paper as ln x . T/K ¼ 298.15 W. E. Acree, Jr. 1

Auxiliary Information Experimental Values Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with x a x b,c 2 1 shaking for several days at constant temperature. After equilibrium was 0.9999 0.00000317 attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 μm a pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were x2: mole fraction of component 2 in the saturated solution. b determined by spectrophotometric measurements at 284 nm. The reported x1: mole fraction solubility of the solute. c solubility represents the average of at least three independent determinations. Experimental value was reported in the paper as ln x1. The density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions.

Source and Purity of Chemicals: (1) Purity not given, USPA, France, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided.

Estimated Error: Temperature: 0.1 K.

x1: 2% (relative error).

28.4. Sodium diclofenac solubility data in esters Experimental Values

a T/K s1 Components: Original Measurements: (1) 2-(2,6-Dichloroanilino)- 164P. Bustamante, M. A. Peña, and 293.15 0.00119 phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, 298.15 0.00126 (Sodium diclofenac); 975 (1998). 303.15 0.00140 308.15 0.00160 C14H10Cl2NNaO2; [15307-79-6] a (2) Ethyl ethanoate; C4H8O2; s1: mass/mass solubility of the solute in units of grams of solute per gram of [141-78-6] solution. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Auxiliary Information Method/Apparatus/Procedure: Experimental Values Constant-temperature shaker bath, ultrasonic bath, and an UV/visible spectrophotometer. Excess solute and solvent were placed in sealed flasks, agitated in an ultrasonic a b,c x2 x1 bath, and then transferred to a constant-temperature shaker bath for at least 0.9843 0.01569 48 h. After phase equilibrium was attained, the excess solid was removed by μ a filtration using a 0.20 m pore size membrane filter, and the filtrate was diluted x2: mole fraction of component 2 in the saturated solution. b with dimethyl sulfoxide. The concentration of the dissolved solute was x1: mole fraction solubility of the solute. c determined spectrometrically at 285 nm. Experimental value was reported in the paper as ln x1. Source and Purity of Chemicals: (1) Purity not given, Pharmaceutical Company, Novo mesto, Slovenia, was Auxiliary Information used as received. The water content of the drug was determined to be 0.49 Method/Apparatus/Procedure: mass % by Karl Fischer titration. Constant-temperature bath and an ultraviolet/visible spectrophotometer. (2) 99.8+%, Analytical or Chromatographic grade, Merck Chemical Excess solute and solvent were placed in flasks and allowed to equilibrate with Company, was used as received. shaking for several days at constant temperature. After equilibrium was attained, aliquots of saturated solutions were removed, filtered through 0.2 μm Estimated Error: pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were Temperature: 0.1 K. % determined by spectrophotometric measurements at 284 nm. The reported s1: 5 (relative error, estimated by compiler). solubility represents the average of at least three independent determinations. The density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions. Components: Original Measurements: Source and Purity of Chemicals: (1) 2-(2,6-Dichloroanilino)- 81M. A. H. M. Kamal, N. Imura, (1) Purity not given, USPA, France, no purification details were provided. phenylacetic acid sodium salt T. Nabekura, and S. Kitagawa, (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical (Sodium diclofenac); Chem. Pharm. Bull. 55, 368 source not specified, no purification details were provided. C14H10Cl2NNaO2; [15307-79-6] (2007). (2) 1-Methylethyl tetradecanoate; Estimated Error: C17H34O2; [110-27-0] Temperature: 0.1 K. Variables: Prepared by: x1: 2% (relative error). T/K ¼ 310 W. E. Acree, Jr.

Experimental Values Components: Original Measurements: 191 ¼ (1) 2-(2,6-Dichloroanilino)- L. F. Zilnik, A. Jazbinsek, The measured solubility was reported to be c1 0.000071 3 phenylacetic acid sodium salt A. Hvala, F. Vrecer, and A. Klamt, mol dm . (Sodium diclofenac); Fluid Phase Equilib. 261, 140 C H Cl NNaO ; [15307-79-6] (2007). 14 10 2 2 Auxiliary Information (2) Ethyl ethanoate; C4H8O2; [141-78-6] Method/Apparatus/Procedure: Very few experimental details were given in the paper. Excess solute and Variables: Prepared by: solvent were allowed to equilibrate at 310 K for a period of 24 h. An aliquot of Temperature W. E. Acree, Jr. the solution was removed and quickly centrifuged for 2 min. The concentration of the dissolved solute in the supernatant was determined by high-performance liquid chromatographic analysis.

Source and Purity of Chemicals: (1) Purity not given, Wako Pure Chemical Industries, Osaka, Japan, no puriﬁcation details were given in the paper. (2) Purity not given, Nascalai Tesque, Kyoto, Japan, no puriﬁcation details were provided in the paper.

Estimated Error: Source and Purity of Chemicals: Temperature: Insufﬁcient information given in the paper to estimate. (1) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka,

c1: 10% (relative error, estimated by compiler). Japan, no puriﬁcation details were provided in the paper. (2) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Japan, no puriﬁcation details were provided in the paper.

Estimated Error: Components: Original Measurements: (1) 2-(2,6-Dichloroanilino)- 100K. Takahashi, H. Sakano, Temperature: 0.2 K (estimated by compiler). c % phenylacetic acid sodium salt N. Numata, S. Kuroda, and 1: 5 (relative error, estimated by compiler). (Sodium diclofenac); N. Mizuno, Drug Develop. Ind.

C14H10Cl2NNaO2; [15307-79-6] Pharm. 28, 1285 (2002). (2) Diethyl butanedioate; C8H14O4; [123-25-1] Components: Original Measurements: (1) 2-(2,6-Dichloroanilino)- 100K. Takahashi, H. Sakano, Variables: Prepared by: phenylacetic acid sodium salt N. Numata, S. Kuroda, and T/K ¼ 305.15 W. E. Acree, Jr. (Sodium diclofenac); N. Mizuno, Drug Develop. Ind.

C14H10Cl2NNaO2; [15307-79-6] Pharm. 28, 1285 (2002). (2) Diisopropyl hexanedioate; Experimental Values C12H22O4; [6938-94-9] The measured solubility was reported to be c1 ¼ 0.1286 3 Variables: Prepared by: mol dm . T/K ¼ 305.15 W. E. Acree, Jr.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: Constant-temperature bath and a high-performance liquid chromatograph. The measured solubility was reported to be c1 ¼ 0.0928 Excess solute and solvent were allowed to equilibrate with agitation for 24 h at mol dm 3. constant temperature. The saturated solution was removed and filtered through a 0.45 μm membrane filter. The concentration of the dissolved solute was Auxiliary Information determined by high-performance liquid chromatographic analysis. Method/Apparatus/Procedure: Source and Purity of Chemicals: Constant-temperature bath and a high-performance liquid chromatograph. (1) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Excess solute and solvent were allowed to equilibrate with agitation for 24 h at Japan, no purification details were provided in the paper. constant temperature. The saturated solution was removed and filtered through (2) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, a 0.45 μm membrane filter. The concentration of the dissolved solute was Japan, no purification details were provided in the paper. determined by high-performance liquid chromatographic analysis.

Estimated Error: Source and Purity of Chemicals: Temperature: 0.2 K (estimated by compiler). (1) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka,

c1: 5% (relative error, estimated by compiler). Japan, no puriﬁcation details were provided in the paper. (2) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Japan, no puriﬁcation details were provided in the paper.

C14H10Cl2NNaO2; [15307-79-6] Pharm. 28, 1285 (2002). (2) Diethyl hexanedioate; C10H18O4; [141-28-6] Components: Original Measurements: (1) 2-(2,6-Dichloroanilino)- 100K. Takahashi, H. Sakano, Variables: Prepared by: phenylacetic acid sodium salt N. Numata, S. Kuroda, and T/K ¼ 305.15 W. E. Acree, Jr. (Sodium diclofenac); N. Mizuno, Drug Develop. Ind.

C14H10Cl2NNaO2; [15307-79-6] Pharm. 28, 1285 (2002). (2) Diethyl decanedioate; C H O ; Experimental Values 14 26 4 [110-40-7] The measured solubility was reported to be c1 ¼ 0.1418 3 Variables: Prepared by: mol dm . T/K ¼ 305.15 W. E. Acree, Jr.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-(2,6-Dichloroanilino)- 164P. Bustamante, M. A. Peña, and Constant-temperature bath and a high-performance liquid chromatograph. phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, Excess solute and solvent were allowed to equilibrate with agitation for 24 h at (Sodium diclofenac); 975 (1998). constant temperature. The saturated solution was removed and filtered through C14H10Cl2NNaO2; [15307-79-6] a 0.45 μm membrane filter. The concentration of the dissolved solute was (2) 1,4-Dioxane; C4H8O2; [123-91-1] determined by high-performance liquid chromatographic analysis. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Japan, no purification details were provided in the paper. Experimental Values (2) Purity not given, Wako Pure Chemical Industries Company, Ltd., Osaka, Japan, no purification details were provided in the paper. x a x b,c Estimated Error: 2 1 Temperature: 0.2 K (estimated by compiler). 0.9999 0.0000535 % a c1: 5 (relative error, estimated by compiler). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

28.5. Sodium diclofenac solubility data in ethers Auxiliary Information Method/Apparatus/Procedure: / Components: Original Measurements: Constant-temperature bath and an ultraviolet visible spectrophotometer. (1) 2-(2,6-Dichloroanilino)- 164P. Bustamante, M. A. Peña, and Excess solute and solvent were placed in flasks and allowed to equilibrate with phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, shaking for several days at constant temperature. After equilibrium was μ (Sodium diclofenac); 975 (1998). attained, aliquots of saturated solutions were removed, filtered through 0.2 m % / C H Cl NNaO ; [15307-79-6] pore size membranes, and diluted with 96 ethanol (v v). Concentrations were 14 10 2 2 determined by spectrophotometric measurements at 284 nm. The reported (2) 1,1′-Oxybisethane; C4H10O; [60-29-7] solubility represents the average of at least three independent determinations. The density of the saturated solution was determined in order to convert the Variables: Prepared by: measured molar solubilities in units of mol dm3 to mole fractions. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, USPA, France, no purification details were provided. Experimental Values (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided.

a b,c x2 x1 Estimated Error: 0.9995 0.000527 Temperature: 0.1 K. % a x1: 2 (relative error). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. 28.6. Sodium diclofenac solubility data in Auxiliary Information haloalkanes, haloalkenes, and haloaromatic Method/Apparatus/Procedure: hydrocarbons Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with shaking for several days at constant temperature. After equilibrium was Components: Original Measurements: μ attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 m (1) 2-(2,6-Dichloroanilino)- 164P. Bustamante, M. A. Peña, and % / pore size membranes, and diluted with 96 ethanol (v v). Concentrations were phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, determined by spectrophotometric measurements at 284 nm. The reported (Sodium diclofenac); 975 (1998). solubility represents the average of at least three independent determinations. C14H10Cl2NNaO2; [15307-79-6] The density of the saturated solution was determined in order to convert the 3 (2) Trichloromethane; CHCl3; measured molar solubilities in units of mol dm to mole fractions. [67-66-3]

Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, USPA, France, no purification details were provided. T/K ¼ 298.15 W. E. Acree, Jr. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided.

Estimated Error: Temperature: 0.1 K.

x1: 2% (relative error).

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-(2,6-Dichloroanilino)- 164P. Bustamante, M. A. Peña, and Constant-temperature bath and an ultraviolet/visible spectrophotometer. phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, Excess solute and solvent were placed in flasks and allowed to equilibrate with (Sodium diclofenac); 975 (1998). shaking for several days at constant temperature. After equilibrium was C14H10Cl2NNaO2; [15307-79-6] attained, aliquots of saturated solutions were removed, filtered through 0.2 μm (2) Chlorobenzene; C6H5Cl; pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were [108-90-7] determined by spectrophotometric measurements at 284 nm. The reported Variables: Prepared by: solubility represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr. The density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions. Experimental Values Source and Purity of Chemicals: (1) Purity not given, USPA, France, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x a x b,c source not specified, no purification details were provided. 2 1 0.9999 0.0000220 a Estimated Error: x2: mole fraction of component 2 in the saturated solution. b Temperature: 0.1 K. x1: mole fraction solubility of the solute. % c x1: 2 (relative error). Experimental value was reported in the paper as ln x1.

Auxiliary Information / / Components: Original Measurements: Method Apparatus Procedure: / (1) 2-(2,6-Dichloroanilino)- 164P. Bustamante, M. A. Peña, and Constant-temperature bath and an ultraviolet visible spectrophotometer. phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with (Sodium diclofenac); 975 (1998). shaking for several days at constant temperature. After equilibrium was attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 μm C14H10Cl2NNaO2; [15307-79-6] (2) 1,2-Dichloroethane; C H Cl ; pore size membranes, and the solvent evaporated. The solid residue was then 2 4 2 % / [107-06-2] dissolved and diluted with 96 ethanol (v v). Concentrations were determined by spectrophotometric measurements at 284 nm. The reported solubility Variables: Prepared by: represents the average of at least three independent determinations. The T/K ¼ 298.15 W. E. Acree, Jr. density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions.

Auxiliary Information 28.7. Sodium diclofenac solubility data in alcohols Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with Components: Original Measurements: 164 ñ shaking for several days at constant temperature. After equilibrium was (1) 2-(2,6-Dichloroanilino)- P. Bustamante, M. A. Pe a, and attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 μm phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were (Sodium diclofenac); 975 (1998). [ ] determined by spectrophotometric measurements at 284 nm. The reported C14H10Cl2NNaO2; 15307-79-6 [ ] solubility represents the average of at least three independent determinations. (2) Methanol; CH4O; 67-56-1 The density of the saturated solution was determined in order to convert the Variables: Prepared by: 3 measured molar solubilities in units of mol dm to mole fractions. T/K ¼ 298.15 W. E. Acree, Jr.

Experimental Values Components: Original Measurements: (1) 2-(2,6-Dichloroanilino)- 192A. A. Saei, F. Jabbaribar, M. A.

a b,c phenylacetic acid sodium salt A. Fakhree, W. E. Acree, Jr., and x2 x1 (Sodium diclofenac); A. Jouyban, J. Drug Delivery Sci.

0.9401 0.05988 C14H10Cl2NNaO2; [15307-79-6] Technol. 18, 149 (2008). a (2) Ethanol; C2H6O; [64-17-5] x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Variables: Prepared by: c Experimental value was reported in the paper as ln x1. T/K ¼ 298.15 W. E. Acree, Jr.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: ¼ Constant-temperature bath and an ultraviolet/visible spectrophotometer. The measured solubility was reported to be c1 0.5202 3 Excess solute and solvent were placed in flasks and allowed to equilibrate with mol dm . shaking for several days at constant temperature. After equilibrium was μ attained, aliquots of saturated solutions were removed, filtered through 0.2 m Auxiliary Information pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 284 nm. The reported Method/Apparatus/Procedure: solubility represents the average of at least three independent determinations. Shaker and an UV/visible spectrophotometer. The density of the saturated solution was determined in order to convert the Excess solute and solvent were placed in glass bottles and allowed to measured molar solubilities in units of mol dm3 to mole fractions. equilibrate at 298 K with shaking for 24 h. Aliquots of saturated solutions were removed, quickly filtered using a 0.45 μm hydrophilic filter (Millipore, Source and Purity of Chemicals: Durapore, Ireland), and the concentration of the dissolved drug was (1) Purity not given, USPA, France, no purification details were provided. determined by spectrophotometric analysis at 275 nm after suitable dilution (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical with water. source not specified, no purification details were provided. Source and Purity of Chemicals: Estimated Error: (1) Purity not given, Sobhan Pharmaceutical Company, Rasht, Iran, no Temperature: 0.1 K. purification details were provided in the paper.

x1: 2% (relative error). (2) Purity not given, Absolute, Merck Chemical Company, no puriﬁcation details were provided in the paper.

Estimated Error: Components: Original Measurements: Temperature: 0.2 K. 192 (1) 2-(2,6-Dichloroanilino)- A. A. Saei, F. Jabbaribar, M. A. c1: 3% (relative error, estimated by compiler). phenylacetic acid sodium salt A. Fakhree, W. E. Acree, Jr., and (Sodium diclofenac); A. Jouyban, J. Drug Delivery Sci.

C14H10Cl2NNaO2; [15307-79-6] Technol. 18, 149 (2008). (2) Methanol; CH O; [67-56-1] 4 Components: Original Measurements: Variables: Prepared by: (1) 2-(2,6-Dichloroanilino)- 164P. Bustamante, M. A. Peña, and T/K ¼ 298.15 W. E. Acree, Jr. phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, (Sodium diclofenac); 975 (1998).

C14H10Cl2NNaO2; [15307-79-6] Experimental Values (2) Ethanol; C2H6O; [64-17-5]

The measured solubility was reported to be c1 ¼ 1.0466 Variables: Prepared by: mol dm 3. T/K ¼ 298.15 W. E. Acree, Jr. Auxiliary Information Method/Apparatus/Procedure: Experimental Values Shaker and an UV/visible spectrophotometer. Excess solute and solvent were placed in glass bottles and allowed to a b,c equilibrate at 298 K with shaking for 24 h. Aliquots of saturated solutions were x2 x1 removed, quickly filtered using a 0.45 μm hydrophilic filter (Millipore, 0.9920 0.007983 Durapore, Ireland), and the concentration of the dissolved drug was a x2: mole fraction of component 2 in the saturated solution. determined by spectrophotometric analysis at 275 nm after suitable dilution b x1: mole fraction solubility of the solute. with water. c Experimental value was reported in the paper as ln x1. Source and Purity of Chemicals: (1) Purity not given, Sobhan Pharmaceutical Company, Rasht, Iran, no purification details were provided in the paper. (2) Purity not given, HPLC grade, Caledon, Georgetown, Canada, no purification details were provided in the paper.

Estimated Error: Temperature: 0.2 K.

c1: 3% (relative error, estimated by compiler).

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-(2,6-Dichloroanilino)- 192A. A. Saei, F. Jabbaribar, M. A. Constant-temperature bath and an ultraviolet/visible spectrophotometer. phenylacetic acid sodium salt A. Fakhree, W. E. Acree, Jr., and Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with (Sodium diclofenac); A. Jouyban, J. Drug Delivery Sci. shaking for several days at constant temperature. After equilibrium was C14H10Cl2NNaO2; [15307-79-6] Technol. 18, 149 (2008). attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 μm (2) 2-Propanol; C3H8O; [67-63-0] pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were Variables: Prepared by: determined by spectrophotometric measurements at 284 nm. The reported T/K ¼ 298.15 W. E. Acree, Jr. solubility represents the average of at least three independent determinations. The density of the saturated solution was determined in order to convert the 3 measured molar solubilities in units of mol dm to mole fractions. Experimental Values

Source and Purity of Chemicals: The measured solubility was reported to be c1 ¼ 0.0256 (1) Purity not given, USPA, France, no purification details were provided. mol dm 3. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Auxiliary Information Estimated Error: Method/Apparatus/Procedure: Temperature: 0.1 K. Shaker and an UV/visible spectrophotometer. x1: 2% (relative error). Excess solute and solvent were placed in glass bottles and allowed to equilibrate at 298 K with shaking for 24 h. Aliquots of saturated solutions were removed, quickly filtered using a 0.45 μm hydrophilic filter (Millipore, Durapore, Ireland), and the concentration of the dissolved drug was Components: Original Measurements: determined by spectrophotometric analysis at 275 nm after suitable dilution (1) 2-(2,6-Dichloroanilino)- 89U. Domanska, A. Pobudkowska, with water. phenylacetic acid sodium salt and A. Pelczarska, J. Phys. Chem. (Sodium diclofenac); B 115, 2547 (2011). Source and Purity of Chemicals: (1) Purity not given, Sobhan Pharmaceutical Company, Rasht, Iran, no C14H10Cl2NNaO2; [15307-79-6] purification details were provided in the paper. (2) Ethanol; C2H6O; [64-17-5] (2) Purity not given, Absolute, Merck Chemical Company, no purification Variables: Prepared by: details were provided in the paper. Temperature W. E. Acree, Jr. Estimated Error: Temperature: 0.2 K. Experimental Values c1: 3% (relative error, estimated by compiler).

a b T/K x2 x1 292.1 0.9897 0.0103 Components: Original Measurements: 295.5 0.9895 0.0105 (1) 2-(2,6-Dichloroanilino)- 164P. Bustamante, M. A. Peña, and 313.1 0.9891 0.0109 phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, 333.5 0.9882 0.0118 (Sodium diclofenac); 975 (1998). 335.3 0.9877 0.0123 C14H10Cl2NNaO2; [15307-79-6] a [ ] x2: mole fraction of component 2 in the saturated solution. (2) 1-Pentanol; C5H12O; 71-41-0 bx : mole fraction solubility of the solute. 1 Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Auxiliary Information Method/Apparatus/Procedure: Experimental Values Thermostated water bath, analytical balance, stirrer, and electronic thermometer. Solubilities were determined using a dynamic method. Known amounts of x a x b,c solute and solvent were placed inside a Pyrex glass equilibrium cell, which was 2 1 then placed in a thermostated water bath. The sample was slowly heated 0.9927 0.007293 a (approximately 5 K/h) with continuous stirring. Temperature at which the last x2: mole fraction of component 2 in the saturated solution. b crystals disappeared was taken as the temperature of the solution-crystal x1: mole fraction solubility of the solute. c equilibrium. Experimental value was reported in the paper as ln x1.

Source and Purity of Chemicals: (1) 99+%, Sigma-Aldrich Chemical Company, St. Louis, Missouri, USA, was used as received. (2) 99.8+%, Sigma-Aldrich Chemical Company, was stored over freshly active molecular sieves of type 4 Å.

Estimated Error: Temperature: 0.1 K.

x1: 3% (relative error, estimated by compiler).

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-(2,6-Dichloroanilino)- 193A. Fini, G. Fazio, and A. M. Constant-temperature bath and an ultraviolet/visible spectrophotometer. phenylacetic acid sodium salt Rabasco, Acta Technol. Legis Excess solute and solvent were placed in flasks and allowed to equilibrate with (Sodium diclofenac); Med. 4, 33 (1993). shaking for several days at constant temperature. After equilibrium was C14H10Cl2NNaO2; [15307-79-6] attained, aliquots of saturated solutions were removed, filtered through 0.2 μm (2) 1-Octanol; C8H18O; [111-87-5] pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were Variables: Prepared by: determined by spectrophotometric measurements at 284 nm. The reported T/K ¼ 298.15 W. E. Acree, Jr. solubility represents the average of at least three independent determinations. The density of the saturated solution was determined in order to convert the 3 measured molar solubilities in units of mol dm to mole fractions. Experimental Values Source and Purity of Chemicals: (1) Purity not given, USPA, France, no purification details were provided. x a x b,c (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 2 1 source not specified, no purification details were provided. 0.9721 0.02788 a x2: mole fraction of component 2 in the saturated solution. b Estimated Error: x1: mole fraction solubility of the solute. Temperature: 0.1 K. cExperimental value was reported in the paper as a mass percent. x1: 2% (relative error).

Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: An ultraviolet/visible spectrophotometer. 164 (1) 2-(2,6-Dichloroanilino)- P. Bustamante, M. A. Peña, and Excess solute and solvent were placed in ﬂasks and allowed to pre-equilibrate phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, at 323 K to facilitate saturation. The temperature was then lowered to 298 K, (Sodium diclofenac); 975 (1998). and the salt excess crystallized. The sample was allowed to equilibrate at 298 K [ ] C14H10Cl2NNaO2; 15307-79-6 for one week. An aliquot of the sample was removed, centrifuged, and the [ ] (2) 1-Octanol; C8H18O; 111-87-5 concentration of the dissolved solute determined spectroscopically at 276 nm Variables: Prepared by: after dilution with ethanol. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, IBSA, Lugano, Switzerland, no puriﬁcation details were Experimental Values provided. (2) Purity not given, Analytical Reagent grade, Carlo Erba, Milano, Italy, was used as received. a b,c x2 x1 Estimated Error: 0.9999 0.0000293 Temperature: 0.1 K (estimated by compiler). a x2: mole fraction of component 2 in the saturated solution. x1: 4% (relative error, estimated by compiler). b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Components: Original Measurements: Auxiliary Information (1) 2-(2,6-Dichloroanilino)- 89U. Domanska, A. Pobudkowska, Method/Apparatus/Procedure: phenylacetic acid sodium salt and A. Pelczarska, J. Phys. Chem. Constant-temperature bath and an ultraviolet/visible spectrophotometer. (Sodium diclofenac); B 115, 2547 (2011). Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with C14H10Cl2NNaO2; [15307-79-6] shaking for several days at constant temperature. After equilibrium was (2) 1-Octanol; C8H18O; [111-87-5] attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 μm Variables: Prepared by: pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were Temperature W. E. Acree, Jr. determined by spectrophotometric measurements at 284 nm. The reported solubility represents the average of at least three independent determinations. The density of the saturated solution was determined in order to convert the Experimental Values measured molar solubilities in units of mol dm3 to mole fractions.

Source and Purity of Chemicals: T/K x a x b (1) Purity not given, USPA, France, no purification details were provided. 2 1 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 293.0 0.9943 0.0057 source not specified, no purification details were provided. 293.4 0.9933 0.0067 297.1 0.9917 0.0083 Estimated Error: 303.3 0.9902 0.0098 Temperature: 0.1 K. 319.8 0.9810 0.0190 % a x1: 2 (relative error). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-(2,6-Dichloroanilino)- 164P. Bustamante, M. A. Peña, and Thermostated water bath, analytical balance, stirrer, and electronic phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, thermometer. (Sodium diclofenac); 975 (1998). Solubilities were determined using a dynamic method. Known amounts of C14H10Cl2NNaO2; [15307-79-6] solute and solvent were placed inside a Pyrex glass equilibrium cell, which was (2) 1,2-Propanediol; C3H8O2; then placed in a thermostated water bath. The sample was slowly heated [57-55-6] (approximately 5 K/h) with continuous stirring. Temperature at which the last Variables: Prepared by: crystals disappeared was taken as the temperature of the solution-crystal T/K ¼ 298.15 W. E. Acree, Jr. equilibrium.

Source and Purity of Chemicals: Experimental Values (1) 99+%, Sigma-Aldrich Chemical Company, St. Louis, Missouri, USA, was used as received. (2) 99.8+%, Sigma-Aldrich Chemical Company, was stored over freshly active x a x b,c molecular sieves of type 4 Å. 2 1 0.9999 0.0000126 a Estimated Error: x2: mole fraction of component 2 in the saturated solution. b Temperature: 0.1 K. x1: mole fraction solubility of the solute. % c x1: 3 (relative error, estimated by compiler). Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: 164 (1) 2-(2,6-Dichloroanilino)- P. Bustamante, M. A. Peña, and Constant-temperature bath and an ultraviolet/visible spectrophotometer. phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with (Sodium diclofenac); 975 (1998). shaking for several days at constant temperature. After equilibrium was [ ] C14H10Cl2NNaO2; 15307-79-6 attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 μm (2) 1,2-Ethanediol; C2H6O2; pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were [107-21-1] determined by spectrophotometric measurements at 284 nm. The reported Variables: Prepared by: solubility represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr. The density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 2-(2,6-Dichloroanilino)- 194P. Minghetti, F. Cilurzo, Constant-temperature bath and an ultraviolet/visible spectrophotometer. phenylacetic acid sodium salt A. Casiraghi, L. Montanari, and Excess solute and solvent were placed in flasks and allowed to equilibrate with (Sodium diclofenac); A. Fini, J. Pharm. Sci. 96, 814 shaking for several days at constant temperature. After equilibrium was C14H10Cl2NNaO2; [15307-79-6] (2007). attained, aliquots of saturated solutions were removed, filtered through 0.2 μm (2) 1,2-Propanediol; C3H8O2; pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were [57-55-6] determined by spectrophotometric measurements at 284 nm. The reported Variables: Prepared by: solubility represents the average of at least three independent determinations. T/K ¼ 305 W. E. Acree, Jr. The density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions. Experimental Values Source and Purity of Chemicals: (1) Purity not given, USPA, France, no purification details were provided. The measured solubility was reported to be c1 ¼ 0.00178 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical mol dm 3. source not specified, no purification details were provided.

Estimated Error: Temperature: 0.1 K.

x1: 2% (relative error).

Auxiliary Information 28.8. Sodium diclofenac solubility data in ketones Method/Apparatus/Procedure: Magnetic stirrer and a high-performance liquid chromatograph. Excess solute and solvent were allowed to equilibrate at 305 K with vigorous Components: Original Measurements: stirring for 72 h. Aliquots of saturated solutions were removed, quickly filtered (1) 2-(2,6-Dichloroanilino)- 164P. Bustamante, M. A. Peña, and using a membrane filter, and the concentration of the dissolved drug was phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, determined by high-performance liquid chromatographic analysis at 254 nm (Sodium diclofenac); 975 (1998). after suitable dilution with methanol. C14H10Cl2NNaO2; [15307-79-6] (2) Propanone; C3H6O; [67-64-1] Source and Purity of Chemicals: (1) 99+%, Dipharma, UD, Italy, no purification details were provided in the Variables: Prepared by: / ¼ paper. T K 298.15 W. E. Acree, Jr. (2) Purity not given, Pharmaceutical grade, Carlo Erba Reagenti, Milano, Italy, no purification details were provided in the paper. Experimental Values Estimated Error: Temperature: 1K. x a x b,c c1: 6% (relative error). 2 1 0.9999 0.00000657 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Components: Original Measurements: Experimental value was reported in the paper as ln x1. (1) 2-(2,6-Dichloroanilino)- 164P. Bustamante, M. A. Peña, and phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, (Sodium diclofenac); 975 (1998). Auxiliary Information C H Cl NNaO ; [15307-79-6] 14 10 2 2 Method/Apparatus/Procedure: (2) 1,2,3-Propanetriol (Glycerol); Constant-temperature bath and an ultraviolet/visible spectrophotometer. C H O ; [56-81-5] 3 8 3 Excess solute and solvent were placed in flasks and allowed to equilibrate with Variables: Prepared by: shaking for several days at constant temperature. After equilibrium was T/K ¼ 298.15 W. E. Acree, Jr. attained, aliquots of saturated solutions were removed, filtered through 0.2 μm pore size membranes, and the solvent evaporated. The solid residue was then dissolved and diluted with 96% ethanol (v/v). Concentrations were determined Experimental Values by spectrophotometric measurements at 284 nm. The reported solubility represents the average of at least three independent determinations. The density of the saturated solution was determined in order to convert the a b,c 3 x2 x1 measured molar solubilities in units of mol dm to mole fractions. 0.8237 0.1763 a Source and Purity of Chemicals: x2: mole fraction of component 2 in the saturated solution. b (1) Purity not given, USPA, France, no purification details were provided. x1: mole fraction solubility of the solute. c (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Experimental value was reported in the paper as ln x1. source not specified, no purification details were provided.

Estimated Error: Auxiliary Information Temperature: 0.1 K. % Method/Apparatus/Procedure: x1: 2 (relative error). Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with shaking for several days at constant temperature. After equilibrium was μ attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 m Components: Original Measurements: % / 191 pore size membranes, and diluted with 96 ethanol (v v). Concentrations were (1) 2-(2,6-Dichloroanilino)- L. F. Zilnik, A. Jazbinsek, A. determined by spectrophotometric measurements at 284 nm. The reported phenylacetic acid sodium salt Hvala, F. Vrecer, and A. Klamt, solubility represents the average of at least three independent determinations. (Sodium diclofenac); Fluid Phase Equilib. 261, 140 The density of the saturated solution was determined in order to convert the C14H10Cl2NNaO2; [15307-79-6] (2007). measured molar solubilities in units of mol dm3 to mole fractions. (2) Propanone; C3H6O; [67-64-1]

Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, USPA, France, no purification details were provided. Temperature W. E. Acree, Jr. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided.

Estimated Error: Temperature: 0.1 K.

x1: 2% (relative error).

Experimental Values Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. T/K s a 1 Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with 293.15 0.00449 shaking for several days at constant temperature. After equilibrium was 298.15 0.00445 attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 μm 303.15 0.00467 pore size membranes, and the solvent evaporated. The solid residue was then 308.15 0.00488 dissolved and diluted with 96% ethanol (v/v). Concentrations were determined 313.15 0.00525 by spectrophotometric measurements at 284 nm. The reported solubility a represents the average of at least three independent determinations. The s1: mass/mass solubility of the solute in units of grams of solute per gram of solution. density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions.

Source and Purity of Chemicals: Auxiliary Information (1) Purity not given, USPA, France, no purification details were provided. Method/Apparatus/Procedure: (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Constant-temperature shaker bath, ultrasonic bath, and an UV/visible source not specified, no purification details were provided. spectrophotometer. Excess solute and solvent were placed in sealed flasks, agitated in an ultrasonic Estimated Error: bath, and then transferred to a constant-temperature shaker bath for at least 48 h. Temperature: 0.1 K. % After phase equilibrium was attained, the excess solid was removed by filtration x1: 2 (relative error). using a 0.20 μm pore size membrane filter, and the solvent evaporated. The solid residue was then dissolved and diluted with dimethyl sulfoxide. The concentration of the dissolved solute was determined spectrometrically at 285 nm. 28.9. Sodium diclofenac solubility data in miscellaneous organic solvents Source and Purity of Chemicals: (1) Purity not given, Pharmaceutical Company, Novo mesto, Slovenia, was used as received. The water content of the drug was determined to be 0.49 mass % by Karl Fischer titration. Components: Original Measurements: 164 ñ (2) 99.8+%, Analytical or Chromatographic grade, Merck Chemical (1) 2-(2,6-Dichloroanilino)- P. Bustamante, M. A. Pe a, and Company, was used as received. phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, (Sodium diclofenac); 975 (1998). [ ] Estimated Error: C14H10Cl2NNaO2; 15307-79-6 [ ] Temperature: 0.1 K. (2) Ethanoic acid; C2H4O2; 64-19-7 % s1: 4 (relative error, estimated by compiler). Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

Components: Original Measurements: Experimental Values (1) 2-(2,6-Dichloroanilino)- 164P. Bustamante, M. A. Peña, and phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, a b,c (Sodium diclofenac); 975 (1998). x2 x1

C14H10Cl2NNaO2; [15307-79-6] 0.9956 0.004448 (2) Acetophenone; C8H8O; [98-86-2] a x2: mole fraction of component 2 in the saturated solution. b Variables: Prepared by: x1: mole fraction solubility of the solute. c T/K ¼ 298.15 W. E. Acree, Jr. Experimental value was reported in the paper as ln x1.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. a b,c Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with x2 x1 shaking for several days at constant temperature. After equilibrium was 0.9999 0.0000508 attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 μm a x2: mole fraction of component 2 in the saturated solution. pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were b x1: mole fraction solubility of the solute. determined by spectrophotometric measurements at 284 nm. The reported c Experimental value was reported in the paper as ln x1. solubility represents the average of at least three independent determinations. The density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions.

Estimated Error: Temperature: 0.1 K.

x1: 2% (relative error).

Auxiliary Information Components: Original Measurements: (1) 2-(2,6-Dichloroanilino)- 164P. Bustamante, M. A. Peña, and Method/Apparatus/Procedure: phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, Constant-temperature bath and an ultraviolet/visible spectrophotometer. (Sodium diclofenac); 975 (1998). Excess solute and solvent were placed in flasks and allowed to equilibrate with C14H10Cl2NNaO2; [15307-79-6] shaking for several days at constant temperature. After equilibrium was (2) Propanoic acid; C3H6O2; attained, aliquots of saturated solutions were removed, filtered through 0.2 μm [79-09-4] pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements at 284 nm. The reported Variables: Prepared by: solubility represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr. The density of the saturated solution was determined in order to convert the measured molar solubilities in units of mol dm3 to mole fractions. Experimental Values Source and Purity of Chemicals: (1) Purity not given, USPA, France, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x a x b,c 2 1 source not specified, no purification details were provided. 0.9604 0.03964 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 0.1 K. c % Experimental value was reported in the paper as ln x1. x1: 2 (relative error).

Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: 164 Constant-temperature bath and an ultraviolet/visible spectrophotometer. (1) 2-(2,6-Dichloroanilino)- P. Bustamante, M. A. Peña, and Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, shaking for several days at constant temperature. After equilibrium was (Sodium diclofenac); 975 (1998). [ ] attained, aliquots of saturated solutions were removed, ﬁltered through 0.2 μm C14H10Cl2NNaO2; 15307-79-6 pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were (2) N,N-Dimethylformamide; [ ] determined by spectrophotometric measurements at 284 nm. The reported C3H7NO; 64-19-7 solubility represents the average of at least three independent determinations. Variables: Prepared by: The density of the saturated solution was determined in order to convert the T/K ¼ 298.15 W. E. Acree, Jr. measured molar solubilities in units of mol dm3 to mole fractions.

Auxiliary Information Components: Original Measurements: (1) 2-(2,6-Dichloroanilino)- 164P. Bustamante, M. A. Peña, and Method/Apparatus/Procedure: phenylacetic acid sodium salt J. Barra, J. Pharm. Pharamcol. 50, Constant-temperature bath and an ultraviolet/visible spectrophotometer. (Sodium diclofenac); 975 (1998). Excess solute and solvent were placed in flasks and allowed to equilibrate with C14H10Cl2NNaO2; [15307-79-6] shaking for several days at constant temperature. After equilibrium was (2) Formamide; CH3NO; [75-12-7] attained, aliquots of saturated solutions were removed, filtered through 0.2 μm pore size membranes, and diluted with 96% ethanol (v/v). Concentrations were Variables: Prepared by: determined by spectrophotometric measurements at 284 nm. The reported T/K ¼ 298.15 W. E. Acree, Jr. solubility represents the average of at least three independent determinations. The density of the saturated solution was determined in order to convert the 3 Experimental Values measured molar solubilities in units of mol dm to mole fractions. Source and Purity of Chemicals: (1) Purity not given, USPA, France, no purification details were provided. x a x b,c 2 1 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 0.9434 0.05659 source not specified, no purification details were provided. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: c Experimental value was reported in the paper as ln x1. Temperature: 0.1 K. x1: 2% (relative error).

Auxiliary Information Components: Original Measurements: (1) 2-(2,6-Dichloroanilino)- 191L. F. Zilnik, A. Jazbinsek, A. Method/Apparatus/Procedure: phenylacetic acid sodium salt Hvala, F. Vrecer, and A. Klamt, Magnetic stirrer and a high-performance liquid chromatograph. (Sodium diclofenac); Fluid Phase Equilib. 261, 140 Excess solute and solvent were allowed to equilibrate at 305 K with vigorous C14H10Cl2NNaO2; [15307-79-6] (2007). stirring for 72 h. Aliquots of saturated solutions were removed, quickly filtered (2) Dimethyl sulfoxide; C2H6OS; using a membrane filter, and the concentration of the dissolved drug was [67-68-5] determined by high-performance liquid chromatographic analysis at 254 nm after suitable dilution with methanol. Variables: Prepared by: Temperature W. E. Acree, Jr. Source and Purity of Chemicals: (1) 99+%, Dipharma, UD, Italy, no purification details were provided in the Experimental Values paper. (2) Purity not given, Pharmaceutical grade, Polichimica, Bologna, Italy, no purification details were provided in the paper. T/K s a 1 Estimated Error: 293.15 0.112 Temperature: 1K. 298.15 0.135 c1: 6% (relative error). 303.15 0.151 308.15 0.182 313.15 0.212 a / s1: mass mass solubility of the solute in units of grams of solute per gram of Components: Original Measurements: solution. (1) 2-(2,6-Dichloroanilino)- 195A. K. Nayak, Chemistry 19, phenylacetic acid sodium salt 121 (2010). (Sodium diclofenac); Auxiliary Information C14H10Cl2NNaO2; [15307-79-6] Method/Apparatus/Procedure: (2) Olive oil / Constant-temperature shaker bath, ultrasonic bath, and an UV visible Variables: Prepared by: spectrophotometer. Temperature W. E. Acree, Jr. Excess solute and solvent were placed in sealed flasks, agitated in an ultrasonic bath, and then transferred to a constant-temperature shaker bath for at least 48 h. After phase equilibrium was attained, the excess solid was removed by filtration Experimental Values using a 0.20 μm pore size membrane filter, and diluted with dimethyl sulfoxide. The concentration of the dissolved solute was determined spectrometrically at 285 nm. a T/K s1 Source and Purity of Chemicals: 300 0.00292 (1) Purity not given, Pharmaceutical Company, Novo mesto, Slovenia, was 305 0.00300 310 0.00308 used as received. The water content of the drug was determined to be 0.49 mass % by Karl Fischer titration. 315 0.00331 a 3 (2) 99.5+%, Analytical or Chromatographic grade, Merck Chemical s1: mass/volume solubility of the solute in units of grams of solute per cm of Company, was used as received. solution.

Estimated Error: Temperature: 0.1 K. Auxiliary Information s : 5% (relative error, estimated by compiler). 1 Method/Apparatus/Procedure: Analytical balance and an UV/visible spectrophotometer. Very few experimental details were provided in the paper. Excess solute and solvent were allowed to equilibrate with agitation for 24 h. An aliquot of the Components: Original Measurements: solution was removed and ﬁltered through a 0.45 μm pore size membrane ﬁlter. (1) 2-(2,6-Dichloroanilino)- 194P. Minghetti, F. Cilurzo, The concentration of the dissolved drug was determined by phenylacetic acid sodium salt A. Casiraghi, L. Montanari, and spectrophotometric analysis after dilution with methanol. (Sodium diclofenac); A. Fini, J. Pharm. Sci. 96, 814

C14H10Cl2NNaO2; [15307-79-6] (2007). Source and Purity of Chemicals: (2) (9Z)-Octadecenoic acid (Oleic (1) Purity not given, Techno Remedies, Kolkata, India, no puriﬁcation details acid); C18H34O2; [112-80-1] were given in the paper. (2) Purity not given, RP Oomerbhoy Pvt. Ltd., India, no puriﬁcation details Variables: Prepared by: were given in the paper. T/K ¼ 305 W. E. Acree, Jr. Estimated Error: Experimental Values Temperature: No information given in the paper. s1: 15% (relative error, estimated by compiler). The measured solubility was reported to be c1 ¼ 0.0000786 mol dm3.

Auxiliary Information Components: Original Measurements: (1) 2-(2,6-Dichloroanilino)- 195A. K. Nayak, Chemistry 19, Method/Apparatus/Procedure: phenylacetic acid sodium salt 121 (2010). Analytical balance and an UV/visible spectrophotometer. (Sodium diclofenac); Very few experimental details were provided in the paper. Excess solute and C14H10Cl2NNaO2; [15307-79-6] solvent were allowed to equilibrate with agitation for 24 h. An aliquot of the (2) Castor oil solution was removed and filtered through a 0.45 μm pore size membrane filter. The concentration of the dissolved drug was determined by Variables: Prepared by: spectrophotometric analysis after dilution with methanol. Temperature W. E. Acree, Jr. Source and Purity of Chemicals: Experimental Values (1) Purity not given, Techno Remedies, Kolkata, India, no purification details were given in the paper. (2) Purity not given, B. D. & Company, India, no purification details were a given in the paper. T/K s1 300 0.01608 Estimated Error: 305 0.01632 Temperature: No information given in the paper. 310 0.01650 s1: 5% (relative error, estimated by compiler). 315 0.01712 a 3 s1: mass/volume solubility of the solute in units of grams of solute per cm of solution. Components: Original Measurements: (1) 2-(2,6-Dichloroanilino)- 195A. K. Nayak, Chemistry 19, Auxiliary Information phenylacetic acid sodium salt 121 (2010). Method/Apparatus/Procedure: (Sodium diclofenac); [ ] Analytical balance and an UV/visible spectrophotometer. C14H10Cl2NNaO2; 15307-79-6 Very few experimental details were provided in the paper. Excess solute and (2) Sunflower oil solvent were allowed to equilibrate with agitation for 24 h. An aliquot of the Variables: Prepared by: μ solution was removed and filtered through a 0.45 m pore size membrane filter. Temperature W. E. Acree, Jr. The concentration of the dissolved drug was determined by spectrophotometric analysis after dilution with methanol. Experimental Values Source and Purity of Chemicals: (1) Purity not given, Techno Remedies, Kolkata, India, no purification details were given in the paper. a T/K s1 (2) Purity not given, BD Pharmaceutical Works, India, no purification details were given in the paper. 300 0.00520 305 0.00538 Estimated Error: 310 0.00560 Temperature: No information given in the paper. 315 0.00608 a / 3 s1: 5% (relative error, estimated by compiler). s1: mass volume solubility of the solute in units of grams of solute per cm of solution.

Components: Original Measurements: ethanoate), one dialkyl ether (1,1′-oxybisethane) and one (1) 2-(2,6-Dichloroanilino)- 195A. K. Nayak, Chemistry 19, cyclic ether (1,4-dioxane), two chloroalkanes (trichloro- phenylacetic acid sodium salt 121 (2010). methane and 1,2-dichloroethane) and one chlorinated aro- (Sodium diclofenac); matic hydrocarbon (chlorobenzene), seven alcohols C14H10Cl2NNaO2; [15307-79-6] (2) Soybean oil (methanol, ethanol, 1-pentanol, 1-octanol, 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol, and 1,2,3- Variables: Prepared by: propanetriol), one alkanone (propanone) and one aromatic Temperature W. E. Acree, Jr. ketone (acetophenone), and five miscellaneous organic solvents (ethanoic acid, propanoic acid, formamide, N-methyl- Experimental Values formamide, and N,N-dimethylformamide) at 298 K and atmospheric pressure. Results of the experimental measurements were used in conjunction with the modified extended T/K s a 1 Hansen method to calculate partial solubility parameters of 300 0.00309 305 0.00312 sodium salts of carboxylic acids containing a single hydrogen 310 0.00330 bonding group (ibuprofen/sodium ibuprofen and benzoic acid/ 315 0.00363 sodium benzoate). Critical evaluation of the experimental data a 3 s1: mass/volume solubility of the solute in units of grams of solute per cm of is not possible because the measurements were performed at solution. only a single temperature, and there are no independent experimental solubility data for sodium ibuprofen in the 25 solvents studied by Bustamante et al. Auxiliary Information The experimental solubility data for sodium ibuprofen in Method/Apparatus/Procedure: organic solvents are in Secs. 29.2–29.9. Analytical balance and an uv/visible spectrophotometer. Very few experimental details were provided in the paper. Excess solute and solvent were allowed to equilibrate with agitation for 24 h. An aliquot of the 29.2. Sodium ibuprofen solubility data in saturated μ solution was removed and filtered through a 0.45 m pore size membrane filter. hydrocarbons (including cycloalkanes) The concentration of the dissolved drug was determined by spectrophotometric analysis after dilution with methanol.

Source and Purity of Chemicals: Components: Original Measurements: (1) Purity not given, Techno Remedies, Kolkata, India, no puriﬁcation details (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and were given in the paper. benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117

(2) Purity not given, Adani Wilmer Ltd., India, no puriﬁcation details were (Sodium ibuprofen); C13H17NaO2; (2000). given in the paper. [31121-93-4]

(2) Heptane; C7H16; [142-82-5] Estimated Error: Variables: Prepared by: Temperature: No information given in the paper. T/K ¼ 298.15 W. E. Acree, Jr. s1: 10% (relative error, estimated by compiler).

Experimental Values 29. Solubility of Sodium Ibuprofen in a b,c Organic Solvents x2 x1 0.9999 0.0000124 29.1. Critical evaluation of experimental solubility a x2: mole fraction of component 2 in the saturated solution. b data x1: mole fraction solubility of the solute. cExperimental value was reported in the paper as ln x . Sodium ibuprofen tablets contain the active ingredient 1 ibuprofen, which is commonly used in pain treatment therapies Auxiliary Information for dysmenorrhea, headache, rheumatism, and arthritis. Ibu- profen free acid is the most commonly used form of ibuprofen Method/Apparatus/Procedure: / in commercial pharmaceutical formulations. Poor solubility of Constant-temperature bath and an ultraviolet visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with ibuprofen in aqueous solutions lessens the drug’s dissolution shaking for five days at constant temperature. Aliquots of saturated solutions and adsorption rates into the bloodstream. The sodium salt, were removed and diluted with 96% ethanol (v/v). Concentrations were however, more readily dissolves in water and overcomes many determined by spectrophotometric measurements. The reported solubility of these problems. There has been one study involving the represents the average of at least three independent determinations. solubility of sodium ibuprofen in organic solvents. Busta- 93 Source and Purity of Chemicals: mante et al. measured the mole-fraction solubility of sodium (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no ibuprofen in 25 different organic solvents, including two purification details were provided. saturated hydrocarbons (heptane and cyclohexane), one aro- (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical matic hydrocarbon (benzene), one alkyl alkanoate (ethyl source not specified, no purification details were provided.

Estimated Error: Experimental Values Temperature: 0.2 K.

x1: 2% (relative error). a b,c x2 x1 0.9999 0.00000454 ax : mole fraction of component 2 in the saturated solution. Components: Original Measurements: 2 bx : mole fraction solubility of the solute. (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and 1 cExperimental value was reported in the paper as ln x . benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 1

(Sodium ibuprofen); C13H17NaO2; (2000). [31121-93-4] Auxiliary Information (2) Cyclohexane; C6H12; [110-82-7] Method/Apparatus/Procedure: Variables: Prepared by: Constant-temperature bath and an ultraviolet/visible spectrophotometer. T/K ¼ 298.15 W. E. Acree, Jr. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and the solvent evaporated. The solid residue was then dissolved Experimental Values and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements. The reported solubility represents the a b,c average of at least three independent determinations. x2 x1 0.9999 0.00000854 Source and Purity of Chemicals: a x2: mole fraction of component 2 in the saturated solution. (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no b x1: mole fraction solubility of the solute. purification details were provided. c Experimental value was reported in the paper as ln x1. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided.

Auxiliary Information Estimated Error: Temperature: 0.2 K. Method/Apparatus/Procedure: x1: 2% (relative error). Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with shaking for ﬁve days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements. The reported solubility 29.4. Sodium ibuprofen solubility data in esters represents the average of at least three independent determinations.

Source and Purity of Chemicals: Components: Original Measurements: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and purification details were provided. benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical (Sodium ibuprofen); C13H17NaO2; (2000). source not specified, no purification details were provided. [31121-93-4]

(2) Ethyl ethanoate; C4H8O2; Estimated Error: [141-78-6] Temperature: 0.2 K.

x1: 2% (relative error). Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

Experimental Values 29.3. Sodium ibuprofen solubility data in aromatic hydrocarbons a b,c x2 x1 0.9994 0.000620 Components: Original Measurements: a 93 x2: mole fraction of component 2 in the saturated solution. (1) α-Methyl-4-(2-methylpropyl)- P. Bustamante, M. A. Peña, and b x1: mole fraction solubility of the solute. benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 c Experimental value was reported in the paper as ln x1. (Sodium ibuprofen); C13H17NaO2; (2000). [31121-93-4]

(2) Benzene; C6H6; [71-43-2] Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x a x b,c source not specified, no purification details were provided. 2 1 0.9998 0.000164 a Estimated Error: x2: mole fraction of component 2 in the saturated solution. b Temperature: 0.2 K. x1: mole fraction solubility of the solute. % c x1: 2 (relative error). Experimental value was reported in the paper as ln x1.

Auxiliary Information / / 29.5. Sodium ibuprofen solubility data in ethers Method Apparatus Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with shaking for ﬁve days at constant temperature. Aliquots of saturated solutions Components: Original Measurements: were removed and diluted with 96% ethanol (v/v). Concentrations were (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and determined by spectrophotometric measurements. The reported solubility benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 represents the average of at least three independent determinations.

(Sodium ibuprofen); C13H17NaO2; (2000). [31121-93-4] Source and Purity of Chemicals:

(2) 1,1′-Oxybisethane; C4H10O; (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no [60-29-7] purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Variables: Prepared by: source not specified, no purification details were provided. T/K ¼ 298.15 W. E. Acree, Jr. Estimated Error: Temperature: 0.2 K. Experimental Values x1: 2% (relative error).

a b,c x2 x1 29.6. Sodium ibuprofen solubility data in 0.9994 0.000605 a haloalkanes, haloalkenes, and haloaromatic x2: mole fraction of component 2 in the saturated solution. b hydrocarbons x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Components: Original Measurements: Auxiliary Information (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 Method/Apparatus/Procedure: (Sodium ibuprofen); C H NaO ; (2000). Constant-temperature bath and an ultraviolet/visible spectrophotometer. 13 17 2 [31121-93-4] Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with (2) Trichloromethane; CHCl ; shaking for ﬁve days at constant temperature. Aliquots of saturated solutions 3 [67-66-3] were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements. The reported solubility Variables: Prepared by: represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr.

Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Experimental Values purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a b,c source not specified, no purification details were provided. x2 x1 0.9996 0.000413 Estimated Error: a Temperature: 0.2 K. x2: mole fraction of component 2 in the saturated solution. b x : 2% (relative error). x1: mole fraction solubility of the solute. 1 c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and Constant-temperature bath and an ultraviolet/visible spectrophotometer. benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 Excess solute and solvent were placed in flasks and allowed to equilibrate with (Sodium ibuprofen); C13H17NaO2; (2000). shaking for five days at constant temperature. Aliquots of saturated solutions [31121-93-4] were removed and the solvent evaporated. The solid residue was then dissolved (2) Chlorobenzene; C6H5Cl; and diluted with 96% ethanol (v/v). Concentrations were determined by [108-90-7] spectrophotometric measurements. The reported solubility represents the Variables: Prepared by: average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Experimental Values purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. a b,c x2 x1 Estimated Error: 0.9999 0.00000234 a Temperature: 0.2 K. x2: mole fraction of component 2 in the saturated solution. % b x1: 2 (relative error). x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Components: Original Measurements: Auxiliary Information 93 (1) α-Methyl-4-(2-methylpropyl)- P. Bustamante, M. A. Peña, and Method/Apparatus/Procedure: benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 Constant-temperature bath and an ultraviolet/visible spectrophotometer. (Sodium ibuprofen); C13H17NaO2; (2000). Excess solute and solvent were placed in flasks and allowed to equilibrate with [31121-93-4] shaking for five days at constant temperature. Aliquots of saturated solutions (2) 1,2-Dichloroethane; C2H4Cl2; were removed and diluted with 96% ethanol (v/v). Concentrations were [107-06-2] determined by spectrophotometric measurements. The reported solubility Variables: Prepared by: represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Experimental Values purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. a b,c x2 x1 Estimated Error: 0.9999 0.0000374 Temperature: 0.2 K. a x2: mole fraction of component 2 in the saturated solution. x1: 2% (relative error). b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information 29.7. Sodium ibuprofen solubility data in alcohols Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in flasks and allowed to equilibrate with (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and shaking for five days at constant temperature. Aliquots of saturated solutions benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 were removed and diluted with 96% ethanol (v/v). Concentrations were (Sodium ibuprofen); C H NaO ; (2000). determined by spectrophotometric measurements. The reported solubility 13 17 2 [31121-93-4] represents the average of at least three independent determinations. (2) Methanol; CH4O; [67-56-1] Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no T/K ¼ 298.15 W. E. Acree, Jr. purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values

Estimated Error: a b,c Temperature: 0.2 K. x2 x1 % x1: 2 (relative error). 0.7306 0.2694 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and Constant-temperature bath and an ultraviolet/visible spectrophotometer. benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 Excess solute and solvent were placed in flasks and allowed to equilibrate with (Sodium ibuprofen); C13H17NaO2; (2000). shaking for five days at constant temperature. Aliquots of saturated solutions [31121-93-4] were removed and diluted with 96% ethanol (v/v). Concentrations were (2) 1-Pentanol; C5H12O; [71-41-0] determined by spectrophotometric measurements. The reported solubility Variables: Prepared by: represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Experimental Values purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. a b,c x2 x1 Estimated Error: 0.9433 0.05669 a Temperature: 0.2 K. x2: mole fraction of component 2 in the saturated solution. % b x1: 2 (relative error). x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a b,c source not specified, no purification details were provided. x2 x1 0.9225 0.07751 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. Temperature: 0.2 K. b x1: mole fraction solubility of the solute. x1: 2% (relative error). c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and Constant-temperature bath and an ultraviolet/visible spectrophotometer. benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 Excess solute and solvent were placed in flasks and allowed to equilibrate with (Sodium ibuprofen); C13H17NaO2; (2000). shaking for five days at constant temperature. Aliquots of saturated solutions [31121-93-4] were removed and diluted with 96% ethanol (v/v). Concentrations were (2) 1-Octanol; C8H18O; [111-87-5] determined by spectrophotometric measurements. The reported solubility Variables: Prepared by: represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Experimental Values purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. a b,c x2 x1 Estimated Error: 0.9329 0.06708 a Temperature: 0.2 K. x2: mole fraction of component 2 in the saturated solution. % b x1: 2 (relative error). x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and Constant-temperature bath and an ultraviolet/visible spectrophotometer. benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 Excess solute and solvent were placed in flasks and allowed to equilibrate with (Sodium ibuprofen); C13H17NaO2; (2000). shaking for five days at constant temperature. Aliquots of saturated solutions [31121-93-4] were removed and diluted with 96% ethanol (v/v). Concentrations were (2) 1,2-Propanediol; C3H8O2; determined by spectrophotometric measurements. The reported solubility [57-55-6] represents the average of at least three independent determinations. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. Experimental Values (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. x a x b,c Estimated Error: 2 1 Temperature: 0.2 K. 0.7570 0.2430 % a x1: 2 (relative error). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a b,c source not specified, no purification details were provided. x2 x1 0.4915 0.5085 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. Temperature: 0.2 K. b x1: mole fraction solubility of the solute. x1: 2% (relative error). c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and Constant-temperature bath and an ultraviolet/visible spectrophotometer. benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 Excess solute and solvent were placed in flasks and allowed to equilibrate with (Sodium ibuprofen); C13H17NaO2; (2000). shaking for five days at constant temperature. Aliquots of saturated solutions [31121-93-4] were removed and diluted with 96% ethanol (v/v). Concentrations were (2) 1,3-Propanediol; C3H8O2; determined by spectrophotometric measurements. The reported solubility [504-63-2] represents the average of at least three independent determinations. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. Experimental Values (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. x a x b,c Estimated Error: 2 1 Temperature: 0.2 K. 0.8905 0.1095 % a x1: 2 (relative error). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and Constant-temperature bath and an ultraviolet/visible spectrophotometer. benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 Excess solute and solvent were placed in flasks and allowed to equilibrate with (Sodium ibuprofen); C13H17NaO2; (2000). shaking for five days at constant temperature. Aliquots of saturated solutions [31121-93-4] were removed and diluted with 96% ethanol (v/v). Concentrations were (2) 1,2,3-Propanetriol (Glycerol); determined by spectrophotometric measurements. The reported solubility C3H8O3; [56-81-5] represents the average of at least three independent determinations. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. Experimental Values (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. x a x b,c Estimated Error: 2 1 Temperature: 0.2 K. 0.7178 0.2822 % a x1: 2 (relative error). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a b,c source not specified, no purification details were provided. x2 x1 0.7547 0.2453 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. Temperature: 0.2 K. b x1: mole fraction solubility of the solute. x1: 2% (relative error). c Experimental value was reported in the paper as ln x1.

Auxiliary Information 29.8. Sodium ibuprofen solubility data in ketones Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with Components: Original Measurements: shaking for five days at constant temperature. Aliquots of saturated solutions (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and were removed and diluted with 96% ethanol (v/v). Concentrations were benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 determined by spectrophotometric measurements. The reported solubility (Sodium ibuprofen); C H NaO ; (2000). represents the average of at least three independent determinations. 13 17 2 [31121-93-4] (2) Propanone; C H O; [67-64-1] Source and Purity of Chemicals: 3 6 (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Variables: Prepared by: purification details were provided. T/K ¼ 298.15 W. E. Acree, Jr. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values Estimated Error: Temperature: 0.2 K. % a b,c x1: 2 (relative error). x2 x1 0.9996 0.000377 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information 29.9. Sodium ibuprofen solubility data in Method/Apparatus/Procedure: miscellaneous organic solvents Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions Components: Original Measurements: were removed and diluted with 96% ethanol (v/v). Concentrations were (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and determined by spectrophotometric measurements. The reported solubility benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 represents the average of at least three independent determinations. (Sodium ibuprofen); C13H17NaO2; (2000). [31121-93-4] Source and Purity of Chemicals: (2) Ethanoic acid; C H O ; [64-19-7] (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no 2 4 2 purification details were provided. Variables: Prepared by: (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical T/K ¼ 298.15 W. E. Acree, Jr. source not specified, no purification details were provided.

Estimated Error: Experimental Values Temperature: 0.2 K.

x1: 2% (relative error). a b,c x2 x1 0.9667 0.03334 a x2: mole fraction of component 2 in the saturated solution. Components: Original Measurements: b x1: mole fraction solubility of the solute. α 93 ñ c (1) -Methyl-4-(2-methylpropyl)- P. Bustamante, M. A. Pe a, and Experimental value was reported in the paper as ln x1. benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117

(Sodium ibuprofen); C13H17NaO2; (2000). [31121-93-4] Auxiliary Information (2) Acetophenone; C8H8O; [98-86-2] Method/Apparatus/Procedure: Variables: Prepared by: Constant-temperature bath and an ultraviolet/visible spectrophotometer. T/K ¼ 298.15 W. E. Acree, Jr. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with shaking for ﬁve days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Experimental Values determined by spectrophotometric measurements. The reported solubility represents the average of at least three independent determinations.

a b,c x2 x1 Source and Purity of Chemicals: 0.9999 0.0000428 (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no a purification details were provided. x2: mole fraction of component 2 in the saturated solution. b (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x1: mole fraction solubility of the solute. c source not specified, no purification details were provided. Experimental value was reported in the paper as ln x1. Estimated Error: Temperature: 0.2 K. Auxiliary Information x1: 2% (relative error). Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions Components: Original Measurements: were removed and the solvent evaporated. The solid residue was then dissolved (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and and diluted with 96% ethanol (v/v). Concentrations were determined by benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 spectrophotometric measurements. The reported solubility represents the (Sodium ibuprofen); C H NaO ; (2000). average of at least three independent determinations. 13 17 2 [31121-93-4] (2) Propanoic acid; C H O ; Source and Purity of Chemicals: 3 6 2 [79-09-4] (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. Variables: Prepared by: (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical T/K ¼ 298.15 W. E. Acree, Jr. source not specified, no purification details were provided.

Estimated Error: Experimental Values Temperature: 0.2 K.

x1: 2% (relative error). a b,c x2 x1 0.9695 0.03054 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and Constant-temperature bath and an ultraviolet/visible spectrophotometer. benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 Excess solute and solvent were placed in flasks and allowed to equilibrate with (Sodium ibuprofen); C13H17NaO2; (2000). shaking for five days at constant temperature. Aliquots of saturated solutions [31121-93-4] were removed and diluted with 96% ethanol (v/v). Concentrations were (2) N-Methylformamide; C2H5NO; determined by spectrophotometric measurements. The reported solubility [123-39-7] represents the average of at least three independent determinations. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. Experimental Values (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. x a x b,c Estimated Error: 2 1 Temperature: 0.2 K. 0.9981 0.00190 % a x1: 2 (relative error). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Components: Original Measurements: (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and Auxiliary Information benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 Method/Apparatus/Procedure: (Sodium ibuprofen); C13H17NaO2; (2000). Constant-temperature bath and an ultraviolet/visible spectrophotometer. [31121-93-4] Excess solute and solvent were placed in flasks and allowed to equilibrate with [ ] (2) Formamide; CH3NO; 75-12-7 shaking for five days at constant temperature. Aliquots of saturated solutions Variables: Prepared by: were removed and the solvent evaporated. The solid residue was then dissolved % / T/K ¼ 298.15 W. E. Acree, Jr. and diluted with 96 ethanol (v v). Concentrations were determined by spectrophotometric measurements. The reported solubility represents the average of at least three independent determinations. Experimental Values Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no a b,c purification details were provided. x2 x1 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 0.9784 0.02158 source not specified, no purification details were provided. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: c Experimental value was reported in the paper as ln x1. Temperature: 0.2 K. x1: 2% (relative error).

Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in flasks and allowed to equilibrate with (1) α-Methyl-4-(2-methylpropyl)- 93P. Bustamante, M. A. Peña, and shaking for five days at constant temperature. Aliquots of saturated solutions benzeneacetic acid, sodium salt J. Barra, Int. J. Pharm. 194, 117 were removed and diluted with 96% ethanol (v/v). Concentrations were (Sodium ibuprofen); C13H17NaO2; (2000). determined by spectrophotometric measurements. The reported solubility [31121-93-4] represents the average of at least three independent determinations. (2) N,N-Dimethylformamide; C3H7NO; [64-19-7] Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no T/K ¼ 298.15 W. E. Acree, Jr. purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values Estimated Error: Temperature: 0.2 K. a b,c x2 x1 x1: 2% (relative error). 0.9988 0.00115 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information 30.2. Sodium naproxen solubility data in alcohols Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with Components: Original Measurements: shaking for ﬁve days at constant temperature. Aliquots of saturated solutions (1) (S)-6-Methoxy-α-methyl-2- 197K. J. Chavez and R. W. were removed and the solvent evaporated. The solid residue was then dissolved naphthaleneacetic acid (Sodium Rousseau, Cryst. Growth Des. 10, and diluted with 96% ethanol (v/v). Concentrations were determined by naproxen); C14H13NaO3; 3802 (2010). spectrophotometric measurements. The reported solubility represents the [26159-34-2] average of at least three independent determinations. (2) Methanol; CH4O; [67-56-1]

Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Temperature W. E. Acree, Jr. purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values

Estimated Error: / a Temperature: 0.2 K. T K s1

x1: 2% (relative error). 283.6 214 288.5 216 293.6 224 298.5 244 30. Solubility of Sodium Naproxen in 303.1 242 307.6 243 Organic Solvents 312.1 243 a 30.1. Critical evaluation of experimental solubility s1: solubility of component 1 in the saturated solution in units of grams of solute per kilogram of saturated solution. data Sodium naproxen is a NSAID that is used to provide relief Auxiliary Information from mild to moderate aches and pains. There have been two experimental studies196,197 reporting the solubility of sodium Method/Apparatus/Procedure: naproxen in organic solvents. Delgado et al.196 determined the Constant-temperature water bath, mechanical stirrer, and a high-performance liquid chromatograph equipped with UV/visible detection. solubility of sodium naproxen in binary aqueous-ethanol Slurry solutions were prepared by batch cooling crystallization. Solvent was solvent mixtures over the entire composition range, including allowed to reach the desired temperature, and then sodium naproxen was the two pure solvents. Measurements were performed in 5 K slowly added with stirring until the added solid no longer dissolved. The increments between 278 and 308 K. The internal consistency temperature of the solution was then raised to about 10 °C above the desired of the Delgado et al. dataset was assessed by curve-fitting the equilibrium temperature so that all of the existing crystals dissolved. The solution was then cooled at an approximate rate of 0.6 °C/min to the desired measured mole-fraction solubility data to the Modified Apel- equilibrium temperature. The solution was allowed to equilibrate for at least blat model [Eq. (8)] to yield the following representation: 15 h. Samples of the saturated solution were then removed by syringe and filtered through a 0.2 μm filter. The concentration of the solute was determined 17:656 by high-performance liquid chromatographic analysis. ln x ¼37:951 þ þ 6:049 ln T: ð36Þ 1 T Source and Purity of Chemicals: The mean absolute relative deviation between the observed (1) Purity not given, anhydrous, Albermarle Corporation, was used as received. experimental data and back-calculated values based on (2) Purity not given, HPLC grade, Fisher Scientific, USA, was dried overnight Eq. (36) of MARD ¼ 6.8% is slightly larger in magnitude over molecular sieves prior to use. than the experimental uncertainty associated with the mea- Estimated Error: sured values. Temperature: No information provided. 197 Chavez and Rousseau measured the solubility of sodium s1: 4% (relative error). naproxen in binary aqueous-methanol and aqueous-ethanol solvent mixtures as a function of composition from 283 to 313 K. Analysis of the experimental data using van’t Hoff ln x1 versus 1/T graphs indicated that different crystalline forms Components: Original Measurements: (1) (S)-6-Methoxy-α-methyl-2- 196D. R. Delgado, M. A. Ruidiaz, (hydrates, alcohol solvates, and anhydrates) existed in the naphthaleneacetic acid (Sodium S. M. Go´mez, and F. Martínez, different binary solvent composition–temperature regions. naproxen); C14H13NaO3; Quim. Nova 33, 1923 (2010). The authors used thermal analysis and powder x-ray diffrac- [26159-34-2] [ ] tion to confirm the different forms of the equilibrated solid (2) Ethanol; C2H6O; 64-17-5 residue. Variables: Prepared by: The experimental solubility data for sodium naproxen in Temperature W. E. Acree, Jr. alcohols are given in Sec. 30.2.

Experimental Values Auxiliary Information Method/Apparatus/Procedure: Constant-temperature water bath, mechanical stirrer, and a high-performance T/K x a x b 2 1 liquid chromatograph equipped with UV/visible detection. 278.15 0.9822 0.01781 Slurry solutions were prepared by batch cooling crystallization. Solvent was 283.15 0.9793 0.02065 allowed to reach the desired temperature, and then sodium naproxen was 288.15 0.9761 0.02392 slowly added with stirring until the added solid no longer dissolved. The 293.15 0.9728 0.02723 temperature of the solution was then raised to about 10 °C above the desired 298.15 0.9693 0.03074 equilibrium temperature so that all of the existing crystals dissolved. The 303.15 0.9646 0.03538 solution was then cooled at an approximate rate of 0.6 °C/min to the desired 308.15 0.9609 0.03913 equilibrium temperature. The solution was then allowed to equilibrate for at a least 15 h. Samples of the saturated solution were then removed by syringe and x2: mole fraction of component 2 in the saturated solution. b ﬁltered through a 0.2 μm ﬁlter. The concentration of the solute was determined x1: mole fraction solubility of the solute. by high-performance liquid chromatographic analysis.

Auxiliary Information Source and Purity of Chemicals: (1) Purity not given, anhydrous, Albermarle Corporation, was used as received. / / Method Apparatus Procedure: (2) Purity not given, HPLC grade, VWR Scientific, USA, was dried overnight Mechanical shaker, constant-temperature water bath, and an analytical over molecular sieves prior to use. balance. Excess solute and solvent were placed in a stoppered glass flask and stirred in a Estimated Error: mechanical shaker for 4 h. The flasks were then transferred to a constant- Temperature: No information provided. temperature bath where the solution equilibrated for at least seven days. A s1: 3%–6% (relative error). weighed aliquot of the saturated solution was removed, isothermally filtered, and the solvent was allowed to evaporate until a constant mass was obtained. The solubility of dissolved solute was calculated from the mass of solid residue and the mass of the sample analyzed. The reported values represent the average of at least three determinations. The densities of the saturated solutions were 31. Solubility of Sodium Salicylate in measured in order to convert the molar solubilities given in mol dm3 to mole Organic Solvents fractions. 31.1. Critical evaluation of experimental solubility Source and Purity of Chemicals: data (1) 99.9%, chemical source not specified, no purification details were given in the paper. Sodium salicylate is the sodium salt of salicylic acid and is (2) 99.9%, Merck Chemical Company, Germany, no purification details were used in medicine as a pain reliever and fever reducer. Pub- given in the paper. lished studies have shown that sodium salicylate induces 198 Estimated Error: apoptosis in Myeloid Leukemia cell lines and in human 199 Temperature: 0.05 K. lung adenocarcinoma cells. There have been several 77,200,201 x1: 2% (relative error). studies involving the solubility of sodium salicylate in organic solvents. Most notably, Barra et al.77 measured the mole-fraction solubility of sodium salicylate in 22 different organic solvents, including two saturated hydrocar- Components: Original Measurements: bons (heptane and cyclohexane), one aromatic hydrocarbon (1) (S)-6-Methoxy-α-methyl-2- 197K. J. Chavez and R. W. naphthaleneacetic acid (Sodium Rousseau, Cryst. Growth Des. 10, (benzene), one alkyl alkanoate (ethyl ethanoate), one dialkyl ′ naproxen); C14H13NaO3; 3802 (2010). ether (1,1 -oxybisethane) and one cyclic ether (1,4-dioxane), [26159-34-2] two chloroalkanes (trichloromethane and 1,2-dichloroethane) [ ] (2) Ethanol; C2H6O; 64-17-5 and one chlorinated aromatic hydrocarbon (chlorobenzene), Variables: Prepared by: seven alcohols (methanol, ethanol, 1-pentanol, 1-octanol, Temperature W. E. Acree, Jr. 1,2-ethanediol, 1,2-propanediol, and 1,2,3-propanetriol), one alkanone (propanone) and one aromatic ketone (acetophe- Experimental Values none), and four miscellaneous organic solvents (ethanoic acid, propanoic acid, formamide, and N,N-dimethylformamide) at 298 K and atmospheric pressure. Puruta and Mauger201 inves- / a T K s1 tigated the solubility of sodium salicylate at 298 K in binary 284.2 14 solvent mixtures containing water with either 1,4-dioxane, 288.8 16 methanol, ethanol, 1-propanol, or propanone. The experimen- 293.7 19 tal data were presented only in graphical format in the paper, 298.3 23 302.9 26 and did include the solubilities in the five neat organic 307.7 28 cosolvents. 312.6 30 The experimental solubility data for sodium salicylate in a s1: solubility of component 1 in the saturated solution in units of grams of organic solvents are in Secs. 31.2–31.9. solute per kilogram of saturated solution.

31.2. Sodium salicylate solubility data in saturated Auxiliary Information hydrocarbons (including cycloalkanes) Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions Components: Original Measurements: were removed and diluted with 96% ethanol (v/v). Concentrations were (1) 2-Hydroxybenzoic acid, sodium 77J. Barra, M.-A. Peña, and P. determined by spectrophotometric measurements. The reported solubility salt (Sodium salicylate); C H NaO ; Bustamante, Eur. J. Pharm. Sci. 7 5 3 represents the average of at least three independent determinations. [54-21-7] 10, 153 (2000). (2) Heptane; C H ; [142-82-5] 7 16 Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Sigma Chemical Company, USA, no purification details T/K ¼ 298.15 W. E. Acree, Jr. were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values Estimated Error: Temperature: 0.2 K. a b,c x2 x1 x1: 2% (relative error). 0.9999 0.0000246 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. 31.3. Sodium salicylate solubility data in aromatic hydrocarbons

Auxiliary Information

Method/Apparatus/Procedure: Components: Original Measurements: Constant-temperature bath and an ultraviolet/visible spectrophotometer. (1) 2-Hydroxybenzoic acid, sodium 77J. Barra, M.-A. Peña, and P.

Excess solute and solvent were placed in flasks and allowed to equilibrate with salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. shaking for five days at constant temperature. Aliquots of saturated solutions [54-21-7] 10, 153 (2000). % / were removed and diluted with 96 ethanol (v v). Concentrations were (2) Benzene; C6H6; [71-43-2] determined by spectrophotometric measurements. The reported solubility represents the average of at least three independent determinations. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, USA, no purification details Experimental Values were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical

source not speciﬁed, no puriﬁcation details were provided. a b,c x2 x1 Estimated Error: 0.9999 0.0000356 Temperature: 0.2 K. a x2: mole fraction of component 2 in the saturated solution. x : 2% (relative error). b 1 x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Components: Original Measurements: Auxiliary Information 77 ñ (1) 2-Hydroxybenzoic acid, sodium J. Barra, M.-A. Pe a, and P. Method/Apparatus/Procedure: salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. Constant-temperature bath and an ultraviolet/visible spectrophotometer. [ ] 54-21-7 10, 153 (2000). Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with [ ] (2) Cyclohexane; C6H12; 110-82-7 shaking for ﬁve days at constant temperature. Aliquots of saturated solutions Variables: Prepared by: were removed and diluted with 96% ethanol (v/v). Concentrations were T/K ¼ 298.15 W. E. Acree, Jr. determined by spectrophotometric measurements. The reported solubility represents the average of at least three independent determinations.

Experimental Values Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, USA, no purification details were provided. a b,c x2 x1 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. 0.9999 0.0000330 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 0.2 K. cExperimental value was reported in the paper as ln x . 1 x1: 2% (relative error).

31.4. Sodium salicylate solubility data in esters Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in flasks and allowed to equilibrate with (1) 2-Hydroxybenzoic acid, sodium 77J. Barra, M.-A. Peña, and P. shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. [54-21-7] 10, 153 (2000). determined by spectrophotometric measurements. The reported solubility represents the average of at least three independent determinations. (2) Ethyl ethanoate; C4H8O2; [141-78-6] Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Sigma Chemical Company, USA, no purification details / ¼ T K 298.15 W. E. Acree, Jr. were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values Estimated Error: Temperature: 0.2 K. x a x b,c 2 1 x1: 2% (relative error). 0.9986 0.001415 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Components: Original Measurements: (1) 2-Hydroxybenzoic acid, sodium 77J. Barra, M.-A. Peña, and P. Auxiliary Information salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. [54-21-7] 10, 153 (2000). / / Method Apparatus Procedure: (2) 1,4-Dioxane; C4H8O2; [123-91-1] Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with Variables: Prepared by: / ¼ shaking for five days at constant temperature. Aliquots of saturated solutions T K 298.15 W. E. Acree, Jr. were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements. The reported solubility Experimental Values represents the average of at least three independent determinations.

Source and Purity of Chemicals: a b,c (1) Purity not given, Sigma Chemical Company, USA, no purification details x2 x1 were provided. 0.9991 0.000870 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a x2: mole fraction of component 2 in the saturated solution. source not specified, no purification details were provided. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Estimated Error: Temperature: 0.2 K. % x1: 2 (relative error). Auxiliary Information Method/Apparatus/Procedure: / 31.5. Sodium salicylate solubility data in ethers Constant-temperature bath and an ultraviolet visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Components: Original Measurements: determined by spectrophotometric measurements. The reported solubility (1) 2-Hydroxybenzoic acid, sodium 77J. Barra, M.-A. Peña, and P. represents the average of at least three independent determinations.

salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. [54-21-7] 10, 153 (2000). Source and Purity of Chemicals:

(2) 1,1′-Oxybisethane; C4H10O; (1) Purity not given, Sigma Chemical Company, USA, no purification details [60-29-7] were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Variables: Prepared by: source not specified, no purification details were provided. T/K ¼ 298.15 W. E. Acree, Jr. Estimated Error: Temperature: 0.2 K. Experimental Values x1: 2% (relative error).

a b,c x2 x1 0.9991 0.000871 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

31.6. Sodium salicylate solubility data in Auxiliary Information haloalkanes, haloalkenes, and haloaromatic Method/Apparatus/Procedure: hydrocarbons Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Components: Original Measurements: determined by spectrophotometric measurements. The reported solubility 77 ñ (1) 2-Hydroxybenzoic acid, sodium J. Barra, M.-A. Pe a, and P. represents the average of at least three independent determinations. salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. [ ] 54-21-7 10, 153 (2000). Source and Purity of Chemicals: (2) Trichloromethane; CHCl3; (1) Purity not given, Sigma Chemical Company, USA, no purification details [ ] 67-66-3 were provided. Variables: Prepared by: (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical T/K ¼ 298.15 W. E. Acree, Jr. source not specified, no purification details were provided.

Estimated Error: Experimental Values Temperature: 0.2 K. x1: 2% (relative error).

a b,c x2 x1 0.9999 0.0000461 a Components: Original Measurements: x2: mole fraction of component 2 in the saturated solution. 77 b (1) 2-Hydroxybenzoic acid, sodium J. Barra, M.-A. Peña, and P. x1: mole fraction solubility of the solute. c salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. Experimental value was reported in the paper as ln x1. [54-21-7] 10, 153 (2000).

(2) Chlorobenzene; C6H5Cl; [ ] Auxiliary Information 108-90-7 Method/Apparatus/Procedure: Variables: Prepared by: / ¼ Constant-temperature bath and an ultraviolet/visible spectrophotometer. T K 298.15 W. E. Acree, Jr. Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with shaking for ﬁve days at constant temperature. Aliquots of saturated solutions Experimental Values were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements. The reported solubility

represents the average of at least three independent determinations. a b,c x2 x1 Source and Purity of Chemicals: 0.9999 0.0000351 (1) Purity not given, Sigma Chemical Company, USA, no purification details a x2: mole fraction of component 2 in the saturated solution. were provided. b x1: mole fraction solubility of the solute. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical c Experimental value was reported in the paper as ln x1. source not specified, no purification details were provided.

Estimated Error: Auxiliary Information Temperature: 0.2 K. Method/Apparatus/Procedure: x1: 2% (relative error). Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were Components: Original Measurements: determined by spectrophotometric measurements. The reported solubility 77 ñ (1) 2-Hydroxybenzoic acid, sodium J. Barra, M.-A. Pe a, and P. represents the average of at least three independent determinations. salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. [ ] 54-21-7 10, 153 (2000). Source and Purity of Chemicals: (2) 1,2-Dichloroethane; C2H4Cl2; (1) Purity not given, Sigma Chemical Company, USA, no purification details [ ] 107-06-2 were provided. Variables: Prepared by: (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical T/K ¼ 298.15 W. E. Acree, Jr. source not specified, no purification details were provided.

Estimated Error: Experimental Values Temperature: 0.2 K. x1: 2% (relative error).

a b,c x2 x1 0.9999 0.0000547 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

31.7. Sodium salicylate solubility data in alcohols Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with (1) 2-Hydroxybenzoic acid, sodium 77J. Barra, M.-A. Peña, and P. shaking for ﬁve days at constant temperature. Aliquots of saturated solutions were removed and diluted with 96% ethanol (v/v). Concentrations were salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. [54-21-7] 10, 153 (2000). determined by spectrophotometric measurements. The reported solubility represents the average of at least three independent determinations. (2) Methanol; CH4O; [67-56-1]

Variables: Prepared by: Source and Purity of Chemicals: / ¼ T K 298.15 W. E. Acree, Jr. (1) Purity not given, Sigma Chemical Company, USA, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical Experimental Values source not specified, no purification details were provided.

Estimated Error: a b,c x2 x1 Temperature: 0.2 K.

0.9460 0.05399 x1: 2% (relative error). a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Components: Original Measurements: (1) 2-Hydroxybenzoic acid, sodium 200W. Schnellbach, Am. J. Pharm.

Auxiliary Information salt (Sodium salicylate); C7H5NaO3; 101, 586 (1929). [54-21-7] Method/Apparatus/Procedure: (2) Ethanol; C H O; [64-17-5] Constant-temperature bath and an ultraviolet/visible spectrophotometer. 2 6 Excess solute and solvent were placed in ﬂasks and allowed to equilibrate with Variables: Prepared by: shaking for ﬁve days at constant temperature. Aliquots of saturated solutions T/K ¼ 298.15 W. E. Acree, Jr. were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements. The reported solubility represents the average of at least three independent determinations. Experimental Values

Source and Purity of Chemicals: a b,c (1) Purity not given, Sigma Chemical Company, USA, no purification details x2 x1 were provided. 0.9631 0.03686 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a x2: mole fraction of component 2 in the saturated solution. source not specified, no purification details were provided. b x1: mole fraction solubility of the solute. c Estimated Error: Experimental value was reported in the paper as 11.74 g of sodium salicylate Temperature: 0.2 K. present in 100 g of solution.

x1: 2% (relative error). Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: Constant-temperature water bath, mechanical stirring apparatus, and an (1) 2-Hydroxybenzoic acid, sodium 77J. Barra, M.-A. Peña, and P. analytical balance. Excess solute and solvent were placed in a tightly stoppered Pyrex glass test salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. [54-21-7] 10, 153 (2000). tube, and constantly shaken by mechanical stirring in a constant-temperature water bath. After four days, a portion of the solution was withdrawn and (2) Ethanol; C2H6O; [64-17-5] quickly filtered. A portion of the solution was then weighed in a weighing Variables: Prepared by: bottle and the solvent was allowed to evaporate. The solid residue was dried at / ¼ T K 298.15 W. E. Acree, Jr. 373 K until a constant mass was obtained. The solubility was calculated from the mass of the solid residue and the mass of the saturated sample taken for analysis. Experimental Values Source and Purity of Chemicals: (1) Purity not given, chemical source not specified, no purification details were a b,c x2 x1 provided. 0.9875 0.01246 (2) Purity not given, USP, no purification details were provided. a x2: mole fraction of component 2 in the saturated solution. b Estimated Error: x1: mole fraction solubility of the solute. c Temperature: 0.005 K. Experimental value was reported in the paper as ln x1. x1: 4% (relative error, estimated by compiler).

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Sigma Chemical Company, USA, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x a x b,c 2 1 source not specified, no purification details were provided. 0.9966 0.003397 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 0.2 K. c % Experimental value was reported in the paper as ln x1. x1: 2 (relative error).

Auxiliary Information Method/Apparatus/Procedure: Components: Original Measurements: 77 Constant-temperature bath and an ultraviolet/visible spectrophotometer. (1) 2-Hydroxybenzoic acid, sodium J. Barra, M.-A. Peña, and P. Excess solute and solvent were placed in flasks and allowed to equilibrate with salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. shaking for five days at constant temperature. Aliquots of saturated solutions [54-21-7] 10, 153 (2000). were removed and diluted with 96% ethanol (v/v). Concentrations were (2) 1,2-Ethanediol; C2H6O2; determined by spectrophotometric measurements. The reported solubility [107-21-1] represents the average of at least three independent determinations. Variables: Prepared by: T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, USA, no purification details were provided. Experimental Values (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. a b,c x2 x1 Estimated Error: Temperature: 0.2 K. 0.7358 0.2642 a x1: 2% (relative error). x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Components: Original Measurements: Auxiliary Information (1) 2-Hydroxybenzoic acid, sodium 77J. Barra, M.-A. Peña, and P.

salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. Method/Apparatus/Procedure: [54-21-7] 10, 153 (2000). Constant-temperature bath and an ultraviolet/visible spectrophotometer. (2) 1-Octanol; C8H18O; [111-87-5] Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions Variables: Prepared by: were removed and diluted with 96% ethanol (v/v). Concentrations were T/K ¼ 298.15 W. E. Acree, Jr. determined by spectrophotometric measurements. The reported solubility represents the average of at least three independent determinations. Experimental Values Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, USA, no purification details were provided. x a x b,c 2 1 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical 0.9947 0.005253 source not specified, no purification details were provided. a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. Estimated Error: c Experimental value was reported in the paper as ln x1. Temperature: 0.2 K. x1: 2% (relative error).

Auxiliary Information Components: Original Measurements: (1) 2-Hydroxybenzoic acid, sodium 77J. Barra, M.-A. Peña, and P. Method/Apparatus/Procedure: salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. Constant-temperature bath and an ultraviolet/visible spectrophotometer. [54-21-7] 10, 153 (2000). Excess solute and solvent were placed in flasks and allowed to equilibrate with (2) 1,2-Propanediol; C3H8O2; shaking for five days at constant temperature. Aliquots of saturated solutions [57-55-6] were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements. The reported solubility Variables: Prepared by: represents the average of at least three independent determinations. T/K ¼ 298.15 W. E. Acree, Jr. Source and Purity of Chemicals: Experimental Values (1) Purity not given, Sigma Chemical Company, USA, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a b,c source not specified, no purification details were provided. x2 x1 0.7971 0.2029 Estimated Error: a x2: mole fraction of component 2 in the saturated solution. Temperature: 0.2 K. b % x1: mole fraction solubility of the solute. x1: 2 (relative error). c Experimental value was reported in the paper as ln x1.

Auxiliary Information 31.8. Sodium salicylate solubility data in ketones Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with Components: Original Measurements: shaking for five days at constant temperature. Aliquots of saturated solutions (1) 2-Hydroxybenzoic acid, sodium 77J. Barra, M.-A. Peña, and P. were removed and diluted with 96% ethanol (v/v). Concentrations were salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. determined by spectrophotometric measurements. The reported solubility [54-21-7] 10, 153 (2000). represents the average of at least three independent determinations. (2) Propanone; C3H6O; [67-64-1] Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Sigma Chemical Company, USA, no purification details T/K ¼ 298.15 W. E. Acree, Jr. were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values

Estimated Error: a b,c Temperature: 0.2 K. x2 x1 % x1: 2 (relative error). 0.9877 0.01230 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1. Components: Original Measurements: (1) 2-Hydroxybenzoic acid, sodium 77J. Barra, M.-A. Peña, and P. salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. Auxiliary Information [54-21-7] 10, 153 (2000). / / (2) 1,2,3-Propanetriol (Glycerol); Method Apparatus Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. C3H8O3; [56-81-5] Excess solute and solvent were placed in flasks and allowed to equilibrate with Variables: Prepared by: shaking for five days at constant temperature. Aliquots of saturated solutions T/K ¼ 298.15 W. E. Acree, Jr. were removed and diluted with 96% ethanol (v/v). Concentrations were determined by spectrophotometric measurements. The reported solubility represents the average of at least three independent determinations. Experimental Values Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, USA, no purification details a b,c x2 x1 were provided. 0.8832 0.1168 (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical a source not specified, no purification details were provided. x2: mole fraction of component 2 in the saturated solution. bx : mole fraction solubility of the solute. 1 Estimated Error: cExperimental value was reported in the paper as ln x . 1 Temperature: 0.2 K.

x1: 2% (relative error).

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Sigma Chemical Company, USA, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x a x b,c 2 1 source not specified, no purification details were provided. 0.9999 0.0000456 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 0.2 K. c % Experimental value was reported in the paper as ln x1. x1: 2 (relative error).

Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, USA, no purification details Experimental Values were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. a b,c x2 x1 Estimated Error: 0.9762 0.02378 a Temperature: 0.2 K. x2: mole fraction of component 2 in the saturated solution. b x1: 2% (relative error). x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Auxiliary Information 31.9. Sodium salicylate solubility data in miscellaneous organic solvents Method/Apparatus/Procedure: Constant-temperature bath and an ultraviolet/visible spectrophotometer. Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions Components: Original Measurements: were removed and diluted with 96% ethanol (v/v). Concentrations were 77 ñ (1) 2-Hydroxybenzoic acid, sodium J. Barra, M.-A. Pe a, and P. determined by spectrophotometric measurements. The reported solubility salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. represents the average of at least three independent determinations. [54-21-7] 10, 153 (2000). [ ] (2) Ethanoic acid; C2H4O2; 64-19-7 Source and Purity of Chemicals: Variables: Prepared by: (1) Purity not given, Sigma Chemical Company, USA, no purification details T/K ¼ 298.15 W. E. Acree, Jr. were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values Estimated Error: Temperature: 0.2 K. a b,c x : 2% (relative error). x2 x1 1 0.9916 0.00835 a x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. c Experimental value was reported in the paper as ln x1.

Source and Purity of Chemicals: Experimental Values (1) Purity not given, Sigma Chemical Company, USA, no purification details were provided. (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical x a x b,c 2 1 source not specified, no purification details were provided. 0.8009 0.1991 a x2: mole fraction of component 2 in the saturated solution. Estimated Error: b x1: mole fraction solubility of the solute. Temperature: 0.2 K. c % Experimental value was reported in the paper as ln x1. x1: 2 (relative error).

Auxiliary Information Method/Apparatus/Procedure: 32. Solubility of Tenoxicam in Organic Constant-temperature bath and an ultraviolet/visible spectrophotometer. Solvents Excess solute and solvent were placed in flasks and allowed to equilibrate with shaking for five days at constant temperature. Aliquots of saturated solutions 32.1. Critical evaluation of experimental solubility % / were removed and diluted with 96 ethanol (v v). Concentrations were data determined by spectrophotometric measurements. The reported solubility represents the average of at least three independent determinations. Tenoxicam (more formally named 4-hydroxy-2-methyl- N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide- Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, USA, no purification details 1,1-dioxide) is a NSAID used to relieve pain and inflammation were provided. in individuals having osteoarthritis, rheumatoid arthritis, bur- (2) Purity not given, Spectroscopic or Analytical Reagent grade, chemical sitis, tendinitis, and periarthritis of the shoulders or hips. There source not specified, no purification details were provided. have been four published studies64,65,202,203 involving the solubility of tenoxicam in organic solvents. Yeh et al.202 Estimated Error: Temperature: 0.2 K. determined the molar solubility of tenoxicam in ethyl ethano-

x1: 2% (relative error). ate, dichloromethane, trichloromethane, methanol, ethanol, 1,2-propanediol, propanone, dimethyl sulfoxide, N,N- dimethylformamide, and N,N-dimethylacetamide at 298 K as part of a study regarding improving the solubility and bioa- Components: Original Measurements: vailability of poorly water-soluble drugs through the use of 77 ñ (1) 2-Hydroxybenzoic acid, sodium J. Barra, M.-A. Pe a, and P. aqueous-organic cosolvent systems. Gwak and Chun203 exam- salt (Sodium salicylate); C7H5NaO3; Bustamante, Eur. J. Pharm. Sci. [54-21-7] 10, 153 (2000). ined the effect of pharmaceutical formulation vehicles and (2) N,N-Dimethylformamide; penetration enhancers on the in vitro permeation of tenoxicam

C3H7NO; [64-19-7] through hairless mouse skin from saturated solutions. The Variables: Prepared by: authors measured the solubility of tenoxicam in 1-methylethyl T/K ¼ 298.15 W. E. Acree, Jr. tetradecanoate (commonly called isopropyl myristate), ethanol, 1,2-propanediol, 2-(2-methoxyethoxy)ethanol, and polyethylene glycol 400 (PEG 400) at 305 K. Wenkers and Experimental Values Lippold64 reported solubility data for ten NSAIDs (aspirin, diclofenac, diﬂunisal, ﬂufenamic acid, ibuprofen, ketoprofen, a b,c x2 x1 nabumetone, naproxen, piroxicam, and tenoxicam) in light 0.6098 0.3902 mineral oil at 305 K. It is not possible to perform a critical a evaluation as most of the measurements were performed at x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. only a single temperature, and there are at most only two c Experimental value was reported in the paper as ln x1. independent experimental values for the common solvents studied by both groups. Rytting et al.65 studied the solubility of tenoxicam in PEG 400 at ambient room temperature. The experimental solubility data for tenoxicam in organic solvents are in Secs. 32.2–32.7.

32.2. Tenoxicam solubility data in esters Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Components: Original Measurements: Excess solute and solvent were placed in sealed bottles and allowed to (1) 4-Hydroxy-2-methyl-N- 202M.-K. Yeh, L.-C. Chang, and equilibrate with shaking at a constant temperature for 48 h. Aliquots of 2-pyridinyl-2H-thieno[2,3-e]-1, A. H.-J. Chiou, AAPS saturated solutions were removed, centrifuged at 10 000 rpm for 5 min, and the 2-thiazine-3-carboxamide-1, PharmSciTech 10, 166 (2009). concentration of the dissolved drug in the supernatant was determined by high- 1-dioxide (Tenoxicam); performance liquid chromatographic analysis after suitable dilution.

C13H11N3O4S2; [59804-37-4] Source and Purity of Chemicals: (2) Ethyl ethanoate; C4H8O2; [141-78-6] (1) Purity not given, Dong-A Pharmaceutical Company, Ltd., Seoul, South Korea, no puriﬁcation details were provided. Variables: Prepared by: (2) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no / ¼ T K 298 W. E. Acree, Jr. puriﬁcation details were provided.

Estimated Error: Experimental Values Temperature: 0.5 K (estimated by compiler). c : 20% (relative error). The measured solubility was reported to be c1 ¼ 0.00841 1 mol dm3.

Auxiliary Information 32.3. Tenoxicam solubility data in haloalkanes, Method/Apparatus/Procedure: haloalkenes, and haloaromatic hydrocarbons Constant-temperature bath and a high-performance liquid chromatograph. 500 mg of tenoxicam was dissolved in 5 cm3 of solvent in a tightly closed test tube within a water bath, and then the test tubes were kept on a rotary shaker at a speed of 125 rpm for 48 h to attain equilibrium. 3 cm3 of the saturated solution Components: Original Measurements: 202 was then filtered through a 0.45 μm pore size filter. The concentration of the (1) 4-Hydroxy-2-methyl-N- M.-K. Yeh, L.-C. Chang, and dissolved solute was determined by high-performance liquid chromatographic 2-pyridinyl-2H-thieno[2,3-e]-1, A. H.-J. Chiou, AAPS analysis. 2-thiazine-3-carboxamide-1, PharmSciTech 10, 166 (2009). 1-dioxide (Tenoxicam); [ ] Source and Purity of Chemicals: C13H11N3O4S2; 59804-37-4 (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no (2) Dichloromethane; CH2Cl2; purification details were provided. [75-09-2] (2) Purity not given, Analytical Reagent grade, chemical source not specified, Variables: Prepared by: no purification details were provided. T/K ¼ 298 W. E. Acree, Jr.

Estimated Error: Temperature: 1 K (estimated by compiler). Experimental Values c1: 5% (relative error, estimated by compiler). The measured solubility was reported to be c1 ¼ 0.0474 mol dm3.

Components: Original Measurements: Auxiliary Information (1) 4-Hydroxy-2-methyl-N- 203H. S. Gwak and I. K. Chun, Int. Method/Apparatus/Procedure: 2-pyridinyl-2H-thieno[2,3-e]-1, J. Pharm. 236, 57 (2002). Constant-temperature bath and a high-performance liquid chromatograph. 2-thiazine-3-carboxamide-1, 500 mg of tenoxicam was dissolved in 5 cm3 of solvent in a tightly closed test 1-dioxide (Tenoxicam); tube within a water bath, and then the test tubes were kept on a rotary shaker at a C H N O S ; [59804-37-4] 13 11 3 4 2 speed of 125 rpm for 48 h to attain equilibrium. 3 cm3 of the saturated solution (2) 1-Methylethyl tetradecanoate; was then filtered through a 0.45 μm pore size filter. The concentration of the C H O ; [110-27-0] 17 34 2 dissolved solute was determined by high-performance liquid chromatographic Variables: Prepared by: analysis. T/K ¼ 305.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Experimental Values purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, The measured solubility was reported to be c1 ¼ 0.000474 no purification details were provided. mol dm 3. Estimated Error: Temperature: 1 K (estimated by compiler).

c1: 5% (relative error, estimated by compiler).

Auxiliary Information Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 202M.-K. Yeh, L.-C. Chang, and Method/Apparatus/Procedure: 2-pyridinyl-2H-thieno[2,3-e]-1, A. H.-J. Chiou, AAPS Constant-temperature bath and a high-performance liquid chromatograph. 2-thiazine-3-carboxamide-1, PharmSciTech 10, 166 (2009). 500 mg of tenoxicam was dissolved in 5 cm3 of solvent in a tightly closed test 1-dioxide (Tenoxicam); tube within a water bath, and then the test tubes were kept on a rotary shaker at a 3 C13H11N3O4S2; [59804-37-4] speed of 125 rpm for 48 h to attain equilibrium. 3 cm of the saturated solution (2) Trichloromethane; CHCl3; was then filtered through a 0.45 μm pore size filter. The concentration of the [67-66-3] dissolved solute was determined by high-performance liquid chromatographic analysis. Variables: Prepared by: T/K ¼ 298 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Experimental Values purification details were provided. (2) Purity not given, HPLC grade, Fisher Scientific Chemical Company, no The measured solubility was reported to be c1 ¼ 0.0544 purification details were provided. mol dm3. Estimated Error: Temperature: 1 K (estimated by compiler). Auxiliary Information c1: 5% (relative error, estimated by compiler). Method/Apparatus/Procedure: Constant-temperature bath and a high-performance liquid chromatograph. 500 mg of tenoxicam was dissolved in 5 cm3 of solvent in a tightly closed test tube within a water bath, and then the test tubes were kept on a rotary shaker at a 3 Components: Original Measurements: speed of 125 rpm for 48 h to attain equilibrium. 3 cm of the saturated solution (1) 4-Hydroxy-2-methyl-N- 203H. S. Gwak and I. K. Chun, Int. μ was then filtered through a 0.45 m pore size filter. The concentration of the 2-pyridinyl-2H-thieno[2,3-e]-1, J. Pharm. 236, 57 (2002). dissolved solute was determined by high-performance liquid chromatographic 2-thiazine-3-carboxamide-1, analysis. 1-dioxide (Tenoxicam);

C13H11N3O4S2; [59804-37-4] Source and Purity of Chemicals: (2) Ethanol; C2H6O; [64-17-5] (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. Variables: Prepared by: (2) Purity not given, Analytical Reagent grade, chemical source not specified, T/K ¼ 305.15 W. E. Acree, Jr. no purification details were provided.

Estimated Error: Experimental Values Temperature: 1 K (estimated by compiler). The measured solubility was reported to be c ¼ 0.00205 % 1 c1: 5 (relative error, estimated by compiler). mol dm3.

Auxiliary Information 32.4. Tenoxicam solubility data in alcohols Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. Excess solute and solvent were placed in sealed bottles and allowed to equilibrate with shaking at a constant temperature for 48 h. Aliquots of Components: Original Measurements: saturated solutions were removed, centrifuged at 10 000 rpm for 5 min, and the (1) 4-Hydroxy-2-methyl-N- 202M.-K. Yeh, L.-C. Chang, and concentration of the dissolved drug in the supernatant was determined by high- 2-pyridinyl-2H-thieno[2,3-e]-1, A. H.-J. Chiou, AAPS performance liquid chromatographic analysis after suitable dilution. 2-thiazine-3-carboxamide-1, PharmSciTech 10, 166 (2009). 1-dioxide (Tenoxicam); Source and Purity of Chemicals: C H N O S ; [59804-37-4] 13 11 3 4 2 (1) Purity not given, Dong-A Pharmaceutical Company, Ltd., Seoul, South (2) Methanol; CH O; [67-56-1] 4 Korea, no purification details were provided. Variables: Prepared by: (2) Purity not given, Analytical Reagent grade, chemical source not specified, T/K ¼ 298 W. E. Acree, Jr. no purification details were provided.

Estimated Error: Experimental Values Temperature: 0.5 K (estimated by compiler).

c1: 30% (relative error). The measured solubility was reported to be c1 ¼ 0.00191 mol dm3.

Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 202M.-K. Yeh, L.-C. Chang, and 2-pyridinyl-2H-thieno[2,3-e]-1, A. H.-J. Chiou, AAPS 2-thiazine-3-carboxamide-1, PharmSciTech 10, 166 (2009). 1-dioxide (Tenoxicam);

C13H11N3O4S2; [59804-37-4] (2) Ethanol; C2H6O; [64-17-5]

Variables: Prepared by: T/K ¼ 298 W. E. Acree, Jr. Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 202M.-K. Yeh, L.-C. Chang, and 2-pyridinyl-2H-thieno[2,3-e]-1, A. H.-J. Chiou, AAPS Experimental Values 2-thiazine-3-carboxamide-1, PharmSciTech 10, 166 (2009). 1-dioxide (Tenoxicam); ¼ The measured solubility was reported to be c1 0.000987 C13H11N3O4S2; [59804-37-4] 3 mol dm . (2) 1,2-Propanediol; C3H8O2; [57-55-6] Auxiliary Information Variables: Prepared by: T/K ¼ 298 W. E. Acree, Jr. Method/Apparatus/Procedure: Constant-temperature bath and a high-performance liquid chromatograph. 500 mg of tenoxicam was dissolved in 5 cm3 of solvent in a tightly closed test Experimental Values tube within a water bath, and then the test tubes were kept on a rotary shaker at a 3 speed of 125 rpm for 48 h to attain equilibrium. 3 cm of the saturated solution The measured solubility was reported to be c1 ¼ 0.00254 was then filtered through a 0.45 μm pore size filter. The concentration of the mol dm3. dissolved solute was determined by high-performance liquid chromatographic analysis. Auxiliary Information Source and Purity of Chemicals: Method/Apparatus/Procedure: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Constant-temperature bath and a high-performance liquid chromatograph. purification details were provided. 500 mg of tenoxicam was dissolved in 5 cm3 of solvent in a tightly closed test (2) Purity not given, Analytical Reagent grade, chemical source not specified, tube within a water bath, and then the test tubes were kept on a rotary shaker at a no purification details were provided. speed of 125 rpm for 48 h to attain equilibrium. 3 cm3 of the saturated solution was then filtered through a 0.45 μm pore size filter. The concentration of the Estimated Error: dissolved solute was determined by high-performance liquid chromatographic Temperature: 1 K (estimated by compiler). analysis. c1: 5% (relative error, estimated by compiler). Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. Components: Original Measurements: (2) Purity not given, Analytical Reagent grade, chemical source not specified, (1) 4-Hydroxy-2-methyl-N- 203H. S. Gwak and I. K. Chun, Int. no purification details were provided. 2-pyridinyl-2H-thieno[2,3-e]-1, J. Pharm. 236, 57 (2002). 2-thiazine-3-carboxamide-1, Estimated Error: 1-dioxide (Tenoxicam); Temperature: 1 K (estimated by compiler). c : 5% (relative error, estimated by compiler). C13H11N3O4S2; [59804-37-4] 1 (2) 1,2-Propanediol; C3H8O2; [57-55-6] Variables: Prepared by: T/K ¼ 305.15 W. E. Acree, Jr. 32.5. Tenoxicam solubility data in alkoxyalcohols

Experimental Values Components: Original Measurements: (1) 4-Hydroxy-2-methyl-N- 203H. S. Gwak and I. K. Chun, Int. The measured solubility was reported to be c1 ¼ 0.00282 [ ] mol dm 3. 2-pyridinyl-2H-thieno 2,3-e -1, J. Pharm. 236, 57 (2002). 2-thiazine-3-carboxamide-1, 1-dioxide (Tenoxicam);

Auxiliary Information C13H11N3O4S2; [59804-37-4] Method/Apparatus/Procedure: (2) 2-(2-Methoxyethoxy)ethanol; [ ] Constant-temperature bath and an UV/visible spectrophotometer. C5H12O3; 111-77-3 Excess solute and solvent were placed in sealed bottles and allowed to Variables: Prepared by: equilibrate with shaking at a constant temperature for 48 h. Aliquots of T/K ¼ 305.15 W. E. Acree, Jr. saturated solutions were removed, centrifuged at 10 000 rpm for 5 min, and the concentration of the dissolved drug in the supernatant was determined by high- performance liquid chromatographic analysis after suitable dilution. Experimental Values ¼ Source and Purity of Chemicals: The measured solubility was reported to be c1 0.01405 3 (1) Purity not given, Dong-A Pharmaceutical Company, Ltd., Seoul, South mol dm . Korea, no purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided.

Estimated Error: Temperature: 0.5 K (estimated by compiler).

c1: 20% (relative error).

Auxiliary Information 32.7. Tenoxicam solubility data in miscellaneous Method/Apparatus/Procedure: organic solvents Constant-temperature bath and an UV/visible spectrophotometer Excess solute and solvent were placed in sealed bottles and allowed to equilibrate with shaking at a constant temperature for 48 h. Aliquots of Components: Original Measurements: saturated solutions were removed, centrifuged at 10 000 rpm for 5 min, and the (1) 4-Hydroxy-2-methyl-N- 202M.-K. Yeh, L.-C. Chang, and concentration of the dissolved drug in the supernatant was determined by high- 2-pyridinyl-2H-thieno[2,3-e]-1, A. H.-J. Chiou, AAPS performance liquid chromatographic analysis after suitable dilution. 2-thiazine-3-carboxamide-1, PharmSciTech 10, 166 (2009). 1-dioxide (Tenoxicam); Source and Purity of Chemicals: C H N O S ; [59804-37-4] (1) Purity not given, Dong-A Pharmaceutical Company, Ltd., Seoul, South 13 11 3 4 2 (2) Dimethyl sulfoxide; C H OS; Korea, no purification details were provided. 2 6 [67-68-5] (2) Purity not given, chemical source not specified, no purification details were provided. Variables: Prepared by: T/K ¼ 298 W. E. Acree, Jr. Estimated Error: Temperature: 0.5 K (estimated by compiler).

c1: 2% (relative error). Experimental Values

The measured solubility was reported to be c1 ¼ 0.210 mol dm3. 32.6. Tenoxicam acid solubility data in ketones Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and a high-performance liquid chromatograph. Components: Original Measurements: 500 mg of tenoxicam was dissolved in 5 cm3 of solvent in a tightly closed test (1) 4-Hydroxy-2-methyl-N- 202M.-K. Yeh, L.-C. Chang, and tube within a water bath, and then the test tubes were kept on a rotary shaker at a 2-pyridinyl-2H-thieno[2,3-e]-1, A. H.-J. Chiou, AAPS speed of 125 rpm for 48 h to attain equilibrium. 3 cm3 of the saturated solution 2-thiazine-3-carboxamide-1, PharmSciTech 10, 166 (2009). was then filtered through a 0.45 μm pore size filter. The concentration of the 1-dioxide (Tenoxicam); dissolved solute was determined by high-performance liquid chromatographic C H N O S ; [59804-37-4] 13 11 3 4 2 analysis. (2) Propanone; C3H6O; [67-64-1] Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 298 W. E. Acree, Jr. (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, Experimental Values no purification details were provided.

The measured solubility was reported to be c1 ¼ 0.01033 3 Estimated Error: mol dm . Temperature: 1 K (estimated by compiler).

c1: 5% (relative error, estimated by compiler). Auxiliary Information Method/Apparatus/Procedure: Constant-temperature bath and a high-performance liquid chromatograph. 500 mg of tenoxicam was dissolved in 5 cm3 of solvent in a tightly closed test Components: Original Measurements: 202 tube within a water bath, and then the test tubes were kept on a rotary shaker at a (1) 4-Hydroxy-2-methyl-N- M.-K. Yeh, L.-C. Chang, and speed of 125 rpm for 48 h to attain equilibrium. 3 cm3 of the saturated solution 2-pyridinyl-2H-thieno[2,3-e]-1, A. H.-J. Chiou, AAPS was then filtered through a 0.45 μm pore size filter. The concentration of the 2-thiazine-3-carboxamide-1, PharmSciTech 10, 166 (2009). dissolved solute was determined by high-performance liquid chromatographic 1-dioxide (Tenoxicam); [ ] analysis. C13H11N3O4S2; 59804-37-4 (2) N,N-Dimethylformamide; [ ] Source and Purity of Chemicals: C3H7NO; 64-19-7 (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Variables: Prepared by: purification details were provided. T/K ¼ 298 W. E. Acree, Jr. (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. Experimental Values Estimated Error: ¼ Temperature: 1 K (estimated by compiler). The measured solubility was reported to be c1 0.0502 3 c1: 5% (relative error, estimated by compiler). mol dm .

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 4-Hydroxy-2-methyl-N- 203H. S. Gwak and I. K. Chun, Int. Constant-temperature bath and a high-performance liquid chromatograph. 2-pyridinyl-2H-thieno[2,3-e]-1, J. Pharm. 236, 57 (2002). 500 mg of tenoxicam was dissolved in 5 cm3 of solvent in a tightly closed test 2-thiazine-3-carboxamide-1, tube within a water bath, and then the test tubes were kept on a rotary shaker at a 1-dioxide (Tenoxicam); 3 speed of 125 rpm for 48 h to attain equilibrium. 3 cm of the saturated solution C13H11N3O4S2; [59804-37-4] was then filtered through a 0.45 μm pore size filter. The concentration of the (2) Polyethylene glycol 400 dissolved solute was determined by high-performance liquid chromatographic (PEG 400) analysis. Variables: Prepared by: T/K ¼ 305.15 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no purification details were provided. Experimental Values (2) Purity not given, Analytical Reagent grade, chemical source not specified, no purification details were provided. The measured solubility was reported to be c1 ¼ 0.03260 mol dm3. Estimated Error: Temperature: 1 K (estimated by compiler). Auxiliary Information c1: 5% (relative error, estimated by compiler). Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer Excess solute and solvent were placed in sealed bottles and allowed to Components: Original Measurements: equilibrate with shaking at a constant temperature for 48 h. Aliquots of (1) 4-Hydroxy-2-methyl-N- 202M.-K. Yeh, L.-C. Chang, and saturated solutions were removed, centrifuged at 10 000 rpm for 5 min, and the 2-pyridinyl-2H-thieno[2,3-e]-1, A. H.-J. Chiou, AAPS concentration of the dissolved drug in the supernatant was determined by high- 2-thiazine-3-carboxamide-1, PharmSciTech 10, 166 (2009). performance liquid chromatographic analysis after suitable dilution. 1-dioxide (Tenoxicam); Source and Purity of Chemicals: C13H11N3O4S2; [59804-37-4] (2) N,N-Dimethylacetamide; (1) Purity not given, Dong-A Pharmaceutical Company, Ltd., Seoul, South Korea, no purification details were provided. C4H9NO; [127-19-5] (2) Purity not given, chemical source not specified, no purification details were Variables: Prepared by: provided. T/K ¼ 298 W. E. Acree, Jr. Estimated Error: Temperature: 0.5 K (estimated by compiler). Experimental Values c1: 2% (relative error).

The measured solubility was reported to be c1 ¼ 0.1143 mol dm3.

Components: Original Measurements: Auxiliary Information (1) 4-Hydroxy-2-methyl-N- 65E. Rytting, K. A. Lentz, X.-Q. Method/Apparatus/Procedure: 2-pyridinyl-2H-thieno[2,3-e]-1, Chen, F. Qian, and S. Venkatesh, Constant-temperature bath and a high-performance liquid chromatograph. 2-thiazine-3-carboxamide-1, AAPS J. 7, E78 (2005). 500 mg of tenoxicam was dissolved in 5 cm3 of solvent in a tightly closed test 1-dioxide (Tenoxicam); tube within a water bath, and then the test tubes were kept on a rotary shaker at a C13H11N3O4S2; [59804-37-4] speed of 125 rpm for 48 h to attain equilibrium. 3 cm3 of the saturated solution (2) Polyethylene glycol 400 was then filtered through a 0.45 μm pore size filter. The concentration of the (PEG 400) dissolved solute was determined by high-performance liquid chromatographic Variables: Prepared by: analysis. T/K ¼ 296 W. E. Acree, Jr. Source and Purity of Chemicals: (1) Purity not given, Sigma Chemical Company, St. Louis, Missouri, USA, no Experimental Values purification details were provided. (2) Purity not given, Analytical Reagent grade, chemical source not specified, The measured solubility was reported to be c1 ¼ 0.0158 no purification details were provided. mol dm 3.

Estimated Error: Auxiliary Information Temperature: 1 K (estimated by compiler).

c1: 5% (relative error, estimated by compiler). Method/Apparatus/Procedure: Centrifuge and a high-performance liquid chromatograph equipped with a photo-diode array detector. Excess solute and solvent were placed in sealed vials and shaken at ambient room temperature for at least 24 h. The vials were then centrifuged for 15 min to separate the saturated solution from the excess solute. The supernatant was then ﬁltered and the concentration of the dissolved solute determined by high- performance liquid chromatographic analysis.

Source and Purity of Chemicals: memory as determined using Morris water maze and y-maze (1) Purity not given, Sigma-Aldrich Chemical Company, St. Louis, Missouri, 86,206 USA, no purification details were provided. experiments. There have been two published studies (2) Purity not given, J. T. Baker Chemical Company, Phillipsburg, New Jersey, reporting solubility data involving tolfenamic acid in organic USA, no purification details were provided. solvents. Persson et al.206 measured the solubility of 30 diverse drug molecules in soybean oil and polyethylene glycol 400 Estimated Error: (PEG 400) at 310 K. Tolfenamic acid was one of the drug Temperature: 2 K (estimated by compiler). molecules studied. The solubility data were reported in the c1: 10% (relative error, estimated by compiler). paper in the form of a bar graph. Surov et al.86 determined the solubility of tolfenamic acid in both hexane and 1-octanol at five temperatures from 293 to 315 K using a spectrophoto- Components: Original Measurements: metric method of analysis. The internal consistency of the two (1) 4-Hydroxy-2-methyl-N- 64B. P. Wenkers and B. C. datasets was assessed by curve-fitting the measured mole [ ] 2-pyridinyl-2H-thieno 2,3-e -1, Lippold, J. Pharm. Sci. 88, 1326 fraction solubility data to the Modified Apelblat model 2-thiazine-3-carboxamide-1, (1999). [ ] 1-dioxide (Tenoxicam); Eq. (8) to yield the following representations: C H N O S ; [59804-37-4] 13 11 3 4 2 113:777 (2) Mineral oil ln x ¼137:503 þ þ 22:219 ln T ð37Þ 1 T Variables: Prepared by: T/K ¼ 305.15 W. E. Acree, Jr. 114:917 ln x ¼43:449 þ þ 6:958 ln T ð38Þ 1 T Experimental Values for solubilities in hexane and 1-octanol, respectively. The The measured solubility was reported to be c1 ¼ 0.0000264 mol dm3. mean absolute relative deviations between the observed experimental data and back-calculated values based on Eqs. (37) and (38) of MARD ¼ 1.1% and MARD ¼ 1.7% Auxiliary Information are less than the experimental uncertainty associated with the / / Method Apparatus Procedure: measured values. Constant-temperature bath and an UV/visible spectrophotometer. Excess solute and solvent were placed in sealed bottles and allowed to The experimental solubility data for tolfenamic acid in equilibrate at a constant temperature with rotation for 24 h. Aliquots of organic solvents are given in Secs. 33.2–33.3. saturated solutions were removed, filtered through a 0.45 μm cellulose acetate membrane filter, and diluted quantitatively for spectroscopic analysis. Reported values represent the average of three experimental measurements. 33.2. Tolfenamic acid solubility data in saturated hydrocarbons (including cycloalkanes) Source and Purity of Chemicals: (1) Purity not given, Hoffmann-La Roche, Basel, Switzerland, no purification details were provided. Components: Original Measurements: (2) Purity not given, Bayer Leverkusen and Rhone Poulenc Rorer, Cologne, (1) 2-[(3-Chloro-2-methylphenyl)- 86A. O. Surov, P. Szterner, W. Germany, no purification details were provided. amino]benzoic acid (Tolfenamic Zielenkiewicz, and G. L. acid); C H ClNO ; [13710-19-5] Perlovich, J. Pharm. Biomed. Estimated Error: 14 12 2 (2) Hexane; C H ; [110-54-3] Anal. 50, 831 (2009). Temperature: 0.5 K (estimated by compiler). 6 14 c1: 10% (relative error). Variables: Prepared by: Temperature W. E. Acree, Jr.

33. Solubility of Tolfenamic Acid in Organic Experimental Values Solvents T/K x a x b,c 33.1. Critical evaluation of experimental solubility 2 1 293.2 0.9999 0.0000182 data 298.2 0.9999 0.0000274 Tolfenamic acid (more formally named 2-[(3-chloro-2- 303.2 0.9999 0.0000386 ] 310.2 0.9999 0.0000628 methylphenyl)amino benzoic acid) is an orally administered 315.2 0.9999 0.0000900 NSAID used to treat symptoms of migraines and headaches. a x2: mole fraction of component 2 in the saturated solution. Tolfenamic acid has recently been reported to inhibit tumor b x1: mole fraction solubility of the solute. growth and lung, esophageal, breast, pancreatic, and colon cSolubility of the white form of tolfenamic acid. cancer cell growth.204 Subaiea et al.205 found that short-term treatment of Alzheimer’s disease mice attenuated long-term

Auxiliary Information Estimated Error: Temperature: 0.1 K. Method/Apparatus/Procedure: x1: 2.5% (relative error). Air thermostat, analytical balance, and an UV/visible spectrophotometer. Excess solute and solvent were placed in a glass ampoule and allowed to equilibrate with rotation at constant temperature in an air thermostat for 24 h. An aliquot of the saturated solution was removed with isothermal filtration (Acrodisc CR syringe filter, PTFE, 0.2 μm pore size), and diluted 34. Solubility of Valdecoxib in Organic quantitatively. The molar solubility of the drug was determined by Solvents spectrophotometric analysis. The solubility determination was repeated three times. 34.1. Critical evaluation of experimental solubility data Source and Purity of Chemicals: (1) 99.8+%, Sigma Chemical Company, St. Louis, Missouri, USA, was used as There have been four publications207–210 reporting the received. solubility of valdecoxib (more formally named 4-(5-methyl- (2) Purity not given, Analytical Reagent Grade, Solvents Documentation 3-phenylisoxazol-4-yl)benzenesulfonamide) in organic sol- Syntheses (SDS), Peypin, France, no purification details were given in the 208,209 paper. vents. Liu and co-workers determined the molar solubility of valdecoxib in ethanol, 1,2-propanediol, 1,2,3- Estimated Error: propanetriol, and propylene glycol 400 (PEG 400) at only Temperature: 0.1 K. three temperatures from 298 to 308 K. The studies examined % x1: 2.5 (relative error). the effect of the cosolvent on enhancing the solubility of drugs exhibiting low aqueous solubility. At the time of the experi- 33.3. Tolfenamic acid solubility data in alcohols mental measurements, valdecoxib had been recently recommended as a NSAID for the management of osteoarthritis, pain, and dysmenorrhea. Very poor aqueous solubility of Components: Original Measurements: valdecoxib, however, led to difficulties in the design of both (1) 2-[(3-Chloro-2-methylphenyl)- 86A. O. Surov, P. Szterner, W. oral and injectable pharmaceutical formulations. Later, val- amino]benzoic acid (Tolfenamic Zielenkiewicz, and G. L. decoxib was withdrawn from the world market because of its [ ] 207 acid); C14H12ClNO2; 13710-19-5 Perlovich, J. Pharm. Biomed. association with cardiovascular risk. Desai and Park mea- [ ] Anal. 50, 831 (2009). (2) 1-Octanol; C8H18O; 111-87-5 sured the molar solubility of valdecoxib in methanol, ethanol, Variables: Prepared by: and 1,2,3-propanetriol at 310 K, and Chaudhar et al.210 Temperature W. E. Acree, Jr. reported the solubility of valdecoxib in PEG 400 at 298 K. The solubility data of Liu et al. for valdecoxib in PEG 400 at Experimental Values 298 K differs significantly from that reported by Chaudhar 3 et al.; a value of c1 ¼ 0.00679 mol dm (Ref. 207) versus c1 ¼ 0.117 mol dm3 (Ref. 210). The difference between the two / a b,c T K x2 x1 sets of independent experimental measurements is more than 293.2 0.9708 0.0292 would be expected based on differences in chemical purities 298.2 0.9668 0.0332 and experimental methodologies. It is not possible to perform a 303.2 0.9640 0.0360 310.2 0.9561 0.0439 critical evaluation of the experimental data as there are too few 315.2 0.9536 0.0464 measurements in any common solvent to permit a meaningful a analysis. x2: mole fraction of component 2 in the saturated solution. b x1: mole fraction solubility of the solute. The experimental solubility data for valdecoxib in organic cSolubility of the white form of tolfenamic acid. solvents are given in Secs. 34.2 and 34.3.

Auxiliary Information 34.2. Valdecoxib solubility data in alcohols Method/Apparatus/Procedure: Air thermostat, analytical balance, and an UV/visible spectrophotometer. Excess solute and solvent were placed in a glass ampoule and allowed to Components: Original Measurements: equilibrate with rotation at constant temperature in an air thermostat for 24 h. 207 An aliquot of the saturated solution was removed with isothermal filtration (1) 4-(5-Methyl-3-phenylisoxazol- K. G. H. Desai and H. J. Park, (Acrodisc CR syringe filter, PTFE, 0.2 μm pore size), and diluted 4-yl)benzenesulfonamide Drug Develop. Res. 62, 41 (2004). quantitatively. The molar solubility of the drug was determined by (Valdecoxib); C16H14N2O3S; [ ] spectrophotometric analysis. The solubility determination was repeated three 181695-72-7 [ ] times. (2) Methanol; CH4O; 67-56-1 Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 310.15 W. E. Acree, Jr. (1) 99.8+%, Sigma Chemical Company, St. Louis, Missouri, USA, was used as received. (2) Purity not given, Analytical Reagent Grade, Sigma Chemical Company, no Experimental Values purification details were given in the paper. The measured solubility was reported to be c1 ¼ 0.212 mol dm3.

Auxiliary Information Experimental Values Method/Apparatus/Procedure: Constant-temperature bath and an UV/visible spectrophotometer. T/K c a Excess solute and solvent were placed in closed-cap test tubes and allowed to 1 equilibrate in a constant-temperature shaker bath for 48 h. An aliquot of the 298.15 0.0307 saturated solution was removed, ﬁltered through a 0.2 μm membrane ﬁlter 303.15 0.0431 (Millipore USA), and diluted for spectroscopic analysis at 203 nm. Reported 308.15 0.0493 values represent the average of three experimental determinations. a 3 c1: molar solubility of the solute in units of mol dm .

Source and Purity of Chemicals: Auxiliary Information (1) Purity not given, Cipla Ltd., Mumbai, India, no purification details were given in the paper. Method/Apparatus/Procedure: (2) Purity not given, Duksan Chemicals, Kyungkido, South Korea, no Constant-temperature bath, analytical balance, and an UV/visible purification details were provided. spectrophotometer. Excess solute and solvent were placed in closed-cap tubes and allowed to Estimated Error: equilibrate in a constant-temperature shaker bath for 24 h. An aliquot of the Temperature: 0.5 K (estimated by compiler). saturated solution was removed, filtered through a 0.22 μm membrane filter, % c1: 1 (relative error). and diluted for spectroscopic analysis at 201 nm.

Source and Purity of Chemicals: (1) 99.6%, Cipla Ltd., Mumbai, India, no puriﬁcation details were given in the Components: Original Measurements: paper. (1) 4-(5-Methyl-3-phenylisoxazol- 207K. G. H. Desai and H. J. Park, (2) Purity not given, Showa Chemical Company, Tokyo, Japan, no puriﬁcation 4-yl)benzenesulfonamide Drug Develop. Res. 62, 41 (2004). details were given in the paper.

(Valdecoxib); C16H14N2O3S; [181695-72-7] Estimated Error: Temperature: 0.1 K. (2) Ethanol; C2H6O; [64-17-5] c1: 2.5% (relative error, estimated by compiler). Variables: Prepared by: T/K ¼ 310.15 W. E. Acree, Jr.

Experimental Values Components: Original Measurements: (1) 4-(5-Methyl-3-phenylisoxazol- 209C. Liu, K. G. H. Desai, X. Chen, The measured solubility was reported to be c1 ¼ 0.0454 4-yl)benzenesulfonamide and X. Tang, J. Chem. Eng. Data 3 mol dm . (Valdecoxib); C16H14N2O3S; 50, 1736 (2005). [181695-72-7] (2) 1,2-Propanediol; C H O ; Auxiliary Information 3 8 2 [57-55-6] Method/Apparatus/Procedure: Variables: Prepared by: Constant-temperature bath and an UV/visible spectrophotometer. Temperature W. E. Acree, Jr. Excess solute and solvent were placed in closed-cap test tubes and allowed to equilibrate in a constant-temperature shaker bath for 48 h. An aliquot of the saturated solution was removed, filtered through a 0.2 μm membrane filter Experimental Values (Millipore USA), and diluted for spectroscopic analysis at 203 nm. Reported values represent the average of three experimental determinations. T/K c a Source and Purity of Chemicals: 1 (1) Purity not given, Cipla Ltd., Mumbai, India, no purification details were 298.15 0.00456 given in the paper. 303.15 0.00613 (2) Purity not given, Duksan Chemicals, Kyungkido, South Korea, no 308.15 0.00934 a 3 purification details were provided. c1: molar solubility of the solute in units of mol dm .

Estimated Error: Auxiliary Information Temperature: 0.5 K (estimated by compiler).

c1: 1% (relative error). Method/Apparatus/Procedure: Constant-temperature bath, analytical balance, and an UV/visible spectrophotometer. Excess solute and solvent were placed in closed-cap tubes and allowed to Components: Original Measurements: equilibrate in a constant-temperature shaker bath for 24 h. An aliquot of the μ (1) 4-(5-Methyl-3-phenylisoxazol- 208C. Liu, K. G. H. Desai, and C. saturated solution was removed, ﬁltered through a 0.22 m membrane ﬁlter, 4-yl)benzenesulfonamide Liu, J. Chem. Eng. Data 49, 1847 and diluted for spectroscopic analysis at 201 nm.

(Valdecoxib); C16H14N2O3S; (2004). [181695-72-7] Source and Purity of Chemicals: (1) 99.6%, Cipla Ltd., Mumbai, India, no puriﬁcation details were given in the (2) Ethanol; C2H6O; [64-17-5] paper. Variables: Prepared by: (2) Purity not given, Showa Chemical Company, Tokyo, Japan, no puriﬁcation Temperature W. E. Acree, Jr. details were given in the paper.

Estimated Error: Auxiliary Information Temperature: 0.1 K. Method/Apparatus/Procedure: c1: 2.5% (relative error, estimated by compiler). Constant-temperature bath and an UV/visible spectrophotometer. Excess solute and solvent were placed in closed-cap test tubes and allowed to equilibrate in a constant-temperature shaker bath for 48 h. An aliquot of the saturated solution was removed, filtered through a 0.2 μm membrane filter Components: Original Measurements: (Millipore USA), and diluted for spectroscopic analysis at 203 nm. Reported 209 (1) 4-(5-Methyl-3-phenylisoxazol- C. Liu, K. G. H. Desai, X. Chen, values represent the average of three experimental determinations. 4-yl)benzenesulfonamide and X. Tang, J. Chem. Eng. Data (Valdecoxib); C16H14N2O3S; 50, 1736 (2005). Source and Purity of Chemicals: [ ] 181695-72-7 (1) Purity not given, Cipla Ltd., Mumbai, India, no purification details were (2) 1,2,3-Propanetriol (Glycerol); given in the paper. [ ] C3H8O3; 56-81-5 (2) Purity not given, Sigma Chemical Company, Steinhein, Germany, no Variables: Prepared by: purification details were provided. Temperature W. E. Acree, Jr. Estimated Error: Temperature: 0.5 K (estimated by compiler). % Experimental Values c1: 2 (relative error).

a T/K c1 298.15 0.000160 34.3. Valdecoxib solubility data in miscellaneous 303.15 0.000180 organic solvents 308.15 0.000192 a 3 c1: molar solubility of the solute in units of mol dm . Components: Original Measurements: (1) 4-(5-Methyl-3-phenylisoxazol- 209C. Liu, K. G. H. Desai, X. Chen, Auxiliary Information 4-yl)benzenesulfonamide and X. Tang, J. Chem. Eng. Data Method/Apparatus/Procedure: (Valdecoxib); C16H14N2O3S; 50, 1736 (2005). Constant-temperature bath, analytical balance, and an UV/visible [181695-72-7] spectrophotometer. (2) Polyethylene glycol 400 Excess solute and solvent were placed in closed-cap tubes and allowed to (PEG 400) equilibrate in a constant-temperature shaker bath for 24 h. An aliquot of the Variables: Prepared by: μ saturated solution was removed, ﬁltered through a 0.22 m membrane ﬁlter, Temperature W. E. Acree, Jr. and diluted for spectroscopic analysis at 201 nm.

Source and Purity of Chemicals: Experimental Values (1) 99.6%, Cipla Ltd., Mumbai, India, no puriﬁcation details were given in the paper. (2) Purity not given, Showa Chemical Company, Tokyo, Japan, no puriﬁcation a T/K c1 details were given in the paper. 298.15 0.00679 Estimated Error: 303.15 0.00950 Temperature: 0.1 K. 308.15 0.01418 a 3 c1: 5% (relative error, estimated by compiler). c1: molar solubility of the solute in units of mol dm .

Auxiliary Information Components: Original Measurements: Method/Apparatus/Procedure: (1) 4-(5-Methyl-3-phenylisoxazol- 207K. G. H. Desai and H. J. Park, Constant-temperature bath, analytical balance, and an UV/visible 4-yl)benzenesulfonamide Drug Develop. Res. 62, 41 (2004). spectrophotometer. (Valdecoxib); C16H14N2O3S; Excess solute and solvent were placed in closed-cap tubes and allowed to [181695-72-7] equilibrate in a constant-temperature shaker bath for 24 h. An aliquot of the (2) 1,2,3-Propanetriol (Glycerol); saturated solution was removed, filtered through a 0.22 μm membrane filter, C3H8O3; [56-81-5] and diluted for spectroscopic analysis at 201 nm. Variables: Prepared by: Source and Purity of Chemicals: T/K ¼ 310.15 W. E. Acree, Jr. (1) 99.6%, Cipla Ltd., Mumbai, India, no purification details were given in the paper. Experimental Values (2) Purity not given, Showa Chemical Company, Tokyo, Japan, no purification details were given in the paper. The measured solubility was reported to be c1 ¼ 0.000193 mol dm 3. Estimated Error: Temperature: 0.1 K.

c1: 2.5% (relative error, estimated by compiler).

13N. A. Nussmeier, A. A. Whelton, M. T. Brown, R. M. Langford, A. Hoeft, Components: Original Measurements: J. L. Parlow, S. W. Boyce, and K. M. Verburg, N. Eng. J. Med. 352, 1081 (1) 4-(5-Methyl-3-phenylisoxazol- 210P. Chaudhar, P. Sharma, N. (2005). 4-yl)benzenesulfonamide Barhate, P. Kulkarni, and C. 14R. Shiri, J. Koskimaki, J. Hakkinen, T. L. J. Tammela, A. Auvinen, and M. (Valdecoxib); C16H14N2O3S; Mistry, Curr. Sci. 92, 1586 (2007). Hakama, J. Urol. 175, 1812 (2006). [ ] 181695-72-7 15C. K. S. Ong, P. Lirk, C. H. Tan, and R. A. Seymour, Clin. Med. Res. 5,19 (2) Polyethylene glycol 400 (2007). (PEG 400) 16J. M. Prausnitz, Molecular Thermodynamics of Fluid Phase Equilibria Variables: Prepared by: (Prentice-Hall, Englewood Cliffs, NJ, 1969). 17H. Buchowski, A. Ksizczak, and S. J. Pietrzyk, J. Phys. Chem. 84, 975 T/K ¼ 298 W. E. Acree, Jr. (1980). 18H. Buchowski and A. Khiat, Fluid Phase Equilib. 25, 273 (1986). 19M. H. Abraham, Chem. Soc. Rev. 22, 73 (1993). Experimental Values 20M. H. Abraham, A. Ibrahim, and A. M. Zissimos, J. Chromatogr. A 1037, The measured solubility was reported to be c1 ¼ 0.117 29 (2004). 21 mol dm3. K. R. Hoover, K. Pop, W. E. Acree, Jr., and M. H. Abraham, S. Afr. J. Chem. 58, 25 (2005). 22K. R. Hoover, D. M. Stovall, E. Pustejovsky, R. Coaxum, K. Pop, W. E. Auxiliary Information Acree, Jr., and M. H. Abraham, Can. J. Chem. 82, 1353 (2004). 23A. K. Charlton, C. R. Daniels, R. M. Wold, E. Pustejovsky, W. E. Acree, Method/Apparatus/Procedure: Jr., and M. H. Abraham, J. Mol. Liq. 116, 19 (2005). / Mechanical shaker and an UV visible spectrophotometer. 24K. R. Hoover, R. Coaxum, E. Pustejovsky, D. M. Stovall, W. E. Acree, Jr., Excess solute and solvent were placed in closed-cap test tubes and allowed to and M. H. Abraham, Phys. Chem. Liq. 42, 339 (2004). equilibrate with shaking for 24 h. An aliquot of the saturated solution was 25A. K. Charlton, C. R. Daniels, W. E. Acree, Jr., and M. H. Abraham, J. removed, filtered through a 0.45 μm membrane filter, and diluted with ethanol Solution Chem. 32, 1087 (2003). for spectroscopic analysis at 246.5 nm. 26D. M. Stovall, C. Givens, S. Keown, K. R. Hoover, R. Barnes, C. Harris, J. Lozano, M. Nguyen, E. Rodriguez, W. E. Acree, Jr., and M. H. Abraham, Source and Purity of Chemicals: Phys. Chem. Liq. 43, 351 (2005). (1) Purity not given, Alembic Ltd., Baroda, India, no purification details were 27C. R. Daniels, A. K. Charlton, R. M. Wold, W. E. Acree, Jr., and M. H. given in the paper. Abraham, Can. J. Chem. 81, 1492 (2003). (2) Purity not given, Qualigen Chemical Company, India, no purification 28M. H. Abraham, R. E. Smith, R. Luchtefeld, A. J. Boorem, R. Luo, and W. details were given. E. Acree, Jr., J. Pharm. Sci. 99, 1500 (2010). 29T. W. Stephens, A. N. Quay, V. Chou, M. Loera, C. Shen, A. Wilson, W. E. Estimated Error: Acree, Jr., and M. H. Abraham, Global J. Phys. Chem. 3,1/1 (2012). 30 Temperature: 2 K (estimated by compiler). T. W. Stephens, A. Wilson, N. Dabadge, A. Tian, H. J. Hensley, M. Zimmerman, W. E. Acree, Jr., and M. H. Abraham, Global J. Phys. Chem. c1: 1% (relative error). 3,9/1 (2012). 31M. Saifullah, S. Ye, L. M. Grubbs, N. E. La Rosa, W. E. Acree, Jr., and M. H. Abraham, J. Solution Chem. 40, 2082 (2011). 32T. W. Stephens, M. Loera, A. N. Quay, V. Chou, C. Shen, A. Wilson, W. E. 35. References Acree, Jr., and M. H. Abraham, Open Thermodyn. J. 5, 104 (2011). 33T. W. Stephens, N. E. De La Rosa, M. Saiffullah, S. Ye, V. Chou, A. N. Quay, W. E. Acree, Jr., and M. H. Abraham, Fluid Phase Equilib. 309,30 1A. Goto, H. Miyamoto, M. Salomon, R. Goto, H. Fukuda, E. Königsber- (2011). 34 ger, and L.-C. Königsberger, J. Phys. Chem. Ref. Data 40, 013101 (2011). T. W. Stephens, N. E. De La Rosa, M. Saifullah, S. Ye, V. Chou, A. N. 308 2A. Goto, H. Miyamoto, M. Salomon, R. Goto, H. Fukuda, E. Königsber- Quay, W. E. Acree, Jr., and M. H. 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