US008232265B2

(12) United States Patent (10) Patent No.: US 8,232,265 B2 Rogers et al. (45) Date of Patent: Jul. 31, 2012

(54) MULTI-FUNCTIONAL IONIC LIQUID 25. A 8. 3. MadeuZZi et al...... : COMPOSITIONS FOR OVERCOMING 4,491,574 A 1/1985 Seifter et al...... 424/10 POLYMORPHISMAND IMPARTING 4,761,164 A 8, 1988 Pez et al...... 55/16 IMPROVED PROPERTIES FORACTIVE 4,973,456 A 1 1/1990 Quinn et al. 423,210.5

PHARMACEUTICAL, BIOLOGICAL, 539W - I A s 3: E.OCSC heral Cal...... $2. NUTRITIONAL AND ENERGETIC 5,679,146 A 10/1997 Kalt et al...... 106,166.01 INGREDIENTS 5,683,832 A 1 1/1997 Bonhote et al...... 429,111 5,731, 101 A 3, 1998 Sherifet al...... 429,102 (75) Inventors: Robin D. Rogers, Tuscaloosa, AL (US); 5,792,399 A 8, 1998 Meister et al. . ... 264/101 Daniel T. Daly, Tuscaloosa, AL (US); 5,827,602 A 10, 1998 Koch et al...... 429,194 Richard P. Swatloski, Tuscaloosa, AL 993,--- f $3. E.urgard et al...... 428/402.2 556,119 (US); Whitney L. Hough, Albertville, 6,774,240 B2 8/2004 Seddon et al...... 548/347.1 AL (US); James Hilliard Davis, Jr., 6,808,557 B2 10/2004 Holbrey et al...... 106,163.01 Mobile, AL (US); Marcin Smiglak, 6,824,599 B2 11/2004 Swatloski et al...... 106,163.01 6,846,926 B1 1/2005 Koppes et al...... 544,198 oznanCNE (PL); Scottork K. Spear,St. EasSLOn, 6,906,0046,924.341 B2 * 8/20056/2005 ParrishMays et et al. al...... 504,127526,89 AL (US) 6,939,882 B1 9/2005 Cooke et al...... 514,336 6,939,974 B2 9/2005 Earle et al. .. 548/347.1 (73) Assignee: Board of Trustees of the University of 7,166,641 B2 * 1/2007 Lee et al...... 514,561 Alabama, Tuscaloosa, AL (US) 2002/0010291 A1 1/2002 Murphy ...... 526,133 s s 2002/0161261 A1 10, 2002 Bahrmann et all 564,281 - 2003, OO73604 A1 4, 2003 McGolfetal. . 510,441 (*) Notice: Subject to any disclaimer, the term of this 2004.0007693 A1 1/2004 Moulton ...... 252/.364 patent is extended or adjusted under 35 2004/0026.666 A1 2/2004 Chauvin et al...... 252/364 U.S.C. 154(b) by 1208 days. 2004/0146549 A1 7/2004 Ben-Sasson et al...... 424/449 2004/0234966 Al 11/2004 Bryning et al...... 435/6 (21) Appl No.: 11A545,938 2005/OO587O2 A1 3/2005 Ben-Sasson et al...... 424/452 y x- - - 9 2005/0136103 A1 6/2005 Ben-Sasson et al...... 424/449 (22) Filed: Oct. 10, 2006 (Continued) (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2007/0093462 A1 Apr. 26, 2007 CA 2619367 A1 T 2009 (Continued) Related U.S. Application Data (60) Provisional application No. 60/764,850, filed on Feb. OTHER PUBLICATIONS 2, 2006, provisional application No. 60/724,604, filed Avent et al., “Evidence for hydrogen bonding in solutions of 1-Ethyl on Oct. 7, 2005, provisional application No. 3-imidazolium Halides, and its implications for ambient temperature 60/724,605, filed on Oct. 7, 2005. Halogenoaluminate(III) ionic liquids.” J. Chem. Soc., Dalton Trans., 3405 (1994). (51) Int. Cl. Bates et al., "CO2 capture by a task-specific ionic liquid.” J. Am. A6 IK3I/33 (2006.01) Chem. Soc. 124(6): 926-927 (2002). A6 IK3I/445 (2006.01) Bernstein, “Polymorphism of high energy materials.” Polymorphism A6 IK3I/21 (2006.01) in Molecular Crystals, 275-296 (2002). A6 IK3I/24 (2006.01) Bernstein, “Introduction and historical background.” Polymorphism A6 IK3I/6 (2006.01) in Molecular Crystals, 1-28 (2002). AOIN 43/90 (2006.01) Bernstein, “Crystal structure prediction and polymorphism.” ACA AOIN 37/30 (2006.01) Transactions, 39:14-23 (2004). AOIN37/18 (2006.01) (52) U.S. Cl...... 514/183; 514/306; 514/330; 514/513; (Continued) 514/535; 514/555 Primary Examiner — Alton Pryor (58) Fieldee application t state file for completeSeash - -search ------hhi history. ------None &(74) Curfman, Attorney, LLC Agent, or Firm — McKeon, Meunier, Carlin (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS Disclosed are ionic liquids and methods of preparing ionic 1943,176 A 1/1934 Graenacher ...... 260/100 liquid compositions of active pharmaceutical, biological, 2,004,891 A * 6/1935 Goldberg ...... 514,533 nutritional, and energetic ingredients. Also disclosed are 3,223,704 A 12, 1965 Shibe ...... 260,247.1 methods of using the compositions described herein to over 3. As A 3. E. St...... 364;2. come polymorphism, overcome solubility and delivery prob 3.47 1423 A 10, 1969 Elmer ...... 260/22 lems, to control release rates, add functionality, enhance effi 4,104,368 A 8, 1978 Lala et al. . 424,60 cacy (synergy), and improve ease of use and manufacture. 4,171,352 A * 10/1979 Wolgemuth et al. . ... 436/86 4,188,263. A 2, 1980 Hulsmann et al...... 439/179 9 Claims, 6 Drawing Sheets US 8,232,265 B2 Page 2

U.S. PATENT DOCUMENTS Cuppen et al., “Crystal structure and growth behavior of aspartame 2005, 0194561 A1 9/2005 Davis ...... 252/67 form I-A.” Crystal Growth & Design, 5(3) 917-923 (2005). 2005/0232981 A1 10, 2005 Ben-Sasson ...... 424/448 Davis et al., “Thiazolium-ion based organic ionic liquids (OILS). 2006, O159632 A1 7/2006 Ishibashi et al. Novel OILs which promote the benzoin condensation.” Tetrahedron 2007/0053939 A1 3/2007 Yokoyama et al. Lett. 40: 1621-1622 (1999). 2007/0054952 A1 3/2007 Hamamoto et al. Davis et al., From curiosities to commodities: Ionic liquids begin the 2009,0264664 A1 10, 2009 Endo et al. 2010, 0004608 A1 1/2010 Hamamoto et al. transformation, Chem. Comm. 1209-1211 (2003). 2010.00297.04 A1 2/2010 Hanma et al. Domagk, "A new class of disinfectants.” Deut. Med. Wochenschr. 61:829 (1935). FOREIGN PATENT DOCUMENTS Dupont et al., “Room temperature molten salts: Neuteric "Green” DE 93-43O8410 3, 1993 Solvents for chemical reactions and processes.” Braz. Chem. 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WO WO95/21872 8, 1995 Freemantle, “Eyes on ionic liquids.” Chem. Eng. News, 78(2):37-50 WO WO 97/43012 11, 1997 (2000). WO WO 98.51283 11, 1998 Fukumoto et al., “Room temperature ionic liquids from 20 natural WO WO98.51283 A1 11, 1998 amino acids.” J. Am. Chem. Soc. 2398-2399 (2005). WO WOO3,O29329 4/2003 WO WO 2004/O75877 9, 2004 Geppi et al., “Molecular properties of ibuprofen and its solid disper WO WO 96.06593 3, 2006 sions with eudragit RL100 studied by Solid-state nuclear magnetic WO WO 2009/060629 A1 5, 2009 resonance.” Pharm. Res., 22(9) 1544-1555 (2005). WO WO 2009,066457 A1 5/2009 Gordon et al., "Fused organic salts. 8. Properties of molten straight WO WO 2009,075094 A1 6, 2009 chain isomers of tetra-N-pentylammonium salts.” J. Amer: Chem. WO WO 2009,119836 A1 10/2009 Soc. 100(24):7445-7454 (1978). 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Jacobs et al., “On a new group of bactericidal Substances obtained Butcher et al., “Initial screening trials of some quaternary ammonium from hexamethylenetetramine.” Proc. Nat. Acad. Sci. USA, 1:226 228 (1915). compounds and amine Salts as wood preservatives. For: Prod. J., Jacobs et al., “The quaternary salts of hexamethylene-tetramine. J. 27:19-22 (1977). Biol. Chem. 20:659-683 (1915). Butcher et al., “Efficacy of acidic and alkaline solutions of alkylam Jacobs et al., “The bactericidal properties of the quaternary salts of monium compounds as wood preservatives.” J. For: Sci., 8:403-408 hexamethylenetetramine.” J. Exptl. Med., 23:569-576 (1916). (1978). Katritzky et al., “1-Butyl-3-methylimidazolium 3,5-dinitro-1,2,4- Campanella et al., “Benzylpenicillin PVC membrane electrode for triazolate: a novel ionic liquid containing a rigid, planar energetic the determination of antibiotics in formulations.” J. Pharm. Biomed. anion.” Chem. Comm., 868-870 (2005). 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MacFarlane et al., “Pyrrolidinium imides: A new family of molten Reutzel-Edens et al., “Anhydrates and hydrates of olanzapine: Crys salts and conductive plastic crystal phases. J. Phys. Chem. tallization Solid-state characterization, and structural relationships.” 103:4164-4170 (1999). Crystal Growth & Design, 3(6):897-907 (2003). Martino et al., “Influence of crystal habit on the compression and Rogers et al., “Ionic liquids—Solvents of the future.” Science, 302:792-793 (2003). densification mechanism of ibuprofen.” J. Crystal Growth, 243:345 Seddon, “Ionic liquids for clean technology.” J. Chem. Tech. 355 (2002). Biotechnol. 68:351-356 (1997). Matsumoto et al., “Room temperature ionic liquids based on Small Swatlowski et al., “Ionic liquids are not always green: Hydroanalysis aliphatic ammonium cations and asymmetric amide anions.” Chem. of 1-butyl-3-methylimidazolium hexafluorophosphate.” Green Comm. 1726-1727 (2002). Chem. 5:361-363 (2003). Meguro et al., “Crystal structure of the low-humidity form of Trasket al., “Screening for crystalline salts via mechanochemistry.” aspartame Sweetener.” J. Peptide Res., 56.97-104 (2000). Chem. Comm., 51-53 (2006). Merrigan et al., “New fluorous ionic liquids function as Surfactants in Visser et al., Task-specific ionic liquids for the extraction of metal ions from aqueous solutions, Chem. Comm. 135-136 (2001). conventional room-temperature ionic liquids.” Chem. Comm. 2051 Visser et al., “Hydrophobic ionic liquids incorporating 2052 (2000). N-alkylisoquinolinium cations and their utilization in liquid-liquid Morrison et al., “Base-promoted reactions in ionic liquid solvents. separation.” Chem. Comm. 2484-2485 (2001). The Knoevenagel and Robinson annulation reactions.” Tetrahedron Wasserscheid et al., “Ionic liquids-new “solutions” for transition Lett. 42:6053-6057 (2001). metal catalysis.” Angew. Chem. Int. Ed, Engl. 39:3772-3789 (2000). Ngo et al., “Thermal properties of imidazolium ionic liquids.” Welton, “Room temperature ionic liquids, Solvents for synthesis and Thermochimica Acta, 357-358:97-102 (2000). catalysis.” Chem. Rev. 99:2071-2083 (1999). Oertel, Novel hard to wash-out water soluble wood protecting agents Wilkes et al., “Air and water stable 1-ethyl-3-methylimidazolium and their application, Holztechnologie, 1965, 6:243. based ionic liquids.” J. Chem. Soc., 965-967 (1992). Ohno et al., “A new type of polymer gel electrolyte: Zwitterionic Application No. 200680046195.7, Sep. 9, 2010, First Office Action. liquid polar polymer mixture.” Electrochimica Acta, 48(14 Extended European Search Report for Application No. 06774039.9 16): 2079-2083 (2003). dated Jul. 8, 2011. Okamoto et al., “Synthesis, spectra, and reactions of International Preliminary Report on Patentability and Written Opin N-triphenylmethylpyridinium salts. Reactions of triphenylmethyl ion for PCT/US2009/069652 dated Jul. 7, 2011. chloride with pyridine under high pressure.” J. Org. Chem. office Action for AU Patent Application No. 2006302237 dated Aug. 35(11):3752-3756 (1970). 23, 2011. Oldham et al., “Unusual solvent system shows potential to Response to Office Action for AU Patent Application No. revoluntionize separation and purification technologies. The 2006302237 dated Feb. 6, 2010. Actinide Research Quarterly, 1 Quarter 50-53 (2004). Response to Office Action for CN Patent Application No. Pernak et al., “Phosphonium acesulfamate based ionic liquids.” Eur: 200680046.195 dated Mar. 23, 2012. J. Org. Chem, 650-652 (2005). Okutucuetal. Covalent Attachment of Oligonucleotides to Cellulose Quinn et al., “Salt hydrates: New reversible absorbents for carbon Acetate Membrances, Artificial Cells, Blood Sbustitutes, and dioxide.” J. Am. Chem. Soc. 117:329-335 (1995). Biotechnology, 32(4): 599-608 (2004). Rasenack et al., “Properties of ibuprofen crystallized under various Stöllner et al., Activation of Cellulose Membrances with 1, 1'- conditions: A comparative study.” Drug Dev. Industrial Pharm., Carbonyldiimidazole or 1-Cyano-4-dimethylaminopyridinium 28(9) 1077-1089 (2002). tetrafluoroborate as a Basis for the Development of Immunosensors, Remenar et al., “Salt selection and simultaneous polymorphism Analytical Biochemistry, 304: 157-165 (2002). assessment via high-throughput crystallization: The case of sertraline.” Org. Proc. Res. & Dev. 7(6): 990-996 (2003). * cited by examiner U.S. Patent Jul. 31, 2012 Sheet 1 of 6 US 8,232,265 B2

Figure 1

Hex)Sulfacetamide, HexCl & Na Sulfacetamide Dissolution

1.25

1.OO

0. 7 5

0. 5O

0.25

0.00 - 10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 Time (min)

Cation HexCl Anion NaSulfacetamide Ionic Liquid HexSulfacetamide U.S. Patent Jul. 31, 2012 Sheet 2 of 6 US 8,232,265 B2

Figure 2

Hex Sulfacetamide and DDA Sulfacetamide Dissolution

É

O 50 100 150 200

Hex Sulfacetamide Time (min) - DDA Sulfacetamide

U.S. Patent Jul. 31, 2012 Sheet 4 of 6 US 8,232,265 B2

Figure 4A

Figure 4B 100mM-MPE

6 -G-L-HC 5 -O-LD

% 4. M 3 P 2 E 1 O O 3 6 9 12 TIME U.S. Patent Jul. 31, 2012 Sheet 5 of 6 US 8,232,265 B2

Figure 5

46 OO 2 O

O

pConcentration (m ') U.S. Patent Jul. 31, 2012 Sheet 6 of 6 US 8,232,265 B2

Figure 6

És

-8 O

-100 O 1 2 3 pConcentration (m') US 8,232,265 B2 1. 2 MULTI-FUNCTIONAL IONIC LIOUID pharmaceutical compounds have been reported to exist as COMPOSITIONS FOR OVERCOMING hemi-hydrates (0.5 water molecules) through decahydrates POLYMORPHISMAND IMPARTING (10 water molecules). (Morris, “Structural Aspect of IMPROVED PROPERTIES FORACTIVE Hydrates and Solvates.' Ch. 4 in Polymorphism in Pharma PHARMACEUTICAL, BIOLOGICAL, ceutical Solids, in Brittain, H. G., Ed., Vol. 95 of Drugs and NUTRITIONAL AND ENERGETIC the Pharmaceutical Sciences, Marcel Dekker, Inc., New INGREDIENTS York, N.Y., 1999, 125-181) The possibility of polymorphism orpseudo-polymorphism CROSS-REFERENCE TO RELATED may exist for any particular compound, but the conditions APPLICATIONS 10 required to prepare as yet unknown polymorphs or pseudo polymorphs are not easily determined (see e.g., Bernstein, This patent application claims the benefit of priority to U.S. “Crystal Structure Prediction and Polymorphism.” Am Crys Provisional Application No. 60/764,850, filed Feb. 2, 2006, tallographic Assoc Trans, 2004, 39:14-23). The knowledge U.S. Provisional Application No. 60/724,604, filed Oct. 7, that one type of polymorph or pseudo-polymorph of a crys 2005, and U.S. Provisional Application No. 60/724,605, filed 15 talline form of a compound exists, or that a given set of Oct. 7, 2005, which are each incorporated by reference herein crystallization conditions leads to the production of one type in their entireties. of polymorph or pseudo-polymorph, does not typically allow researchers to predict what other types of polymorph or FIELD pseudo-polymorph might exist, or what type of polymorph or pseudo-polymorph would be produced by other crystalliza The subject matter disclosed herein generally relates to tion conditions (Guillory, “Generation of Polymorphs, ionic liquids and to methods of preparing ionic liquid com Hydrates, Solvates, and Amorphous Solids.' Ch. 5 in Poly positions of active pharmaceutical, biological, nutritional, morphism in Pharmaceutical Solids, Brittain, H. G., Ed., Vol. and energetic ingredients. Also the Subject matter disclosed 95 of Drugs and the Pharmaceutical Sciences, Marcel Dek herein generally relates to methods of using the compositions 25 ker, Inc., New York, N.Y., 1999, pp. 183-226). described hereinto overcome polymorphism, overcome solu The existence of various polymorphs or pseudo-polymor bility and delivery problems, to control release rates, add phs can greatly affect a pharmaceutical's performance since functionality, enhance efficacy (synergy), and improve ease each form can have different physical and chemical proper of use and manufacture. ties. For example, one particular polymorph pseudo-poly 30 morph may be more bioavailable, more stable (e.g., longer BACKGROUND shelflife), or more easily formulated or tableted than another polymorph. Similarly, one polymorph pseudo-polymorph Polymorphism is the ability of a substance to exist in two or may be more active or less toxic than another. Some specific more crystalline forms that have a different arrangement and/ examples of the dramatic difference that can exist between or conformation of molecules in a crystalline lattice (see e.g., 35 various pharmaceutical polymorphs are described in, e.g., Chawla and Bansal, CRIPS 2004, 5(1):9-12: Bernstein, Brittain et al., J Pharm Sci 2002, 91: 1573-1580 and Moris “Polymorphism in Molecular Crystals.” IUCR Monographs sette et al., Proc Natl AcadSci USA 2003, 100:2180-2184. on Crystallography 14, Oxford Science Publications, 2002, The effects of polymorphism and pseudo-polymorphism pp. 1-28, 240-256). It has been estimated that a large number on quality and performance of a drug is widely recognized. of pharmaceuticals exhibit polymorphism. For example, 70% 40 The exact Solid state polymorph (or pseudo-polymorph) of a of barbiturates, 60% of sulfonamides, and 23% of steroids are compound determines its physical properties such as disso believed to exist in different polymorphic forms or “polymor lution rate, solubility, bioavailability, crystal habit, mechani phs” (Haleblian et al., J Pharm Sci 1975, 64:1269-1288). cal strength, etc. (Datta et al., Nature Reviews-Drug Discov In some cases, when crystals of a compound are forming ery, 2004, 3:42-57). The delivery of an exact dosage in (e.g., crystallizing from a solution), solvent molecules may 45 manufacture and the manufacturing process itself often become entrapped or bound within the crystal lattice. The depend on which of several possible polymorphs or pseudo presence of the entrapped solvent molecules may affect the polymorphs are present. three-dimensional crystal lattice that eventually crystallizes. The variation in properties among different polymorphs (or The occurrence of a compound (target molecule) crystalliz pseudo-polymorphs) usually means that one crystalline form ing in different three-dimensional lattices based upon the 50 is desired or preferred over other forms. Obtaining a particu presence of solvent molecules has been termed “pseudo lar form can be difficult, however. Typically, researchers have polymorphism.” Akin to polymorphs, such “pseudo-poly to experiment with a multitude of variables in crystallization morphs,” also known as “solvates” (or “hydrates' when the conditions, such as aqueous solvent mixtures, amount of Solvent is water), are crystalline solids containing either sto water, amount of target compound, relative humidity, tem ichiometric (i.e., whole number ratios of target molecules to 55 perature of incubation, incubation time, etc., in a process Solvent molecules) or non-stoichiometric (i.e., non-whole characterized by trial and error. Further, the search for salts of number ratios of target molecules to solvent molecules) crystalline forms (usually sought after to control dissolution amounts of a solvent incorporated within the crystal structure. rate and solubility) can require extensive experimentation. In general, different crystalline forms of molecules (e.g., Each salt of a drug or each different solvent used to crystallize pharmaceutical compounds) can exist in the same or different 60 the drug or a salt of the drug may lead to polymorphs or hydrated or solvated states. pseudo-polymorphs that have to be fully investigated and that The Cambridge Structural Database (Allen, “The Cam have different properties (see e.g., Reutzel-Edens et al., bridge Structural Database: a quarter of a million crystal Anhydrates and hydrates of olanzapine: Crystallization, structures and rising.” Acta Crystallographica, 2002, B58, Solid-state characterization, and structural relationships.” 380-388) is a database of over 300,000 organic crystal struc 65 Crystal Growth & Design, 2003, 3:897-907). tures and is a widely used reference source in crystallography. Moreover, the inadvertent production of an undesired poly One survey of the Cambridge Structural Database shows that morph (or pseudo-polymorph), or the spontaneous transfor US 8,232,265 B2 3 4 mation from the desired crystalline form to an undesired solubility are possible. Methods of preparing and using Such form, can result in crystalline forms of a drug that are less compositions are also needed. Further methods of converting effective or even toxic. Thus, the existence and control of a compound that is difficult to solubilize into a more soluble polymorphism and pseudo-polymorphism can be the biggest form are also desired. The compositions and methods dis challenge to obtaining a drug product of constant quality. 5 closed herein meet these and other needs including the intro Another important issue regarding polymorphism and duction of enhanced or new functionality. pseudo-polymorphism is that there can be considerable regu latory hurdles for a drug that exists in various crystalline SUMMARY forms. The FDA's regulatory guidelines emphasize control of In accordance with the purposes of the disclosed materials, crystal form and the use of appropriate techniques to detect 10 compounds, compositions, devices, and methods, as embod and characterize different forms of a drug (see Guidance for ied and broadly described herein, the disclosed subject mat Industry ANDAS: Pharmaceutical Solid Polymorphism ter, in one aspect, relates to compounds and compositions and Chemistry, Manufacturing, and Controls Information, U.S. methods for preparing and using such compounds and com Department of Health and Human Services, FDA, 2004). positions. In a further aspect, the disclosed subject matter Thus, an applicant seeking FDA approval of a drug must 15 relates to ionic liquid compositions that can be used for or in demonstrate the ability to maintain a constant crystalline biological, pharmaceutical, nutritional, cosmetic, industrial, form throughout the life of the product. Such an endeavor is and commercial compositions. Methods for making the dis costly and can be extremely difficult or even impossible. closed ionic liquid compositions are also disclosed. Also Similar challenges can exist when one seeks approval of a disclosed are methods of preparing ionic liquid compositions generic product by filing an Abbreviated New Drug Applica of active pharmaceutical, biological, nutritional, and ener tion (ANDA), in which case the applicant must show equiva getic ingredients. Also the disclosed are methods of using the lence between the generic drug and an approved drug. Such a compositions described herein to overcome polymorphism, showing can be complicated when various polymorphic and/ overcome solubility and delivery problems, to control release or pseudo-polymorphic forms exist for the drug. rates, add functionality, enhance efficacy (synergy), and Amorphous forms of drugs are now being studied because 25 improve ease of use and manufacture. they are higher energy forms that have higher dissolution Additional advantages will be set forth in part in the rates and solubilities since there is no lattice structure to description that follows, and in part will be obvious from the overcome or to inhibit solvation (Bernstein, “Polymorphism description, or may be learned by practice of the aspects in Molecular Crystals.” IUCR Monographs on Crystallogra described below. The advantages described below will be phy 14, Oxford Science Publications, 2002, pp. 240-256). 30 realized and attained by means of the elements and combina This increasing attention to amorphous forms has also shown, tions particularly pointed out in the appended claims. It is to however, that the amorphous forms have a tendency to crys be understood that both the foregoing general description and tallize spontaneously to a lower energy crystalline form, usu the following detailed description are exemplary and ally at inopportune times. explanatory only and are not restrictive. The phenomenon of polymorphism and pseudo-polymor 35 phism is not limited to pharmaceuticals as many other (if not BRIEF DESCRIPTION OF THE FIGURES all) organic and inorganic compounds can crystallize into different forms. Thus, the existence of various forms of a The accompanying Figures, which are incorporated in and given compound (e.g., a pesticide, herbicide, nutraceutical, constitute a part of this specification, illustrate several aspects cosmetic, food additive, explosive, etc.) can result in the same 40 described below. synthetic, analytical, regulatory, and commercial difficulties FIG. 1 is a graph of absorbance at 258 nanometers (nm) that plague the pharmaceutical industry because of polymor over time (minutes) for hexadecylpyridinium Sulfacetamide phic and pseudo-polymorphic drugs. In each of these indus (Hex sulfacetamide), hexadecylpyridinium chloride (Hex tries, it is not currently possible to simply alter the chemical ICl), and Sodium sulfacetamide dissolution. nature of the active compound in order to tune the chemical 45 FIG. 2 is a graph of absorbance at 258 nm over time for (e.g., rate of dissolution and solubility) or physical (crystal hexadecylpyridinium sulfacetamide and didecyldimethylam habit, mechanical strength) properties. Rather, it is often the monium (DDA) sulfacetamide dissolution. strategy to search for polymorphs or pseudo-polymorphs that FIG.3 is a schematic of a computer model used to identify have the most desirable “obtainable' properties. ion combinations Suitable for the disclosed ionic liquid com Another common problem that exists with many pharma 50 binations. ceuticals is low solubility. Low solubility can make formu FIG. 4A is a graph showing a comparison of lidocaine lating aparticular compound difficult, and generally low solu hydrochloride and lidocaine docusate at Imillmolar concen bility translates into low bioavailability. Much research is tration. FIG. 4B is a graph showing a comparison of lidocaine conducted on finding ways to improve a compound's solubil hydrochloride and lidocaine docusate at 100 millimolar con ity and availability. Typically methods include complex deliv 55 centration. ery devices and chemical modifications of the drug. FIG. 5 is a graph showing molar conductivity for Camim Given that polymorphism and pseudo-polymorphism can C1 solutions at variable temperature: () 291.0 K; (O) 295.3 not be predicted; that the exact crystalline state affects chemi K; (V) 300.2 K; (A) 305.0 K in water and (()) in DMSO at cal properties (e.g., dissolution rate, solubility), biological 295.3 K. properties (e.g., bioavailability, pharmacokinetics), mechani 60 FIG. 6 is a graph showing the difference in calculated cal and physical properties, and manufacturing processes, limiting slope and actually measured (D) CamimCl in H2O and that polymorphs and pseudo-polymorphs can inconve at 295.3 K: (()) CamimCl in DMSO at 295.3 K. niently interconvert, what are needed are compositions that are at least effective for their intended purpose, but can also DETAILED DESCRIPTION have controlled and tunable chemical, biological, and physi 65 cal properties, are in a form that is not subject to polymor The materials, compounds, compositions, articles, and phism, and for which controlled, tunable dissolution and methods described herein may be understood more readily by US 8,232,265 B2 5 6 reference to the following detailed description of specific between two particular units are also disclosed. For example, aspects of the disclosed subject matter and the Examples if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also included therein. disclosed. Before the present materials, compounds, compositions, As used herein, by a “subject' is meant an individual. Thus, articles, devices, and methods are disclosed and described, it the “subject' can include domesticated animals (e.g., cats, is to be understood that the aspects described below are not dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, limited to specific synthetic methods or specific reagents, as etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, Such may, of course, vary. It is also to be understood that the etc.), and birds. "Subject' can also include a mammal, such as terminology used herein is for the purpose of describing a primate or a human. particular aspects only and is not intended to be limiting. 10 Also, throughout this specification, various publications By “reduce” or otherforms of the word, such as “reducing are referenced. The disclosures of these publications in their or “reduction is meant lowering of an event or characteristic entireties are hereby incorporated by reference into this appli (e.g., microorganism growth or Survival). It is understood that cation in order to more fully describe the state of the art to this is typically in relation to Some standard or expected value, which the disclosed matter pertains. The references disclosed 15 in other words it is relative, but that it is not always necessary are also individually and specifically incorporated by refer for the standard or relative value to be referred to. For ence herein for the material contained in them that is dis example, “reduces bacteria growth' means lowering the cussed in the sentence in which the reference is relied upon. amount of bacteria relative to a standard or a control. General Definitions By "prevent' or other forms of the word, such as “prevent In this specification and in the claims that follow, reference ing’ or “prevention, is meant to stop a particular event or will be made to a number of terms, which shall be defined to characteristic, to stabilize or delay the development or pro have the following meanings: gression of a particular event or characteristic, or to minimize Throughout the description and claims of this specification the chances that a particular event or characteristic will occur. the word “comprise' and other forms of the word, such as Prevent does not require comparison to a control as it is “comprising and "comprises.” means including but not lim 25 typically more absolute than, for example, reduce. As used ited to, and is not intended to exclude, for example, other herein, something could be reduced but not prevented, but additives, components, integers, or steps. Something that is reduced could also be prevented. Likewise, As used in the description and the appended claims, the Something could be prevented but not reduced, but something singular forms “a” “an.” and “the include plural referents that is prevented could also be reduced. It is understood that unless the context clearly dictates otherwise. Thus, for 30 where reduce or prevent are used, unless specifically indi example, reference to “a composition' includes mixtures of cated otherwise, the use of the other word is also expressly two or more such compositions, reference to “an ionic liquid” disclosed. includes mixtures of two or more Suchionic liquids, reference By “treat' or other forms of the word, such as “treated' or to “the compound includes mixtures of two or more such “treatment, is meant to administer a composition or to per compounds, and the like. 35 form a method in order to reduce, prevent, inhibit, break "Optional' or “optionally’ means that the subsequently down, or eliminate a particular characteristic or event (e.g., described event or circumstance can or cannot occur, and that microorganism growth or survival). The term “control is the description includes instances where the event or circum used synonymously with the term “treat.” stance occurs and instances where it does not. By “antimicrobial' is meant the ability to treat or control Ranges can be expressed herein as from “about one par 40 (e.g., reduce, prevent, inhibit, break-down, or eliminate) ticular value, and/or to “about another particular value. microorganism growth or Survival at any concentration. Simi When Such a range is expressed, another aspect includes from larly, the terms “antibacterial.” “antiviral.” and “antifungal' the one particular value and/or to the other particular value. respectively mean the ability to treat or control (e.g., reduce, Similarly, when values are expressed as approximations, by prevent, inhibit, break-down, or eliminate) bacterial, viral, use of the antecedent “about it will be understood that the 45 and filmgal growth or Survival at any concentration. particular value forms another aspect. It will be further under It is understood that throughout this specification the iden stood that the endpoints of each of the ranges are significant tifiers “first and “second are used solely to aid in distin both in relation to the other endpoint, and independently of guishing the various components and steps of the disclosed the other endpoint. It is also understood that there are a subject matter. The identifiers “first and “second are not number of values disclosed herein, and that each value is also 50 intended to imply any particular order, amount, preference, or herein disclosed as “about that particular value in addition to importance to the components or steps modified by these the value itself. For example, if the value “10 is disclosed, terms. then “about 10' is also disclosed. It is also understood that Chemical Definitions when a value is disclosed, then “less than or equal to the References in the specification and concluding claims to value, “greater than or equal to the value.” and possible ranges 55 parts by weight of a particular element or component in a between values are also disclosed, as appropriately under composition denotes the weight relationship between the ele stood by the skilled artisan. For example, if the value “10 is ment or component and any other elements or components in disclosed, then “less than or equal to 10” as well as “greater the composition or article for which a part by weight is than or equal to 10” is also disclosed. It is also understood that expressed. Thus, in a compound containing 2 parts by weight throughout the application data are provided in a number of 60 of component X and 5 parts by weight component Y. X and Y different formats and that this data represent endpoints and are present at a weight ratio of 2:5, and are present in Such starting points and ranges for any combination of the data ratio regardless of whether additional components are con points. For example, if a particular data point “10 and a tained in the compound. particular data point “15” are disclosed, it is understood that A weight percent (wt.%) of a component, unless specifi greater than, greater than or equal to, less than, less than or 65 cally stated to the contrary, is based on the total weight of the equal to, and equal to 10 and 15 are considered disclosed as formulation or composition in which the component is well as between 10 and 15. It is also understood that each unit included. US 8,232,265 B2 7 8 The term “ion,” as used herein, refers to any molecule, Throughout the specification “alkyl is generally used to portion of a molecule, cluster of molecules, molecular com refer to both unsubstituted alkyl groups and substituted alkyl plex, moiety, or atom that contains a charge (positive, nega groups; however, Substituted alkyl groups are also specifi tive, or both (e.g., Zwitterions)) or that can be made to contain cally referred to herein by identifying the specific a charge. Methods for producing a charge in a molecule, Substituent(s) on the alkyl group. For example, the term portion of a molecule, cluster of molecules, molecular com "halogenated alkyl specifically refers to an alkyl group that plex, moiety, or atom are disclosed herein and can be accom is Substituted with one or more halide, e.g., fluorine, chlorine, plished by methods known in the art, e.g., protonation, depro bromine, or iodine. The term “alkoxyalkyl specifically refers tonation, oxidation, reduction, alkylation, etc. to an alkyl group that is substituted with one or more alkoxy The term “anion' is a type of ion and is included within the 10 groups, as described below. The term “alkylamino” specifi meaning of the term “ion.” An "anion' is any molecule, cally refers to an alkyl group that is substituted with one or portion of a molecule (e.g., Zwitterion), cluster of molecules, more amino groups, as described below, and the like. When molecular complex, moiety, or atom that contains a net nega “alkyl is used in one instance and a specific term Such as tive charge or that can be made to contain a net negative “alkylalcohol is used in another, it is not meant to imply that charge. The term "anion precursor is used herein to specifi 15 the term “alkyl does not also refer to specific terms such as cally refer to a molecule that can be converted to an anion via “alkylalcohol and the like. a chemical reaction (e.g., deprotonation). This practice is also used for other groups described herein. The term “cation' is a type of ion and is included within the That is, while a term such as “cycloalkyl refers to both meaning of the term “ion. A "cation' is any molecule, por unsubstituted and substituted cycloalkyl moieties, the substi tion of a molecule (e.g., Zwitterion), cluster of molecules, tuted moieties can, in addition, be specifically identified molecular complex, moiety, or atom, that contains a net posi herein; for example, a particular Substituted cycloalkyl can be tive charge or that can be made to contain a net positive referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substi charge. The term “cation precursor is used herein to specifi tuted alkoxy can be specifically referred to as, e.g., a "halo cally refer to a molecule that can be converted to a cation via genated alkoxy, a particular Substituted alkenyl can be, e.g., a chemical reaction (e.g., protonation or alkylation). 25 an “alkenylalcohol and the like. Again, the practice of using As used herein, the term “substituted is contemplated to a general term, Such as “cycloalkyl and a specific term, Such include all permissible Substituents of organic compounds. In as “alkylcycloalkyl is not meant to imply that the general a broad aspect, the permissible Substituents include acyclic term does not also include the specific term. and cyclic, branched and unbranched, carbocyclic and het The term “alkoxy” as used herein is an alkyl group bound erocyclic, and aromatic and nonaromatic Substituents of 30 through a single, terminal ether linkage; that is, an “alkoxy” organic compounds. Illustrative Substituents include, for group can be defined as —OA' where A' is alkyl as defined example, those described below. The permissible substituents above. can be one or more and the same or different for appropriate The term “alkenyl' as used herein is a hydrocarbon group organic compounds. For purposes of this disclosure, the het of from 2 to 24 carbon atoms with a structural formula con eroatoms, such as nitrogen, can have hydrogen Substituents 35 taining at least one carbon-carbon double bond. Asymmetric and/or any permissible Substituents of organic compounds structures such as (AA)C=C(AA) are intended to described herein which satisfy the valencies of the heteroat include both the E and Z isomers. This may be presumed in oms. This disclosure is not intended to be limited in any structural formulae herein wherein an asymmetric alkene is manner by the permissible Substituents of organic com present, or it may be explicitly indicated by the bond symbol pounds. Also, the terms “substitution” or “substituted with 40 C=C. The alkenyl group can be substituted with one or more include the implicit proviso that such substitution is in accor groups including, but not limited to, alkyl, halogenated alkyl, dance with permitted valence of the substituted atom and the alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, substituent, and that the substitution results in a stable com carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, pound, e.g., a compound that does not spontaneously undergo silyl, Sulfo-oxo, Sulfonyl, Sulfone, Sulfoxide, or thiol, as transformation Such as by rearrangement, cyclization, elimi 45 described below. nation, etc. The term “alkynyl as used herein is a hydrocarbon group “A.” “A,” “A” and “A” are used herein as generic of 2 to 24 carbon atoms with a structural formula containing symbols to represent various specific Substituents. These at least one carbon-carbon triple bond. The alkynyl group can symbols can be any Substituent, not limited to those disclosed be substituted with one or more groups including, but not herein, and when they are defined to be certain substituents in 50 limited to, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, one instance, they can, in another instance, be defined as some aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, other substituents. ether, halide, hydroxy, ketone, nitro, silyl, Sulfo-oxo, Sulfo The term “aliphatic' as used herein refers to a non-aro nyl, sulfone, sulfoxide, or thiol, as described below. matic hydrocarbon group and includes branched and The term “aryl as used herein is a group that contains any unbranched, alkyl, alkenyl, or alkynyl groups. 55 carbon-based aromatic group including, but not limited to, The term “alkyl as used herein is a branched or benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, unbranched saturated hydrocarbon group of 1 to 24 carbon and the like. The term “aryl also includes "heteroaryl.” atoms, such as methyl, ethyl, n-propyl, isopropyl. n-butyl, which is defined as a group that contains an aromatic group isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl. that has at least one heteroatom incorporated within the ring dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the 60 of the aromatic group. Examples of heteroatoms include, but like. The alkyl group can also be substituted or unsubstituted. are not limited to, nitrogen, oxygen, Sulfur, and phosphorus. The alkyl group can be substituted with one or more groups Likewise, the term “non-heteroaryl, which is also included including, but not limited to, alkyl, halogenated alkyl, alkoxy, in the term “aryl. defines a group that contains an aromatic alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxy group that does not contain a heteroatom. The aryl group can lic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, 65 be substituted or unsubstituted. The aryl group can be substi sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described tuted with one or more groups including, but not limited to, below. alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, het US 8,232,265 B2 9 10 eroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy hydroxy, ketone, nitro, silyl, Sulfo-oxo, Sulfonyl, Sulfone, cloalkenyl group described above. sulfoxide, or thiol as described herein. The term “biary1' is a The term “ketone' as used herein is represented by the specific type of aryl group and is included in the definition of formula A'C(O)A, where A' and A can be, independently, aryl. Biaryl refers to two aryl groups that are bound together 5 an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, via a fused ring structure, as in naphthalene, or are attached cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy via one or more carbon-carbon bonds, as in biphenyl. cloalkenyl group described above. The term “cycloalkyl as used herein is a non-aromatic The term “halide' as used herein refers to the halogens carbon-based ring composed of at least three carbon atoms. fluorine, chlorine, bromine, and iodine. Examples of cycloalkyl groups include, but are not limited to, 10 The term “hydroxyl as used herein is represented by the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The formula—OH. term "heterocycloalkyl is a cycloalkyl group as defined The term “nitro” as used herein is represented by the for above where at least one of the carbon atoms of the ring is mula—NO. substituted with a heteroatom such as, but not limited to, The term “silyl as used herein is represented by the for nitrogen, oxygen, Sulfur, or phosphorus. The cycloalkyl 15 mula - SiAAA, where A, A, and A can be, indepen group and heterocycloalkyl group can be substituted or dently, hydrogen, alkyl, halogenated alkyl, alkoxy, alkenyl, unsubstituted. The cycloalkyl group and heterocycloalkyl alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocy group can be substituted with one or more groups including, cloalkyl, or heterocycloalkenyl group described above. but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, het The term “sulfo-oxo' as used herein is represented by the eroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, formulas —S(O)A', S(O)A', OS(O)A", or —OS(O) hydroxy, ketone, nitro, silyl, Sulfo-oxo, Sulfonyl, Sulfone, OA', where A' can be hydrogen, an alkyl, halogenated alkyl, sulfoxide, or thiol as described herein. alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, The term “cycloalkenyl' as used herein is a non-aromatic heterocycloalkyl, or heterocycloalkenyl group described carbon-based ring composed of at least three carbon atoms 25 above. Throughout this specification “S(O) is a short hand and containing at least one double bound, i.e., C=C. notation for S=O. Examples of cycloalkenyl groups include, but are not limited The term "sulfonyl is used herein to refer to the sulfo-oxo to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopenta group represented by the formula—S(O)A', where A' can dienyl, cyclohexenyl, cyclohexadienyl, and the like. The term be hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, "heterocycloalkenyl is a type of cycloalkenyl group as 30 aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, defined above, and is included within the meaning of the term or heterocycloalkenyl group described above. “cycloalkenyl,” where at least one of the carbonatoms of the The term "sulfonylamino” or "sulfonamide” as used herein ring is substituted with a heteroatom Such as, but not limited is represented by the formula—S(O)NH-. to, nitrogen, oxygen, Sulfur, or phosphorus. The cycloalkenyl The term “sulfone' as used herein is represented by the group and heterocycloalkenyl group can be substituted or 35 formula A'S(O).A., where A' and A can be, independently, unsubstituted. The cycloalkenyl group and heterocycloalk an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, enyl group can be substituted with one or more groups includ cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy ing, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, cloalkenyl group described above. heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, The term "sulfoxide’ as used herein is represented by the halide, hydroxy, ketone, nitro, silyl, Sulfo-oxo, Sulfonyl, Sul 40 formula A'S(O)A, where A' and A can be, independently, fone, sulfoxide, or thiol as described herein. an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, The term “cyclic group' is used hereinto refer to eitheraryl cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy groups, non-aryl groups (i.e., cycloalkyl, heterocycloalkyl, cloalkenyl group described above. cycloalkenyl, and heterocycloalkenyl groups), or both. The term “thiol as used herein is represented by the for Cyclic groups have one or more ring systems that can be 45 mula—SH. Substituted or unsubstituted. A cyclic group can contain one “R',” “R” “R” “R”,” etc., where n is some integer, as or more aryl groups, one or more non-aryl groups, or one or used herein can, independently, possess one or more of the more aryl groups and one or more non-aryl groups. groups listed above. For example, if R is a straight chain The term "aldehyde' as used herein is represented by the alkyl group, one of the hydrogenatoms of the alkyl group can formula—C(O)H. Throughout this specification “C(O) is a 50 optionally be substituted with a hydroxyl group, an alkoxy short hand notation for C=O. group, an amine group, an alkyl group, a halide, and the like. The terms “amine' or "amino” as used herein are repre Depending upon the groups that are selected, a first group can sented by the formula NAAA, where A, A, and Acan be, be incorporated within second group or, alternatively, the first independently, hydrogen, an alkyl, halogenated alkyl, alk group can be pendant (i.e., attached) to the second group. For enyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, het 55 example, with the phrase “an alkyl group comprising an erocycloalkyl, or heterocycloalkenyl group described above. amino group, the amino group can be incorporated within The term “carboxylic acid as used herein is represented by the backbone of the alkyl group. Alternatively, the amino the formula —C(O)OH. A “carboxylate” as used herein is group can be attached to the backbone of the alkyl group. The represented by the formula—C(O)O. nature of the group(s) that is (are) selected will determine if The term “ester” as used herein is represented by the for 60 the first group is embedded or attached to the second group. mula —OC(O)A' or C(O)CA', where A' can be an alkyl, The term “bioactive property” is any local or systemic halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, biological, physiological, or therapeutic effect in a biological cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy system. For example, the bioactive property can be the control cloalkenyl group described above. of infection or inflammation, enhancement or Suppression of The term “ether as used herein is represented by the for 65 growth, action as an analgesic, anti-viral, pesticidal, herbi mula AOA, where A' and A can be, independently, an cidal, or nutrientional action, etc. Many examples of bioactive alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, properties are disclosed herein. US 8,232,265 B2 11 12 The term “energetic' is used to described a compound Further, the disclosed ionic liquid compositions are mate having a heat of combustion of greater than about 500 kcal/ rials composed of at least two different ions; each of which mol (e.g., about 750, 1000, 1500 kcal/mol or more). can independently and simultaneously introduce a specific Unless stated to the contrary, a formula with chemical characteristic to the composition not easily obtainable with bonds shown only as Solid lines and not as wedges or dashed traditional dissolution and formulation techniques. Thus, by lines contemplates each possible isomer, e.g., each enanti providing different ions and ion combinations, one can omer, diastereomer, and meso compound, and a mixture of change the characteristics or properties of the disclosed ionic isomers, such as a racemic or scalemic mixture. liquid compositions in a way not seen by simply preparing Reference will now be made in detail to specific aspects of various crystalline salt forms. Examples of characteristics 10 that can be controlled in the disclosed compositions include, the disclosed materials, compounds, compositions, articles, but are not limited to, melting, solubility control, and rate of and methods, examples of which are illustrated in the accom dissolution. It is this multi-nature/functionality of the dis panying Examples. closed ionic liquid compositions which allows one to fine Materials and Compositions tune or design in very specific desired material properties. Certain materials, compounds, compositions, and compo 15 It is further understood that the disclosed ionic liquid com nents disclosed herein can be obtained commercially or positions can include solvent molecules (e.g., water); how readily synthesized using techniques generally known to ever, these solvent molecules should not be present in excess those of skill in the art. For example, the starting materials and in the sense that the disclosed ionic liquid compositions are reagents used in preparing the disclosed compounds and dissolved in the Solvent, forming a solution. That is, the compositions are either available from commercial Suppliers disclosed ionic liquid compositions contain no or minimal such as Aldrich Chemical Co., (Milwaukee, Wis.). Acros amounts of solvent molecules that are free and not bound or Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, associated with the ions present in the ionic liquid composi Pa.), Sigma (St. Louis, Mo.), Pfizer (New York, N.Y.), Glaxo tion. Thus, the disclosed ionic liquid compositions can be SmithKline (Raleigh, N.C.), Merck (Whitehouse Station, liquid hydrates or Solvates, but not solutions. N.J.), Johnson & Johnson (New Brunswick, N.J.), Aventis 25 Ionic liquids have been of general interest because they are (Bridgewater, N.J.), AstraZeneca (Wilmington, Del.), Novar environmentally-friendly alternatives to organic solvents for tis (Basel, Switzerland), Wyeth (Madison, N.J.), Bristol-My various chemical processes, e.g., liquid/liquid extractions, ers-Squibb (New York, N.Y.), Roche (Basel, Switzerland), catalysis, separations, and electrochemistry. Ionic liquids Lilly (Indianapolis, Id.), Abbott (Abbott Park, Ill.), Schering have also become popular alternative media for chemical Plough (Kenilworth, N.J.), or Boehringer Ingelheim (Ingel 30 synthesis because of their low volatility and low toxicity. See heim, Germany), or are prepared by methods known to those e.g., Wasserscheid and Keim, Angew Chem Int Ed Engl, 2000, skilled in the art following procedures set forth in references 39:3772; and Wasserscheid, “Ionic Liquids in Synthesis.” 1 such as Fieser and Fieser’s Reagents for Organic Synthesis, Ed., Wiley-VCH, 2002. Further, ionic liquids can reduce Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chem costs, disposal requirements, and hazards associated with istry of Carbon Compounds, Volumes 1-5 and Supplementals 35 Volatile organic compounds. Other exemplary properties of (Elsevier Science Publishers, 1989); Organic Reactions, Vol ionic liquids are high ionic conductivity, non-volatility, non umes 1-40 (John Wiley and Sons, 1991); March's Advanced flammability, high thermal stability, wide temperature for Organic Chemistry, (John Wiley and Sons, 4th Edition); and liquid phase, highly solvability, and non-coordinating. For a Larock's Comprehensive Organic Transformations (VCH review of ionic liquids see, for example, Welton, Chem Rev. Publishers Inc., 1989). Other materials, such as the active 40 1999,99:2071-2083; and Carlinet al., Advances in Nonague pharmaceutical ingredients, pesticides, herbicides, and other ous Chemistry, Mamantov et al. Eds. VCH Publishing, New biological agents disclosed herein can be obtained from com York, 1994. mercial Sources. The specific physical properties (e.g., melting point, vis In one aspect, disclosed herein are ionic liquid composi cosity, density, water solubility, etc.) of ionic liquids are tions. The term "ionic liquid” has many definitions in the art, 45 determined by the choice of cation and anion, as is disclosed but is used herein to refer to salts (i.e., compositions compris more fully herein. As an example, the melting point for an ing cations and anions) that are liquid at a temperature of at or ionic liquid can be changed by making structural modifica below about 150° C. That is, at one or more temperature tions to the ions or by combining differentions. Similarly, the ranges or points at or below about 150° C. the disclosed ionic particular chemical properties (e.g., bioactivity, toxicity, liquid compositions are liquid; although, it is understood that 50 pharmacokinetics, etc.), can be selected by changing the con they can be solids at other temperature ranges or points. Since stituentions of the ionic liquid. the disclosed ionic liquid compositions are liquid, and thus The ionic liquid compositions disclosed herein are com not crystalline Solids, at a given temperature, the disclosed prised of at least one kind of anion and at least one kind of compositions do not suffer from the problems of polymor cation. The at least one kind of cation, the at least one kind of phism associated with crystalline solids. 55 anion, or both can be a pharmaceutical active, a pesticidal The use of the term “liquid to describe the disclosed ionic active, a herbicidal active, a food additive, a nutraceutical, or liquid compositions is meant to describe a generally amor the like, including any combination thereof, as is disclosed phous, non-crystalline, or semi-crystalline State. For herein. It is contemplated that the disclosed ionic liquid com example, while Some structured association and packing of positions can comprise one kind of cation with more than one cations and anions can occurat the atomic level, the disclosed 60 kind of anion (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different ionic liquid compositions have minor amounts of Such kinds of anions). Likewise, it is contemplated that the dis ordered structures and are therefore not crystalline solids. The closed ionic liquid compositions can comprise one kind of compositions disclosed herein can be fluid and free-flowing anion with more than one kind of cation (e.g., 2, 3, 4, 5, 6, 7, liquids or amorphous Solids such as glasses or waxes at a 8, 9, 10, or more different kinds of cations). Further, the temperature at or below about 150°C. In particular examples 65 disclosed ionic liquids can comprise more than one kind of disclosed herein, the disclosed ionic liquid compositions are anion (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different kinds of liquid at the body temperature of a subject. anions) with more than one kind of cation (e.g., 2, 3, 4, 5, 6, US 8,232,265 B2 13 14 7, 8, 9, 10 or more different kinds of cations). Specific from about 20°C. to about 100° C., from about 30°C. to about examples include, but are not limited to, one kind of cation 90° C., from about 40°C. to about 80°C., from about 50° C. with 1,2,3,4,5,6,7,8,9, 10, or more kinds of anions, 2 kinds to about 70° C., from about -30° C. to about 50° C., from of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of about -30° C. to about 90° C., from about -30° C. to about anions, 3 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 5 110° C., from about -30° C. to about 130° C., from about more kinds of anions, 4 kinds of cations with 1, 2, 3, 4, 5, 6, -30°C. to about 150° C. from about 30° C. to about 90° C., 7, 8, 9, 10, or more kinds of anions, 5 kinds of cations with 1, from about 30°C. to about 110°C., from about 30°C. to about 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of anions, 6 kinds of 130°C., from about 30° C. to about 150° C., from about 0°C. cations with 1,2,3,4,5,6,7,8,9, 10, or more kinds of anions, to about 100°C., from about 0°C. to about 70° C., from about 7 kinds of cations with 1,2,3,4,5,6,7,8,9, 10, or more kinds 10 0° to about 50° C., and the like. ofanions, 8 kinds of cations with 1, 2, 3, 4, 5, 6,7,8,9, 10, or Further, in some examples the disclosed ionic liquid com more kinds of anions, 9 kinds of cations with 1, 2, 3, 4, 5, 6, positions can be liquid over a wide range oftemperatures, not 7, 8, 9, 10, or more kinds of anions, 10 kinds of cations with just a narrow range of say, 1-2 degrees. For example, the 1,2,3,4,5,6,7,8,9, 10, or more kinds of anions, or more than disclosed ionic liquid compositions can be liquids over a 10 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more 15 range of at least about 4, 5, 6, 7, 8, 9, 10, or more degrees. In kinds of anions. other example, the disclosed ionic liquid compositions can be Other specific examples include, but are not limited to, one liquid over at least about a 11, 12, 13, 14, 15, 16, 17, 18, 19. kind of anion with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of 20, or more degree temperature range. Such temperature cations, 2 kinds of anions with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or ranges can begin and/or end at any of the temperature points more kinds of cations, 3 kinds of anions with 1, 2, 3, 4, 5, 6, disclosed in the preceding paragraph. 7, 8, 9, 10, or more kinds of cations, 4 kinds of anions with 1, In many examples disclosed herein the disclosed ionic 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of cations, 5 kinds of liquid compositions are liquid at the temperature at which anions with 1,2,3,4,5,6,7,8,9, 10, or more kinds of cations, they will be used or processed. For example, many of the 6 kinds of anions with 1,2,3,4,5,6,7,8,9, 10, or more kinds disclosed ionic liquid compositions can be used for therapeu of cations, 7 kinds of anions with 1, 2, 3, 4, 5, 6,7,8,9, 10, or 25 tic or nutritional purposes in a subject. In this case, the dis more kinds of cations, 8 kinds of anions with 1, 2, 3, 4, 5, 6, closed ionic liquid compositions can be liquid at the Subjects 7, 8, 9, 10, or more kinds of cations, 9 kinds of anions with 1, body temperature (e.g., about 37° C. for a human). Other 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of cations, 10 kinds of examples include compositions that can be used as herbicides anions with 1,2,3,4,5,6,7,8,9, 10, or more kinds of cations, or pesticides, which are liquid at the temperature of their use or more than 10 kinds of anions with 1,2,3,4,5,6,7,8,9, 10, 30 (e.g., ambient temperature). In still other examples, the dis or more kinds of cations. closed compositions can be liquid at the temperature at which In addition to the cations and anions, the ionic liquid com they are formulated or processed. positions disclosed herein can also contain nonionic species, It is understood, however, that the disclosed ionic liquid Such as solvents, preservatives, dyes, colorants, thickeners, compositions can, though need not, be solubilized, and solu Surfactants, viscosity modifiers, mixtures and combinations 35 tions of the disclosed ionic liquids are contemplated herein. thereof and the like. However, the amount of such nonionic Further, the disclosed ionic liquid compositions can be for species is typically low (e.g., less than about 10,9,8,7,6, 5, mulated in an extended or controlled release vehicle, for 4, 3, 2, or 1 wt.% based on the total weight of the composi example, by encapsulating the ionic liquids in microspheres tion). In some examples described herein, the disclosed ionic or microcapsules using methods known in the art. Still fur liquid compositions are neat; that is, the only materials 40 ther, the disclosed ionic liquid compositions can themselves present in the disclosed ionic liquids are the cations and be solvents for other solutes. For example, the disclosed ionic anions that make up the ionic liquid compositions. It is under liquids can be used to dissolve a particular nonionic or ionic stood, however, that with neat compositions, some additional pharmaceutical active. These and other formulations of the materials or impurities can sometimes be present, albeit at disclosed ionic liquids are disclosed elsewhere herein. low to trace amounts (e.g., less than about 10,9,8,7,6, 5, 4, 45 In some examples, the disclosed ionic liquids are not solu 3, 2, or 1 wt.% based on the total weight of the composition). tions where ions are dissolved in a solute. In other examples, The disclosed ionic liquid compositions are liquid at Some the disclosed ionic liquid compositions do not contain ionic temperature range or point at or below about 150° C. For exchange resins. In still other examples, the disclosed ionic example, the disclosed ionic liquids can be a liquid at or liquids are substantially free of water. By substantially free is below about 150, 149,148,147,146,145,144, 143, 142,141, 50 meant that water is present at less than about 10,9,8,7,6, 5, 140, 139, 138, 137, 136, 135, 134, 133, 132, 131, 130, 129, 4, 3, 2, 1, 0.5, 0.25, or 0.1 wt.%, based on the total weight of 128, 127, 126, 125, 124, 123, 122, 121, 120, 119, 118, 117, the composition. 116, 115, 114, 113, 112, 111, 110, 109, 108, 107, 106, 105, The disclosed ionic liquid compositions can be prepared by 104, 103, 102,101,100,99,98, 97,96, 95, 94.93, 92,91,90, methods described herein. Generally, the particular cation(s) 89, 88,87, 86, 85, 84, 83,82, 81,80, 79,78, 77,76, 75, 74,73, 55 and anion(s) used to prepare the disclosed ionic liquids are 72, 71, 70, 69,68, 67, 66, 65, 64, 63, 62,61, 60, 59,58, 57,56, selected as described herein. Then, with the particular 55, 54,53, 52, 51, 50,49, 48,47, 46, 45, 44, 43,42, 41, 40, 39, cation(s) and anion(s) in hand, they can be combined, result 38, 37, 36,35, 34,33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, ing in ionic liquid compositions as disclosed herein. Addi 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10,9,8,7,6, 5, 4, 3, tionally, the method for the preparation of the disclosed ionic 2, 1, 0, -1, -2, -3, -4, -5,-6, -7, -8, -9, -10, -11, -12, -13, 60 liquid compositions can include the reaction in which two -14, -15, -16, -17, -18, -19, -20, -21, -22, -23, -24, -25, neutral species: an anion precursor (e.g., in the form of an -26, -27, -28, -29, or -30°C., where any of the stated values inorganic acid, carboxylic organic acid, non-carboxylic acid, can form an upper or lower endpoint when appropriate. In or Zwitterion species) and a cation precursor (e.g., inorganic further examples, the disclosed ionic liquids can be liquid at base, organic base, Zwitterion species) are combined result any point from about -30°C. to about 150° C., from about 65 ing in ionic liquid compositions as disclosed herein. -20°C. to about 140°C., -10°C. to about 130°C., from about Providing ions used to prepare the disclosed ionic liquids 0° C. to about 120° C., from about 10° C. to about 110° C., depends, in one aspect, on the desired properties of the result US 8,232,265 B2 15 16 ing ionic liquid composition. As described herein, the dis forming ionic liquids with functionality crafted into the com closed ionic liquid compositions can have multiple desired bination of the ions, as disclosed herein. properties, which, at least in part, come from the properties of As another example, the first drug ion may be combined the cation(s) and/or anion(s) used to prepare the ionic liquid. with a second drug ion that has properties complimentary to Thus, to prepare the disclosed ionic liquids, one or more kinds the first. Examples of this can include, but are not limited to, of cations with a desired property(ies) are provided. One or an ion having anesthetic properties being combined with an more kinds of anions with a desired property(ies) that is ion having antibacterial properties, an ion having anesthetic similar or different to that of the cation(s) can likewise be properties being combined with an ion having coagulation provided. Of course, providing a desired anion(s) and properties, or an ion having coagulation properties being 10 combined with an ion having antibacterial properties. Ionic cation(s) can be done in any order, depending on the prefer liquids resulting from Such combinations could find uses in ence and aims of the practitioner. For example, a particular wound repair, for example. Still other examples of desirable cation(s) can be provided and then aparticular anion(s) can be combination include ions having therapeutic or prophylactic provided. Alternatively, a particular anion(s) can be provided efficacy being combined with ions having taste enhancement and then a particular cation(s) can be provided. Further, the 15 properties (i.e., taste modifiers). Ionic liquids resulting from cation(s) and anion(s) can be provided simultaneously. this combination can be useful in enhancing the taste and As noted, providing a suitable ion can be based on selecting palatability of medicines. Still further examples can include an ion that possesses a property that is desired (e.g., the ion two differently charged ions each with similar uses but with has a property that is desired to be possessed by the resulting different mechanisms of action. Specific examples of Such ionic liquid). Examples of properties that could be desired in combinations can include, but are not limited to, combina a suitable cation and/or anion (and thus the ionic liquid made tions of ions with antineoplastic properties or antiviral prop therefrom) include, but are not limited to, biological, thera erties. Ionic liquids prepared from Suchion combinations can peutic, prophylactic, nutritional, pesticidal, and/or herbicidal be useful as drug “cocktails, where two or more bioactive activity. Inertness, taste, viscosity modulation, solubility agents are present in a single ionic liquid combination. modulation, stability, and toxicity are other properties of a 25 According to the methods and compositions disclosed given ion that could be desired and considered. While more herein, ion identification and combination, as disclosed specific properties are disclosed elsewhere herein, the dis herein, can involve any ion, not justionic drugs, as long as the closed methods and compositions are not limited to any par combination results in an ionic liquid. For example, ions that ticular combination of properties, as such will depend on the have pesticidal properties can be combined with oppositely preferences and goals of the practitioner. 30 charged ions having pesticidal, herbicidal, antimicrobial Typically, the desired properties of the cation(s) and properties, and the like. In other examples, ions with antibac anion(s) will be different or complimentary to one another. In terial properties can be combined with oppositely charges this way, the resulting ionic liquid can possess multiple ions that have preservative properties, taste modifiers, etc. In desired properties: those properties imparted by the cation(s) still other examples, an ion with one therapeutic or prophy and those imparted by the anion(s). In other words, some or 35 lactic property can be combined with another therapeutic or all of the ions present in the disclosed ionic liquids can inde prophylactic ion. As should be appreciated, the various com pendently and simultaneously introduce a specific function binations of ions according to the disclosed methods are ality or property to the disclosed ionic liquid compositions. It numerous, and depend only on the desired combination of is this multiple functionality characteristic that can allow one properties and whether the resulting ion combination is an to fine-tune or design very specific physical, chemical, and 40 ionic liquid as defined herein. bioactive properties in the disclosed ionic liquid composi Specific examples of properties that can be exhibited by the tions. Additional functionality can be obtained by using the disclosed compositions include antibacterial, FDA approved disclosed ionic liquid compositions as solvents to dissolve a dyes, anti-acne, antibiotic, UV blocker, wetting agents, pre Solute(s) with another desired property, thus resulting in a servative, emollient, anti-inflammatory, and vitamin. solution where the ions of the ionic liquid as well as the solute 45 Ions contribute desired properties to the composition. General and The disclosed ionic liquids contain at least one kind of specific examples of various combinations of ions and their cation and at least one kind of anion. Examples of Suitable associated properties are disclosed herein. cations and anions are disclosed herein. It should be under In some particular examples, one or more ions in the dis stood that when a particular compound is disclosed as being closed ionic liquid composition (e.g., the anions, cations, or 50 a cation, for example, it can also, in other circumstances, be both) can be a pharmaceutical active, e.g., an existing drug an anion and Vice versa. Many compounds are known to exist that is ionic or that can be made ionic. Many drugs exist as cations in Some environments and anions in other environ naturally or at physiological conditions as an ion, or they can ments. Further, many compounds are known to be convertible be converted to ions via simple chemical transformations to cations and anions through various chemical transforma (e.g., alkylation, protonation, deprotonation, etc.). As such, 55 tions. Examples of Such compounds are disclosed herein. these drugs can be used to prepare anionic liquid composition The materials, compounds, compositions, and components as disclosed herein. Such drugs can possess any therapeutic or that can be used for, can be used in conjunction with, can be prophylactic activity, many of which are described herein. used in preparation for, or are products of the disclosed meth Combining Such drugs with other ions to prepare an ionic ods and compositions are disclosed herein. It is understood liquid, as is disclosed herein, can result in the modification 60 that when combinations, Subsets, interactions, groups, etc. of and/or enhancement of the drug's properties. For example, a these materials are disclosed that while specific reference of first drug ion with a given property can be combined with an each various individual and collective combinations and per oppositely charged second ion with another property to effect mutation of these compounds may not be explicitly disclosed, the controlled release, controlled delivery, biological impact, each is specifically contemplated and described herein. For taste, physical properties (stability, Solubility, toxicity, melt 65 example, if an ionic liquid composition is disclosed and a ing point, etc.), or to overcome polymorphism in the first drug number of modifications that can be made to a number of ion. In this way, new drug compositions can be created by components of the ionic liquid composition are discussed, US 8,232,265 B2 17 18 each and every combination and permutation that are possible a catalyst in phase-transfer catalysis, and they show anti are specifically contemplated unless specifically indicated to electrostatic and anticorrosive properties. They exertantibac the contrary. Thus, if a class of cations A, B, and C are terial action against both Gram-positive and Gram-negative disclosed as well as a class of anions D, E, and F and an bacterial as well as against Some pathogen species of fungi example of a ionic liquid A-D is disclosed, then even if each 5 and protozoa. These multifunctional salts have also been used is not individually recited, each is individually and collec in wood preservation, their application promoted in the tively contemplated. Thus, in this example, each of the ionic papers of Oertel and Butcher et al. (Oertel, Holztechnologie, liquids A-E, A-F B-D, B-E, B-F, C-D, C-E, and C-F are 1965, 6:243; Butcher et al., For Prod.J., 1977, 27:19: Butcher specifically contemplated and should be considered disclosed et al., J. For Sci, 1978, 8:403). from disclosure of A, B, and C: D, E, and F; and the example 10 QACs are also widely used as skin antiseptics, disinfec ionic liquid A-D. Likewise, any Subset or combination of tants, fabric softeners, antistatic agents, cleaning agents, and these is also specifically contemplated and disclosed. Thus, preservatives. Detergent properties and antimicrobial activi for example, the sub-group of A-E, B-F, and C-E are specifi ties of QACs have made them useful for general environmen cally contemplated and should be considered disclosed from tal sanitations, for examples, in hospitals and food production disclosure of A, B, and C, D, E, and F; and the example 15 facilities. In pharmacological preparations they are used Such combination A-D. This concept applies to all aspects of this as mouth rinses, lozenges, sprays and gels. disclosure including, but not limited to, steps in methods of In humans and animals QACs have been considered too making and using the disclosed compositions. Thus, if there toxic for systematic applications, but are accepted to be safe are a variety of additional steps that can be performed it is for topical applications. Furthermore, QACs have recently understood that each of these additional steps can be per been used as penetration enhancers for transnasal and trans formed with any specific aspect or combination of aspects of buccal drug delivery, as well as in nasal vaccination (Klinguer the disclosed methods, and that each Such combination is et al., Vaccine, 2001, 19:4236). This ability to penetrate and specifically contemplated and should be considered dis open cell membrane has been widely used in drug delivery via closed. liposomes (mainly QACs with two long alkyl chains) and Cations 25 non-viral gene delivery (Liu and Huang, J. Contr Rel, 2002, Particular examples of cationic compounds that can be 78:259). Many examples of compounds having nitrogen present in the disclosed ionic liquid compositions are com atoms, which exist as quaternary ammonium species or can pounds that contain nitrogenatoms. Nitrogenatoms can exist be converted into quaternary ammonium species, are dis or can be converted to positively-charged quaternary ammo closed herein. nium species, for example, through alkylation or protonation 30 In some examples, when the cation is a quaternary ammo of the nitrogen atom. Thus compounds that possess a quater nium compound, the anion is not an inorganic anion, nary nitrogen atom (known as quaternary ammonium com examples of which are disclosed herein. In other examples, pounds (QACs)) are typically cations. According to the meth where the cation is a quaternary ammonium compound, the ods and compositions disclosed herein, any compound that anion is not a halide. contains a quaternary nitrogen atom or a nitrogen atom that 35 can be converted into a quaternary nitrogen atom can be a Aliphatic Heteroaryls Suitable cation for the disclosed ionic liquid compositions. QACs can have numerous biological properties that one Some specific QACs suitable for use herein are aliphatic may desire to be present in the disclosed ionic liquid compo heteroaryls. An aliphatic heteroaryl cation is a compound that sitions. For example, many QACs are known to have antibac 40 comprises an aliphatic moiety bonded to a heteroaryl moiety. terial properties. The antibacterial properties of QACs were In the aliphatic heteroaryl cation, the aliphatic moiety can be first observed toward the end of the 19" century among the any alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl group, carbonium dyestuffs, such as auramin, methyl violet, and as described herein. Generally, the aliphatic moiety can com malachite green. These types of compounds are effective prise at least 10, at least 12, at least 14, at least 16, at least 18, chiefly against the Gram-positive organisms. Jacobs and 45 or at least 20 carbon atoms. In other examples, the aliphatic Heidelberger first discovered QACs antibacterial effect in moiety can comprise a mixture of aliphatic groups having a 1915 studying the antibacterial activity of substituted hexam range of carbon atoms. For example, the aliphatic moiety can ethylene-tetrammonium salts (Jacobs and Heidelberger, Proc comprise from 10 to 40, from 12 to 38, from 14 to 36, from 16 Nat AcadSci USA, 1915, 1:226: Jacobs and Heidelberger, J to 34, from 18 to 32, from 14 to 18, or from 20 to 30 carbon Biol Chem, 1915, 20:659; Jacobs and Heidelberger, J Exptl 50 atoms. In some specific examples, the aliphatic moiety can Med, 1916, 23:569). contain 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, Browning et al. found great and somewhat less selective 25, 26, 27, 28, 29, 30, 31, 32,33, 34,35, 36, 37,38, 39, 40, 41, bactericidal powers among quaternary derivatives of pyri 42, 43, 44, or 45 carbonatoms, where any of the stated values dine, quinoline, and phenazine (Browning et al., Proc Roy Soc can form an upper or lower endpoint when appropriate. London, 1922, 93B:329; Browning et al., Proc Roy Soc Lon 55 Examples of specific aliphatic moieties that can be used don, 1926, 100B:293). Hartman and Kagi observed antibac include, but are not limited to, decyl, dodecyl (lauryl), tet terial activity in QACs of acylated alkylene diamines (Hart radecyl (myristyl), hexadecyl (palmityl or cetyl), octadecyl man and Kagi, ZAngew Chem, 1928, 4:127). (Stearyl), eicosyl (arachidyl), and linolenyl groups, including In 1935, Domagk synthesized long-chain QACs, including branched derivatives thereof and any mixtures thereof. In the benzalkonium chloride, and characterized their antibacterial 60 aliphatic heteroaryl cations, the aliphatic moiety is bonded to activities (Domagk, Deut Med Wochenschr, 1935, 61:829). a heteroatom in the heteroaryl moiety. He showed that these salts are effective against a wide variety In the aliphatic heteroaryl cation, the heteroaryl moiety can of bacterial strains. This study of the use of QACs as germi be any heteroaryl moiety as described herein. For example, cides was greatly stimulated. the heteroaryl moiety can be an aryl group having one or more Many scientists have focused their attention on water 65 heteroatoms (e.g., nitrogen, oxygen, Sulfur, phosphorous, or soluble QACs because they exhibit a range of properties: they halonium). Examples of specific heteroaryl moieties that can are surfactants, they destroy bacteria and fungi, they serve as be used in the aliphatic heteroaryl cations include, but are not US 8,232,265 B2 19 20 limited to, pyrazole, pyridine, pyrazine, pyrimidine, pry C-C alkoxyalkyl group, a C-C alkoxy group, or an ener idazine, indolizine, isoindole, indole, indazole, imidazole, getic Substituents such as nitro, amino, cyano, azido, alkyl oxazole, triazole, thiazole, purine, isoquinoline, quinoline, nitro, alkyl amino, alkyl cyano, alkyl azido, alkoxy nitro, phthalazine, quinooxaline, phenazine, and the like, including alkoxy amino, alkoxy cyano, and alkoxy azido. In other substituted derivatives and mixtures thereof. In the aliphatic 5 examples, both R" and R groups are C-C alkyl, with one heteroaryl cations, a heteroatom in the heteroaryl moiety is being methyl, and R-R, when present, are H. Exemplary bonded to the aliphatic moiety. When the heteroatom of the C-C alkyl groups and C-C alkyl groups include methyl, heteroaryl is nitrogen, this forms a quaternary ammonium ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl, pentyl, cation, as described herein. iso-pentyl, hexyl, 2-ethylbutyl, 2-methylpentyl, and the like. Further examples of aliphatic heteroaryl cations are those 10 Corresponding C-C alkoxy groups contain the above C-C, having the following structures: alkyl group bonded to an oxygen atom that is also bonded to the cation ring. An alkoxyalkyl group contains an ether group R4 R4 bonded to an alkyl group, and here contains a total of up to six 15 carbon atoms. It is to be noted that there are two isomeric 1,2,3-triazoles. In some examples, all R groups not required for cation formation can be H. OO R5 O5 R5 The phrase “when present is often used herein in regard to R7 R6 R6 . substituent R group because not all cations have all of the RI R1 numbered R groups. All of the contemplated cations contain PYRIDINIUM PYRIDAZINIUM at least four R groups, which can be H, although R need not R4 be present in all cations. In one example, all R groups that are not required for cation R3 R3 N R4 25 formation; i.e., those other than R' and R for compounds other than the imidazolium, pyrazolium, and triazolium cat ions shown above, are H. R6 R5 R6 R5 A cation that contains a single five-membered ring that is RI R1 free offusion to other ring structures is suitable for use herein. PYRIMIDINIUM PYRAZINIUM 30 Exemplary cations are illustrated below wherein R', R, and R-R, when present, are as defined before.

Y Y Y R4 R3 R4 R3 R3 , RI Y R2 R2 N R5 R1 35 R3 R1 R4 Y (O N Y {O N Y O) IMIDAZOLIUM PYRAZOLIUM OXAZOLIUM R1 N- YR2 RI s R1 N R4 R4 R3 R4 R3 R3 R2 M R2 N 40 1,2,3-TRIAZOLIUM 1,2,4-TRIAZOLIUM RI Y Os-ON? NR2 R11 N? RI l'O)Y N R4 k R5 R3 R4 R5 R3 R4 45 1,2,3-TRIAZOLIUM 1,2,4-TRIAZOLIUM R5 R3 R4 R5 R4 Y O. Y O\, Y 'O R1 Y RI Y Nr. 21 N. R5 R4 R3 Y (O), R3 R5 J.-- 50 RI -- R6 N R2 THIAZOLIUM IMIDAZOLIUM PYRAZOLIUM R7 N R6 / V R4 R? Ye R1 R2 THIAZOLIUM PIPERIDINIUM PYRROLIDINIUM R5 R4 R4 R3 55 R5 R3 R6 R3 R R9 )-( O O R7 R9 R6 NRI 60 -9 R4 R8 R1 R7 R8 OXAZOLIUM QUINOLIUM ISOQUINOLIUM Of the cations that contain a single five-membered ring free wherein R' and Rare, independently, a C-C alkyl group or 65 of fusion to other ring structures, an imidazolium cation that a C-C alkoxyalkyl group, and R,R,R,R,R,R, and R' corresponds in structure to Formula A is also suitable, (R-R), when present, are independently H, a C-C alkyl, a wherein R', R, and R-R, are as defined before. US 8,232,265 B2 21 22 (stearyl), or eicosyl (arachidyl) group, and R'' and R' can (A) each be, independent of one another, a methyl, ethyl, propyl. butyl, pentyl, or hexyl group. In another aspect, the aliphatic benzylalkyl ammonium cation can include, but are not limited to, alkyl dimethyl benzyl ammonium cations. Specific examples of alkyl dim ethylbenzyl ammonium cations include, but are not limited to, cetyl dimethylbenzyl ammonium, lauryl dimethylbenzyl ammonium, myristyl dimethyl benzyl ammonium, Stearyl In a further example, an N,N-1,3-di-(C-C alkyl)-substi 10 dimethylbenzyl ammonium, and arachidyl dimethylbenzyl ammonium. tuted-imidazolium ion can be used; i.e., an imidazolium cat In yet another aspect, the aliphatic benzylalkyl ammonium ion wherein R-R of Formula A are each H, and R' and Rare cation can include, but are not limited to, alkyl methylethyl independently each a C-C alkyl group or a C-C alkoxy benzyl ammonium cations. Specific examples of alkyl meth alkyl group. In yet another example, the cation illustrated by 15 ylethylbenzyl ammonium cations include, but are not limited a compound that corresponds instructure to Formula B. to, cetyl methylethylbenzyl ammonium, lauryl methylethyl below, wherein R-R of Formula Aare each hydrogen and R' benzyl ammonium, myristyl methylethylbenzyl ammonium, is a C-C-alkyl group or a C-C alkoxyalkyl group. Stearyl methylethylbenzyl ammonium, and arachidyl meth ylethylbenzyl ammonium. (B) Dialiphatic Dialkyl Ammonium Y ON2 Still further examples of QACs that can be used in the RI CH3 disclosed ionic liquid compositions are dialiphatic dialkyl 25 ammonium cations. A dialiphatic dialkyl ammonium cation is a compound that comprises two aliphatic moieties and two Aliphatic Benzylalkyl Ammonium alkyl moieties bonded to a nitrogen atom. The aliphatic moi eties can be the same or different and can be any aliphatic The disclosed ionic liquid compositions can also comprise group as described above. The alkyl moieties can be the same an aliphatic benzylalkyl ammonium cation. An aliphatic ben 30 or different can be any alkyl group as described above. In the Zylalkyl ammonium cation is a cation that comprises an ali disclosed dialiphatic dialkyl ammoniums cations, the two phatic moiety bonded to the nitrogen atom of a benzylalkyl aliphatic moieties can have 10 or more carbon atoms and the amine moiety. The aliphatic moiety can be as described two alkyl moieties can have less than 10 carbon atoms. In herein. The benzylalkyl amine moiety can be a benzyl amine another alternative, the two aliphatic moieties can have less where the amine is bonded to an alkyl or cyclic alkyl group, as 35 than 10 carbon atoms and the two alkyl moieties can have 10 described herein. One or more types of aliphatic benzylalkyl or more carbon atoms. One or more types of dialiphatic dialkyl ammonium cations can be used in the ionic liquid ammonium cation can be used in the ionic liquid composi compositions disclosed herein. tions disclosed herein. The aliphatic benzylalkyl ammonium In Some particular examples, the dialiphatic dialkyl ammo cation suitable for use herein can be prepared by methods 40 known in the art or can be obtained from commercial sources. nium cation can be di-dodecyl dimethyl ammonium, di-tet In one aspect, the aliphatic benzylalkyl ammonium cation radecyl dimethyl ammonium, dihexadecyl dimethyl ammo can be represented by the following formula: nium, and the like, including combinations thereof. Tetraalkyl Ammonium 45 R11 The disclosed ionic liquid compositions can also comprise a tetraalkyl ammonium cation. Suitable tetraalkyl ammonium N-R12No cations comprise four alkyl moieties, as disclosed herein. In one example, a tetraalkyl ammonium cation can comprise one 50 long chain alkyl moiety (e.g., 10 or more carbon atoms in wherein R' is analiphatic group, as described above, R'' and length) and three short chain alkyl moieties (e.g., less than 10 R" are, independent of one another, alkyl groups or cyclic carbon atoms in length). alkyl groups as described herein. In some examples, one or Some specific examples of tetraalkyl ammonium cations more of the “R” substituents can be a long chain alkyl group that can be included in the disclosed ionic liquid composi (e.g., the number of carbon atoms is 10 or greater). In other 55 tions include, but are not limited to, cetyl trimethyl ammo examples, one or more of the “R” substituents can be a short nium, lauryl trimethylammonium, myristyltrimethyl ammo chain alkyl group (e.g., the number of carbon atoms is less nium, Stearyl trimethyl ammonium, arachidyl trimethyl than 10). In still other examples, one of the “R” substituents is ammonium, or mixtures thereof. Other examples include, but a long chain alkyl group and the other two “R” substituents are not limited to, cetyl dimethylethyl ammonium, lauryl are short chain alkyl groups. 60 dimethylethyl ammonium, myristyl dimethylethyl ammo In one aspect, the aliphatic benzylalkyl ammonium cation nium, Stearyl dimethylethyl ammonium, arachidyl dimethyl can have any of the aliphatic moieties disclosed herein ethyl ammonium, or mixtures thereof. bonded to any benzylalkyl amine moieties disclosed herein. In some specific examples, R' in the formula of aliphatic Other Cations benzylalkyl ammonium cation can be an aliphatic group of 65 from 10 to 40 carbon atoms, e.g., a decyl, dodecyl (lauryl), Other cations that are suitable for use in the disclosed tetradecyl (myristyl), hexadecyl (palmitylor cetyl), octadecyl methods and compositions are compounds that contain met US 8,232,265 B2 23 24 als. According to the methods and compositions disclosed potassium salt, are in widespread use in foodstuffs as non herein, any compound that contains a metal atom can be a nutritive Sweeteners. Such anions can be used when one Suitable cation. Organometallic compounds or metal com desires to prepare an ionic liquid composition that has Sweet plexes commonly have one or more metal atom in a positive ness as one of its desired properties. For example, Saccharin oxidation state. Examples of metals that can be present in a and acesulfame can be combined with pharmaceutically suitable cation include, but are not limited to, lithium, active cations to prepare Sweet tasting ionic liquids that have Sodium, potassium beryllium, magnesium, calcium, stron pharmaceutical activity. tium, chromium, manganese, iron, cobalt, nickel, copper, and Specific examples of other anions include piperacillin, Zinc. Silver nanoparticles can also be used. Examples of folic acid, ibuprofen, fast green FCF, docusate, acesulfamate, Suitable organometallic cations include, but are not limited to, 10 metallocenium, alkylgermanyl, alkyltin, or alkylsilyl (e.g., penicillin G, Colawet MA-80, salicylic acid, saccharinate, trimethylsilylium, triethylsilylium, tris(trimethylsilyl)sily Sulfacetamide, naproxen, benzoate, diclofenac, and trans-cin lium, tribenzylsilylium, triphenylsilylium, tricyclohexylsily namic acid. lium, and dimethyloctadecylsilylium). Other suitable anions include, but are not limited to, Sub Another suitable group of quaternary ammonium cations 15 stituted and un-Substituted imidazolates, 1,2,3-triazolates, are those that have been prepared by esterifying a compound and 1,2,4-triazolates, benzimidazolates, benz-1.2.3-triaz containing a carboxylic acid moiety or transesterifying a olates, as shown below: compound with an ester moiety with a choline moiety. Such choline esters can be biofriendly, permanent ions that are amenable to being added to various compounds while still R13 R13 R 14 being easily cleavable under physiological conditions. The N N N choline esters can be used to increase the solubility and bio \ W { availability of many neutral compounds. Futher examples of cations include (2-hydroxyethyl)dim R 14 > R 14 / --- ethylundecyloxymethylammonium, (2-acetoxyethyl)hepty 25 imidazolate 1,2,3-triazolate 1,2,4-triazolate loxymethyldimethylammonium, and (2-acetoxyethyl)dode R13 R13 cyloxymethyldimethylammonium, mepenZolate, 14 14 Sulfathiazole, thimerosal, and valproic acid. R N R N In other examples, the cation can be an energetic cation as disclosed in Katritzky et al., “ILs Based on Energetic Imida 30 MX-R" MY Zolium Cations: Nitro- and Nitrile-substituted N,N'Dialky R 15 N R15 N limidazolium Salts' New J Chem 30:349, 2006, which is incorporated by reference herein at least for its teachings of R 16 R 16 energetic ions. benzimidazolate benz-1,2,3-triazolate Anions 35 Particular examples of anionic compounds that can be wherein R', R', R', R. R'7, (R-7), when present, are present in the disclosed ionic liquids are compounds that independently H, a C-C alkyl, a C-C alkoxyalkyl group, a contain oxygen atoms. Oxygen atoms can exist or can be C-C alkoxy group, or energetic Substituents like nitro, converted to negatively charged, anionic species, for amino, cyano, azido, alkyl nitro, alkyl amino, alkyl cyano, example, through deprotonation of alcohols or acids, through 40 alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, and saponification of esters, or through alkylation of ketones. alkoxyazido. Exemplary C-C alkyl groups and C-C alkyl Likewise, compounds that contain Sulfur atoms can also exist or be converted to anionic species through similar reactions. groups include methyl, ethyl, propyl, iso-propyl, butyl, sec Still further, compounds that contain nitrogen atoms, espe butyl, iso-butyl, pentyl, iso-pentyl, hexyl, 2-ethylbutyl, 2-me cially nitrogen atoms adjacent to electron withdrawing 45 thylpentyl, and the like. Corresponding C-C alkoxy groups groups or resonance stabilizing structures, can be converted contain the above C-C alkyl group bonded to an oxygen to anions through deprotonation. According to the methods atom that is also bonded to the cation ring. An alkoxyalkyl and compositions disclosed herein, any compound that con group contains an ether 10 group bonded to an alkyl group, tains an oxygen, Sulfur, or nitrogen atom can be a Suitable and here contains a total of up to six carbon atoms. It is to be anion for the disclosed ionic liquid compositions. 50 noted that there are two isomeric 1,2,3-triazoles. In some Other suitable anions include, but are not limited to, halides examples, all R groups not required for anion formation can (e.g., fluoride, chloride, bromide, and iodide), Sulfates be H. (SO), carbonates, bicarbonates, phosphates, phosphates, Further examples of suitable energetic anions are disclosed nitrates (NO), nitrites (NO), acetates (CHCO), and the in Katritzky et al., “ILs Based on Energetic Azolate Anions.” like. Other examples of anions include, but are not limited to 55 Chem Eur J 12:4630, 2006, which is incorporated by refer PF, that is immiscible in water and BF, that is miscible in ence herein at least for its teachings of energetic anions. water depending on the ratio of ionic liquid to water, system Compound that Exist that as Both: Anion or Cation temperature, and alkyl chain length of cation. Other anions Examples of compounds that exist as cations in Some envi include triflate (TfG); CFSO), nonaflate (NfO; CF (CF). ronments and anions in other environments include, but are SO), bis(triflyl)amide (Tf.N. (CFSO)N), trifluoroac 60 not limited to, 1,3-dimethylimidazolium, 1-butyl-3-meth etate (TA; CFCO), and heptaflurorobutanoate (HB; CF ylimidazolium, 1,2,3-triazolium, tetrazolium, 1,2,4-triaZo (CF)SO). Other types of ionic liquids include haloalumi lium, 1,3-dimethyl-1,2,3-triazolium, and 1,3-dimethyl-4-ni nates, such as chloroaluminate. troimidazolium, which exist as a cations, and Other Suitable anions contemplated herein are saccharin 4-nitroimidazolate, 4,5-dinitroimidazolate, 3,5-dinitro-1,2, and acesulfame. Saccharin, as an alkali metal salt, and 65 4-triazolate, tetraZolate, 5-aminotetraZolate, 2-nitroimida acesulfame (6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one Zolate, which exist as an anion. Those separate ions can still 2,2-dioxide), which has previously only been offered as form single productionic liquids. US 8,232,265 B2 25 26 Examples of compounds that can change from an anion in Some specific examples of pharmaceutical actives that can one environment to a cation in another environment due to be used in the disclosed ionic liquids include, but are not chemical modifications are the Sulfur ylides through the reac limited to, aspirin, LIBRIUMTM, isoniazid, penicillin, tion of a sulfide with methyliodide to form the sulfonium ion. PRONTOSILTM, cisplatin, 6-mercaptopurine, RITUXANTM, TAXOLTM, phenobarbital, PROZACTM, ALLEGRATM, Specific Examples of Pharmaceutical Actives VIOXXTM, quinine, ivermectin, L-dopa, THORAZINETM, When pharmaceutical activity is a desired property of the salvarsan, TAGAMETTM, AZT, crixivan, salbutamol, disclosed ionic liquids, one or more of the ions in the dis digoxin, fluride, LOVASTATINTM, erythropoietin, hydrocor closed ionic liquid compositions can be a pharmaceutical tisone, insulin, oral contraceptives, oxytocin, PRE active. Pharmaceutical actives that exist as ions or can be MARINTM, RU-486, thyroxine, thalidomide, cyclosporine, converted to ions, and which are Suitable for use in preparing 10 fentanyl, methadone, morphine, botox, vitamins, FOSA the disclosed ionic liquid compositions, include the following MAXTM, RITALINTM, and VIAGRATM, including ionic categories and specific examples. It is not intended that the derivatives thereof. category be limited by the specific examples. Those of ordi- Other examples of pharmaceutical active ions or pharma nary skill in the art will be able to readily identify those 15 ceutical actives that can be made ionic include, but are not pharmaceutical actives that can be used in the disclosed meth- limited to, pantoprazole, sold under the trade names PRO ods and compositions. For example, one can identify a com- TONLXTM and PANTOZOLTM, and rabeprazole, sold under pound with a given property or activity by consulting various the trade names ACIPHEXTM and PARIETTM, which are used sources, such as the Merck Index (13" Edition, Wiley, 2001), to treat gastrointestinal disorders. Risedronate, sold under the The United States Pharmacopeia-National Formulary (USP- 2O trade name ACTONELTM, and alendronate, sold under the NF), and the FDA's Orange book, which are each incorpo- trade name FOSAMAXTM, are used to treat osteoporosis and rated by reference herein at least for their teachings of phar- are further examples of Suitable compounds that can be used maceutical actives. Once a compound with a desired property to prepare the disclosed ionic liquid compositions. Further is identified, the skilled artisan can determine whether the examples include losartan, sold under the trade names NU compound is ionic or can be made ionic. Such determinations 25 LOTANTM, COZAARTM, and HYZAARTM, and fosinopril, can be performed based on the compound's structure, which sold under the trade name MONOPRILTM, which are used to can readily be determined by consulting the sources men- treat hypertension and are other examples of Suitable com tioned herein or experimentally. Knowing a compounds pounds that can be used to prepare the disclosed ionic liquid structure can readily reveal if the compound is ionic. In fact, compositions. Atorvastatin, sold under the trade name LIPI many pharmaceutical actives exist as salts and are thus Suit- 30 TORTM, and pravastatin, sold under the trade name PRAVA able for use in preparing the disclosed ionic liquid composi- CHOLTM, are used to treat cholesterol and are further tions. Further, if a compound is not ionic, but contains an ion examples of suitable compounds that can be used to prepare forming moiety (e.g., nitrogen, oxygen, Sulfur, or metal the disclosed ionic liquid compositions. A further example is atoms, as described herein), the compound can be converted montelukast, which is used to treat asthma and is sold under to an ion and then combined with a Suitable counterion to 35 the trade name SINGULAIRTM. prepare the disclosed ionic liquid compositions. Those of The following table illustrates further examples of phar ordinary skill in the art will recognize numerous other com- maceutical actives that are ionic or can be made ionic and pounds that fall within the categories and that are usefuil combined with other ions to form the disclosed ionic liquid according to the disclosed compositions and methods. compositions. TABLE 1

Name Compound MP Patent No. Other Names

Function: Abortifacient Interceptive

Prosta- 66-68 U.S. Pat. PGE2, U-12062, glandin No. Cerviprost, E. 3598858 Minprostin E2, Prepidil, Propess, Prostarmon-E, Prostin E2

Prosta- 25-35 U.S. Pat. PGF2A, U-14583, glandin No. Enzaprost F, F24 3657327 Glandin, Prostarmon F US 8,232,265 B2 28 TABLE 1-continued

Name Compound MP Patent No. Other Names

Sulprostone U.S. Pat. Nalador No. 4024179

Function: ACE-Inhibitor (Antihypertensive)

Cetapril 155 U.S. Pat. Alacepril 156° No. 4248883

Benzaepril 148 U.S. Pat. 149° No. 4410520

Captopril 103 U.S. Pat. Acediur, Acepril, 104° Nos. Alopresin, 4046889 Acepress, 4105776 Capoten, Captolane, Captoril, Cesplon, Dilabar, Garranil, Hipertil, Lopirin, Lopril, Tensobon, Tensoprel Function: A-Adrenergic Agonist

Methyl U.S. Pat. Forthane hexaneamine Nos. 23S0318 2386273

Synephrine OH 184 DE 566578 Analeptin, 185 Ethaphene, Oxedrine, Parasympatol, YCH, Simpalon, Synephrin, Synthenale HO

Function: B-Adrenergic Agonist

Isoetharine 212 DE 6386SO WIN-3046, 213 Dilabron, Neoisuprel US 8,232,265 B2 30 TABLE 1-continued

Name Compound MP Patent No. Other Names

Methoxy- NH 97-99 JP 612921 phen amine CH CH OCH

Function: A-Adrenergic Blocker

Tamsulosin 228 U.S. Pat. Flomaz, Harnali, 230° No. Omnic, Pradif 4703063

Tolazoline H 1749 U.S. Pat. Lambral, Priscol, N No. Priscoline, Vasco 2161938 Dilatan HCI N

Function: B-Adrenergic Blocker

Bufuralol 146 U.S. Pat. Angium No. 3929836

Nadoxolol 1889 U.S. Pat. Bradyl No. 3819702

Function: Analgesic (non-narcotic)

Acetylsalicyl 1549 Salicylic acid

Ammonium Salicylate

OH US 8,232,265 B2 31 32 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Anesthetic (Intravenous)

Buthalital Baytinal, Buthaliton Sodium Sodium, Thialiso bumalnatrium, Transithal, Ulbreval

Thiopental U.S. Pat. Sodium Nos. 2153729 2876225 3109001

Function: Anesthetic (Local) Isobutyl p Cycloform, Isobutyl Amino Kelofom, Isocaine benzo ate

N

Phenol OH

Function: Anorexic

Clortermine 116 U.S. Pat. 118° No. 3415937 CH CH

Fenproporex 126 U.S. Pat. 127C No. CN 3485924 CH3

Function: Antacid

Dermatol US 8,232,265 B2 33 34 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Anthelmintic (Cesodes) Nicosamide 225- U.S. Pat. OH C 230° Nos. 3079297 NH 3 113067 C

O NO

Pelletierine H Punicine N CH3

O

Function: Anthelimintic (Nematodes) Dithiazanine U.S. Pat. Anelmid, Iodide No. Anguifugan, 2412815 Delvex, Dejo, Deselmine, Dilombrin, Dizan, Nectocyd, Partel, Telmicid, Telmid

Thia- 3O4- U.S. Pat. Thibenzole, bendazole 305 No. Equizole, 3O17415 Mertect, Storite, TBZ, Tecto

Function: Anthelmintic (Schistosoma) Antimony Sodium Thio glycolate

Niridazole 260- BE 632989 Ba-32644, Ciba 262 32644-Ba, Ambilinar

Function: Antiacne

Isotretinoin 174- U.S. Pat. Accitame, Isotrex, 175o No. Oratane, Roaccutane 45565.18

Function: Antiallergic

Lodoxamide 2120 U.S. Pat. No. 39936.79 US 8,232,265 B2 35 36 TABLE 1-continued

Name Compound MP Patent No. Other Names

Ramatroban 134 U.S. Pat. 135° No. 4965258

Function: Antialopecia Agent

Finasteride -257 U.S. Pat. Chibro-Proscar, No. Finasid, Propecia, 476OO71 Proscar, Prostide

Minoxidi 248 U.S. Pat. Alopexil, Alostil, Nos. Loniten, Lonolox, 3382247 Minoximen, 3644364 Normoxidil, Prexidil, Regaine, Rogaine, Tricoxidi

Function: Antiamebic

Carbarisone 1749 JPS84418 Amabevan, Amebian, Amibiarson, Arsambide, Carb-O- Selo, Histocarb, Fenarsone, Leucarsone, Aminarsone, Amebarsone

Diphetarsone Amebarsin, Bemarsal, Rodameb US 8,232,265 B2 37 38 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Antiandrogen

Flutamide 111.5- U.S. Pat. Drogenil, Eulexin, 112.5° No. Euflex, Flucinom, 384.7988 Flutamin, Fugerel

Nilutamide 149° U.S. Pat. RU-23908, No. Anandron, 4097578 Nilandron

Function: Antianginal

Nicorandil 92-930 U.S. Pat. Adancor, Ikorel, No. Perisalol, Sigmart 42OO640

OZagrel 223 224

Bunitrolol 163 U.S. Pat. 1650 No. 3541130

Ipratropium 230 U.S. Pat. Atem, Atrovent, Bromide 232 o No. Bitrop, 3505337 Itrop, Narilet, Inatec US 8,232,265 B2 39 40 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Anti-arteriosclerotic

Pyridinol 136- Anginin, Carbamate 1370 Angioxione, Aterosan, Atover, Cicloven, Colesterinex, Duvaline, Morecil, Prodectin, Ravenil, Sospitan, Vasagin, Vasapril, Vasocil, Vasoverin

Function: Antiarthritic Antiheumatic

Bucillamine 139- U.S. Pat. Rimatil 140° No. 4305958

Diacerein 217- U.S. Pat. Artrodar, Fisiodar 218 No. 4244968

Function: Antiasthmatic (Non-bronchodilator)

Amlexanox >300 U.S. Pat. Aphthasol, No. Elics, Solfa 4143042 US 8,232,265 B2 41 42 TABLE 1-continued

Name Compound MP Patent No. Other Names

Cromolyn Aarane, Alercrom, Alerion, Allegocrom, Colimune, Cromoret, Firent, Gastro frenal, Inostral, Intal, Introl, Irtan Lomudal, Lomupren, Lomusol, Lomuspray, Nalcrom, Nalcron, Nasalcrom, Nasmil, Opticrom, Opticron, Rynacrom, Sofro, Vicrom, Vividrin

Function: Antibacterial (Antibiotics)

AZidam 1070 U.S. Pat. Berlicetin, fenicol No. Leukomycin-N, 2882275 Posifenicol, Thilocanifol

Thi 1643- U.S. Pat. Hyrazin, Igralin, amphenicol 166.3° Nos. Neomyson, Rigelon, 2759927 Thiamcol, 2759970 Thionicol, 2759971 Thiophenicol, 2759972 Urfamycine, 2759976 Urophenil

Function: Antibacterial (Synthetic)

Brodimo 225- U.S. Pat. Hyprim, Unitrim prim 228 No. 4024145

Tetroxoprim 153- U.S. Pat. 156° No. 39923.79 US 8,232,265 B2 43 44 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Antibacterial (Leprostatic)

Acetosulfone -285 U.S. Pat. Sodium No. 2358365

Dapsone 175- FR 829926 Avlosulfon, 1760 Croysulfone, Diphenasone, Disulone, Dumitone, Eporal, Novophone, Sulfona-Mae, Sulphadione, Udolac

Function: Antibacterial (Tuberculostatic)

Benzoylpas 260- GB 6.76363 261 H s N O COOH

Cyamelide

Function: Anticoagulant

Picotamide 1249 U.S. Pat. No. 3973O26

Function: Anticonvulsant

Acetylphen- 100- U.S. Pat. Crampol eturide 1010 No 3110728 US 8,232,265 B2 45 46 TABLE 1-continued

Name Compound MP Patent No. Other Names Albutoin 21O Euprax 211o

Function: Antidepressant

Caroxazone 2O3- U.S. Pat. Timostenil 2050 No. 3427313

Indalpine U.S. Pat. Upstene No. 4O642SS

NH

Function: Antidiabetic

Calcium Dec. JP 524157 Mesoxan Mesoxalate 21O- JP 607463 220° C.

Buformin U.S. Pat. No. 2.961377

Function: Antidiarrheal

Alkofanone Dec. U.S. Pat. Alfone 221- No. 223°C. 2421836

Metformin U.S. Pat. DMG5, LA-6023 No. 3174901

Function: Antidote (Curare)

Edrphomium Dec. U.S. Pat. Antirex, Enlon, Chloride 162- No. Reversol, Tensiolon 1630 2647924 US 8,232,265 B2 48 TABLE 1-continued

Name Compound MP Patent No. Other Names

Neostigmine Dec. U.S. Pat 167 No. 1905990

Function: Antidote (Cyanide) p-Aminopro- O 140° DMSO piophenon CH3

HN

Methylene Blue

Function: Antidote (Folic Acid Antagonists)

Folinic Acid Dec. U.S. Pat. 240 No. 2500 2741608

Function: Antidote (Heavy Metal Poisoning)

Tiopronin 95-97 Acadione, Capen, Epatiol, Mucolysin, Thiola, Thiosol

Function: Antidote (Methanol and Ethylene Glycol Poisoning)

Fomepizole H 15.5- N N 18.55o US 8,232,265 B2 49 50 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Antidote (Organophophate poisoning)

AsOxime 145- U.S. Pat. Chloride 1470 No. 3773775

Obidoxime Syn: U.S. Pat. Toksobidin, Chloride 23S- No. Toxogonin 236 3137702 Anti: 218 220

Function: Antidyskinetic

Chloride H 130° U.S. Pat. ( N y- C 32O2660No. NH C

Tiapride 123- GB 125° C. 1394.563

Function: Antiemetic

Alizapride 1390 U.S. Pat. No. 4O93672

Bromopride U.S. Pat. Emepride, Emoril, No. Vladi 3177252

Function: Antifibrotic

Potassiump- COOK Potaba Amino benzo ate

NH2 US 8,232,265 B2 51 52 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: (synthetic)

Chlordantoin

Bromo 238 U.S. Pat. Multifungin Salicylchlor OH 243 No. anilide 28O2O29

Br

C

Function: Antiglaucoma

Aceta 2S8 U.S. Pat. Acetamox, Zolamide 2590 No. Atenezol, 2554816 Defiltran, Diamox, Didoc, Diuriwas, DonmoX, Edemox, Fonurit, Glaupax

Benfunolol 160° U.S. Pat. Versus, Zildasac No. 34701.94

Function: Antigout

Allopurinol above U.S. Pat. 360° No. 3474O98

Carprofen 197 U.S. Pat. Imadyl, Rimadyl 1989 No. 38961.45

C US 8,232,265 B2 53 54 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Antihistaminic

Acrivastine Dec. U.S. Pat. Semprex 222 o No. 45O1893

Metron S 84-85

Function: Anti-hyperlipoproteninemic

Acifran 1760 U.S. Pat. Reductol O COOH No. 424.4958

H3C O

Benfluorex U.S. Pat. No. CH 36O7909 O N-1SN CF H O

Function: Anti-hypertensive

Chlorisoncl U.S. Pat. Ecolid, Ecolid amine No. Chloride Chloride 3O2S294 /N/ N' CI (CH3)3 N CH3

Penta Penthonium, methon Lytensium ium Bromide Function: Anti-hyperthyroid

2-Amino U.S. Pat. thiazole No. 2242237

Methylthio Dec. Alkiron, Antibason, uracil 326 Basecil, Basethyrin, 3310 Methiacil, Methicil, Methiocil, Muracil, Prostrumyil, Strumacil, Thimecil, Thyreostat I US 8,232,265 B2 55 56 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Anti-hypotensive

Amexinium 1760 U.S. Pat. Regulton, Risumic, Methyl No. Supratonin Sulfate 363.1038

Dopamine Dec. Cardiosteril, Hydro HO 241 Dopastat, chloride Dynatra, Inovan, HCI Inotropin HO

Function: Anti-Inflammatory (Gastrointestinal)

Balsalazide >3500 U.S. Pat. No. 4412992

Mesalamine dec. GB 751386 COOH Asacol, Ascolitin, 280° Claversal, Lixacol, Mesasal, Pentasa, OH Rowasa, Salofalk

HN

Function: Anti-Inflammatory (Nonsteroidal)

Enfenamic COOH 116 IN 103066 Tromaril Acid 117o IN 114805

Menfenamic Acid

Flufenamic COO Alfenamin, Opyrin Acid Aluminum Salt US 8,232,265 B2 57 58 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Antimalarial

Berberine 145°

Chloguanide H 1290 FR N CH 1 OO1548 NH CH

Function: Antimanic Valproic liquid Convulex, Acid H3C Depakene, Mylproin OH H3C O

Function: Antimigraine

Lisuride 186°

Naratriptan 17O- U.S. Pat. 1710 No. 4997841

Function: Antimuscarinic

Ambutonium 228 Bromide 229° US 8,232,265 B2 59 60 TABLE 1-continued

Name Compound MP Patent No. Other Names Benzilonium 2O3- GP821436 Minelsin, Minelcin, Bromide 204° Portyn, Ulcoban

Function: Antineoplastic

9-Amino- 300° JP KoKai camptothecin 59.51289 (to Yakult Honsha)

TenuaZonic Acid

Function: Antiobsessional

Clometo- U.S. Pat. Rixapen cillin No. 3OO792O

Fluoxetine 157- U.S. Pat. Adofen, Fluctin, Hydro- 158° No. Fluoxeren, Fontex, chloride 4314081 Foxetin, Lovan, Prozac, Reneuron, Sarafem

Function: Antiosteoporotic

Pamidronic U.S. Pat. Acid No 4327039 US 8,232,265 B2 61 62 TABLE 1-continued

Name Compound MP Patent No. Other Names

Risedronate U.S. Pat. Acetonel, Optinate Sodium No. 5583122

Function: Antiparkinsonian

Benserazide 146 U.S. Pat. Hydro 148 No. chloride 3.178476

Carbidopa 2O3 U.S. Pat. Lodosyn 2050 No. 3462S36

Function: Antipheochromoc-ytoma

Metyrosine U.S. Pat. Demser No. 28688.18

Phentol 174 U.S. Pat. amine 175o No. 2503059

Function: Anti-pneumocystic

Elfornithine 1830 Hydro chloride monohydrate

Sulfa 1670 U.S. Pat. Gantanol, Sinomin methox No. azole 28884S5 US 8,232,265 B2 63 64 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Antiprostatic Hypertrophy

Tamsulosin 228 U.S. Pat. Flomax, Harnal, Hydro 230° No. Omnic Pradif chloride 4703063

Terazosin 272 U.S. Pat. 274 No. 4026894 U.S. Pat. No. 42S1532

Function: Antiprotozoal Cryptosporidium

Nitazoxanide U.S. Pat. CryptaZ No. 39SO3S1

Function: Antiprotozoal (Giardia)

Acrani 237 U.S. Pat. 238° No. 2113357 US 8,232,265 B2 65 66 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Antiprotozoal (Leishmania)

Hydroxystill 235o U.S. Pat. bamidine No. 2S10047

Pentamidine HN dec. U.S. Pat. 186° No. 2394,003

HN

Function: Antiprotozoal (Toxoplasma)

Pyri 233- U.S. Pat. Chloridin, methamine 234 No. Daraprim, 268.0740 Malcoide, Tindurin

Function: Antiprotozoal (Trichomonas)

AcetarSone 240 Gynoplix, Orarsan, 2500 Spirocid, Stovarsol US 8,232,265 B2

TABLE 1-continued

Name Compound MP Patent No. Other Names

Aminitrozole 264- U.S. Pat. Tritheon, Trichorad, 265 No. Enheptin-A 253,1756

Function: Antiprotozoal (Trypanosoma)

Benzinida- 188- GB Radani zole 190° 1138,529

Eflornithine 1830 Ornidyl Hydro chloride

Function: Antipsoriatic

Acitretin 228- U.S. Pat. Neotigason, 230° No. Soriatane 4105681

6-AZauridine 160 1619

Function: Antipsychotic

Amisulpride 126- U.S. Pat. Deniban, Socian, 127C No Solian, Sulamide 4401822 US 8,232,265 B2 69 70 TABLE 1-continued

Name Compound MP Patent No. Other Names

Remoxipride 1730 U.S. Pat. Roxiam Hydro- No. chloride 4232O37 Monohydrate

Function: Antipyretic

Bufexamac 153- U.S. Pat. Droxaryl, Feximac, 1550 No Malipuran, 3479396 Mofenar, Norfemae, Parfenac, Parfenal

Bumadizon 116- U.S. Pat. 117o No. 3455999

Ol N COOH CH

Function: Antirickettsial

Chloram- 1SO- U.S. Pat. phenicol 1510 No. 2839577

Function: Antiseptic/Disinfectant

Benzox- 107- CH 306648. Absonal, Bactofen, onium 109° Bialcol Chloride

Cetalkonium 590 U.S. Pat. Banicol, Acetoquate Chloride No. CDAC, 2075958 Ammonyx G, Zettyn, Ammonyx T. Cetol US 8,232,265 B2 71 72 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Antispasmodic

Alibendol O 95o U.S. Pat. Cebera No. 3668.238 HO n1n N H

HO OCH

Ambutonium 228 Bromide 229°

Function: Antisyphilitic

Arsh- U.S. Pat. Ehrlich 606, penamine No. Salvarsan 98.6148

Sodium O Arsamin, Atoxyl, Arsanilate Nuarsol, Protoxyl, Soamin AS-O- Sonate, sPiglet OH Pro-Gen V, Trypoxyl HN

Function: Antithrom-boxythemic

Anagrelide >280 U.S. Pat. Agrylin No 4146718 US 8,232,265 B2 73 74 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Antihrombotic

Beraprost U.S. Pat. Dorner, Procylin No. 44748O2

Cilostazol 159- BE 878548 Pletal 160°

Function: Antitussive

Bibenzonium O 144- U.S. Pat. Sedobex, Bromide 1470 No. Lysobex, N-1\,. (CH3)3 291.3459 Lysibex, Thoragol, Lysbex, Medipectol

Sodium O dec. Labaz, Dibunate N-1N, (CH3)3 >3000 Becantal, Becantex, Dibunafon, Keuten, Linctussal

Function: Antiulcerative

Aldioxa. 230° U.S. Pat. Alanetorin, Alusa, No. Arlanto, 276.1867 Ascomp, Chlokale, Isalon, Nische, Peptilate

Cimetidine 141- U.S. Pat. Acibilin, Acinil, 1439 No. Cimal, Cimetag, 395.0333 Cimetum, Edalene, Dyspamet, Eureceptor, Gastromet, Peptol US 8,232,265 B2 75 76 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Antiurolithic

Allopurinol >350 U.S. Pat. No. 3474O98

Succinimide 125- Orotric H g O NY O 127

Function: Antiviral

Foscarnet >250 U.S. Pat. Foscavir Sodium No. 421.5113

Efavirenz 139- U.S. Pat. 141 No. 5519021

Function: Anxiolytic

Etifoxine 90-92 U.S. Pat. No. 372S4O4

Val- 113- Axiquel, Nirvanil noctamide 114

Function: Atriopeptidase Inhibitor

Cannabinol 76-77 US 8,232,265 B2 77 78 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Bronchodilator

Oxitropium 2O3- U.S. Pat. Oxivent, Tersigat, Bromide 204° No. Ventilat 3472861

Tiotropium 218- EP 418716 Bromide 220

Function: Calcium Channel Blocker

Fendiline 204- U.S. Pat. Cordan, Fendilar, Hydro 2050 No. Sensit chloride H 3262977 N

CH3 HCI

Prenylamine 36-37 U.S. Pat. Elecor No. H 3152173 N

CH3

Function: Carbonic Anhydrase Inhibitor

Aceta 2S8- U.S. Pat. Acetamox, Zolamide 2590 No. Atenezol, 2554816 Diamox, Didoc, Diuriwas, Donmox, Edemox, Fonurit, Glaupax US 8,232,265 B2 79 80 TABLE 1-continued

Name Compound MP Patent No. Other Names

Flumeth 3OS U.S. Pat. Ademol, Fludemil iazide 307 No. 3040042

Function: Cardioprotective

Acadesine 213 Arasine, Protara 214

Cariporide 90-94 U.S. Pat. No. 5591754

Function: Cardotonic

Levo 21O U.S. Pat. Simdax simendan 214 No. 5569657

Pimobendan 311o U.S. Pat. Hydro No. chloride 4361S63 US 8,232,265 B2 81 82 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Cholelitholytic Agent Ursodiol Actigall, Arsacol, Cholit-Ursan, Delursan, Desol, Destolit, Deursil, Litursol, Lyeton, Peptarom, Solutrat, Urdes, Ursacol, Urso, Ursochol, Ursofalk, Ursolvan.

Chenodiol 119° Chendol, Chenix, Chenocedon, Chenocol, Chenodex, Chenofaulk, Chenossil, Chenosaure, Cholanorm, Fluibil, Hekbilin, Ulmenide

Function: Choleretic

Cholic Acid 1989 Colalin Monohydrate

Clanobutin 115 U.S. Pat. Bykahepar 116° No. 3780095

Function: Cholinergic

Echo 138° U.S. Pat. thiophate No. Iodide 2911430

Edro 162 U.S. Pat. Antirex, Enlon, phonium 1630 No. Eversol, Tensilon Chloride 2647924 US 8,232,265 B2 83 84 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Cholinesterase Inhibitor

Amben 196 DE Mytelase onium 1990 1024517 Chloride

Distigmine dec U.S. Pat. Ubretide Bromide 1439 No. 2789981

Function: Cholinesterase Reactivator

AsOxime 145 U.S. Pat. Chloride 1470 No. 3773775

Obidoxime dec U.S. Pat. Toksobidin, Chloride 225o No. Toxogonin 3137702

Function: CNS Stimulant

Pemoline 256 U.S. Pat. AZOkSodon, Cylert, 257o No. Deltamine, 2892753 Hyton Asa, Kethamed, Nitan, Pioxol, Pondex, Senior, Sigmadyin, Stimul, Tradon, Wolital

Phen liquid U.S. Pat. metrazine No. 283,5669

N H CH US 8,232,265 B2 85 86 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Cyclooxygenase-2 Inhibitor

Celecoxib 157 WO Celebrex 1590 9515316

Function: Cytoprotectant (Gastric)

Cetraxate 200 U.S. Pat. 280° No. 3699149

Irsogladine 268 U.S. Pat. 269 No. 3.966728

Function: Decongestant Naphazoline 255 U.S. Pat. Ak-con, Albalon, Hydro 260° No. Clera, chloride 2161938 Coldan, Iridina, Naphcon, Niazol, OpconRhinantin, HCI Phinoperd, Sanorin, Sanorin-Spofa, Strictylon

Nordefrin 178 U.S. Pat. Corbasil, Cobefrin Hydro 1790 No. chloride HO 1948.162

HO

Function: Dermatitis Herpetiformis Suppressant Dapsone 175 Avlosulfon, 1760 Croysulfone, Diphenasone, Disulone, Dumitone, Eporal, Novophone, Sulfona-Mae, Sulphadine, Udolac US 8,232,265 B2 87 88 TABLE 1-continued

Name Compound MP Patent No. Other Names

Sulfa 190 U.S. Pat. Isopiridina, pyridine 1910 No. Soludagenan Sodium Salt 22753.54

Function: Diuretic

Mercapto 1SO U.S. Pat. merin 1550 No. Sodium 2576349

Mercuma 155 U.S. Pat. tilin 160° No. Sodium 2667442

Function: Dopamine Receptor Agonist

Pergolid 2O6 U.S. Pat. 209 No. 4166182

Pramipexole 296 U.S. Pat. Mirapex, Mirapexin, Dihydro 298 No. Sifrol chloride 488.6812

Function: Dopamine Receptor Antagonist

Amisulpride 126 U.S. Pat. 127C No. 4401822 US 8,232,265 B2 89 90 TABLE 1-continued

Name Compound MP Patent No. Other Names

Sulpiride 178 U.S. Pat. Alilit, Aiglonyl, 180° No. Coolspan, Dobren, 3342826 Dogmatil, Dogmatyl, Dolmatil, Guastil, Meresa, Miradol, Mierbanil, Misulvan, Neogama, Omperan, Pyrikappl, Sernevin, Splotin, Sulpitil, Sursumid, Trilan

Function: Emetic

Cephaeline 115 116°

Function: Expectorant

Bromhexine 237 BE 62SO22 238°

Br

CH3

Br

Ambroxol 233 U.S. Pat. Abramen, Ambril, Hydro 234 No. Bronchopront, chloride 3.536713 Duramucal, Fluibron, Fluixol, Frenopect, Lindoxyl, Motosol, Mucofar, Muscolvan, Mucoclear, Mucovent, Pect, Solvolan, Stas Hustenloser, Surbronc, Surfactal

Function: Gastric & Pancreatic Secretion Stimulant

Carnitine U.S. Pat. Nos. 42SS449 4315944 US 8,232,265 B2 91 92 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Gastroprokinetic

Cinitapride U.S. Pat. Tartate, Cidine No. SO26858

Cisapride 109.8 U.S. Pat. Acenalin, Alimix, No. Cipril, Prepulsick, 4.962115 Propulside, Risamol

Function: Glucocorticoid

Cortivazol 160 U.S. Pat. 1650 No. 306.7194f U.S. Pat. No. 3300483

Enoxolone 296 GB 83.31.84 US 8,232,265 B2 93 94 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Gonad-Stimulating Principle

Clomiphene 116- U.S. Pat. Citrate, Clomid, 118° No. Clomphid, Clomricl, 2914563 Clostilbeggit, Dyneric, Ikaclomine, Pergotime, Serophene C

Function: Hemorheologic Agent

Pentoxi 1050 U.S. Pat. Oxpentifylline, fylline No. Vasofirin, 3422107 AZOpentat, Dorapental, Rentglin, Torental, Trental

Function: Hemostatic

Adrenalone CH3 235o DE 152814 Adrenone, Stryphon N DE 277540

OH

OH

Carbazo 227- GB 795184 AC17, Adenaron, chrome 228 Adona, Carbazon, Sodium Donaseren, Emex, Sulfonate Odanon, Tazin

Function: Hepatoprotectant

Thioctic U.S. Pat. Biletan, Thioctacid, Acid Nos. Thioctan, Tioctan 2980716 3O49549 3223712

Timonacid FR 1731.84 Norgemen, Thioproline, Detokepa, Hepalidine, Heparegen, Thiazolidin US 8,232,265 B2 95 96 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Immono modulator

Pidotimod 194 U.S. Pat. 1989 No. 4839387

Bucillamine 139 U.S. Pat. Rimatil 140° No. 4305958 Function: Immono suppressant

6-Mercapto 313 U.S. Pat. Leuberin, purine 3149 Nos. Mercaleubin 2697709 2721866

Brequinar 315 U.S. Pat. 317o No. 468O299

COOH

Function: Keratolytic

Retinoic 180 U.S. Pat. Aberd, Airol, Arite, Acid 1810 No. Eudgna, Kerlocal, 3746730 Renova

Salicylic COOH 1590 Acnisal, Duofilm, Acid Duoplant, Keralyt, OH Occlusal, Verrugon

Function: Lexative? Cathartic

Docusate U.S. Pat. Sofale Calcium Nos. (Sodium) 3035973 2028091 US 8,232,265 B2 97 98 TABLE 1-continued

Name Compound MP Patent No. Other Names

Picosolfate 272- U.S. Pat. Guttalax-Fher, Sodium N 275o Nos. Laxoberal, 3528986 Laxoberon, N 2 3SS8643 Neopax, Pico-Salax

-OSO OSO3

Function: Leukotriene Antagonist

Ibudilast 53-54 U.S. Pat. Ketas No. 3850941

Zafirlukast 138- U.S. Pat. Accolate 140° No. 4859692

Function: Lipotropic

Choline U.S. Pat. Biocolina, Chloride No. Hepacholine, 2623901 Lipotril

Methionine O 28O- Acimethin 282° S HC1 OH NH2

Function: Lupos Erythematosos Suppressant

Bismuth U.S. Pat. Bistrimate Sodium No. Tri- 2348,984 glycollam ate

Chloroquine of N 193- U.S. Pat. Aralen, Articlin, n 1950 No. Bemaphate, 2233970 Capquin, Nivaquine B, 2 Reamachlor, Sanoquin US 8,232,265 B2

TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Matrix Metallo-proteinase Inhibitor

Prinomastat 149.8° WO 972O824

Function: Miotic

Carbachol 2070 U.S. Pat. Doryl, Isopto No. Carbachol, Zestryl, 1894.162 Miostat

Neostigmine 1670 U.S. Pat. No. 1905990

Function: Mucolytic

Acetyl- 109- U.S. Pat. Bronac, Fabrol, cysteine 110° No. Fluimueil, Mocosil, 31.8450S Moeret

Bromhexine 237.50 BE 625022

Br N

NH2 Br

Function: Muscle Relaxant (Skeletal)

Tetrazepam 144 U.S. Pat. Muscaril, Muokelat, No Myolastan 3426O14 US 8,232,265 B2 101 102 TABLE 1-continued

Name Compound MP Patent No. Other Names Tizanidine 221 U.S. Pat. 223 No. 3843668

Function: Mydriatic

Tropicamide 96-97 U.S. Pat. Mydriacyl, No. Mydriaticum 2726245

Phenyl OH 140 U.S. Pat. Adrianol, Ak-Dilate, ephrine 145° No. Alc-Nefrin, Hydro HO 1932347. Isophirin, chloride U.S. Pat. m-Sympatol, NCH, No. Neophryn 1954.389

Function: Naroctic Antagonist

Cyclazocine 2O1 BE 611OOO 2049 N CH HO

CH3

Ami 163 Dizol, Daptazole, phenazole 1649 Daptazile, Fenamizol

Function: Neuraminidase Inhibitor

Zanamivir 256° WO 91.1632O

Succinyl 156 choline 1630 US 8,232,265 B2 103 104 TABLE 1-continued

Name Compound MP Patent No. Other Names

Fazadinium 2150 U.S. Pat. Fazadon Bromide No. 3773746

Function: Neutral Endopetidase Inhibitor

Omapatrilat 218- U.S. Pat. Vauler 220 No. 5508272

Function: Neuroprotective

Riluzole 119° U.S. Pat. Rilutek No. 4370338

Repinotan 192- U.S. Pat. 1949 No. 5137901

Function: Nootropic

Indeloxazine U.S. Pat. Elen, Noin Hydro- No. chloride Cy 4109088

Donepezil 211- U.S. Pat. Aricept N 2120 No. O 4895841 US 8,232,265 B2 105 106 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Oxytocic

Carboprost 55-56 U.S. Pat. No. 3728.382

Function: Potassium Channel Activator? Opener

Pinacidil 164 U.S. Pat. Pindac 1650 No. 4057636

Nicorandil 92-93 U.S. Pat. Adamcor, Ikorel, No. Perisalol, Sigmart 42OO640

Function: Potassium Channel Blocker

Fampridine 158 1590

Tedisamil 195 U.S. Pat. 1970 No. 45SO112

Function: Prolactin Inhibitor

Cabergoline 102 U.S. Pat. Cabaser, Dostinex No. 4526892 US 8,232,265 B2 107 108 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Prostaglandin

Beraprost U.S. Pat. No. 44798O2

Function: Respiratory Stimulant

Dimefline 213- U.S. Pat. 214 No. 3147258

Fominoben 122- U.S. Pat. 123° No. 3661903

Function: Sclerosing Agent

2-Hexyl 140 decanoic 1500 Acid COOH

CH3

Sodium Sotradecol, Tergitol Tetradecyl OSO Sulfate US 8,232,265 B2 109 110 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Sedative? Hypnotic

Flurazepam 77-82 U.S. Pat. Felmeme, Nos. Noctosom, 3299053 Stacuroderm 3567710

Etodroxizine liquid GB 8172321

Hexafluor- 188- U.S. Pat. Mylexen enium 1890 No. Bromide 2783.237

Function: Tocolytic

Ritodrine 88-90 U.S. Pat. OH No. H 3410944 N

CH HO OH

Terbutaline CH 119- U.S. Pat. 3 H 122° No. HO N 393,7838 US 8,232,265 B2 111 112 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Ultraviolet Screen p-Amino- 187- U.S. Pat. Pabanol benzoic Acid COOH 187.5° Nos. 2878282 2947781 2735.865

Soliso- SOH 145° GB Songard, Uvinol benzone 1136525 OCH

O OH

Function: Uricosuric

Ticrynafen 148 U.S. Pat. No 3758506

Orotic Acid 345° U.S. Pat. Oropor, Orotyl Nos. 2937175

Function: Vasodilator (Cerebral)

Nafronyl 190° U.S. Pat. Dubimax, Gevatran No. 3334096 US 8,232,265 B2 113 114 TABLE 1-continued

Name Compound MP Patent No. Other Names

Nicametate 155- Eucast 157o

Function: Vasodilator (Coronary)

Perhexiline 243- GB 245.5° 1025578

Cloricromen 147- U.S. Pat. 148 No. 4452811

Function: Vasodilator (Peripheral)

Ciclonicate 127- DE 128° 1910481 24O6849

Cinepazide 135° U.S. Pat. No. 3634411 US 8,232,265 B2 115 116 TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Vasprotectant

Chromocarb U.S. Pat. O COOH 251 o No. 381.6470

Dobesilate >3000 U.S. Pat. Calcium OH No. 3509207

SO

Function: Vitamin Vitamin Source

Thiamine dec (Vit. B) 248

Pyridoxine 20S U.S. Pat. Hydro 2120 Nos. chloride 268.0743 (Vit. Bs) 2734O63 29O4SS1 3O24244

Function: Vulnerary

Oxaceprol 133 U.S. Pat. 1349 Nos. 38606O7 38.91765 3932638

Acetyl 109 U.S. Pat. Brunac, Fabrol, cysteine 110° No. Fluimucil, 31.8450S Fluprowit, Mucomgst, Mocosil, Tixair

Function: Wilson's Disease Treatment

Penicill 2O2 Depen, Distamine, amine SH COOH 2O6 Mercaptyl, Sofortan, Trolovo US 8,232,265 B2

TABLE 1-continued

Name Compound MP Patent No. Other Names

Function: Xanthine Oxidase Inhibitor

Allopurinol >350 U.S. Pat. Adenoal, Aloral, Nos. CoSonic, Remid, 28688O3 Riball 3474O98

Further examples of pharmaceutical actives that are ionic 15 fate, conorphone hydrochloride, cyclazocine, dexoxadrol or can be made ionic and combined with other ions to form the hydrochloride, dexpemedolac, dezocine, diflunisal, dihydro disclosed ionic liquid compositions are detailed below, along codeine bitartrate, dimefadane, dipyrone, doXpicomine with their typically pharmaceutical use. hydrochloride, drinidene, enadoline hydrochloride, epirizole, Adrenergic: adrenalone, amidephrine mesylate, apracloni ergotamine tartrate, ethoxazene hydrochloride, etofenamate, dine hydrochloride, brimonidine tartrate, dapiprazole hydro eugenol, fenoprofen, fenoprofen calcium, fentanyl citrate, chloride, deterenol hydrochloride, diplivefrin, dopamine floctafenine, flufenisal, flunixin, flunixin meglumine, flupir hydrochloride, ephedrine Sulfate, epinephrine, epinephrine tine maleate, fluproduaZone, fluradoline hydrochloride, flur bitartrate, epinephryl borate, esproquin hydrochloride, biprofen, hydromorphone hydrochloride, ibufenac, indopro etafedrine hydrochloride, hydroxyamphetamine hydrobro 25 fen, ketazocine, ketorfanol, ketorolac tromethamine, letimide mide, levonordefrin, mephentermine Sulfate, metaraminol hydrochloride, levomethadyl acetate, levomethadyl acetate bitartrate, metizoline hydrochloride, naphazoline hydrochlo hydrochloride, levonantradol hydrochloride, levorphanol tar ride, norepinephrine bitartrate, oxidopamine, oxymetazoline trate, lofemizole hydrochloride, lofentanil oxalate, lorcina hydrochloride, phenylephrine hydrochloride, phenylpro dol, lomoxicam, magnesium salicylate, mefenaamic acid, panolamine hydrochloride, phenylpropanolamine polistirex, 30 menabitan hydrochloride, meperidine hydrochloride, prenalterol hydrochloride, propylhexedrine, pseudoephe meptazinol hydrochloride, methadone hydrochloride, meth drine hydrochloride, tetrahydrozoline hydrochloride, trama adyl acetate, methopholine, methotrimeprazine, metkepha Zoline hydrochloride, Xylometazoline hydrochloride. mid acetate, mimbane hydrochloride, mirfentanil hydrochlo Adrenocortical steroid: ciprocinonide, desoxycorticoster ride, molinaZone, morphine Sulfate, moxazocine, nabitan one acetate, desoxycorticosterone pivalate, dexamethasone 35 hydrochloride, nalbuphine hydrochloride, nalmexone hydro acetate, fludrocortisone acetate, flumoxonide, hydrocorti chloride, namoxyrate, nantradol hydrochloride, naproxen, Sone hemisuccinate, methylprednisolone hemisuccinate, naproxen Sodium, naproxol, nefopam hydrochloride, nexeri naflocort, procinonide, timobesone acetate, tipredane. dine hydrochloride, noracymethadol hydrochloride, ocfenta Adrenocortical Suppressant: aminoglutethimide, trilos nil hydrochloride, octaZamide, olvanil, oxetorone fuimarate, tane. 40 oxycodone, oxycodone hydrochloride, oxycodone terephtha Alcohol deterrent: disulfiram. late, oxymorphone hydrochloride, pemedolac, pentamor Aldosterone antagonist: canrenoate potassium, canrenone, phone, pentazocine, pentazocine hydrochloride, pentazocine dicirenone, mexrenoate potassium, prorenoate potassium, lactate, phenazopyridine hydrochloride, phenyramidol spironolactone. hydrochloride, picenadol hydrochloride, pinadoline, pirfeni Amino acid: alanine, aspartic acid, cysteine hydrochloride, 45 done, piroxicam olamine, pravadoline maleate, prodilidine cystine, histidine, isoleucine, leucine, lysine, lysine acetate, hydrochloride, profadol hydrochloride, propirarn fumarate, lysine hydrochloride, methionine, phenylalanine, proline, propoxyphene hydrochloride, propoxyphene napsylate, serine, threonine, tryptophan, tyrosine, Valine. proxazole, proxazole citrate, proXorphan tartrate, pyrro Ammonia detoxicant: arginine: arginine glutamate, argin liphene hydrochloride, remifentanil hydrochloride, salcolex, ine hydrochloride. 50 Salethamide maleate, salicylamide, Salicylate meglumine, Anabolic: bolandiol dipropionate, bolasterone, boldenone Salsalate, Sodium salicylate, spiradoline mesylate, Sufentanil, undecylenate, bolenol, bolnantalate, ethylestrenol, meth Sufentanil citrate, talmetacin, talniflumate, talosalate, tazad enolone acetate, methenolone enanthate, mibolerone, nan olene Succinate, tebufelone, tetrydamine, tifurac sodium, tili drolone cyclotate, norbolethone, pizotyline, quinbolone, dine hydrochloride, tiopinac, tonazocine mesylate, tramadol Stenbolone acetate, tibolone, Zeranol. 55 hydrochloride, trefentanil hydrochloride, trolamine, Verado Analeptic: modafinil. line hydrochloride, verilopam hydrochloride, volazocine, Analgesic: acetaminophen, alfentanil hydrochloride, ami Xorphanol mesylate, Xylazine hydrochloride, Zenazocine nobenzoate potassium, aminobenzoate sodium, anidoxime, mesylate, Zomepirac sodium, Zucapsaicin. anileridine, anileridine hydrochloride, anilopam hydrochlo Androgen: fluoxymesterone, mesterolone, methyltest ride, anirolac, antipyrine, aspirin, benoxaprofen, benzy 60 osterone, nandrolone decanoate, nandrolonephenpropionate, damine hydrochloride, bici fadine hydrochloride, brifentanil nisterime acetate, Oxandrolone, oxymetholone, silandrone, hydrochloride, bromadoline maleate, bromfenac sodium, stanozolol, testosterone, testosterone cypionate, testosterone buprenorphine hydrochloride, butacetin, butixirate, butor enanthate, testosterone ketolaurate, testosterone phenylac phanol, butorphanol tartrate, carbamazepine, carbaspirin cal etate, testosterone propionate, trestolone acetate. cium, carbiphene hydrochloride, carfentanil citrate, ciprefa 65 Anesthesia, adjunct to: Sodium oxybate. dol Succinate, ciramadol, ciramadol hydrochloride, Anesthetic: alliflurane, benoximate hydrochloride, ben clonixeril, clonixin, codeine, codeine phosphate, codeine Sul Zocaine, biphenamine hydrochloride, bupivacaine hydro US 8,232,265 B2 119 120 chloride, butamben, butamben picrate, chloroprocaine hydro Anti-allergic: amlexanoX, astemizole, azelastine hydro chloride, cocaine, cocaine hydrochloride, cyclopropane, chloride, eclaZolast, minocromil, nedocromil, nedocromil desflurane, dexivacaine, diamocaine cyclamate, dibucaine, calcium, nedocromil Sodium, nivimedone sodium, pemiro dibucaine hydrochloride, dyclonine hydrochloride, enflu last potassium, pentigetide, pirquinozol, poisonoak extract, rane, ether, ethyl chloride, etidocaine, etoxadrol hydrochlo probicromil calcium, proXicromil, repirinast, tetraZolast ride, euprocin hydrochloride, fluroxene, halothane, isob meglumine, thiazinamium chloride, tiacrilast, tiacrilast utamben, isoflurane, ketamine hydrochloride, levoxadrol Sodium, tiprinast meglumine, tixanoX. hydrochloride, lidocaine, lidocaine hydrochloride, mepiv Anti-amebic: berythromycin, bialamicol hydrochloride, acaine hydrochloride, methohexital sodium, methoxyflurane, chloroquine, chloroquine hydrochloride, chloroquine phos midazolam hydrochloride, midazolam maleate, minaxolone, 10 phate, clamoxyquin hydrochloride, clioquinol, emetine nitrous oxide, norflurane, octodrine, oxethazaine, phencycli hydrochloride, iodoquinol, paromomycin Sulfate, quinfa dine hydrochloride, pramoxine hydrochloride, prilocaine mide, Symetime hydrochloride, teclozan, tetracycline, tetra hydrochloride, procaine hydrochloride, propanidid, propara cycline hydrochloride. caine hydrochloride, propofol, propoxycaine hydrochloride, anti-androgen: benorterone, cioteronel, cyproterone pyrrocaine, risocaine, rodocaine, roflurane, Salicyl alcohol, 15 acetate, delmadinone acetate, oxendolone, topterone, Zanot sevoflurane, teflurane, tetracaine, tetracaine hydrochloride, CO. thiamylal, thiamylal Sodium, thiopental Sodium, tiletamine Anti-anemic: epoetin alfa, epoetin beta, ferrous Sulfate, hydrochloride, Zolamine hydrochloride. dried, leucovorin calcium. Anorectic compounds including dexfenfluramine. Anti-anginal: amlodipine besylate, amlodipine maleate, Anorexic: aminorex, amphecloral, chlorphentermine betaxolol hydrochloride, bevantolol hydrochloride, buto hydrochloride, clominorex, clortermine hydrochloride, prozine hydrochloride, carvedilol, cinepazet maleate, meto diethylpropion hydrochloride, fenfluramine hydrochloride, prolol Succinate, molsidomine, monatepil maleate, primi fenisorex, fludorex, fluminorex, levamfetamine Succinate, dolol, ranolazine hydrochloride, tosifen, Verapamil mazindol, mefenorex hydrochloride, phenmetrazine hydro hydrochloride. chloride, phentermine, sibutramine hydrochloride. 25 Anti-anxiety agent: adatanserin hydrochloride, alpidem, Antagonist: atipamezole, atosiban, bosentan, cimetidine, binospirone mesylate, bretazenil, glemanserin, ipsapirone cimetidine hydrochloride, clentiazem maleate, detirelix hydrochloride, mirisetron maleate, ocinaplon, ondansetron acetate, devaZepide, donetidine, etintidine hydrochloride, hydrochloride, panadiplon, pancopride, paZinaclone, Seraza famotidine, fenmetozole hydrochloride, flumazenil, icatibant pine hydrochloride, tandospirone citrate, Zalospirone hydro acetate, icotidine, isradipine, metiamide, nadide, nalmefene, 30 chloride. nalmexone hydrochloride, naloxone hydrochloride, naltrex Anti-arthritic: lodelaben. one, nilvadipine, oxilorphan, oxmetidine hydrochloride, Anti-asthmatic: ablukast, ablukast sodium, azelastine oXimetidine mesylate, quadazocine mesylate, ranitidine, ran hydrochloride, bunaprolast, cinalukast, crornitrile Sodium, itidine bismuth citrate, ranitidine hydrochloride, sufotidine, cromolyn Sodium, enofelast, isamoxole, ketotifen fumarate, teludipine hydrochloride, tiapamil hydrochloride, tiotidine, 35 levcromakalim, lodoxamide ethyl, lodoxamide vapiprost hydrochloride, Zaltidine hydrochloride. tromethamine, montelukast sodium, Ontazolast, oxarbazole, Anterior pituitary activator: epimestrol. oXatomide, piriprost, piriprost potassium, pirolate, pobi Anterior pituitary Suppressant: danazol. lukastedamine, quaZolast, repirinast, ritolukast, Sulukast, tet Anthelmintic: albendazole, anthelmycin, bromoxanide, razolast meglumine, tiaramide hydrochloride, tibenelast bunamidine hydrochloride, butonate, cambendazole, carban 40 Sodium, tomelukast, tranilast, Verlukast, Verofylline, Zar tel lauryl Sulfate, clioxanide, closantel, cyclobendazole, irlukast. dichlorvos, diethylcarbamazine citrate, dribendazole, Anti-atherosclerotic: mifobate, timefuronc. dymanthine hydrochloride, etibendazole, fenbendazole, Anticholelithic: monoctanoin. furodazole, hexylresorcinol, mebendazole, morantel tartrate, Anticholelithogenic: chenodiol, ursodiol. niclosamide, nitramisole hydrochloride, nitrodan, oxantel 45 Anticholinergic: alverinc citrate, anisotropine methylbro pamoate, Oxfendazole, Oxibendazole, parbendazole, pipera mide, atropine, atropine oxide hydrochloride, atropine Sul mide maleate, piperazine, piperazine citrate, piperazine ede fate, belladonna, benapryzine hydrochloride, benzetimide tate calcium, proclonol, pyrantel pamoate, pyrantel tartrate, hydrochloride, benzilonium bromide, biperiden, biperiden pyrvinium pamoate, rafoxanide, stilbazium iodide, tetrami hydrochloride, biperiden lactate, clidinium bromide, cyclo sole hydrochloride, thiabendazole, ticarbodine, tioxidazole, 50 pentolate hydrochloride, dexetimide, dicyclomine hydro triclofenol piperazine, Vincofos, Zilantel. chloride, dihexyverine hydrochloride, domazoline fumarate, Anti-acne: adapalene, erythromycin Salnacedin, inocoter elantrine, elucaine, ethybenztropine, eucatropine hydrochlo One acetate, acCutane. ride, glycopyrrolate, heteronium bromide, homatropine Anti-adrenergic: acebutolol, alprenolol hydrochloride, hydrobromide, homatropine methylbromide, hyoscyamine, atenolol, bretylium tosylate, bunolol hydrochloride, carteolol 55 hyoscyamine hydrobromide, hyoscyamine Sulfate, isopropa hydrochloride, celiprolol hydrochloride, cetamolol hydro mide iodide, mepenZolate bromide, methylatropine nitrate, chloride, cicloprolol hydrochloride, dexpropranolol hydro metoquizine, oxybutynin chloride, parapenzolate bromide, chloride, diacetolol hydrochloride, dihydroergotamine mesy pentapiperium methylsulfate, phencarbamide, poldine meth late, dilevalol hydrochloride, esmolol hydrochloride, ylsulfate, proglumide, propantheline bromide, propenZolate exaprolol hydrochloride, fenspiride hydrochloride, flestolol 60 hydrochloride, Scopolamine hydrobromide, tematropium sulfate, labetalol hydrochloride, levobetaxolol hydrochlo methylsulfate, tiquinamide hydrochloride, tofenacin hydro ride, levobunolol hydrochloride, metalol hydrochloride, chloride, toguizine, triampyZine Sulfate, trihexyphenidyl metoprolol, metoprolol tartrate, nadolol, pamatolol Sulfate, hydrochloride, tropicamide. penbutolol Sulfate, phentolamine mesylate, practolol, propra Anticoagulant: ancrod, anticoagulant citrate dextrose solu nolol hydrochloride, proroxanhydrochloride, solypertine tai 65 tion, anticoagulant citrate phosphate dextrose adenine solu trate, Sotalol hydrochloride, timolol, timolol maleate, tipre tion, anticoagulant citrate phosphate dextrose solution, anti nolol hydrochloride, tolamolol, Zollertine hydrochloride. coagulant heparin Solution, anticoagulant sodium citrate US 8,232,265 B2 121 122 Solution, ardeparin Sodium, bivalirudin, bromindione, dalte human, insulin human, isophane, insulin human Zinc, insulin parin Sodium, desirudin, dicumnarol, heparin calcium, hep human Zinc, extended, insulin, isophane, insulin lispro, insu arin Sodium, lyapolate sodium, nafamo.stat mesylate, phen lin, neutral, insulin Zinc, insulin Zinc, extended, insulin Zinc, procoumon, tinzaparin Sodium, warfarin Sodium. prompt, linogliride, linogliride fumarate, metformin, methyl Anticoccidal: maduramicin. palmoxirate, palmoxirate Sodium, pioglitaZone hydrochlo Anticonvulsant: albutoin, ameltolide, atolide, buramate, ride, pirogliride tartrate, proinsulin human, Seglitide acetate, carbamazepine, cinromide, citenamide, clonazepam, cyhep tolaZamide, tolbutamide, tolpyrramide, troglitaZone, Zopolr tamide, dezinamide, dimethadione, divalproex sodium, eter estat, and Sitagliptin. obarb, ethosuximide, ethotoin, flurazepam hydrochloride, Antidiarrheal: rolgamidine, diphenoxylate hydrochloride fluzinamide, fosphenytoin Sodium, gabapentin, ilepcimide, 10 (lomotil), metronidazole (flagyl), methylprednisolone lamotrigine, magnesium sulfate, mephenytoin, mephobar (medrol), Sulfasalazine (aZulfidine). bital, methetoin, methsuximide, millacemide hydrochloride, Antidiuretic: argipressin tannate, desmopressin acetate, nabazenil, nafimidone hydrochloride, nitrazepam, phenace lypressin. mide, phenobarbital, phenobarbital Sodium, phensuximide, Antidote: dimercaprol, edrophonium chloride, fomepi phenytoin, phenytoin Sodium, primidone, progabide, ralito 15 Zole, leucovorin calcium, levoleucovorin calcium, methylene line, remacemide hydrochloride, ropizine, sabeluzole, stirip blue, protamine Sulfate. entol, Sulthiame, thiopental Sodium, tiletamine hydrochlo Antidyskinetic: selegiline hydrochloride. ride, topiramate, trimethadione, Valproate sodium, Valproic Anti-emetic: alosetron hydrochloride, batanopride hydro acid, vigabatrin, ZonicleZole hydrochloride, Zonisamide. chloride, bemesetron, benzquinamide, chlorpromazine, chlo Antidepressant: adatanserin hydrochloride, adinazolam, rpromazine hydrochloride, clebopride, cyclizine hydrochlo adinazolam mesylate, alaproclate, aletamine hydrochloride, ride, dimenhydrinate, diphenidol, diphenidol hydrochloride, amedalin hydrochloride, amitriptyline hydrochloride, amox diphenidol pamoate, dolasetron mesylate, domperidone, apine, aptazapine maleate, azaloxan fluimarate, azepindole, dronabinol, fluidorex, flumeridone, galdansetron hydrochlo azipramine hydrochloride, bipenamol hydrochloride, bupro ride, granisetron, granisetron hydrochloride, lurosetron pion hydrochloride, butacetin, butriptyline hydrochloride, 25 mesylate, meclizine hydrochloride, metoclopramide hydro caroxazone, cartaZolate, ciclaZindol, cidoxepin hydrochlo chloride, metopimazine, ondansetron hydrochloride, panco ride, cilobamine mesylate, clodazon hydrochloride, clomi pride, prochlorperazine, prochlorperazine edisylate, prochlo pramine hydrochloride, cotinine fumarate, cyclindole, cype rperazine maleate, promethazine hydrochloride, namine hydrochloride, cyprolidol hydrochloride, thiethylperazine, thiethylperazine malate, thiethylperazine cyproximide, daledalin tosylate, dapoxetine hydrochloride, 30 maleate, trimethobenzamide hydrochloride, Zacopride daZadrol maleate, dazepinil hydrochloride, desipramine hydrochloride. hydrochloride, dexamisole, deximafen, dibenzepin hydro Anti-epileptic: felbamate, loreclezole, tolgabide. chloride, dioxadrol hydrochloride, dothiepin hydrochloride, Anti-estrogen: clometherone, dehnadinone acetate, doxepin hydrochloride, dulloxetine hydrochloride, eclan nafoxidine hydrochloride, nitromifene citrate, raloxifene amine maleate, encyprate, etoperidone hydrochloride, fantri 35 hydrochloride, tamoxifen citrate, toremifene citrate, triox done hydrochloride, fehmetozole hydrochloride, fenmetra ifene mesylate. mide, fezolamine fumarate, fluotracen hydrochloride, Antifibrinolytic: nafamo.stat mesylate. fluoxetine, fluoxetine hydrochloride, fluparoxan hydrochlo Antifungal: acrisorcin, ambruticin, amphotericin b, aza ride, gamfexine, guanoxyfen Sulfate, imafen hydrochloride, conazole, azaserine, basifluingin, bifonazole, biphenamine imiloxan hydrochloride, imipramine hydrochloride, indelox 40 hydrochloride, bispyrithione magSulfex, butoconazole azine hydrochloride, intriptyline hydrochloride, iprindole, nitrate, calcium undecylenate, candicidin, carbol-fuichsin, isocarboxazid, ketipramine fumarate, lofepramine hydro chlordantoin, ciclopiroX, ciclopiroX olamine, cillofungin, chloride, lortalamine, maprotiline, maprotiline hydrochlo cisconazole, clotrimazole, cuprimyxin, denofungin, dipy ride, melitracen hydrochloride, millacemide hydrochloride, rithione, doconazole, econazole, econazole nitrate, enilcona minaprine hydrochloride, mirtazapine, moclobemide, moda 45 Zole, ethonam nitrate, fenticonazole nitrate, filipin, flucona line Sulfate, napactadine hydrochloride, napamezole hydro Zole, flucytosine, fingimycin, griseofulvin, hamycin, chloride, nefazodone hydrochloride, nisoxetine, nitrafudam isoconazole, itraconazole, kalafungin, ketoconazole, hydrochloride, nomifensine maleate, nortriptyline hydro lomofimgin, lydimycin, mepartricin, miconazole, micona chloride, octriptyline phosphate, opipramol hydrochloride, Zole nitrate, monensin, monensin Sodium, naftifine hydro oxaprotiline hydrochloride, oxypertine, paroxetine, 50 chloride, neomycin undecylenate, nifuratel, nifulrmerone, phenelZine Sulfate, pirandamine hydrochloride, pizotyline, nitralamine hydrochloride, nystatin, octanoic acid, orcona pridefine hydrochloride, prolintane hydrochloride, protrip Zole nitrate, oxiconazole nitrate, oxifungin hydrochloride, tyline hydrochloride, quipazine maleate, rolicyprine, seproX parconazole hydrochloride, partricin, potassium iodide, pro etine hydrochloride, sertraline hydrochloride, sibutramine clonol, pyrithione Zinc, pyrrolnitrin, rutamycin, sangui hydrochloride, Sulpiride, Suritozole, tametraline hydrochlo 55 narium chloride, Saperconazole, scopafungin, selenium Sul ride, tampramine fimarate, tandamine hydrochloride, thiaz fide, sinefungin, Sulconazole nitrate, terbinafine, terconazole, esim hydrochloride, thozalinone, tomoxetine hydrochloride, thiram, ticlatone, tioconazole, tolciclate, tolindate, tolnaftate, trazodone hydrochloride, trebenzomine hydrochloride, trimi triacetin, triafungin, undecylenic acid, virido fulvin, Zinc pramine, trimipramine maleate, Venlafaxine hydrochloride, undecylenate, Zinoconazole hydrochloride. One specific anti viloxazine hydrochloride, Zimeldine hydrochloride, 60 fungal that is Suitable is itraconazole. Zometapine. Antiglaucoma agent: alprenoXime hydrochloride, col Antidiabetic: acetohexamide, buformin, butoxamine forsin, dapiprazole hydrochloride, diplivefrin hydrochloride, hydrochloride, camiglibose, chlorpropamide, ciglitaZone, naboctate hydrochloride, pilocarpine, pimabine. englitaZone sodium, etoformin hydrochloride, gliamilide, Antihemophilic: antihemophilic factor. glibornuride, glicetanile Sodium, gliflumide, glipizide, gluca 65 Antihemorrhagic: poliglusam. gon, glyburide, glyhexamide, glymidine sodium, glyocta Antihistaminic: acrivastine, antazoline phosphate, astemi mide, glyparamide, insulin, insulin, dalanated, insulin Zole, azatadine maleate, barmastine, bromodiphenhydramine US 8,232,265 B2 123 124 hydrochloride, brompheniramnine maleate, carbinoxamine menidine, tiamenidine hydrochloride, ticrynafen, tinabinol, maleate, cetirizine hydrochloride, chlorpheniramine maleate, tiodazosin, tipentosin hydrochloride, trichlormethiazide, tri chlorpheniramine polistirex, cinnarizine, clemastine, clemas maZosin hydrochloride, trimethaphan camsylate, trimox tine fluimarate, closiramine aceturate, cycliramine maleate, aamine hydrochloride, tripamide, Xipamide, Zankiren hydro cyclizine, cyproheptadine hydrochloride, dexbrompheniram chloride, Zofenoprilat arginine. nine maleate, dexchlorpheniramine maleate, dimethindene Antihypotensive: ciclafrine hydrochloride, midodrine maleate, diphenhydramine citrate, diphenhydramnine hydro hydrochloride. chloride, dorastine hydrochloride, doxylamine Succinate, Anti-infective: difloxacin hydrochloride, lauryl isoquino ebastine, levocabastine hydrochloride, loratadine, mianserin linium bromide, moxalactam disodium, omidazole, pentiso hydrochloride, noberastine, orphenadrine citrate, pyrabrom, 10 micin, Sarafloxacin hydrochloride, protease inhibitors of hiv pyrilamine maleate, pyroxaminine maleate, rocastine hydro and other retroviruses, integrase inhibitors of hiv and other chloride, rotoxamine, tazifylline hydrochloride, temelastine, retroviruses, cefaclor (CECLORTM), acyclovir (ZOVI terfenadine, tripelennamine citrate, tripelennamine hydro RAXTM), norfloxacin (NOROXINTM), cefoxitin (ME chloride, triprolidine hydrochloride, Zolamine hydrochloride. FOXINTM), cefuroxime axetil (CEFTINTM), ciprofloxacin Antihyperlipidemic: cholestyramine resin, clofibrate, 15 (CIPROTM). colestipol hydrochloride, crilvastatin, dalvastatin, dextrothy Anti-infective, topical: alcohol, aminacrine hydrochloride, roxine Sodium, fluvastatin Sodium, gemfibrozil, lecimibide, benzethonium chloride: bithionolate sodium, bromchlo lovastatin, niacin, pravastatin Sodium, probucol, simvastatin, renone, carbamide peroxide, cetalkonium chloride, cetylpy tiqueside, Xenbucin. ridinium chloride: chlorhexidine hydrochloride, clioquinol. Antihyperlipoproteinemic: acifran, beloxamide, beZafi domiphen bromide, fenticlor, fludazonium chloride, fuchsin, brate, boxidine, butoxamine hydrochloride, cetaben sodium, basic, furazolidone, gentian violet, halquinols, hexachlo ciprofibrate, gemcadiol, halofenate, lifibrate, meglutol, rophene: hydrogen peroxide, ichthammol, imidecyl iodine, nafenopin, pimetime hydrochloride, theofibrate, tibric acid, iodine, isopropyl alcohol, mafenide acetate, meralein treloxinate. Sodium, mercufenol chloride, mercury, ammoniated, methyl Antihypertensive: alfuZosin hydrochloride, alipamide, 25 benzethonium chloride, nitrofuraZone, nitromersol, octeni althiazide, amiquinsin hydrochloride, amlodipine besylate, dine hydrochloride, oxychlorosene, oxychlorosene Sodium, amlodipine maleate, anaritide acetate, atiprosin maleate, bel parachlorophenol, camphorated, potassium permanganate, fosdil, bemitradine, bendacalol mesylate, bendroflumethiaz poVidone-iodine, sepazonium chloride, silver nitrate, Sulfa ide, benzthiazide, betaxolol hydrochloride, bethanidine sul diazine, silver, Symclosene, thimerfonate sodium, thimero fate, bevantolol hydrochloride, biclodil hydrochloride, 30 sal: troclosene potassium. bisoprolol, bisoprolol fumarate, bucindolol hydrochloride, Anti-inflammatory: acetominophen, alclofenac, aldlom bupicomide, buthiazide: candoxatril, candoxatrilat, captopril, etaSone dipropionate, algestone acetonide, alpha amylase, carvedilol, ceronapril, chlorothiazide Sodium, cicletanine, amcinafal, amcinafide, amfenac sodium, amiprilose hydro cilaZapril, clonidine, clonidine hydrochloride, clopamide, chloride, anakinra, anirolac, anitraZafen, apaZone, bal cyclopenthiazide, cyclothiazide, darodipine, debrisoquin Sul 35 Salazide disodium, bendazac, benoxaprofen, benzydamine fate, delapril hydrochloride, diapamide, diazoxide, dilevalol hydrochloride, bromelains, broperamole, budesonide, car hydrochloride, diltiazem malate, ditekiren, doxazosin mesy profen, cicloprofen, cintaZone, cliprofen, clobetasol propi late, ecadotril, enalapril maleate, enalaprilat, enalkiren, onate, clobetaSone butyrate, clopirac, cloticaSone propionate, endralazine mesylate, epithiazide, eprosartan, eprosartan cormethasone acetate, cortodoxone, deflazacort, desonide, mesylate, fenoldopam mesylate, flavodilol maleate, flo 40 desoximetaSone, dexamethasone dipropionate, diclofenac rdipine, floseduinan, fosinopril sodium, fosinoprilat, guana potassium, diclofenac sodium, diflorasone diacetate, diflumi benz, guanabenZ acetate, guanacline Sulfate, guanadrel Sul done sodium, diflunisal, difluprednate, diftalone, dimethyl fate, guancydine, guanethidine monosulfate, guanethidine Sulfoxide, drocinonide, endrysone, enlimomab, enolicam Sulfate, guanfacine hydrochloride, guanisoquin Sulfate, gua Sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, noclor Sulfate, guanoctine hydrochloride, guanoxabenz, gua 45 fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fen noxan Sulfate, guanoxyfen Sulfate, hydralazine hydrochlo tiazac, flazalone, fluazacort, flufenamic acid, flumizole, ride, hydralazine polistirex, hydroflumethiazide, flunisolide acetate, flunixin, flunixin meglumine, fluocortin indacrinone, indapamide, indolaprif hydrochloride, butyl, fluorometholone acetate, fluguaZone, flurbiprofen, indoramin, indoramin hydrochloride, indorenate hydrochlo fluretofen, fluticasone propionate, furaprofen, furobufen, hal ride, lacidipine, leniquinsin, levcromakalim, lisinopril, 50 cinonide, halobetasol propionate, halopredone acetate, lofexidine hydrochloride, losartan potassium, losulazine ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, hydrochloride, mebutamate, mecamylamine hydrochloride, ilonidap, indomethacin, indomethacin Sodium, indoprofen, medroxalol, medroxalol hydrochloride, methalthiazide, indoxole, intrazole, isoflupredone acetate, isoxepac, isoxi methyclothiazide, methyldopa, methyldopate hydrochloride, cam, ketoprofen, lofemizole hydrochloride, lomoxicam, metipranolol, metolaZone, metoprolol fumarate, metoprolol 55 loteprednol etabonate, meclofenamate sodium, meclofe Succinate, metyrosine, minoxidil , monatepil maleate, namic acid, meclorisone dibutyrate, mefenamic acid, muZolimine, nebivolol, nitrendipine.ofomine, pargyline mesalamine, meseclaZone, methylprednisolone Suleptanate, hydrochloride, paZOxide, pelanserin hydrochloride, perin momiflumate, nabumetone, naproxen, naproxen Sodium, dopril erbumine, phenoxybenzamine hydrochloride, pinaci naproXol, nimaZone, olSalazine sodium, orgotein, orpanoxin, dil, pivopril, polythiazide, praZosin hydrochloride, primi 60 oxaprozin, oxyphenbutaZone, paranyline hydrochloride, pen dolol, prizidilol hydrochloride, quinapril hydrochloride, tosan polysulfate Sodium, phenbutaZone sodium glycerate, quinaprilat, quinaZosin hydrochloride, quinelorane hydro pirfenidone, piroXicam, piroxicam cinnamate, piroxicamola chloride, quinpirole hydrochloride, quinuclium bromide, mine, pirprofen, prednazate, prifelone, prodolic acid, produa ramipril, rauwolfia serpentina, reserpine, saprisartan potas Zone, proxazole, proxazole citrate, rimexolone, romazarit, sium, Saralasin acetate, sodium nitroprusside, Sulfinalol 65 salcolex, Salnacedin, Salsalate, sanguinarium chloride, secla hydrochloride, tasosartan, teludipine hydrochloride, temoca Zone, Sermetacin, Sudoxicam, Sulindac, Suprofen, talmetacin, pril hydrochloride, terazosin hydrochloride, terlakiren, tia talniflumate, talosalate, tebufelone, tenidap, tenidap Sodium, US 8,232,265 B2 125 126 tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tiXocor cin, strontium chloride Sr 89, Sulofenur, talisomycin, taxane, tol pivalate, tolmetin, tolmetin Sodium, triclonide, triflumi taxoid, tecogalan Sodium, tegafur, teloxantrone hydrochlo date, Zidometacin, Zomepirac sodium. ride, temoporfin, teniposide, teroxirone, testolactone, thiami Antikeratinizing agent: doretinel, linarotene, pelretin. prine, thioguanine, thiotepa, tiazofurin, tirapazamine, topo Antimalarial: acedapsone, amodiaquine hydrochloride, tecan hydrochloride, toremifene citrate, trestolone acetate, amduinate, arteflene, chloroquine, chloroquine hydrochlo triciribine phosphate, trimetrexate, trimetrexate glucuronate, ride, chloroquine phosphate, cycloguanil pamoate, empiroline triptorelin, tubulozole hydrochloride, uracil mustard, ure phosphate, halofantrine hydrochloride, hydroxychloroquine depa, Vapreotide, verteporfin, vinblastine Sulfate, Vincristine Sulfate, mefloquine hydrochloride, menoctone, mirincamy Sulfate, vindesine, Vindesine Sulfate, vinepidine Sulfate, Ving cin hydrochloride, primaquine phosphate, pyrimethamine, 10 lycinate sulfate, vinleurosine sulfate, vinorelbine tartrate, quinine Sulfate, tebuquine. Vinrosidine Sulfate, Vinzolidine Sulfate, Vorozole, Zeniplatin, Antimicrobial: aztreonam, chlorhexidine gluconate, imi Zinostatin, Zorubicin hydrochloride. durea, lycetamine, nibroxane, piraZmonam sodium, propi Other anti-neoplastic compounds include: 20-epi-1,25 onic acid, pyrithione sodium, Sanguinarium chloride, tige dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubi monam dicholine. 15 cin, acylfuilvene, adecypenol, adoZelesin, aldesleukin, ALL Antimigraine: dolasetron mesylate, naratriptanhydrochlo TKantagonists, altretamine, ambamustine, amidox, amifos ride, Sergolexole maleate, Sumatriptan Succinate, Zatosetron tine, aminolevulinic acid, amrubicin, atrsacrine, anagrelide, maleate. anastroZole, andrographolide, angiogenesis inhibitors, Antimitotic: podofilox. antagonist D, antagonist G, antarelix, anti-dorsalizing mor Antimycotic: amorolfine. phogenetic protein-1, antiandrogen, prostatic carcinoma, Antinauseant: buclizine hydrochloride, cyclizine lactate, antiestrogen, antineoplaston, antisense oligonucleotides, naboctate hydrochloride. aphidicolin glycinate, apoptosis gene modulators, apoptosis Antineoplastic: acivicin, aclarubicin, acodazole hydro regulators, apurinic acid, ara-CDP-DL-PTBA, arginine chloride, acrqnine, adoZelesin, aldesleukin, altretamine, deaminase, asulacrine, atamestane, atrimustine, axinastatin ambomycin, ametantrone acetate, aminoglutethimide, amsa 25 1, axinastatin 2, axinastatin 3, aZasetron, azatoxin, azaty crine, anastroZole, anthramycin, asparaginase, asperlin, aza rosine, baccatin III derivatives, balanol, batimastat, BCR/ citidine, azetepa, azotomycin, batimastat, benzodepa, ABL antagonists, benzochlorins, benzoylstaurosporine, beta bicalutamide, bisantrene hydrochloride, bisnafide dimesy lactam derivatives, beta-alethine, betaclamycin B, betulinic late, bizelesin, bleomycin Sulfate, brequinar Sodium, bropir acid, bFGF inhibitor, bicalutamide, bisantrene, bisaziridinyl imine, buSulfan, cactinomycin, calusterone, caracemide, car 30 spermine, bisnafide, bistratene A, bizelesin, breflate, bropir betimer, carboplatin, carmustine, carubicin hydrochloride, imine, budotitane, buthionine Sulfoximine, calcipotriol, carzelesin, cedefingol, chlorambucil, cirolemycin, cisplatin, calphostin C, camptothecin derivatives, canarypox IL-2, cladribine, crisinatol mesylate, cyclophosphamide, cytara capecitabine, carboxamide-amino-triazole, carboxyamidot bine, dacarbazine, dactinomycin, daunorubicin hydrochlo riazole, CaRest M3, CARN 700, cartilage derived inhibitor, ride, decitabine, dexormaplatin, deZaguanine, deZaguanine 35 carzelesin, casein kinase inhibitors (ICOS), castanospermine, mesylate, diaziquone, docetaxel, doxorubicin, doxorubicin cecropin B. cetrorelix, chlorins, chloroquinoxaline Sulfona hydrochloride, droloxifene, droloxifene citrate, dromo mide, cicaprost, cis-porphyrin, cladribine, clomifene ana stanolone propionate, duaZomycin, edatrexate, eflomithine logues, clotrimazole, collismycin A, collismycin B, combre hydrochloride, elsamitrucin, enloplatin, enpromate, epipro tastatin A4, combretastatin analogue, conagenin, pidine, epirubicin hydrochloride, erbulozole, esorubicin 40 crambescidin 816, crisinatol, cryptophycin 8, cryptophycin A hydrochloride, estramustine, estramustine phosphate derivatives, curacin A, cyclopentanthraquinones, cyclo Sodium, etanidazole, ethiodized oil I 131, etoposide, etopo platam, cypemycin, cytarabine ocfosfate, cytolytic factor, side phosphate, etoprine, fadrozole hydrochloride, faZara cytostatin, dacliximab, decitabine, dehydrodidemnin B, bine, fenretinide, floxuridine, fludarabine phosphate, fluo deslorelin, dexifosfamide, dexraZoxane, dexVerapamil, diazi rouracil, flurocitabine, fosquidone, fostriecin Sodium, 45 quone, didemnin B, didox, diethylnorspermine, dihydro-5- gemcitabine, gemcitabine hydrochloride, gold au 198, azacytidine, dihydrotaxol. 9-dioxamycin, diphenyl spiro hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofos mustine, docosanol, dolasetron, doxifluridine, droloxifene, ine, interferon alfa-2a, interferon alfa-2b, interferon alfa-N1, dronabinol, duocannycin SA, ebselen, ecomustine, edelfos interferon alfa-N3, interferon beta-la, interferon gamma-Ib, ine, edrecolomab, eflomithine, elemene, emitefur, epirubicin, iproplatin, irinotecan hydrochloride, lanreotide acetate, letro 50 epristeride, estramustine analogue, estrogen agonists, estro Zole, leuprolide acetate, liarozole hydrochloride, lometrexol gen antagonists, etanidazole, etoposide phosphate, exemes Sodium, lomustine, losoxantrone hydrochloride, masoprocol, tane, fadrozole, faZarabine, fenretinide, filgrastim, finas maytansine, mechlorethamine hydrochloride, megestrol teride, flavopiridol, flezelastine, fluasterone, fludarabine, acetate, melengestrol acetate, melphalan, menogaril, mercap fluorodaunorunicin hydrochloride, forfenimex, formestane, topurine, methotrexate, methotrexate Sodium, metoprine, 55 fostriecin, fotemustine, gadolinium texaphyrin, gallium meturedepa, mitindomide, mitocarcin, mitocromin, mitogil nitrate, galocitabine, ganirelix, gelatinase inhibitors, gemcit lin, mitomalcin, mitomycin, mitosper, mitotane, mitox abine, glutathione inhibitors, hepsulfam, heregulin, hexam antrone hydrochloride, mycophenolic acid, nocodazole, ethylene bisacetamide, hypericin, ibandronic acid, idarubi nogalamycin, Ormaplatin, oxiSuran, paclitaxel, pegaspargase, cin, idoxifene, idramantone, ilmofosine, illomastat, peliomycin, pentamustine, peplomycin Sulfate, perfosfa 60 imidazoacridones, imiquimod, immunostimulant peptides, mide, pipobroman, piposulfan, piroXantrone hydrochloride, insulin-like growth factor-1 receptor inhibitor, interferon plicamycin, plomestane, porfimer Sodium, porfiromycin, agonists, interferons, interleukins, iobenguane, iododoxoru prednimustine, procarbazine hydrochloride, puromycin, bicin, ipomeanol, 4-irinotecan, iroplact, irsogladine, isoben puromycin hydrochloride, pyrazofurin, riboprine, rogletim gazole, isohomohalicondrin B, itasetron, jasplakinolide, ide, safmgol, Safingol hydrochloride, Semustine, simtraZene, 65 kahalalide F, lamellarin-N triacetate, lanreotide, leinamycin, sparfosate Sodium, sparsomycin, spirogermanium hydro lenograstim, lentinan Sulfate, leptolstatin, letrozole, leukemia chloride, Spiromustine, spiroplatin, streptonigrin, StreptoZo inhibiting factor, leukocyte alpha interferon, leuprolide--es US 8,232,265 B2 127 128 trogen-progesterone, leuprorelin, levamisole, liarozole, lin phostins, UBC inhibitors, ubenimex, urogenital sinus-de ear polyamine analogue, lipophilic disaccharide peptide, rived growth inhibitory factor, urokinase receptor lipophilic platinum compounds, lissoclinamide 7, lobaplatin, antagonists, vapreotide, variolin B. vector system, erythro lombricine, lometrexol, lonidamine, losoxantrone, lovasta cyte gene therapy, Velaresol, Veramine, Verdins, verteporfin, tin, loxoribine, lurtotecan, lutetium texaphyrin, lysofylline, Vinorelbine, Vinxaltine, vitaxin, Vorozole, Zanoterone, Zeni lytic peptides, maitansine, mannostatin A, marimastat, maso platin, Zilascorb, Zinostatin stimalamer. procol, maspin, matrilysin inhibitors, matrix metalloprotein Anti-cancer Supplementary potentiating agents: tricyclic ase inhibitors, menogaril, merbarone, meterelin, methioni anti-depressant drugs (e.g., imipramine, desipramine, amit nase, metoclopramide, MIF inhibitor, mifepristone, ryptyline, clomiprainine, trimipramine, doxepin, nortrip miltefosine, mirimostim, mismatched double stranded RNA, 10 tyline, protriptyline, amoxapine and maprotiline), non-tricy mitoguaZone, mitolactol, mitomycin analogues, mitonafide, clic anti-depressant drugs (e.g., Sertraline, traZodone and mitotoxin fibroblast growth factor-Saporin, mitoxantrone, citalopram), Ca" antagonists (e.g., Verapamil, nifedipine, mofarotene, molgramostim, monoclonal antibody, human nitrendipine and caroverine), calmodulin inhibitors (e.g., pre chorionic gonadotrophin, monophosphoryllipid A+myobac nylamine, trifluoroperazine and clomipramine), amphoteri terium cell wall sk, mopidamol, multiple drug resistance 15 cin B, triparanol analogues (e.g., tamoxifen), antiarrhythmic genie inhibitor, multiple tumor Suppressor 1-based therapy, drugs (e.g., quinidine), antihypertensive drugs (e.g., reser mustard anticancer agent, mycaperoxide B, mycobacterial pine), thiol depleters (e.g., buthionine and Sulfoximine) and cell wall extract, myriaporone, N-acetyldinaline, N-substi Multiple Drug Resistance reducing agents such as Crema tuted benzamides, nafarelin, nagrestip, naloxone +pentazo phor EL. cine, napavin, naphterpin, nartograstim, nedaplatin, memoru Antineutropenic: filgrastim, lenograstim, molgramoStim, bicin, neridronic acid, neutral endopeptidase, nilutamide, regramos tim, Sargramostim. nisamycin, nitric oxide modulators, nitroxide antioxidant, Antiobsessional agent: fluvoxamine maleate. nitrullyn, O6-benzylguanine, octreotide, okicenone, oligo Antiparasitic: abamectin, clorSulon, ivermectin. nucleotides, onapristone, ondansetron, ondansetron, oracin, Antiparkinsonian: benztropine mesylate, biperiden, oral cytokine inducer, ormaplatin, osaterone, oxaliplatin, 25 biperiden hydrochloride, biperiden lactate, carmantadine, oxaunomycin, paclitaxel analogues, paclitaxel derivatives, ciladopa hydrochloride, dopamantine, ethopropazine hydro palauamine, palmitoylrhizoxin, pamidronic acid, panax chloride, lazabemide, levodopa, lometraline hydrochloride, ytriol, panomifene, parabactin, paZelliptine, pegaspargase, mofegiline hydrochloride, naxagolide hydrochloride, parep peldesine, pentosan polysulfate sodium, pentostatin, pentro tide Sulfate, procyclidine hydrochloride, quinetorane hydro Zole, perflubron, perfosfamide, perillyl alcohol, phenazino 30 chloride, ropinirole hydrochloride, selegiline hydrochloride, mycin, phenylacetate, phosphatase inhibitors, picibanil, pilo tolcapone, trihexyphenidyl hydrochloride. antiperistaltic: carpine hydrochloride, pirarubicin, piritrexim, placetin A, difenoximide hydrochloride, difenoxin, diphenoxylate placetin B, plasminogen activator inhibitor, platinum com hydrochloride, fluperamide, lidamidine hydrochloride, lop plex, platinum compounds, platinum-triamine complex, por eramide hydrochloride, malethamer, nufenoXole, paregoric. fimer Sodium, porfiromycin, propyl bis-acridone, prostaglan 35 Antipneumocystic: atovaquone. din J2, proteasome inhibitors, protein A-based immune Antiproliferative agent: piritreximisethionate. modulator, protein kinase Cinhibitor, protein kinase Cinhibi Antiprostatic hypertrophy: sitogluside. tors, microalgal, protein tyrosine phosphatase inhibitors, Antiprotozoal: amodiaquine, azanidazole, bamnidazole, purine nucleoside phosphorylase inhibitors, purpurins, pyra carnidazole, chlortetracycline bisulfate, chlortetracycline Zoloacridine, pyridoxylated hemoglobin polyoxyethylene 40 hydrochloride, flubendazole, flunidazole, halofuginone conjugate, rafantagonists, raltitrexed, ramosetron, ras fame hydrobromide, imidocarb hydrochloride, ipronidazole, met syl protein transferase inhibitors, ras inhibitors, ras-GAP ronidazole, misonidazole, moXnidazole, nitarSone, partricin, inhibitor, retelliptine demethylated, rhenium Re 186 etidr puromycin, puromycin hydrochloride, ronidazole, Sulnida onate, rhizoxin, ribozymes, RII retinamide, rogletimide, rohi Zole, tinidazole. tukine, romurtide, roquinimex, rubiginone B1, ruboxyl, saf 45 Antipruritic: cyproheptadine hydrochloride, methdilazine, ingol, Saintopin, SarCNU, sarcophytol A, SargramoStim, Sdi methdilazine hydrochloride, trimeprazine tartrate. 1 mimetics, semustine, Senescence derived inhibitor 1, sense Antipsoriatic: acitretin, anthralin, azaribine, calcipotriene, oligonucleotides, signal transduction inhibitors, signal trans cycloheximide, enaZadrem phosphate, etretinate, liaroZole duction modulators, single chain antigen binding protein, fumarate, lonapalene, tepoxalin. sizofiran, Sobuzoxane, Sodium borocaptate, sodium pheny 50 Antipsychotic: acetophenazine maleate, alentemol hydro lacetate, Solverol. Somatomedin binding protein, Sonermin, bromide, alpertine, azaperone, batelapine maleate, benperi sparfosic acid, Spicamycin D, Spiromustine, splenopentin, dol, benzindopyrine hydrochloride, brofbxine, bromperidol, spongistatin 1, squalamine, stem cell inhibitor, stem-cell divi bromperidol decanoate, butaclamol hydrochloride, butapera sion inhibitors, stipiamide, Stromelysin inhibitors, sulfi Zine, butaperazine maleate, carphenazine maleate, carvotro nosine, Superactive vasoactive intestinal peptide antagonist, 55 line hydrochloride, chlorpromazine, chlorpromazine hydro Suradista, Suramin, Swainsonine, synthetic glycosaminogly chloride, chlorprothixene, cinperene, cintriamide, clomacran cans, tallimustine, tamoxifen methiodide, tauromustine, taZ phosphate, clopenthixol, clopimozide, clopipazan mesylate, arotene, tecogalan Sodium, tegafur, tellurapyrylium, telom cloroperone hydrochloride, clothiapine, clothixamide male erase inhibitors, temoporfin, temozolomide, teniposide, ate, clozapine, cyclophenazine hydrochloride, droperidol. tetrachlorodecaoxide, tetrazomine, thaliblastine, thalido 60 etazolate hydrochloride, fenimide, flucindole, flumezapine, mide, thiocoraline, thrombopoietin, thrombopoietin mimetic, fluphenazine decanoate, fluiphenazine enanthate, fluphena thymalfasin, thymopoietin receptor agonist, thymotrinan, Zine hydrochloride, fluspiperone, fluspirilene, flutroline, gev thyroid stimulating hormone, tin ethyl etiopurpurin, tira otroline hydrochloride, halopemide, haloperidol, haloperidol paZamine, titanocene dichloride, topotecan, top sentin, decanoate, illoperidone, imidoline hydrochloride, lenperone, toremifene, totipotent stem cell factor, translation inhibitors, 65 maZapertine Succinate, mesoridazine, mesoridazine besylate, tretinoin, triacetyluridine, triciribine, trimetrexate, triptore metiapine, milemperone, millipertine, molindone hydrochlo lin, tropisetron, turosteride, tyrosine kinase inhibitors, tyr ride, naranol hydrochloride, neflumozidehydrochloride, oca US 8,232,265 B2 129 130 peridone, olanzapine, oxiperomide, penfluridol, pentiapine hydrochloride, reproterol hydrochloride, rimiterol hydrobro maleate, perphenazine, pimozide, pinoxepin hydrochloride, mide, Salmeterol, Salmeterol Xinafoate, Soterenol hydrochlo pipamperone, piperacetazine, pipotiazine palniitate, piquin ride, sulfonterol hydrochloride, Suloxifen oxalate, terbutaline done hydrochloride, prochlorperazine edisylate, prochlor Sulfate, theophylline, Xanoxate Sodium, Zindotrine, Zinterol perazine maleate, promazine hydrochloride, remoxipride, hydrochloride. remoxipride hydrochloride, rimcazole hydrochloride, seperi Carbonic anhydrase inhibitor: acetazolamide, acetazola dol hydrochloride, sertindole, Setoperone, spiperone, thior mide sodium, dichlorphenamide, dorzolamide hydrochlo idazine, thioridazine hydrochloride, thiothixene, thiothixene ride, methazolamide, seZolamide hydrochloride. hydrochloride, tioperidone hydrochloride, tiospirone hydro Cardiac depressant: acecainide hydrochloride, acetylcho chloride, trifluoperazine hydrochloride, trifluperidol, triflu 10 line chloride, actisomide, adenosine, amiodarone, aprindine, promazine, triflupromazine hydrochloride, Ziprasidone aprindine hydrochloride, artilide fumarate, azimilide Dihy hydrochloride. drochloride, bidisomide, bucainide maleate, bucromarone, Antirheumatic: auranofin, aurothioglucose, bindarit, butoprozine hydrochloride, capobenate Sodium, capobenic lobenzarit Sodium, phenylbutaZone, piraZolac, prinomide acid, cifenline, cifenline Succinate, clofilium phosphate, dis tromethamine, Seprilose. 15 obutamide, disopyramide, disopyramide phosphate, dolfetil Antischistosomal: becanthone hydrochloride, hycanthone, ide, drobuline, edifolone acetate, emilium tosylate, encainide lucanthone hydrochloride, niridazole, oxamniquine, pararo hydrochloride, flecainide acetate, ibutilide fuimarate, saniline pamoate, teroxalene hydrochloride. indecainide hydrochloride, ipazilide fumarate, lorajmine Antiseborrheic: chloroxine, piroctone, piroctone olamine, hydrochloride, lorcainide hydrochloride, meobentine sulfate, resorcinol monoacetate. antisecretory: arbaprostil, deprostil, mexiletine hydrochloride, modecainide, moricizine, oxira fenoctimine Sulfate, octreotide, octreotide acetate, omepra mide, pirmenol hydrochloride, pirolazamide, pranolium Zole Sodium, rioprostil, trimoprostil. chloride, procainamide hydrochloride, propafenone hydro Antispasmodic: Stilonium iodide, tizanidine hydrochlo chloride, pyrinoline, quindonium bromide, quinidine glucon ride. ate, quinidine Sulfate, recainam hydrochloride, recainam Antithrombotic: anagrelide hydrochloride, bivalirudin, 25 tosylate, risotilide hydrochloride, ropitoin hydrochloride, dalteparin Sodium, danaparoid sodium, daZOXiben hydro sematilide hydrochloride, Suricainide maleate, tocainide, chloride, efegatran Sulfate, enoxaparin Sodium, ifetroban, tocainide hydrochloride, transcainide. ifetroban Sodium, tinzaparin sodium, trifenagrel. Cardioprotectant: dexraZOxane, draflazine. Antitussive: benzonatate, butamirate citrate, chlophedi Cardiotonic: actodigin, amrinone, bemoradan, butopam anol hydrochloride, codeine polistirex, codoxime, dex 30 ine, carbaZeran, carsatirin Succinate, deslanoside, digitalis, tromethorphan, dextromethorphan hydrobromide, dex digitoxin, digoxin, dobutamine, dobutamine hydrochloride, tromethorphan polistirex, ethyl dibunate, guaiapate, dobutamine lactobionate, dobutamine tartrate, enoXimone, hydrocodone bitartrate, hydrocodone polistirex, levopro imaZodan hydrochloride, indolidan, isomazole hydrochlo poxyphene napsylate, noscapine, pemerid nitrate, ride, levdobutamine lactobionate, lixazinone Sulfate, pipazethate, SuXemerid Sulfate. 35 medorinone, milrinone, pelrinone hydrochloride, pimoben Anti-ulcerative: aceglutamide aluminum, cadexomer dan, piroXimone, prinoXodan, proscillaridin, quaZinone, iodine, cetraxate hydrochloride, enisoprost, isotiquimide, tazolol hydrochloride, Vesnarinone. lansoprazole, lavoltidine Succinate, misoprostol, nizatidine, Cardiovascular agent: dopexamine, dopexamine hydro nolinium bromide, pantoprazole, pifarnine, pirenzepine chloride. hydrochloride, rabeprazole sodium, remiprostol, roXatidine 40 Choleretic: dehydrocholic acid, fencibutirol, hymec acetate hydrochloride, Sucralfate. Sucrosofate potassium, romone, piprozolin, sincalide, tocamphyl. tolimidone. Cholinergic: aceclidine, bethanechol chloride, carbachol, Anti-urolithic: cysteamine, cysteamine hydrochloride, demecarium bromide, dexpanthenol, echothiophate iodide, tricitrates. isoflurophate, methacholine chloride, neostigmine bromide, Appetite Suppressant: dexfenfluramine hydrochloride, 45 neostigmine methylsulfate, physostigmine, physostigmine phendimetrazine tartrate, phentermine hydrochloride. salicylate, physostigmine Sulfate, pilocarpine, pilocarpine Benign prostatic hyperplasia therapy agent: tamsulosin hydrochloride, pilocarpine nitrate, pyridostigmine bromide. hydrochloride. Cholinergic agonist: Xanomeline, Xanomeline tartrate. Blood glucose regulators: human insulin, glucagon, tolaza Cholinesterase deactivator obidoxime chloride, prali mide, tolbutamide, chloropropamide, acetohexamide and 50 doXime chloride, pralidoxime iodide, pralidoxime mesylate. glipizide. Coccidiostat: arprinocid, narasin, semduramicin, semdu Bone resorption inhibitor: alendronate sodium, etidronate ramicin Sodium. disodium, pamidronate disodium. Dognition adjuvant: ergoloid mesylates, piracetam, Bronchodilator: albuterol, albuterol sulfate, azanator male pramiracetam hydrochloride, pramiracetam Sulfate, tacrine ate, bamifylline hydrochloride, bitolterol mesylate, butap 55 hydrochloride. rost, carbuterol hydrochloride, clorprenaline hydrochloride, Cognition enhancer: besipirdine hydrochloride, linopird colterol mesylate, doxaprost, doxofylline, dyphylline, ine, Sibopirdine. enprofylline, ephedrine, ephedrine hydrochloride, fenoterol, Depressant: omeprazole. fenprinast hydrochloride, guaithylline, hexoprenaline Sul Diagnostic aid: aminohippurate sodium, anazolene fate, hoquizil hydrochloride, ipratropium bromide, isoet 60 Sodium, arclofenin, arginine, bentiromide, benzylpenicilloyl harine, isoetharine hydrochloride, isoetharine mesylate, iso polylysine, butedronate tetrasodium, butilfenin, coccidioidin, proterenol hydrochloride, isoproterenol Sulfate, corticorelin ovine triflutate, corticotropin, repository, corti metaproterenol polistirex, metaproterenol Sulfate, nisbuterol cotropin Zinc hydroxide, diatrizoate meglumine, diatrizoate mesylate, oxtriphylline, picumeterol fumarate, piquizil Sodium, diatrizoic acid, diphtheria toxin for Schick test, dis hydrochloride, pirbuterol acetate, pirbuterol hydrochloride, 65 ofenin, edrophonium chloride, ethiodized oil, etifenin, exam procaterol hydrochloride, pseudoephedrine Sulfate, quaZod etazime, ferristenc, ferumoxides, ferumoXsil, fluorescein, ine, quinterenol Sulfate, racepinephrine, racepinephrine fluorescein Sodium, gadobenate dimeglumine, gadoteridol. US 8,232,265 B2 131 132 gadodiamide, gadopentetate dimeglumine, gadoversetamide, Valerate, medrysone, methylprednisolone, methylpredniso histoplasmin, impromidine hydrochloride, indigotindisul lone acetate, methylprednisoloime Sodium phosphate, meth fonate sodium, indocyanine green, lobenguane sulfate I'', ylprednisolone sodium Succinate, nivaZol, paramethasone iobenzamic acid, iocarmate meglumine, locarmic acid, ioc acetate, prednicarbate, prednisolone, prednisolone acetate, etamic acid, iodamide, lodamide megiumine, iodipamide prednisolone hemisuccinate, prednisolone sodium phos meglumine, iodixanol, iodoxamate meglumine, iodoxamic phate, prednisolone sodium Succinate, prednisolone tebutate, acid, ioglicic acid, ioglucol, ioglucomide, ioglycamic acid, prednisone, prednival, ticabesone propionate, tralonide, tri iogulamide, lohexol, iomeprol, iopamidol, iopanoic acid, amcinolone, triamcinolone acetonide, triamcinolone iopentol, iophendylate, iprofenin, iopronic acid, ioprocemic acetonide Sodium, triamcinolone diacetate, triamcinolone acid, iopydol, iopydone, iosefamic acid, io.seric acid, ioSula 10 hexacetonide. mide meglumine, ioSumetic acid, iotasul, iotetric acid, Gonad-stimulating principle: buserelin acetate, clomi iothalamate meglumine, iothalamate sodium, iothalamic phene citrate, ganirelix acetate, gonadorelin acetate, gona acid, iotrolan, iotroxic acid, ioVersol, ioxaglate meglumine, dorelin hydrochloride, gonadotropin, chorionic, menotro ioxagiate Sodium, ioxaglic acid, ioxilan, ioxotrizoic acid, ipo pins. date calcium, ipodate sodium, isosulfan blue, leukocyte typ 15 ing serum, lidofenin, mebrofenin, meglumine, metrizamide, Hair growth stimulant: minoxidil. metrizoate Sodium, metyrapone, metyrapone tartrate, mumps Hemostatic: aminocaproic acid, OXamarin hydrochloride, skin test antigen, pentetic acid, propyliodone, quinaldine Sulmarin, thrombin, tranexarnic acid. blue, sermorelin acetate, sodium iodide I'', sprodiamide, Histamine H2 receptor antagonists: ranitidine (ZAN Stannous pyrophosphate, Stannous Sulfur colloid, Succimer, TACTM), famotidine (PEPCIDTM), cimetidine (TAGAMETM), teriparatide acetate, tetrofosmin, tolbutamide Sodium, tuber nizatidine (AXIDTM). culin, tyropanoate Sodium, Xylose. Hormone: diethylstilbestrol, progesterone, 17 hydroxy Diuretic: ambuphylline, ambuside, amiloride hydrochlo progesterone, medroxyprogesterone, norgestrel, norethyno ride, azolimine, azosemide, brocrinat, bumetanide, chlorothi drel, estradiol, megestrol (megace), norethindrone, levonorg azide, chlorthalidone, clazolimine, clorexolone, ethacrynate 25 estrel, ethyndiol, ethinyl estradiol, mestranol, estrone, equi Sodium, ethacrynic acid, etoZolin, fenduizone, furosemide, lin, 17 alpha dihydroequilin, equilenin, 17 alpha hydrochlorothiazide, isosorbide, mannitol, mefruside, oZoli dihydroequilenin, 17 alpha estradiol, 17 beta estradiol, leu none, piretanide, spiroXasone, torsemide, triamterene, triflo prolide (LUPRONTM), glucagon, testolactone, clomiphene, cin, urea. human menopausal gonadotropins, human chorionic gona Dopaminergic agent: ibopamine. 30 dotropin, urofollitropin, bromocriptine, gonadorelin, lutein Ectoparasiticide: nifluridide, permethrin. izing hormone releasing hormone and analogs, gonadotro Emetic: apomorphine hydrochloride. pins, danazol, testosterone, dehydroepiandrosterone, Enzyme inhibitor: acetohydroxamic acid, alrestatin androstenedione, dihydroestosterone, relaxin, oxytocin, Sodium, aprotinin, benazepril hydrochloride, benazeprilat, vasopressin, folliculostatin, follicle regulatory protein, gona benurestat, bromocriptine, bromocriptine mesylate, cilastatin 35 doctrinins, oocyte maturation inhibitor, insulin growth factor, Sodium, flurofamide, lergotrile, lergotrile mesylate, levcy follicle stimulating hormone, luteinizing hormone, tamox closerine, libenzapril, pentopril, pepstatin, perindopril, polig ifen, corticorelinovine triftutate, coSyntropin, metogest, pitu nate Sodium, Sodium amylosulfate, Sorbinil, spirapril hydro itary, posterior, seractide acetate, Somalapor, somatrem, chloride, spiraprilat, taleranol, teprotide, tolfamide, Somatropin, somenopor, somidobove. Zofenopril calcium. 40 Hypocholesterolemic: lifibrol. Estrogen: chlorotrianisene, dienestrol, diethylstilbestrol, Hypoglycemic: darglitaZone sodium: glimepiride. diethylstilbestrol diphosphate, equilin, estradiol, estradiol Hypolipidemic: azalanstat dihydrochloride, colestolone, cypionate, estradiolenanthate, estradiol undecylate, estradiol Surfomer, Xenalipin. Valerate, estraZinol hydrobromide, estriol, estrofurate, estro Hypotensive: viprostol. gens, conjugated, estrogens, esterified, estrone, estropipate, 45 Hmgcoa reductase inhibitors: lovastatin (MEVACORTM), ethinyl estradiol, fenestrel, mestranol, nylestriol, quinestrol. simvastatin (ZOCORTM), pravastatin (PRAVACHOLTM), flu Fibrinolytic: anistreplase, bisobrin lactate, brinolase. vasatin (LESCOLTM). Free oxygen radical scavenger: pegorgotein. Immunizing agent: antirabies serum, antivenin (latrodec Gastrointestinal motility agents: cisapride (PROPUL tus mactans), antivenin (micrurus fulvius), antivenin (crotal SIDTM), metoclopramide (REGLANTM), hyoscyamine 50 idae) polyvalent, BCG vaccine, botulism antitoxin, cholera (LEVSINTM). vaccine, diphtheria antitoxin, diphtheria toxoid, diphtheria Glucocorticoid: amcinonide, beclomethasone dipropi toxoid adsorbed, globulin, immune, hepatitis b immune onate, betamethasone, betamethasone acetate, betametha globulin, hepatitis B virus vaccine inactivated, influenza virus Sone benzoate, betamethasone dipropionate, betamethasone vaccine, measles virus vaccine live, meningococcal polysac Sodium phosphate, betamethasone Valerate, carbenoXolone 55 charide vaccine group A, meningococcal polysaccharide vac Sodium, clocortolone acetate, clocortolone pivalate, clopred cine group C, mumps virus vaccine live, pertussis immune nol, corticotropin, corticotropin, repository, corticotropin globulin, pertussis vaccine, pertussis vaccine adsorbed, Zinc hydroxide, cortisone acetate, cortivaZol, descinolone plague vaccine, poliovirus vaccine inactivated, poliovirus acetonide, dexamethasone, dexamethasone sodium phos vaccine live oral, rabies immune globulin, rabies vaccine, Rh phate, diflucortolone, diflucortolone pivalate, flucloronide, 60 (D) immune globulin, rubella virus vaccine live, Smallpox flumethasone, flumethasone pivalate, flunisolide, fluocino vaccine, tetanus antitoxin, tetanus immune globulin, tetanus lone acetonide, fluocinonide, fluocortolone, fluocortolone toxoid, tetanus toxoid adsorbed, typhoid vaccine, yellow caproate, fluorometholone, fluperolone acetate, flupredniso fever vaccine, Vaccinia immune globulin, varicella-Zoster lone, fluprednisolone Valerate, flurandrenolide, formocortal, immune globulin. hydrocortisone, hydrocortisone acetate, hydrocortisone 65 Immunomodulator: dimepranol acedoben, imiquimod, buteprate, hydrocortisone butyrate, hydrocortisone sodium interferon beta-Ib, lisofylline, mycophenolate mofetil, preza phosphate, hydrocortisone sodium Succinate, hydrocortisone tide copper acetate. US 8,232,265 B2 133 134 Immunoregulator: azarole, fanetizole mesylate, frentizole, Prostaglandin: cloprostenol sodium, fluprostenol Sodium, oxamisole hydrochloride, ristianol phosphate, thymopentin, gemeprost, prostalene, Sulprostone. tilomisole. Prostate growth inhibitor: pentomone. Immunostimulant: loxoribine, teceleukin. Prothyrotropin: protirelin. Immunosuppressant: azathioprine, azathioprine Sodium, Psychotropic: minaprine. cyclosporine, daltroban, gusperimus trihydrochloride, siroli Pulmonary surface: beractant, colfosceril palmitate. mus, tacrolimus. Radioactive agent: fibrinogen I'', fludeoxyglucose F. Impotence therapy adjunct: deleduanine hydrochloride. fluorodopa F, insulin I'', insulin I'', iobenguane I'', Inhibitor: acarbose, atorvastatin calcium, benserazide, bro iodipamide sodium I'', iodoantipyrine I'', iodocholesterol cresine, carbidopa, clavulanate potassium, daZmegrel, doce 10 I'', iodohippurate sodium I', iodohippurate sodium I'', benone, epoprostenol, epoprostenol sodium, epristeride, fin iodohippurate sodium I'', iodopyracet I'', iodopyracet asteride, flurbiprofen sodium, furegrelate sodium, lufironil, I'', iofetamine hydrochloride I'', iomethin I'', iomethin miglitol, orlistat, pimagedine hydrochloride, pirmagrel, I'', iothalamate sodium I'', iothalamate sodium I'', ioty ponalrestat, ridogrel, Sulbactam benzathine, Sulbactampiv rosine I'', liothyronine I'', liothyronine I'', merisoprol oxil, Sulbactam Sodium, Suronacrine maleate, taZobactam, 15 acetate Hg', merisoprolacetate Hg', merisoprol Hg', taZobactam Sodium, ticlopidine hydrochloride, tirilazad selenomethionine Se7, technetium Tc’"antimony trisulfide mesylate, tolrestat, Velnacrine maleate, Zifrosilone, Zileuton. colloid, technetium Tc’"bicisate, technetium Tc'" disofe Keratolytic: alcloxa, aldioxa, benzoyl peroxide, diben nin, technetium Tc" etidronate, technetium Tc" exameta Zothiophene, etarotene, isotretinoin, motretinide, picotrin Zime, technetium Tc’" furifosmin, technetium Tc’" glu diolanine, resorcinol, resorcinol monoacetate, salicylic acid, ceptate, technetium Tc" lidofenin, technetium Tc’" Sumarotene, tazarotene, tetroquinone, tretinoin. mebrofenin, technetium Tc’" medronate, technetium Tc'" LHRL agonist: deslorelin, goserelin, histrelin, lutrelin medronate disodium, technetium Tc" mertiatide, techne acetate, nafarelin acetate. tium Tc" oxidronate, technetium Tc’” pentetate, techne Liver disorder treatment: malotilate. tium Tc"99. pentetate calcium trisodium, technetium Tc'" Luteolysin: fenprostalene. 25 sestamibi, technetium Tc'" siboroxime, technetium Tc 99. Memory adjuvant: dimoxamine hydrochloride, ribaminol. succimer, technetium Tc'" sulfur colloid, technetium Tc'" Mental performance enhancer: aniracetam. teboroxime, technetium Tc" tetrofosmin, technetium Mood regulator: fengabine. Tc'"tiatide, thyroxine I'', thyroxine I'', tolpovidone I'', Mucolytic: acetylcysteine, carbocysteine, domiodol. triolein I'', triolein I''. Mucosal protective agents: misoprostol (CYTOTECTM). 30 Regulator: calcifediol, calcitonin, calcitriol, clodronic Mydriatic: berefrine. acid, dihydrotachysterol, etidronic acid, oxidronic acid, piri Nasal decongestant: nemazoline hydrochloride, pseu dronate sodium, risedronate sodium, secalciferol. doephedrine polistirex. Relaxant: adiphenine hydrochloride, alcuronium chloride, Neuroleptic: duoperone fumarate, risperidone. aminophylline, azumolene sodium, baclofen, benzoctamine Neuromuscular blocking agent: atracurium besylate, cisa 35 hydrochloride, carisoprodol, chlorphenesin carbamate, chlo tracurium besylate, doxacurium chloride, gallamine triethio rZoxazone, cinflumide, cinnamedrine, clodanolene, dide, metocurine iodide, mivacurium chloride, pancuronium cyclobenzaprine hydrochloride, dantrolene, dantrolene bromide, pipecuronium bromide, rocuronium bromide, suc sodium, femalamide, fenyripol hydrochloride, fetoxylate cinylcholine chloride, tubocurarine chloride, vecuronium hydrochloride, flavoxate hydrochloride, fletazepam, flume bromide. 40 tramide.-flurazepam hydrochloride, hexafluorenium bro Neuroprotective: dizocilpine maleate. mide, isomylamine hydrochloride, lorbamate, mebeverine NMDA antagonist: selfotel. hydrochloride, meSuprine hydrochloride, metaxalone, Non-hormonal sterol derivative: pregnenolone succinate. methocarbamol, methixene hydrochloride, nafomine malate, Oxytocic: carboprost, carboprost methyl, carboprost neleZaprine maleate, papaverine hydrochloride, pipoxolan. tromethamine, dinoprost, dinoprost tromethamine, dinopro 45 Hydrochloride, quinctolate, ritodrine, ritodrine hydrochlo stone, ergonovine maleate, meteneprost, methylergonovine ride, rolodine, theophylline sodium glycinate, thiphenamil maleate, oxytocin, Sparteine Sulfate. hydrochloride, xilobam. Plasminogen activator: alteplase, urokinase. Repartitioning agent: cimaterol. Platelet activating factor antagonist: lexipafant. Scabicide: amitraz, crotamiton. Platelet aggregation inhibitor: acadesine, beraprost, bera 50 Sclerosing agent: ethanolamine oleate, morrhuate Sodium, prost sodium, ciprostene calcium, itaZigrel, lifarizine, tribenoside. OXagrelate. Sedative: propiomazine. Post-stroke and post-head trauma treatment: citicoline Sedative-hypnotic: allobarbital, alonimid, alprazolam, Sodium. amobarbital sodium, bentazepam, brotizolam, butabarbital, Potentiator: pentostatin, talopram hydrochloride. 55 butabarbital sodium, butalbital, capuride, carbocloral, chloral Progestin: algestone acetophenide, amadinone acetate, betaine, chloral hydrate, chlordiazepoxide hydrochloride, anagestone acetate, chlormadinone acetate, cingestol, cloge cloperidone hydrochloride, clorethate, cyprazepam, dex stone acetate, clomegestone acetate, desogestrel, dimethister clamol hydrochloride, diazepam, dichloralphenaZone, esta one, dydrogesterone, ethynerone, ethynodiol diacetate, Zolam, ethchlorVynol, etomidate, fenobam, flunitrazepam, etonogestrel, flurogestone acetate, gestaclone, gestodene, 60 fosazepam, glutethimide, halazepam, lormetazepam, meclo gestonorone caproate, gestrinone, haloprogesterone, hydrox qualone, meprobamate, methaqualone, midaflur, paralde yprogesterone caproate, levonorgestrel, lynestrenol, hyde, pentobarbital, pentobarbital sodium, perlapine, medrogestone, medroxyprogesterone acetate, methynodiol prazepam, quazepam, reclazepam, roletamide, secobarbital, diacetate, norethindrone, norethindrone acetate, norethyno secobarbital Sodium, Suproclone, thalidomide, tracazolate, drel, norgestimate, norgestomet, norgestrel, oxogestone 65 trepipam maleate, triazolam, tricetamide, triclofos Sodium, phenpropionate, progesterone, quingestanol acetate, trimetozine, uldazepam, Zaleplon, Zolazepam hydrochloride, quingestrone, tigestol. Zolpidem tartrate. US 8,232,265 B2 135 136 Selective adenosine alantagonist: apaxifylline. 22-oxacalcitriol, 20VV, 3-isobutyl GABA, 6-FUDCA, Serotonin antagonist: altanserin tartrate, ameSergide, ket 7-methoxytacrine, abamectin, abanoquil, abecarnil, abirater anserin, ritanserin. one, acadesine, acamprosate, acarbose, aceclofenac, aceman Serotonin inhibitor: cinanserin hydrochloride, fenclonine, nan, acetomepregenol, acetyl-L-carnitine, acetylcysteine, fonazine mesylate, Xylamidine tosylate. N-acetylmethadol, acifran, acipimoX, acitemate, acitretin, Serotonin receptor antagonist: tropanserin hydrochloride. aclarubicin, aclatonium, napadisilate, aconiazide, acrivasti Steroid: dexamethasone aceflirate, mometasone furoate. net, adafenoxate, adapalene, adatanserin, adecypenol, ade Stimulant: amfonelic acid, amphetamine Sulfate, ampyZine fovir dipivoxil, adelmidrol, ademetionine, adinazolam, adi Sulfate, arbutamine hydrochloride, azabon, caffeine, ceru posin, adoZelesin, adrafinil, alacepril, aladapcin, alaptide, letide, ceruletide diethylamine, cisapride, dazopride fluima 10 albendazole, albolabrin, aldecalmycin, aldesleukin, allen rate, dextroamphetamine, dextroamphetamine Sulfate, dronic acid, alentemol, alfacalcidol, alfuizosin, alglucerase, difluanine hydrochloride, dimefline hydrochloride, dox alinastine, alosetron, alpha idoSone, alprostadil, altretamine, apram hydrochloride, etryptamine acetate, ethamivan, fen altromycin B. ambamustine, amelometaSone, ameSergide, ethylline hydrochloride, flubanilate hydrochloride, flurothyl, amezinium metilsulfate, amfebutamone, amidox, amifloxa histamine phosphate, indriline hydrochloride, mefexamide, 15 cin, amifostine, amiodarone, amisulpride, amlexanoX, amlo methanphetamine hydrochlo ride, methylphenidate hydro dipine, amlodipine, ampiroxicam, aminone, amrubicin, chloride, pemoline, pyrovalerone hydrochloride, Xamoterol, amsacrine, amylin, amythiamicin, anagrelide, anakinra, Xamoterol fumarate. ananain, anaritide, anastroZole, andrographolide, anordrin, Suppressant: amfliutizole, coXchicine, taZofelone. apadoline, apafant, apaxifylline, aphidicolin glycinate, apra Symptomatic multiple Sclerosis: fampiridine. clonidine, aprosulate Sodium, aptiganel, apurinic acid, arani Synergist: proadifen hydrochloride. dipine, arbekacin, arbidol, arbutamine, ardeparin Sodium, Thyroid hormone: levothyroxine sodium, liothyronine arecatannin B1, argatroban, aripiprazol, arotinolol, asimado Sodium, liotrix. line, aspalatone, asperfuran, aspoxicillin, astemizole, asula Thyroid inhibitor: methimazole, propyithiouracil. crine, atamestanie, atenolol, S-atevirdine, atosiban, atova Thyromimetic: thyromedan hydrochloride. 25 quone, atpenin B, atrimustine, atrinositol, aureobasidin A, Tranquilizer: bromazepam, buspirone hydrochloride, azadirachtine, azasetron, azatyrosine, azelaic acid, azelas chlordiazepoxide, claZolam, clobazam, cloraZepate dipotas tine, azelnidipine, azimilide, azithromycin, aZosemide, aztre sium, cloraZepate monopotassium, demoxepam, dexmedeto onam, baccatin III, bacoside A, bacoside B, bactobolamine, midine, enciprazine hydrochloride, gepirone hydrochloride, balaZipone, balhimycin, balofloxacin, balsalazide, bam hydroxyphenamate, hydroxy Zine 30 buterol, baohuoside 1, bamidipine, basifingin, batebulast, Hydrochloride, hydroxy Zine pamoate, ketazolam, batimastat, beauvericin, becaplermin, becliconazole, lorazepam, lorZafone, loxapine, loxapine succinate, befloxatone, belfosdil, bellenamine, benflumetol, benidipine, medazepam hydrochloride, nabilone, nisobamate, benzisoxazole, benzochlorins, benzoidazoxan, benzoylstau oxazepam, pentabamate, piremperone, ripazepam, rolipram, rosporine, benztropine, bepridil, beractant, beraprost, ber Sulazepam, taciamine hydrochloride, temazepam, trifluba 35 lafenone, bertosamil, besipirdine, beta-alethine, betaclamy Zam, tybamate, Valnoctamide. cin B, betamipron, betaxolol, betulinic acid, bevantolol, Amyotrophic lateral Sclerosis agents: riluzole. bicalutamide, bifemelane, bimakalim, bimithil, binospirone, Cerebral ischemia agents: dextrorphan hydrochloride. bioxalomycin alpha2, biriperone, bis-benzimidazole A, bis Paget’s disease agents: tiludronate disodium. benzimidazole B, bisantrene, bisaramil, bisaziridinylsper Unstable angina agents: tirofiban hydrochloride. 40 mine, bisnafide, bisoprolol, bistramide D, bistramide K, bis UricoSuric: benzbromarone, irtemazole, probenecid, tratene A, boldine, bopindolol, brefeldin, breflate, Sulfinpyrazone. brimonidine, bromfenac, bromperidol, bropirimine, bucin Vasoconstrictor: angiotensin amide, fely pressin, methy dolol, budesonide, budlpine, budotitane, bunaprolast, Sergide, methysergide maleate. bunaZosin, butenafine, buthionine Sulfoximine, butiXocort Vasodilator: alprostadil, azaclorzine hydrochloride, bam 45 propionate, cadexomer iodine, calanolide A, calcipotriol, ethan sulfate, bepridil hydrochloride, buterizine, cetiedil cit calphostin C, camonagrel, candesartan, candesartancilexetil, rate, chromonar hydrochloride, clonitrate, diltiazem hydro candoXatril, candoXatrilat, capecitabine, capromab, capsai chloride, dipyridamole, droprenilamine, erythrityl cin, captopril, carbazomycin C, carbetocin, carbovir, car tetranitrate, felodipine, flunarizine hydrochloride, fostedil, boxamide-amino-triazole, carboxyamidotriazole, carboxym hexobendine, inositol niacinate, iproxamine hydrochloride, 50 ethylated B-1,3-glucan, carperitide, carteolol, carumonam, isosorbide dinitrate, isosorbide mononitrate, isoXSuprine carvedilol, carvotroline, carZelesin, castanospermine, hydrochloride, lidoflazine, mefenidil, mefenidil fumarate, cebaracetan, cecropin B, cefcapene pivoxil, cefdaloxime pen mibefradil dihydrochloride, mioflazine hydrochloride, mixi texil tosilate, cefdinir, cefditoren pivoxil, cefepime, cefe dine, nafronyl oxalate, nicardipine hydrochloride, nicer tamet, cefetamet pivoxil, cefixime, cefluprenam, cefinneta goline, nicorandil, nicotinyl alcohol, nifedipine, nimodipine, 55 Zole, cefinninox, cefodizime, cefoselis, cefotetan, cefotiam, nisoldipine, Oxfenicine, oXprenolol hydrochloride, pen cefotiam hexetil, cefoZopran, cefpimizole, ce?piramide, cef taerythritol tetranitrate, pentoxifylline, pentrinitrol, perhexil pirome, cefpodoxime proxetil, cefprozil, cefsulodin, ine maleate, pindolol, pirsidomine, prenylamine, propatyl cefteram, ceftibuten, cefiriaxone, cefuroxime axetil, cellas nitrate, Suloctidil, terodiline hydrochloride, tipropidil hydro trol, celikalim, celiprolol, cepacidine A, cericlamine, ceriv chloride, tolazoline hydrochloride, Xanthinol niacinate. 60 astatin, ceronapril, certoparin Sodium, cetiedil, cetirizine, Vulnerary: allantoin. chloroorienticin A, chloroorienticin B, chloroquinoxaline Wound healing agent: erSofermin. Sulfonamide, cibenzoline, cicaprost, ciclesonide, cicletanine, Xanthine oxidase inhibitor: allopurinol, oxypurinol. cicloprolol, cidofovir, cilansetron, cilaZapril, cilnidipine, Other pharmaceutical agents include: 1-decpyrrolidinone, cilobradine, cilostazol, cimetropium bromide, cinitapride, 1-dodecpyrrolidinone, 16C.-fluoroestradiol, 16-epiestriol, 65 cinolazepam, cioteronel, ciprofibrate, ciprofloxacin, cipros 16C.-gitoxin, 17O estradiol, 17 Bestradiol. 1 alpha-hydroxyvi tene, cis-porphyrin, cisapride, cisatracurium besilate, cistin tamin D2,2'-nor-cGMP, 20-epi-1.25 dihydroxyvitamin D3, exine, citalopram, citicoline, citreamicin alpha, cladribine, US 8,232,265 B2 137 138 clarithromycin, clausenamide, clebopride, clinafloxacin, clo cin, hatomarubigin A, hatomarubigin B, hatomarubigin C, bazam, clobetaSone butyrate, clodronic acid, clomethiazole, hatomarubigin D, ibogaine, ibopamine, ibudilast, illi clopidogrel, clotrimazole, colestimide, colfosceril palmitate, maquinone, ilmofosine, illomastat, illoperidone, iloprost, imi collismycin A, collismycin B, combretastatin A4, complesta dapril, imidazenil, indinavir, indolidan, indometacin farnesil, tin, conagenin, contignasterol, contortrostatin, cosalane, cos indometacin, tropine ester, indoramin, inocoterone, inogat tatolide, cotinine, coumermycin A1, cucumariosid, curacin ran, inolimomab, interferon alfa, interferon alfa-2a, inter A, curdlan sulfate, curiosin, cyclazosin, cyclic HPMPC, feron alfa-2B, interferon alfa-N 1, interferon alfa-N3, inter cyclobenzaprine, cyclobut A, cyclobut G, cyclocapron, cyclo feron B, interferon B-1 A1, interferon B-1B, interferon platam, cyclosin, cyclothialidine, cyclothiazomycin, cype gamma-1A, interferon gamma-1B, interferon omega, inter mycin, cyproterone, cytarabine ocfosfate, cytochalasin B, 10 feron, consensus, interleukin-1, interleukin-1 alpha, interleu dacliximab, dactimicin, daidzein, daidzin, dalfopristin, dalte kin-1 B, interleukin-10, interleukin-11, interleukin-12, inter parin Sodium, danaparoid, daphnodorin A, dapiprazole, dapi leukin-12, interleukin-15, interleukin-2, interleukin-3, tant, darifenacin, darlucin A, darsidomine, ddUTP, decitab interleukin-4, interleukin-5, interleukin-7, interleukin-8, ine, deferiprone, deflazacort, dehydrodidemrnin B, iobenguane, iobitridol, iodoamiloride, iododoxorubicin, iof dehydroepiandrosterone, delapril, deleguamine, delfapra 15 ratol, iomeprol, iopentol, iopromide, iopyrol, iotriside, iover Zine, delmopinol, delphinidin, deoxypyridinoline, depro Sol, ioxilan, ipazilide, IpdR, ipenoxazone, ipidacrine, done, depsidomycin, deramciclane, dermatan Sulfate, desflu ipomeanol, 4-ipriflavone, ipsapirone, irbesartan, irinotecan, rane, desirudin, deslorelin, desmopressin, desogestrel, irloxacin, irsogladine, irtemazole, isalsteine, isbogrel, isepa desoxoamiodarone, detajmium bitartrate, dexifosfamide, micin, isobengaZole, isofloxythepin, isohomohalicondrin B, dexketoprofen, dexloxiglumide, dexmedetomidine, dex isopropyl unoprostone, isradipine, itameline, itasetron, ito pemedolac, dexraZOxane, dexSotalol, dextrin2-Sulphate, dex pride, itraconazole, ketoprofen, R-ketoprofen, S-ketorolac, Verapamil, dezinamide, dezocine, diaziquone, diclofenac lacidipine, lactitol, lactivicin, laennec, lafutidine, lamel digolil, diclofenac potassium, dicranin, didemnin B, didox, rarin-N triacetate, lamifiban, lamivudine, lamotrigine, lano dienogest, diethylhomospermine, diethylnorspermine, dihy conazole, lanperisone, lanreotide, lanSoprazole, latanoprost, drexidine, dihydro-5-azacytidine, dimethyl prostaglandin 25 lateritin, laurocapram, lazabemide, lemefloxacin, lemil A1, dimethylhomospennine, dimiracetam, dioxamycin, dipine, leminoprazole, lenercept, lenograstim, lentinan Sul diphency prone, diphenyl spiromustine, diprafenone, dipro fate, leptin, leptolstatin, lercanidipine, lerisetron, lesopitron, pylnorspermine, dirithromycin, discodermolide, disulfiram, letraZuril, letrozole, leucomyzin, leuprorelin, levcromakalim, ditekiren, docarpamine, docosanol. 1-dofetilide, dolasetron, levetiracetam, levobetaxolol, levobunolol, levobupivacaine, domitroban, dopexamine, dorzolamide, doSmalfate, dotariz 30 levocabastine, levocamitine, levodropropizine, levofloxacin, ine, doxacurium chloride, doxazosin, doxifluridine, doxofyl levomoprolol, levonorgestrel, leVormeloxifene, levosimen line, draculin, draflazine, droloxifene, dronabinol, drosperi dan, levosulpiride, linotroban, linsidomine, lintitript, linto done, drotaverine acephyllinate, droxicam, ebiratide, pride, liothyronine sodium, lirexapride, lisinopril, lobaplatin, ebrotidine, ebselen, ecabapide, ecabet, ecadotril, ecdlisteron, lobucavir, lodoxamide, lombricine, lomefloxacin, lomeriZ echicetin, echistatin, ecomustine, ecteinascidin 722, ectein 35 ine, lometrexol, lonazolac, lonidamine, loracarbef, lorata ascidin 729, ecteinascidin 743, edaravone, edelfosine, edoba dine, lorglumide, lomoxicam, losartan, losigamone, losox comab, edrecolomab, efegatran, eflornithine, efonidipine, antrone, loteprednol, loviride, loxoribine, lubeluzole, egualen, elcatonin, eletriptan, elgodipine, eliprodil, eltenac, lurtotecan, luteinizing hormone, lutetium, luzindole, lydica emakalim, emedastine, emiglitate, emitefur, emoctakin, ena mycin, lysofylline, lysostaphin, magainin2 amide, magnolol. doline hydrochloride, enalapril, enaZadrem, englitaZone, 40 mallotochromene, mallotojaponin, malotilate, mangafodipir, enlimomab, enoxacin, enoxaparin sodium, enoXimone, enta manidipine, maniwamycin A, mannostatin A, manumycin E, capone, enterostatin, epoprostenol, epoxymexrenone, epris manumycin F. mapinastine, marimastat, masoprocol, teride, eprosartan, eptastigmine, erdosteine, ersentilide, erso maspin, massetolide, meterelin, methoxatone, methylhista fermin, erytlritol, esuprone, etanidazole, etanterol, ethacizin, mine, R-alpha, methylinosine monophosphate, methylpred ethinylestradiol, etizolam, etodolac, etoposide phosphate, 45 nisolone aceponate, methylprednisolone Suleptanate, metipa etrabamine, everninomicin, examorelin, exemestane, fadro mide, metoclopramide, metoprolol. S-metrifonate, Zole, faerieflungin, famciclovir, fampiridine, fantofarone, faro mibefradil, michellamine B, microcolin A, midodrine, mife penem, fasidotril, fasudil, faZarabine, fedotozine, felbamate, pristone, miglitol, millacemide, milameline, mildronate, mil fenofibrate, fenoldopam, fenretinide, fenspiride, fenticona nacipran, mihinone, miltefosine, minaprine, miokamycin, Zole, fepradinol, ferpifosate sodium, ferristene, ferrixan, 50 mipragoside, mirfentanil, mirimostim, mirtazapine, miso ferumoxsil, fexofenadine, flavopiridol, flecainide, fle prostol, mitoguaZone, mitolactol, mitonafide, mitoxantrone, robuterol, fleroxacin, flesinoxan, flezelastine, flobufen, flo mivacurium chloride, mivaZerol, mixanpril, mizolastine, moxef, florfenicol, florifenine, flosatidil, fluasterone, flu mizoribine, moclobemide, modafinil, moexipril, mofarotene, conazole, fludarabine, flumazenil, flumecinol, flumequine, mofeZolac, molgramoStim, mometasone, montirelin, mopi flunarizine, fluocalcitriol, fluorodaunorunicin hydrochloride, 55 damol, moracizine, mosapramine, mosapride, motilide, mox fluoxetine, R-fluoxetine, S-fluparoxan, flupirtine, flurbipro iraprine, moxonidine, nadifloxacin, nadroparin calcium, fen axetil, flurithromycin, fluticaSone propionate, flutrima nafadotride, nafamo.stat, nafarelin, naftopidil, naglivan, Zole, fluvastatin, fluvoxamine, forasartan, forfenimex, form nagrestip, nalmefene, naphterpin, napsagatran, naratriptan, estane, formoterol, formoterol, R.R-fosfomycin, trometamol. nartograstim, nasaruplase, nateplase, niperotidine, nirav fosinopril, fosphenytoin, fostriecin, fotemustine, gabapentin, 60 oline, nisamycin, nisin, nisoldipine, nitazoxanide, niteca gadobenic acid, gadobutrol, gadodiamide, gadodiamnide pone, nitrendipine, nitrendipine, S-nitrofurantoin monohy EOB-DTPA, gadolinium texaphyrin, gadoteric acid, gadot drate, nitrullyn, nizatidine, ofloxacin, okicenone, olanzapine, eridol, gadoversetamide, galantamine, galdansetron, gallo olopatadine, olprinone, olSalazine, omeprazole, onapristone, pamil, galocitabine, gamolenic acid, ganirelix, gepirone, ondansetron, ondansetron, R-OntaZolast, oracin, otenZepad, gestrinone, girisopam, glaspimod, glaucocalyxin A, glutapy 65 oxaliplatin, oxamisole, Oxandrolone, Oxaprozin, oxaunomy rone, glycopine, glycopril, granisetron, grepafloxacin, hali cin, oXcarbazepine, oxiconazole, oxiracetam, oxodipine, oza chondrin B, halofantrine, halomon, halopredone, hatomami grel, palauamine, palinavir, palmitoylrhizoxin, pamaqueside, US 8,232,265 B2 139 140 pamicogrel, pamidronic acid, panamesine, panaxytriol, Verapamil, S-Verdins, Veroxan, Verteporfin, Vesnarinone, panipenem, panipenum, pannorin, panomifene, pantethine, Vexibinol, vigabatrin, vinbumine citrate, vinburnine resinate, pantoprazole, parabactin, pamaparin Sodium, paroxetine, Vinconate, Vinorelbine, Vinpocetine, Vinpocetine citrate, Vin parthenolide, paZelliptine, paZufloxacin, pefloxacin, pegas toperol, Vinxaltine, Voriconazole, Vorozole, Voxergolide, pargase, peldesine, pemedolac, pemirolast, penciclovir, pen Xemilofiban, Ximoprofen, yangambin, Zabicipril, Zacopride, tafuside, pentamidine, pentamorphone, pentigetide, pen Zacopride, R-Zafirlukast, Zalcitabine, Zaleplon, Zalospirone, tosan, pentostatin, pentroZole, perflubron, perfosfamide, Zaltoprofen, Zanamivir, Zankiren, Zanoterone, Zatebradine, pergolide, perindoprilat, peroSpirone, phenaridine, phenazi Zatosetron, Zenarestat, Zeniplatin, Zifrosilone, Zilascorb, nomycin, phenserine, phensuccinal, phentolamine mesilate, Zileuton, Zinostatin stimalamer, Ziprasidone, Zoledronic acid, phenylacetate, phenylalanylketoconazole, picenadol, piciba 10 Zolmitriptan, Zolpidem, Zonisamide, Zopiclone, Zopiclone, nil, picroliv, picumeterol, pidotimod, pilocarpine hydrochlo S-Zopolrestat, Zotepine. ride, pilsicainide, pimagedine, pimilprost, pimobendan, pina Specific Examples of Antibacterials cidil, pinocebrin, pioglitaZone, pipecuronium bromide, When antibacterial activity is a desired property of the pirarubicin, piretanide, pirfenidone, piritrexim, pirlindole, disclosed ionic liquids, one or more of the ions in the dis pirmagrel, pirmenol, pirodavir, pirodomast, piroXicam cin 15 closed ionic liquids can be an antibacterial. That is the one or namate, propagermanium, propentofylline, propionylcam more kinds of cations, one or more kinds of anions, or both itine, L-propiram, propiram +paracetamol, propiverine, pro cations and anions can be an antibacterial. Many of Suitable pyl bis-acridone, prostaglandin J2, prostratin, protegrin, antibacterial have already been disclosed herein (e.g., many protoSufloxacin, prulifloxacin, pyrazoloacridine, quazepam, QACs have antibacterial properties). Further examples of quetiapine, quiflapon, quinagolide, quinapril, quinfamide, Suitable antibacterial agents include, but are not limited to, quinupristin, raloxifene, raltitrexed, ramatroban, ramipril, acedapsone, acetosulfone sodium, alamecin, alexidine, amdi ramosetron, ranelic acid, ranitidine bismuth citrate, ranola nocillin, amdinocillin pivoxil, amicycline, amifloxacin, ami Zine, recainam, regavirumab, relaxin, repirinast, resinfera floxacin meSylate, amikacin, amikacin Sulfate, aminosali toxin, reticulon, reviparin sodium, revizinone, ricasetron, cyhc acid, aminosalicylate sodium, amoxicillin, ridogrel, rifabutin, rifapentine, rifaximin, rilopiroX, riluzole, 25 amphomycin, amplicillin, amplicillin Sodium, apalcillin rimantadine, rimexolone, rimoprogin, riodipine, ripisartan, Sodium, apramycin, aspartocin, astromicin Sulfate, avilamy risedronic acid, rispenzepine, risperidone, ritanserin, riti cin, avoparcin, azithromycin, azlocillin, azlocillin Sodium, penem, ritipenemacoxil, ritolukast, ritonavir, rizatriptan ben bacampicillin hydrochloride, bacitracin, bacitracin methyl Zoate, rohitukine, rokitamycin, ropinirole, ropivacaine, ene disalicylate, bacitracin Zinc, bambermycins, benzoylpas roquinimex, roXatidine, roXindole, roXithromycin, rubigi 30 calcium, berythromycin, betamicin Sulfate, biapenem, binira none B1, ruboxyl, rufloxacin, rupatidine, ruzadolane, Safin mycin, biphenamine hydrochloride, bispyrithione mag gol, safironil, saintopin, salbutamol, R-salmeterol, salme sulfex, butikacin, butirosin sulfate, capreomycin sulfate, car terol, R-Sainacedin, sameridine, Sampatrilat, Sanfetrinem, badox, carbenicillin disodium, carbenicillin indanyl Sodium, Saprisartan, sapropterin, saquinavir, sarcophytol A Sargra carbenicillin phenyl sodium, carbenicillin potassium, caru mostim, Sarpogrelate, Saruplase, Saterinone, satigrel, Satumo 35 monam sodium, cefaclor, cefadroxil, cefamandole, cefaman mab pendetide, selegiline, selenium thiosemicarbazone, dole nafate, cefamandole sodium, cefaparole, cefatrizine, sematilide, semduramicin, Semotiadil, Semustine, sermore cefazaflur Sodium, cefazolin, cefazolin Sodium, cefbupera lin, Sertaconazole, sertindole, Sertraline, setiptiline, Zone, cefdinir, cefepime, cefepime hydrochloride, cefetecol, Sevirumab, sevoflurane, seZolamide, silipide, silteplase, sim cefixime, cefinenoxime hydrochloride, cefimetazole, cefimne endan, simvastatin, sinitrodil, sinnabidol, sipatrigine, siroli 40 tazole Sodium, cefonicid monosodium, cefonicid sodium, mus, sizofiran, Somatomedin B, Somatomedin C, somatrem, cefoperaZone sodium, ceforanide, cefotaxime Sodium, Somatropin, Sonermin, Stalol, staurosporine, stavudine, cefotetan, cefotetan disodium, cefotiam hydrochloride, stepronin, stipiamide, Stiripentol, Stobadine, Succibun, cefoxitin, cefoxitin Sodium, cefpimizole, cefpimizole Sucralfate, SulfaSalazine, Sulfmnosine, Sulfoxamine, Sodium, cefpiramide, ce?piramide sodium, cefpirome Sulfate, Sulopenem, Sultamicillin, Sultopride, Sulukast, Sumatriptan, 45 cefpodoxime proxetil, cefprozil, cefroxadine, cefsulodin Symakalim, tandospirone, tapgen, taprostene, tasosartan, Sodium, ceftazidime, ceftibuten, ceftizoxime Sodium, ceftri taZanolast, tazarotene, teicoplanin, telenzepine, tellurapyry aXone sodium, cefuroxime, cefuroxime axetil, cefuroxime lium, telmesteine, telmisartan, temocapril, temoporfin, temo pivoxetil, cefuroxime Sodium, cephacetrile sodium, cephal Zolomide, tenidap, teniposide, tenosal, tenoxicam, tepirin exin, cephalexin hydrochloride, cephaloglycin, cephalori dole, tepoxalin, teraZosin, terbinafine, terfenadine, 50 dine, cephalothin Sodium, cephapirin Sodium, cephradine, terflavoxate, terguride, terlakiren, terlipressin, terodiline, ter cetocycline hydrochloride, cetophenicol, chloramphenicol, tatolol, testosterone buciclate, tetrachlorodecaoxide, tetra chloramphenicol palmitate, chloramphenicol pantothenate Zomine, thaliblastine, thalidomide, thiocoraline, thiofedrine, complex, chloramphenicol sodium Succinate, chlorhexidine thiomarinol, thioperamide, thyroid stimulating hormone, phosphanilate, chloroxylenol, chlortetracycline bisulfate, tiagabine, tianeptine, tiapafant, tibolone, ticlopidine, tienox 55 chlortetracycline hydrochloride, cinoxacin, ciprofloxacin, olol, tilisolol, tilnoprofen arbamel, tiludronic acid, tinzaparin ciprofloxacin hydrochloride, cirolemycin, clarithromycin, Sodium, tiotropium bromide, tipredane, tiqueside, tirandaly clinafloxacin hydrochloride, clindamycin, clindamycin digin, tirapazamine, tirilazad, tirofiban, tiropramide, topsen hydrochloride, clindamycin palmitate hydrochloride, clinda tin, torasemide, toremifene, to Sufloxacin, trafermin, trandola mycin phosphate, clofazimine, cloxacillin benZathine, clox pril, traXanox, tretinoin, tretinoin tocoferil, triacetyluridine, 60 acillin Sodium, cloxyquin, colistimethate sodium, colistin tricaprilin, trichohyalin, trichosanthin, alpha, triciribine, tri Sulfate, coumermycin, coumermycin Sodium, cyclacillin, entine, triflavin, trimegestone, triptorelin, troglitaZone, trom cycloserine, dalfopristin, dapsone, daptomycin, demeclocy bodipine, tropisetron, trospectomycin, trovafloxacin, troVir cline, demeclocycline hydrochloride, demecycline, denofun dine, tucaresol, tulobuterol, tylogenin, urapidil, uridine gin, diaveridine, dicloxacillin, dicloxacillin Sodium, dihy triphosphate, Valaciclovir, Valproate magnesium, valproate 65 drostreptomycin Sulfate, dipyrithione, dirithromycin, semisodium, Valsartan, Vamicamide, Vanadeine, Vaninolol. doxycycline, doxycycline calcium, doxycycline fosfatex, Vapreotide, variolin B. Velaresol, Venlafaxine, Veramine, doxycycline hyclate, droxacin sodium, enoxacin, epicillin, US 8,232,265 B2 141 142 epitetracycline hydrochloride, erythromycin, erythromycin Vancomycin hydrochloride, Virginiamycin, and Zorbamycin. acistrate, erythromycin estolate, erythromycin ethylsucci Penicillin G, which is used as an antibacterial agent for infec nate, erythromycin gluceptate, erythromycin lactobionate, tions including pneumonia, meningitis, and skin, bone, joint, erythromycin propionate, erythromycin Stearate, ethambutol stomach, blood, and heart valve infections, is a particular hydrochloride, ethionamide, fleroxacin, floxacillin, fludala example suitable for use herein. tazobactum, sold under the nine, flumequine, fosfomycin, fosfomycin tromethamine, trade names ZOSYNTM and TAZOCINTM, ceftrioxone, sold fumoxicillin, furazolium chloride, furazolium tartrate, fusi under the trade name ROCEPHINTM, and metronidazol, sold date sodium, fusidic acid, gentamicin Sulfate, gloXimonam, under the trade name FLAGYLTM, are also used to treat gramicidin, haloprogin, hetacillin, hetacillin potassium, bacterial infections and are further examples of suitable com hexedine, ibafloxacin, imipenem, isoconazole, isepamicin, 10 pounds that can be used to prepare the disclosed ionic liquids. isoniazid, josamycin, kanamycin Sulfate, kitasamycin, levo These and other suitable antibacterials can be identified furaltadone, levopropylcillin potassium, lexithromycin, lin based on the desired properties of the antibacterial and comycin, lincomycin hydrochloride, lomefloxacin, lom whether the antibacterial active is or can be converted into an efloxacin hydrochloride, lomefloxacin mesylate, loracarbef, ion. As noted, identification of whetheran antibacterial active mafenide, meclocycline, meclocycline Sulfosalicylate, mega 15 is an ion or can be converted into an ion can be done by a lomicin potassium phosphate, medulidox, meropenem, meth skilled artisan inspecting the chemical structure of the anti acycline, methacycline hydrochloride, methenamine, meth bacterial. enamine hippurate, methenamine mandelate, methicillin Specific Examples of Antiviral Sodium, metioprim, metronidazole hydrochloride, metron When antiviral activity is a desired property of the dis idazole phosphate, mezlocillin, meZlocillin Sodium, minocy closed ionic liquids, one or more of the ions in the disclosed cline, minocycline hydrochloride, mirincamycin hydrochlo ionic liquids can be an antiviral. Examples of Suitable antivi ride, monensin, monensin Sodiumr, nafcillin Sodium, ral actives include, but are not limited to, acemannan, acyclo nalidixate sodium, nalidixic acid, natainycin, nebramycin, Vir, acyclovir Sodium, adefovir, alovudine, alvircept Sudotox, neomycin palmitate, neomycin Sulfate, neomycin unde amantadine hydrochloride, aranotin, arildone, atevirdine cylenate, netilmicin Sulfate, neutramycin, nifuradene, 25 mesylate, avridine, cidofovir, cipamfylline, cytarabine nifuraldezone, nifuratel, nifuratrone, nifurdazil, nifurimide, hydrochloride, delavirdine mesylate, desciclovir, didanosine, nifiupirinol, nifurquinazol, nifurthiazole, nitrocycline, nitro disoxaril, edoxudine, enviradene, enviroXime, famciclovir, furantoin, nitromide, norfloxacin, novobiocin Sodium, famotine hydrochloride, fiacitabine, fialuridine, fosarilate, ofloxacin, onnetoprim, oxacillin sodium, oximonam, oxi foScamet Sodium, foSfonet Sodium, ganciclovir, ganciclovir monam Sodium, oxolinic acid, oxytetracycline, oxytetracy 30 Sodium, idoxuridine, kethoxal, lamivudine, lobucavir, memo cline calcium, oxytetracycline hydrochloride, paldimycin, tine hydrochloride, methisaZone, nevirapine, penciclovir, parachlorophenol, paulomycin, pefloxacin, pefloxacin mesy pirodavir, ribavirin, rimantadine hydrochloride, saquinavir late, penamecillin, penicillin G benzathine, penicillin G mesylate, Somantadine hydrochloride, Sorivudine, statolon, potassium, penicilling procaine, penicilling sodium, peni stavudine, tillorone hydrochloride, trifluridine, Valacyclovir cillin V, penicillin V benzathine, penicillin V hydrabamine, 35 hydrochloride, vidarabine, Vidarabine phosphate, vidarabine penicillin V potassium, pentizidone sodium, phenyl ami Sodium phosphate, Viroxime, Zalcitabine, Zidovudine, Zin nosalicylate, piperacillin Sodium, pirbenicillin Sodium, piri viroxime, and Tamiflu. dicillin Sodium, pirlimycin hydrochloride, pivampicillin These and other suitable antivirals can be identified based hydrochloride, pivampicillin pamoate, pivampicillin on the desired properties of the antiviral and whether the probenate, polymyxin B sulfate, porfiromycin, propikacin, 40 antiviral is or can be converted into an ion. As noted, identi pyrazinamide, pyrithione Zinc, quindecamine acetate, quinu fication of whether an antiviral is an ion or can be converted pristin, racephenicol, ramoplanin, ranimycin, relomycin, into an ion can be done by a skilled artisan inspecting the repromicin, rifabutin, rifametane, rifamexil, rifamide, chemical structure of the antiviral. rifampin, rifapentine, rifaximin, rollitetracycline, rollitetracy Specific Examples of Pesticidal Actives cline nitrate, rosaramicin, rosaramicin butyrate, rosaramicin 45 When pesticidal activity is a desired property of the dis propionate, rosaramicin Sodium phosphate, rosaramicin closed ionic liquids, one or more of the ions in the disclosed Stearate, rosoxacin, roXarsone, roXithromycin, Sancycline, ionic liquids can be a pesticide. Included within the meaning Sanfetrinem Sodium, Sarmoxicillin, Sarpicillin, scopafungin, of "pesticide' are insecticides and fingicides. Examples of Sisomicin, sisomicin Sulfate, sparfloxacin, spectinomycin suitable pesticides include, but are not limited to, carfentra hydrochloride, spiramycin, stallimycin hydrochloride, Steffi 50 Zone-ethyl, SulfentraZone, clomaZone, diclofop-methyl, mycin, Streptomycin Sulfate, streptonicozid, Sulfabenz, Sul oxamyl propargite, prosulfuron, pyridate, pyriftalid, S-meto fabenzamide, Sulfacetamide, Sulfacetamide Sodium, Sulfacy lachlor, simazine, terbuthylazine, terbutryn, triasulfuron, tri tine, Sulfadiazine, Sulfadiazine sodium, Sulfadoxine, floxysulfuron, trinexapac-ethyl, ametryn, atrazine, benoxa Sulfalene, Sulfamerazine, Sulfameter, Sulfamethazine, Sul cor, bifenthrin, butafenacil, choline azide, chlortoluron, famethizole, Sulfamethoxazole, Sulfamonomethoxine, Sulfa 55 cinosulfuron, clodinafop, cloquintocet, DEET, desmetryn, moXole, Sulfanilate Zinc, Sulfanitran, Sulfasalazine, Sulfa dicamba, dimethachlor, dimethametryn, DTPA NaFe, Somizole, Sulfathiazole, Sulfazamet, Sulfisoxazole, EDDHA NaFe, fenclorim, flumetralin, fluometuron, fluthi Sulfisoxazole acetyl, Sulfisboxazole diolamine, Sulfomyxin, acetmethyl, halosulfuron, isoproturon, metobromuron, meto Sulopenem, Sultamricillin, Suncillin Sodium, talampicillin lachlor, norflurazon, oxasulfuron, piperophos, pretilachlor, hydrochloride, teicoplanin, temafloxacin hydrochloride, 60 primisulfuron, prometryn, propaquizafop, acilbenzolar-s-me temocillin, tetracycline, tetracycline hydrochloride, tetracy thyl, chlorothalonil, cyproconazole, cyprodinil, difenocona cline phosphate complex, tetroXoprim, thiamphenicol, Zole, fenpropidin, fenpropimorph, furalaxyl, metalaxyl, thiphencillin potassium, ticarcillin cresyl Sodium, ticarcillin metalaxyl-m, oxadixyl, penconazole, propiconazole, disodium, ticarcillin monosodium, ticlatone, tiodonium chlo pyrifenox, thiabendaZol, abamectin, bromopropylate, cyper ride, tobramycin, tobramycin Sulfate, to Sufloxacin, trimetho 65 methrin, cypermethrin high-cis, cyromazine, diafenthiuron, prim, trimethoprim Sulfate, trisulfapyrimidines, troleando diazinon, dichlorvos, disulfoton, emamectinbenzoate, mycin, trospectomycin Sulfate, tyrothricin, Vancomycin, fenoxycarb, formothion, furathiocarb, lufenuron, methi US 8,232,265 B2 143 144 dathion, permethrine, codilemone, phosphamidon, profeno Specific Examples of Energetics fos, pymetrozine, quinalphos, terrazole, thiamethoxam, thio The disclosed ionic liquid compositions can also include cyclam, thiometon, triallate, trifloxystrobin, VincloZolin, high energy ingredients as well as explosive materials. The Zetacypermethrin, and the like. Prohexadione is a FDA ability to prepare a particular composition with high energy approved reduced risk fungicide and is also useful for the content Substituents (fuel) on one ion and high oxygen bal disclosed ionic liquids. Further examples of suitable pesti ance (oxidizers) on the other ion opens wide applicability in cides can be found in The Pesticide Manual, 11" Edition, today's high energy compounds industry. The ability to inde British Crop Protection Council, 1997, which is incorporated pendently form differentially functionalized groups of ions, by reference herein at least for its teaching of pesticides. then chose two of interest and combining them on demand to These and other suitable pesticides can be identified based 10 form desired strength energetic material (Scheme 1) opens on the desired properties of the pesticide and whether the the doors for the quick preparation of customizable energetic pesticide is or can be converted into an ion. As noted, identi materials (e.g., explosives with pre-designed power) and fication of whether a pesticide is an ion or can be converted more safe storage technique of those energetic materials since into an ion can be done by a skilled artisan inspecting the the components are separated before usage. The disclosed chemical structure of the pesticide. 15 compositions can be prepared according to one of the follow Specific Examples of Herbicidal Actives ing reaction protocols. When herbicidal activity is a desired property of the dis closed ionic liquids, one or more of the ions in the disclosed ionic liquids can be a herbicide. Examples of suitable herbi Scheme 1: Protocol 1. cides include, but are not limited to, carfentraZone, imazapyr, benefin, acifluorfen, and 2-2-chloro-3-(2.2.2-trifluoroet hoxymethyl)-4-methylsulfonylbenzoylcyclohexane-1. e/ Other suitable herbicides include inhibitors of the biosyn En f y IAC I. thesis of branched amino acids such as ethoxysulfuron, flu N metSulam, halosulfuron, imaZamox, imazapyr, imaZaquin, 25 imazethapyr, metoSulam, nicosulfuron, primisulfuron, pro R sulfuron, rimsulfuron, thifensulfuron-methyl, triflusulfuron, N-(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl-2-dim ambient conditions ethylaminocarbonyl-5-formylaminobenzenesulfonamide He harmless solvent (Foramsulfuron), and the like. Still further, suitable herbi 30 cides include inhibitors of the photosynthesis electron trans N-N (e.g. H2O, EtOH) port such as ametryne, atrazine, bromoxynil, cyanazine, diu R ron, hexaZinone, metribuzin, pyridate, terbuthylazine, and the gy O like. In yet further examples, suitable herbicides for the dis tify En N En closed ionic liquids include synthetic auxins such as copy 35 ralid, dicamba, diflufenzopyr, fluroxypyr, and the like. Inhibi &y ||Y( - tors of fatty acid biosynthesis, such as butylate, EPTC, N-N fenoxaprop-P-ethyl, and the like, can also be used in the R disclosed ionic liquid compositions. In other examples, Suit able herbicides can include inhibitors of cell division such as 40 Ice ise acetochlor, alachlor, dimethenamid, flufenacet, mefenacet, metolachlor, S-metolachlor, thenylchlor, and the like. In still other examples, the herbicide can be an inhibitor of protopor where En is an energetic functional group containing either phyrinogen oxidase, Such as fluthiacet-methyl, carfentra high oxygen or nitrogen content (including but not limited to: Zone-ethyl, and the like. Inhibitors of hydroxyphenylpyruvate 45 nitro, amino, cyano, azido, alkyl nitro, alkyl amino, alkyl dioxygenase, Such as isoxaflutole, mesotrione, Sulcotrione, cyano, alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, 4-(4-trifluoromethyl-2-methylsulfonylbenzoyl)-5-hydroxy and alkoxy azido), IA is an innocuous anion, IC+ is an 1-methyl-3-methylpyrazole, and the like, can also be used. innocuous cation, and ICIA is an easily removable and Further examples of suitable herbicides include, but are not harmless byproduct from the metathesis reaction. The reac limited to, glyphosate, pendimethalin, trifluralin, asulam, tri 50 tion proceeds via ion exchange reaction in Solvent system aziflam, diflufenican, glufosinate-ammonium, and the like. media (solvent system is the solvent or the mixture of the Clofencet, fluroxpyr, mesosulfuron, diflufenzopyr are further Solvents in which at least one of the starting materials dis examples of suitable herbicides and they are FDA approved. solves). The solvents (or solvent) with substrates dissolved in Specific Examples of Other Ions them separately are being combined, the byproduct is being In addition to the pharmaceutical, antibacterial, antiviral, 55 separated from the product (by solvent extraction or precipi pesticidal, and herbicidal actives disclosed herein, other com tation) (Katritzky et al., “1-Butyl-3-methylimidazolium 3.5- pounds that are ions or can be converted to ions can be used in dinitro-1,2,4-triazolate: a Novel IL Containing a Rigid, Pla the disclosed ionic liquid compositions. Specific examples of nar Energetic Anion.” Chem Commun 868, 2005, which is these include, but are not limited to, the food additives Allura incorporated by reference herein). Red AC (FD&C Red No.40), Tartrazine (FD&C Yellow No. 60 Examples of those ionic liquid compositions include, but 5), Indigotine (FD&C Blue No.2), Erythrosine (FD&C Red are not limited to, the mixture of at least two components of No.3), and Sunset Yellow (FD&C Yellow No. 6), which are functionalized 5- and 6-membered, and bicyclic fused ring FDA-approved color additives for food use. Further, nutra heterocyclic cations and anions containing 1, 2, 3, 4, or 5 ceuticals such as fatty acids, cholesterols, vitamins, minerals, atoms of nitrogen in the ring structure, where all carbon and and trace elements can be suitable ions for the disclosed ionic 65 nitrogen atoms in the ring structure can be functionalized liquid compositions. SEA-NIN-211 is an antifoulant that can with additional Substituents such as alkyl, allyl, aryl, nitro, be used as an ionid the disclosed compositions. nitrile, azido, hydroxyl, carboxylic acid, ester, amide, amine, US 8,232,265 B2 145 146 aldehyde, ketone, epoxy, or functionalized alkyl and aryl -continued groups (with any functional mentioned above). Examples of R R 7 R R 7 Such components (cations and/or anions) are shown below. R 2 NA R2 NM 5 M} R 6 MN N R6 R4 R4 R3 N R3 N R N R3 R N R3 R4 Rs R4 Rs

10 R6 4. R2 R6 2 n where R', R. R. R. , R, and R', are, independent of one another, not present, H. alkyl, alkenyl, alkynyl, allyl, aryl, RI RI nitro, amino, cyano, azido, alkyl nitro, alkyl amino, alkyl R4 R4 cyano, alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, 15 and alkoxy azido, nitrile, isonitrile, carboxylic acid, ester, R R3 R3 N R3 ether, CONR, CONHR, CONH, amine, NHR, NR, nN.1 n ketone, aldehyde, or epoxy, wherein R is H. alkyl alkenyl, alkynyl, allyl, aryl, carboxylic acid, ester, ether, ketone, or 2 2 aldehyde. R6 N R2 R6 N R2 y k k 2O R4 R4 R nN.1 R3 R3 l s R3 N-N * ONSene N-NO)y l N 25 C y lo - INN - rise rise N Prefer RI RI O R4 R4 -- 30 R N R3 R3 l R3 MeOH SN1 N1 n 1 R -- A 6 a Na 2NS N R N R2 R6 N R2 35 CyN ON-NeN-NO)Y i? R R N N-N R4 f OH R 1. R3 R3 N R3 3 NN n N1 NN1 n 40

l 2 l* a 2.2 N* a ii A 120°O C. -CO R6 R2 R6 R2 rt. DMSO RI RI R4 45 -- R R4 R3 R4 R3 N-N ON N NO R N R3 2 N-N N N --- N NR2 R 5 N R42 R5 N / 'N R 50 RI R R 4 R4 R3 R4 R3 R4 R3 - A M V Utilizing this protocol, model compounds (4), which may N N N undergo further modification interms of introduced functions / > W WN 4.f \ N 55 (on thergo Turucation precursor (1), anion precursors (2), and R5 N R2 R5 N1 YR2 R5 YNR2 homologous heterocycle core (both 1, and 2) (e.g., but not limited to: imidazole, triazole, tetrazole, benzimidazole, and R R R benztriazole systems) can be formed. 4 3 4 3 The protocol for the formation of azolium azolate salts via R , R , 60 the reaction of two neutral components requires: Zwitterionic N-N N-N cation precursor (1) with carboxylate group appended on the f \ 4. \ heterocycle core, and neutral heterocycle (2) with the pKa R5 N1 YR2 R51 NR2 value lower then that of carboxylate group in cation precursor (1). The reaction can be carried in any solvent systems (pure R R 65 solvent or mixture of solvents) that allows for the dissolution of both components, or without solvents at all. The reaction protocol comprises the following steps: US 8,232,265 B2 147 148 Protontransferreactions (protonation of carboxylate group -continued in Zwitterionic cation precursor (1): (step i) which is thermo R4 R4 dynamically favored due to the difference in the pKa values of R R3 R3 l R3 the Zwitterionic salt carboxylate group and azolate anion (formed from deprotonation of anion precursor (2)). r is Decarboxylation of the system containing the protonated R6 2 N YR2 R6 2 N NR2 carboxylic acid group on the cation precursor in the interme diate (cationic part of compound 3) (step ii). The decarboxy k R4 R4 altion may be performed in the presence of either polar sol 10 vents (e.g., but not limited to, DMSO, DMF, THF, 5 3 5 3 trialkylamine, H2O) or heat (temp between 25°C.-150° C.). R s -R RS ~'s Additionally, the driving force for this conversion is the N N production of gaseous CO which, upon removal from the R6 2 YR2 R6 2 YR2 reaction mixture, shifts the thermodynamic equilibrium in 15 k k favor of product formation. R4 R4

Examples of those ionic liquid compositions made utiliz 5 3 5 3 ing above protocol include, but are not limited to, the mixture of at least two components of functionalized 5-, 6-membered, *s-s-s s's and bicyclic fused ring heterocyclic cation precursors and - - - anion precursors containing 1, 2, 3, 4, or 5 atoms of nitrogen --- YR2 R6 2 NR2 in the ring structure. k 4 The cation precursors are neutral, Zwitterionic species R4 R3 R4 R3 (neutral molecule that within itself contains both: cation and 25 anion species) containing at least one cationic site (e.g., but N1N S1NN W \ / \ not limited to, protonated oralkylated nitrogenatom) and one R N R3 RS anionic site (carboxylate (COO—) group). In the cation pre R6 l - NR2 R5 N R2 R5 N1 n cursors all carbon and nitrogenatoms in the ring structure can 30 RI R R beftunctionalized with additional substituents such as alkyl, R4 R3 R4 R3 R4 R3 allyl, aryl, nitro, nitrile, azido, hydroxyl, carboxylic acid, A A V ester, amide, amine, aldehyde, ketone, epoxy, or functional N N N ized alkyl and aryl groups (with any functional mentioned / > / \ -C \, above). 35 R5 R2 R5 N1 YR2 R5 1NR2 The anion precursors are neutral, Substituted, or not Sub stituted, heterocyclic species containing at least one acidic R R R R4 R3 R4 R3 proton site on any of the nitrogenatoms. This hydrogenatom V A V M will be utilized for the proton transfer reaction and consecu N-N N-N tive decarboxylation reaction to form final azolium azolate 40 product (4) as described in the protocol above. In the anion ( \, ( \, precursors all carbon and nitrogenatoms in the ring structure R5 N1 YR2 R51 Y NR2 can be functionalized with additional substituents such as R R alkyl, allyl, aryl. nitro, nitrile, azido, hydroxyl, carboxylic R R R7 R7 acid, ester, amide, amine, aldehyde, ketone, epoxy, or func 45 M A tionalized alkyl and aryl groups (with any functional men tioned above). Examples of Such components (cation precursors and/or /X-R 6 /Y. R6 anion precursors) are shown below. R3 V R3 V 50 R4 Rs R4 Rs R4 R4 R R3 R3 R3 where for the cation precursor: at least one of the R'-R N N Substituent groups (only among the ones directly appended to 55 carbon in heterocyclic ring) can be a carboxylate anion group. 2 2 N The remaining groups can be, independent of one another, not R6 R2 R6 NR2 present, H, alkyl, alkenyl, alkynyl, allyl, aryl, nitro, amino, RI RI cyano, azido, alkyl nitro, alkyl amino, alkyl cyano, alkyl R4 60 azido, alkoxy nitro, alkoxy amino, alkoxy cyano, and alkoxy R R3 R3 N R3 azido, isonitrile, carboxylic acid, ester, ether, CO.NR, n Y n CONHR, CONH, amine, NHR, NR, ketone, aldehyde, epoxy, wherein R is H, alkyl, alkenyl, alkynyl, allyl, aryl, R6 als R2 R6 2 R2 carboxylic acid, ester, ether, ketone, or aldehyde. 65 And, where for the anion precursor: at least one of the RI RI R'-R substituent groups (only among the once directly appended to nitrogen in heterocyclic ring) can be an H atom US 8,232,265 B2 149 150 suitable for deprotonation to form stable heterocyclic azolate be varied or adjusted by adding other ions, so long as there is anion. The remaining groups can be, independent of one a balance of charge and the final composition is an ionic another, not present, H. alkyl, alkenyl, alkynyl, allyl, aryl, liquid. nitro, amino, cyano, azido, alkyl nitro, alkyl amino, alkyl When the disclosed ionic liquid compositions have two or cyano, alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, more ions with a bioactive property (e.g., pharmaceutical and alkoxy azido, isonitrile, carboxylic acid, ester, ether, active ingredients, pesticidal actives, herbicidal actives, and CO2NR, CONHR, CONH, amine, NHR, NR, the like), these compositions can be particularly desired ketone, aldehyde, or epoxy, wherein R is H, alkyl, alkenyl, because each of the active ingredients in the composition alkynyl, allyl, aryl, carboxylic acid, ester, ether, ketone, or would have the same solubility and would dissolve together aldehyde. 10 when formulated or administered. This can be particularly Specific Ionic Liquids useful when overcoming formulation, solubility, bioavail Because the disclosed ionic liquid compositions can have ability, size, and polymorphism issues. Further, when exact multiple functionalities or properties, each arising from the dosages of an active ingredient are needed, the active ingre various ions that make up the ionic liquid, the disclosed ionic dient as an ion can be combined with a counterion that is liquid compositions can be custom designed for numerous 15 uses. As disclosed herein, any combination of cations and innocuous or GRAS (generally recognized as safe). As noted anions, as disclosed herein, can be made as long as the com above, for example, if one active ingredient (cation) is needed bination results in an ionic liquid as described herein. That is, at half the dosage of another active ingredient (anion), then an any compound or active disclosed herein that has a given innocuous cation could be used as filler to balance the charge or can be made to have a given charge (the “first charges. This same concept applies if more cation is needed ion(s)) can be combined with any other compound or active than anion. disclosed herein having a charge opposite to that of the first A few specific examples of ionic liquid compositions pre ion(s) or any compound that can be made to have a charge pared from combinations of quaternary ammonium com opposite to that of the firstion(s). Thus, in many examples, the pounds and Saccharinates or acesulfamates have been dem ionic liquid compositions can have one type of cation and one 25 onstrated. Burgard disclosed a process for preparing type of anion, in a 1:1 relationship, so that the net charge of the hexadecylpyridinium acesulfamate and its use in the oral ionic liquid is Zero. hygiene sector (Eur Pat Appl 2003-1270580A1; US Pat Appl Furthermore, many of the ions disclosed herein can have 2003-023084 A1). Hydrophilic quaternary ammonium sac multiple charges. Thus, when one ion having a multiple chrinates and acesulfamates and hydrophobic phosphonium charge is used, more counterion(s) is needed, which will 30 affect the ratio of the two ions. For example, ifa cation having acesulfamates have been recently published (Carter et al., a plus 2 charge is used, then twice as much anion having a Chem Comm, 2004, 630-631; Pernaket al., EurJ Org Chem, minus 1 charge is needed. If a cation having a plus 3 charge is 2005, 650-652). Saccharin, acting as a weak acid, can form used, then three times as much anion having a minus 1 charge salts with basic active pharmaceutical ingredients including is needed, and so on. While the particular ratio of ions will 35 tertiary amines to form quaternary nitrogen atoms (Bhatt et depend on the type of ion and their respective charges, the al., Chem Comm, 2005, 1073-1075). Also known in the lit disclosed ionic liquids can have a cation to anion ratio of 1:1:. erature is N-hexadecylpyridinium saccharinate (CAS No. 2:1, 3:1, 4:1, 1:3, 2:1, 3:2, 2:3, and the like. 7428-34-4). Many of the ionic liquid compositions disclosed hereincan Some other specific examples of the disclosed ionic liquids also have more than one different kind of cation and/or more 40 include, but are not limited to, ionic liquids where any of the than one different kind of anion. The use of more than one cations in the ionic liquid are aliphatic benzylalkyl ammo kind of cation and/or anion can be particularly beneficial nium cations (e.g., benzalkonium), dialiphatic dialkyl ammo when one prepares an ionic liquid composition comprising nium cations (e.g., didecyldimethylammonium), and ali two or more bioactive ions that are not desired to be in a 1:1 phatic heteroaryl cations (e.g., hexadecylpyridinium) are relationship. In other words, according to the disclosed meth 45 combined with any of the anions of sulfacetamide, ibuprofen, ods, ionic liquid compositions that contain varying effective and saccharinate. amounts (or doses) of active Substances can be prepared by Benzalkonium (BA) is used chiefly as an antiseptic and varying the ratios of ions in the composition, as long as the disinfectant. It is found in many over the counter and pre total amount of cations is balanced by the total amount of Scription eye products, disinfectants, shampoos, and deodor anions. For example, an ionic liquid composition disclosed 50 ants. It also acts as a preservative in many pharmaceutical herein can contain one type of cation with a given property preparations. Didecyldimethylammonium (DDA) is used as and two different anions (e.g., a first and second anion), each an antiseptic and surfactant. N-hexadecylpyridinium (HEX) with another different property. The resulting ionic liquid in is used as an antiseptic agent alone or in combination with this example will be 1 part cation, 0.5 part first anion, and 0.5 other drugs for oral and throat care. HEX is essentially non part second anion. Another example of this adjustment in ion 55 toxic and can be applied to the skin or mucous membranes. amounts can arise when one ionis particularly potent and thus Sulfacetamide is used to control antibacterial activity and dilution is desired. For example, a first cation that is particu is sold under the trade name KLARONTM in the treatment of larly potent can be combined with a second (or third, forth, acne. Ibuprofen is used as an anti-inflammatory and pain etc.) cation that is inert or has so other property that is desired. reliever. Saccharinate is used as a Sweetener. When these cations are combined with one or more kinds of 60 Some specific examples of Suitable ionic liquids include, anions to form an ionic liquid, the amount of the first cation is but are not limited to, benzalkonium sulfacetamide (BA-sul diluted by the other the cation(s). As will be appreciated, facetamide), didecyldimethylammonium Sulfacetamide many other Such variations in the amount of cations and (DDA-sulfacetamide), N-hexadecylpyridinium sulfaceta anions can be present in the disclosed methods and compo mide (HEX-sulfacetamide), benzalkonium ibuprofen (BA sitions. Thus, while specific ionic liquid compositions having 65 ibuprofen), didecyldimethylammonium ibuprofen (DDA particular combinations of cations and anions are disclosed ibuprofen), N-hexadecylpyridinium ibuprofen (HEX herein, it is understood that the ratio of the particular ions can ibuprofen), and benzalkonium acesulfamate, US 8,232,265 B2 151 didecyldimethylammonium acesulfamate, N-hexadecylpyri dinium acesulfamate, and benzalkonium saccharinate (BA XIII SAC). In other examples, anion that is antiseptic can be combined with an ion that is antibacterial agent. For example, an ionic liquid can comprise benzalkonium and Sulfacetamide, which is shown in formula X. CH 10 HC 8

Also, the ionic liquid composition can comprise didecyldim 15 ethylammonium and ibuprofen, which is shown in formula H3C CH3 XIV.

O | e XIV HN -n-coch, O CH C10H2 GE) CH3 O C10H2 De- CH3 CH O 25 HC O Another example is the combination of didecyldimethylam monium sulfacetamide, which is shown in formula XI. Further, the ionic liquid composition can comprise N-hexa decylpyridinium and ibuprofen, which is shown in formula 30 XV.

XI XV

35 CH3 C10H2 inte-CH3 O N n HN -N-COCH CoH.1 CH3 / \ O I N-CH CH3 O H3C G 40

In other examples of ionic liquid compositions disclosed Still another example is the combination of N-hexadecylpy herein, an ion that is an antibacterial can be combined with an ridinium sulfacetamide, which is shown in formula XII. ion that is a Sweetener. Such compositions can be used to 45 improve the taste of medicines and hygiene products and can be used in, for example, toothpaste, and children's medicine. XII Some specific examples of Such ionic liquids is prepared by combining the antibacterial agents benzalkonium, dide N-CH3 cyldimethylammonium, or N-hexadecylpyridinium and the 50 sweetener acesulfamate, as shown in formulas XVI, XVII, | e and XVIII, respectively. HN S-N-COCH

XVI 55 O G-C12H25 Such antiseptic/antibacterial compositions can be used in the - G treatment of wounds, for example, wounds near the scalp Hi?3 Yh3 2O where a composition with both disinfectant and antibacterial O -Š O 60 properties is desirable. Such compounds could also be used XVII for skin care, e.g., to treat acne. O In still further examples, an ion that is antibacterial can be C10H2 in G-CH3 G -NN N combined with an anti-inflammatory and/or pain reliever. C10H2 CH leo Such compositions can be used as a disinfectant and for pain 65 S relief. For example, an ionic liquid can comprise benzalko 1soSa nium and ibuprofen, which is shown in formula XIII. US 8,232,265 B2 153 154 -continued -continued XVIII XXIV O O 9 O le N-CH O N

The antibacterial agents benzalkonium, didecyldimethylam 10 monium, and N-hexadecylpyridinium can also be combined In still other examples, the disclosed ionic liquids can with the Sweetener saccharinate, as shown in formulas XIV, comprise an ion that is an antibacterial and an ion that can XX, and XXI, respectively. provide wetting and controls reaction rate, particle size, vis cosity, polymer molecular weight, and stability in emulsion 15 polymerization systems, e.g., sodium dihexylsulfoSuccinate XIX (e.g., Colawet MA-80 from Colonial Chemicals, South Pitts O burg, Tenn.)). Specific examples of Such compositions G) -C2H25 $1 C include, but are not limited to, compositions where the cation / V N is an antibacterial agent Such as benzalkonium, didecyldim HC CH / S ethylammonium, or n-hexadecylpyridinium, and the anion is M\ Colawet MA-80, as shown in formulas XXV. XXVI, and O O XX XXVII, respectively. O C10H2 ag-CH3 25 N C XXV N C10H2 CH3 / O 7\ C12H2s C6H13 O O e- No XXI 30 O M Yeh3 O GE CH-1 Sg N-CH3 G \ / N O M 35 O7\ O XXVI In still other examples, the ionic liquid composition can O comprise an ion that is an antibacterial agent with an ion that C10H2 C6H13 is a UV-blocker, Such as trans-cinnamate. Such compositions 40 NG/ CH n O can be used as disinfectants and for protection against UV CnH /NCH O radiation, as would be desirable for treating wounds exposed Oll 3 CH-1 Sg to the Sun's radiation. Specific examples of Such composition include, but are not limited to, compositions where the cation O is an antibacterial agent Such as benzalkonium, didecyldim 45 ethylanimonium, or N-hexadecylpyridinium, and the anion is XXVII trans-cinnamate, as is shown in formulas XXII, XXIII, and O XXIV respectively. o C6H13 50 No XXII \ N-calls O O CH-1 Sg O GE --CH 1225 g 1 55 / V HC CH In further examples, the disclosed ionic liquid composi tions can comprise an ion that is antibacterial and an ion that is a food colorant. Examples of Such ionic liquid composi XXIII O 60 tions include, but are not limited to, compositions where the O cation is an antibacterial agent such as benzalkonium, dide O C10H2 in G-CH3 cyldimethylammonium, or N-hexadecylpyridinium, and the N o anion is Fast Green FCF, an FDA approved color additive that CoH,1 n CH3 provides a sea green hue and is used in products Such as 65 beverages, puddings, ice cream, sherbet, cherries, confec tions, baked goods, and dairy products. Other food coloring anions, which are well known in the art, can be used as well. US 8,232,265 B2

XXVIII e-C12H25, C10H2 ing-CH3, or G-C12H25 N N 91 / V M \, H3C CH3 C10H2 CH3 HC CH

Cation GE) \ -ed. 10 G CO2 C2H5N O r O N CH H N N s CH3 15 O N S H H O O Ph

Anion

Still further specific examples of the disclosed ionic liquid XXIX compositions are those where the anion is benzoate and the C10H2Net-CH3N cation comprises one or more of (2-acetoxyethyl)-dodecy CoH,1 n CH3 loxymethyldimethylammonium, (2-acetoxyethyl)-hepty 25 loxymethyldimethylammonium, (2-hydroxyethyl)-cy clododecyloxymethyldimethylammonium, O (2-hydroxyethyl)-dimethylundecyloxymethylammonium. Other examples of the disclosed ionic liquid compositions are those where the cation comprises benzalkonium, dide cyldimethylammonium, or N-hexadecylpyridinium and the anion comprises one or more of acesulfamate, benzoate, colawet ma-80, fast green FCF, ibuprofen, penicillin G, pip eracillin, Saccharinate, Salicylate, Salicylate, Sulfacetamide, trans-cinnamate, Sulfathiazole, thimerosal, Valproic acid, 35 mepenZolate, docusate. In three specific examples, benzalko nium is combined with mepenZolate and docusate in a 1:1:2 ratio, a 2:1:3 ratio, or a 1:2:3 ration. In another example, benzalkonium is combined with Sulfathiazole and sacchari nate in a 2:1:1 ratio. 40 Further specific examples of the disclosed ionic liquid XXX compositions are those where the cation is didecyldimethy lammonium and the anion comprises one or more of saccha rinate, (S)-6-methoxy-O-methyl-2-naphthaleneacetate, 2-(2,6-dichlorophenyl)amino-benzeneacetate, 2-(2,6- 45 dichlorophenyl)amino-benzeneacetate, 2-acetoxybenzoate, acesulfamate, benzoate, colawet ma-80, fast green FCF, ibu profen, mandelate, N-4-(2-amino-1,4-dihydro-4-oxo-6- pteridinyl)methylaminobenzoyl-L-glutamate, nicotinate, penicillin G, piperacillin, p-toluenesulfonate, Salicylate, Sul 50 facetamide, or trans-cinnamate. Other specific examples of the disclosed ionic liquid com positions are those where the cation is hexadecylpyridinium and the anion comprises one or more of colawet ma-80, fast green FCF, penicillin G, piperacillin, or sulfacetamide. 55 Still further specific examples of the disclosed ionic liquid compositions are those where the cation is hexadecylpyri dinium and the anion comprises one or more of clofencet, fluroxypyr, diflufenZopyr, mesosulfuron, prohexadione, pan In still further examples, the disclosed ionic liquid compo toprazole, risedronate, losartan, rabeprazole, fosinopril, ceft sitions can comprise a cation that is an antibacterial and an 60 ioxone, atorvastatin, pravastatin, alendronate, montelukast, anion that is an antibacterial. For example, the cationic anti taZobactam, Allura Red AC, tartrazine, indigotine, eryth bacterial agents disclosed herein can be combined with the rosine, or Sunset Yellow. anionic piperacillin, which is an extended-spectrum penicil Further specific examples of the disclosed ionic liquid lin. Piperacillin is primarily used in the treatment of suscep compositions are those where the cation is didecyldimethy tible infections such as septicemia, acute and chronic respi 65 lamrnonium and the anion comprises one or more of clofen ratory tract infections, skin and soft tissue infections, and cet, fluroxypyr, diflufenZopyr, mesosulfuron, prohexadione, urinary tract infections. pantoprazole, risedronate, losartan, rabeprazole, fosinopril, US 8,232,265 B2 157 158 ceftioxone, atorvastatin, pravastatin, alendronate, mon Methods telukast, taZobactam, Allura Red AC, tartrazine, indigotine, The disclosed ionic liquid compositions can be prepared by erythrosine, or Sunset Yelow. combining one or more kinds of cations or cation precursors Other specific examples of the disclosed ionic liquid com with one or more kinds of anions or anion precursor. Provid positions are those where the cation is benzalkonium and the ing of the particular ions is largely based on the identifying anion comprises one or more of clofencet, fluroxypyr, desired properties of the ion (e.g., its charge and whether it diflufenZopyr, mesosulfuron, prohexadione, pantoprazole, has a particular bioactivity that is desired to be present in the risedronate, losartan, rabeprazole, fosinopril, ceftioxone, resulting ionic liquid). Methods of identifying Suitable ions atorvastatin, pravastatin, alendronate, montelukast, taZobac are disclosed herein, for example, by considering the chemi 10 cal structure and charge of the compounds and whether the tam, Allura Red AC, tartrazine, indigotine, erythrosine, or ion combination will produce an ionic liquid. Sunset Yellow. Typically, when preparing an ionic liquid composition as Still further examples include the compositions docusate disclosed herein, an ion that minimizes coulombic interac lidocaine, miconazole?econazole docusate, streptomycin tions by diffusing its charge over several atoms in the ion is docusate, and isoniazide docusate. Docusate combined with 15 identified. An example of this is the alkylheteroaryl cations any of the cationic 5 and 6 membered quaternary ammonium disclosed herein where the positive charge is spread over the ring compounds disclosed herein are also contemplated atoms of the heteroaryl ring. Then a weakly coordinating herein. counterion, which also delocalizes charge over several atoms, Still further examples include a cation that is an anticho is chosen. In general, more-complex and higher molecular linergic like mepenZolate and the anion is docusate. weight cations and anions have a greater number of intermo Another example comprises itraconazole, which inhibits lecular contacts, which serves to raise melting point and cytochrome p540 oxidase mediated Snthesis of ergosterol. increase the Viscosity of the ionic liquid composition. Itraconazole is a 1:1:1 racemic mixture offourdiastereomers Further, when preparing an ionic liquid composition as comprising 2 enantiomeric pairs. Generally, it has poor disclosed herein, molecular asymmetry can be particularly adsorption especially when givenin capsule form. This is 25 desired. Low-symmetry cations and anions typically reduce though to occur because 99.8% of the drug becomes bound to packing efficiency in the crystalline State and lower melting proteins in the body. It has been shown that absorption is points. improvedwit acid as the pKa is 3.70; therefore, it is recom It is also desirable that the cation should not be more mended that this drug be taken with orange juice. The com nucleophilic than the neutral form of the cation. If this is the 30 case, then Suitable anions can be selected by considering their pound is insoluble in water, slightly soluble in alcohol, and pKa. For example, by utilizing the pKa of acid functionalized freely soluble in dichloromethane. This compound can be compounds and the pKb of base functionalized compounds, combined with any of the anions disclosed herein, for one can combine the neutral species of acids and bases into example, Sulfacetamide, colawet MA-80, and docusate. one neutral compound possessing the functions of both com Also contemplated are ionic liquids that are prodrugs. A 35 pounds. To Successfully produce an ionic liquid by this prodrug is a pharmacologically inactive compound that is method, the pKa or pKb of compound A should be different converted to an active drug by a metabolic biotransformation. by approximately 5 orders of magnitude from the pKa or pKb Prodrugs are used when there are concerns regarding a drugs of compound B. This insures that the acidity or basicity at that solubility, absorption and distribution, site specificity, stabil hydrogen is Sufficient to remove or add a hydrogen at that ity, prolonged release, toxicity, patient acceptability, and for 40 position. This will then produce an anion on the acidic com mulation concerns. Carrier linked prodrugs are also contem pound and a cation on the basic compound. plated. A carrier linked prodrug is a compound thatcontains One method for identifying a suitable ion combination for an active drug linked to a carrier group that can be removed preparing an ionic liquid as disclosed herein is by computer enzymatically, such as an ester, which is hydrolyzed to an program. It is also possible to use a computer to select various active carboxylicacid containing drug. Other types of carrier 45 cation and anion combinations. For example, the program linkages include alcohols and carboxylic acids, amines, and called ERWINTM, sold by Computer Associates (Islandia, carbonyl compounds. Also contemplatedare mutual pro N.Y.), can be used. This computer program is comprised of drugs, which comprise two drugs attached to each other two models: a forward model which predicts the melting where one is the carrier for the other and vice versa. points and drug delivery rates of a formulation of ionic liq Still further examples include compositions comprising 50 uids, and a backwards model will allow the user to select lidocaine and silver. This composition has a component that is which type of pharmaceutical agents that are desired along functional for topical anesthesia (lidocaine) with one Ag+ with liquid range and delivery rates and the program will give that has antimicrobial properties. This can be used in con all the formulations which meet these criterion. junction with lidocaine docusate, as described herein, to cre FIG. 3 illustrates how the two models interact. ate ointments or bandage materials that are capable of pro 55 CODESSATM (Semichem, Inc. Shawnee Mission, Kans.) can viding a palliative effect as well as Suppression of be used to calculate the descriptors that can be used to con microorganism growth. Similarly, silver docusate can be pre struct the forward model. For example, ifa researcher desires pared, which can provide a lipophilic salt of silver that would a formulation to have antibacterial and painkilling therapeu be soluble in lidocaine docusate, other ILS, or even non-IL tic agents as well as the formulation to exist as a liquid at room creme bases, for end-use as a topical antimicrobial agent. 60 temperature and have a delivery rate of 1 gram absorbed per Still further examples include compositions comprising minute, the researcher would feed this request into the pro ranitidine and docusate. This compound can generate a rather gram and all of the formulations meeting these requirements lipophilic, hydrophobic version of ranitidine, which would be and being composed entirely of a balanced ionic liquid for both non-crystalline and Sufficiently sluggish in its rate of mula would be suggested to the researcher. dissolution against biofluids that it could serve as a slow 65 Once the desired ions are provided, the ions can be com release form of the drug. Lidocain docusate is another bined to form the disclosed ionic liquids. There are generally example contemplated herein. two methods for preparing an ionic liquid: (1) metathesis of a US 8,232,265 B2 159 160 salt of the desired cation (e.g., a halide salt) with a salt of the liquid compositions also make having compositions with desired anion (e.g., transition metal, like Ag, salt, Group I or additional functionality possible. II metal salt, or ammonium salt). Such reactions can be per One notable advantage of the disclosed ionic liquid com formed with many different types of salts; and (2) an acid positions is that they can be used to alleviate the problems base neutralization reaction. Another method for forming the associated with polymorphism. For example, a compound disclosed ionic liquid compostions involves a reaction Subject to polymorphism can be used as an ion in the dis between a salt of a desired cation, say CationX where X is an closed ionic liquid compositions. In this way, the compound appropriate balancing anion (including but not necessarily a will become part of the ionic liquid composition and thus not halide), and an acid to yield the ionic liquid and HX byprod a crystalline solid that is subject to polymorphism. Alterna 10 tively, polymorphism can be prevented by dissolving the uct. Conversely, the disclosed ionic liquid compositions can compound in the ionic liquid. An advantage of having ionic be formed by reacting a salt of a desired anion, Say YAnion liquid compositions is that the solubility and bioavailability where Y is an appropaite balancing cation, with a base to yield can be known and predicted. This allows homogeneous and the ionic liquid and Ybase byproduct. predictable dosing and tableting. Many of the bioactive compounds (e.g., pharmaceutical 15 Another notable advantage is that the disclosed ionic liquid actives, pesticidal actives, herbicidal actives, etc.) and ener compositions can be used to alleviate side effects associated getic compounds disclosed herein are cationic or can be made with various compounds. For example, the disclosed ionic cationic, the identification of which can be made by simple liquid compositions can contain anion from a drug known to inspection of the chemical structure as disclosed herein. Fur have an undesirable side effect along with a counterion that is ther, many of these compounds are commercially available as a drug known to alleviate or counteract that side effect. An their halide salts or can be converted to their halide salts by example of this is an ionic liquid composition that comprises reactions with acids (e.g., HF, HCl, HBr, or HI) or by treating the ions of morphine and docusate. Sucha composition can be a halogenated compound with a nucleophile Such as an used to treat pain due to the presence of morphine and relieve amine. Further many of the anions disclosed herein are com constipation due to the presence of docusate. Along the same mercially available as metal salts, Group I or II metal salts, or 25 lines, many pharmaceuticals are known to cause constipation, ammonium salts. Combining Such cations and anions in a and ionic liquids of these compounds with docusate or other Solvent with optional heating can thus produce the ionic liq laxatives are contemplated herein. uid compositions. For a review of the synthesis of ionic liq Generally, any use that exists for one or more of the ionic uids see, for example, Welton, Chem Rev 1999, 99:2071 components in the ionic liquid is also a use for the ionic liquid 2083, which is incorporated by reference herein for at least its 30 composition itself. For example, if one of the ions in an ionic teachings of ionic liquid synthesis. liquid composition disclosed herein is a pharmaceutical Ionic liquids which are immiscible with water are often active, then the ionic liquid composition can also be used for conveniently prepared by the combination of aqueous solu the same indication as the pharmaceutical active. In fact, tions of two precursor salts, each of which contains one of the many of the compounds disclosed herein as being Suitable two requisite ions of the targeted ionic liquids. On combina 35 ions for the disclosed ionic liquids have already been proven tion, the desired salt forms a separate phase from the aqueous to be effective alone or in some other preparation. Many of the admixture. Such phases are readily washed free of byproduct disclosed compounds are even FDA approved. When such salts with additional water, and may Subsequently subjected compounds are prepared as part of an ionic liquid, as dis to other procedures (e.g., as disclosed in the Examples) to closed herein, they can still maintain their efficacy, and can separate them from non-water soluble impurities. In certain 40 even have their efficacy enhanced by being part of the ionic cases, it is also possible to prepare water immiscible ionic liquid composition. For example, when an ionic liquid having liquids by the addition to a neutral amine-containing com a pharmaceutical active as one or more of its cations oranions pound (e.g., an active pharmaceutical ingredient) of an acid is administered to a subject, the pharmaceutical active will such as aqueous HTf.N. Certain Tf.N. salts of N—H con dissociate from the ionic liquid and be available to the subject taining cations are known to be water-immiscible. 45 in the same way as had a solid form (e.g., tablet) or solution of The purification of ionic liquids can be accomplished by the pharmaceutical active been administered. This effect is techniques familiar to those skilled in the art of organic and also observed for the antibacterial, antiviral, pesticidal, her inorganic synthesis, with the notable exception of purification bicidal, nutritional, food additives and other compounds and by distillation of the ionic liquid. One particularly useful actives disclosed herein. approach is the use of conventional or reverse-phase chroma 50 Other uses of the disclosed ionic liquid compositions tography to separate the salt of interest from other ionic or include the dissolution of the ionic liquid into liquid ban non-ionic materials, followed by the separation of the ionic dages. Liquid bandages are available from commercial Sup liquid from the eluting solvent, commonly by evaporation of pliers such as Johnson and Johnson. By dissolving the dis the latter. In some cases, ionic liquids can be purified by closed ionic liquid compositions into a liquid bandage, the crystallization or thermal Zone crystallization at appropriate 55 various ions in the ionic liquid (e.g., antiinfective, Steroidal, conditions of temperature and pressure. Such techniques can anesthetic, etc. ions) can be released into a wound and provide include the use of a solvent from which the ionic liquid can be beneficial effects. crystallized at an appropriate temperature. Other purification Further, the disclosed ionic liquids can be coated onto a techniques include exchange column chromatography and cellulosic bandage (e.g., a gauze or dressing). Thus, by Soak supercritical CO fluid extraction. 60 ing, spraying, or otherwise contacting a bandage with the Uses disclosed ionic liquid compositions, the bandage will contain The disclosed ionic liquid compositions have many uses. the various active ions of the ionic liquid along with their For example, the disclosed ionic liquid compositions can be associated functionality. In this regard, it may be desirable to used to allow fine tuning and control of the rate of dissolution, use an ionic liquid composition that melts at or around body solubility, and bioavailability, to allow control over physical 65 temperature. In this way, the ionic liquid composition can properties and mechanical strength, to improve homogenous “leach out of the bandage and onto the site contacted by the dosing, and to allow easier formulations. The disclosed ionic bandage. US 8,232,265 B2 161 162 Additionally, the disclosed ionic liquids can be melted by a population or the particular individual: (1) a Subject's physi consumer or physician (e.g., with hot water) and then cal condition is shown to be improved, (2) the progression of “painted onto an area of interest. It would then cool as a thin, the disease or condition is shown to be stabilized, or slowed, Solid coating of the ionic liquid. This use can provide a slow or reversed, or (3) the need for other medications for treating release form of the API in the ionic liquid or imparta desirable the disease or condition is lessened or obviated, then a par barrier on the area of interest. ticular treatment regimen will be considered efficacious. Depending on the particular ions, the disclosed ionic liquid Many of the disclosed ionic liquid compositions can be compositions can be used to treat a subject diagnosed with, used therapeutically as neationic liquids. Also, the disclosed for example, endocrine disorders, diabetes, infertility, hor ionic liquids can be used in combination with a pharmaceu mone deficiencies, osteoporosis, ophthalmological disorders, 10 tically acceptable carrier. By “pharmaceutically acceptable' neurodegenerative disorders, Alzheimer's disease, dementia, is meant a material that is not biologically or otherwise unde Parkinson's disease, multiple Sclerosis, Huntington's dis sirable, i.e., the material may be administered to a subject ease, cardiovascular disorders, atherosclerosis, hyper-coagu without causing any undesirable biological effects or inter lable states, hypo-coagulable states, coronary disease, cere acting in a deleterious manner with any of the other compo brovascular events, metabolic disorders, obesity, Vitamin 15 nents of the pharmaceutical formulation in which it is con deficiencies, renal disorders, renal failure, haematological tained. The carrier would naturally be selected to minimize disorders, anemia of different entities, immunologic and any degradation of the active ingredient and to minimize any rheumatologic disorders, autoimmune diseases, immune adverse side effects in the subject, as would be well known to deficiencies, infectious diseases, viral infections, bacterial one of skill in the art. In another aspect, many of the disclosed infections, fungal infections, parasitic infections, neoplastic ionic liquids can be used prophylactically, i.e., as a preventa diseases, multi-factorial disorders, impotence, chronic pain, tive agent, either neat or with a pharmaceutically acceptable depression, and different fibrosis states. carrier. The ionic liquid compositions disclosed herein can be Similarly, with herbicidal and pesticidal actives, the ionic conveniently formulated into pharmaceutical compositions liquid compositions disclosed herein that contain ionic pes composed of neat ionic liquid or in association with a phar ticidal and herbicidal actives can be used in the same way as 25 maceutically acceptable carrier. See e.g., Remington's Phar the actives themselves. Thus, any use contemplated for a maceutical Sciences, latest edition, by E. W. Martin Mack pesticidal and herbicidal active is contemplated herein for an Pub.Co., Easton, Pa., which discloses typical carriers and ionic liquid composition containing that active. conventional methods of preparing pharmaceutical composi Furthermore, because the disclosed ionic liquid composi tions that can be used in conjunction with the preparation of tions are liquid at a given temperature, they avoid problems 30 formulations of the compounds described herein and which is associated with polymorphism. For example, one can vary the incorporated by reference herein. Such pharmaceutical carri individual ions and the combination of ions to fine tune the ers, most typically, would be standard carriers for adminis characteristics of the compositions, thus obtaining a compo tration of compositions to humans and non-humans, includ sition with desired properties (e.g., better dissolution, Solu ing solutions such as sterile water, Saline, and buffered bility, or bioavailability). This can lead to easier dosing and 35 Solutions at physiological pH. Other compounds can be formulating of the actives in the compositions. By preparing administered according to standard procedures used by those and using the disclosed ionic liquid compositions, one need skilled in the art. For example, pharmaceutical compositions not need to prepare, Screen, and characterize numerous crys can also include one or more additional active ingredients talline forms of the actives. Such as antimicrobial agents, anti-inflammatory agents, anes In one aspect, disclosed herein are methods for using ionic 40 thetics, and the like. liquid compositions that comprise administering an effective Examples of pharmaceutically-acceptable carriers amount of at least one ionic liquid composition as disclosed include, but are not limited to, Saline, Ringer's solution and herein. By the term “effective amount of a compound as dextrose solution. The pH of the solution is preferably from provided herein is meant a nontoxic but Sufficient amount to about 5 to about 8, and more preferably from about 7 to about provide the desired result. As will be pointed out below, the 45 7.5. Further carriers include sustained release preparations exact amount required will vary from Subject to Subject, Such as semipermeable matrices of Solid hydrophobic poly depending on the species, age, and general condition of the mers containing the disclosed compounds, which matrices subject, the severity of the disease that is being treated, the are in the form of shaped articles, e.g., films, liposomes, particular compound used, its mode of administration, and microparticles, or microcapsules. It will be apparent to those the like. Thus, it is not possible to specify an exact “effective 50 persons skilled in the art that certain carriers can be more amount. However, an appropriate effective amount can be preferable depending upon, for instance, the route of admin determined by one of ordinary skill in the art using only istration and concentration of composition being adminis routine experimentation. The dose, schedule of doses, and tered. Other compounds can be administered according to route of administration can be varied. standard procedures used by those skilled in the art. The efficacy of administration of a particular dose of the 55 Pharmaceutical formulations can include additional carri ionic liquid compositions according to the methods described ers, as well as thickeners, diluents, buffers, preservatives, herein can be determined by evaluating the particular aspects Surface active agents and the like in addition to the com of the medical history, signs, symptoms, and objective labo pounds disclosed herein. Pharmaceutical formulations can ratory tests that are known to be useful in evaluating the status also include one or more additional active ingredients such as of a subject in need of attention for the treatment of a disease 60 antimicrobial agents, anti-inflammatory agents, anesthetics, and/or condition. These signs, symptoms, and objective labo and the like. ratory tests will vary, depending upon the particular disease or The pharmaceutical formulation can be administered in a condition being treated or prevented, as will be known to any number of ways depending on whether local or systemic clinician who treats such patients or a researcher conducting treatment is desired, and on the area to be treated. Adminis experimentation in this field. For example, if, based on a 65 tration may be topically (including ophthalmically, vaginally, comparison with an appropriate control group and/or knowl rectally, intranasally), orally, by inhalation, or parenterally, edge of the normal progression of the disease in the general for example by intravenous drip, Subcutaneous, intraperito US 8,232,265 B2 163 164 neal or intramuscular injection. The disclosed compounds that disinfectants, pesticides, or herbicides applied to plant can be administered intravenously, intraperitoneally, intra leaves can be less prone to be lost by rain even if it follows muscularly, Subcutaneously, intracavity, or transdermally as application. is described more fully elsewhere herein. When one or more ions in the disclosed ionic liquid com Administration and Delivery positions are an antibacterial, an effective amount of the com In one aspect, disclosed herein are uses of a delivery device position can be contacted (i.e., administered) to any surface to deliver an ionic liquid composition as disclosed herein to a that has bacteria. Similarly, when one or more ions in the subject. Further, disclosed are methods for delivering anionic disclosed ionic liquid composition are a pesticidal active, an liquid composition to a Subject by administering to the Sub effective amount of the composition can be administered to ject any of the nutritional Supplements, pharmaceutical for 10 an area to control pests. When one or more ions in the dis mulations, controlled release vehicles, delivery and/or closed ionic liquid composition are a herbicidal active, an devices. effective amount of the composition can be administered to The compositions described herein can be administered to an area to control plants. Techniques for contacting Such the Subject in a number of ways depending on whether local 15 Surfaces and areas with the disclosed ionic liquid composi or systemic treatment is desired, and on the area to be treated. tions can include, spraying, coating, dipping, immersing, or Thus, for example, a composition described herein can be pouring the composition into or onto the Surface or area. The administered as an ophthalmic solution and/or ointment to the precise technique will depend on Such factors as the type and Surface of the eye. Moreover, a compound or pharmaceutical amount of infestation or contamination, the size of the area, composition can be administered to a Subject vaginally, rec the amount of composition needed, preference, cost and the tally, intranasally, orally, by inhalation, or parenterally, for like. example, by intradermal, Subcutaneous, intramuscular, intra Delivery Devices peritoneal, intrarectal, intraarterial, intralymphatic, intrave Any of the compounds described herein can be incorpo nous, intrathecal and intratracheal routes. Parenteral admin rated into a delivery device. Examples of delivery devices istration, if used, is generally characterized by injection. 25 include, but are not limited to, microcapsules, microspheres, Injectables can be prepared in conventional forms, either as nanospheres or nanoparticles, liposomes, noisome, nano liquid solutions or Suspensions, Solid forms suitable for solu erythrosome, Solid-liquid nanoparticles, gels, gel capsules, tion or Suspension in liquid prior to injection, or as emulsions. tablets, lotions, creams, sprays, emulsions, or powders. Other A more recently revised approach for parenteral administra examples of delivery devices that are suitable for non-oral 30 administration include pulmospheres. Examples of particular tion involves use of a slow release or Sustained release system delivery devices usefuil herein are described below. such that a constant dosage is maintained. In one example an The disclosed compounds can be incorporated into lipo ionic liquid composition Such as lidocaine docusate is con Somes. AS is known in the art, liposomes are generally derived tacted to the skin of a subject to provide an anesthetic effect. from phospholipids or other lipid Substances. Liposomes are Preparations for parenteral administration include sterile 35 formed by mono- or multi-lamellar hydrated liquid crystals aqueous or non-aqueous solutions, Suspensions, and emul that are dispersed in an aqueous medium. Any non-toxic, sions which can also contain buffers, diluents and other Suit physiologically acceptable and metabolizable lipid capable able additives. Examples of non-aqueous solvents are propy of forming liposomes can be used. The disclosed composi lene glycol, polyethylene glycol, vegetable oils such as olive tions in liposome form can contain, in addition to a compound oil, and injectable organic esters such as ethyl oleate. Aque 40 disclosed herein, stabilizers, preservatives, excipients, and ous carriers include water, alcoholic/aqueous Solutions, the like. Examples of suitable lipids are the phospholipids and emulsions or Suspensions, including saline and buffered the phosphatidylcholines (lecithins), both natural and Syn media. Parenteral vehicles include sodium chloride solution, thetic. Methods of forming liposomes are known in the art. Ringer's dextrose, dextrose and sodium chloride, lactated See, e.g., Prescott, Ed., Methods in Cell Biology, Volume Ringer's, or fixed oils. Intravenous vehicles include fluid and 45 XIV. Academic Press, New York, p. 33 et seq., 1976, which is nutrient replenishers, electrolyte replenishers (such as those hereby incorporated by reference herein for its teachings of based on Ringer's dextrose), and the like. Preservatives and liposomes and their preparation. other additives, such as antimicrobials, anti-oxidants, chelat In other examples, the liposomes can be cationic liposomes ing agents, and inert gases and the like, can also be present. (e.g., DOTMA, DOPE, DC cholesterol) or anionic lipo Formulations for topical administration can include oint 50 Somes. Liposomes can further comprise proteins to facilitate ments, lotions, creams, gels, drops, suppositories, sprays, targeting a particular cell, if desired. Administration of a liquids and powders. The disclosed ionic liquid compositions composition comprising a compound and a cationic liposome having hydrophobic ions can be particularly useful in Such can be administered to the blood afferent to a target organ or applications because they can adhere to the Surface longer inhaled into the respiratory tract to target cells of the respira when exposed to water or other fluids than would a similar 55 tory tract. Regarding liposomes, see, e.g., Brigham, et al., Am hydrophilic salt. Likewise, ionic liquids comprising disinfec J Resp Cell Mol Biol. 1:95-100, 1989: Felgner, et al., Proc Natl tant, herbicide, or pesticide ions and hydrophobic counterions AcadSci USA 84:7413-7, 1987; and U.S. Pat. No. 4,897,355, can be expected to resisterosion from rainfall. Conventional which are incorporated by reference hereinfortheir teachings pharmaceutical carriers, aqueous, powder or oily bases, of liposomes. As one example, delivery can be via a liposome thickeners and the like can be necessary or desirable. When 60 using commercially available liposome preparations such as applied to skin or mucous tissues (e.g., oral applications) LIPOFECTIN, LIPOFECTAMINE (GIBCO-BRL, Inc., ionic liquid compositions containing pharmaceutical actives Gaithersburg, Md.), SUPERFECT (Qiagen, Inc. Hilden, Ger formulated with highly hydrophobic anions or cations (as many) and TRANSFECTAM (Promega Biotec, Inc., Madi appropriate) can have longer durations of adhesion when son, Wis.), as well as other liposomes developed according to exposed to water or other fluids than would similar hydro 65 procedures standard in the art. Liposomes where the diffusion philic salts applied in these environments. This would be of the compound or delivery of the compound from the lipo particularly beneficial for sun screens. It should also be noted Some is designed for a specific rate or dosage can also be used. US 8,232,265 B2 165 166 As described herein, niosomes are delivery devices that can are usually prepared by Supercritical fluid condensation tech be used to deliver the compositions disclosed herein. Noi nology. Co-spray-drying with certain matrices, such as car Somes are multilamellar or unilamellar vesicles involving bohydrates, human serum albumin, etc., can improve the non-ionic Surfactants. An aqueous solution of Solute is stability of proteins and peptides (e.g., insulin) and other enclosed by a bilayer resulting from the organization of Sur biomolecules for pulmonary delivery. This type of delivery factant macromolecules. Similar to liposomes, noisomes are could be also accomplished with micro-emulsions and lipid used in targeted delivery of for example, anticancer drugs, emulsions, which are ultra fine, thin, transparent oil-in-water including methotrexate, doxorubicin, and immunoadjuvants. (ofw) emulsions formed spontaneously with no significant They are generally understood to be different from transfer input of mechanical energy. In this technique, an emulsion oSomes, vesicles prepared from amphiphilic carbohydrate 10 and amino group containing polymers, e.g., chitosan. can be prepared at a temperature, which should be higher than As described herein, nanoerythrosomes are delivery the phase inversion temperature of the system. At elevated devices that can be used to deliver the compositions disclosed temperature the emulsion is of water-in-oil (w/o) type and as herein. NanoerythroSomes are nano-vesicles made of red it cools at the phase inversion temperature, this emulsion is blood cells via dialysis through filters of defined pore size. 15 inverted to become of w. Due to their very small inner phase, These vesicles can be loaded with a diverse array of biologi they are extremely stable and used for sustained release of cally active molecules, including proteins and the composi steroids and vaccines. Lipid emulsions comprise a neutral tions disclosed herein. They generally serve as ideal carriers lipid core (i.e., triglycerides) stabilized by a monolayer of for antineoplastic agents like bleomycin, actinomycin D, but amphiphilic lipid (i.e., phospholipid) using Surfactants like can be used for steroids, other lipids, etc. egg lecithin triglycerides and miglyol. They are Suitable for Artificial red blood cells, as described herein, are further passive and active targeting. delivery devices that can be used to deliver the compositions There are other oral delivery systems under investigation disclosed herein. Artificial red blood cells can be generated by that are based on osmotic pressure modulation, pH modula interfacial polymerization and complex emulsion methods. tion, Swelling modulation, altered density and floating sys Generally, the “cell' wall is made of polyphtaloyl L-lysine 25 tems, mucoadhesiveness etc. These formulations and time polymer/polystyrene and the core is made of a hemoglobin delayed formulations to deliver drugs in accordance with Solution from sheep hemolysate. Hemoglobin loaded micro circadian rhythm of disease that are currently in use or inves spheres typically have particle sizes of from about 1 to about tigation can be applied for delivery of the compositions dis 10 mm. Their size, flexibility, and oxygen carrying capacity is closed herein. similar to red blood cells. 30 Solid-lipid nanoparticles, as described herein, are other It is also contemplated that the disclosed ionic liquid com delivery devices that can be used to deliver the compositions positions can be formulated as part of a controlled release disclosed herein. Solid-lipid nanoparticles are nanoparticles, vehicle. For example, microspheres and microcapsules, which are dispersed in an aqueous Surfactant Solution. They implants, and the like containing liquid bioactive agents are are comprised of a solid hydrophobic core having a mono 35 well known, as are methods for their preparation. As such, layer of a phospholipid coating and are usually prepared by these methods can be used with the disclosed ionic liquid high-pressure homogenization techniques. Immunomodulat compositions to produce controlled release vehicles that can ing complexes (ISCOMS) are examples of solid-lipid nano release the disclosed ionic liquid composition with a desired particles. They are cage-like 40 nm Supramolecular assem release profile. blies comprising of phospholipid, cholesterol, and 40 Also contemplated are pills prepared from the disclosed hydrophobic antigens and are used mostly as immunoadju ionic liquid compositions that are glasses. For example, a vants. For instance, ISCOMs are used to prolong blood glass ionic liquid composition can be cooled to form a pill. plasma levels of Subcutaneously injected cyclosporine. That is, glasses are “cast-able' above their glass transition Microspheres and micro-capsules, as described herein, are temperature (T) into shapes with specific surface areas, yet other delivery devices that can be used to deliver the 45 allowing predictable release/pharmacokinetic properties. compositions disclosed herein. In contrast to liposomal deliv Below T, these disclosed glass ionic liquid composition can ery systems, microspheres and micro-capsules typically do be milled into specific shapes and sizes. Alternatively, the not have an aqueous core but a solid polymer matrix or mem disclosed ionic liquid compositions can be tableted as liquids brane. These delivery devices are obtained by controlled pre that upon cooling form glasses. Such a method can allow the cipitation of polymers, chemical cross-linking of soluble 50 homogeneous distribution of a pharmaceutical active into the polymers, and interfacial polymerization of two monomers or tablet. high-pressure homogenization techniques. The encapsulated A particular example includes ionic liquid compositions compound is gradually released from the depot by erosion or that are in the glass form but melt at or slightly above body diffusion from the particles. Successful formulations of short temperature. Such compositions can allow formulation as a acting peptides, such as LHRH agonists like leuprorelin and 55 solid, but have known solubility, bioavailability, etc. as a triptoreline, have been developed. Poly(lactide co-glycolide liquid. These compositions can have uses in, for example, (PLGA) microspheres are currently used as monthly and bandages, patches, or wound dressings. Further, glass com three monthly dosage forms in the treatment of advanced positions that “melt slightly above room temperature can be prostrate cancer, endometriosis, and other hormone respon "melted by a consumer or physician with, e.g., hot water or sive conditions. Leuprolide, an LHRH Superagonist, was 60 body heat, and “painted onto an area of interest (infected incorporated into a variety of PLGA matrices using a solvent area). Cooling of the composition can then provide a thin, extraction/evaporation method. As noted, all of these delivery solid coating of material which is both a slow release form of devices can be used in the methods disclosed herein. an active ingredient ion (e.g., anti-infective, Steroid, anes Pulmospheres are still other examples of delivery devices thetic, or combination thereof), plus serve as a physical bar that can be used herein. Pulmospheres are hollow porous 65 rier. particles with a low density (less than about 0.1 gm/mL). Further, the disclosed ionic liquids can be used as carriers Pulmospheres typically have excellent re-dispersibility and for other active compounds, many of which are disclosed US 8,232,265 B2 167 168 herein. For example, prodrugs, ionic and neutral active mol able in cold and warm water. Thermal stability of this salt is ecules can be dissolved in the disclosed ionic liquid compo presented in Table 2. Synthesized salt appear to be sweet and sitions. active against microorganisms. The activity is high in com Further methods of administration can include incorporat parison with starting material, didecyldimethylammonium ing the disclosed ionic liquid composition into a foodstuffor chloride, which is confirmed by MIC and MBC values (Table beverage, which can be ingested by a Subject. 3 and Table 4). The disclosed ionic liquids can also be encapsulated in a polymer matrix by methods known in the art. Elemental analysis: CHN: CHNOS (508.80) calcu Also, the disclosed ionic liquid compositions can be dis lated values: C=68.46%, H=10.30% i N=5.51%; experimen solved in a suitable solvent or carrier as are disclosed herein. 10 tal values C=68.78%, H=10.69%, N=5.31%. "H NMR This method can enhance the delivery of one or more active (DMSO-d) cation: 3.22 (m, 4H); 3.00 (s, 6H); 1.63 (m, 4H); ions in the ionic liquid. Further, as is disclosed herein, this 1.24 (m. 28H): 0.85 (t, J=7 Hz, 6H); anion: 7.58 (m, 4H); 'C method can create a synergistic effect among the various ions NMR cation: 62.7: 49.9; 31.2: 28.8; 28.7; 28.6; 28.4; 25.6; present. While not wishing to be bound by theory, the disso 22.0: 21.6; 13.8; anion: 167.7: 145.2: 1348; 131.3,130.8; ciate coefficient of various ions in an ionic liquid can be 15 122.3; 118.9. different in different solvents. Thus, ions in an ionic liquid can dissociate freely in one solvent and cluster in another. This TABLE 2 phenomenon can be utilized to provide formulations of com pound that are difficult to deliver (e.g., increase the water Thermal stability data of synthesized salts solubility of steroids). That is, compounds can beformed into an ionic liquid, as described herien, and then dissolved in a Temperature BASac DDA)Sac (BAAce DDAAce suitable solvent to provide an easily deliverable solution. A Tg -52.5 -58 synertistic effect can be observed upon administration to a T 21.5 18.0 26.4 -45.5 Subject, when ions cluster and act together, rather than inde Ts-s 65.5 pendently. 25 Tn 82.5 22.5 89 -29 Tonset(5%) 176 184 186 182 EXAMPLES Tonset 2O6 211 (203)258 2O1 T. 227 221 (225)273 245 The following examples are set forth below to illustrate the T-glass transition. methods and results according to the disclosed subject matter. 30 T - crystallization temperature recorded by the DSC. These examples are not intended to be inclusive of all aspects T - solid-solid transitions recorded by the DSC. of the subject matter disclosed herein, but rather to illustrate T - melting point recorded by the DSC. representative methods and results. These examples are not Teso- onset temperature for 5% of the decomposition, intended to exclude equivalents and variations of the present T - onset temperature of the decomposition, invention which are apparent to one skilled in the art. 35 T - temperature of total decomposition, Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated TABLE 3 otherwise, parts are parts by weight, temperature is in C. or MIC values for investigated salts is at ambient temperature, and pressure is at or near atmo 40 spheric. There are numerous variations and combinations of BA) DDA) BA) DDA reaction conditions, e.g., component concentrations, tem culture Sac Sac Ace Ace BAC** DDAC*** peratures, pressures and other reaction ranges and conditions S. airetts 4 4 4 8 2 2 that can be used to optimize the product purity and yield E. faecium 8 8 8 8 4 4 obtained from the described process. Only reasonable and 45 E. coi 16 16 31.2 16 8 8 C. albicans 16 16 16 16 8 8 routine experimentation will be required to optimize Such Average 11 11 14.8 12 5.5 5.5 process conditions. All chemicals used were of analytical value grade, purchased from Sigma-Aldrich (Milwaukee, Wis.), and used without further purification unless otherwise noted. *in ppm. 50 benzalkonium chloride. Example I ***didecyldimethylammonium chloride

Didecyidimethylammonium Saccharinate TABLE 4 DDAISac 55 MBC values for investigated Salts. To the reaction flask, equipped with stirring bar and ther BA) DDA BA (DDA) mometer, 0.03 mol of didecyldimethylammonium bromide Culture Sac Sac Ace Ace BAC** DDAC*** and 0.03 mol of saccharin sodium salt, and 50 mL of water were put in. The mixture was intensively stirred for one hour S. airetts 31.2 62.5 31.2 16 62.5 31.2 E. faecium 16 16 31.2 31.2 31.2 31.2 at room temperature. Afterwards 50 mL of chloroform was 60 E. coi 62.5 16 125 62.5 62.5 31.2 added. After phases separated, chloroform phase was isolated C. albicans 31.2 16 31.2 16 16 16 (separated), and washed with fresh distilled water (so many Average 35.2 27.6 54.7 31.4 43.1 27.4 times) until all chloride ions were washed out (removed). value Chloroform was distilled off (evaporated) and the residue *in ppm. (remains) was dried at 60°C. in vacuum. Saccharinate inform 65 benzalkonium chloride. of liquid, with high viscosity was obtained in 95% yield. It is ***didecyldimethylammonium chloride hydrophobic liquid (fluid), lighter than water, poorly dissolv US 8,232,265 B2 169 170 Example II of acesulfamate potassium salt were put in (placed) into the reactor. The mixture was stirred for 1 h at the room tempera Benzalkonium Saccharinate BASac ture. Afterwards 50 mL of chloroform was added. Water phase was separated and chloroform phase was washed with To the Saturated water Solution of Saccharin Sodium, the 5 fresh distilled water (so many times) util all chloride ions water solution of benzalkonium chloride (alkyl substituent— dodecyl and tetradecyl) was added in the molar ratio of 1:1.5. were washed out (removed). The progress was monitored by The mixture was stirred for 1 h at the temperature of 60° C. using water solution of AgNO. After the chloroform was After the mixture was cooled down to the room temperature, evaporated, the liquid (fluid) was obtained with 94% yield, white wax was formed. The wax was dissolved in chloroform. and dried at 65° C. in vacuum. Chloroform phase was washed with fresh distilled water (so 10 The hydrophobic, sweet liquid, with high viscosity, lighter many times) until all chloride ions were washed out (re than water and thermally stable was obtained (Table 2). Cal moved). The progress was monitored by using water Solution culated MIC and MBC values are shown in the Table 3 and of AgNO. Afterwards chloroform was distilled off (evapo Table 4. Comparing average values of MIC and MBC for the rated) and the residue (remains) wax was dried at 50° C. in synthesized salt with the values for didecyldimethylammo vacuum. Synthesized benzalkonium saccharinate was 15 nium chloride the only slight difference in the biological obtained with 98% yield. It is very sweet in taste. Obtained activity is seen (recorded). wax is poorly dissolvable in cold and warm water. Crystalline Elemental analysis: CHN: CHNOS (488.77) calcu benzalkonium saccharinate, with the melting point of 80-82° lated values C=63.89%, H=10.72% iN=5.73%; experimental C., was obtained form the mixture of dry (no water) acetone values C=64.09%, H=10.99%, N=5.41%. "H NMR (DMSO and diethylether in the volume ratio of 10:1. 2O d) cation: 3.22 (m, 4H), 2.99 (s. 6H), 1.63 (m, 4H), 1.26 (m, "H NMR (DMSO-d)7.59 (m, 9H), 4.53 (s. 2H), 3.24 (m, 28H), 0.86 (t, J–7 Hz, 6H), anion: 5.26 (q, J=1 Hz, 1H), 1.89 2H), 2.95 (s, 6H), 1.77 (m, 2H), 1.24 (m, 20H), 0.85 (t, J=7 (d, J-2 Hz,3H); 'CNMR cation: 62.7, 49.8, 31.2, 28.8, 28.7, Hz, 3H); 'C NMR cation: 132.8, 130.1, 128.8, 128.0, 66.1, 28.6, 28.4, 25.7, 22.0, 21.6, 13.8, anion: 167.6, 159.4, 102.0, 63.4, 49.0, 31.2, 28.9, 28.85, 28.7, 28.6, 28.4, 25.7, 22.0, 21.7, 19.3. 13.8, anion: 167.7, 145.2, 1348, 1314, 130.8, 122.3, 118.9. In the biological activity measurements (tests) following Example III bacteria were used: Staphylococcus aureus ATCC 6538, Enterococcus faecium ATCC 49474, Escherichia coli ATCC 25922 and fungi Candida albicans ATCC 10231. Benzalkonium Acesulfamate BAAce Microbiological activity tests were performed using disso To the reactor the water solution of 1 mol of benzalkonium. " lution method. Determinations were performed on liquid chloride (alkyl substituent is the mixture of the following base (background): Mueller-Hinton for bacteria and Sab groups: octyl, decyl, dodecyl, tetradecyl, hexadecyl and octy ouraud for fungi. Starting solution had the concentration of 1 decyl) and water solution of 1.5 mol of acesulfamate sodium g/cm. From this solution, all other solutions (lower concen were put in (placed). The mixture was stirred for 1 h at the trations) were prepared. To those solutions, 0.1 cm of the temperature of 60°C. After the mixture was cooled down to 35 Suspensions of standard microorganisms at a concentration of the room temperature. Formed wax was dissolved in chloro 10° cfu cm were added. The samples with bacteria were form and separated water phase was removed. Chloroform incubated for 24hat the temperature of 37°C., and with fungi phase was washed with fresh distilled water (so many times) there were incubated for 48 h at the temperature of 22°C. until all chloride ions were washed out (removed). The After incubation time the MIC, Minimal Inhibitory Concen progress was monitored by using water Solution of AgNO. 40 tration, minimal concentration of the investigated compound Chloroform was distilled off (evaporated) and the product at which the growth of the microorganisms is stopped (visu dried at 60°C. in vacuum. Obtained wax, with the 95% yield, ally), was specified (recorded) for every sample. To define the was crystallized out (re-crystallized) from the mixture of MBC, Minimal Bactericidal Concentration, additionally to THF, acetone and diethylether in the volume ratio of 10:10:1. each solution the 10 cm of the inactivator was added on the Crystalline benzalkonium acesulfamate, which has Sweet taste, melts between 90 and 91 ° C. The melting point 45 base (background) (0.3% lecithin, 3% polysorbate 80 and recorded on the by the DSC (diffraction scanning calorim 0.1% L-cysteine). The samples with bacteria were incubated eter) was 89° C. This salt is poorly dissolvable in cold and for 48 h in the temperature of 37°C. The fungi samples were Warm Water. incubated for 5 days at the temperature of 22°C. MBC values Measured thermal decomposition temperature of obtained were defined (specified) as the concentration at which the salt are placed in Table 2, while biological activity data in 50 level of the reduction of the microorganisms was not lower Table 3 and Table 4. Calculated average values for MIC and than 99.99%. MBC indicate high activity of the salt, slightly lower than that of the starting benzalkonium chloride Example V H NMR (DMSO-d) cation: 7.52 (m, 5H), 4.53 (s. 2H), 3.24 (m, 2H), 2.95 (s, 6H), 1.78 (m, 2H), 1.25 (m, 20H), 0.85 55 Benzalkonium Sulfacetamide (t, J=7 Hz, 3H), anion: 5.28 (s, 1H), 1.90 (s, 3H); C NMR cation: 132.8, 130.1, 128.8, 128.0, 66.1, 63.4, 49.0, 31.2, Benzalkonium chloride (0.001 mol) was dissolved in 60 28.9, 28.87, 28.7, 28.6, 28.4, 25.7, 22.0, 21.7, 13.8, anion: mL of distilled water by gentle heating and stirring. Sodium 1676, 159.5, 102.0, 19.3. sulfacetamide (0.001 mol) was dissolved in 60 mL of distilled 60 water by gentle heating and stirring. The two solutions were Example IV combined and the reaction mixture was heated and stirred for 30 minutes. The reaction mixture cooled to room temperature Didecyldimethylammonium Acesulfamate and then 60 mL of chloroform was added. The reaction mix DDAAce ture was stirred for an additional 30 minutes. The two phases 65 were separated and the chloroform phase was washed several 0.03 mol of didecyldimethylammonium bromide, in form times with cool distilled water to remove any inorganic salt. of gel (75%) in water, and water solution of 0.03 mol (6.04 g) The presence of chloride anions was monitored by silver US 8,232,265 B2 171 172 nitrate test. A rotary evaporator removed the chloroform and point (hot plate apparatus)=C. Thermogravimetric analysis: a yellowish gel was obtained in 76.99% yield. "H and 'C T -41.1° C., Tso-133° C. and T-153° C. NMR (DMSO) were obtained. Melting point (hot plate appa ratus)=35-40°C. Thermal data determined by thermalgravi Example IX metric analysis (TGA): T =164° C. and T = 181° C. 5 orses-6 dasei Didecyldimethylammonium Ibuprofen Example VI Didecyldimethylammonium bromide (0.001 mol) was dis Didecyldimethylammonium Sulfacetamide solved in 60 mL of distilled water by gentle heating and 10 stirring. Ibuprofen (0.001 mol) was dissolved in 60 mL of Didceyldimethylammonium bromide (0.001 mol) was dis distilled water by gentle heating and stirring. The two solu solved in 60 mL of distilled water by gentle heating and tions were combined and the reaction mixture was heated and stirring. Sodium sulfacetamide (0.001 mol) was dissolved in stirred for 30 minutes. The reaction mixture cooled to room 60 mL of distilled water by gentle heating and stirring. The temperature and then 60 mL of chloroform was added. The two solutions were combined and the reaction mixture was 15 reaction mixture was stirred for an additional 30 minutes. The heated and stirred for 30 minutes. The reaction mixture two phases were separated and the chloroform phase was cooled to room temperature and then 60 mL of chloroform washed several times with cool distilled water to remove any was added. The reaction mixture was stirred for an additional inorganic salt. The presence of chloride anions was monitored 30 minutes. The two phases were separated and the chloro by silver nitrate test. A rotary evaporator removed the chlo form phase was washed several times with cool distilled water roform and a % yield. "H and 'C NMR (DMSO) were to remove any inorganic salt. The presence of chloride anions obtained. Melting point (hot plate apparatus)= C. Thermo was monitored by silver nitrate test. A rotary evaporator gravimetric analysis: T-57.1° C., Torses-6 =153° C. and removed the chloroform and a yellowish gel was obtained in T =1720 C. 87.74% yield. H and 'C NMR (DMSO) were obtained. dasei Melting point (hot plate apparatus)=25-30°C. Thermal data 25 Example X determined by thermalgravimetric analysis (TGA): Tso. 183.3°C. and T-200.2°C. Didecyldimethylammonium trans-Cinnamate Example VII Didecyldimethylammonium bromide (0.001 mol) was dis 30 solved in 50 mL of hot distilled water. trans-Cinnamic acid Hexadecylpyridinium Sulfacetamide (0.001 mol) was added to the didecyldimethylammonium solution. The reaction solution was stirred at 90° C. for 4 h. Hexadecylpyridinium chloride (0.001 mol) was dissolved The reaction Solution was cooled to room temperature and in 60 mL of distilled water by gentle heating and stirring. then 60 mL of chloroform was added. The two phases were Sodium sulfacetanide (0.001 mol) was dissolved in 60 mL of 35 separated and the chloroform phase was washed several times distilled water by gentle heating and stirring. The two solu with cool distilled water to remove any inorganic salt. The tions were combined and the reaction mixture was heated and presence of chloride anions was monitored by silver nitrate stirred for 30 minutes. The reaction mixture cooled to room test. A rotary evaporator removed the chloroform and a wax temperature and then 60 mL of chloroform was added. The was obtained in 93% yield. Hand 'C NMR (DMSO) were reaction mixture was stirred for an additional 30 minutes. The 40 obtained. Melting point (hot plate apparatus)=54-55° C. two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any Example XI inorganic salt. The presence of chloride anions was monitored by silver nitrate test. A rotary evaporator removed the chlo Benzalkonium trans-Cinnamate roform and an orange wax was obtained in 99.22% yield. "H 45 and 'C NMR (DMSO) were obtained. Melting point (hot Benzalkonium chloride (0.001 mol) was dissolved in warm plate apparatus)-30-40°C. Thermal data determined by ther distilled water. trans-Cinnamic acid (0.001 mol) was added to malgravimetric analysis (TGA): Tso.OS8 211° C. and the benzalkonium solution. The reaction solution was stirred T=2199dasei C. at 90° C. for 4 hours. The reaction solution was cooled to 50 room temperature then 60 mL of chloroform was added. The Example VIII two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any Benzalkonium Ibuprofen inorganic salt. The presence of chloride anions was monitored by silver nitrate test. A rotary evaporator removed the chlo Benzalkonium chloride (0.001 mol) was dissolved in 60 55 roform and an orange viscous liquid was obtained in 90% mL of distilled water by gentle heating and stirring. Ibuprofen yield. H and 'C NMR (DMSO) were obtained. Melting (0.001 mol) was dissolved in 60 mL of distilled water by point (hot plate apparatus) liquid at room temperature. gentle heating and stirring. The two solutions were combined and the reaction mixture was heated and stirred for 30 min Example XII utes. The reaction mixture cooled to room temperature and 60 then 60 mL of chloroform was added. The reaction mixture Hexadecylpyridinium Cola wet MA-80 was stirred for an additional 30 minutes. The two phases were separated and the chloroform phase was washed several times Hexadecylpyridinium chloride (0.001 mol) was dissolved with cool distilled water to remove any inorganic salt. The in 60 mL of distilled water by gentle heating and stirring. presence of chloride anions was monitored by silver nitrate 65 Sodium dihexylsulfosuccinate (Colawet MA-80 from Colo test. A rotary evaporator removed the chloroform and a % nial Chemicals, South Pittsburg, Tenn., 0.001 mol) was dis yield. H and 'C NMR (DMSO) were obtained. Melting solved in 60 mL of distilled water by gentle heating and US 8,232,265 B2 173 174 stirring. The two solutions were combined and the reaction stirring. Fast Green FCF (0.001 mol) was dissolved in 60 mL mixture was heated and stirred for 30 minutes. The reaction of distilled water by gentle heating and stirring. The two mixture cooled to room temperature and then 60 mL of chlo Solutions were combined and the reaction mixture was heated roform was added. The reaction mixture was stirred for an and stirred for 30 minutes. The reaction mixture cooled to additional 30 minutes. The two phases were separated and the chloroform phase was washed several times with cool dis room temperature and then 60 mL of chloroform was added. tilled water to remove any inorganic salt. The presence of The reaction mixture was stirred for an additional 30 minutes. chloride anions was monitored by silver nitrate test. A rotary The two phases were separated and the chloroform phase was evaporator removed the chloroform and a yellowish viscous washed several times with cool distilled water to remove any liquid was obtained in 96.93% yield. H and 'C NMR inorganic salt. The presence of chloride anions was monitored (DMSO) were obtained. Melting point (hot plate apparatus)= by silver nitrate test. A rotary evaporator removed the chlo liquid at room temperature. Thermal data determined by ther roform and a dark blue liquid was obtained in 65.54% yield. malgravimetric analysis (TGA): Tso. 248° C. and Melting point (hot plate apparatus) liquid at room tempera Tdasei =262° C. ture. Thermal data determined by thermalgravimetric analy sis (TGA): Tso-194° C. and Tdasei 200° C. Example XIII 15 Example XVII Didecyldimethylammonium Cola wet MA-80 Hexadecylpyridinium Fast Green FCF Decyldimethylammonium bromide (0.001 mol) was dis solved in 60 mL of distilled water by gentle heating and Hexadecylpyridinium chloride (0.003 mol) was dissolved stirring. Sodium dihexylsulfosuccinate (Colawet MA-80 in 100 mL of distilled water by gentle heating and stirring. from Colonial Chemicals, South Pittsburg, Tenn., 0.001 mol) Fast Green FCF (0.001 mol) was dissolved in 60 mL of was dissolved in 60 mL of distilled water by gentle heating distilled water by gentle heating and stirring. The two solu and stirring. The two solutions were combined and the reac tions were combined and the reaction mixture was heated and tion mixture was heated and stirred for 30 minutes. The reac 25 stirred for 30 minutes. The reaction mixture cooled to room tion mixture cooled to room temperature and then 60 mL of temperature and then 60 mL of chloroform was added. The chloroform was added. The reaction mixture was stirred for reaction mixture was stirred for an additional 30 minutes. The an additional 30 minutes. The two phases were separated and two phases were separated and the chloroform phase was the chloroform phase was washed several times with cool washed several times with cool distilled water to remove any distilled water to remove any inorganic salt. The presence of 30 inorganic salt. The presence of chloride anions was monitored chloride anions was monitored by silver nitrate test. A rotary by silver nitrate test. A rotary evaporator removed the chlo evaporator removed the chloroform and a yellowish viscous roform and a dark blue soild was obtained in 28.14% yield. liquid was obtained in 96.93% yield. H and 'C NMR Melting point (hot plate apparatus)=40-50° C. Thermal data (DMSO) were obtained. Melting point (hot plate apparatus)= determined by thermalgravimetric analysis (TGA): 35 liquid at room temperature. Thermal data determined by ther Torses-6 =216? C. and T=218dasei CF307 CFSO4° C. malgravimetric analysis (TGA): Torses-6 =2.18° C. and T=226°dasei C. Example XVIII Example XIV Benzalkonium Fast Green FCF 40 Benzalkonium ColawetMA-80 Benzalkonium chloride (0.003 mol) was dissolved in 100 mL of distilled water by gentle heating and stirring. Fast Benzalkonium chloride (0.001 mol) was dissolved in 60 Green FCF (0.001 mol) was dissolved in 60 mL of distilled mL of distilled water by gentle heating and stirring. Sodium water by gentle heating and stirring. The two solutions were dihexylsulfosuccinate (Colawet MA-80 from Colonial 45 combined and the reaction mixture was heated and stirred for Chemicals, South Pittsburg, Tenn., 0.001 mol) was dissolved 30 minutes. The reaction mixture cooled to room temperature in 60 mL of distilled water by gentle heating and stirring. The and then 60 mL of chloroform was added. The reaction mix two solutions were combined and the reaction mixture was ture was stirred for an additional 30 minutes. The two phases heated and stirred for 30 minutes. The reaction mixture were separated and the chloroform phase was washed several cooled to room temperature and then 60 mL of chloroform 50 times with cool distilled water to remove any inorganic salt. was added. The reaction mixture was stirred for an additional The presence of chloride anions was monitored by silver 30 minutes. The two phases were separated and the chloro nitrate test. A rotary evaporator removed the chloroform and form phase was washed several times with cool distilled water a dark bluegel was obtained in 91.52% yield. Melting point to remove any inorganic salt. The presence of chloride anions (hot plate apparatus)=35-45°C. Thermal data determined by was monitored by silver nitrate test. A rotary evaporator 55 thermalgravimetric analysis (TGA): Tso-136° C. and removed the chloroform and a clear viscous liquid was Tdasei = 1950 C. obtained in 75.56% yield. H and 'C NMR (DMSO) were obtained. Melting point (hot plate apparatus) liquid at room Example XX temperature. Thermal data determined by thermalgravimetric 60 analysis (TGA): Tso. 223° C. and T-262dasei C. Hexadecylpyridinium Piperacillin Example XV Hexadecylpyridinium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. Didecyldimethylammonium Fast Green FCF Sodium piperacillin (0.001 mol) was dissolved in 60 mL of 65 distilled water by gentle heating and stirring. The two solu Didecyldimethylammonium bromide (0.003 mol) was dis tions were combined and the reaction mixture was heated and solved in 100 mL of distilled water by gentle heating and stirred for 30 minutes. The reaction mixture cooled to room US 8,232,265 B2 175 176 temperature, and then 60 mL of chloroform was added. The by silver nitrate test. A rotary evaporator removed the chlo reaction mixture was stirred for an additional 30 minutes. The roform and a yellowish soft solid was obtained in 93.60% two phases were separated and the chloroform phase was yield. H and 'C NMR (DMSO) were obtained. Melting washed several times with cool distilled water to remove any point (hot plate apparatus)-30-40°C. inorganic salt. The presence of chloride anions was monitored by silver nitrate test. A rotary evaporator removed the chlo Example XXIII roform and a soft orange solid was obtained in 58.66% yield. Melting point (hot plate apparatus)-30-40°C. Didecyldimethylammonium Penicillin G Example XX 10 Didecyldimethylammonium bromide (0.001 mol) was dis solved in 60 mL of distilled water by gentle heating and Didecyidimethylammonium Piperacillin stirring. Potassium penicillin G (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. The Didceyldimethylammonium bromide (0.001 mol) was dis two solutions were combined and the reaction mixture was solved in 60 mL of distilled water by gentle heating and 15 heated and stirred for 30 minutes. The reaction mixture stirring. Sodium piperacillin (0.001 mol) was dissolved in 60 cooled to room temperature and then 60 mL of chloroform mL of distilled water by gentle heating and stirring. The two was added. The reaction mixture was stirred for an additional Solutions were combined and the reaction mixture was heated 30 minutes. The two phases were separated and the chloro and stirred for 30 minutes. The reaction mixture cooled to form phase was washed several times with cool distilled water room temperature and then 60 mL of chloroform was added. to remove any inorganic salt. The presence of chloride anions The reaction mixture was stirred for an additional 30 minutes. was monitored by silver nitrate test. A rotary evaporator The two phases were separated and the chloroform phase was removed the chloroform and an orange gel was obtained in washed several times with cool distilled water to remove any 76% yield. "Hand 'C NMR (DMSO) were obtained. Melt inorganic salt. The presence of chloride anions was monitored ing point (hot plate apparatus)=25-30°C. by silver nitrate test. A rotary evaporator removed the chlo 25 roform and a clear gel was obtained in 50.65% yield. Hand Example XXIV 'C NMR (DMSO) were obtained. Melting point (hot plate apparatus)=25-30°C. Thermal data determined by thermal Hexadecylpyridinium Penicillin G gravimetric analysis (TGA): Torses-6 = 181° C. and 30 T=2059dasei C. Hexadecylpyridinium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. Example XXI Potassium penicillin G (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. The two solu Benzalkonium Piperacillin tions were combined and the reaction mixture was heated and 35 stirred for 30 minutes. The reaction mixture cooled to room Benzalkonium chloride (0.001 mol) was dissolved in 60 temperature and then 60 mL of chloroform was added. The mL of distilled water by gentle heating and stirring. Sodium reaction mixture was stirred for an additional 30 minutes. The piperacillin (0.001 mol) was dissolved in 60 mL of distilled two phases were separated and the chloroform phase was water by gentle heating and stirring. The two solutions were washed several times with cool distilled water to remove any combined and the reaction mixture was heated and stirred for 40 inorganic salt. The presence of chloride anions was monitored 30 minutes. The reaction mixture cooled to room temperature by silver nitrate test. A rotary evaporator removed the chlo and then 60 mL of chloroform was added. The reaction mix roform and an orange gel was obtained in about 99% yield. ture was stirred for an additional 30 minutes. The two phases Melting point (hot plate apparatus)=35-40°C. were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. 45 Example XXV The presence of chloride anions was monitored by silver nitrate test. A rotary evaporator removed the chloroform and Didecyldimethylammonium Salicylate a cloudy solid was obtained in 26.12% yield. H and 'C NMR (DMSO) were obtained. Melting point (hot plate appa Didecyldimethylammonium bromide (0.03 mol) (tech., ratus)-30-40°C. Thermal data determined by thermalgravi 50 75% gel in water) was dissolved in 50 mL hot, distilled water. metric analysis (TGA): Tso 165° C. and T-177°C. Salicylic acid (0.03 mol) was added to the solution. The mixture was stirred vigorously at 90° C. for 4 h. After cooling Example XXII to room temperature, 60 mL of chloroform was added. Chlo roform phase was washed with distilled water until bromide Benzalkonium Penicillin G 55 ions were no longer detected using AgNO. The obtained wax (93% yield) was dried in vacuum. Thermogravimetric analy Benzalkonium chloride (0.001 mol) was dissolved in 60 sis: T -1.0° C., T-30.4° C., TonsetS9% = 169° C. and mL of distilled water by gentle heating and stirring. Potas dasei =200° C. "Hand 'C NMR (DMSO) were obtained. sium penicillin G (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. The two solu 60 Example XXVI tions were combined and the reaction mixture was heated and stirred for 30 minutes. The reaction mixture cooled to room Benzalkonium Salicylate temperature and then 60 mL of chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The Benzalkonium chloride (0.03 mol) was disolved in warm two phases were separated and the chloroform phase was 65 distilled water and Stechiometric amount of salicylic acid was washed several times with cool distilled water to remove any added. The reaction mixture was stirred at 90° C. for 4h. After inorganic salt. The presence of chloride anions was monitored cooling, chloroform was added. The organic phase was US 8,232,265 B2 177 178 washed with distilled water until chloride ions were no longer mL of hexane and used in the next step without further puri detected using AgNO. Organic solvent was removed and the fication. The crude (2-acetooxyethyl)-dodecyloxymeth residue was dried in vacuum. Benzalkonium salicylate was yldimethylammonium chloride was dissolved in 30 mL of obtained with 90% yield as wax at room temperature; it is water and aqueous solution of potassium benzoate (0.065 soluble in hot water. Thermogravimetric analysis: T-43.5° mol) was added. After 30 min, 30 mL of chloroform was C., Tso-150° C., and T-180° C. "Hand iic NMR added. The chloroform phase was separated and washed with (DMSO) were obtained. distilled water until chloride ions were no longer detected using AgNO. The obtained grease was dried under vacuum. Example XXVII The product was obtained as grease in 67% yield. Thermo 10 gravimetric analysis: T-122° C. "H and 'C NMR (2-hydroxyethyl)dimethylundecyloxymethylammonium (DMSO) were obtained. Benzoate Example XXX 2-(dimethylamino)ethanol (0.05 mol) was dissolved in anhydrous hexane (20 mL) and a solution of chloromethyl 15 Didecyldimethylammonium Salicylate undecyl ether (0.05 mol) was added dropwise at room tem perature. The reaction mixture was stirred for 15 minutes. The Didecyldimethylammonium chloride (0.03 mol) was dis obtained precipitate was washed with dry hexane (40 mL). solved in 50 mL distilled water and sodium salicylate (0.04 The material was used in the next step, without further puri mol) was added to solution. The mixture was stirred at 40°C. fication. The prepared ammonium chloride was dissolved in i for 1 h. After cooling to room temperature, 60 mL of chlo water and an aqueous solution of sodium benzoate (0.07 mol) roform was added. The chloroform phase was separated and was added. The solution was stirring for 15 min. After 10 h. washed with distilled water until chloride ions were no longer the reaction mixture was concentrated using a rotary evapo detected using AgNO. The didecyldimethylammonium sali rator. To a dry crude product, anhydrous acetone (30 mL) was cylate was obtained in 95% yield. The product is insoluble in added. The solid product was filtered and acetone was 25 water and was dried under vacuum. removed. The product was dried for 10 hat 50° C. in vacuum to obtain (2-hydroxyethyl)dimethylundecyloxymethylam Example XXXI monium benzoate as a grease in 80% yield. Thermogravimet ric analysis: TF127° C. "Hand 'C NMR (DMSO) were Didecyidimethylammonium Salicylate (Alternative obtained. 30 Synthesis) Example XXVIII The stechiometric amounts of didecyldimethylammonium saccharinate and sodium salicylate were mixed in distilled (2-acetoxyethyl)beptyloxymethyldimethylammonium water and stirred at 60° C. for 2 h. After that time the solution Benzoate 35 was cooled to room temperature. The product was extracted from the aqueous solution with chloroform. The chloroform In a two-necked, round bottomed flask, equipped with a phase was removed and solvent was evaporated. Synthesized condenser and addition funnel, 2-(dimethylamino)ethyl didecyldimethylammonium salicylate (90% yield) was dried acetate (0.1 mol) was mixed with 150 mL of anhydrous hex under vacuum. ane. Chloromethylhexyl ether (0.1 mol) was slowly added 40 over 15 minutes. After 30 minutes, the reaction mixture was Example XXXII cooled to the temperature of minus 18° C. and the crude product was separated. The crude product was washed with Benzalkonium Salicylate 100 mL of hexane and used in the next step without further purification. The material was dissolved in 100 mL of water 45 Benzalkonium saccharinate (0.01 mol) and benzoic acid and aqueous Solution of sodium benzoate was added in sto (0.01 mol) were dissolved in 25 mL of hot acetone. The ichiometric amount. After 30 minutes, two phases were sepa mixture was stirred at room temperature for 5 h. Distilled rated. The water phase was removed and 100 mL of anhy water was added. The organic phase was separated and drous acetone was added to the residue. Precipitated NaCl washed with distilled water. Organic phase was evaporated was filtered off and the obtained liquid product, (2-acetoxy 50 and the product, benzalkonium salicylate, was dried under ethyl)heptyloxymethyldimethylammonium benzoate, was vacuum. "Hand 'C NMR (DMSO) were obtained. dried for 12 hat 60°C. in vacuum. The product was obtained as Viscous liquid in 65% yield. Thermogravimetric analysis: Example XXXIII T-120°dasei C. "Hand 'C NMR (DMSO) were obtained. 55 Didecyldimethylammonium Example XXIX 2-(2,6-dichlorophenyl)aminobenzeneacetate (2-acetoxyethyl)dodecyloxymethyldimethylammonium Didecyldimethylammonium chloride (0.03 mol) was dis Benzoate solved in 40 mL distilled water and diclofenac sodium salt 60 (0.04 mol) was added to the solution. The solution was stirred In a two-necked, round bottomed flask, equipped with a at room temperature for 30 min. Chloroform (40 mL) was condenser and addition funnel, the 2-(dimethylamino)ethyl added to the reaction mixture and the mixture was stirred. acetate (0.05 mol) was mixed with 30 mL of anhydrous hex After separation of the phases, the organic phase was washed ane. Chloromethyl dodecyl ether (0.055 mol) was slowly with 40 mL distilled, cold water until chloride ions were no added over 5 minutes. After 15 minutes, the reaction mixture 65 longer detected using AgNO. Chloroform was removed and was cooled to the temperature of minus 18°C. and the crude the residue was dried at 50° C. in vacuum. The product, product was separated. The precipitate was washed with 30 didecyldimethylammonium 2-(2,6-dichlorophenyl)amino US 8,232,265 B2 179 180 benzeneacetate (100% yield), was obtained as a grease that is uccinate sodium salt (0.0188 mol) was dissolved in 50 mL. soluble in chloroform, acetone, and DMSO. The product The two solutions were combined and stirred for two hours, lacks miscibility with water and hexane. Thermogravimetric during this time a white precipitate (NaCl) formed. The methanol was removed by rotary evaporation which leaves a analysis: Tso-162°C., and T-183°dasei C. "H and 'C white sticky solid. To this solid, 150 mL of chloroform was NMR (DMSO) were obtained. added. A portion of the product dissolved the chloroform while the byproduct (NaCl) remained as a suspended solid. Example XXXIVV The NaCl was removed by filitration, and the solvent was removed by rotary evaporation. The product, lidocaine docu Didecyldimethylammonium sate, is a colorless syrup and is dried under high vacuum. "H 2-1 (2,6-dichlorophenyl)aminobenzeneacetate 10 and 'C NMR (CDC1) were obtained. (Alternative Synthesis) Example XXXVIII A solution of didecyldimethylammonium acesulfamate (0.01 mol) in acetone was prepared. The aqueous solution of Didecyldimethylammonium Benzoate sodium diclofenac (0.02 mol) was added and the reaction 15 mixture was stirred at 60° C. for 2 h. The solution was Didecyldimethylammonium chloride (0.02 mol) was dis extracted with ethyl acetate. Organic phase was separated and solved in distilled water and 0.015 mol of benzoic acid evaporated. The product, didecyldimethylammonium 2-(2, sodium salt was added. The solution was stirred at 80°C. for 6-dichlorophenyl)aminobenzeneacetate (88% yield), was 7h. The reaction mixture was extracted by chloroform. Chlo dried under vacuum. H and 'C NMR (DMSO) were roform phase was removed and washed with distilled, cold obtained. water until chloride ions were no longer detected using AgNO. Then chloroform was removed. Obtainede benzoate Example XXXV in 85% yield was dried in vacuum. "H NMR and 'C NMR (CDC1) were obtained. Didecyidimethylammonium N-4-(2-amino-1,4- 25 dibydro4-oxo-6-pteridinyl)methylaminobenzoyl Example XXXIX L-glutamate Benzalkonium Benzoate Didecyldimethylammonium chloride (0.025 mol) was dis 10g of benzalkonium chloride (in which alkyl represents a solved in 40 mL distilled water and the folic acid sodium salt 30 mixture of the alkyls from CH, to CH-7) was soluble in (0.01 mol) was added. The solution was stirred at room tem distilled water and 7.2 g of sodium benzoate was added. The perature for 30 min. After separation of the phases, the reaction mixture was stirred at 90° C. for 6h. After cooling, 50 organic phase was washed with distilled, cold water until mL of chloroform was added. The organic phase was washed chloride ions were no longer detected using AgNO. The with distilled water until chloride ions were detected using organic phase was separated and solvent was evaporated. The 35 AgNO. Chloroform was removed and the residue was dried product (90% yield), didecyldimethylammonium N-4-(2- in vacuum. Benzoate was obtained with 84% yield. amino-1,4-dihydro-4-oxo-6-pteridinyl)methylaminoben Zoyl-L-glutamate, was dried at 50° C. under vacuum. Product Example XL is soluble in chloroform, acetone, DMSO. It lacks miscibility (2-hydroxyethyl)cyclododecyloxymethyldimethy with water and hexane. H and 'C NMR (DMSO) were 40 obtained. Thermogravimetric analysis: Tso-153° C. lammonium Benzoate and T-201°disei C. Hand 'CNMR (DMSO) were obtained. 0.1 mol of (2-hydroxyethyl)cyclododecyloxymethyldim ethylammonium chloride was dissolved in 100 mL of anhy Example XXXVI drous acetone and sodium benzoate was added. After 5 h of 45 stirring, NaCl was filterd and the reaction mixture was con Didecyidimethylammonium centrated using a rotary evaporator. The obtained was dried (S)-6-methoxy-O-methyl-2-naphthaleneacetate for 10 h at 50° C. in vacuum. The stoichiometric mixture (0.025 mol) of didecyldim Example XLI ethylammonium chloride and naproxen Sodium salt were dis 50 solved in distilled water and stirred at room temperature for 1 Didecyldimethylammonium Mandelate h. The product was extracted by ethyl acetate and organic phase was separated and then washed with distilled water. To 0.03 mol of didecyldimethylammonium chloride dis Ethyl acetate phase was removed and solvent evaporated. The solved in 50 mL distilled water was added 0.03 mol of man product, didecyldimethylammonium (S-6-methoxy-O-me 55 delic acid and 0.03 mol of NaOH. The mixture was stirred at thyl-2-naphthaleneacetate (95% yield), was dried under 50° C. for 2 h. After cooling to room temperature, 60 mL of vacuum. The product is soluble in chloroform, acetone, and chloroform was added. Chloroform phase was washed with DMSO. It lacks miscibility with water and hexane. Thermo distilled water until chloride ions were no longer detected gravimetric analysis: Tso-156°C., and T-190° C. using AgNO. The obtained mandelate with 96% yield is 'Hand 'C NMR (DMSO) were obtained. 60 insoluble in water and was dried in vacuum. Example XXXVII Example XLII Lidocaine Docusate Didecyldimethylammonium 2-acetoxybenzoate 65 Lidocaine hydrochloride (0.0188 mol) was dissolved in 50 A stoichiometric mixture of didecyldimethylammonium mL methanol and Sodium docusate bis(2-ethylhexyl)sulfos chloride, acetylsalicyclic acid, and NaOH in distilled water US 8,232,265 B2 181 182 was stirred at 60° C. for 2 hand then cooled to room tempera Example XLVI ture. The aqueous solution was extracted by chloroform. Chloroform was removed and prepared didecyldimethylam Lidocaine Complex of Ag+ monium 2-acetoxybenzoate with 90% yield was dried in WaCUU. 5 In a reaction vessel charged with a magnetic stirbar and shielded from light, 1.0 g (5.9 mmol) AgNO was dissolved in Example XLIII approximately 25 mL of deionized water. In a separate reac tion vessel, similarly chared with a stirbar and shielded from Didecyldimethylammonium p-toluenesulfonate light, 5.5lg (0.024 mol) of lidocaine (free-base form) was 10 dissolved/suspended in 25 mL of deionized water. To the 0.015 mol of didecyldimethylammonium chloride, 0.01 latter solution was added in one portion the aqueous solution mol of p-toluenesulfonic acid, 0.01 mol of NaOH and 100 mL of silver nitrate. A copious white precipitate forms quickly, of distilled water were charged to a round bottomed flaskand which (all the while protected from light) was quickly iso heated. The mixture was stirred for 2 hat 40°C., whence the lated by suction filtration. The recovered solid was dried in phases were allowed to separate. The organic layer was then 15 vacuum, and Subsequently recrystallized by slow evaporation washed three times with distilled water. The aqueous phases of a methanol/acetonitrile solution to give well-formed col were tested for the presence of chloride ion using silver nitrate orless crystals that are moderately light-stable. Solution. Finally, the organic layer was vacuum stripped to remove water. The obtained didecyldimethylammoniump Example XLVII toluenesulfonate with 95% yield is soluble in chloroform, acetone, DMSO, and insoluble in water and hexane. Ranitidine Docusate Example XLIV In a reaction vessel charged with a magnetic stirbar, 2.50 g (7.12 mmol) of Ranitidine hydrochloride was dissolved in Didecyldimethylammonium Nicotiate 25 approximately 25 mL of deionized water. In a separate reac tion vessel, similarly charged with a stirbar, 3.17 g (7.12 To 0.002 mol of didecyldimethylammonium bromide mmol) of sodium docusate was dissolved/suspended in 25 (tech. 75% gel in water) dissolved in 60 mL hot, distilled mL of warm, deionized water. To the latter solution was added water was added 0.002 mol of nicotinic acid. The mixture was in one portion the aqueous solution of Sodium docusate. The stirred vigorously at 90° C. for 4 h. After cooling to room 30 deep orange-brown milieu was stirred overnight, after which temperature 60 mL of chloroform was added. Chloroform time the aqueous system was repeatedly extracted with 100 phase was washed with distilled water until bromide ions mL portions of chloroform. Emulsification of the two phases were no longer detected using AgNO. The obtained waxy, was quite pronounced, so each time the system was heated to white solid was dried in vacuum. about 60 °C., then allowed to cool and settle for 5-7 days, 35 after which point the dark chloroform phase was separated, Example XLV dried over anhydrous MgSO, filtered, and rotary evaporated to yield a viscous, deep brown-orange oil (Ranitidine docu MultiComponent Ionic Liquids sate). The two ions have known histamine H2-receptor antagonist and an emollient properties, respectively. Multicomponent ionic liquids containing 3 or more differ 40 entions were prepared to show the tenability of the disclosed Example XLVIII compositions and methods. Three ionic liquids were prepared 1. benzalkonium, acesulfamate, and saccharinate Silver Docusate 2. benzalkonium, mepenZolate, and docusate 3. hexadecylpyridinium, acesulfamate, and saccharinate 45 The ionic liquids were prepared by dissolving each com pound in a common solvent such as water, methanol, or ethanol. The solutions were combined and stirred. The sol vent was then evaporated to reveal the ionic liquid and the inorganic salt. The ionic liquid was purified by dissolving it in 50 a solvent, such as hexane, methanol, or ethanol. The inorganic salt was fitered off. The solvent was evaporated to produce the pure ionic liquid.

55 Ionic Ratio of Liquid ions Form Melting Point (C.) 9% Yield 1 2:1:1 Brownish solid 40-45 75.4% 1 3:1:2 White Solid 30-40 82.7% 1 3:2:1 Orange solid 35-45 72.2% 60 3 2:1:1 Yellow Solid 30-35 95.8% 3 3:1:2 Yellow Solid 30-40 76.8% 3 3:2:1 Orange solid 30-35 87.3% In a reaction vessel charged with a magnetic stirbar and 2 2:1:3 Colorless gel 2 1:2:3 Clear wax protected from light, 5.0 g (29 mmol) of silver nitrate was 2 1:1:2 Whitish gel 65 dissolved in approximately 100 mL of deionized water. To the stirred solution was added, is small portions, 13.1 g (29 mmol) of Sodium docusate. As the docusate was added, the