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USOO8802596B2

(12) United States Patent (10) Patent No.: US 8,802,596 B2 Rogers et al. (45) Date of Patent: Aug. 12, 2014

(54) MULTI-FUNCTIONAL IONIC LIQUID (58) Field of Classification Search COMPOSITIONS FOR OVERCOMING None POLYMORPHISMAND IMPARTING See application file for complete search history. IMPROVED PROPERTIES FORACTIVE PHARMACEUTICAL, BIOLOGICAL, NUTRITIONAL AND ENERGETIC (56) References Cited INGREDIENTS U.. PATENT DOCUMENTS Inventors: (75) Robin . Rogers, Tuscaloosa, AL (US); 1943,176 A 1/1934 Graenacher Daniel . Daly, Tuscaloosa, AL (US); 3,223,704 A 12, 1965 Shibe Richard P. Swatloski, Tuscaloosa, AL 3,344,018 A 9, 1967 Shibe (US); Whitney . Hough-Troutman, 3.414,569 A 12/1968 Wieden Tuscaloosa, AL (US); James Hilliard 3.47 1423 A 10, 1969 Elmer 4,097.666 A 6, 1978 Johnson et al. Davis, Jr., Mobile, AL (US); Marcin 4,104,368 A 8, 1978 Lala et al. Smiglak, Tuscaloosa, AL (US); Juliusz 4,188,263. A 2, 1980 Hulsmann et al. Pernak, Pozan (PL); Scott . Spear, 4,224,319 A 9, 1980 Marcadet Bankston, AL (US) 4,228, 162 A 10, 1980 Luzzi et al. 4,491,574 A 1/1985 Seifter et al. (73) Assignee: Board of Trustees of the University of 4,520,105 A 5, 1985 Sinner et al. Alabama, Tuscaloosa, AL (US) 4,637,830 A 1/1987 Dyer et al. 4,761,164 A 8, 1988 Pez et al. (*) Notice: Subject to any disclaimer, the term of this 4,973,456 A 1 1/1990 Quinn et al. patent is extended or adjusted under 35 5,175,353 A 12/1992 Jones et al. U.S.. 154() by 0 days. 5,221,758 A 6/1993 Maynard 5,246,716 A 9, 1993 Sedun et al. (21) Appl. No.: 13/491,053 5,275,820 A 1/1994 Chang 5,428,000 A 6/1995 Innami et al. (22) Filed: Jun. 7, 2012 5,654,337 A 8, 1997 Roentsch et al. (65) Prior Publication Data 5,679,146 A 10, 1997 Kalt et al. 5,683,832 A 11/1997 Bonhote et al. US 2012/O264605 A1 Oct. 18, 2012 (Continued) Related U.S. Application Data FOREIGN PATENT DOCUMENTS (62) Division of application No. 1 1/545,938, filed on Oct. 10, 2006, now Pat. No. 8,232,265. CA 2619367 T 2009 (60) Provisional application No. 60/764,850, filed on Feb. DE 93-43O8410 3, 1993 2, 2006, provisional application No. 60/724,604, filed (Continued) on Oct. 7, 2005, provisional application No. 60/724,605, filed on Oct. 7, 2005. OTHER PUBLICATIONS Int. C. Office Action for Application No. JP 2008-534766 dated Sep. 13, (51) 2012. AOIN 57/18 (2006.01) Avent et al., Evidence for hydrogen bonding in solutions of 1-Ehtyl AOIN 43/707 (2006.01) 3-imidazolium Halides, and its implications for ambient temperature AOIN 43/66 (2006.01) Halogenoaluminate (III) ionic liquids, . Chem. Soc. Dalton Trans. AOIN 43/68 (2006.01) 3405-3413 (1994). AOIN 43/58 (2006.01) Bates et al., CO2 capture by a task-specific ionic liquid, J. Am. Chem AOIN 43/82 (2006.01) Soc., 124(6):926-927 (2002). AOIN 43/78 (2006.01) AOIN 43/76 (2006.01) (Continued) AOIN 43/80 (2006.01) AOIN 43/653 (2006.01) Primary Examiner — Alton Pryor AOIN 43/10 (2006.01) (74) Attorney, Agent, or Firm — Meunier Carlin & Curfman, AOIN37/00 (2006.01) LLC AOIN37/18 (2006.01) AOIN33/18 (2006.01) AOIN 43/90 (2006.01) (57) ABSTRACT AOIN 43/54 (2006.01) Disclosed are ionic liquids and methods of preparing ionic AOIN 43/40 (2006.01) liquid compositions of active pharmaceutical, biological, AOIN 43/42 (2006.01) nutritional, and energetic ingredients. Also disclosed are AOIN 43/48 (2006.01) methods of using the compositions described herein to over (52) U.S. C. come polymorphism, overcome solubility and delivery prob USPC ...... 504/206:504/229; 504/231:504/232: lems, to control release rates, add functionality, enhance effi 504/236:504/238; 504/262:504/267: 504/270; cacy (synergy), and improve ease of use and manufacture. 504/271; 504/272; 504/289; 504/307: 504/334; 504/347; 504/241; 504/243; 504/244; 504/247; 504/253: 504/255 13 Claims, 6 Drawing Sheets US 8,802,596 B2 Page 2

(56) References Cited Bernstein, Crystal structure prediction and polymorphism, ACA Transactions, 39:14-23 (2004). U.S. PATENT DOCUMENTS Black et al., Increased chemical purity using a hydrage, Crystal Growth & Design, 4(3):539-544 (2004). 5,731, 101 A 3, 1998 Sherifet al. Bonhote et al., Hydrophobic, highly conductive ambient-temperature 5,792,399 A 8, 1998 Miester et al. 5,827,602 A 10, 1998 Koch et al. molten salts, Inorg. Chem., 35:1 168-1178 (1996). 5,856,513 A 1/1999 Ueet al. Bowlas et al., Liquid crystalline ionic liquids, Chem. Comm., 1625 5,908,697 A 6, 1999 Roux et al. 1626 (1996). 6,759,544 B2 7/2004 Burgard Browning et al., Relationships between action and chemi 6,774,240 B2 8, 2004 Seddon et al. cal constitution with special reference to compounds of the , 6,808,557 B2 10/2004 Holbrey et al. , and phenazine seriers, Proc. Royal Soc. London, 6,824,599 B2 11/2004 Swatloski et al. 6,846,926 B1 1/2005 Koppes et al. 93(653):329-366 (1922). 6,906,004 B2 6, 2005 Parrish et al. 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Analysis, 6(3):299-305 (1988). 2005. O136103 A1 6/2005 Ben-Sasson et al. 2005, 0194561 A1 9, 2005 Davis Campanella et al., Polymeric membrane electrodes for analysis, 2005/0232981 A1 10, 2005 Ben-Sasson J. Pharm Biomed. Analysis, 6:717-723 (1988). 2006/01 18755 A1 6/2006 Fujioka et al. Carmichael. A solution in sight, Chem. Britia, 36 (2000). 2006, O159632 A1 7/2006 Ishibashi et al. Carter et al., Sweet Success: Ionic liquids derived from non-nutritive 2007/0053939 A1 3/2007 Yokoyama et al. Sweeteners, Chem. Comm., 630-631 (2004). 2007/0054952 A1 3/2007 Hamamoto et al. Chawala et al., Challenges in polymorphism of pharmaceuticals, 2008. O190013 A1 8/2008 Argyropoulos 2008/0207452 A1* 8, 2008 Kramer et al...... 504,127 CRISPS, 5(1):9-12 (2004). 2009,0264664 A1 10, 2009 Endo et al. Cole et al., Novel Bronstead acidic ionic liquids and their use as dual 2010, 0004608 A1 1/2010 Hamamoto et al. solvent catalysts, J. Am. Chem. Soc., 124:5962-5963 (2002). 2010.00297.04 A1 2/2010 Hanma et al. Cuppen et al., Crystal structure and growth behavior of aspartame 2010/0280090 A1 11/2010 Hamamoto et al. form I-A, Crystal Growth & Design, 5(3):917-923 (2005). Davis et al. Thiazolium- based organic ionic liquids (OILS). FOREIGN PATENT DOCUMENTS Novel OILs which promote the benzoinc condensation, Tetrahedron Lett., 40: 1621-1622 (1999). 8406412 4f1983 Davis et al., From curiosities to commodities: Ionic liquids begin the FR 1404697 5, 1965 transformation, Chem. Comm. 1209-1212 (2003). GB 869149 5, 1961 Domagk, A new class of disinfectants, Deut. Med. Wochenschr, GB 1067094 5, 1964 GB 1473.603 5, 1977 61:829-832 (1935). JP 61-236818 10, 1986 Dupont et al., Room temperature molten salts: Neuteric "Green” JP 62-198609 9, 1987 Solvents for chemical reactions and processes, Braz. Chem. Soc. JP 63-0565O1 3, 1988 11(4):337-344 (2000). JP 2OO1525820 3, 2005 Elaiwi et al., Hydrogen bonding in Imidazolium salts and its impli JP 2005082512 3, 2005 cations for ambient-temperature Halogenoaluminate (III) ionic liq NL 3O2478 10, 1965 uids, J. Chem. Soc. Dalton Trans., 3467-3472 (1995). WO 91f13552 9, 1991 Extended European Search Report for Application No. 06774039.9 WO 95/21806 8, 1995 dated Jul. 8, 2011. WO 95/21871 8, 1995 Fannin et a. Properties of 1,3-Dialkylimidazolium chloride-alumi WO 95/21872 8, 1995 num chloride ionic liquids. 2. Phase transitions, densities, electrical WO 96.06593 3, 1996 WO 97,43012 11, 1997 conductivities, and viscosities, J. Phys. Chem.88:2614-2621 (1984). WO 98.51283 11, 1998 Fraga-Dubreuil et al., Grafted ionic liquid-phase-supported synthesis WO O3,O29329 4/2003 of small organic molecules, Tetrahedron Lett., 42:6097-6100 (2001). WO 2004 O75877 9, 2004 Freemantle, Ionic liquids show promise for clean separation technol WO 2005/0284.46 3, 2005 ogy, Chem. . New, 76(34): 12 (1998). WO 2005/097731 10/2005 Freemantle, Eyes on ionic liquids, Chem. Eng. News, 78(2):37-50 WO 2007/005470 1, 2007 (2000). WO 2007/044693 4/2007 Fukumoto et al., Room temperature ionic liquids from 20 natural WO 2009/060629 5, 2009 amino acids, J. Am. Chem. Soc., 127(8):2398-2399 (2005). WO 2009/066457 5, 2009 Geppi et al., Molecular properties of and its solid idper WO 2009,075094 6, 2009 sions with eudragit RL 100 studied by Solid-state nuclear magnetic WO 2009,119836 10/2009 resonance, Pharm. Res., 22(9): 1544-1555 (2005). Gordon et al., Fused organic salts. 8. Properties of molten straight OTHER PUBLICATIONS chain of tetra--Pentylammonium salts, J. Amer. Chem. Soc., 100(24):7445-7454 (1978). Bernstein, Polymorphism of high energy materials, Polymorphism in Hamaguchi et al., Structure of ionic liquids and ionic compounds: Molecular Crystals, 275-296 (2002). Are ionic liquids genuine liquids in the convention sense, Advances Bernstein, Introduction and historical background, Polymorphism in in Chem. Physics, 131:85-104 (2005). Molecular Crystals, 1-28 (2002). Hartman et al., Acid soaps, J. Applied Chem., 41: 137 (1928). US 8,802,596 B2 Page 3

(56) References Cited Office Action for AU Patent Application No. 2006302237 dated Aug. 23, 2011. OTHER PUBLICATIONS Ohno et al. A new type of polymer gel electrolyte: Zwitterionic liquid polar polymer mixture, Electrochimica Acta, 48:2079-2083 Hayes et al., Occurrence of pharmaceutically acceptable anions and (2003). cations in the Cambridge structural database, J. Pharm. Sci., Okamato et al., Synthesis, spectra, and reactions of 94(10):2111-2120 (2005). Holbrey et al. The Phase Behaviour of 1-Alkyl-3-Methlimidazolium N-triphenylmethylpyridinium salts. Reactions of Triphenylmethyl Tetrafluoroborates; Ionic Liquids and Ionic Liquid Crystals, J. Chem. chlordie with pyridine under high pressure, J. Org. Chem. Soc. Dalton Trans., 2133-2139 (1999). 35(11):3752-3756 (1970). Huddleston et al., Characterization and Comparison of Hydrophilic Okutucuetal. Covalent Attachment of Oligonucleotides to Cellulose and Hydrophobic Room Temperature Ionic Liquids Incorporating Membranes, Artificial Cells, Blood Substitutes, and the Imidazolium Cation, Green Chem., 3:156-164 (2001). Biotechnology, 32(4): 599-608 (2004). International Preliminary Report on Patentability and Written Opin Oldham et al., Unusual solvent system shows potential to ion for PCT/US2009/069652 dated Jul. 7, 2011. revoluntionize separation and purification technologies, The International Search Report and Written Opinion of the International Actinide Research Quarterly, 1st Quarter, 50-53 (2004). Searching Authority for PCT/US06/39454, 2010. Pernak et al., Phosphonium acesulfamate based ionic liquids, Eur, J. Jacobs et al. On a New Group of Bactericidal Substances Obtained Org. Chem. 650-652 (2005). from Hexamethylenetetramine, Proc. Nat. Acad. Sci. USA, 1:226 Picquet et al., Ionic liquids: media for better molecular catalysis, 228 (1915). Topics in Catalysis, 29(3-4): 139-143 (2004). Jacobs et al., The Quaternary Salts of Hexamethylenetetramine. I. Quinn et al., Salt hydrates: New reversible absorbents for carbon Substituted Benzyl Halides and the Hexamethylenetetraminium dioxide, J. Am. Chem. Soc., 117:329-335 (1995). Salts Derived Therefrom, J. Biol. Chem. 20:659-683 (1915). Rasenack et al., Properties of ibuprofen crystallized under various Jacobs et al., The bactericidal properties of the quaternary Salts of conditions: A comparative study, Drug Dev. Industrial Pharm., hexamethylenetetramine, J. Exptl. Med., 23:569-576 (1916). 28(9): 1077-1089 (2002). Katritzky et al., 1-Butyl-3-methylimidazolium 3,5-dinitro-1,2,4- Remenar et al., Salt selection and simultaneous polymorphism triazolate: a novel ionic liquid containing a rigid planar energetic assessment via high-throughput crystallization: The case of anion, Chem. Comm. 868-870 (2005). Katritzky et al., ILs Based on Energetic Imidazolium Cations: Nitro , Org. Proc. Res. & Dev. 7(6):990-996 (2003). and Nitrile-substituted N,N' Dialkylimidazolium Salts, New J. Reutzel-Edens et al., Anhydrates and hydrates of : Crys Chem., 30:349-358 (2006). tallization Solid-state characterization, and structural relationships, Katritzky et al., ILS Based on Energetic AZolate Anions, Chem. Eur. Crystal Growth & Design, 3(6):897-907 (2003). J., 12:4630-4641 (2006). Rogers et al., Ionic Liquids—Solvents of the Future? Science, Klinguer et al., Lipophilic quaternary ammonium Salt acts as 302:792-793 (2003). muscosal adjuvant when co-administered by the nasal route with Seddon et al., Ionic liquids for clean technology, J. Chem. Tech. vaccine antigens, Vaccine, 19:4236-4244 (2001). Biotechnol. 68:351-356 (1997). Lee et al., Ionic liquid-mediated selective extraction of lighin from Stöllner et al., Activation of Cellulose Membranes with 1, 1'- wood leading to enhanced enzymatic cellulose hydrolsis, Carbonyldiimidazole or 1-Cyano-4-dimethylaminopyridinium Biotechnology and Bioengineering. Published online Oct. 24, 2008, tetrafluoroborate as a Basis for the Development of Immunosensors, in Wiley InterScience (www.wileyinterscience.com). DOI 10.1002/ Analytical Biochemistry, 304: 157-165 (2002). bit.22179. p. 1372, Table 2. Swatloski et al., Ionic liquids are not always green: Hydroanalysis of Liu et al., Development of non-viral vectors for systemic gene deliv 1-butyl--methylimidazoliums hexafluorophosphate, Green Chem. ery, J. Contr. Rel.., 78:259-266 (2002). 5:361-363 (2003). MacFarlane et al., Pyrrolidinium imides: A new family of molten Trask et al., Screening for crystalline salts via mechanochemistry, salts and conductive plastic crystal phases, J. Phys. Chem... 103:4164 Chem. Comm., 51-53 (2006). 4170 (1999). Visser et al., Task Specific Ionic Liquids for the Extraction of Metal Martion et al., Influence of crystal habit on the compression and from Aqueous Solutions, Chem. Commun., 135-136 (2001). densification mechanism of ibuprofen, J. Crystal Growth, 243:345 Visser et al., Hydrophobic ionic liquids incorporating 355 (2002). N-alkylisoquinolinium cations and their utilization in liquid separa Matsumoto et al., Room temperature ionic liquids based on Small tion, Chem. Comm. 2484-2485 (2001). aliphalic ammonium cations and asymmetric anions, Chem. Wasserscheidet al., Ionic liquids-new “solutions” for transition metal Comm. 1726-1727 (2002). catalysis, Angew Chem. Int. Ed. Engl., 39:3772-3789 (2000). Meguro et al., Crystal structure of the low-humidity form of Welton, Room temperature ionic liquids, solvents for synthesis and aspartame Sweetener, J. Re., 56.97-104 (2000). catalysis, Chem. Rev.99:2071-2083 (1999). Merrigan et al., New fluorous ionic liquids function as Surfactants in Wilkes et al., Air and stable 1-ethyl-3-methylimidazolium conventional room-termperature ionic liquids, Chem. Comm., 2051 based ionic liquids, J. Chem. Soc., 965-967 (1992). 2052 (2000). Office Action for U.S. Appl. No. 13/808,790 dated Jan. 22, 2014. Morrison et al., Base-promoted reactions in ionic liquid solvents. The BAF Corporation Safety Data Sheet for 2-(2-Aminoethoxy), Knoevenagel and Robinson annulations reactions, Tetrahedron Lett. Version 1.0 (obtained online with printed date: Oct. 21, 2011), 8 42:6053-6057 (2001). pageS. Ngo et al., Thermal Properties of Imidazolium Ionic Liquids, Office Action for Application No. JP 2012-186605 dated Nov. 15, Thermochimica Acta, 357-358:97-102 (2000). 2013. Oertel, Novel hard to wash-out water soluble wood protecting agents and their application, Holztechnologie, 6:243 (1965). * cited by examiner U.S. Patent Aug. 12, 2014 Sheet 1 of 6 US 8,802,596 B2

Figure 1

HexSulfacetamide, i.eXC & Na Stifacetamide Dissolution

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Figure 2

Hex. and DDA Suifacetamide Dissolution

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U.S. Patent Aug. 12, 2014 Sheet 4 of 6 US 8,802,596 B2

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Figure 6

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3. Concentration ( ') US 8,802,596 B2 1. 2 MULTI-FUNCTIONAL IONIC LIOUID tures and is a widely used reference source in crystallography. COMPOSITIONS FOR OVERCOMING One survey of the Cambridge Structural Database shows that POLYMORPHISMAND IMPARTING pharmaceutical compounds have been reported to exist as IMPROVED PROPERTIES FORACTIVE hemi-hydrates (0.5 water molecules) through decahydrates PHARMACEUTICAL, BIOLOGICAL, (10 water molecules). (Morris, “Structural Aspect of NUTRITIONAL AND ENERGETIC Hydrates and Solvates.' . 4 in Polymorphism in Pharma INGREDIENTS ceutical Solids, in Brittain, . G., Ed., Vol. 95 of and the Pharmaceutical Sciences, Marcel Dekker, Inc., New CROSS-REFERENCE TO RELATED York, N.., 1999, 125-181) APPLICATIONS 10 The possibility of polymorphism orpseudo-polymorphism may exist for any particular compound, but the conditions This patent application is a divisional of U.S. application required to prepare as yet unknown polymorphs or pseudo Ser. No. 1 1/545,938 filed Oct. 10, 2006, whose status is polymorphs are not easily determined (see e.g., Bernstein, allowed, and which 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, 15 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 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, 25 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 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 30 each form can have different physical and chemical proper of use and manufacture. ties. For example, one particular polymorph pseudo-poly 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 35 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., 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, 40 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% The exact Solid state polymorph (or pseudo-polymorph) of a of , 60% of sulfonamides, and 23% of are compound determines its physical properties such as disso believed to exist in different polymorphic forms or “polymor lution rate, solubility, , crystal habit, mechani phs” (Haleblian et al., J Pharm Sci 1975, 64:1269-1288). 45 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 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. 50 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 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 55 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 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. 60 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 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 65 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 Crystal Growth & Design, 2003, 3:897-907). US 8,802,596 B2 3 4 Moreover, the inadvertent production of an undesired poly cal properties, are in a form that is not subject to polymor morph (or pseudo-polymorph), or the spontaneous transfor phism, and for which controlled, tunable dissolution and 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 5 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. 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 10 SUMMARY forms. The FDA's regulatory guidelines emphasize control of crystal form and the use of appropriate techniques to detect In accordance with the purposes of the disclosed materials, and characterize different forms of a drug (see Guidance for compounds, compositions, devices, and methods, as embod Industry ANDAS: Pharmaceutical Solid Polymorphism ied and broadly described herein, the disclosed subject mat Chemistry, Manufacturing, and Controls Information, U.S. 15 Department of Health and Human Services, FDA, 2004). ter, in one aspect, relates to compounds and compositions and Thus, an applicant seeking FDA approval of a drug must methods for preparing and using such compounds and com demonstrate the ability to maintain a constant crystalline positions. In a further aspect, the disclosed subject matter form throughout the life of the product. Such an endeavor is relates to ionic liquid compositions that can be used for or in costly and can be extremely difficult or even impossible. biological, pharmaceutical, nutritional, cosmetic, industrial, Similar challenges can exist when one seeks approval of a and commercial compositions. Methods for making the dis generic product by filing an Abbreviated New Drug Applica closed ionic liquid compositions are also disclosed. Also tion (ANDA), in which case the applicant must show equiva disclosed are methods of preparing ionic liquid compositions lence between the and an approved drug. Such a of active pharmaceutical, biological, nutritional, and ener showing can be complicated when various polymorphic and/ 25 getic ingredients. Also the disclosed are methods of using the or pseudo-polymorphic forms exist for the drug. compositions described herein to overcome polymorphism, Amorphous forms of drugs are now being studied because overcome solubility and delivery problems, to control release they are higher energy forms that have higher dissolution rates, add functionality, enhance efficacy (synergy), and rates and solubilities since there is no lattice structure to improve ease of use and manufacture. overcome or to inhibit solvation (Bernstein, “Polymorphism 30 Additional advantages will be set forth in part in the in Molecular Crystals.” IUCR Monographs on Crystallogra description that follows, and in part will be obvious from the phy 14, Oxford Science Publications, 2002, pp. 240-256). description, or may be learned by practice of the aspects This increasing to amorphous forms has also shown, described below. The advantages described below will be however, that the amorphous forms have a tendency to crys realized and attained by means of the elements and combina tallize spontaneously to a lower energy crystalline form, usu 35 tions particularly pointed out in the appended claims. It is to ally at inopportune times. be understood that both the foregoing general description and The phenomenon of polymorphism and pseudo-polymor the following detailed description are exemplary and phism is not limited to pharmaceuticals as many other (if not explanatory only and are not restrictive. all) organic and inorganic compounds can crystallize into different forms. Thus, the existence of various forms of a 40 BRIEF DESCRIPTION OF THE FIGURES given compound (e.g., a , herbicide, nutraceutical, cosmetic, food additive, explosive, etc.) can result in the same The accompanying Figures, which are incorporated in and synthetic, analytical, regulatory, and commercial difficulties constitute a part of this specification, illustrate several aspects that plague the pharmaceutical industry because of polymor described below. phic and pseudo-polymorphic drugs. In each of these indus 45 FIG. 1 is a graph of absorbance at 258 nanometers (nm) tries, it is not currently possible to simply alter the chemical over time (minutes) for hexadecylpyridinium Sulfacetamide nature of the active compound in order to tune the chemical (Hexsulfacetamide), hexadecylpyridinium chloride (Hex (e.g., rate of dissolution and solubility) or physical (crystal ICl), and sulfacetamide dissolution. habit, mechanical strength) properties. Rather, it is often the FIG. 2 is a graph of absorbance at 258 nm over time for strategy to search for polymorphs or pseudo-polymorphs that 50 hexadecylpyridinium sulfacetamide and didecyldimethylam have the most desirable “obtainable' properties. monium (DDA) sulfacetamide dissolution. Another common problem that exists with many pharma FIG.3 is a schematic of a computer model used to identify ceuticals is low solubility. Low solubility can make formu ion combinations Suitable for the disclosed ionic liquid com lating aparticular compound difficult, and generally low solu binations. bility translates into low bioavailability. Much research is 55 FIG. 4A is a graph showing a comparison of conducted on finding ways to improve a compound's solubil hydrochloride and lidocaine at 1 millmolar concen ity and availability. Typically methods include complex deliv tration. ery devices and chemical modifications of the drug. FIG. 4B is a graph showing a comparison of lidocaine Given that polymorphism and pseudo-polymorphism can hydrochloride and lidocaine docusate at 100 millimolar con not be predicted; that the exact crystalline state affects chemi 60 centration. cal properties (e.g., dissolution rate, solubility), biological FIG. 5 is a graph showing molar conductivity for Camim properties (e.g., bioavailability, ), mechani C1 solutions at variable temperature; () 291.0 K; (O) 295.3 cal and physical properties, and manufacturing processes, K; () 300.2 K; (A) 305.0 K in water and (()) in DMSO at and that polymorphs and pseudo-polymorphs can inconve 295.3 K. niently interconvert, what are needed are compositions that 65 FIG. 6 is a graph showing the difference in calculated are at least effective for their intended purpose, but can also limiting slope and actually measured (D) CamimCl in H2O have controlled and tunable chemical, biological, and physi at 295.3 K; (()) CamimCl in DMSO at 295.3 K. US 8,802,596 B2 5 6 DETAILED DESCRIPTION starting points and ranges for any combination of the data points. For example, if a particular data point “10 and a The materials, compounds, compositions, articles, and particular data point “15” are disclosed, it is understood that methods described herein may be understood more readily by greater than, greater than or equal to, less than, less than or reference to the following detailed description of specific equal to, and equal to 10 and 15 are considered disclosed as aspects of the disclosed subject matter and the Examples well as between 10 and 15. It is also understood that each unit included therein. between two particular units are also disclosed. For example, Before the present materials, compounds, compositions, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also articles, devices, and methods are disclosed and described, it disclosed. is to be understood that the aspects described below are not 10 As used herein, by a “subject' is meant an individual. Thus, limited to specific synthetic methods or specific reagents, as the “subject' can include domesticated animals (e.g., cats, Such may, of course, vary. It is also to be understood that the dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, terminology used herein is for the purpose of describing etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, particular aspects only and is not intended to be limiting. etc.), and birds. "Subject' can also include a mammal, such as Also, throughout this specification, various publications 15 a primate or a human. are referenced. The disclosures of these publications in their By “reduce” or otherforms of the word, such as “reducing entireties are hereby incorporated by reference into this appli or “reduction is meant lowering of an event or characteristic cation in order to more fully describe the state of the art to (e.g., microorganism growth or Survival). It is understood that which the disclosed matter pertains. The references disclosed this is typically in relation to Some standard or expected value, are also individually and specifically incorporated by refer in other words it is relative, but that it is not always necessary ence herein for the material contained in them that is dis for the standard or relative value to be referred to. For cussed in the sentence in which the reference is relied upon. example, “reduces bacteria growth' means lowering the amount of bacteria relative to a standard or a control. GENERAL DEFINITIONS By "prevent' or other forms of the word, such as “prevent 25 ing’ or “prevention, is meant to stop a particular event or In this specification and in the claims that follow, reference characteristic, to stabilize or delay the development or pro will be made to a number of terms, which shall be defined to gression of a particular event or characteristic, or to minimize have the following meanings: the chances that a particular event or characteristic will occur. Throughout the description and claims of this specification Prevent does not require comparison to a control as it is the word “comprise' and other forms of the word, such as 30 typically more absolute than, for example, reduce. As used “comprising and "comprises.” means including but not lim herein, something could be reduced but not prevented, but ited to, and is not intended to exclude, for example, other something that is reduced could also be prevented. Likewise, additives, components, integers, or steps. Something could be prevented but not reduced, but something As used in the description and the appended claims, the that is prevented could also be reduced. It is understood that singular forms “a” “an.” and “the include plural referents 35 where reduce or prevent are used, unless specifically indi unless the context clearly dictates otherwise. Thus, for cated otherwise, the use of the other word is also expressly example, reference to “a composition' includes mixtures of disclosed. two or more such compositions, reference to “an ionic liquid By “treat' or other forms of the word, such as “treated' or includes mixtures of two or more Suchionic liquids, reference “treatment, is meant to administer a composition or to per to “the compound includes mixtures of two or more such 40 form a method in order to reduce, prevent, inhibit, break compounds, and the like. down, or eliminate a particular characteristic or event (e.g., "Optional' or “optionally’ means that the subsequently microorganism growth or survival). The term “control is described event or circumstance can or cannot occur, and that used synonymously with the term “treat.” the description includes instances where the event or circum By “antimicrobial' is meant the ability to treat or control stance occurs and instances where it does not. 45 (e.g., reduce, prevent, inhibit, break-down, or eliminate) Ranges can be expressed herein as from “about one par microorganism growth or Survival at any concentration. Simi ticular value, and/or to “about another particular value. larly, the terms “antibacterial.” “antiviral.” and “' When Such a range is expressed, another aspect includes from respectively mean the ability to treat or control (e.g., reduce, the one particular value and/or to the other particular value. prevent, inhibit, break-down, or eliminate) bacterial, viral, Similarly, when values are expressed as approximations, by 50 and fungal growth or Survival at any concentration. use of the antecedent “about it will be understood that the It is understood that throughout this specification the iden particular value forms another aspect. It will be further under tifiers “first and “second are used solely to aid in distin stood that the endpoints of each of the ranges are significant guishing the various components and steps of the disclosed both in relation to the other endpoint, and independently of subject matter. The identifiers “first and “second are not the other endpoint. It is also understood that there are a 55 intended to imply any particular order, amount, preference, or number of values disclosed herein, and that each value is also importance to the components or steps modified by these herein disclosed as “about that particular value in addition to terms. the value itself. For example, if the value “10 is disclosed, 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 60 value, “greater than or equal to the value.” and possible ranges References in the specification and concluding claims to between values are also disclosed, as appropriately under parts by weight of a particular element or component in a stood by the skilled artisan. For example, if the value “10 is composition denotes the weight relationship between the ele disclosed, then “less than or equal to 10” as well as “greater ment or component and any other elements or components in than or equal to 10” is also disclosed. It is also understood that 65 the composition or article for which a part by weight is throughout the application data are provided in a number of expressed. Thus, in a compound containing 2 parts by weight different formats and that this data represent endpoints and of component and 5 parts by weight component Y. X and Y US 8,802,596 B2 7 8 are present at a weight ratio of 2:5, and are present in Such like. The alkyl group can also be substituted or unsubstituted. ratio regardless of whether additional components are con The alkyl group can be substituted with one or more groups tained in the compound. including, but not limited to, alkyl, halogenated alkyl, alkoxy, A weight percent (wt.%) of a component, unless specifi alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxy cally stated to the contrary, is based on the total weight of the lic acid, ester, , halide, hydroxy, ketone, nitro, silyl, formulation or composition in which the component is sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described included. below. 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 10 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 substitu a charge. Methods for producing a charge in a molecule, ent(s) on the alkyl group. For example, the term "halogenated portion of a molecule, cluster of molecules, molecular com alkyl specifically refers to an alkyl group that is substituted plex, moiety, or atom are disclosed herein and can be accom with one or more halide, e.g., fluorine, , bromine, or plished by methods known in the art, e.g., protonation, depro 15 . The term “alkoxyalkyl specifically refers to an alkyl tonation, oxidation, reduction, alkylation, etc. group that is Substituted with one or more alkoxy groups, as The term “anion' is a type of ion and is included within the described below. The term “alkylamino” specifically refers to meaning of the term “ion.” An "anion' is any molecule, an alkyl group that is Substituted with one or more amino portion of a molecule (e.g., Zwitterion), cluster of molecules, groups, as described below, and the like. When “alkyl is used molecular complex, moiety, or atom that contains a net nega in one instance and a specific term Such as “alkylalcohol is tive charge or that can be made to contain a net negative used in another, it is not meant to imply that the term “alkyl charge. The term "anion precursor is used herein to specifi does not also refer to specific terms such as “alkylalcohol cally refer to a molecule that can be converted to an anion via 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 25 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 30 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). 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 35 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 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 40 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 , can have hydrogen Substituents 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 isomers. This may be presumed in oms. This disclosure is not intended to be limited in any 45 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 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 50 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 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 55 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 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 60 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. carbon-based aromatic group including, but not limited to, The term “alkyl as used herein is a branched or , , 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, 65 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 dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the of the aromatic group. Examples of heteroatoms include, but US 8,802,596 B2 9 10 are not limited to, nitrogen, oxygen, , and phosphorus. halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, Likewise, the term “non-heteroaryl, which is also included cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy in the term “aryl. defines a group that contains an aromatic cloalkenyl group described above. group that does not contain a heteroatom. The aryl group can The term “ether as used herein is represented by the for be substituted or unsubstituted. The aryl group can be substi 5 mula A'OA, where A' and A can be, independently, an tuted with one or more groups including, but not limited to, alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, het cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy eroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, cloalkenyl group described above. hydroxy, ketone, nitro, silyl, Sulfo-oxo, Sulfonyl, Sulfone, The term “ketone' as used herein is represented by the sulfoxide, or thiol as described herein. The term “biary1' is a 10 formula A'C(O)A, where A' and A can be, independently, specific type of aryl group and is included in the definition of an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, aryl. Biaryl refers to two aryl groups that are bound together cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy via a fused ring structure, as in naphthalene, or are attached cloalkenyl group described above. via one or more carbon-carbon bonds, as in biphenyl. The term “halide' as used herein refers to the The term “cycloalkyl as used herein is a non-aromatic 15 fluorine, chlorine, bromine, and iodine. carbon-based ring composed of at least three carbon atoms. The term “hydroxyl as used herein is represented by the Examples of cycloalkyl groups include, but are not limited to, formula—OH. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The The term “nitro” as used herein is represented by the for term "heterocycloalkyl is a cycloalkyl group as defined mula—NO. above where at least one of the carbon atoms of the ring is The term “silyl as used herein is represented by the for substituted with a heteroatom such as, but not limited to, mula - SiAAA, where A, A, and A can be, indepen nitrogen, oxygen, Sulfur, or phosphorus. The cycloalkyl dently, hydrogen, alkyl, halogenated alkyl, alkoxy, alkenyl, group and heterocycloalkyl group can be substituted or alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocy unsubstituted. The cycloalkyl group and heterocycloalkyl cloalkyl, or heterocycloalkenyl group described above. group can be substituted with one or more groups including, 25 The term “sulfo-oxo' as used herein is represented by the but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, het formulas —S(O)A', S(O)A', (O)-A", or —OS(O) eroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, OA', where A' can be hydrogen, an alkyl, halogenated alkyl, hydroxy, ketone, nitro, silyl, Sulfo-oxo, Sulfonyl, Sulfone, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, sulfoxide, or thiol as described herein. heterocycloalkyl, or heterocycloalkenyl group described The term “cycloalkenyl' as used herein is a non-aromatic 30 above. Throughout this specification “S(O) is a short hand carbon-based ring composed of at least three carbon atoms notation for S=O. and containing at least one double bound, i.e., C=C. The term "sulfonyl' is used hereinto refer to the sulfo-oxo Examples of cycloalkenyl groups include, but are not limited group represented by the formula—S(O)A', where A' can to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopenta be hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, dienyl, cyclohexenyl, cyclohexadienyl, and the like. The term 35 aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, "heterocycloalkenyl is a type of cycloalkenyl group as or heterocycloalkenyl group described above. defined above, and is included within the meaning of the term The term "sulfonylamino” or “' as used herein “cycloalkenyl, where at least one of the carbon atoms of the is represented by the formula—S(O)-. ring is substituted with a heteroatom Such as, but not limited The term “sulfone' as used herein is represented by the to, nitrogen, oxygen, Sulfur, or phosphorus. The cycloalkenyl 40 formula A'S(O).A., where A' and A can be, independently, group and heterocycloalkenyl group can be substituted or an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, unsubstituted. The cycloalkenyl group and heterocycloalk cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy enyl group can be substituted with one or more groups includ cloalkenyl group described above. ing, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, The term "sulfoxide’ as used herein is represented by the heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, 45 formula A'S(O)A, where A' and A can be, independently, halide, hydroxy, ketone, nitro, silyl, Sulfo-oxo, Sulfonyl, Sul an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, fone, sulfoxide, or thiol as described herein. cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy The term “cyclic group' is used hereinto refer to eitheraryl cloalkenyl group described above. groups, non-aryl groups (i.e., cycloalkyl, heterocycloalkyl, The term “thiol as used herein is represented by the for cycloalkenyl, and heterocycloalkenyl groups), or both. 50 mula—. Cyclic groups have one or more ring systems that can be “R',” “R” “R” “R”,” etc., where n is some integer, as Substituted or unsubstituted. A cyclic group can contain one used herein can, independently, possess one or more of the or more aryl groups, one or more non-aryl groups, or one or groups listed above. For example, if R is a straight chain more aryl groups and one or more non-aryl groups. alkyl group, one of the hydrogenatoms of the alkyl group can The term "aldehyde' as used herein is represented by the 55 optionally be substituted with a hydroxyl group, an alkoxy formula—C(O)H. Throughout this specification “C(O) is a group, an amine group, an alkyl group, a halide, and the like. short hand notation for C=O. Depending upon the groups that are selected, a first group can The terms “amine' or "amino” as used herein are repre be incorporated within second group or, alternatively, the first sented by the formula NAAA, where A, A, and Acan be, group can be pendant (i.e., attached) to the second group. For independently, hydrogen, an alkyl, halogenated alkyl, alk 60 example, with the phrase “an alkyl group comprising an enyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, het amino group, the amino group can be incorporated within erocycloalkyl, or heterocycloalkenyl group described above. the backbone of the alkyl group. Alternatively, the amino The term “carboxylic acid as used herein is represented by group can be attached to the backbone of the alkyl group. The the formula —C(O)OH. A “carboxylate” as used herein is nature of the group(s) that is (are) selected will determine if represented by the formula—C(O)O. 65 the first group is embedded or attached to the second group. The term “ester” as used herein is represented by the for The term “bioactive property” is any local or systemic mula–OC(O)A' or C(O)OA', where A' can be an alkyl, biological, physiological, or therapeutic effect in a biological US 8,802,596 B2 11 12 system. For example, the bioactive property can be the control liquids or amorphous Solids such as glasses or waxes at a of or , enhancement or Suppression of temperature at or below about 150°C. In particular examples growth, action as an , anti-viral, pesticidal, herbi disclosed herein, the disclosed ionic liquid compositions are cidal, or nutrientional action, etc. Many examples of bioactive liquid at the body temperature of a Subject. properties are disclosed herein. 5 Further, the disclosed ionic liquid compositions are mate The term “energetic' is used to described a compound rials composed of at least two different ions; each of which having a heat of combustion of greater than about 500 kcal/ can independently and simultaneously introduce a specific mol (e.g., about 750, 1000, 1500 kcal/mol or more). characteristic to the composition not easily obtainable with Unless stated to the contrary, a formula with chemical traditional dissolution and formulation techniques. Thus, by bonds shown only as Solid lines and not as wedges or dashed 10 providing different ions and ion combinations, one can lines contemplates each possible , e.g., each enanti change the characteristics or properties of the disclosed ionic omer, diastereomer, and meso compound, and a mixture of liquid compositions in a way not seen by simply preparing isomers, such as a racemic or scalemic mixture. various crystalline salt forms. Examples of characteristics Reference will now be made in detail to specific aspects of that can be controlled in the disclosed compositions include, the disclosed materials, compounds, compositions, articles, 15 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 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 25 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 Ionic liquids have been of general interest because they are (Bridgewater, N.J.), AstraZeneca (Wilmington, Del.), Novar 30 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, Ind.), Abbott (Abbott Park, Ill.), Schering have also become popular alternative media for chemical Plough (Kenilworth, N.J.), or Boehringer Ingelheim (Ingel synthesis because of their low volatility and low toxicity. See heim, Germany), or are prepared by methods known to those 35 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 Volatile organic compounds. Other exemplary properties of (Elsevier Science Publishers, 1989); Organic Reactions, Vol 40 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 1999,99:2071-2083; and Carlinet al., Advances in Nonague pharmaceutical ingredients, , herbicides, and other 45 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., , 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, determined by the choice of cation and anion, as is disclosed but is used herein to refer to salts (i.e., compositions compris 50 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 pharmacokinetics, etc.), can be selected by changing the con they can be solids at other temperature ranges or points. Since 55 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. anion, or both can be a pharmaceutical active, a pesticidal The use of the term “liquid to describe the disclosed ionic 60 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 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 65 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, US 8,802,596 B2 13 14 8, 9, 10, or more different kinds of cations). Further, the further examples, the disclosed ionic liquids can be liquid at disclosed ionic liquids can comprise more than one kind of any point from about -30°C. to about 150° C., from about anion (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different kinds of -20°C. to about 140°C., -10°C. to about 130°C., from about anions) with more than one kind of cation (e.g., 2, 3, 4, 5, 6, 0° C. to about 120° C., from about 10° C. to about 110° C., 7, 8, 9, 10 or more different kinds of cations). Specific 5 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 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, 10 -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 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 15 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 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, 25 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 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, 30 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, (e.g., ambient temperature). In still other examples, the dis or more kinds of cations. 35 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 tions of the disclosed ionic liquids are contemplated herein. thereof and the like. However, the amount of such nonionic 40 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 ther, the disclosed ionic liquid compositions can themselves present in the disclosed ionic liquids are the cations and 45 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, In some examples, the disclosed ionic liquids are not solu 3, 2, or 1 wt.% based on the total weight of the composition). 50 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, 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, 55 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, 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, 60 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, liquid compositions can include the reaction in which two -14, -15, -16, -17, -18, -19, -20, -21, -22, -23, -24, -25, 65 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 US 8,802,596 B2 15 16 base, organic base, Zwitterion species) are combined result taste, physical properties (stability, Solubility, toxicity, melt ing in ionic liquid compositions as disclosed herein. ing point, etc.), or to overcome polymorphism in the first drug Providing ions used to prepare the disclosed ionic liquids ion. In this way, new drug compositions can be created by depends, in one aspect, on the desired properties of the result forming ionic liquids with functionality crafted into the com ing ionic liquid composition. As described herein, the dis bination of the ions, as disclosed herein. closed ionic liquid compositions can have multiple desired As another example, the first drug ion may be combined properties, which, at least in part, come from the properties of with a second drug ion that has properties complimentary to the cation(s) and/or anion(s) used to prepare the ionic liquid. the first. Examples of this can include, but are not limited to, Thus, to prepare the disclosed ionic liquids, one or more kinds an ion having properties being combined with an of cations with a desired property(ies) are provided. One or 10 ion having antibacterial properties, an ion having anesthetic more kinds of anions with a desired property(ies) that is properties being combined with an ion having coagulation similar or different to that of the cation(s) can likewise be properties, or an ion having coagulation properties being provided. Of course, providing a desired anion(s) and 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 15 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 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 25 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 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 30 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. 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 35 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 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 40 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 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 45 disclosed compositions include antibacterial, FDA approved disclosed ionic liquid compositions as solvents to dissolve a dyes, anti-, , 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 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 50 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 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 55 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, 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 60 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 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 65 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 US 8,802,596 B2 17 18 example, if an ionic liquid composition is disclosed and a Many scientists have focused their attention on water number of modifications that can be made to a number of soluble QACs because they exhibit a range of properties: they components of the ionic liquid composition are discussed, are surfactants, they destroy bacteria and fungi, they serve as 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 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 10 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 QACs are also widely used as skin , 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, 15 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 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 25 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 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 30 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 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 35 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 Aliphatic Heteroaryls can be converted into a quaternary nitrogen atom can be a Some specific QACs suitable for use herein are aliphatic Suitable cation for the disclosed ionic liquid compositions. 40 heteroaryls. An aliphatic heteroaryl cation is a compound that QACs can have numerous biological properties that one comprises an aliphatic moiety bonded to a heteroaryl moiety. may desire to be present in the disclosed ionic liquid compo In the aliphatic heteroaryl cation, the aliphatic moiety can be sitions. For example, many QACs are known to have antibac any alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl group, terial properties. The antibacterial properties of QACs were as described herein. Generally, the aliphatic moiety can com first observed toward the end of the 19" century among the 45 prise at least 10, at least 12, at least 14, at least 16, at least 18, carbonium dyestuffs, such as auramin, methyl violet, and or at least 20 carbon atoms. In other examples, the aliphatic malachite green. These types of compounds are effective moiety can comprise a mixture of aliphatic groups having a chiefly against the Gram-positive organisms. Jacobs and range of carbon atoms. For example, the aliphatic moiety can Heidelberger first discovered QACs antibacterial effect in comprise from 10 to 40, from 12 to 38, from 14 to 36, from 16 1915 studying the antibacterial activity of substituted hexam 50 to 34, from 18 to 32, from 14 to 18, or from 20 to 30 carbon -tetrammonium salts (Jacobs and Heidelberger, Proc atoms. In some specific examples, the aliphatic moiety can Nat AcadSci USA, 1915, 1:226: Jacobs and Heidelberger, J contain 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, Biol Chem, 1915, 20:659; Jacobs and Heidelberger, J Exptl 25, 26, 27, 28, 29, 30, 31, 32,33, 34,35, 36, 37,38, 39, 40, 41, Med, 1916, 23:569). 42, 43, 44, or 45 carbonatoms, where any of the stated values Browning et al. found great and somewhat less selective 55 can form an upper or lower endpoint when appropriate. bactericidal powers among quaternary derivatives of pyri Examples of specific aliphatic moieties that can be used dine, quinoline, and phenazine (Browning et al., Proc Roy Soc include, but are not limited to, decyl, dodecyl (lauryl), tet London, 1922, 93B:329; Browning et al., Proc Roy Soc Lon radecyl (myristyl), hexadecyl (palmityl or cetyl), octadecyl don, 1926, 100B:293). Hartman and Kagi observed antibac (Stearyl), eicosyl (arachidyl), and linolenyl groups, including terial activity in QACs of acylated alkylene diamines (Hart 60 branched derivatives thereof and any mixtures thereof. In the man and Kagi, ZAngew Chem, 1928, 4:127). aliphatic heteroaryl cations, the aliphatic moiety is bonded to In 1935, Domagk synthesized long-chain QACs, including a heteroatom in the heteroaryl moiety. benzalkonium chloride, and characterized their antibacterial In the aliphatic heteroaryl cation, the heteroaryl moiety can activities (Domagk, Deut Med Wochenschr, 1935, 61:829). be any heteroaryl moiety as described herein. For example, He showed that these salts are effective against a wide variety 65 the heteroaryl moiety can be an aryl group having one or more of bacterial strains. This study of the use of QACs as germi heteroatoms (e.g., nitrogen, oxygen, Sulfur, phosphorous, or cides was greatly stimulated. halonium). Examples of specific heteroaryl moieties that can US 8,802,596 B2 19 be used in the aliphatic heteroaryl cations include, but are not -continued limited to, , pyridine, , , pry R5 R4 R4 R3 idazine, indolizine, , , , , R R3 R3 R9 , , , , , quinoline, , quinooxaline, phenazine, and the like, including substituted derivatives and mixtures thereof. In the aliphatic R7 O R9 R6 C ) NR heteroaryl cations, a heteroatom in the heteroaryl moiety is bonded to the aliphatic moiety. When the heteroatom of the R8 R1 R7 R8 heteroaryl is nitrogen, this forms a quaternary ammonium QUINOLIUM ISOQUINOLIUM cation, as described herein. 10 Further examples of aliphatic heteroaryl cations are those having the following structures:

15 wherein R' and Rare, independently, a C-C alkyl group or R4 R4 a C-C alkoxyalkyl group, and R,R,R,R,R,R, and R' (R-R), when present, are independently H, a C-C alkyl, a C-C alkoxyalkyl group, a C-C alkoxy group, or an ener getic Substituents such as nitro, amino, cyano, azido, alkyl ()O R5 OÖr R5 nitro, alkyl amino, alkyl cyano, alkyl azido, alkoxy nitro, R7 R6 R6 2 alkoxy amino, alkoxy cyano, and alkoxy azido. In other R1 RI examples, both R" and R groups are C-C alkyl, with one PYRIDINIUM PYRIDAZINIUM being methyl, and R-R, when present, are H. Exemplary C-C alkyl groups and C-C alkyl groups include methyl, R4 25 ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl, pentyl, R3 R3 N R4 iso-pentyl, hexyl, 2-ethylbutyl, 2-methylpentyl, and the like. Corresponding C-C alkoxy groups contain the above C-C, alkyl group bonded to an oxygen atom that is also bonded to O IOC the cation ring. An alkoxyalkyl group contains an ether group 30 R6 2. R5 R6 R5 bonded to an alkyl group, and here contains a total of up to six R1 RI carbon atoms. It is to be noted that there are two isomeric PYRIMIDINIUM PYRAZINIUM 1,2,3-. In some examples, all R groups not required R4 R5 R3 R4 for cation formation can be H. 35 The phrase “when present is often used herein in regard to substituent R group because not all cations have all of the O. O. numbered R groups. All of the contemplated cations contain R11 Y NR2 R21 NR5 at least four R groups, which can be H, although R need not be present in all cations. R3 RI 40 IMIDAZOLIUM PYRAZOLIUM In one example, all R groups that are not required for cation R5 R3 R4 R3 R4 R3 formation; i.e., those other than R' and R for compounds other than the imidazolium, pyrazolium, and triazolium cat ions shown above, are H. 45 O. (O. Y O. A cation that contains a single five-membered ring that is R11 R11 N% YR2 R1 s free offusion to other ring structures is suitable for use herein. Exemplary cations are illustrated below wherein R', R, and R4 R2 R-R, when present, are as defined before. OXAZOLIUM 1,2,3-TRIAZOLIUM R5 R3 50 R4 R3 R3 R2 R4 R3 R3 R2 \ O), M N O N N N 1 -2 R1'N,Cy R4 YR4 55 1. O,NYNs: rS4 R11 (O)N21 ns R2 1,2,4-TRIAZOLIUM THIAZOLIUM 1,2,4-TRLAZOLIUM R4 1,2,3-TRIAZOLIUM R5 R4 R5 R3 R4 R5 R3 R5 60 (O), 'O R7 N R6 R' N R3 M V / V R11 Y R11 Y NR2 R1 R2 R1 R2 R4 R3 65 PIPERIDINIUM PYRROLIDINIUM THIAZOLIUM IMIDAZOLIUM US 8,802,596 B2 21 22 -continued (e.g., the number of carbon atoms is 10 or greater). In other R5 examples, one or more of the “R” substituents can be a short chain alkyl group (e.g., the number of carbon atoms is less than 10). In still other examples, one of the “R” substituents is (O O. a long chain alkyl group and the other two “R” substituents R21 s R5 R11 Y are short chain alkyl groups. In one aspect, the aliphatic benzylalkyl ammonium cation R1 R4 can have any of the aliphatic moieties disclosed herein PYRAZOLIUM OXAZOLIUM bonded to any benzylalkyl amine moieties disclosed herein. 10 In some specific examples, R' in the formula of aliphatic benzylalkyl ammonium cation can be an aliphatic group of Of the cations that contain a single five-membered ring free from 10 to 40 carbon atoms, e.g., a decyl, dodecyl (lauryl), of fusion to other ring structures, an imidazolium cation that tetradecyl (myristyl), hexadecyl (palmitylor cetyl), octadecyl corresponds in structure to Formula A is also Suitable, (stearyl), or eicosyl (arachidyl) group, and R'' and R' can wherein R', R, and R-R, are as defined before. 15 each be, independent of one another, a methyl, ethyl, propyl. butyl, pentyl, or hexyl group. In another aspect, the aliphatic benzylalkyl ammonium (A) R4 R5 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 RI Y 9 N R2 dimethylbenzyl ammonium, and arachidyl dimethylbenzyl ammonium. 25 In yet another aspect, the aliphatic benzylalkyl ammonium In a further example, an N,N-1,3-di-(C-C alkyl)-substi cation can include, but are not limited to, alkyl methylethyl tuted-imidazolium ion can be used; i.e., an imidazolium cat benzyl ammonium cations. Specific examples of alkyl meth ion wherein R-Rof Formula A are each H, and R' and Rare ylethylbenzyl ammonium cations include, but are not limited independently each a C-C alkyl group or a C-C alkoxy to, cetyl methylethylbenzyl ammonium, lauryl methylethyl alkyl group. In yet another example, the cation illustrated by 30 benzyl ammonium, myristyl methylethylbenzyl ammonium, a compound that corresponds in structure to Formula B. Stearyl methylethylbenzyl ammonium, and arachidyl meth below, wherein R-R of Formula A are each hydrogen and R' ylethylbenzyl ammonium. is a C-C-alkyl group or a C-C alkoxyalkyl group. Dialiphatic Dialkyl Ammonium Still further examples of QACs that can be used in the 35 disclosed ionic liquid compositions are dialiphatic dialkyl (B) ammonium cations. A dialiphatic dialkyl ammonium cation is a compound that comprises two aliphatic moieties and two alkyl moieties bonded to a nitrogen atom. The aliphatic moi R11 O),N2 NCH, eties can be the same or different and can be any aliphatic Aliphatic Benzylalkyl Ammonium 40 group as described above. The alkyl moieties can be the same or different can be any alkyl group as described above. In the disclosed dialiphatic dialkyl ammoniums cations, the two The disclosed ionic liquid compositions can also comprise aliphatic moieties can have 10 or more carbon atoms and the an aliphatic benzylalkyl ammonium cation. An aliphatic ben two alkyl moieties can have less than 10 carbon atoms. In Zylalkyl ammonium cation is a cation that comprises an ali 45 another alternative, the two aliphatic moieties can have less phatic moiety bonded to the nitrogen atom of a benzylalkyl than 10 carbon atoms and the two alkyl moieties can have 10 amine moiety. The aliphatic moiety can be as described or more carbon atoms. One or more types of dialiphatic herein. The benzylalkyl amine moiety can be a benzyl amine dialkyl ammonium cations can be used in the ionic liquid where the amine is bonded to an alkyl or cyclic alkyl group, as compositions disclosed herein. described herein. One or more types of aliphatic benzylalkyl 50 In Some particular examples, the dialiphatic dialkyl ammo ammonium cation can be used in the ionic liquid composi nium cation can be di-dodecyl dimethyl ammonium, di-tet tions disclosed herein. The aliphatic benzylalkyl ammonium radecyl dimethyl ammonium, dihexadecyl dimethyl ammo cation suitable for use herein can be prepared by methods nium, and the like, including combinations thereof. known in the art or can be obtained from commercial sources. Tetraalkyl Ammonium In one aspect, the aliphatic benzylalkyl ammonium cation 55 The disclosed ionic liquid compositions can also comprise can be represented by the following formula: a tetraalkyl ammonium cation. Suitable tetraalkyl ammonium cations comprise four alkyl moieties, as disclosed herein. In one example, a tetraalkyl ammonium cation can comprise one long chain alkyl moiety (e.g., 10 or more carbon atoms in 60 length) and three short chain alkyl moieties (e.g., less than 10 carbon atoms in length). Some specific examples of tetraalkyl ammonium cations that can be included in the disclosed ionic liquid composi wherein R' is analiphatic group, as described above, R'' and tions include, but are not limited to, cetyl trimethyl ammo R" are, independent of one another, alkyl groups or cyclic 65 nium, lauryl trimethylammonium, myristyltrimethyl ammo alkyl groups as described herein. In some examples, one or nium, Stearyl trimethyl ammonium, arachidyl trimethyl more of the “R” substituents can be a long chain alkyl group ammonium, or mixtures thereof. Other examples include, but US 8,802,596 B2 23 24 are not limited to, cetyl dimethylethyl ammonium, lauryl etate (TA; CFCO), and heptafluororobutanoate (HB; CF dimethylethyl ammonium, myristyl dimethylethyl ammo (CF)SO). Other types of ionic liquids include haloalumi nium, Stearyl dimethylethyl ammonium, arachidyl dimethyl nates, such as chloroaluminate. ethyl ammonium, or mixtures thereof. Other Suitable anions contemplated herein are saccharin Other Cations and acesulfame. Saccharin, as an alkali metal salt, and Other cations that are suitable for use in the disclosed acesulfame (6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one methods and compositions are compounds that contain met 2,2-dioxide), which has previously only been offered as als. According to the methods and compositions disclosed 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 10 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, , active cations to prepare Sweet tasting ionic liquids that have Sodium, potassium beryllium, , , stron pharmaceutical activity. tium, chromium, manganese, iron, cobalt, nickel, copper, and 15 Specific examples of other anions include , . Silver can also be used. Examples of folic acid, ibuprofen, fast green FCF, docusate, acesulfamate, Suitable organometallic cations include, but are not limited to, G, Colawet MA-80, , saccharinate, metallocenium, alkylgermanyl, alkyltin, or alkylsilyl (e.g., Sulfacetamide, , benzoate, , and trans-cin trimethylsilylium, triethylsilylium, tris(trimethylsilyl)sily namic acid. lium, tribenzylsilylium, triphenylsilylium, tricyclohexylsily Other suitable anions include, but are not limited to, Sub lium, and dimethyloctadecylsilylium). stituted and un-Substituted imidazolates, 1,2,3-triazolates, Another suitable group of quaternary ammonium cations 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 moiety. Such 25 choline esters can be biofriendly, permanent ions that are R13 R13 R 14 amenable to being added to various compounds while still being easily cleavable under physiological conditions. The N N N choline esters can be used to increase the solubility and bio \ { availability of many neutral compounds. 30 R 14 > R 15 R14 - - Further examples of cations include (2-hydroxyethyl)- dimethylundecyloxymethylammonium, (2-acetoxyethyl)- imidazolate 1,2,3-triazolate 1,2,4-triazolate heptyloxymethyldimethylammonium, and (2-acetoxyethyl)- R13 R13 dodecyloxymethyldimethylammonium, , 14 14 R N R N , thimerosal, and valproic acid. 35 In other examples, the cation can be an energetic cation as X- R17 Y disclosed in Katritzky et al., “ILs Based on Energetic Imida M W Zolium Cations: Nitro- and Nitrile-substituted N,N'Dialky R 15 N R15 N limidazolium Salts' New J Chem 30:349, 2006, which is R 16 R 16 incorporated by reference herein at least for its teachings of 40 energetic ions. benzimidazolate benz-1,2,3-triazolate Anions 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 45 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 or acids, through 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 groups include methyl, ethyl, propyl, iso-propyl, butyl, sec or be converted to anionic species through similar reactions. 50 butyl, iso-butyl, pentyl, iso-pentyl, hexyl, 2-ethylbutyl, 2-me Still further, compounds that contain nitrogen atoms, espe thylpentyl, and the like. Corresponding C-C alkoxy groups cially nitrogen atoms adjacent to electron withdrawing contain the above C-C alkyl group bonded to an oxygen groups or resonance stabilizing structures, can be converted atom that is also bonded to the cation ring. An alkoxyalkyl to anions through deprotonation. According to the methods group contains an ether 10 group bonded to an alkyl group, and compositions disclosed herein, any compound that con 55 and here contains a total of up to six carbon atoms. It is to be tains an oxygen, Sulfur, or nitrogen atom can be a Suitable noted that there are two isomeric 1,2,3-triazoles. In some anion for the disclosed ionic liquid compositions. examples, all R groups not required for anion formation can Other suitable anions include, but are not limited to, halides be H. (e.g., fluoride, chloride, , and iodide), Further examples of suitable energetic anions are disclosed (SO), carbonates, bicarbonates, phosphates, phosphates, 60 in Katritzky et al., “ILs Based on Energetic Azolate Anions.” (NO), (NO), (CHCO), and the Chem Eur J 12:4630, 2006, which is incorporated by refer like. Other examples of anions include, but are not limited to ence herein at least for its teachings of energetic anions. PF, that is immiscible in water and BF, that is miscible in 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 65 include triflate (TfG); CFSO), nonaflate (NfO; CF (CF). Examples of compounds that exist as cations in Some envi SO), bis(triflyl)amide (Tf.N. (CFSO)N), trifluoroac ronments and anions in other environments include, but are US 8,802,596 B2 25 26 not limited to, 1,3-dimethylimidazolium, 1-butyl-3-meth prepare the disclosed ionic liquid compositions. Those of ylimidazolium, 1,2,3-triazolium, tetrazolium, 1,2,4-triazo ordinary skill in the art will recognize numerous other com lium, 1,3-dimethyl-1,2,3-triazolium, and 1,3-dimethyl-4-ni pounds that fall within the categories and that are useful troimidazolium, which exist as a cations, and according to the disclosed compositions and methods. 4-nitroimidazolate, 4,5-dinitroimidazolate, 3,5-dinitro-1,2, Some specific examples of pharmaceutical actives that can 4-triazolate, tetraZolate, 5-aminotetraZolate, 2-nitroimida be used in the disclosed ionic liquids include, but are not Zolate, which exist as an anion. Those separate ions can still limited to, , LIBRIUMTM, , penicillin, form single productionic liquids. PRONTOSILTM, cisplatin, 6-mercaptopurine, RITUXANTM, Examples of compounds that can change from an anion in TAXOLTM, , PROZACTM, ALLEGRATM, one environment to a cation in another environment due to 10 VIOXXTM, , , L-dopa, THORAZINETM, chemical modifications are the Sulfur ylides through the reac salvarsan, TAGAMETTM, AZT, crixivan, , tion of a sulfide with methyliodide to form the sulfonium ion. , fluride, LOVASTATINTM, erythropoietin, hydrocor Specific Examples of Pharmaceutical Actives tisone, insulin, oral contraceptives, oxytocin, PRE 15 MARINTM, RU-486, thyroxine, , cyclosporine, When pharmaceutical activity is a desired property of the , , , botox, vitamins, FOSA disclosed ionic liquids, one or more of the ions in the dis MAXTM, RITALINTM, and VIAGRATM, including ionic closed ionic liquid compositions can be a pharmaceutical derivatives thereof. active. Pharmaceutical actives that exist as ions or can be Other examples of pharmaceutical active ions or pharma converted to ions, and which are Suitable for use in preparing ceutical actives that can be made ionic include, but are not the disclosed ionic liquid compositions, include the following limited to, , sold under the trade names PRO categories and specific examples. It is not intended that the TONIXTM and PANTOZOLTM, and , sold under category be limited by the specific examples. Those of ordi the trade names ACIPHEXTM and PARIETTM, which are used nary skill in the art will be able to readily identify those to treat gastrointestinal disorders. Risedronate, sold under the pharmaceutical actives that can be used in the disclosed meth 25 trade name ACTONELTM, and alendronate, sold under the ods and compositions. For example, one can identify a com trade name FOSAMAXTM, are used to treat and pound with a given property or activity by consulting various are further examples of Suitable compounds that can be used sources, such as the (13" Edition, Wiley, 2001), to prepare the disclosed ionic liquid compositions. Further The United States Pharmacopeia-National Formulary (USP examples include , sold under the trade names NU NF), and the FDA's Orange book, which are each incorpo 30 LOTANTM, COZAARTM, and HYZAARTM, and , rated by reference herein at least for their teachings of phar sold under the trade name MONOPRILTM, which are used to maceutical actives. Once a compound with a desired property treat and are other examples of suitable com is identified, the skilled artisan can determine whether the pounds that can be used to prepare the disclosed ionic liquid compound is ionic or can be made ionic. Such determinations compositions. , sold under the trade name LIPI can be performed based on the compound's structure, which 35 TORTM, and , sold under the trade name PRAVA can readily be determined by consulting the sources men CHOLTM, are used to treat and are further tioned herein or experimentally. Knowing a compounds examples of Suitable compounds that can be used to prepare structure can readily reveal if the compound is ionic. In fact, the disclosed ionic liquid compositions. A further example is many pharmaceutical actives exist as salts and are thus Suit , which is used to treat and is sold under able for use in preparing the disclosed ionic liquid composi 40 the trade name SINGULAIRTM. tions. Further, if a compound is not ionic, but contains an ion The following table illustrates further examples of phar forming moiety (e.g., nitrogen, oxygen, Sulfur, or metal maceutical actives that are ionic or can be made ionic and atoms, as described herein), the compound can be converted combined with other ions to form the disclosed ionic liquid to an ion and then combined with a Suitable counterion to compositions. TABLE 1

Name Compound MP Pat. No. Other Names Function: Interceptive

Prostaglandin 66-68 U.S. Pat. No. PGE2, U-12062, E. 3,598,858 Cerviprost, Minprostin E2, Prepidil, Propess, Prostarmon-E, Prostin E2

Prostaglandin 25-35 U.S. Pat. No. PGF2A, U-14583

F24 3,657,327 Enzaprost F. Glandin, Prostarmon F US 8,802,596 B2 27 28 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Sulprostone U.S. Pat. No. Nalador 4,024, 179

Cetapril 155-156 U.S. Pat. No. Alacepril 4,248,883

CH COOH

Benzaepril CH3-N-O O O 148-149 U.S. Pat. No. 4.410,520

H

Captopril O COOH 103-104° U.S. Pat. Nos. Acediur, Acepril, 4,046,889 Alopresin, Acepress, 4,105,776 Capoten, Captolane, Captoril, Cesplon, SH ~. N Dilabar, Garranil, H CH Hipertil, Lopirin, Lopril, Tensobon, Tensoprel Function: A-

Methyl U.S. Pat. Nos. Forthane hexaneamine 2,350,318 2,386,273

Synephrine OH 184-185 DE 566578 Analeptin, Ethaphene, Oxedrine, Parasympatol, NCH, Simpalon, Synephrin, Synthenale

O Function: B-

Isoetharine OH 212-213 DE 6386SO Win -3046, Dilabron, Neoisuprel CH3 in HO OH CH

Methoxyphenamine NH 97-99 JP 612921

CH3 CH3 OCH US 8,802,596 B2 29 30 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: A-Adrenergic Blocker

Tamsulosin 228-230° U.S. Pat. No. Flomaz, Harnali, 4,703,063 Omnic, Pradif

Tolazoline 1749 U.S. Pat. No. Lambral, Priscol, 2,161,938 Priscoline, Vasco Dilatan HCI

Function: B-Adrenergic Blocker

Bufuralol 146 U.S. Pat. No. Angium 3,929,836

O H\ / HCI OH

Nadoxolol N-OH 1889 U.S. Pat. No. Bradyl re 3,819,702 OH NH2 HCI

Function: Analgesic (non-)

Acetylsalicyl 1549 Salicylic acid s" O COOH

Ammonium COONH4+ Salicylate

OH

Function: Anesthetic (Intravenous)

Buthalital Baytinal, Buthaliton Sodium Sodium, Thialisobumalnatrium, Transithal, Ulbreval

CH US 8,802,596 B2 31 32 TABLE 1-continued

Name Compound MP Pat. No. Other Names Thiopental H U.S. Pat. Nos. Sodium O N SNat 2,153,729 2,876,225 3,109,001

CH, O Function: Anesthetic (Local) Isobutyl p O Cycloform, Isobutyl Aminobenzoate Kelofom, Isocaine CH3

r CH3 NH

Phenol OH

Function: Anorexic

Clortermine NH2 116-118° U.S. Pat. No. 3,415,937 CH, CH C N 126-127 U.S. Pat. No. N-1Ne. 3,485,924 CH3

Function: Antacid

Dermatol HOOC O N Bi-OH M O

OH Function: Anthelmintic (Cesodes)

Nicosamide OH 225-230° U.S. Pat. No. C 3,079,297 H 3,113,067 N C

O NO

Pelletierine H Punicine N CH

O

Function: Anthelimintic (Nematodes) Dithiazanine U.S. Pat. No. Anelmid, Anguifugan, Iodide 2,412,815 Delvex, Dejo, Deselmine, Dilombrin, X-CIO Dizan, Nectocyd, Partel, Telmicid, -/ Telmid US 8,802,596 B2 34 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Thiabendazole H 304-30S U.S. Pat. No. Thibenzole, Equizole, N 3,017,415 Mertect, Storite, TBZ, Tecto O N2X-O {N

Function: Anthelmintic (Schistosoma) Antimony O OS COONa Sodium s1N1 Thioglycolate N S/

Niridazole O 260-262 BE 632989 Ba-32644, Ciba 32644-Ba, Ambilinar NO SX-\u X N

Function: Antiacne

Isotretinoin H3C CH3 CH3 CH3 174-1750 U.S. Pat. No. Accitame, Isotrex, 4,556,518 Oratane, Roaccutane S1s1s-1s

COOH CH3

Function: Antiallergic

Lodoxamide CN 2120 U.S. Pat. No. 3,993,679 orsO lsoO H N CL

Ramatroban 134-135° U.S. Pat. No. 4,965,258

Function: Antialopecia Agent

Finasteride -257 U.S. Pat. No. Chibro-Proscar, 4,760,071 Finasid, Propecia, Proscar, Prostide US 8,802,596 B2 35 36 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Minoxidi 248 U.S. Pat. Nos. Alopexil, Alostil, 3,382.247 Loniten, Lonolox, 3,644,364 Minoximen, N NN NH2 Normoxidil,Regaine, Rogaine, Prexidil, Tricoxidi 2 Na O NH2

Function: Antiamebic

Carbarisone O 1749 JPS84418 Amabevan, Ameban, O Amibiarson, AS-OH Arsambide, Carb-O- us Selo, Histocarb, NH N OH Fenarsone, H Leucarsone, Aminarsone, Amebarsone

Diphetarsone O - T --- Amebarsin, Bemarsal, V ONa Rodameb As OH N-1NN g H O'Ns n? O

Function:

Flutamide CF3 1115-112.5° U.S. Pat. No. Drogenil, Eulexin, NO 3,847,988 Euflex, Flucinom, Flutamin, Fugerel

O

N CH3 HC

Nilutamide H3C H 149° U.S. Pat. No. RU-23908, Anandron, CH S- 4,097,578 Nilandron

N O CF

NO

Function:

Nicorandil N 92-93 U.S. Pat. No. Adamcor, Ikorel, n 4,200,640 Perisalol, Sigmart 2 n1n ONO

O

OZagrel 2N. 223-224 N 2 N US 8,802,596 B2 37 38 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Antiarrhythmic

Bunitrolol CN OH 163-165° U.S. Pat. No. 3,541,130 N-N- n C(CH3)3

Br

Ipratropium Br 230-232 U.S. Pat. No. Atem, Atrovent, Bromide HC 3,505,337 Bitrop, Itrop, Narilet, HC 2-c. Inatec aNN, 2. Function: Anti-arteriosclerotic

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

Function: Antiarthritic Antiheumatic

Bucillamine O COOH 139-140° U.S. Pat. No. Rimatil 4,305,958 HC SH 3 1 HC SH

Diacerein O 217-218 U.S. Pat. No. Artrodar, Fisiodar 4,244,968 COOH

N” O N" O O US 8,802,596 B2 39 40 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Antiasthmatic (Non-)

Amlexanox O N NH2 >300 U.S. Pat. No. Aphthasol, Elics, Solfa N 4,143,042 H3C 41 yeooh

CH3 O

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

O O

COONat

Function: Antibacterial (Antibiotics)

AZidamfenicol O OH 107° U.S. Pat. No. Berlicetin, N 2,882,275 Leukomycin-N, NO Posifenicol, N Thilocanifol H

HO

Thiamphenicol CL 1643-166.3° U.S. Pat. Nos. Hyrazin, Igralin, 2,759,927 Neomyson, Rigelon, 2,759,970 Thiamcol, Thionicol, C 2,759,971 Thiophenicol, 2,759,972 Urfamycine, 2,759,976 Urophenil

Function: Antibacterial (Synthetic)

Brodimoprim OCH 225-228 U.S. Pat. No. Hyprim, Unitrim 4,024,145

Tetroxoprim OCH 153-156 U.S. Pat. No. 3,992,379 US 8,802,596 B2 41 42 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Antibacterial (Leprostatic)

Acetosulfone Na" -285 U.S. Pat. No. Sodium 2,358,365 N CH O=1K 3 \% O NH

Dapsone O O 175-176° FR 829926 Avlosulfon, M/ Croysulfone, \/ Diphenasone, Disulone, Dumitone, Eporal, Novophone, Sulfona-Mae. HN Sulphadione, Udolac

Function: Antibacterial (Tuberculostatic)

Benzoylpas 260-261 GB 6.76363

H HO N

O COOH Cyamelide NS" O O

NH

Function: Anticoagulant

Picotamide O O 1249 U.S. Pat. No. 3,973,026 N1 N N N NN H H 21 OCH 2

Function:

Acetylpheneturide CH 100-101 U.S. Pat. No. Crampol H CH 3,110,728 H N s O O O

Albutoin NH S 21O-211 g Euprax HC Y N US 8,802,596 B2 43 44 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function:

Caroxazone 203-205 U.S. Pat. No. Timostenil 3,427,313

Indalpine U.S. Pat. No. Upstene 4,064,255

NH

Function: Antidiabetic

Calcium COO Ca2+ Dec. JP 524157 Mesoxan Mesoxalate 210-220° C. JP 607463

Buformin U.S. Pat. No. 2.961377

Alkofanone Dec. U.S. Pat. No. Alfone 221-223 2,421,836

Metformin CH U.S. Pat. No. DMG5, -6023 3,174,901 . . .N.2 CH1. r r NH NH

Function: Antidote ()

Edrphomium OH CH3 Dec. U.S. Pat. No. Antirex, Enlon, Chloride 162-1639 2,647,924 Reversol, Tensiolon | N-CH3

Neostigmine Dec. U.S. Pat. No. 167 1,905,990 US 8,802,596 B2 46 TABLE 1-continued

Name Compound MP Pat. No. Other Names

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

HN

Methylene 3H2O Blue N 2 21 H3C N CH3 n N s N 1. C CH3 CH3 Function: Antidote (Folic Acid Antagonists)

Folinic Acid H H Dec. U.S. Pat. No. "N N 240-2SO 2,741,608 | H N N N O eCH COOH O O COOH Function: Antidote (Heavy Metal Poisoning) O 95-97 Acadione, Capen, Epatiol, Mucolysin, H3C Thiola, Thiosol s N1NcooHH SH Function: Antidote ( and Ethylene Glycol Poisoning) Fomepizole H 15.5-18.5 N

HC Function: Antidote (Organophophate poisoning)

AsOxime O 145-147 U.S. Pat. No. Chloride 3,773,775 21 SNOH 21 NH2 NCTN N-N-SO N N Obidoxime "C- "C- Syn: U.S. Pat. No. Toksobidin, Chloride 2n.21-1a, 1s 235-236 3,137,702 Toxogonin Anti: to 21s 4So 218-220 Function: Antidyskinetic

H g Chloride N N C 130 U.S. Pat. No. 3,202,660

().NH C US 8,802,596 B2 47 48 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Tiapride CH3 123-125° C. GB O O O r 1394.563 HC1\/ 1- N n-1'''CH

OCH

Function:

Alizapride Z O 139° U.S. Pat. No. CH/N 4,093,672 N N N

M N H

Bromopride U.S. Pat. No. Emepride, Emoril, 3,177,252 Vladi Br 1a- N N-"CH H

SH OCH

Function: Antifibrotic

Potassiump COOK Potaba Aminobenzoate

Function: (synthetic)

Chlordantoin CH H N O HC y 3 N V O S-CC1

Bromo OH 238-243 U.S. Pat. No. Multifungin Salicylchloranilide 2,802,029 H N Br

C

Function: Antiglaucoma

Acetazolamide O O 258-259 U.S. Pat. No. Acetamox, Atenezol, V/ 2,554,816 Defiltran, Diamox, S S Didoc, Diuriwas, DonmoX, Edemox, Sir YNH, Fonurit, Glaupax HC N(N-N O US 8,802,596 B2 49 50 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Benfunolol 160° U.S. Pat. No. Versus, Zildasac 3,470,194

N Y. A N COOH

Function: Antigout

Allopurinol N H above U.S. Pat. No. N-yN 360° 3,474,098 NNeN/

OH

Carprofen NH COOH 197-1989 U.S. Pat. No. Imadyl, Rimadyl 3,896,145

C

Function: Antihistaminic

Acrivastine O Dec. U.S. Pat. No. Semprex 222 o 4,501,893 1n-1 COOH H NSN

HO COOH

Metron S CH CH CH 84-85 HC ---> N H

Function: Anti-hyperlipoproteninemic

Acifran 1760 U.S. Pat. No. Reductol COOH 4,244,958

Benfluorex U.S. Pat. No. CH 3,607,909

CF US 8,802,596 B2

TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Anti-hypertensive

Chlorisonclamine C 258-265 U.S. Pat. No. Ecolid, Ecolid Chloride 3,025,294 Chloride C N"CI(CH) CiN NCH, C

C Pentamethonium 1N1N1\ Penthonium, Bromide (HC). Br"N NBr (CH) Lytensium Function: Anti-hyperthyroid

2-Aminothiazole S NH2 93 U.S. Pat. No. Sir 2,242,237 N

Methylthio- CH S Dec. Alkiron, Antibason, 3 326-331 Basecil, Basethyrin, Methiacil, Methicil, NH Methiocil, Muracil, Prostrumyil, Strumacil, Thimecil, Thyreostat I O Function: Anti-hypotensive

Amexinium 1760 U.S. Pat. No. Regulton, Risumic, Methyl 3,631,038 Supratonin

OCH N SNSa CH3SO4 21

NH2

Dopamine HO NH2 Dec. Cardiosteril, Dopastat, Hydrochloride 241 Dynatra, Inovan, HCI Inotropin HO Function: Anti-Inflammatory (Gastrointestinal)

Balsalazide O >350 U.S. Pat. No. 4,412,992 NHN1 NcooH N nNS.

HO

COOH

Mesalamine COOH dec. GB 751386 Asacol, Ascolitin, 280° Claversal, Lixacol, OH Mesasal, Pentasa, Rowasa, Salofalk US 8,802,596 B2 53 54 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Anti-Inflammatory ()

Enfenamic COOH 116-117 IN 103066 Tromaril Acid IN 114805

N

Menfenamic Acid

Flufenamic COO Alfenamin, Opyrin Acid Aluminum CF Salt

Function: Antimalarial

Berberine 145°

HCO OCH

Chloguanide H H H 1290 FR N-N-N-" 1OO1548 NH NH CH3 C

Function: Antimanic

Valproic liquid Convulex, Depakene, Acid Mylproin

O

Function: Antimigraine

Lisuride 186°

HN 1.-->N CH3

CH3

CH3 H US 8,802,596 B2 55 56 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Naratriptan HN 170-1710 U.S. Pat. No. 4,997,841 SW. Na CH

Function: Antimuscarinic

Ambutonium O 228-229° Bromide NH2 NCH3N-1''' CH CH

Benzilonium 203-204° GP 821436 Minelsin, Minelcin, Bromide Portyn, Ulcoban

Function: Antineoplastic

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

TenuaZonic CH Acid H HC N O

o CH

HO O

Function: Antiobsessional

Clometocillin U.S. Pat. No. Rixapen 3,007,920 US 8,802,596 B2 57 58 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Fluoxetine 157-158° U.S. Pat. No. Adofen, Fluctin, Hydrochloride O 4,314,081 Fluoxeren, Fontex, NCH, Foxetin, Lovan, Prozac, Reneuron, HCI Sarafem FC

Function: Antiosteoporotic

Pamidronic U.S. Pat. No. Acid 4,327,039

HN % Yoh

Risedronate N O U.S. Pat. No. Acetonel, Optinate Sodium S HO || 5,583,122 21 OH o? PYon O

Function: Antiparkinsonian

Benserazide NH2 OH 146-148 U.S. Pat. No. Hydrochloride 3,178,476 HO OH n N H O HCI OH

Carbidopa HO COOH 203-205 U.S. Pat. No. Lodosyn

A. 3,462,536 A H3C NH-NH2 HO H2O

Function: Antipheochromoc-ytoma

Metyrosine 310-31.5° U.S. Pat. No. Demser 2,868,818

Phentolamine 174-1750 U.S. Pat. No. 2,503,059 NH

N OH

HC1

Function: Anti-pneumocystic

Elfornithine NaH F 1830 Hydrochloride HCI monohydrate HO HN COOH F US 8,802,596 B2 59 60 TABLE 1-continued

Name Compound MP Pat. No. Other Names o o N 1670 U.S. Pat. No. Gantanol, Sinomin V/ || y-CH 2,888,455 Sn N H

HN

Function: Antiprostatic Hypertrophy

Tamsulosin 228-230 U.S. Pat. No. Flomax, Harnal, Hydrochloride 4,703,063 Omnic, Pradif O O V/ HN

Terazosin 272-274 U.S. Pat. No. 4,026,894 U.S. Pat. No. 4,251,532

HCO

Function: Cryptosporidium

Nitazoxanide NO O 2O2 U.S. Pat. No. CryptaZ 3,950,351 a No o --

\=K N H

Function: Antiprotozoal (Giardia)

Acrani HO fSCH, 237-238 U.S. Pat. No. l 2,113,357 HN CH

N OCH 2 HCI 2 C N US 8,802,596 B2 61 62 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Antiprotozoal (Leishmania)

Hydroxystill HN NH2 235o U.S. Pat. No. bamidine 2,510,047

OH

HN NH

Pentamidine HN NH2 dec. U.S. Pat. No. 186° 2,394,003

O

O

HN NH

Function: Antiprotozoal (Toxoplasma)

Pyrimethamine N NH2 233-234 U.S. Pat. No. Chloridin, Daraprim, terr 2,680,740 Malcoide, Tindurin N N

NH2 C Function: Antiprotozoal (Trichomonas)

AcetarSone OH 240-2SO Gynoplix, Orarsan, O Spirocid, Stovarsol

As N ls CH Ho1 NoH H

Aminitrozole OH 264-265 U.S. Pat. No. Tritheon, Trichorad, O Enheptin-A ls 2,531,756 Ho1As NoH NH CH US 8,802,596 B2

TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Antiprotozoal (Trypanosoma)

Benzinidazole 188-190° GB Radani 1138,529 H N ON ( N C, ! N

Eflornithine N2H F 1830 Ornidyl Hydrochloride HN COOH F Function: Antipsoriatic

Acitretin CH CH CH 228-230 U.S. Pat. No. Neotigason, Soriatane 4,105,681 H3C S N S S COOH

HCO CH3

6-AZauridine O 160-161

HN

HO O1. N1 N O

OH OH

Function:

Amisulpride 126-127 U.S. Pat. No. Deniban, Socian, 4,401,822 Solian, Sulamid

HC

Remoxipride 1730 U.S. Pat. No. ROXiam Hydrochloride 4,232,037 Monohydrate US 8,802,596 B2 65 66 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Antipyretic 153-1550 U.S. Pat. No. Droxaryl, Feximac, N 3,479,396 Malipuran, Mofenar, YOH Norfemae, Parfenac, Parfenal H3C 1N1 a O

Bumadizon 116-117 U.S. Pat. No. 3,455,999

COOH

N CH3 N Y H O

Function: Antirickettsial

Chloramphenicol C 150-1510 U.S. Pat. No. H 2,839,577 N s No.OH 6

Function: Antiseptic/Disinfectant

BenZOxonium CH3 107-109 CH3O6648 Absonal, Bactofen, Chloride Bialcol

Cetalkonium 590 U.S. Pat. No. Banicol, Acetoquate Chloride 2,075,958 CDAC, Ammonyx G, Zettyn, Ammonyx T. Cetol

Function:

Alibendol O U.S. Pat. No. Cebera 3,668,238 HOS-1a N H

HO OCH

Ambutonium 228-229° Bromide NH2 CH3 M N US 8,802,596 B2 67 68 TABLE 1-continued

Name Compound MP Pat. No. Other Names Function: Antisyphilitic Arshpenamine OH U.S. Pat. No. Ehrlich 606, Salvarsan 986,148 NH2

2 HC AS

As

NH2 OH Sodium O Arsamin, Atoxyl, Arsanilate Nuarsol, Protoxyl, -O- Soamin, Sonate, Piglet Pro-Gen V. Trypoxyl

HN O OH Function: Antithrom-boxythemic

Anagrelide >2800 U.S. Pat. No. Agrylin 4,146,718

C HCI H2O

Function: Antihrombotic

Beraprost U.S. Pat. No. Dorner, Procylin HOOC 4,474,802

Cilostazol 159-16O BE 878548 Pletal

Function: Antitussive

Bibenzonium O 144-147 U.S. Pat. No. Sedobex, Bromide 2,913,459 Lysobex, Lysibex, C N-1\,. (CH3)3 Thoragol, Lysbex, Medipectol US 8,802,596 B2 69 70 TABLE 1-continued

Name Compound MP Pat. No. Other Names

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

Function: Antiulcerative

Aldioxa. 230° U.S. Pat. No. Alanetorin, Alusa, HN2 N O OH 2,761,867 Arlanto, Ascomp, Chlokale, ry Y-S- Isalon, Nische, O NH OH Peptilate O

Cimetidine H 141-143 U.S. Pat. No. Acibilin, Acinil, 3,950,333 Cimal, Cimetag, Cimetum Edalene, Dyspamet, HC us S N Eureceptor, Gastromet, 3 NN 1N1 O Peptol H H

Function: Antiurolithic

Allopurinol >3500 U.S. Pat. No. N1N 3,474,098 -

OH

Succinimide 125-127 Orotric

Foscarnet >250 U.S. Pat. No. Foscavir Sodium 4,215,113

Efavirenz 139-141 U.S. Pat. No. 5,519,021

Function:

Etifoxine H 90-92 U.S. Pat. No. Nsin N CH 3,725.404 O C CH3 US 8,802,596 B2 71 72 TABLE 1-continued

Name Compound MP Pat. No. Other Names Walnoctamide CH 113-114 Axiquel, Nirvanil ~. NH2 CH, O Function: Atriopeptidase Inhibitor Cannabinol CH3 76-77

OH

H3C O CH3 CH3

Function: Bronchodilator

Oxitropium 203-204° U.S. Pat. No. Oxivent, Tersigat, Bromide 3,472,861 Ventilat

OH

Tiotropium 218-220 EP 418716 Bromide

Function: Blocker

Fendiline 204-205 U.S. Pat. No. Cordan, Fendilar, Hydrochloride 3,262,977 Sensit

CH3 HCI

Prenylamine 36-37 U.S. Pat. No. Elecor 3,152,173

CH US 8,802,596 B2 73 74 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Carbonic Anhydrase Inhibitor 258-259 U.S. Pat. No. Acetamox, Atenezol, H V / 2,554,816 Diamox, Didoc, HC N S Sn Diuriwas, Donmox, Edemox, Fonurit, y y- NH2 Glaupax O N-N

Flumethiazide O O O O 305-307 U.S. Pat. No. Ademol, Fludemil \/ \/ 3,040,042 HN1 n h

FC H ! Function: Cardioprotective Acadesine O 213-214 Arasine, Protara HN W N HOHN y

O

OH OH

Cariporide O O O NH 90-94 U.S. Pat. No. V/ 5,591,754 HC-S N NH2 H H3C

CH3

Function: Cardotonic

Levosimendan 21O-214 U.S. Pat. No. Simdax s 5,569,657 HN1 N

H3C s NH

O

Pimobendan 311o U.S. Pat. No. Hydrochloride n N 4,361,563

CH3 OCH

N HCI US 8,802,596 B2 75 76 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Cholelitholytic Agent

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

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

Cholic Acid 1989 Colalin Monohydrate COOH

Clanobutin C 115-116 U.S. Pat. No. Bykahepar or-n 3,780,095 N

O HCO

Function:

Echothiophate CH3 138° U.S. Pat. No. Iodide 2,911,430

HC O-P- N11 N1)N ch O

Edrophonium 162-1639 U.S. Pat. No. Antirex, Enlon, Chloride fH, CH3 2,647,924 Eversol, Tensilon HO i-/ US 8,802,596 B2 77 78 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Inhibitor

Ambenonium H3C C 196-1999 DE 1024S17 Mytelase Chloride "N H O 1n 1 N 1- N+l l O CH C NH

Distigmine CH, CH dec U.S. Pat. No. Ubretide Bromide HC O O 143° 2,789,981 3 NN n | N N -CH3 21 O O le n = 6

Function: Cholinesterase Reactivator

AsOxime O 145-147 U.S. Pat. No. Chloride 3,773,775 S1 S.No. 21 NH2 2 NS-1'Nu-Ns HO

Obidoxime dec U.S. Pat. No. Toksobidin, Chloride 225o 3,137,702 Toxogonin HON N

Function: CNS

Pemoline 256-2S7 U.S. Pat. No. AZOkSodon, Cylert, 2,892,753 Deltamine, Hyton Asa, Kethamed, Nitan, O Pioxol, Pondex, Senior, Sigmadyin, M NH2 Stimul, Tradon, Wolital O N

Phenmetrazine liquid U.S. Pat. No. 2,835,669

N CH3 H US 8,802,596 B2 80 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Cyclooxygenase-2 Inhibitor

Celecoxib O O 157-1590 WO95 Celebrex \/ 15316 HN1

N- NN CF S.

HC

Function: Cytoprotectant (Gastric)

Cetraxate H 200-280° U.S. Pat. No. 3,699,149 O HN O H COOH

Irsogladine C 268-269 U.S. Pat. No. 3,966,728

C N21 h

HN ls N 1 NH2

Function: Decongestant

Naphazoline 255-260° U.S. Pat. No. Ak-con, Albalon, Hydrochloride 2,161,938 Clera, Coldan, Iridina, ) Naphcon, Niazol, N OpconRhinantin, H Phinoperd, Sanorin, Sanorin-Spofa, HCI Strictylon

Nordefrin OH 178-1790 U.S. Pat. No. Corbasil, Cobefrin Hydrochloride 1,948,162 HO NH2

CH HO

Function: Herpetiformis Suppressant

Dapsone O O 175-176° Avlosulfon, V/ Croysulfone, S Diphenasone, Disulone, Dumitone, Eporal, Novophone, Sulfona-Mae. HN NH2 Sulphadine, Udolac US 8,802,596 B2 81 82 TABLE 1-continued

Name Compound MP Pat. No. Other Names 190-191 U.S. Pat. No. IZopiridina, Sodium Salt o o N1 2,275,354 Soludagenan Y NN S H

HN

Function:

Mercaptomerin 150-1550 U.S. Pat. No. Sodium 2,576,349

Mercumatilin 155-160° U.S. Pat. No. Sodium 2,667,442

2 COO Function: Agonist

Pergolid SCH 206-209 U.S. Pat. No. 4,166,182

N N-1\ch,

H

HN

Pramipexole 296-298 U.S. Pat. No. Mirapex, Mirapexin, Dihydro 4,886,812 Sifrol chloride He1\-1 s SX-NH. N 2 HC Function: Antagonist

Amisulpride 126-127 U.S. Pat. No. 4,401,822 H N N OCH \-CH

c1),O O NH,

Sulpiride CH3 178-180° U.S. Pat. No. Alilit, Aiglonyl, 3,342,826 Coolspan, Dobren, t O r Dogmatil, Dogmatyl, O N Dolmatil, Guastil, / N Meresa, Miradol, Mierbanil, Misulvan, Neogama, Omperan, OCH Pyrikappl, Sernevin, Splotin, Sulpitil, Sursumid, Trilan US 8,802,596 B2 83 84 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Emetic

Cephaeline HCO 115-116

OCH

OH

Function: Expectorant

Bromhexine 237-238 BE 62SO22

Br

CH NH2 Br

Ambroxol OH 233-234 U.S. Pat. No. Abramen, Ambril, Hydrochloride 3,536,713 Bronchopront, Duramucal, Fluibron, Br a Fluixol, Frenopect, Lindoxyl, Motosol, N Mucofar, Muscolvan, Mucoclear, Mucovent, NH2 Pect, Solvolan, Stas Hustenloser, Surbronc, Br Surfactal

Function: Gastric & Pancreatic Secretion Stimulant

Carnitine U.S. Pat. Nos. OH t 4,255.449 CH 4,315,944 to sulukV C H3

Function: Gastroprokinetic

Cinitapride U.S. Pat. No. Tartate, Cidine O N 5,026,858 ON N H

HN O 1N CH

Cisapride HCO NH2 109.8 U.S. Pat. No. Acenalin, Alimix, HCO H 4,962,115 Cipril, Prepulsick, N Propulside, Risamol C O ON-1-N-N US 8,802,596 B2 85 86 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function:

Cortivazol 160-165° U.S. Pat. No. 3,067,194 U.S. Pat. No. 3,300,483

Enoxolone 296 GB 83.31.84

Function: Gonad-Stimulating Principle

Clomiphene 116-118° U.S. Pat. No. Citrate, Clomid, 2,914,563 Clomphid, Clomricl, Clostilbeggt, Dyneric, Ikaclomine, Pergotime, Serophene

Function: Hemorheologic Agent

Pentoxifylline O 1050 U.S. Pat. No. Oxpentifylline, 3,422,107 VaSofirin, AZOpentat, Dorapental, Rentglin, Torental, Trental

CH US 8,802,596 B2

TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Hemostatic

Adrenalone O -CH3 235o DE 152814 Adrenone, Stryphon N DE 277540 H

OH

OH

Carbazo- CH3 227-228 GB 795184 AC17, Adenaron, chrome O / Adona, Carbazon, Sodium N Donaseren, Emex, Sulfonate SO3- Odanon, Tazin H 3 HN N NN2

O Function: Hepatoprotectant Thioctic Acid H U.S. Pat. Nos. Biletan, Thioctacid, COOH 2,980,716 Thioctan, Tioctan 3,049,549 3,223,712 S-S

Timonacid S FR 1731.84 Norgemen, Thioproline, Detokepa, Hepalidine, NH Heparegen, Thiazolidin HOOC

Function: Immono modulator

Pidotimod O 194-198 U.S. Pat. No. H £OOH 4,839,387 O N a. Ny N s Bucillamine 139-140° U.S. Pat. No. Rimatil 4,305,958 Function: Immono suppressant 6-Mercapto- SH 313-314 U.S. Pat. Nos. Leuberin, Mercaleubin purine H 2,697,709 N1 N X 2,721,866

le/N N

Brequinar 315-317 U.S. Pat. No. 4,680,299

N O N F afne

COOH US 8,802,596 B2

TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function:

Retinoic H3C CH3 CH3 CH3 18O-181 U.S. Pat. No. Aberd, Airol, Arite, Acid 3,746,730 Eudgna, Kerlocal, N N N N COOH Renova

CH3

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

Function: Lexative? Cathartic

Docusate CH3 U.S. Pat. Nos. Sofale Calcium O 3,035,973 Sodium O CH3 2,028,091 H3C O SO3- O H3C

Picosolfate N 272-275 U.S. Pat. Nos. Guttalax-Fher, Sodium 3,528,986 Laxoberal, Laxoberon, 3,558,643 Neopax, Pico-Salax N 2

-OSO OSO

Function: Antagonist

Ibudilast 53-54° U.S. Pat. No. Ketas 3,850,941

Zafirlukast OH3 138-140° U.S. Pat. No. Accolate N 4,859,692 OJOl A NO O HC HC Function: Lipotropic

Choline U.S. Pat. No. Biocolina, Chloride 1 Noh 2,623,901 Hepacholine, Lipotril

C

Methionine O 28O-282° Acimethin

S HC1 OH US 8,802,596 B2

TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Lupos Erythematosos Suppressant

Bismuth Na+ U.S. Pat. No. Bistrimate Sodium 2348,984 Triglycollamate -CHCOO BO- - \s +HNN CHCOO CHCOO

Chloroquine C N 193-195° U.S. Pat. No. Aralen, Artriclin, n 2,233,970 Bemaphate, Capquin, Nivaquine B, 2 Reamachlor, Sanoquin HN --> r Function: Matrix Metallo-proteinase Inhibitor

Prinomastat O 149.8° WO 97 2O824 HO1 O O H3C \/ Y^S n Ol 1sO

Function: Miotic

Carbachol O 2070 U.S. Pat. No. Doryl, Isopto

ls 1,894,162 MiostatCarbachol, Zestryl, HN r--

Neostigmine 1670 U.S. Pat. No. N+- 1,905,990

O

O ul CH3 CH3

Function: Mucolytic

Acetylcysteine O 109-110 U.S. Pat. No. Bronac, Fabrol, 3,184,505 Fluimueil, Mocosil, Moeret HS OH int O

Bromhexine 237.5o BE 62SO22

Br N

NH2 Br US 8,802,596 B2 93 94 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: (Skeletal)

Tetrazepam 144 U.S. Pat. No. Muscaril, Muokelat, 3,426,014 Myolastan C |

Tizanidine 221-223 U.S. Pat. No. 2- \ 3,843,668 N / C N

N NH NH

Function: Mydriatic

Tropicamide OH CH 96-97 U.S. Pat. No. Mydriacyl, 2,726,245 Mydriaticum N N

Phenylephrine OH 140-145° U.S. Pat. No. Adrianol, Ak-Dilate, Hydrochloride 1932,347/ Alc-Nefrin, Isophirin, HO U.S. Pat. No. m-Sympatol, CH 1,954,389 Neophryn

Function: Naroctic Antagonist

Cyclazocine 201-204° BE 611 OOO

CH3 HO

CH3

Amiphenazole 163-164? Dizol, Daptazole, Daptazile, Fenamizol

HN US 8,802,596 B2 95 96 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Neuraminidase Inhibitor

Zanamivir 256° WO91 COOH 1632O

o, HG NH NH NH Hd H3N

Function: Neuromuscular Blocking Agent

Succinyl O 156-1639 choline Bromide? Chloride? Iodide --~~--O

Fazadinium 2150 U.S. Pat. No. Fazadon Bromide 3,773,746

N-- NS CH n SSN ^- 3 21 N+

Function: Neutral Endopetidase Inhibitor

Omapatrilat H 218-220 U.S. Pat. No. Vauler SN 5,508,272 O

issus N COOH O

Function: Neuroprotective

Riluzole FCO S 119° U.S. Pat. No. Rilutek X1 NH2 4,370,338 N

Repinotan 192-194 U.S. Pat. No. O O 5,137,901 -1N1N1N N1\% US 8,802,596 B2 97 98 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function:

Indeloxazine U.S. Pat. No. Elen, Noin Hydrochloride 4,109,088

Donepezil 211-212 U.S. Pat. No. Aricept 4,895,841

Function: Oxytocic

Carboprost 55-56 U.S. Pat. No. 3,728,382

Pinacidil in 164-165° U.S. Pat. No. Pindac 4,057,636 in1s-s H H

Nicorandil N 92-93 U.S. Pat. No. Adamcor, Ikorel, n 4,200,640 Perisalol, Sigmart 2 N1 NoNo.

Function: Potassium

Fampridine N 158-1590 n 2

NH2

Tedisamil 195-1970 U.S. Pat. No. 4,550,112 US 8,802,596 B2 99 100 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Inhibitor

Cabergoline H 102° U.S. Pat. No. Cabaser, Dostinex N 4,526,892 N

Function: Prostaglandin

Beraprost U.S. Pat. No. HOOC 4,479,802

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

3,147,258

HCO

Fominoben 122-123 U.S. Pat. No. O t 3,661,903 N

r N H O C N

O

Function: Sclerosing Agent

2-Hexyl H3C 140-150° decanoic Acid COOH

CH3 US 8,802,596 B2 101 102 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Sodium OSO Sotradecol, Tergitol Tetradecyl Sulfate

Function: ?

Flurazepam 77-82 U.S. Pat. Nos. Felmeme, Noctosom, 3,299,053 Stacuroderm ls 3,567,710

C leN

Etodroxizine liquid GB 8172321

N N-11a1'N-1so Function: Succinylcholine Synergist

Hexafluorenium 188-189 U.S. Pat. No. Mylexen Bromide 2,783,237

HC CH 3 v M 3 O) NS-1-1-1s N-- A V HC CH

Function: Tocolytic

Ritodrine OH 88-90 U.S. Pat. No. 3,410,944

CH HO OH

Terbutaline CH3 119-122 U.S. Pat. No. ro- NgH 3,937,838 OH US 8,802,596 B2 104 TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Ultraviolet Screen p-Amino COOH 187-187-5 U.S. Pat. Nos. Pabanol 2,878,282 2,947,781 2,735,865

NH2

Solisobenzone SOH 145° GB Songard, Uvinol 1136525 OCH

O OH

Function: Uricosuric

Ticrynafen O 148 U.S. Pat. No. 3,758,506

\ S 1N C O COOH

C

Orotic Acid 345° U.S. Pat. Nos. Oropor, Orotyl 2.937,175 O N 3,086,917 N NH

COOH

Function: Vasodilator (Cerebral)

Nafronyl O 190° U.S. Pat. No. Dubimax, Gevatran 3,334,096

'N-1a1n . O

Nicametate O 155-1570 Eucast

'N-1a1a. O US 8,802,596 B2

TABLE 1-continued

Name Compound MP Pat. No. Other Names

Function: Vasodilator (Coronary)

Perhexiline 243-245.5 GB 1025578 H N

Cloricromen O C 147-148 U.S. Pat. No. 4,452,811 1n O O O O

Function: Vasodilator (Peripheral) Ciclonicate H3C CH3 127-128 DE 1910481 24O6849 O H ^ N O CH, H 2 N

Cinepazide O 135° U.S. Pat. No. 3,634,411 H3CO S N

HCO O N OCH N

Function: Vasprotectant

Chromocarb O COOH 2SO-2S19 U.S. Pat. No. 3,816,470

O

Dobesilate OH >3000 U.S. Pat. No. Calcium 3,509,207

HO SO3

Function: Vitamin Vitamin Source

Thiamine S dec (Vit. B) "s's NH2 248 Na2 N 7 OH US 8,802,596 B2

TABLE 1-continued

Name Compound MP Pat. No. Other Names Pyridoxine N CH3 2O5-212 U.S. Pat. Nos. Hydrochloride n HCI 2,680,743 (Vit. Bs) 2,734,063 21 2,904,551 HO OH 3,024,244

OH Function: Vulnerary

Oxaceprol HO O 133-134 U.S. Pat. Nos. 3,860,607 3,891,765 OH 3,932,638 N -" O

Acetylcysteine O 109-110 U.S. Pat. No. Brunac, Fabrol, HS 3,184,505 Fluimucil, Fluprowit, Mucomgst, MocoSil, OH Tixair HNy- O

Function: Wilson's Disease Treatment

Penicillamine SH COOH 202-206 Depen, Distamine, Mercaptyl, Sofortan, Trolovo NH,

Function: Oxidase Inhibitor Allopurinol N H >3500 U.S. Pat. Nos. Adenoal, Aloral, n N 2,868,803 CoSonic, Remid, N 3,474,098 Ribal Na2 /

OH

Further examples of pharmaceutical actives that are ionic 45 Adrenocortical Suppressant: , trilos or can be made ionic and combined with other ions to form the tane. disclosed ionic liquid compositions are detailed below, along deterrent: disulfuram. with their typically pharmaceutical use. antagonist: canrenoate potassium, , Adrenergic: , mesylate, apracloni , , , dine hydrochloride, , hydro 50 . chloride, hydrochloride, diplivefrin, dopamine Amino acid: , , hydrochloride, hydrochloride, Sulfate, epinephrine, epinephrine cystine, , isoleucine, leucine, , lysine acetate, bitartrate, epinephryl borate, esproquin hydrochloride, lysine hydrochloride, , , , hydrochloride, hydroxyamphetamine hydrobro , threonine, , , Valine. mide, levonordefrin, Sulfate, 55 Ammonia detoxicant: : arginine glutamate, argin bitartrate, metizoline hydrochloride, hydrochlo ine hydrochloride. ride, bitartrate, , Anabolic: dipropionate, , hydrochloride, hydrochloride, phenylpro undecylenate, , bolnantalate, , meth panolamine hydrochloride, polistirex, enolone acetate, methenolone enanthate, , nan hydrochloride, , pseudoephe 60 drolone cyclotate, norbolethone, pizotyline, , drine hydrochloride, tetrahydrozoline hydrochloride, trama acetate, , . Zoline hydrochloride, hydrochloride. Analeptic: . Adrenocortical : , desoxycorticoster Analgesic: acetaminophen, hydrochloride, ami one acetate, desoxycorticosterone pivalate, nobenzoate potassium, aminobenzoate sodium, anidoxime, acetate, acetate, , hydrocorti 65 , anileridine hydrochloride, hydrochlo Sone hemisuccinate, hemisuccinate, ride, anirolac, antipyrine, aspirin, , benzy , , acetate, . damine hydrochloride, bici fadine hydrochloride, US 8,802,596 B2 109 110 hydrochloride, maleate, sodium, hydrochloride, midazolam maleate, , hydrochloride, butacetin, butixirate, butor , norflurane, , oxethazaine, phencycli phanol, tartrate, , carbaspirin cal dine hydrochloride, pramoxine hydrochloride, prilocalne cium, carbiphene hydrochloride, citrate, ciprefa hydrochloride, hydrochloride, , propara dol Succinate, , ciramadol hydrochloride, caine hydrochloride, , hydrochloride, clonixeril, , , codeine phosphate, codeine Sul pyrrocaine, , rodocaine, , Salicyl alcohol, fate, conorphone hydrochloride, , dexoxadrol , , , tetracaine hydrochloride, hydrochloride, dexpemedolac, , , dihydro , thiamylal Sodium, thiopental sodium, codeine bitartrate, dimefadane, dipyrone, hydrochloride, hydrochloride. hydrochloride, drinidene, hydrochloride, , 10 compounds including . tartrate, ethoxazene hydrochloride, , Anorexic: a minorex, amphecloral, , , fenoprofen calcium, fentanyl citrate, hydrochloride, , hydrochloride, , flufenisal, , flunixin , flupir diethylpropion hydrochloride, hydrochloride, tine maleate, fluproduaZone, fluradoline hydrochloride, flur , fluidorex, , levamfetamine Succinate, biprofen, hydrochloride, ibufenac, indopro 15 , hydrochloride, hydro fen, , , tromethamine, letimide chloride, , hydrochloride. hydrochloride, levomethadyl acetate, levomethadyl acetate Antagonist: , atosiban, , , hydrochloride, hydrochloride, tar cimetidine hydrochloride, maleate, detirelix trate, lofemizole hydrochloride, oxalate, lorcina acetate, , donetidine, etintidine hydrochloride, dol, lomoxicam, , , , hydrochloride, , icatibant menabitan hydrochloride, meperidine hydrochloride, acetate, icotidine, , , nadide, , hydrochloride, methadone hydrochloride, meth hydrochloride, hydrochloride, naltrex adyl acetate, methopholine, methotrimeprazine, metkepha one, , , hydrochloride, mid acetate, mimbane hydrochloride, hydrochlo oXmetidine mesylate, mesylate, , ran ride, molinaZone, morphine Sulfate, , 25 itidine bismuth citrate, ranitidine hydrochloride, Sufotidinei, hydrochloride, hydrochloride, nalmexone hydro teludipine hydrochloride, tiapamil hydrochloride, tiotidine, chloride, namoxyrate, nantradol hydrochloride, naproxen, vapiprost hydrochloride, Zaltidine hydrochloride. naproxen Sodium, naproXol, hydrochloride, nexeri Anterior pituitary activator: . dine hydrochloride, hydrochloride, ocfenta Anterior pituitary Suppressant: . nil hydrochloride, octaZamide, olvanil, fumarate, 30 Anthelmintic: , anthelmycin, bromoxanide, , oxycodone hydrochloride, oxycodone terephtha bunamidine hydrochloride, butonate, cambendazole, carban late, hydrochloride, pemedolac, pentamor tel lauryl sulfate, clioxanide, closantel, cyclobendazole, phone, , pentazocine hydrochloride, pentazocine dichlorvos, citrate, dribendazole, lactate, hydrochloride, phenyramidol dymanthine hydrochloride, etibendazole, , hydrochloride, hydrochloride, pinadoline, pirfeni 35 furodazole, hexylresorcinol, mebendazole, tartrate, done, olamine, pravadoline maleate, niclosamide, nitramisole hydrochloride, nitrodan, oxantel hydrochloride, hydrochloride, propirarn fumarate, pamoate, Oxfendazole, oxibendazole, parbendazole, pipera propoxyphene hydrochloride, propoxyphene napsylate, mide maleate, , piperazine citrate, piperazine ede , proxazole citrate, tartrate, pyrro tate calcium, proclonol, pamoate, pyrantel tartrate, liphene hydrochloride, hydrochloride, salcolcx, 40 pyrvinium pamoate, rafoxanide, stilbazium iodide, tetrami Salethamide maleate, , Salicylate meglumine, sole hydrochloride, thiabendazole, ticarbodine, tioxidazole, , , mesylate, , triclofenol piperazine, Vincofos, Zilantel. Sufentanil citrate, talmetacin, talniflumate, talosalate, tazad Anti-acne: , Salnacedin, inocoter olene Succinate, tebufelone, tetrydamine, tifurac sodium, tili One acetate, acCutane. dine hydrochloride, tiopinac, mesylate, 45 Anti-adrenergic: , hydrochloride, hydrochloride, hydrochloride, trolamine, Verado , tosylate, bunolol hydrochloride, line hydrochloride, verilopam hydrochloride, , hydrochloride, hydrochloride, hydro mesylate, hydrochloride, chloride, hydrochloride, dexpropranolol hydro mesylate, sodium, Zucapsaicin. chloride, hydrochloride, mesy : , , methyltest 50 late, dilevalol hydrochloride, hydrochloride, osterone, decanoate, nandrolonephenpropionate, hydrochloride, hydrochloride, acetate, , , , sulfate, hydrochloride, hydrochlo , , , testosterone ride, hydrochloride, metalol hydrochloride, enanthate, testosterone ketolaurate, testosterone phenylac , metoprolol tartrate, , Sulfate, etate, , acetate. 55 Sulfate, mesylate, , propra , adjunct to: . nolol hydrochloride, proroxanhydrochloride, solypertine tai Anesthetic: alliflurane, benoximate hydrochloride, ben trate, hydrochloride, , timolol maleate, tipre Zocaine, biphenamine hydrochloride, hydro nolol hydrochloride, , Zollertine hydrochloride. chloride, , butamben picrate, hydro Anti-allergic: , , hydro chloride, , cocaine hydrochloride, , 60 chloride, eclaZolast, minocromil, nedocromil, nedocromil , dexivacaine, diamocainc cyclamate, dibucaine, calcium, nedocromil Sodium, nivimedone sodium, pemiro dibucaine hydrochloride, dyclonine hydrochloride, enflu last potassium, pentigetide, pirquinozol, poisonoak extract, rane, ether, ethyl chloride, , hydrochlo probicromil calcium, proXicromil, repirinast, tetraZolast ride, euprocin hydrochloride, fluoroxene, , isob meglumine, thiazinamium chloride, tiacrilast, tiacrilast utamben, , hydrochloride, levoxadrol 65 Sodium, tiprinast meglumine, tixanoX. hydrochloride, lidocaine, lidocaine hydrochloride, mepiv Anti-amebic: berythromycin, bialamicol hydrochloride, acaine hydrochloride, sodium, , , chloroquine hydrochloride, chloroquine phos US 8,802,596 B2 111 112 phate, clamoxyquin hydrochloride, clioquinol, emetine fluzinamide, fosphenyloin Sodium, , ilepcimide, hydrochloride, iodoquinol, Sulfate, quinfa , , mephenyloin, mephobar mide, Symetime hydrochloride, teclozan, , tetra bital, methetoin, methSuximide, millacemide hydrochloride, cycline hydrochloride. nabazenil, nafimidone hydrochloride, , phenace anti-androgen: , , mide, phenobarbital, phenobarbital Sodium, , acetate, acetate, , , Zanot phenyloin, phenyloin Sodium, , , ralito COC. line, hydrochloride, ropizine, , stirip Anti-anemic: epoetin alfa, epoetin beta, ferrous Sulfate, entol, Sulthiame, thiopental sodium, tiletamine hydrochlo dried, leucovorin calcium. ride, , , sodium, Valproic Anti-anginal: besylate, amlodipine maleate, 10 hydrochloride, hydrochloride, buto acid, , ZonicleZole hydrochloride, . prozine hydrochloride, , maleate, meto Antidepressant: hydrochloride, , prolol Succinate, , maleate, primi adinazolam mesylate, , aletamine hydrochloride, dolol, hydrochloride, tosifen, hydrochloride, hydrochloride, amox hydrochloride. 15 apine, maleate, azaloxan fumarate, , Anti- agent: adatanserin hydrochloride, , hydrochloride, bipenamol hydrochloride, bupro mesylate, , , pion hydrochloride, butacetin, hydrochloride, hydrochloride, mirisetron maleate, , , , , hydrochlo hydrochloride, , pancopride, , Seraza ride, mesylate, clodazon hydrochloride, clomi pine hydrochloride, citrate, hydro pramine hydrochloride, fumarate, cyclindole, cype chloride. namine hydrochloride, cyprolidol hydrochloride, Anti-arthritic: lodelaben. cyproximide, tosylate, hydrochloride, Anti-asthmatic: ablukast, ablukast Sodium, azelastine daZadrol maleate, dazepinil hydrochloride, hydrochloride, bunaprolast, cinalukast, crornitrile Sodium, hydrochloride, dexamisole, deximafen, hydro cromolyn Sodium, enofelast, isamoxole, fumarate, 25 chloride, dioxadrol hydrochloride, dothiepin hydrochloride, levcromakalim, lodoxamide ethyl, lodoxamide hydrochloride, dulloxetine hydrochloride, eclan tromethamine, montelukast sodium, OntaZolast, oxarbazole, amine maleate, encyprate, hydrochloride, fantri , piriprost, piriprost potassium, , pobi done hydrochloride, fehmetozole hydrochloride, fenmetra lukastedamine, quaZolast, repirinast, ritolukast, Sulukast, tet mide, fumarate, hydrochloride, razolast meglumine, tiaramide hydrochloride, tibenelast 30 , fluoxetine hydrochloride, hydrochlo Sodium, tomelukast, tranilast, Verlukast, Verofylline, Zar ride, gamfexine, guanoxyfen Sulfate, imafen hydrochloride, irlukast. imiloxanhydrochloride, hydrochloride, indelox Anti-atherosclerotic: mifobate, timefuronc. azine hydrochloride, hydrochloride, , Anticholelithic: monoctanoin. , ketipramine fumarate, hydro Anticholelithogenic: chenodiol, ursodiol. 35 chloride, , , maprotiline hydrochlo : alverinc citrate, anisotropine methylbro ride, hydrochloride, millacemide hydrochloride, mide, , atropine oxide hydrochloride, atropine Sul hydrochloride, , , moda fate, belladonna, benapryzine hydrochloride, benzetimide line Sulfate, napactadine hydrochloride, napamezole hydro hydrochloride, benzilonium bromide, , biperiden chloride, hydrochloride, , nitrafudam hydrochloride, biperiden lactate, , cyclo 40 hydrochloride, maleate, hydro pentolate hydrochloride, , dicyclomine hydro chloride, phosphate, hydrochloride, chloride, hydrochloride, domazoline fumarate, hydrochloride, , , elantrine, elucaine, ethybenztropine, eucatropine hydrochlo Sulfate, hydrochloride, pizotyline, ride, glycopyrrolate, heteronium bromide, hydrochloride, hydrochloride, protrip hydrobromide, homatropine methylbromide, , 45 tyline hydrochloride, maleate, rolicyprine, seproX hyoscyamine hydrobromide, hyoscyamine Sulfate, isopropa etine hydrochloride, sertraline hydrochloride, sibutramine mide iodide, mepenZolate bromide, , hydrochloride, , Suritozole, hydrochlo metoquizine, chloride, parapenzolate bromide, ride, fumarate, hydrochloride, thiaz pentapiperium methylsulfate, phencarbamide, meth esim hydrochloride, , tomoxetine hydrochloride, ylsulfate, , , propenZolate 50 hydrochloride, trebenzomine hydrochloride, trimi hydrochloride, hydrobromide, tematropium pramine, maleate, hydrochloride, methylsulfate, tiquinamide hydrochloride, hydro hydrochloride, Zimeldine hydrochloride, chloride, toguizine, triampyZine Sulfate, . hydrochloride, . Antidiabetic: , buformin, butoxamine Anticoagulant: ancrod, anticoagulant citrate dextrose solu 55 hydrochloride, camiglibose, , , tion, anticoagulant citrate phosphate dextrose solu englitaZone sodium, etoformin hydrochloride, gliamilide, tion, anticoagulant citrate phosphate dextrose solution, anti , glicetanile Sodium, gliflumide, , gluca coagulant heparin Solution, anticoagulant Sodium citrate gon, glyburide, glyhexamide, glymidine sodium, glyocta Solution, ardeparin Sodium, bivalirudin, bromindione, dalte mide, glyparamide, insulin, insulin, dalanated, insulin parin Sodium, desirudin, dicumnarol, heparin calcium, hep 60 human, insulin human, isophane, insulin human Zinc, insulin arin Sodium, lyapolate sodium, nafamo.stat mesylate, phen human Zinc, extended, insulin, isophane, insulin lispro, insu procoumon, tinzaparin Sodium, warfarin Sodium. lin, neutral, insulin Zinc, insulin Zinc, extended, insulin Zinc, Anticoccidal: maduramicin. prompt, linogliride, linogliride fumarate, , methyl Anticonvulsant: , ameltolide, atolide, buramate, palmoxirate, palmoxirate Sodium, pioglitaZone hydrochlo carbamazepine, cinromide, citenamide, , cyhep 65 ride, pirogliride tartrate, proinsulin human, Seglitide acetate, tamide, dezinamide, dimethadione, divalproex sodium, eter , , tolpyrramide, , Zopolr obarb, , , hydrochloride, estat, and Sitagliptin. US 8,802,596 B2 113 114 Antidiarrheal: rolgamidine, hydrochloride nate, , hydrochloride, , (lomotil), (flagyl), methylprednisolone hydrochloride, noberastine, citrate, (medrol), Sulfasalazine (aZulfidine). pyrabrom, pyrilamine maleate, pyroxamine maleate, rocas Antidiuretic: argipressin tannate, desmopressin acetate, tine hydrochloride, rotoxamine, tazifylline hydrochloride, lypressin. temelastine, , citrate, tripelen Antidote: , edrophonium chloride, fomepi namine hydrochloride, hydrochloride, Zolamine Zole, leucovorin calcium, levoleucovorin calcium, methylene hydrochloride. blue, protamine Sulfate. Antihyperlipidemic: cholestyramine resin, , Antidyskinetic: hydrochloride. hydrochloride, crilvastatin, dalvastatin, dextrothy Anti-emetic: hydrochloride, hydro 10 roxine sodium, Sodium, , lecimibide, chloride, , , , chlo , , pravastatin Sodium, , , rpromazine hydrochloride, , hydrochlo tiqueside, Xenbucin. ride, , diphenidol, diphenidol hydrochloride, Antihyperlipoproteinemic: acifran, beloxamide, beZafi diphenidol pamoate, mesylate, , brate, boxidine, butoxamine hydrochloride, cetaben sodium, , fluidorex, flumeridone, galdansetron hydrochlo 15 , gemcadiol, halofenate, lifibrate, , ride, , granisetron hydrochloride, lurosetron , pimetime hydrochloride, theofibrate, tibric acid, mesylate, hydrochloride, hydro treloxinate. chloride, , ondansetron hydrochloride, panco Antihypertensive: hydrochloride, alipamide, pride, , prochlorperazine edisylate, prochlo althiazide, amiquinsin hydrochloride, amlodipine besylate, rperazine maleate, hydrochloride, amlodipine maleate, anaritide acetate, maleate, bel , thiethylperazine malate, thiethylperazine fosdil, bemitradine, bendacalol mesylate, bendroflumethiaz maleate, hydrochloride, ide, benzthiazide, betaxolol hydrochloride, sul hydrochloride. fate, bevantolol hydrochloride, biclodil hydrochloride, Anti-epileptic: , , tolgabide. , bisoprolol fumarate, hydrochloride, Anti-: clometherone, , 25 , buthiazide: , candoxatrilat, , hydrochloride, citrate, carvedilol, ceronapril, Sodium, , hydrochloride, citrate, citrate, triox cilaZapril, , clonidine hydrochloride, , ifene mesylate. , , , debrisoquin Sul Antifibrinolytic: nafamo.stat mesylate. fate, delapril hydrochloride, diapamide, , dilevalol Antifungal: acrisorcin, ambruticin, , aza 30 hydrochloride, malate, ditekiren, mesy conazole, azaserine, basifungin, bifonazole, biphenamine late, , enalapril maleate, enalaprilat, enalkiren, hydrochloride, bispyrithione magSulfex, butoconazole endralazine mesylate, epithiazide, eprosartan, eprosartan nitrate, calcium undecylenate, candicidin, carbol-fuchsin, mesylate, mesylate, flavodilol maleate, flo chlordantoin, ciclopiroX, ciclopiroX olamine, cillofungin, rdipine, floseduinan, fosinopril sodium, fosinoprilat, guana cisconazole, , cuprimyxin, denofungin, dipy 35 benz, acetate, guanacline Sulfate, Sul rithione, doconazole, econazole, econazole nitrate, enilcona fate, guancydine, monosulfate, guanethidine Zole, ethonam nitrate, fenticonazole nitrate, filipin, flucona Sulfate, hydrochloride, guanisoquin Sulfate, gua Zole, flucytosine, fungimycin, , hamycin, noclor Sulfate, guanoctine hydrochloride, , gua isoconazole, , kalafungin, , noxan Sulfate, guanoxyfen Sulfate, hydrochlo lomofimgin, lydimycin, , , micona 40 ride, hydralazine polistirex, , Zole nitrate, monensin, monensin Sodium, naftifine hydro , , indolaprif hydrochloride, chloride, undecylenate, nifuratel, nifurmerone, , indoramin hydrochloride, hydrochlo nitralamine hydrochloride, nystatin, octanoic acid, orcona ride, , leniquinsin, levcromakalim, lisinopril, Zole nitrate, oxiconazole nitrate, oxifungin hydrochloride, hydrochloride, losartan potassium, losulazine parconazole hydrochloride, partricin, , pro 45 hydrochloride, , hydrochloride, clonol, pyrithione Zinc, pyrrolnitrin, rutamycin, sangui , medroxalol hydrochloride, methalthiazide, narium chloride, Saperconazole, scopafungin, selenium Sul , , methyldopate hydrochloride, fide, sinefungin, Sulconazole nitrate, terbinafine, , , , metoprolol fumarate, metoprolol thiram, ticlatone, tioconazole, tolciclate, tolindate, , Succinate, metyrosine, , monatepil maleate, triacetin, triafungin, undecylenic acid, viridofulvin, Zinc 50 , , , oftormine, undecylenate, Zinoconazole hydrochloride. One specific anti hydrochloride, paZoxide, hydrochloride, perin fungal that is Suitable is itraconazole. dopril erbumine, hydrochloride, pinaci Antiglaucoma agent: alprenoXime hydrochloride, col dil, pivopril, , hydrochloride, primido forsin, dapiprazole hydrochloride, dipivefrin hydrochloride, lot, prizidilol hydrochloride, quinapril hydrochloride, naboctate hydrochloride, , pimabine. 55 quinaprilat, hydrochloride, hydro Antihemophilic: antihemophilic factor. chloride, hydrochloride, quinuclium bromide, Antihemorrhagic: poliglusam. ramipril, rauwolfia serpentina, , Saprisartan potas Antihistaminic: , phosphate, astemi sium, Saralasin acetate, , Zole, maleate, barmastine, bromodiphenhydramine hydrochloride, tasosartan, teludipine hydrochloride, temoca hydrochloride, maleate, 60 pril hydrochloride, hydrochloride, terlakiren, tia maleate, hydrochloride, chlorpheniramine maleate, menidine, hydrochloride, ticrynafen, tinabinol, chlorpheniramine polistirex, , , clemas , tipentosin hydrochloride, , tri tine fumarate, closiramine aceturate, cycliramine maleate, maZosin hydrochloride, trimethaphan camsylate, trimoxam cyclizine, hydrochloride, dexbromphe ine hydrochloride, tripamide, , Zankiren hydrochlo niramine maleate, maleate, dimethin 65 ride, Zofenoprilat arginine. dene maleate, citrate, diphenhydramine Antihypotensive: hydrochloride, hydrochloride, dorastine hydrochloride, Succi hydrochloride. US 8,802,596 B2 115 116 Anti-infective: hydrochloride, lauryl isoquino phosphate, hydrochloride, linium bromide, moxalactam disodium, , pentiso Sulfate, hydrochloride, menoctone, mirincamy micin, hydrochloride, protease inhibitors of hiv cin hydrochloride, phosphate, , and other retroviruses, integrase inhibitors of hiv and other quinine Sulfate, tebuquine. retroviruses, (CECLORTM), acyclovir (ZOVI Antimicrobial: , gluconate, imi RAXTM), (NOROXINTM), (ME durea, lycetamine, nibroxane, piraZmonam sodium, propi FOXINTM), axetil (CEFTINTM), onic acid, pyrithione sodium, Sanguinarium chloride, tige (CIPROTM). monam dicholine. Anti-infective, topical: alcohol, aminacrine hydrochloride, Antimigraine: dolasetron meSylate, naratriptanhydrochlo benzethonium chloride: bithionolate sodium, bromchlo 10 ride, maleate, Succinate, renone, carbamide peroxide, cetalkonium chloride, cetylpy maleate. ridinium chloride: chlorhexidine hydrochloride, clioquinol, Antimitotic: podofilox. domiphen bromide, fenticlor, fludazonium chloride, fuchsin, Antimycotic: amorolfine. basic, , gentian violet, halquinols, hexachlo Antinauseant: hydrochloride, cyclizine lactate, rophene: , ichthammol, imidecyl iodine, 15 naboctate hydrochloride. iodine, , acetate, meralein Antineoplastic: , aclarubicin, acodazole hydro Sodium, mercufenol chloride, mercury, ammoniated, methyl chloride, acronine, adoZelesin, aldesleukin, altretamine, benzethonium chloride, , nitromersol, octeni ambomycin, ametantrone acetate, aminoglutethimide, amsa dine hydrochloride, oxychlorosene, oxychlorosene Sodium, crine, , , asparaginase, asperlin, aza parachlorophenol, camphorated, potassium permanganate, citidine, azetepa, azotomycin, batimastat, benzodepa, poVidone-iodine, sepazonium chloride, silver nitrate, Sulfa , bisantrene hydrochloride, bisnafide dimesy diazine, silver, Symclosene, thimerfonate Sodium, thimero late, bizelesin, bleomycin Sulfate, brequinar Sodium, bropir sal: troclosene potassium. imine, buSulfan, cactinomycin, , caracemide, car Anti-inflammatory: acetominophen, , alclom betimer, carboplatin, carmustine, carubicin hydrochloride, etaSone dipropionate, acetonide, amylase, 25 carzelesin, cedefingol, chlorambucil, cirolemycin, cisplatin, , , sodium, amiprilose hydro cladribine, crisinatol mesylate, , cytara chloride, anakinra, anirolac, , apaZone, bal bine, dacarbazine, dactinomycin, daunorubicin hydrochlo Salazide disodium, , benoxaprofen, ride, decitabine, dexormaplatin, deZaguanine, deZaguanine hydrochloride, bromelains, broperamole, , car mesylate, diaziquone, , doxorubicin, doxorubicin profen, cicloprofen, cintaZone, cliprofen, propi 30 hydrochloride, , droloxifene citrate, dromo onate, butyrate, clopirac, propionate, stanolone propionate, duaZomycin, edatrexate, eflomithine cormethasone acetate, cortodoxone, , , hydrochloride, elsamitrucin, enloplatin, enpromate, epipro , dexamethasone dipropionate, diclofenac pidine, epirubicin hydrochloride, erbulozole, esorubicin potassium, diclofenac sodium, diacetate, diflumi hydrochloride, , done sodium, diflunisal, , diftalone, dimethyl 35 Sodium, etanidazole, ethiodized oil I 131, etoposide, etopo Sulfoxide, , endry Sonc, enlimomab, enolicam side phosphate, etoprine, hydrochloride, faZara Sodium, epirizole, , etofenamate, , fenamole, bine, fenretinide, floxuridine, fludarabine phosphate, fluo , , fenclorac, fendosal, fenpipalone, fen rouracil, fluorocitabine, fosquidone, fostriecin Sodium, tiazac, flazalone, , , , gemcitabine, gemcitabine hydrochloride, gold au 198, acetate, flunixin, flunixin meglumine, 40 hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofos butyl, acetate, fluguaZone, , ine, interferon alfa-2a, interferon alfa-2b, interferon alfa-N1, fluretofen, propionate, furaprofen, furobufen, hal interferon alfa-N3, interferon beta-la, interferon -Ib, cinonide, halobetasol propionate, acetate, iproplatin, irinotecan hydrochloride, lanreotide acetate, letro ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, Zole, leuprolide acetate, liarozole hydrochloride, lometrexol ilonidap, indomethacin, indomethacin Sodium, , 45 Sodium, lomustine, losoxantrone hydrochloride, masoprocol, indoxole, intrazole, acetate, isoxepac, isoxi maytansine, mechlorethamine hydrochloride, cam, , lofemizole hydrochloride, , acetate, acetate, melphalan, menogaril, mercap etabonate, meclofenamate sodium, meclofe topurine, , methotrexate sodium, metoprine, namic acid, dibutyrate, mefenamic acid, meturedepa, mitindomide, mitocarcin, mitocromin, mitogil mesalamine, meseclaZone, methylprednisolone Suleptanate, 50 lin, mitomalcin, mitomycin, mitosper, , mitox , , naproxen, naproxen Sodium, antrone hydrochloride, , nocodazole, naproxol, nimaZone, olSalazine sodium, orgotein, orpanoxin, nogalamycin, Ormaplatin, oxiSuran, , pegaspargase, , , paranyline hydrochloride, pen peliomycin, pentamustine, peplomycin Sulfate, perfosfa tosan polysulfate sodium, phenbutaZone sodium glycerate, mide, pipobroman, piposulfan, piroXantrone hydrochloride, pirfenidone, piroxicam, piroxicam cinnamate, piroxicamola 55 , , porfimer sodium, porfiromycin, mine, , , prifelone, prodolic acid, produa , hydrochloride, puromycin, Zone, proxazole, proxazole citrate, , romazarit, puromycin hydrochloride, , riboprine, rogletim salcolex, Salnacedin, Salsalate, sanguinarium chloride, secla ide, safmgol, Safingol hydrochloride, Semustine, simtraZene, Zone, Sermetacin, Sudoxicam, , , talmetacin, sparfosate Sodium, sparsomycin, spirogermanium hydro talniflumate, talosalate, tebufelone, , tenidap Sodium, 60 chloride, Spiromustine, spiroplatin, streptonigrin, Streptozo , tesicam, tesimide, tetrydamine, tiopinac, tiXocor cin, chloride Sr 89, Sulofenur, talisomycin, taxane, tol pivalate, , tolmetin Sodium, , triflumi taxoid, tecogalan Sodium, tegafur, teloxantrone hydrochlo date, Zidometacin, Zomepirac sodium. ride, temoporfin, teniposide, teroxirone, , thiami Antikeratinizing agent: doretinel, linarotene, pelretin. prine, thioguanine, thiotepa, tiazofurin, tirapazamine, topo Antimalarial: acedapsone, hydrochloride, 65 tecan hydrochloride, toremifene citrate, , amduinate, arteflene, chloroquine, chloroquine hydrochlo triciribine phosphate, , trimetrexate glucuronate, ride, chloroquine phosphate, pamoate, empiroline triptorelin, tubulozole hydrochloride, uracil mustard, ure US 8,802,596 B2 117 118 depa, Vapreotide, Verteporfin, vinblastine Sulfate, Vincristine ase inhibitors, menogaril, merbarone, meterelin, methioni Sulfate, vindesine, Vindesine Sulfate, vinepidine Sulfate, Ving nase, metoclopramide, MIF inhibitor, , lycinate sulfate, vinleurosine sulfate, vinorelbine tartrate, , mirimostim, mismatched double stranded RNA, Vinrosidine Sulfate, Vinzolidine Sulfate, Vorozole, Zeniplatin, mitoguaZone, mitolactol, mitomycin analogues, mitonafide, Zinostatin, Zorubicin hydrochloride. mitotoxin fibroblast growth factor-Saporin, mitoxantrone, Other anti-neoplastic compounds include: 20-epi-1.25 mofarotene, molgramostim, monoclonal antibody, human dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubi chorionic gonadotrophin, monophosphoryl lipid A+myobac cin, acylfulvene, adecypenol, adoZelesin, aldesleukin, ALL terium sk, mopidamol, multiple drug resistance TKantagonists, altretamine, ambamustine, amidox, amifos genie inhibitor, multiple tumor Suppressor 1-based therapy, tine, aminolevulinic acid, amrubicin, atrsacrine, , 10 anastroZole, andrographolide, angiogenesis inhibitors, mustard anticancer agent, mycaperoxide B, mycobacterial antagonist D, antagonist G, antarelix, anti-dorsalizing mor cell wall extract, myriaporone, N-acetyldinalinc, N-substi phogenetic protein-1, antiandrogen, prostatic carcinoma, tuted , nafarelin, nagrestip, naloxone-pentaZo , antineoplaston, antisense oligonucleotides, cine, napavin, naphterpin, nartograstim, nedaplatin, nemoru aphidicolin glycinate, apoptosis gene modulators, apoptosis 15 bicin, neridronic acid, neutral endopeptidase, , regulators, apurinic acid, ara-CDP-DL-PTBA, arginine nisamycin, modulators, nitroxide , deaminase, asulacrine, , , axinastatin nitrullyn, O6-benzylguanine, , okicenone, oligo 1, axinastatin 2, axinastatin 3, , azatoxin, azaty , , ondansetron, ondansetron, oracin, rosine, baccatin III derivatives, balanol, batimastat, BCR/ oral cytokine inducer, ormaplatin, , Oxaliplatin, ABL antagonists, benzochlorins, benzoylstaurosporine, beta oxaunomycin, paclitaxel analogues, paclitaxel derivatives, lactam derivatives, beta-alethine, betaclamycin B, betulinic palauamine, palmitoylrhizoxin, pamidronic acid, panax acid, bFGF inhibitor, bicalutamide, bisantrene, bisaziridinyl ytriol, , parabactin, paZelliptine, pegaspargase, , bisnafide, bistratene A, bizelesin, breflate, bropir peldesine, sodium, pentostatin, pentro imine, budotitane, buthionine Sulfoximine, calcipotriol, Zole, , perfosfamide, perillyl alcohol, phenazino calphostin C, camptothecin derivatives, canarypox IL-2, 25 mycin, phenylacetate, phosphatase inhibitors, picibanil, pilo capecitabine, carboxamide-amino-triazole, carboxyamidot carpine hydrochloride, pirarubicin, piritrexim, placetin A, riazole, CaRest M3, CARN 700, cartilage derived inhibitor, placetin B, plasminogen activator inhibitor, platinum com carzelesin, casein kinase inhibitors (ICOS), castanospermine, plex, platinum compounds, platinum-triamine complex, por cecropin B. , chlorins, chloroquinoxaline Sulfona fimer Sodium, porfiromycin, propyl bis-acridone, prostaglan mide, cicaprost, cis-porphyrin, cladribine, ana 30 din J2, proteasome inhibitors, protein A-based immune logues, clotrimazole, collismycin A, collismycin B, combre modulator, protein kinase Cinhibitor, protein kinase Cinhibi tastatin A4, combretastatin analogue, conagenin, tors, microalgal, protein tyrosine phosphatase inhibitors, crambescidin 816, crisinatol, cryptophycin 8, cryptophycin A purine phosphorylase inhibitors, purpurins, pyra derivatives, curacin A, cyclopentanthraquinones, cyclo Zoloacridine, pyridoxylated hemoglobin polyoxyethylene platam, cypemycin, cytarabine ocfosfate, cytolytic factor, 35 conjugate, rafantagonists, raltitrexed, , ras farne cytostatin, dacliximab, decitabine, dehydrodidemnin B, syl protein transferase inhibitors, ras inhibitors, ras-GAP deslorelin, dexifosfamide, dexraZOxane, dexVerapamil, diazi inhibitor, retelliptine demethylated, rhenium Re 186 etidr quone, didemnin B, didox, diethylnorspermine, dihydro-5- onate, rhizoxin, ribozymes, RII retinamide, rogletimide, rohi azacytidine, dihydrotaxol. 9-dioxamycin, diphenyl spiro tukine, romurtide, roquinimex, rubiginone B1, ruboxyl, saf mustine, docosanol, dolasetron, doxifluridine, droloxifene, 40 ingol, Saintopin, SarCNU, sarcophytol A, SargramoStim, Sdi dronabinol, duocannycin SA, ebselen, ecomustine, edelfos 1 mimetics, semustine, Senescence derived inhibitor 1, sense ine, edrecolomab, , elemene, emitefur, epirubicin, oligonucleotides, signal transduction inhibitors, signal trans , estramustine analogue, estrogen , estro duction modulators, single chain antigen binding protein, gen antagonists, etanidazole, etoposide phosphate, exemes sizofuran, Sobuzoxane, sodium borocaptate, sodium pheny tane, fadrozole, faZarabine, fenretinide, filgrastim, fmas 45 lacetate, Solverol. Somatomedin binding protein, Sonermin, teride, flavopiridol, flezelastine, fluasterone, fludarabine, sparfosic acid, Spicamycin D, Spiromustine, splenopentin, fluorodaunorunicin hydrochloride, forfenimex, , spongistatin 1, squalamine, stem cell inhibitor, stem-cell divi fostriecin, fotemustine, texaphyrin, gallium sion inhibitors, stipiamide, Stromelysin inhibitors, Sulf nitrate, galocitabine, ganirelix, gelatinase inhibitors, gemcit mosine, Superactive vasoactive intestinal peptide antagonist, abine, inhibitors, hepsulfam, heregulin, hexam 50 Suradista, , Swainsonine, synthetic glycosaminogly ethylene bisacetamide, , ibandronic acid, idarubi cans, tallimustine, tamoxifen methiodide, tauromustine, taZ cin, , idramantone, ilmofosine, illomastat, arotene, tecogalan Sodium, tegafur, tellurapyrylium, telom imidazoacridones, imiquimod, immunostimulant , erase inhibitors, temoporfin, temozolomide, teniposide, insulin-like growth factor-1 receptor inhibitor, interferon tetrachlorodecaoxide, tetrazomine, thaliblastine, thalido agonists, interferons, interleukins, , iododoxoru 55 mide, thiocoraline, thrombopoietin, thrombopoietin mimetic, bicin, ipomeanol, 4-irinotecan, iroplact, , isoben thymalfasin, thymopoietin receptor agonist, thymotrinan, gazole, isohomohalicondrin B, itasetron, jasplakinolide, thyroid stimulating hormone, tin ethyl etiopurpurin, tira kahalalide F, lamellarin-N triacetate, lanreotide, leinamycin, paZamine, titanocene dichloride, topotecan, topsentin, lenograstim, lentinan Sulfate, leptolstatin, , leukemia toremifene, totipotent stem cell factor, translation inhibitors, inhibiting factor, leukocyte alpha interferon, leuprolide+es 60 , triacetyluridine, triciribine, trimetrexate, triptore trogen-, , , liarozole, lin lin, , , tyrosine kinase inhibitors, tyr ear polyamine analogue, lipophilic disaccharide peptide, phostins, UBC inhibitors, , urogenital sinus-de lipophilic platinum compounds, lissoclinamide 7, lobaplatin, rived growth inhibitory factor, urokinase receptor lombricine, lometrexol, , losoxantrone, lovasta antagonists, vapreotide, variolin B. vector system, erythro tin, loxoribine, lurtotecan, lutetium texaphyrin, lysofylline, 65 cyte gene therapy, Velaresol, Veramine, Verdins, verteporfin, lytic peptides, maitansine, mannostatin A, marimastat, maso Vinorelbine, Vinxaltine, vitaxin, Vorozole, , Zeni procol, maspin, matrilysin inhibitors, matrix metalloprotein platin, Zilascorb, Zinostatin stimalamer. US 8,802,596 B2 119 120 Anti-cancer Supplementary potentiating agents: dol hydrochloride, , , , thior anti-depressant drugs (e.g., imipramine, desipramine, amit idazine, hydrochloride, thiothixene, thiothixene ryptyline, clomiprainine, trimipramine, doxepin, nortrip hydrochloride, tioperidone hydrochloride, hydro tyline, , and maprotiline), non-tricy chloride, hydrochloride, , triflu clic anti-depressant drugs (e.g., Sertraline, traZodone and 5 , hydrochloride, ), Ca' antagonists (e.g., Verapamil, , hydrochloride. nitrendipine and ), inhibitors (e.g., pre Antirheumatic: auranofin, , bindarit, nylamine, trifluoroperazine and ), amphoteri lobenzarit Sodium, , piraZolac, prinomide cin B, analogues (e.g., tamoxifen), antiarrhythmic tromethamine, Seprilose. drugs (e.g., ), antihypertensive drugs (e.g., reser 10 pine), thiol depleters (e.g., buthionine and Sulfoximine) and Antischistosomal: becanthone hydrochloride, hycanthone, Multiple Drug Resistance reducing agents such as Crema lucanthone hydrochloride, niridazole, oxamniquine, pararo phor . saniline pamoate, teroxalene hydrochloride. Antineutropenic: filgrastim, lenograstim, molgramostim, Antiseborrheic: , piroctone, piroctone olamine, regramos tim, Sargramostim. 15 resorcinol monoacetate. antisecretory: arbaprostil, deprostil, Antiobsessional agent: maleate. fenoctimine Sulfate, octreotide, octreotide acetate, omepra : abamectin, clorSulon, ivermectin. Zole Sodium, rioprostil, trimoprostil. Antiparkinsonian: benztropine mesylate, biperiden, Antispasmodic: stilonium iodide, hydrochlo biperiden hydrochloride, biperiden lactate, carmantadine, ride. hydrochloride, dopamantine, ethopropazine hydro Antithrombotic: anagrelide hydrochloride, bivalirudin, chloride, , levodopa, lometraline hydrochloride, dalteparin Sodium, danaparoid sodium, daZOXiben hydro hydrochloride, naxagolide hydrochloride, parep chloride, efegatran Sulfate, enoxaparin Sodium, ifetroban, tide Sulfate, hydrochloride, quinetorane hydro ifetroban Sodium, tinzaparin sodium, trifenagrel. chloride, hydrochloride, selegiline hydrochloride, Antitussive: , citrate, chlophedi , trihexyphenidyl hydrochloride. antiperistaltic: 25 hydrochloride, codeine polistirex, , dex difenoximide hydrochloride, , diphenoxylate tromethorphan, hydrobromide, dex hydrochloride, fluperamide, lidamidine hydrochloride, lop tromethorphan polistirex, ethyl dibunate, guaiapate, eramide hydrochloride, malethamer, nufenoXole, . bitartrate, hydrocodone polistirex, levopro Antipneumocystic: . poxyphene napsylate, , pemerid nitrate, Antiproliferative agent: piritreximisethionate. 30 pipazethate, SuXemerid Sulfate. Antiprostatic hypertrophy: sitogluside. Anti-ulcerative: aluminum, cadexomer Antiprotozoal: amodiaquine, azanidazole, bamidazole, iodine, hydrochloride, enisoprost, isotiquimide, carnidazole, bisulfate, chlortetracycline , Succinate, , , hydrochloride, flubendazole, flunidazole, halofuginone nolinium bromide, pantoprazole, pifamine, hydrobromide, imidocarb hydrochloride, ipronidazole, met 35 hydrochloride, rabeprazole sodium, remiprostol, roXatidine ronidazole, misonidazole, moXnidazole, nitarSone, partricin, acetate hydrochloride, . Sucrosofate potassium, puromycin, puromycin hydrochloride, ronidazole, Sulnida . Zole, . Anti-urolithic: cysteamine, cysteamine hydrochloride, Antipruritic: cyproheptadine hydrochloride, , tricitrates. methdilazine hydrochloride, trimeprazine tartrate. 40 Appetite Suppressant: dexfenfluramine hydrochloride, Antipsoriatic: acitretin, anthralin, azaribine, calcipotriene, tartrate, phentermine hydrochloride. cycloheximide, enaZadrem phosphate, etretinate, liaroZole Benign prostatic hyperplasia therapy agent: tamsulosin fumarate, lonapalene, . hydrochloride. Antipsychotic: maleate, hydro Blood regulators: human insulin, glucagon, tolaza bromide, alpertine, , maleate, benperi 45 mide, tolbutamide, chloropropamide, acetohexamide and dol, benzindopyrine hydrochloride, brofbxine, , glipizide. bromperidol decanoate, hydrochloride, butapera Bone resorption inhibitor: alendronate sodium, etidronate Zine, maleate, carphenazine maleate, carvotro disodium, pamidronate disodium. line hydrochloride, chlorpromazine, chlorpromazine hydro Bronchodilator: albuterol, albuterol sulfate, azanator male chloride, , cinperene, cintriamide, clomacran 50 ate, hydrochloride, mesylate, butap phosphate, , , clopipazan mesylate, rost, hydrochloride, clorprenaline hydrochloride, cloroperone hydrochloride, clothiapine, clothixamide male mesylate, doxaprost, , dyphylline, ate, , cyclophenazine hydrochloride, . , ephedrine, ephedrine hydrochloride, , hydrochloride, fenimide, , , fenprinast hydrochloride, guaithylline, Sul fluiphenazine decanoate, fluiphenazine enanthate, fluphena 55 fate, hoquizil hydrochloride, , isoet Zine hydrochloride, fluspiperone, , flutroline, gev harine, isoetharine hydrochloride, isoetharine mesylate, iso otroline hydrochloride, halopemide, , haloperidol proterenol hydrochloride, isoproterenol Sulfate, decanoate, illoperidone, imidoline hydrochloride, , metaproterenol polistirex, metaproterenol Sulfate, nisbuterol Succinate, , mesoridazine besylate, mesylate, oxtriphylline, picumeterol fumarate, piquizil , milemperone, millipertine, hydrochlo 60 hydrochloride, acetate, pirbuterol hydrochloride, ride, hydrochloride, neflumozidehydrochloride, oca hydrochloride, Sulfate, quaZod peridone, olanzapine, oxiperomide, , pentiapine ine, quinterenol sulfate, racepinephrine, racepinephrine maleate, , , hydrochloride, hydrochloride, hydrochloride, hydrobro , , palniitate, piquin mide, , Salmeterol Xinafoate, Soterenol hydrochlo done hydrochloride, prochlorperazine edisylate, prochlor 65 ride, sulfonterol hydrochloride, Suloxifen oxalate, maleate, promazine hydrochloride, , Sulfate, , Xanoxate Sodium, Zindotrine, remoxipride hydrochloride, hydrochloride, seperi hydrochloride. US 8,802,596 B2 121 122 Carbonic anhydrase inhibitor: acetazolamide, acetazola meglumine, , iodoxamate meglumine, iodoxamic mide sodium, dichlorphenamide, dorzolamide hydrochlo acid, ioglicic acid, ioglucol, ioglucomide, ioglycamic acid, ride, methazolamide, seZolamide hydrochloride. iogulamide, lohexyl, , , , Cardiac depressant: acecamide hydrochloride, acetylcho , iophendylate, iprofenin, iopronic acid, ioprocemic line chloride, actisomide, , , , acid, , iopydone, iosefamic acid, io.seric acid, ioSula aprindine hydrochloride, artilide fumarate, mide meglumine, ioSumetic acid, iotasul, iotetric acid, Dihydrochloride, bidisomide, bucamide maleate, bucro iothalamate meglumine, iothalamate sodium, iothalamic marone, butoprozine hydrochloride, capobenate Sodium, acid, , , , ioxaglate meglumine, capobenic acid, cifenline, cifenline Succinate, clofilium phos ioxagiate Sodium, , , ioxotrizoic acid, ipo phate, disobutamide, , disopyramide phos 10 date calcium, , isosulfan blue, leukocyte typ phate, , drobuline, edifolone acetate, emilium tosy ing serum, lidofenin, mebrofenin, meglumine, , late, encamide hydrochloride, flecamide acetate, metrizoate sodium, , metyrapone tartrate, mumps fumarate, indecamide hydrochloride, ipazilide fumarate, skin test antigen, , , quinaldine hydrochloride, lorcamide hydrochloride, meoben blue, acetate, sodium iodide I'', sprodiamide, tine Sulfate, hydrochloride, modecamide, mori 15 Stannous pyrophosphate, Stannous Sulfur colloid. Succimer, cizine, oxiramide, pirmenol hydrochloride, pirolazamide, acetate, tetrofosmin, tolbutamide Sodium, tuber pranolium chloride, hydrochloride, pro culin, tyropanoate sodium, Xylose. pafenone hydrochloride, pyrinoline, quindonium bromide, Diuretic: ambuphylline, ambuside, hydrochlo quinidine gluconate, quinidine Sulfate, recainam hydrochlo ride, azolimine, , brocrinat, , chlorothi ride, recainam tosylate, risotilide hydrochloride, ropitoin azide, chlorthalidone, clazolimine, , ethacrynate hydrochloride, sematilide hydrochloride, Suricamide male Sodium, ethacrynic acid, , fenduizone, , ate, tocamide, tocamide hydrochloride, transcamide. , isosorbide, , , oZoli Cardioprotectant: dexraZoxane, draflazine. none, , , torsemide, , triflo Cardiotonic: actodigin, aminone, bemoradan, butopamine, cin, . carbazeran, carsatirin Succinate, deslanoside, digitalis, digi 25 agent: . toxin, digoxin, , dobutamine hydrochloride, dob Ectoparasiticide: nifluridide, . utamine lactobionate, dobutamine tartrate, , ima Emetic: hydrochloride. Zodan hydrochloride, indolidan, isomazole hydrochloride, inhibitor: , alrestatin levdobutamine lactobionate, lixazinone sulfate, medorinone, Sodium, aprotinin, benazepril hydrochloride, benazeprilat, , pelrinone hydrochloride, , piroxi 30 benurestat, , bromocriptine mesylate, mone, prinoXodan, proscillaridin, , hydro Sodium, fluorofamide, , lergotrile mesylate, levcy chloride, . closerine, libenzapril, pentopril, pepstatin, perindopril, polig Cardiovascular agent: , dopexamine hydro nate Sodium, sodium amylosulfate, Sorbinil, spirapril hydro chloride. chloride, spiraprilat, , teprotide, tolfamide, Choleretic: dehydrocholic acid, fencibutirol, hymec 35 Zofenopril calcium. romone, piprozolin, , tocamphyl. Estrogen: , , , Cholinergic: , chloride, , diethylstilbestrol diphosphate, , , estradiol demecarium bromide, dexpanthenol, echothiophate iodide, cypionate, estradiol enanthate, , estradiol isofluorophate, chloride, neostigmine bromide, Valerate, hydrobromide, , , estro neostigmine methylsulfate, physostigmine, physostigmine 40 gens, conjugated, , esterified, , , salicylate, physostigmine Sulfate, pilocarpine, pilocarpine ethinyl estradiol, , , nylestriol, . hydrochloride, pilocarpine nitrate, pyridostigmine bromide. Fibrinolytic: anistreplase, bisobrin lactate, brinolase. Cholinergic agonist: , Xanomeline tartrate. Free oxygen radical scavenger: pegorgotein. Cholinesterase deactivator: obidoxime chloride, prali Gastrointestinal motility agents: (PROPUL doXime chloride, pralidoxime iodide, pralidoxime mesylate. 45 SIDTM), metoclopramide (REGLANTM), hyoscyamine Coccidiostat: arprinocid, narasin, semduramicin, semdu (LEVSINTM) ramicin Sodium. Glucocorticoid: , beclomethasone dipropi Dognition adjuvant: mesylates, , onate, , , betametha hydrochloride, pramiracetam Sulfate, Sone benzoate, betamethasone dipropionate, betamethasone hydrochloride. 50 Sodium phosphate, , Cognition enhancer: besipirdine hydrochloride, linopird Sodium, acetate, , clopred ine, sibopirdine. nol, corticotropin, corticotropin, repository, corticotropin Depressant: . Zinc hydroxide, acetate, , Diagnostic aid: aminohippurate Sodium, anazolene acetonide, dexamethasone, dexamethasone sodium phos Sodium, arclofenin, arginine, bentiromide, benzylpenicilloyl 55 phate, , diflucortolone pivalate, flucloronide, polylysine, butedronate tetrasodium, butilfenin, coccidioidin, flumethasone, flumethasone pivalate, flunisolide, fluocino ovine triflutate, corticotropin, repository, corti lone acetonide, , , fluocortolone cotropin Zinc hydroxide, meglumine, diatrizoate caproate, fluorometholone, acetate, flupredniso Sodium, diatrizoic acid, diphtheria toxin for Schick test, dis lone, Valerate, flurandrenolide, , ofenin, edrophonium chloride, ethiodized oil, etifenin, exam 60 , , hydrocortisone etazime, ferristenc, ferumoxides, ferumoXsil, fluorescein, buteprate, , hydrocortisone sodium fluorescein Sodium, gadobenate dimeglumine, . phosphate, hydrocortisone sodium Succinate, hydrocortisone , gadopentetate dimeglumine, , Valerate, , methylprednisolone, methylpredniso histoplasmin, hydrochloride, indigotindisul lone acetate, methylprednisoloime Sodium phosphate, meth fonate sodium, indocyanine green, lobenguane sulfate I'', 65 ylprednisolone sodium Succinate, nivaZol, , iocarmate meglumine, locarmic acid, ioc acetate, , , , etamic acid, , lodamide megiumine, iodipamide prednisolone hemisuccinate, prednisolone sodium phos US 8,802,596 B2 123 124 phate, prednisolone sodium Succinate, , Immunosuppressant: , azathioprine Sodium, , prednival, propionate, , tri cyclosporine, daltroban, gusperimus trihydrochloride, siroli amcinolone, acetonide, triamcinolone mus, . acetonide Sodium, , triamcinolone Impotence therapy adjunct: deleguamine hydrochloride. hexacetonide. Inhibitor: acarbose, atorvastatin calcium, , bro Gonad-stimulating principle: buserelin acetate, clomi cresine, , clavulanate potassium, daZmegrel, doce phene citrate, ganirelix acetate, gonadorelin acetate, gona benone, epoprostenol, epoprostenol Sodium, epristeride, fin dorelin hydrochloride, , chorionic, menotro asteride, flurbiprofen sodium, furegrelate sodium, lufironil, pins. miglitol, , hydrochloride, pirmagrel, 10 ponalrestat, ridogrel, benzathine, Sulbactampiv Hair growth stimulant: minoxidil. oxil, Sulbactam Sodium, Suronacrine maleate, , Hemostatic: aminocaproic acid, oXamarin hydrochloride, taZobactam Sodium, hydrochloride, Sulmarin, thrombin, tranexarnic acid. mesylate, tolrestat, Velnacrine maleate, Zifrosilone, . H2 receptor antagonists: ranitidine (ZAN Keratolytic: alcloxa, aldioxa, , diben TACTM), famotidine (PEPCIDTM), cimetidine (TAGA 15 Zothiophene, etarotene, , , picotrin METTM), nizatidine (AXIDTM) diolamine, resorcinol, resorcinol monoacetate, Salicylic acid, Hormone: diethylstilbestrol, progesterone, 17 hydroxy Sumarotene, , tetroquinone, tretinoin. progesterone, , , norethyno LHRL agonist: deslorelin, , histrelin, lutrelin drel, estradiol, megestrol (megace), norethindrone, levonorg acetate, nafarelin acetate. estrel, ethyndiol, ethinyl estradiol, mestranol, estrone, equi disorder treatment: malotilate. lin, 17 alpha dihydroequilin, , 17 alpha Luteolysin: femprostalene. dihydroequilenin, 17 alpha estradiol, 17 beta estradiol, leu Memory adjuvant: dimoxamine hydrochloride, ribaminol. prolide (LUPRONTM), glucagon, testolactone, clomiphene, Mental performance enhancer: . human menopausal , human chorionic gona Mood regulator: . dotropin, urofollitropin, bromocriptine, gonadorelin, lutein 25 Mucolytic: acetylcysteine, carbocysteine, . izing hormone releasing hormone and analogs, gonadotro Mucosal protective agents: misoprostol (CYTOTECTM). pins, danazol, testosterone, , Mydriatic: . , dihydroestosterone, relaxin, oxytocin, Nasal decongestant: nemazoline hydrochloride, pseu vasopressin, folliculostatin, follicle regulatory protein, gona doephedrine polistirex. 30 Neuroleptic: duoperone fumarate, . doctrinins, oocyte maturation inhibitor, insulin growth factor, Neuromuscular blocking agent: atracurium besylate, cisa follicle stimulating hormone, luteinizing hormone, tamox tracurium besylate, , gallamine triethio ifen., corticorelin ovine trifiutate, cosyntropin, , dide, iodide, , pancuronium pituitary, posterior, seractide acetate, Somalapor, somatrem, bromide, , , Suc Somatropin, somenopor, somidobove. 35 cinylcholine chloride, , vecuronium Hypocholesterolemic: lifibrol. bromide. Hypoglycemic: darglitaZone sodium: . Neuroprotective: maleate. Hypolipidemic: dihydrochloride, colestolone, NMDA antagonist: . Surfomer, Xenalipin. Non-hormonal sterol derivative: succinate. Hypotensive: viprostol. 40 Oxytocic: carboprost, carboprost methyl, carboprost Hmgcoa reductase inhibitors: lovastatin (MEVACORTM), tromethamine, dinoprost, dinoprost tromethamine, dinopro simvastatin (ZOCORTM), pravastatin (PRAVACHOLTM), flu stone, ergonovine maleate, meteneprost, methylergonovine vasatin (LESCOLTM). maleate, oxytocin, Sulfate. Immunizing agent: antirabies serum, antivenin (latrodec Plasminogen activator: alteplase, urokinase. tus mactans), antivenin (micrurus fulvius), antivenin (crotal 45 Platelet activating factor antagonist: lexipafant. idae) polyvalent, BCG vaccine, botulism antitoxin, cholera Platelet aggregation inhibitor: acadesine, beraprost, bera vaccine, diphtheria antitoxin, diphtheria toxoid, diphtheria prost sodium, ciprostene calcium, itaZigrel, lifarizine, toxoid adsorbed, globulin, immune, hepatitis b immune OXagrelate. globulin, hepatitis B virus Vaccine inactivated, influenza virus Post- and post-head trauma treatment: vaccine, measles virus vaccine live, meningococcal polysac 50 Sodium. charide vaccine group A, meningococcal polysaccharide vac Potentiator: pentostatin, hydrochloride. cine group C, mumps virus vaccine live, pertussis immune Progestin: , acetate, globulin, pertussis vaccine, pertussis vaccine adsorbed, acetate, acetate, , cloge plague vaccine, poliovirus vaccine inactivated, poliovirus stone acetate, acetate, , dimethister vaccine live oral, rabies immune globulin, rabies vaccine, Rh 55 one, , , ethynodiol diacetate, (D) immune globulin, rubella virus vaccine live, Smallpox , fluorogestone acetate, , , vaccine, tetanus antitoxin, tetanus immune globulin, tetanus , , , hydrox toxoid, tetanus toxoid adsorbed, typhoid vaccine, yellow yprogesterone caproate, , , fever vaccine, Vaccinia immune globulin, varicella-Zoster , medroxyprogesterone acetate, methynodiol immune globulin. 60 diacetate, norethindrone, norethindrone acetate, norethyno Immunomodulator: dimepranol acedoben, imiquimod, drel, , , norgestrel, interferon beta-Ib, , mycophenolate mofetil, preza phenpropionate, progesterone, acetate, tide copper acetate. , . Immunoregulator: azarole, mesylate, frentizole, Prostaglandin: cloprostenol sodium, fluprostenol Sodium, oxamisole hydrochloride, ristianol phosphate, thymopentin, 65 gemeprost, prostalene, Sulprostone. tilomisole. growth inhibitor: . Immunostimulant: loxoribine, teceleukin. Prothyrotropin: protirelin. US 8,802,596 B2 125 126 Psychotropic: minaprine. inhibitor: hydrochloride, , Pulmonary surface: beractant, colfosceril palmitate. fonazine mesylate, tosylate. Radioactive agent: fibrinogen I'', fludeoxyglucose F. Serotonin : hydrochloride. F, insulin I°, insulin I'', iobenguane I'', Steroid: dexamethasone aceflirate, furoate. iodipamide sodium I'', iodoantipyrine I'', 5 Stimulant: , Sulfate, ampyZine I'', iodohippurate sodium I', iodohippurate sodium I'', Sulfate, hydrochloride, azabon, , ceru iodohippurate sodium I'', iodopyracet I', iodopyracet letide, diethylamine, cisapride, fuma I'', hydrochloride I'', iomethin I'', iomethin rate, , dextroamphetamine Sulfate, I 131 , iothalamate sodium I'', iothalamate sodium I'', ioty difluanine hydrochloride, dimefline hydrochloride, 10 apram hydrochloride, etryptamine acetate, ethamivan, fen rosine I'', liothyronine I'', liothyronine I'', merisoprol ethylline hydrochloride, flubanilate hydrochloride, fluo acetate Hg', merisoprol acetate Hg' , merisoprol Hg",197 rothyl, histamine phosphate, indriline hydrochloride, selenomethionine Se', technetium Tc'"antimony trisulfide , hydrochlo ride, meth colloid, technetium Tc'" bicisate, technetium Tc'" disofe ylphenidate hydrochloride, , hydro nin, technetium Tc'" etidronate, technetium Tc" exameta 15 chloride, . Xamoterol fumarate. zime, technetium Tc'" furifosmin, technetium Tc" glu Suppressant: amfhutizole, coXchicine, taZofelone. ceptate, technetium Tc" lidofenin, technetium Tc'" Symptomatic multiple Sclerosis: fampiridine. mebrofenin, technetium Tc" medronate, technetium Tc'" Synergist: hydrochloride. medronate disodium, technetium Tc" mertiatide, techne Thyroid hormone: sodium, liothyronine tium Tc'" oxidronate, technetium Tc'" pentetate, techne Sodium, liotrix. tium Tc’”99. pentetate calcium trisodium, technetium Tc’" Thyroid inhibitor: methimazole, propylthiouracil. sestamibi, technetium Tc'" siboroxime, technetium Tc 99. Thyromimetic: thyromedan hydrochloride. succimer, technetium Tc" sulfur colloid, technetium Tc 99. Tranquilizer: , hydrochloride, teboroxime, technetium Tc" tetrofosmin, technetium , , , dipotas Tc'"tiatide, thyroxine I'', thyroxine I'', tolpovidone I'', 25 sium, cloraZepate monopotassium, , dexmedeto triolein I'', triolein I. midine, hydrochloride, hydrochloride, Regulator: , , , clodronic , hydroxy Zine acid, dihydrotachysterol, etidronic acid, oxidronic acid, piri Hydrochloride, hydroxy Zine pamoate, , dronate Sodium, risedronate Sodium, Secalciferol. , lorZafone, , loxapine Succinate, Relaxant: adiphenine hydrochloride, , 30 hydrochloride, , , , azumolene sodium, , , , piremperone, , , hydrochloride, , , chlo , taciamine hydrochloride, , trifluba rZoxazone, cinflumide, , clodanolene, Zam, , . hydrochloride, , dantrolene Amyotrophic lateral Sclerosis agents: . sodium, femalamide, fenyripol hydrochloride, fetoxylate 35 Cerebral ischemia agents: hydrochloride. hydrochloride, hydrochloride, , flume Paget’s disease agents: tiludronate disodium. tramide, -flurazepam hydrochloride, hexafluorenium bro Unstable angina agents: tirofiban hydrochloride. mide, isomylamine hydrochloride, , UricoSuric: , irtemazole, probenecid, hydrochloride, meSuprine hydrochloride, , . , methixene hydrochloride, nafomine malate, 40 Vasoconstrictor: angiotensin amide, fely pressin, methy neleZaprine maleate, hydrochloride, pipoxolan. Sergide, maleate. Hydrochloride, quinctolate, , ritodrine hydrochlo Vasodilator: alprostadil, azaclorzine hydrochloride, bam ride, rolodine, theophylline sodium glycinate, thiphenamil ethan sulfate, hydrochloride, buterizine, cetiedil cit hydrochloride, xilobam. rate, chromonar hydrochloride, clonitrate, diltiazem hydro Repartitioning agent: . 45 chloride, , droprenilamine, erythrityl Scabicide: , crotamiton. tetranitrate, , hydrochloride, , Sclerosing agent: ethanolamine oleate, morrhuate Sodium, , niacinate, iproxamine hydrochloride, tribenoside. , , Sedative: . hydrochloride, , mefenidil, mefenidil fumarate, Sedative-hypnotic: , alonimid, , 50 dihydrochloride, mioflazine hydrochloride, mixi sodium, , , , dine, nafronyl oxalate, hydrochloride, nicer butabarbital sodium, , capuride, carbocloral, goline, nicorandil, , nifedipine, , betaine, , chlordiazepoxide hydrochloride, , Oxfenicine, hydrochloride, pen cloperidone hydrochloride, clorethate, , dex taerythritol tetranitrate, , pentrinitrol, perhexy clamol hydrochloride, , , esta 55 line maleate, , pirsidomine, , propatyl Zolam, , , fenobam, , nitrate, Suloctidil, hydrochloride, tipropidil hydro , , , , meclo chloride, hydrochloride, Xanthinol niacinate. qualone, , , midaflur, paralde Vulnerary: allantoin. hyde, , pentobarbital sodium, , Wound healing agent: erSofermin. , , , roletamide, , 60 Xanthine oxidase inhibitor: allopurinol, oxypurinol. secobarbital Sodium, , thalidomide, , Other pharmaceutical agents include: 1-decpyrrolidinone, maleate, , tricetamide, Sodium, 1-dodecpyrrolidinone, 16C.-fluoroestradiol, 16-, , , , hydrochloride, 16C.-gitoxin, 17C. estradiol, 17 Bestradiol. 1 alpha-hydroxyvi tartrate. tamin D2,2'-nor-cGMP, 20-epi-1.25 dihydroxyvitamin Selective adenosine a1 antagonist: apaxifylline. 65 D3.22-oxacalcitriol, 20VV, 3-isobutyl GABA, 6-FUDCA, Serotonin antagonist: tartrate, , ket 7-methoxytacrine, abamectin, , , abirater anserin, . one, acadesine, acamprosate, acarbose, , aceman US 8,802,596 B2 127 128 nan, acetomepregenol, acetyl-L-carnitine, acetylcysteine, collismycin A, collismycin B, combretastatin A4, complesta N-, acifran, , acitemate, acitretin, tin, conagenin, contignasterol, contortrostatin, cosalane, cos aclarubicin, aclatonium, napadisilate, aconiazide, acrivasti tatolide, cotinine, , cucumariosid, curacin net, , adapalene, adatanserin, adecypenol, ade A, curdlan sulfate, curiosin, cyclazosin, cyclic HPMPC, fovir dipivoxil, adelmidrol, ademetionine, adinazolam, adi cyclobenzaprine, cyclobut A, cyclobut G, cyclocapron, cyclo posin, adoZelesin, , alacepril, aladapcin, alaptide, platam, cyclosin, cyclothialidine, cyclothiazomycin, cype albendazole, albolabrin, aldecalmycin, aldesleukin, allen mycin, cyproterone, cytarabine ocfosfate, cytochalasin B, dronic acid, alentemol, alfacalcidol, alfuizosin, alglucerase, dacliximab, dactimicin, , , dalfopristin, dalte alinastine, alosetron, alpha idoSone, alprostadil, altretamine, parin Sodium, danaparoid, daphnodorin A, dapiprazole, dapi altromycin B. ambamustine, , ameSergide, 10 tant, , darlucin A, darsidomine, ddOTP, decitab amezinium metilsulfate, amfebutamone, amidox, amifloxa ine, deferiprone, deflazacort, dehydrodidemnin B, cin, amifostine, amiodarone, amisulpride, amlexanox, amlo dehydroepiandrosterone, delapril, deleduanine, delfapra dipine, amlodipine, , aminone, amrubicin, Zine, delmopinol, delphinidin, deoxypyridinoline, depro amsacrine, amylin, amythiamicin, anagrelide, anakinra, done, depsidomycin, , dermatan Sulfate, desflu ananain, anaritide, anastroZole, andrographolide, , 15 rane, desirudin, deslorelin, desmopressin, desogestrel, apadoline, apafant, apaxifylline, aphidicolin glycinate, apra desoxoarniodarone, detajmium bitartrate, dexifosfamide, clonidine, aprosulate Sodium, , apurinic acid, arani , dexloxiglumide, , dex dipine, arbekacin, arbidol, arbutamine, ardeparin Sodium, pemedolac, dexraZoxane, dexSotalol, dextrin2-Sulphate, dex arecatannin B1, argatroban, aripiprazol, , asimado Verapamil, dezinamide, dezocine, diaziquone, diclofenac line, aspalatone, asperfuran, aspoxicillin, astemizole, asula digolil, diclofenac potassium, dicranin, didemnin B, didox, crine, atamestanie, atenolol, S-, atosiban, atova , diethylhomospermine, diethylnorspermine, dihy quone, atpenin B, atrimustine, atrinositol, aureobasidin A, drexidine, dihydro-5-azacytidine, dimethyl prostaglandin A azadirachtine, azasetron, azatyrosine, , azelas 1, dimethylhomospermine, , dioxamycin, tine, , azimilide, azithromycin, aZosemide, aztre diphency prone, diphenyl spiromustine, , dipro onam, baccatin III, bacoside A, bacoside B, bactobolamine, 25 pylnorspermine, dirithromycin, discodermolide, disulfuram, balaZipone, balhimycin, , balsalazide, bam ditekiren, docarpamine, docosanol. 1-dofetilide, dolasetron, buterol, baohuoside 1, bamidipine, basifungin, batebulast, domitroban, dopexamine, dorzolamide, doSmalfate, dotariz batimastat, beauvericin, , becliconazole, ine, doxacurium chloride, doxazosin, doxifluridine, doxofyl , belfosdil, bellenamine, benflumetol, , line, draculin, draflazine, droloxifene, dronabinol, drosperi , benzochlorins, benzoidazoxan, benzoylstau 30 done, acephyllinate, , ebiratide, rosporine, benztropine, bepridil, beractant, beraprost, ber , ebselen, ecabapide, ecabet, ecadotril, ecdlisteron, lafenone, bertosamil, besipirdine, beta-alethine, betaclamy echicetin, echistatin, ecomustine, ecteinascidin 722, ectein cin B, betamipron, betaxolol, betulinic acid, bevantolol, ascidin 729, ecteinascidin 743, edaravone, edelfosine, edoba bicalutamide, , birnakalim, bimithil, binospirone, comab, edrecolomab, efegatran, eflornithine, , bioxalomycin alpha2, biriperone, bis- A, bis 35 egualen, elcatonin, , elgodipine, , eltenac, benzimidazole B, bisantrene, bisaramil, bisaziridinylsper emakalim, , emiglitate, emitefur, emoctakin, ena mine, bisnafide, bisoprolol, bistramide D, bistramide K, bis doline hydrochloride, enalapril, enaZadrem, englitaZone, tratene A, boldine, , brefeldin, breflate, enlimomab, , enoxaparin sodium, enoXimone, enta brimonidinc, bromfenac, bromperidol, bropirimine, bucin capone, enterostatin, epoprostenol, epoxymexrenone, epris dolol, budesonide, , budotitane, bunaprolast, 40 teride, eprosartan, eptastigmine, , , erso , butenafine, buthionine Sulfoximine, fermin, erytlritol, , etanidazole, etanterol, ethacizin, propionate, , calanolide A, calcipotriol, , , etodolac, etoposide phosphate, calphostin C, camonagrel, candesartan, candesartan cilexetil, etrabamine, everninomicin, examorelin, , fadro candoXatril, candoXatrilat, capecitabine, capromab, capsai Zole, faerieflungin, famciclovir, fampiridine, , faro cin, captopril, carbazomycin C, carbetocin, carbovir, car 45 , fasidotril, , fazarabine, , felbamate, boxamide-amino-triazole, , carboxym , fenoldopam, fenretinide, fenspiride, fenticona ethylated B-1,3-glucan, carperitide, carteolol, , Zole, fepradinol, ferpifosate sodium, ferristene, ferrixan, carvedilol, carvotroline, carZelesin, castanospermine, ferumoxsil, , flavopiridol, flecamide, fle , cecropin B, pivoxil, cefdaloXime robuterol, , , flezelastine, flobufen, flo pentexiltosilate, , pivoxil, , cefe 50 moxef, florfenicol, florifenine, flosatidil, fluasterone, flu tamet, pivoxil, , , cefimneta conazole, fludarabine, flumazenil, flumecinol, , Zole, cefimninox, , , , , flunarizine, fluocalcitriol, fluorodaunorunicin hydrochloride, cefotiam hexetil, , , , cef fluoxetine, R-fluoxetine, S-fluparoxan, , flurbipro pirome, proxetil, , , fen axetil, flurithromycin, , flutrima , , cefiriaxone, , cellas 55 Zole, fluvastatin, fluvoxamine, forasartan, forfenimex, form trol, celikalim, celiprolol, cepacidine A, , ceriv estane, , formoterol, R.R-, trometamol. astatin, ceronapril, certoparin Sodium, cetiedil, cetirizine, fosinopril, fosphenyloin, fostriecin, fotemustine, gabapentin, chloroorienticin A, chloroorienticin B, chloroquinoxaline , , gadodiamide, gadodiamide Sulfonamide, cibenzoline, cicaprost, , cicletanine, EOB-DTPA, gadolinium texaphyrin, , gadot cicloprolol, cidofovir, , cilaZapril, , 60 eridol, gadoversetamide, , galdansetron, gallo cilobradine, , , , pamil, galocitabine, gamolenic acid, ganirelix, gepirone, , cioteronel, ciprofibrate, ciprofloxacin, cipros gestrinone, , glaspimod, glaucocalyxin A, glutapy tene, cis-porphyrin, cisapride, , cistin rone, glycopine, glycopril, granisetron, , hali exine, citalopram, citicoline, citreamicin alpha, cladribine, chondrin B, halofantrine, halomon, halopredone, hatomami , clausenamide, clebopridc, , clo 65 cin, hatomarubigin A, hatomarubigin B, hatomarubigin C, bazam, , clodronic acid, , hatomarubigin D, , ibopamine, , illi , clotrimazole, colestimide, colfosceril palmitate, maquinone, ilmofosine, illomastat, illoperidone, iloprost, imi US 8,802,596 B2 129 130 dapril, , , indolidan, farnesil, parthenolide, paZelliptine, , , pegas indometacin, tropine ester, indoramin, , inogat pargase, peldesine, pemedolac, , penciclovir, pen ran, inolimomab, interferon alfa, interferon alfa-2a, inter tafuside, , , pentigetide, pen feron alfa-2B, interferon alfa-N1, interferon alfa-N3, inter tosan, pentostatin, pentroZole, perflubron, perfosfamide, feron B, interferon B-1 A1, interferon B-1B, interferon 5 , perindoprilat, , , phenazi gamma-1A, interferon gamma-1B, interferon omega, inter nomycin, phenserine, phensuccinal, phentolamine mesilate, feron, consensus, interleukin-1, interleukin-1 alpha, interleu phenylacetate, phenylalanylketoconazole, picenadol, piciba kin-1 B, interleukin-10, interleukin-11, interleukin-12, inter nil, picroliv, picumeterol, pidotimod, pilocarpine hydrochlo leukin-12, interleukin-15, interleukin-2, interleukin-3, ride, pilsicamide, pimagedine, pimilprost, pimobendan, pina interleukin-4, interleukin-5, interleukin-7, interleukin-8, 10 cidil, pinocebrin, pioglitaZone, pipecuronium bromide, iobenguane, , iodoamiloride, iododoxorubicin, iof pirarubicin, piretanide, pirfenidone, piritrexim, , ratol, iomeprol, iopentol, , iopyrol, iotriside, iover pirmagrel, pirmenol, pirodavir, pirodomast, piroXicam cin Sol, ioxilan, ipazilide, IpdR, ipenoxaZone, ipidacrine, namate, propagermanium, , propionylcam ipomeanol, 4-ipriflavone, ipsapirone, irbesartan, irinotecan, itine, L-, propiram-, , pro irloxacin, irsogladine, irtemazole, isalsteine, isbogrel, isepa 15 pyl bis-acridone, prostaglandin J2, prostratin, protegrin, micin, isobengaZole, isofloxythepin, isohomohalicondrin B, protoSufloxacin, , pyrazoloacridine, quazepam, isopropyl unoprostone, isradipine, itameline, itasetron, ito , quiflapon, , quinapril, quinfamide, pride, itraconazole, ketoprofen, R-ketoprofen, S-ketorolac, quinupristin, raloxifene, raltitrexed, ramatroban, ramipril, lacidipine, lactitol, lactivicin, laennec, , lamel ramosetron, ranelic acid, ranitidine bismuth citrate, ranola rarin-N triacetate, lamifiban, lamivudine, lamotrigine, lano Zine, recainam, regavirumab, relaxin, repirinast, resinfera conazole, , lanreotide, lanSoprazole, latanoprost, toxin, reticulon, reviparin sodium, revizinone, , lateritin, laurocapram, lazabemide, lemefloxacin, lemil ridogrel, , , , rilopiroX, riluzole, dipine, leminoprazole, lenercept, lenograstim, lentinan Sul , rimexolone, rimoprogin, , ripisartan, fate, leptin, leptolstatin, , , , risedronic acid, rispenzepine, risperidone, ritanserin, riti letraZuril, letrozole, leucomyzin, leuprorelin, levcromakalim, 25 penem, ritipenemacoxil, ritolukast, , ben , levobetaxolol, levobunolol, , Zoate, rohitukine, rokitamycin, ropinirole, , levocabastine, levocamitine, , , roquinimex, roXatidine, , , rubigi , levonorgestrel, , levosimen none B1, ruboxyl, , rupatidine, ruzadolane, Safin dan, , linotroban, , lintitript, linto gol, Safironil, Saintopin, salbutamol, R-Salmeterol, salme pride, liothyronine sodium, lirexapride, lisinopril, lobaplatin, 30 terol, R-sainacedin, , Sampatrilat, Sanfetrinem, lobucavir, lodoxamide, lombricine, , lomeriZ Saprisartan, sapropterin, saquinavir, sarcophytol A Sargra ine, lometrexol, , lonidamine, , lorata mostim, , Saruplase, Saterinone, satigrel, Satumo dine, , lornoxicam, losartan, losigamone, losox mab pendetide, selegiline, selenium thiosemicarbazone, antrone, loteprednol, loviride, loxoribine, , sematilide, semduramicin, Semotiadil, Semustine, sermore lurtotecan, luteinizing hormone, lutetium, luZindole, lydica 35 lin, Sertaconazole, sertindole, Sertraline, , mycin, lysofylline, lysostaphin, magainin2 amide, . Sevirumab, sevoflurane, seZolamide, silipide, silteplase, sim mallotochromene, mallotojaponin, malotilate, , endan, simvastatin, sinitrodil, sinnabidol, sipatrigine, siroli , maniwamycin A, mannostatin A, manumycin E, mus, sizofuran, Somatomedin B. Somatomedin C. Somatrem, manumycin F. mapinastine, marimastat, masoprocol, Somatropin, Sonermin, Stalol, staurosporine, stavudine, maspin, massetolide, meterelin, methoxatone, methylhista 40 , stipiamide, , Stobadine, Succibun, mine, R-alpha, methylinosine monophosphate, methylpred Sucralfate, Sulfasalazine, Sulfmosine, Sulfoxamine, nisolone aceponate, methylprednisolone Suleptanate, metipa Sulopenem, , , Sulukast, Sumatriptan, mide, metoclopramide, metoprolol. S-metrifonate, Symakalim, tandospirone, tapgen, taprostene, tasosartan, mibefradil, michellarnine B, microcolin A, midodrine, mife taZanolast, tazarotene, , , tellurapyry pristone, miglitol, millacemide, , mildronate, mil 45 lium, telmesteine, , temocapril, temoporfin, temo nacipran, milrinone, miltefosine, minaprine, miokamycin, Zolomide, tenidap, teniposide, tenosal, tenoxicam, tepirin mipragoside, mirfentanil, mirimostim, mirtazapine, miso dole, tepoxalin, teraZosin, terbinafine, terfenadine, prostol, mitoguaZone, mitolactol, mitonafide, mitoxantrone, terflavoxate, , terlakiren, terlipressin, terodiline, ter mivacurium chloride, , mixanpril, , tatolol, , tetrachlorodecaoxide, tetra mizoribine, moclobemide, modafinil, moexipril, mofarotene, 50 Zomine, thaliblastine, thalidomide, thiocoraline, thiofedrine, , molgramoStim, mometasone, montirelin, mopi thiomarinol, , thyroid stimulating hormone, damol, , , , motilide, mox , , tiapafant, tibolone, ticlopidine, tienox iraprine, , , nadroparin calcium, olol, , tilnoprofen arbamel, tiludronic acid, tinzaparin , nafamo.stat, nafarelin, , naglivan, Sodium, , tipredane, tiqueside, tirandaly nagreStip, nalmefene, naphterpin, napsagatran, , 55 digin, tirapazamine, tirilazad, tirofiban, , topsen nartograstim, nasaruplase, nateplase, , nirav tin, , toremifene, to Sufloxacin, , trandola oline, nisamycin, nisin, nisoldipine, , niteca pril, traXanox, tretinoin, tretinoin tocoferil, triacetyluridine, pone, nitrendipine, nitrendipine, S- monohy tricaprilin, trichohyalin, trichosanthin, alpha, triciribine, tri drate, nitrullyn, nizatidine, , okicenone, olanzapine, entine, triflavin, , triptorelin, troglitaZone, trom , , olSalazine, omeprazole, onapristone, 60 bodipine, tropisetron, trospectomycin, , troVir ondansetron, ondansetron, R-OntaZolast, oracin, , dine, tucaresol, , tylogenin, , oxaliplatin, oxamisole, Oxandrolone, oxaprozin, oxaunomy triphosphate, Valaciclovir, Valproate magnesium, valproate cin, , oxiconazole, , , oza semisodium, Valsartan, Vamicamide, Vanadeine, Vaninolol. grel, palauamine, palinavir, palmitoylrhizoxin, pamaqueside, Vapreotide, variolin B. velaresol, Venlafaxine, Veramine, pamicogrel, pamidronic acid, , panaxytriol, 65 Verapamil, S-Verdins, Veroxan, Verteporfin, Vesnarinone, , panipenum, pannorin, panomifene, pantethine, Vexibinol, vigabatrin, vinbumine citrate, vinbumine resinate, pantoprazole, parabactin, pamaparin Sodium, paroxetine, Vinconate, Vinorelbine, , Vinpocetine citrate, Vin US 8,802,596 B2 131 132 toperol, Vinxaltine, Voriconazole, Vorozole, Voxergolide, acistrate, erythromycin estolate, erythromycin ethylsucci Xemilofiban, Ximoprofen, yangambin, Zabicipril, Zacopride, nate, erythromycin gluceptate, erythromycin lactobionate, Zacopride, R-, Zalcitabine, Zaleplon, Zalospirone, erythromycin propionate, erythromycin Stearate, ethambutol , Zanamivir, Zankiren, Zanoterone, Zatebradine, hydrochloride, ethionamide, fleroxacin, floxacillin, fludala Zatosetron, Zenarestat, Zeniplatin, Zifrosilone, Zilascorb, nine, flumequine, fosfomycin, fosfomycin tromethamine, Zileuton, Zinostatin stimalamer, Ziprasidone, Zoledronic acid, fumoxicillin, furazolium chloride, furazolium tartrate, fusi , Zolpidem, Zonisamide, , Zopiclone, date Sodium, fusidic acid, gentamicin Sulfate, gloXimonam, S-Zopolrestat, . , , , hetacillin potassium, hexedine, ibafloxacin, , isoconazole, isepamicin, Specific Examples of Antibacterials 10 isoniazid, josamycin, kanamycin Sulfate, kitasamycin, levo furaltadone, levopropylcillin potassium, lexithromycin, lin When antibacterial activity is a desired property of the comycin, lincomycin hydrochloride, lomefloxacin, lom disclosed ionic liquids, one or more of the ions in the dis efloxacin hydrochloride, lomefloxacin mesylate, loracarbef, closed ionic liquids can be an antibacterial. That is the one or mafenide, meclocycline, meclocycline Sulfosalicylate, mega more kinds of cations, one or more kinds of anions, or both 15 lomicin potassium phosphate, medulidox, , meth cations and anions can be an antibacterial. Many of Suitable acycline, methacycline hydrochloride, methenamine, meth antibacterial have already been disclosed herein (e.g., many enamine hippurate, methenamine mandelate, QACs have antibacterial properties). Further examples of Sodium, metioprim, metronidazole hydrochloride, metron Suitable antibacterial agents include, but are not limited to, idazole phosphate, , meZlocillin Sodium, minocy acedapsone, acetosulfone sodium, alamecin, alexidine, amdi cline, hydrochloride, mirincamycin hydrochlo nocillin, amdinocillin pivoxil, amicycline, amifloxacin, ami ride, monensin, monensin Sodiumr, Sodium, floxacin meSylate, amikacin, amikacin Sulfate, aminosali nalidixate sodium, , natainycin, nebramycin, cylic acid, aminosalicylate Sodium, , neomycin palmitate, neomycin Sulfate, neomycin unde amphomycin, amplicillin, amplicillin Sodium, apalcillin cylenate, netilmicin Sulfate, neutramycin, nifuiradene, Sodium, apramycin, aspartocin, astromicin Sulfate, avilamy 25 nifuraldezone, nifuratel, nifuratrone, nifurdazil, nifurimide, cin, avoparcin, azithromycin, , azlocillin Sodium, nifiupirinol, , nifurthiazole, nitrocycline, nitro hydrochloride, , bacitracin methyl furantoin, nitromide, norfloxacin, Sodium, ene disalicylate, bacitracin Zinc, bambermycins, benzoylpas ofloxacin, onnetoprim, Sodium, oximonam, oxi calcium, berythromycin, betamicin Sulfate, , binira monam Sodium, , oxytetracycline, oxytetracy mycin, biphenamine hydrochloride, bispyrithione mag 30 cline calcium, oxytetracycline hydrochloride, paldimycin, Sulfex, butikacin, butirosin Sulfate, capreomycin Sulfate, car parachlorophenol, paulomycin, pefloxacin, pefloxacin mesy badox, disodium, carbenicillin indanyl sodium, late, , penicillin G benzathine, penicillin G carbenicillin phenyl Sodium, carbenicillin potassium, caru potassium, penicilling procaine, penicilling sodium, peni monam sodium, cefaclor, , , cefaman cillin V, penicillin V benzathine, penicillin V hydrabamine, dole nafate, cefamandole Sodium, cefaparole, , 35 penicillin V potassium, pentizidone sodium, phenyl ami Sodium, , cefazolin Sodium, cefbupera nosalicylate, piperacillin Sodium, pirbenicillin Sodium, piri Zone, cefdinir, cefepime, cefepime hydrochloride, cefetecol, dicillin Sodium, pirlimycin hydrochloride, cefixime, cefimenoXime hydrochloride, cefimetazole, hydrochloride, pivampicillin pamoate, pivampicillin cefnetazole Sodium, monosodium, cefonicid probenate, B sulfate, porfiromycin, propikacin, Sodium, sodium, , 40 pyrazinamide, pyrithione Zinc, quindecamine acetate, quinu Sodium, cefotetan, cefotetan disodium, cefotiam hydrochlo pristin, racephenicol, , ranimycin, relomycin, ride, cefoxitin, cefoxitin Sodium, cefpimizole, ce?pimizole repromicin, rifabutin, rifametane, rifamexil, rifamide, Sodium, cefpiramide, ce?piramide Sodium, Sulfate, rifampin, rifapentine, rifaximin, rollitetracycline, rollitetracy cefpodoxime proxetil, cefprozil, , cefsulodin cline nitrate, rosaramicin, rosaramicin butyrate, rosaramicin Sodium, , ceftibuten, Sodium, ceftri 45 propionate, rosaramicin Sodium phosphate, rosaramicin aXone sodium, cefuroxime, cefuroxime axetil, cefuroxime Stearate, , roXarsone, roXithromycin, sancycline, pivoxetil, cefuroxime Sodium, cephacetrile sodium, cephal Sanfetrinem Sodium, Sarmoxicillin, Sarpicillin, scopafungin, exin, cephalexin hydrochloride, cephaloglycin, cephalori Sisomicin, Sisomicin Sulfate, , spectinomycin dine, cephalothin Sodium, cephapirin Sodium, cephradine, hydrochloride, , stallimycin hydrochloride, Steffi cetocycline hydrochloride, cetophenicol, chloramphenicol, 50 mycin, Streptomycin Sulfate, streptonicoZid, SulfabenZ, Sul chloramphenicol palmitate, chloramphenicol pantothenate fabenzamide, Sulfacetamide, Sulfacetamide Sodium, Sulfacy complex, chloramphenicol sodium Succinate, chlorhexidine tine, , Sulfadiazine sodium, , phosphanilate, chloroxylenol, chlortetracycline bisulfate, , , Sulfameter, Sulfamethazine, Sul chlortetracycline hydrochloride, , ciprofloxacin, famethizole, Sulfamethoxazole, Sulfamonomethoxine, Sulfa ciprofloxacin hydrochloride, cirolemycin, clarithromycin, 55 moXole, Sulfanilate Zinc, , SulfaSalazine, Sulfa clinafloxacin hydrochloride, , clindamycin Somizole, Sulfathiazole, Sulfazamet, Sulfisoxazole, hydrochloride, clindamycin palmitate hydrochloride, clinda Sulfisoxazole acetyl, Sulfisboxazole diolamine, Sulfomyxin, mycin phosphate, clofazimine, benZathine, clox Sulopenem, Sultamricillin, Suncillin sodium, acillin Sodium, cloxyquin, colistimethate sodium, hydrochloride, teicoplanin, hydrochloride, Sulfate, coumermycin, coumermycin Sodium, cyclacillin, 60 , tetracycline, tetracycline hydrochloride, tetracy , dalfopristin, dapsone, , demeclocy cline phosphate complex, , , cline, hydrochloride, demecycline, denofun thiphencillin potassium, cresyl Sodium, ticarcillin gin, diaveridine, , dicloxacillin Sodium, dihy disodium, ticarcillin monosodium, ticlatone, tiodonium chlo drostreptomycin Sulfate, dipyrithione, dirithromycin, ride, tobramycin, tobramycin Sulfate, to Sufloxacin, trimetho , doxycycline calcium, doxycycline fosfatex, 65 prim, Sulfate, trisulfapyrimidines, troleando doxycycline hyclate, droxacin Sodium, enoxacin, , mycin, trospectomycin Sulfate, , , epitetracycline hydrochloride, erythromycin, erythromycin Vancomycin hydrochloride, Virginiamycin, and Zorbamycin. US 8,802,596 B2 133 134 Penicillin G, which is used as an antibacterial agent for infec methrin, high-cis, cyromazine, diafenthiuron, tions including , meningitis, and skin, bone, joint, diazinon, dichlorvos, disulfoton, emamectinbenzoate, , blood, and heart valve , is a particular fenoxycarb, formothion, furathiocarb, lufenuron, methi example suitable for use herein. tazobactum, sold under the dathion, permethrine, codilemone, phosphamidon, profeno trade names ZOSYNTM and TAZOCINTM, ceftrioxone, sold fos, pymetrozine, quinalphos, terrazole, thiamethoxam, thio under the trade name ROCEPHINTM, and metronidazol, sold cyclam, thiometon, triallate, trifloxystrobin, , under the trade name FLAGYLTM, are also used to treat Zetacypermethrin, and the like. Prohexadione is a FDA bacterial infections and are further examples of suitable com approved reduced risk fungicide and is also useful for the pounds that can be used to prepare the disclosed ionic liquids. disclosed ionic liquids. Further examples of suitable pesti These and other suitable antibacterials can be identified 10 cides can be found in The Pesticide Manual, 11" Edition, based on the desired properties of the antibacterial and British Crop Protection Council, 1997, which is incorporated whether the antibacterial active is or can be converted into an by reference herein at least for its teaching of pesticides. ion. As noted, identification of whetheran antibacterial active These and other suitable pesticides can be identified based is an ion or can be converted into an ion can be done by a on the desired properties of the pesticide and whether the skilled artisan inspecting the chemical structure of the anti 15 pesticide is or can be converted into an ion. As noted, identi bacterial. fication of whether a pesticide is an ion or can be converted into an ion can be done by a skilled artisan inspecting the Specific Examples of Antiviral chemical structure of the pesticide. When antiviral activity is a desired property of the dis Specific Examples of Herbicidal Actives closed ionic liquids, one or more of the ions in the disclosed ionic liquids can be an antiviral. Examples of Suitable antivi When herbicidal activity is a desired property of the dis ral actives include, but are not limited to, acemannan, acyclo closed ionic liquids, one or more of the ions in the disclosed Vir, acyclovir Sodium, adefovir, alovudine, alvircept Sudotox, ionic liquids can be a herbicide. Examples of suitable herbi hydrochloride, aranotin, arildone, atevirdine 25 cides include, but are not limited to, carfentraZone, imazapyr, mesylate, pyridine, cidofovir, cipamfylline, cytarabine benefin, acifluorfen, and 2-2-chloro-3-(2.2.2-trifluoroet hydrochloride, mesylate, desciclovir, didanosine, hoxymethyl)-4-methylsulfonylbenzoylcyclohexane-1. disoxaril, edoxudine, enviradene, enviroXime, famciclovir, Other suitable herbicides include inhibitors of the biosyn famotine hydrochloride, fiacitabine, fialuridine, fosarilate, thesis of branched amino acids such as ethoxysulfuron, flu foscarnet sodium, foSfonet Sodium, ganciclovir, ganciclovir 30 metSulam, halosulfuron, imaZamox, imazapyr, imaZaquin, Sodium, idoxuridine, kethoxal, lamivudine, lobucavir, memo imazethapyr, metoSulam, nicosulfuron, primisulfuron, pro tine hydrochloride, methisazone, , penciclovir, sulfuron, rimsulfuron, thifensulfuron-methyl, triflusulfuron, pirodavir, , rimantadine hydrochloride, saquinavir N-(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl-2-dim mesylate, Somantadine hydrochloride, Sorivudine, statolon, ethylaminocarbonyl-5-formylaminobenzenesulfonamide stavudine, tillorone hydrochloride, trifluridine, Valacyclovir 35 (Foramsulfuron), and the like. Still further, suitable herbi hydrochloride, Vidarabine, Vidarabine phosphate, vidarabine cides include inhibitors of the photosynthesis electron trans Sodium phosphate, Viroxime, Zalcitabine, Zidovudine, Zin port Such as ametryne, , bromoxynil, cyanazine, diu viroxime, and Tamiflu. ron, hexaZinone, metribuzin, pyridate, terbuthylazine, and the These and other suitable antivirals can be identified based like. In yet further examples, suitable herbicides for the dis on the desired properties of the antiviral and whether the 40 closed ionic liquids include synthetic auxins such as copy antiviral is or can be converted into an ion. As noted, identi ralid, dicamba, diflufenZopyr, fluoroxypyr, and the like. fication of whether an antiviral is an ion or can be converted Inhibitors offatty acid , such as butylate, EPTC, into an ion can be done by a skilled artisan inspecting the fenoxaprop-P-ethyl, and the like, can also be used in the chemical structure of the antiviral. disclosed ionic liquid compositions. In other examples, Suit 45 able herbicides can include inhibitors of cell division such as Specific Examples of Pesticidal Actives acetochlor, alachlor, dimethenamid, flufenacet, mefenacet, metolachlor, S-metolachlor, thenylchlor, and the like. In still When pesticidal activity is a desired property of the dis other examples, the herbicide can be an inhibitor of protopor closed ionic liquids, one or more of the ions in the disclosed phyrinogen oxidase, Such as fluthiacet-methyl, carfentra ionic liquids can be a pesticide. Included within the meaning 50 Zone-ethyl, and the like. Inhibitors of hydroxyphenylpyruvate of "pesticide' are insecticides and fungicides. Examples of dioxygenase, Such as isoxaflutole, mesotrione, Sulcotrione, suitable pesticides include, but are not limited to, carfentra 4-(4-trifluoromethyl-2-methylsulfonylbenzoyl)-5-hydroxy Zone-ethyl, SulfentraZone, clomaZone, diclofop-methyl, 1-methyl-3-methylpyrazole, and the like, can also be used. oxamyl propargite, prosulfuron, pyridate, pyriftalid, S-meto Further examples of suitable herbicides include, but are not lachlor, simazine, terbuthylazine, terbutryn, triasulfuron, tri 55 limited to, glyphosate, pendimethalin, trifluralin, asulam, tri floxysulfuron, trinexapac-ethyl, ametryn, atrazine, benoxa aziflam, diflufenican, glufosinate-ammonium, and the like. cor, bifenthrin, butafenacil, choline azide, chlortoluron, Clofencet, fluoroxpyr, mesosulfuron, diflufenzopyr are fur cinosulfuron, clodinafop, cloquintocet, DEET, desmetryn, ther examples of suitable herbicides and they are FDA dicamba, dimethachlor, dimethametryn, DTPA NaFe, approved. EDDHA NaFe, fenclorim, flumetralin, fluometuron, fluthi 60 acetmethyl, halosulfuron, isoproturon, metobromuron, meto Specific Examples of Other Ions lachlor, norflurazon, oxasulfuron, piperophos, pretilachlor, primisulfuron, prometryn, propaquizafop, acilbenzolar-s-me In addition to the pharmaceutical, antibacterial, antiviral, thyl, chlorothalonil, cyproconazole, cyprodinil, difenocona pesticidal, and herbicidal actives disclosed herein, other com Zole, fenpropidin, fempropimorph, furalaxyl, metalaxyl, 65 pounds that are ions or can be converted to ions can be used in metalaxyl-m, oxadixyl, penconazole, propiconazole, the disclosed ionic liquid compositions. Specific examples of pyrifenox, thiabendaZol, abamectin, bromopropylate, cyper these include, but are not limited to, the food additives Allura US 8,802,596 B2 135 136 Red AC (FD&C Red No. 40), Tartrazine (FD&C Yellow No. nar Energetic Anion.” Chem Commun 868, 2005, which is 5), Indigotine (FD&C Blue No. 2), Erythrosine (FD&C Red incorporated by reference herein). No. 3), and Sunset Yellow (FD&C Yellow No. 6), which are Examples of those ionic liquid compositions include, but FDA-approved color additives for food use. Further, nutra are not limited to, the mixture of at least two components of ceuticals such as fatty acids, , vitamins, minerals, functionalized 5- and 6-membered, and bicyclic fused ring and trace elements can be suitable ions for the disclosed ionic heterocyclic cations and anions containing 1, 2, 3, 4, or 5 liquid compositions. SEA-NIN-211 is an antifoulant that can atoms of nitrogen in the ring structure, where all carbon and be used as an ionid the disclosed compositions. nitrogen atoms in the ring structure can be functionalized 10 with additional Substituents such as alkyl, allyl, aryl, nitro, Specific Examples of Energetics nitrile, azido, hydroxyl, carboxylic acid, ester, amide, amine, aldehyde, ketone, epoxy, or functionalized alkyl and aryl The disclosed ionic liquid compositions can also include groups (with any functional mentioned above). Examples of high energy ingredients as well as explosive materials. The Such components (cations and/or anions) are shown below. ability to prepare a particular composition with high energy content Substituents (fuel) on one ion and high oxygen bal 15 ance (oxidizers) on the other ion opens wide applicability in R4 R4 today's high energy compounds industry. The ability to inde R R3 R R3 pendently form differentially functionalized groups of ions, N N then chose two of interest and combining them on demand to form desired strength energetic material (Scheme 1) opens 2 2 N the doors for the quick preparation of customizable energetic R6 R2 R6 NR2 materials (e.g., explosives with pre-designed power) and RI R1 more safe storage technique of those energetic materials since R4 R4 the components are separated before usage. The disclosed compositions can be prepared according to one of the follow 25 R R3 R R3 ing reaction protocols. nN.1 I DC R6 R2 R6 R2 Scheme 1: Protocol 1 30 RI R1 R2 R4 R4 e/ R R3 R R3 En?i y IA)O + n N Y I n N 35 R6 2 na R2 R6 2 n R2 R O RI R1 En N En G. ambient conditions R4 R4 IC ----> y y harmless solvent 40 R R3 R R3 N-N (e.g. H2O, EtOH) R s s 12 N N e/ 2 O R6 n R2 R6 n R2 "gy n En 45 RI R1 1 R4 R4 N N-N R 1. R3 Ri R3 R n N n Y s

IC GD (IA)f 50 2 2 R6 l N a R2 R6 N Ya R2 RI R1 where En is an energetic functional group containing either R4 4 3 high oxygen or nitrogen content (including but not limited to: R R nitro, amino, cyano, azido, alkyl nitro, alkyl amino, alkyl 55 R R3 cyano, alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, and alkoxy azido), IA is an innocuous anion, IC+ is an N 5 2 innocuous cation, and ICIA is an easily removable and R6 l % n R2 R R harmless byproduct from the metathesis reaction. The reac RI R tion proceeds via ion exchange reaction in Solvent system 60 media (solvent system is the solvent or the mixture of the R4 R3 R4 Solvents in which at least one of the starting materials dis solves). The solvents (or solvent) with substrates dissolved in / \ ) them separately are being combined, the byproduct is being R5 N -N R2 R5 N > R2 separated from the product (by solvent extraction or precipi 65 tation) (Katritzky et al., “1-Butyl-3-methylimidazolium 3.5- RI RI dinitro-1,2,4-triazolate: a Novel IL Containing a Rigid, Pla US 8,802,596 B2 137 138 -continued homologous heterocycle core (both 1, and 2) (e.g., but not R4 R3 R4 R3 limited to: imidazole, triazole, , benzimidazole, and benztriazole systems) can be formed. \ Y - ( The protocol for the formation of azolium azolate salts via the reaction of two neutral components requires: Zwitterionic R5 ( N1), Y R2 R5 4 N1 NR2 cation precursor (1) with carboxylate group appended on the k k heterocycle core, and neutral heterocycle (2) with the pKa R4 R R4 R value lower then that of carboxylate group in cation precursor V s V s (1). The reaction can be carried in any solvent systems (pure N-N N-N 10 solvent or mixture of solvents) that allows for the dissolution ( \, ( \, of both components, or without solvents at all. The reaction R5 1NR2 R51 Y NR2 protocol comprises the following steps: Proton transferreactions (protonation of carboxylate group R1 in Zwitterionic cation precursor (1): (step i) which is thermo 7 7 15 dynamically favored due to the difference in the pKa values of the Zwitterionic salt carboxylate group and azolate anion (formed from deprotonation of anion precursor (2)). AX- R6 MY R6 Decarboxylation of the system containing the protonated R3 N R3 N carboxylic acid group on the cation precursor in the interme Rs Rs diate (cationic part of compound 3) (step ii). The decarboxy R4 R4 altion may be performed in the presence of either polar sol vents (e.g., but not limited to, DMSO, DMF, THF, where R', R. R. R. R. R. and R', are, independent of one trialkylamine, HO) or heat (temp between 25°C.-150° C.). another, not present, H. alkyl, alkenyl, alkynyl, allyl, aryl, Additionally, the driving force for this conversion is the pro nitro, amino, cyano, azido, alkyl nitro, alkyl amino, alkyl 25 duction of gaseous CO which, upon removal from the reac cyano, alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, tion mixture, shifts the thermodynamic equilibrium in favor and alkoxy azido, nitrile, isonitrile, carboxylic acid, ester, of product formation. ether, CONR, CONHR, CONH, amine, NHR, NR, Examples of those ionic liquid compositions made utiliz ketone, aldehyde, or epoxy, wherein R is H, alkyl, alkenyl, ing above protocol include, but are not limited to, the mixture alkynyl, allyl, aryl, carboxylic acid, ester, ether, ketone, or 30 of at least two components of functionalized 5-, 6-membered, aldehyde. and bicyclic fused ring heterocyclic cation precursors and anion precursors containing 1, 2, 3, 4, or 5 atoms of nitrogen in the ring structure. Scheme 1: Protocol 2 The cation precursors are neutral, Zwitterionic species R ON N NO 35 (neutral molecule that within itself contains both: cation and + / 2 anion species) containing at least one cationic site (e.g., but N-N f not limited to, protonated oralkylated nitrogenatom) and one C \ O HN-N anionic site (carboxylate (COO—) group). In the cation pre N 2 cursors all carbon and nitrogenatoms in the ring structure can O- proton transfer 40 be functionalized with additional substituents such as alkyl, in MeOH allyl, aryl, nitro, nitrile, azido, hydroxyl, carboxylic acid, -- i ester, amide, amine, aldehyde, ketone, epoxy, or functional MeOH ized alkyl and aryl groups (with any functional mentioned 1 above). R The anion precursors are neutral, Substituted, or not Sub + / 45 N stituted, heterocyclic species containing at least one acidic proton site on any of the nitrogenatoms. This hydrogenatom Nyf will be utilized for the proton transfer reaction and consecu C 3 N -N tive decarboxylation reaction to form final azolium azolate OH product (4) as described in the protocol above. In the anion 50 precursors all carbon and nitrogenatoms in the ring structure can be functionalized with additional substituents such as alkyl, allyl, aryl. nitro, nitrile, azido, hydroxyl, carboxylic A 120° C. acid, ester, amide, amine, aldehyde, ketone, epoxy, or func O -CO2 tionalized alkyl and aryl groups (with any functional men rt. DMSO 55 tioned above). R Examples of Such components (cation precursors and/or -- A N anion precursors) are shown below.

ty se R4 4 N 60 R R3 R R3 N N 2 2 N R6 R2 R6 NR2 Utilizing this protocol, model compounds (4), which may 65 undergo further modification interms of introduced functions RI R1 (on the cation precursor (1), anion precursors (2), and US 8,802,596 B2 139 140 -continued where for the cation precursor: at least one of the R'-R R4 Substituent groups (only among the ones directly appended to carbon in heterocyclic ring) can be a carboxylate anion group. R R3 R3 N R3 The remaining groups can be, independent of one another, not nN.1 C present, H, alkyl, alkenyl, alkynyl, allyl, aryl, nitro, amino, cyano, azido, alkyl nitro, alkyl amino, alkyl cyano, alkyl R6 als R2 R6 2 R2 azido, alkoxy nitro, alkoxy amino, alkoxy cyano, and alkoxy R1 RI azido, isonitrile, carboxylic acid, ester, ether, CO.NR, R4 CONHR, CONH, amine, NHR, NR, ketone, aldehyde, 10 or epoxy, wherein R is H, alkyl, alkenyl, allynyl, allyl, aryl, R R3 R3 N R3 carboxylic acid, ester, ether, ketone, or aldehyde. n N 1. s And, where for the anion precursor: at least one of the N N R'-R substituent groups (only among the once directly R6 2 n R2 R6 2 n R2 appended to nitrogen in heterocyclic ring) can be an H atom 15 suitable for deprotonation to form stable heterocyclic azolate R1 RI anion. The remaining groups can be, independent of one another, not present, H. alkyl, alkenyl, alkynyl, allyl, aryl, f nitro, amino, cyano, azido, alkyl nitro, alkyl amino, alkyl R N R3 R3 N R3 cyano, alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, SN1 NN1 N and alkoxy azido, isonitrile, carboxylic acid, ester, ether, 12 N 2 N CO2NR, CONHR, CONH, amine, NHR, NR, R6 n R2 R6 n R2 ketone, aldehyde, or epoxy, wherein R is H, alkyl, alkenyl, R1 RI alkynyl, allyl, aryl, carboxylic acid, ester, ether, ketone, or R4 aldehyde. 25 Specific Ionic Liquids R 1. R3 Ri N R3 Because the disclosed ionic liquid compositions can have multiple functionalities or properties, each arising from the various ions that make up the ionic liquid, the disclosed ionic l N a N R6 n R2 R6 Ya R2 liquid compositions can be custom designed for numerous 30 uses. As disclosed herein, any combination of cations and R1 RI anions, as disclosed herein, can be made as long as the com i4 R4 R3 bination results in an ionic liquid as described herein. That is, any compound or active disclosed herein that has a given R 1. N Y R3 charge or can be made to have a given charge (the “first 35 ion(s)) can be combined with any other compound or active R6 l 2 N R2 R 5 ( ) R2 disclosed herein having a charge opposite to that of the first ion(s) or any compound that can be made to have a charge R1 R opposite to that of the first ion(s). Thus, in many examples, the R4 R3 R4 R3 ionic liquid compositions can have one type of cation and one M 40 type of anion, in a 1:1 relationship, so that the net charge of the \ N ionic liquid is Zero. Furthermore, many of the ions disclosed herein can have R5 ( y\, YR2 R5 ( ) R2 multiple charges. Thus, when one ion having a multiple R1 R1 charge is used, more counterion(s) is needed, which will 45 affect the ratio of the two ions. For example, ifa cation having R4 R3 R4 R3 a plus 2 charge is used, then twice as much anion having a minus 1 charge is needed. If a cation having a plus 3 charge is W \ Yf - \( used, then three times as much anion having a minus 1 charge R5 N -N R2 R5 N -N R2 is needed, and so on. While the particular ratio of ions will 50 depend on the type of ion and their respective charges, the R1 R1 disclosed ionic liquids can have a cation to anion ratio of 1:1, R4 R3 R4 R3 2:1, 3:1, 4:1, 1:3, 2:1, 3:2, 2:3, and the like. v A v A Many of the ionic liquid compositions disclosed hereincan N-N N-N also have more than one different kind of cation and/or more ( \, ( \, 55 than one different kind of anion. The use of more than one R5 N1 NR2 R51 NR2 kind of cation and/or anion can be particularly beneficial when one prepares an ionic liquid composition comprising R1 R1 two or more bioactive ions that are not desired to be in a 1:1 R R7 R relationship. In other words, according to the disclosed meth R \ R 60 ods, ionic liquid compositions that contain varying effective amounts (or doses) of active Substances can be prepared by 2- R6 varying the ratios of ions in the composition, as long as the total amount of cations is balanced by the total amount of R N R anions. For example, an ionic liquid composition disclosed Rs R4 R4 65 herein can contain one type of cation with a given property and two different anions (e.g., a first and second anion), each with another different property. The resulting ionic liquid in US 8,802,596 B2 141 142 this example will be 1 part cation, 0.5 part first anion, and 0.5 Sulfacetamide is used to control antibacterial activity and part second anion. Another example of this adjustment in ion is sold under the trade name KLARONTM in the treatment of amounts can arise when one ionis particularly potent and thus acne. Ibuprofen is used as an anti-inflammatory and pain dilution is desired. For example, a first cation that is particu reliever. Saccharinate is used as a Sweetener. larly potent can be combined with a second (or third, forth, etc.) cation that is inert or has so other property that is desired. Some specific examples of Suitable ionic liquids include, When these cations are combined with one or more kinds of but are not limited to, benzalkonium sulfacetamide (BA-sul anions to form an ionic liquid, the amount of the first cation is facetamide), didecyldimethylammonium Sulfacetamide diluted by the other the cation(s). As will be appreciated, (DDA-sulfacetamide), N-hexadecylpyridinium sulfaceta many other Such variations in the amount of cations and 10 mide (HEX-sulfacetamide), benzalkonium ibuprofen (BA anions can be present in the disclosed methods and compo ibuprofen), didecyldimethylammonium ibuprofen (DDA sitions. Thus, while specific ionic liquid compositions having ibuprofen), N-hexadecylpyridinium ibuprofen (HEX particular combinations of cations and anions are disclosed ibuprofen), and benzalkonium acesulfamate, herein, it is understood that the ratio of the particular ions can didecyldimethylammonium acesulfamate, N-hexadecylpyri be varied or adjusted by adding other ions, so long as there is 15 dinium acesulfamate, and benzalkonium saccharinate (BA a balance of charge and the final composition is an ionic SAC). liquid. In other examples, anion that is antiseptic can be combined When the disclosed ionic liquid compositions have two or with an ion that is antibacterial agent. For example, an ionic more ions with a bioactive property (e.g., pharmaceutical liquid can comprise benzalkonium and Sulfacetamide, which active ingredients, pesticidal actives, herbicidal actives, and is shown in formula X. the like), these compositions can be particularly desired because each of the active ingredients in the composition would have the same solubility and would dissolve together when formulated or administered. This can be particularly useful when overcoming formulation, solubility, bioavail 25 ability, size, and polymorphism issues. Further, when exact dosages of an active ingredient are needed, the active ingre dient as an ion can be combined with a counterion that is innocuous or GRAS (generally recognized as safe). As noted above, for example, if one active ingredient (cation) is needed at half the dosage of another active ingredient (anion), then an innocuous cation could be used as filler to balance the charges. This same concept applies if more cation is needed than anion. Another example is the combination of didecyldimethylam A few specific examples of ionic liquid compositions pre 35 monium sulfacetamide, which is shown in formula XI. pared from combinations of quaternary ammonium com pounds and Saccharinates or acesulfamates have been dem XI onstrated. Burgard disclosed a process for preparing C10H2 hexadecylpyridinium acesulfamate and its use in the oral NGE/CH N hygiene sector (Eur Pat Appl 2003-1270580A1; US Pat Appl 40 / N 2003-023084 A1). Hydrophilic quaternary ammonium sac C10H21 chrinates and acesulfamates and hydrophobic phosphonium acesulfamates have been recently published (Carter et al., Chem Comm, 2004, 630-631; Pernaket al., EurJ Org Chem, Still another example is the combination of N-hexadecylpy 2005, 650-652). Saccharin, acting as a weak acid, can form 45 ridinium sulfacetamide, which is shown in formula XII. salts with basic active pharmaceutical ingredients including tertiary to form quaternary nitrogen atoms (Bhatt et al., Chem Comm, 2005, 1073-1075). Also known in the lit XII erature is N-hexadecylpyridinium saccharinate (CAS No. 7428-34-4). 50 Some other specific examples of the disclosed ionic liquids / include, but are not limited to, ionic liquids where any of the O cations in the ionic liquid are aliphatic benzylalkyl ammo | e nium cations (e.g., benzalkonium), dialiphatic dialkyl ammo HN -n-coch, nium cations (e.g., didecyldimethylammonium), and ali 55 O phatic heteroaryl cations (e.g., hexadecylpyridinium) are combined with any of the anions of sulfacetamide, ibuprofen, and saccharinate. Such antiseptic/antibacterial compositions can be used in the Benzalkonium (BA) is used chiefly as an antiseptic and treatment of wounds, for example, wounds near the scalp disinfectant. It is found in many over the counter and pre 60 where a composition with both disinfectant and antibacterial Scription eye products, disinfectants, shampoos, and deodor properties is desirable. Such compounds could also be used ants. It also acts as a preservative in many pharmaceutical for skin care, e.g., to treat acne. preparations. Didecyldimethylammonium (DDA) is used as In still further examples, an ion that is antibacterial can be an antiseptic and surfactant. N-hexadecylpyridinium (HEX) combined with an anti-inflammatory and/or pain reliever. is used as an antiseptic agent alone or in combination with 65 Such compositions can be used as a disinfectant and for pain other drugs for oral and throat care. HEX is essentially non relief. For example, an ionic liquid can comprise benzalko toxic and can be applied to the skin or mucous membranes. nium and ibuprofen, which is shown in formula XIII. US 8,802,596 B2 143 144 -continued XVII XIII G) -C12H25 O Y C10H2 CH / V NG/ O H3C CH3 /N N C10H2 CH3 la O CH3 o1 No XVIII O O CH3 10 O G O N-CH N \ | sa120 o1 NoSa Also, the ionic liquid composition can comprise didecyldim 15 ethylammonium and ibuprofen, which is shown in formula XIV. The antibacterial agents benzalkonium, didecyldimethylam monium, and N-hexadecylpyridinium can also be combined with the sweetener saccharinate, as shown in formulas XIV, XIV XX, and XXI, respectively. CH3 XIX O CH3 25 Gel-C12H25 e 8 N M HC/ VCH A SnNo O Further, the ionic liquid composition can comprise N-hexa 30 XX decylpyridinium and ibuprofen, which is shown in formula O XV. C10H21 CH & \e/ 3 s€ XV 35 C10H2M. N.CH3 /MSo / N-CH3 XXI O

CH3 G 40 o N O GE) s€ CH3 \ / N-CH6-l / so O H3C O 45 In still other examples, the ionic liquid composition can In other examples of ionic liquid compositions disclosed comprise an ion that is an antibacterial agent with an ion that herein, an ion that is an antibacterial can be combined with an is a UV-blocker, Such as trans-cinnamate. Such compositions ion that is a Sweetener. Such compositions can be used to can be used as disinfectants and for protection against UV improve the taste of medicines and hygiene products and can 50 radiation, as would be desirable for treating wounds exposed be used in, for example, toothpaste, and children's medicine. to the Sun's radiation. Specific examples of such composition Some specific examples of Such ionic liquids is prepared by include, but are not limited to, compositions where the cation combining the antibacterial agents benzalkonium, dide is an antibacterial agent Such as benzalkonium, didecyldim cyldimethylammonium, or N-hexadecylpyridinium and the ethylammonium, or N-hexadecylpyridinium, and the anion is sweetener acesulfamate, as shown in formulas XVI, XVII, 55 trans-cinnamate, as is shown in formulas XXII, XXIII, and and XVIII, respectively. XXIV respectively.

XXII XVI O 60 G) - C12H25 1 O / V N H3C CH3 le o1 NoSa 65 US 8,802,596 B2 145 146 -continued tions, baked goods, and dairy products. Other food coloring XXIII anions, which are well known in the art, can be used as well. O

C10H21 CH 8 NG/ XXVIII / N G -C12H25 C10H2 CH3 $1 / V HC CH

XXIV O 10 G o O \ N-CH o

15

In still other examples, the disclosed ionic liquids can comprise an ion that is an antibacterial and an ion that can provide wetting and controls reaction rate, particle size, vis cosity, polymer molecular weight, and stability in emulsion polymerization systems, e.g., sodium dihexylsulfoSuccinate XXIX (e.g., Colawet MA-80 from Colonial Chemicals, South Pitts burg, Tenn.)). Specific examples of Such compositions 25 include, but are not limited to, compositions where the cation is an antibacterial agent Such as benzalkonium, didecyldim ethylammonium, or n-hexadecylpyridinium, and the anion is Colawet MA-80, as shown in formulas XXV. XXVI, and XXVII, respectively. 30

XXV O 35 e- C12H2s C6H13 No

H3 / Yeh3 O CH-1 g XXX 40 O XXVI O

C10H2 CH CH61.13 N G/" O 45 /N O C10H2 CH3 C6H13 g

O XXVII O 50 o C6H13 No \ N-CH3 O CH-1 g 55 O

In further examples, the disclosed ionic liquid composi In still further examples, the disclosed ionic liquid compo tions can comprise an ion that is antibacterial and an ion that 60 sitions can comprise a cation that is an antibacterial and an is a food colorant. Examples of Such ionic liquid composi anion that is an antibacterial. For example, the cationic anti tions include, but are not limited to, compositions where the bacterial agents disclosed herein can be combined with the cation is an antibacterial agent Such as benzalkonium, dide anionic piperacillin, which is an extended-spectrum penicil cyldimethylammonium, or N-hexadecylpyridinium, and the lin. Piperacillin is primarily used in the treatment of suscep anion is Fast Green FCF, an FDA approved color additive that 65 tible infections such as septicemia, acute and chronic respi provides a sea green hue and is used in products Such as ratory tract infections, skin and soft tissue infections, and beverages, puddings, ice cream, sherbet, cherries, confec urinary tract infections. US 8,802,596 B2 148 ceftioxone, atorvastatin, pravastatin, alendronate, mon C3H e- 2-125 Co"re-CH, O telukast, taZobactam, Allura Red AC, tartrazine, indigotine, / V N erythrosine, or Sunset Yellow. H3C CH3 M. N. Other specific examples of the disclosed ionic liquid com C10H2 CH3 positions are those where the cation is benzalkonium and the GE) anion comprises one or more of clofencet, fluoroxypyr, diflufenZopyr, mesosulfuron, prohexadione, pantoprazole, \ -edia risedronate, losartan, rabeprazole, fosinopril, ceftioxone, Cation

atorvastatin, pravastatin, alendronate, montelukast, taZobac 10 tam, Allura Red AC, tartrazine, indigotine, erythrosine, or Sunset Yellow. C2H5 Still further examples include the compositions docusate s^ H O lidocaine, miconazole?econazole docusate, streptomycin N N 15 docusate, and isoniazide docusate. Docusate combined with O r any of the cationic 5 and 6 membered quaternary ammonium O O Ph ring compounds disclosed herein are also contemplated herein. Anion Still further examples include a cation that is an anticho linergic like mepenZolate and the anion is docusate. Still further specific examples of the disclosed ionic liquid Another example comprises itraconazole, which inhibits compositions are those where the anion is benzoate and the cytochrome p540 oxidase mediated synthesis of ergosterol. cation comprises one or more of (2-acetoxyethyl)-dodecy Itraconazole is a 1:1:1 of four diastereomers loxymethyldimethylammonium, (2-acetoxyethyl)-hepty comprising 2 enantiomeric pairs. Generally, it has poor loxymethyldimethylammonium, (2-hydroxyethyl)-cy 25 adsorption especially when given in capsule form. This is clododecyloxymethyldimethylammonium, O though to occur because 99.8% of the drug becomes bound to (2-hydroxyethyl)-dimethylundecyloxymethylammonium. proteins in the body. It has been shown that absorption is Other examples of the disclosed ionic liquid compositions improved with acid as the pKa is 3.70: therefore, it is recom are those where the cation comprises benzalkonium, dide mended that this drug be taken with orange juice. The com cyldimethylammonium, or N-hexadecylpyridinium and the 30 anion comprises one or more of acesulfamate, benzoate, pound is insoluble in water, slightly soluble in alcohol, and colawet ma-80, fast green FCF, ibuprofen, penicillin G, pip freely soluble in . This compound can be eracillin, Saccharinate, Salicylate, Salicylate, Sulfacetamide, combined with any of the anions disclosed herein, for trans-cinnamate, Sulfathiazole, thimerosal, Valproic acid, example, Sulfacetamide, colawet MA-80, and docusate. mepenZolate, docusate. In three specific examples, benzalko 35 Also contemplated are ionic liquids that are . A nium is combined with mepenZolate and docusate in a 1:1:2 is a pharmacologically inactive compound that is ratio, a 2:1:3 ratio, or a 1:2:3 ration. In another example, converted to an active drug by a metabolic biotransformation. benzalkonium is combined with Sulfathiazole and sacchari Prodrugs are used when there are concerns regarding a drugs nate in a 2:1:1 ratio. solubility, absorption and distribution, site specificity, stabil Further specific examples of the disclosed ionic liquid 40 ity, prolonged release, toxicity, patient acceptability, and for compositions are those where the cation is didecyldimethy mulation concerns. Carrier linked prodrugs are also contem lammonium and the anion comprises one or more of saccha plated. A carrier linked prodrug is a compound that contains rinate, (S)-6-methoxy-C.-methyl-2-naphthaleneacetate, an active drug linked to a carrier group that can be removed 2-(2,6-dichlorophenyl)amino-benzeneacetate, 2-(2,6- enzymatically, such as an ester, which is hydrolyzed to an dichlorophenyl)amino-benzeneacetate, 2-acetoxybenzoate, 45 active carboxylicacid containing drug. Other types of carrier acesulfamate, benzoate, colawet ma-80, fast green FCF, ibu linkages include alcohols and carboxylic acids, amines, and profen, mandelate, N-4-(2-amino-1,4-dihydro-4-oxo-6- carbonyl compounds. Also contemplated are mutual pro pteridinyl)methylaminobenzoyl-L-glutamate, nicotinate, drugs, which comprise two drugs attached to each other penicillin G, piperacillin, p-toluenesulfonate, Salicylate, Sul where one is the carrier for the other and vice versa. facetamide, or trans-cinnamate. 50 Still further examples include compositions comprising Other specific examples of the disclosed ionic liquid com lidocaine and silver. This composition has a component that is positions are those where the cation is hexadecylpyridinium functional for topical anesthesia (lidocaine) with one Ag+ and the anion comprises one or more of colawet ma-80, fast that has antimicrobial properties. This can be used in con green FCF, penicillin G, piperacillin, or sulfacetamide. junction with lidocaine docusate, as described herein, to cre Still further specific examples of the disclosed ionic liquid 55 ate ointments or bandage materials that are capable of pro compositions are those where the cation is hexadecylpyri viding a palliative effect as well as Suppression of dinium and the anion comprises one or more of clofencet, microorganism growth. Similarly, silver docusate can be pre fluoroxypyr, diflufenZopyr, mesosulfuron, prohexadione, pared, which can provide a lipophilic salt of silver that would pantoprazole, risedronate, losartan, rabeprazole, fosinopril, be soluble in lidocaine docusate, other ILS, or even non-IL ceftioxone, atorvastatin, pravastatin, alendronate, mon 60 creme bases, for end-use as a topical antimicrobial agent. telukast, taZobactam, Allura Red AC, tartrazine, indigotine, Still further examples include compositions comprising erythrosine, or Sunset Yellow. ranitidine and docusate. This compound can generate a rather Further specific examples of the disclosed ionic liquid lipophilic, hydrophobic version of ranitidine, which would be compositions are those where the cation is didecyldimethy both non-crystalline and Sufficiently sluggish in its rate of lammonium and the anion comprises one or more of clofen 65 dissolution against biofluids that it could serve as a slow cet, fluoroxypyr, diflufenZopyr, mesosulfuron, prohexadione, release form of the drug. Lidocain docusate is another pantoprazole, risedronate, losartan, rabeprazole, fosinopril, example contemplated herein. US 8,802,596 B2 149 150 Methods salt of the desired cation (e.g., a halide salt) with a salt of the The disclosed ionic liquid compositions can be prepared by desired anion (e.g., transition metal, like Ag, salt, Group I or combining one or more kinds of cations or cation precursors II metal salt, or ammonium salt). Such reactions can be per with one or more kinds of anions or anion precursor. formed with many different types of salts; and (2) an acid Providing of the particular ions is largely based on the 5 base neutralization reaction. Another method for forming the identifying desired properties of the ion (e.g., its charge and disclosed ionic liquid compostions involves a reaction whether it has a particular bioactivity that is desired to be between a salt of a desired cation, say CationX where X is an present in the resulting ionic liquid). Methods of identifying appropriate balancing anion (including but not necessarily a Suitable ions are disclosed herein, for example, by consider halide), and an acid to yield the ionic liquid and HX byprod ing the chemical structure and charge of the compounds and 10 whether the ion combination will produce an ionic liquid. uct. Conversely, the disclosed ionic liquid compositions can Typically, when preparing an ionic liquid composition as be formed by reacting a salt of a desired anion, Say YAnion disclosed herein, an ion that minimizes coulombic interac where Y is an appropriate balancing cation, with a base to tions by diffusing its charge over several atoms in the ion is yield the ionic liquid and Ybase byproduct. identified. An example of this is the alkylheteroaryl cations 15 Many of the bioactive compounds (e.g., pharmaceutical disclosed herein where the positive charge is spread over the actives, pesticidal actives, herbicidal actives, etc.) and ener atoms of the heteroaryl ring. Then a weakly coordinating getic compounds disclosed herein are cationic or can be made counterion, which also delocalizes charge over several atoms, cationic, the identification of which can be made by simple is chosen. In general, more-complex and higher molecular inspection of the chemical structure as disclosed herein. Fur weight cations and anions have a greater number of intermo ther, many of these compounds are commercially available as lecular contacts, which serves to raise melting point and their halide salts or can be converted to their halide salts by increase the Viscosity of the ionic liquid composition. reactions with acids (e.g., HF, HCl, HBr, or HI) or by treating Further, when preparing an ionic liquid composition as a halogenated compound with a nucleophile Such as an disclosed herein, molecular asymmetry can be particularly amine. Further many of the anions disclosed herein are com desired. Low-symmetry cations and anions typically reduce 25 mercially available as metal salts, Group I or II metal salts, or packing efficiency in the crystalline State and lower melting ammonium salts. Combining such cations and anions in a points. Solvent with optional heating can thus produce the ionic liq It is also desirable that the cation should not be more uid compositions. For a review of the synthesis of ionic liq nucleophilic than the neutral form of the cation. If this is the uids see, for example, Welton, Chem Rev 1999, 99:2071 case, then Suitable anions can be selected by considering their 30 2083, which is incorporated by reference herein for at least its pKa. For example, by utilizing the pKa of acid functionalized teachings of ionic liquid synthesis. compounds and the pKb of base functionalized compounds, Ionic liquids which are immiscible with water are often one can combine the neutral species of acids and bases into conveniently prepared by the combination of aqueous solu one neutral compound possessing the functions of both com tions of two precursor salts, each of which contains one of the pounds. To Successfully produce an ionic liquid by this 35 two requisite ions of the targeted ionic liquids. On combina method, the pKa or pKb of compound A should be different tion, the desired salt forms a separate phase from the aqueous by approximately 5 orders of magnitude from the pKa or pKb admixture. Such phases are readily washed free of byproduct of compound B. This insures that the acidity or basicity at that salts with additional water, and may subsequently Subjected hydrogen is Sufficient to remove or add a hydrogen at that to other procedures (e.g., as disclosed in the Examples) to position. This will then produce an anion on the acidic com 40 separate them from non-water soluble impurities. In certain pound and a cation on the basic compound. cases, it is also possible to prepare water immiscible ionic One method for identifying a suitable ion combination for liquids by the addition to a neutral amine-containing com preparing an ionic liquid as disclosed herein is by computer pound (e.g., an active pharmaceutical ingredient) of an acid program. It is also possible to use a computer to select various such as aqueous HTf.N. Certain Tf.N. salts of N—H con cation and anion combinations. For example, the program 45 taining cations are known to be water-immiscible. called ERWINTM, sold by Computer Associates (Islandia, The purification of ionic liquids can be accomplished by N.Y.), can be used. This computer program is comprised of techniques familiar to those skilled in the art of organic and two models: a forward model which predicts the melting inorganic synthesis, with the notable exception of purification points and drug delivery rates of a formulation of ionic liq by distillation of the ionic liquid. One particularly useful uids, and a backwards model will allow the user to select 50 approach is the use of conventional or reverse-phase chroma which type of pharmaceutical agents that are desired along tography to separate the salt of interest from other ionic or with liquid range and delivery rates and the program will give non-ionic materials, followed by the separation of the ionic all the formulations which meet these criterion. liquid from the eluting solvent, commonly by evaporation of FIG. 3 illustrates how the two models interact. the latter. In some cases, ionic liquids can be purified by CODESSATM (Semichem, Inc. Shawnee Mission, Kans.) can 55 crystallization or thermal Zone crystallization at appropriate be used to calculate the descriptors that can be used to con conditions oftemperature and pressure. Such techniques can struct the forward model. For example, ifa researcher desires include the use of a solvent from which the ionic liquid can be a formulation to have antibacterial and painkilling therapeu crystallized at an appropriate temperature. Other purification tic agents as well as the formulation to exist as a liquid at room techniques include exchange column chromatography and temperature and have a delivery rate of 1 gram absorbed per 60 supercritical CO fluid extraction. minute, the researcher would feed this request into the pro Uses gram and all of the formulations meeting these requirements The disclosed ionic liquid compositions have many uses. and being composed entirely of a balanced ionic liquid for For example, the disclosed ionic liquid compositions can be mula would be suggested to the researcher. used to allow fine tuning and control of the rate of dissolution, Once the desired ions are provided, the ions can be com 65 solubility, and bioavailability, to allow control over physical bined to form the disclosed ionic liquids. There are generally properties and mechanical strength, to improve homogenous two methods for preparing an ionic liquid: (1) metathesis of a dosing, and to allow easier formulations. The disclosed ionic US 8,802,596 B2 151 152 liquid compositions also make having compositions with Additionally, the disclosed ionic liquids can be melted by a additional functionality possible. consumer or physician (e.g., with hot water) and then One notable advantage of the disclosed ionic liquid com “painted onto an area of interest. It would then cool as a thin, positions is that they can be used to alleviate the problems Solid coating of the ionic liquid. This use can provide a slow associated with polymorphism. For example, a compound release form of the API in the ionic liquid or imparta desirable Subject to polymorphism can be used as an ion in the dis barrier on the area of interest. closed ionic liquid compositions. In this way, the compound Depending on the particularions, the disclosed ionic liquid will become part of the ionic liquid composition and thus not compositions can be used to treat a subject diagnosed with, a crystalline solid that is Subject to polymorphism. Alterna for example, endocrine disorders, diabetes, infertility, hor tively, polymorphism can be prevented by dissolving the 10 mone deficiencies, osteoporosis, ophthalmological disorders, compound in the ionic liquid. An advantage of having ionic neurodegenerative disorders, Alzheimer's disease, dementia, liquid compositions is that the solubility and bioavailability Parkinson's disease, multiple Sclerosis, Huntington's dis can be known and predicted. This allows homogeneous and ease, cardiovascular disorders, atherosclerosis, hyper-coagu predictable dosing and tableting. lable states, hypo-coagulable states, coronary disease, cere Another notable advantage is that the disclosed ionic liquid 15 brovascular events, metabolic disorders, obesity, Vitamin compositions can be used to alleviate side effects associated deficiencies, renal disorders, renal failure, haematological with various compounds. For example, the disclosed ionic disorders, anemia of different entities, immunologic and liquid compositions can contain anion from a drug known to rheumatologic disorders, autoimmune diseases, immune have an undesirable along with a counterion that is deficiencies, infectious diseases, viral infections, bacterial a drug known to alleviate or counteract that side effect. An infections, fungal infections, parasitic infections, neoplastic example of this is an ionic liquid composition that comprises diseases, multi-factorial disorders, impotence, chronic pain, the ions of morphine and docusate. Sucha composition can be , and different fibrosis states. used to treat pain due to the presence of morphine and relieve Similarly, with herbicidal and pesticidal actives, the ionic due to the presence of docusate. Along the same liquid compositions disclosed herein that contain ionic pes lines, many pharmaceuticals are known to cause constipation, 25 ticidal and herbicidal actives can be used in the same way as and ionic liquids of these compounds with docusate or other the actives themselves. Thus, any use contemplated for a laxatives are contemplated herein. pesticidal and herbicidal active is contemplated herein for an Generally, any use that exists for one or more of the ionic ionic liquid composition containing that active. components in the ionic liquid is also a use for the ionic liquid Furthermore, because the disclosed ionic liquid composi composition itself. For example, if one of the ions in an ionic 30 tions are liquid at a given temperature, they avoid problems liquid composition disclosed herein is a pharmaceutical associated with polymorphism. For example, one can vary the active, then the ionic liquid composition can also be used for individual ions and the combination of ions to fine tune the the same indication as the pharmaceutical active. In fact, characteristics of the compositions, thus obtaining a compo many of the compounds disclosed herein as being Suitable sition with desired properties (e.g., better dissolution, Solu ions for the disclosed ionic liquids have already been proven 35 bility, or bioavailability). This can lead to easier dosing and to be effective alone or in some other preparation. Many of the formulating of the actives in the compositions. By preparing disclosed compounds are even FDA approved. When such and using the disclosed ionic liquid compositions, one need compounds are prepared as part of an ionic liquid, as dis not need to prepare, Screen, and characterize numerous crys closed herein, they can still maintain their efficacy, and can talline forms of the actives. even have their efficacy enhanced by being part of the ionic 40 In one aspect, disclosed herein are methods for using ionic liquid composition. For example, when an ionic liquid having liquid compositions that comprise administering an effective a pharmaceutical active as one or more of its cations oranions amount of at least one ionic liquid composition as disclosed is administered to a subject, the pharmaceutical active will herein. By the term “effective amount of a compound as dissociate from the ionic liquid and be available to the subject provided herein is meant a nontoxic but Sufficient amount to in the same way as had a solid form (e.g., tablet) or solution of 45 provide the desired result. As will be pointed out below, the the pharmaceutical active been administered. This effect is exact amount required will vary from Subject to Subject, also observed for the antibacterial, antiviral, pesticidal, her depending on the species, age, and general condition of the bicidal, nutritional, food additives and other compounds and subject, the severity of the disease that is being treated, the actives disclosed herein. particular compound used, its mode of administration, and Other uses of the disclosed ionic liquid compositions 50 the like. Thus, it is not possible to specify an exact “effective include the dissolution of the ionic liquid into liquid ban amount. However, an appropriate effective amount can be dages. Liquid bandages are available from commercial Sup determined by one of ordinary skill in the art using only pliers such as Johnson and Johnson. By dissolving the dis routine experimentation. The dose, schedule of doses, and closed ionic liquid compositions into a liquid bandage, the route of administration can be varied. various ions in the ionic liquid (e.g., antiinfective, Steroidal, 55 The efficacy of administration of a particular dose of the anesthetic, etc. ions) can be released into a wound and provide ionic liquid compositions according to the methods described beneficial effects. herein can be determined by evaluating the particular aspects Further, the disclosed ionic liquids can be coated onto a of the medical history, signs, symptoms, and objective labo cellulosic bandage (e.g., a gauze or dressing). Thus, by Soak ratory tests that are known to be useful in evaluating the status ing, spraying, or otherwise contacting a bandage with the 60 of a subject in need of attention for the treatment of a disease disclosed ionic liquid compositions, the bandage will contain and/or condition. These signs, symptoms, and objective labo the various active ions of the ionic liquid along with their ratory tests will vary, depending upon the particular disease or associated functionality. In this regard, it may be desirable to condition being treated or prevented, as will be known to any use an ionic liquid composition that melts at or around body clinician who treats such patients or a researcher conducting temperature. In this way, the ionic liquid composition can 65 experimentation in this field. For example, if, based on a “leach out of the bandage and onto the site contacted by the comparison with an appropriate control group and/or knowl bandage. edge of the normal progression of the disease in the general US 8,802,596 B2 153 154 population or the particular individual: (1) a Subject's physi neal or intramuscular injection. The disclosed compounds cal condition is shown to be improved, (2) the progression of can be administered intravenously, intraperitoneally, intra the disease or condition is shown to be stabilized, or slowed, muscularly, Subcutaneously, intracavity, or transdermally as or reversed, or (3) the need for other for treating is described more fully elsewhere herein. the disease or condition is lessened or obviated, then a par Administration and Delivery ticular treatment regimen will be considered efficacious. In one aspect, disclosed herein are uses of a delivery device Many of the disclosed ionic liquid compositions can be to deliver an ionic liquid composition as disclosed herein to a used therapeutically as neationic liquids. Also, the disclosed subject. Further, disclosed are methods for delivering an ionic ionic liquids can be used in combination with a pharmaceu liquid composition to a Subject by administering to the Sub tically acceptable carrier. By “pharmaceutically acceptable' 10 ject any of the nutritional Supplements, pharmaceutical for is meant a material that is not biologically or otherwise unde sirable, i.e., the material may be administered to a subject mulations, controlled release vehicles, delivery and/or without causing any undesirable biological effects or inter devices. acting in a deleterious manner with any of the other compo The compositions described herein can be administered to nents of the pharmaceutical formulation in which it is con 15 the Subject in a number of ways depending on whether local tained. The carrier would naturally be selected to minimize or systemic treatment is desired, and on the area to be treated. any degradation of the active ingredient and to minimize any Thus, for example, a composition described herein can be adverse side effects in the subject, as would be well known to administered as an ophthalmic solution and/or ointment to the one of skill in the art. In another aspect, many of the disclosed Surface of the eye. Moreover, a compound or pharmaceutical ionic liquids can be used prophylactically, i.e., as a preventa composition can be administered to a subject vaginally, rec tive agent, either neat or with a pharmaceutically acceptable tally, intranasally, orally, by inhalation, or parenterally, for carrier. The ionic liquid compositions disclosed herein can be example, by intradermal, Subcutaneous, intramuscular, intra conveniently formulated into pharmaceutical compositions peritoneal, intrarectal, intraarterial, intralymphatic, intrave composed of neat ionic liquid or in association with a phar nous, intrathecal and intratracheal routes. Parenteral admin maceutically acceptable carrier. See e.g., Remington's Phar 25 istration, if used, is generally characterized by injection. maceutical Sciences, latest edition, by E.W. Martin Mack Injectables can be prepared in conventional forms, either as Pub.Co., Easton, Pa., which discloses typical carriers and liquid solutions or Suspensions, solid forms suitable for solu conventional methods of preparing pharmaceutical composi tion or Suspension in liquid prior to injection, or as emulsions. tions that can be used in conjunction with the preparation of A more recently revised approach for parenteral administra formulations of the compounds described herein and which is 30 incorporated by reference herein. Such pharmaceutical carri tion involves use of a slow release or Sustained release system ers, most typically, would be standard carriers for adminis such that a constant dosage is maintained. In one example an tration of compositions to humans and non-humans, includ ionic liquid composition Such as lidocaine docusate is con ing Solutions such as sterile water, saline, and buffered tacted to the skin of a subject to provide an anesthetic effect. Solutions at physiological pH. Other compounds can be 35 Preparations for parenteral administration include sterile administered according to standard procedures used by those aqueous or non-aqueous solutions, Suspensions, and emul skilled in the art. For example, pharmaceutical compositions sions which can also contain buffers, diluents and other Suit can also include one or more additional active ingredients able additives. Examples of non-aqueous solvents are propy Such as antimicrobial agents, anti-inflammatory agents, anes lene glycol, polyethylene glycol, vegetable oils such as olive thetics, and the like. 40 oil, and injectable organic esters such as ethyl oleate. Aque Examples of pharmaceutically-acceptable carriers ous carriers include water, alcoholic/aqueous Solutions, include, but are not limited to, Saline, Ringer's solution and emulsions or Suspensions, including saline and buffered dextrose solution. The pH of the solution is preferably from media. Parenteral vehicles include sodium chloride solution, about 5 to about 8, and more preferably from about 7 to about Ringer's dextrose, dextrose and sodium chloride, lactated 7.5. Further carriers include sustained release preparations 45 Ringer's, or fixed oils. Intravenous vehicles include fluid and Such as semipermeable matrices of Solid hydrophobic poly nutrient replenishers, electrolyte replenishers (such as those mers containing the disclosed compounds, which matrices based on Ringer's dextrose), and the like. Preservatives and are in the form of shaped articles, e.g., films, liposomes, other additives, such as antimicrobials, anti-oxidants, chelat microparticles, or microcapsules. It will be apparent to those ing agents, and inert gases and the like, can also be present. persons skilled in the art that certain carriers can be more 50 Formulations for topical administration can include oint preferable depending upon, for instance, the route of admin ments, lotions, creams, gels, drops, Suppositories, sprays, istration and concentration of composition being adminis liquids and powders. The disclosed ionic liquid compositions tered. Other compounds can be administered according to having hydrophobic ions can be particularly useful in Such standard procedures used by those skilled in the art. applications because they can adhere to the Surface longer Pharmaceutical formulations can include additional carri 55 when exposed to water or other fluids than would a similar ers, as well as thickeners, diluents, buffers, preservatives, hydrophilic salt. Likewise, ionic liquids comprising disinfec Surface active agents and the like in addition to the com tant, herbicide, or pesticide ions and hydrophobic counterions pounds disclosed herein. Pharmaceutical formulations can can be expected to resisterosion from rainfall. Conventional also include one or more additional active ingredients such as pharmaceutical carriers, aqueous, powder or oily bases, antimicrobial agents, anti-inflammatory agents, , 60 thickeners and the like can be necessary or desirable. When and the like. applied to skin or mucous tissues (e.g., oral applications) The pharmaceutical formulation can be administered in a ionic liquid compositions containing pharmaceutical actives number of ways depending on whether local or systemic formulated with highly hydrophobic anions or cations (as treatment is desired, and on the area to be treated. Adminis appropriate) can have longer durations of adhesion when tration may be topically (including ophthalmically, vaginally, 65 exposed to water or other fluids than would similar hydro rectally, intranasally), orally, by inhalation, or parenterally, philic salts applied in these environments. This would be for example by intravenous drip, Subcutaneous, intraperito particularly beneficial for sun screens. It should also be noted US 8,802,596 B2 155 156 that disinfectants, pesticides, or herbicides applied to plant As described herein, niosomes are delivery devices that can leaves can be less prone to be lost by rain even if it follows be used to deliver the compositions disclosed herein. Noi application. Somes are multilamellar or unilamellar vesicles involving When one or more ions in the disclosed ionic liquid com non-ionic Surfactants. An aqueous solution of Solute is positions are an antibacterial, an effective amount of the com enclosed by a bilayer resulting from the organization of Sur position can be contacted (i.e., administered) to any Surface factant macromolecules. Similar to liposomes, noisomes are that has bacteria. Similarly, when one or more ions in the used in targeted delivery of for example, anticancer drugs, disclosed ionic liquid composition are a pesticidal active, an including methotrexate, doxorubicin, and immunoadjuvants. effective amount of the composition can be administered to They are generally understood to be different from transfer 10 oSomes, vesicles prepared from amphiphilic carbohydrate an area to control pests. When one or more ions in the dis and amino group containing polymers, e.g., chitosan. closed ionic liquid composition are a herbicidal active, an As described herein, nanoerythrosomes are delivery effective amount of the composition can be administered to devices that can be used to deliver the compositions disclosed an area to control plants. Techniques for contacting Such herein. NanoerythroSomes are nano-vesicles made of red Surfaces and areas with the disclosed ionic liquid composi 15 blood cells via dialysis through filters of defined pore size. tions can include, spraying, coating, dipping, immersing, or These vesicles can be loaded with a diverse array of biologi pouring the composition into or onto the Surface or area. The cally active molecules, including proteins and the composi precise technique will depend on Such factors as the type and tions disclosed herein. They generally serve as ideal carriers amount of infestation or contamination, the size of the area, for antineoplastic agents like bleomycin, actinomycin D, but the amount of composition needed, preference, cost and the can be used for steroids, other lipids, etc. like. Artificial red blood cells, as described herein, are further Delivery Devices delivery devices that can be used to deliver the compositions Any of the compounds described herein can be incorpo disclosed herein. Artificial red blood cells can be generated by rated into a delivery device. Examples of delivery devices interfacial polymerization and complex emulsion methods. include, but are not limited to, microcapsules, microspheres, 25 Generally, the “cell' wall is made of polyphtaloyl L-lysine nanospheres or nanoparticles, liposomes, noisome, nano polymer/polystyrene and the core is made of a hemoglobin erythrosome, Solid-liquid nanoparticles, gels, gel capsules, Solution from sheep hemolysate. Hemoglobin loaded micro tablets, lotions, creams, sprays, emulsions, or powders. Other spheres typically have particle sizes of from about 1 to about examples of delivery devices that are suitable for non-oral 10 mm. Their size, flexibility, and oxygen carrying capacity is administration include pulmospheres. Examples of particular 30 similar to red blood cells. delivery devices useful herein are described below. Solid-lipid nanoparticles, as described herein, are other The disclosed compounds can be incorporated into lipo delivery devices that can be used to deliver the compositions Somes. AS is known in the art, liposomes are generally derived disclosed herein. Solid-lipid nanoparticles are nanoparticles, from phospholipids or other lipid substances. Liposomes are which are dispersed in an aqueous Surfactant Solution. They formed by mono- or multi-lamellar hydrated liquid crystals 35 are comprised of a solid hydrophobic core having a mono that are dispersed in an aqueous medium. Any non-toxic, layer of a phospholipid coating and are usually prepared by physiologically acceptable and metabolizable lipid capable high-pressure homogenization techniques. Immunomodulat of forming liposomes can be used. The disclosed composi ing complexes (ISCOMS) are examples of solid-lipid nano tions in liposome form can contain, in addition to a compound particles. They are cage-like 40 nm Supramolecular assem disclosed herein, stabilizers, preservatives, , and 40 blies comprising of phospholipid, cholesterol, and the like. Examples of suitable lipids are the phospholipids and hydrophobic antigens and are used mostly as immunoadju the (), both natural and Syn vants. For instance, ISCOMs are used to prolong blood thetic. Methods of forming liposomes are known in the art. plasma levels of Subcutaneously injected cyclosporine. See, e.g., Prescott, Ed., Methods in Cell Biology, Volume Microspheres and micro-capsules, as described herein, are XIV. Academic Press, New York, p. 33 et seq., 1976, which is 45 yet other delivery devices that can be used to deliver the hereby incorporated by reference herein for its teachings of compositions disclosed herein. In contrast to liposomal deliv liposomes and their preparation. ery systems, microspheres and micro-capsules typically do In other examples, the liposomes can be cationic liposomes not have an aqueous core but a Solid polymer matrix or mem (e.g., DOTMA, DOPE, DC cholesterol) or anionic lipo brane. These delivery devices are obtained by controlled pre Somes. Liposomes can further comprise proteins to facilitate 50 cipitation of polymers, chemical cross-linking of soluble targeting a particular cell, if desired. Administration of a polymers, and interfacial polymerization of two monomers or composition comprising a compound and a cationic liposome high-pressure homogenization techniques. The encapsulated can be administered to the blood afferent to a target organ or compound is gradually released from the depot by erosion or inhaled into the respiratory tract to target cells of the respira diffusion from the particles. Successful formulations of short tory tract. Regarding liposomes, see, e.g., Brigham, et al., Am 55 acting peptides, such as LHRH agonists like leuprorelin and J Resp Cell Mol Biol. 1:95-100, 1989; Feigner, et al., Proc Natl triptoreline, have been developed. Poly(lactide co-glycolide AcadSci USA 84:7413-7, 1987; and U.S. Pat. No. 4,897,355, (PLGA) microspheres are currently used as monthly and which are incorporated by reference hereinfortheir teachings three monthly dosage forms in the treatment of advanced of liposomes. As one example, delivery can be via a liposome prostrate cancer, endometriosis, and other hormone respon using commercially available liposome preparations such as 60 sive conditions. Leuprolide, an LHRH Superagonist, was LIPOFECTIN, LIPOFECTAMINE (GIBCO-BRL, Inc., incorporated into a variety of PLGA matrices using a solvent Gaithersburg, Md.), SUPERFECT (Qiagen, Inc. Hilden, Ger extraction/evaporation method. As noted, all of these delivery many) and TRANSFECTAM (Promega Biotec, Inc., Madi devices can be used in the methods disclosed herein. son, Wis.), as well as other liposomes developed according to Pulmospheres are still other examples of delivery devices procedures standard in the art. Liposomes where the diffusion 65 that can be used herein. Pulmospheres are hollow porous of the compound or delivery of the compound from the lipo particles with a low density (less than about 0.1 gm/mL). Some is designed for a specific rate or dosage can also be used. Pulmospheres typically have excellent re-dispersibility and US 8,802,596 B2 157 158 are usually prepared by Supercritical fluid condensation tech herein. For example, prodrugs, ionic and neutral active mol nology. Co-spray-drying with certain matrices, such as car ecules can be dissolved in the disclosed ionic liquid compo bohydrates, human serum albumin, etc., can improve the sitions. stability of proteins and peptides (e.g., insulin) and other Further methods of administration can include incorporat biomolecules for pulmonary delivery. This type of delivery 5 ing the disclosed ionic liquid composition into a foodstuffor could be also accomplished with micro-emulsions and lipid beverage, which can be ingested by a Subject. emulsions, which are ultra fine, thin, transparent oil-in-water The disclosed ionic liquids can also be encapsulated in a (ofw) emulsions formed spontaneously with no significant polymer matrix by methods known in the art. input of mechanical energy. In this technique, an emulsion Also, the disclosed ionic liquid compositions can be dis can be prepared at a temperature, which should be higher than 10 solved in a suitable solvent or carrier as are disclosed herein. the phase inversion temperature of the system. At elevated This method can enhance the delivery of one or more active temperature the emulsion is of water-in-oil (w/o) type and as ions in the ionic liquid. Further, as is disclosed herein, this method can create a synergistic effect among the various ions it cools at the phase inversion temperature, this emulsion is present. While not wishing to be bound by theory, the disso inverted to become of w. Due to their very small inner phase, 15 ciate coefficient of various ions in an ionic liquid can be they are extremely stable and used for sustained release of different in different solvents. Thus, ions in an ionic liquid can steroids and vaccines. Lipid emulsions comprise a neutral dissociate freely in one solvent and cluster in another. This lipid core (i.e., triglycerides) stabilized by a monolayer of phenomenon can be utilized to provide formulations of com amphiphilic lipid (i.e., phospholipid) using Surfactants like pound that are difficult to deliver (e.g., increase the water egg triglycerides and miglyol. They are Suitable for solubility of steroids). That is, compounds can beformed into passive and active targeting. an ionic liquid, as described herein, and then dissolved in a There are other oral delivery systems under investigation suitable solvent to provide an easily deliverable solution. A that are based on osmotic pressure modulation, pH modula synertistic effect can be observed upon administration to a tion, Swelling modulation, altered density and floating sys Subject, when ions cluster and act together, rather than inde tems, mucoadhesiveness etc. These formulations and time 25 pendently. delayed formulations to deliver drugs in accordance with circadian rhythm of disease that are currently in use or inves EXAMPLES tigation can be applied for delivery of the compositions dis closed herein. The following examples are set forth below to illustrate the It is also contemplated that the disclosed ionic liquid com 30 methods and results according to the disclosed subject matter. positions can be formulated as part of a controlled release These examples are not intended to be inclusive of all aspects vehicle. For example, microspheres and microcapsules, of the subject matter disclosed herein, but rather to illustrate representative methods and results. These examples are not implants, and the like containing liquid bioactive agents are intended to exclude equivalents and variations of the present well known, as are methods for their preparation. As such, 35 invention which are apparent to one skilled in the art. these methods can be used with the disclosed ionic liquid Efforts have been made to ensure accuracy with respect to compositions to produce controlled release vehicles that can numbers (e.g., amounts, temperature, etc.) but some errors release the disclosed ionic liquid composition with a desired and deviations should be accounted for. Unless indicated release profile. otherwise, parts are parts by weight, temperature is in C. or Also contemplated are pills prepared from the disclosed 40 is at ambient temperature, and pressure is at or near atmo ionic liquid compositions that are glasses. For example, a spheric. There are numerous variations and combinations of glass ionic liquid composition can be cooled to form a pill. reaction conditions, e.g., component concentrations, tem That is, glasses are “cast-able' above their glass transition peratures, pressures and other reaction ranges and conditions temperature (T) into shapes with specific surface areas, that can be used to optimize the product purity and yield allowing predictable release/pharmacokinetic properties. 45 obtained from the described process. Only reasonable and Below T, these disclosed glass ionic liquid composition can routine experimentation will be required to optimize Such be milled into specific shapes and sizes. Alternatively, the process conditions. All chemicals used were of analytical disclosed ionic liquid compositions can be tableted as liquids grade, purchased from Sigma-Aldrich (Milwaukee, Wis.), that upon cooling form glasses. Such a method can allow the and used without further purification unless otherwise noted. homogeneous distribution of a pharmaceutical active into the 50 tablet. Example I A particular example includes ionic liquid compositions that are in the glass form but melt at or slightly above body Didecyldimethylammonium Saccharinate temperature. Such compositions can allow formulation as a DDAISac solid, but have known solubility, bioavailability, etc. as a 55 liquid. These compositions can have uses in, for example, To the reaction flask, equipped with stirring and ther bandages, patches, or wound dressings. Further, glass com mometer, 0.03 mol of didecyldimethylammonium bromide positions that “melt slightly above room temperature can be and 0.03 mol of saccharin sodium salt, and 50 mL of water "melted by a consumer or physician with, e.g., hot water or were put in. The mixture was intensively stirred for one hour body heat, and “painted onto an area of interest (infected 60 at room temperature. Afterwards 50 mL of was area). Cooling of the composition can then provide a thin, added. After phases separated, chloroform phase was isolated solid coating of material which is both a slow release form of (separated), and washed with fresh distilled water (so many an active ingredient ion (e.g., anti-infective, steroid, anes times) until all chloride ions were washed out (removed). thetic, or combination thereof), plus serve as a physical bar Chloroform was distilled off (evaporated) and the residue rier. 65 (remains) was dried at 60°C. in vacuum. Saccharinate inform Further, the disclosed ionic liquids can be used as carriers of liquid, with high viscosity was obtained in 95% yield. It is for other active compounds, many of which are disclosed hydrophobic liquid (fluid), lighter than water, poorly dissolv US 8,802,596 B2 159 160 able in cold and warm water. Thermal stability of this salt is Example II presented in Table 2. Synthesized salt appear to be sweet and active against microorganisms. The activity is high in com Benzalkonium Saccharinate BASac parison with starting material, didecyldimethylammonium To the Saturated water Solution of Saccharin Sodium, the chloride, which is confirmed by MIC and MBC values (Table water solution of benzalkonium chloride (alkyl substituent— 3 and Table 4). dodecyl and tetradecyl) was added in the molar ratio of 1:1.5. Elemental analysis: CHN: CHNOS (508.80) calcu The mixture was stirred for 1 h at the temperature of 60° C. lated values: C=68.46%, H=10.30% i N=5.51%; experimen After the mixture was cooled down to the room temperature, white wax was formed. The wax was dissolved in chloroform. tal values C=68.78%, H=10.69%, N=5.31%. "H NMR 10 (DMSO-d) cation: 3.22 (m, 4H); 3.00 (s, 6H); 1.63 (m, 4H); Chloroform phase was washed with fresh distilled water (so many times) until all chloride ions were washed out (re 1.24 (m. 28H): 0.85 (t, J=7 Hz, 6H); anion: 7.58 (m, 4H); 'C moved). The progress was monitored by using water Solution NMR cation: 62.7: 49.9; 31.2: 28.8; 28.7; 28.6; 28.4; 25.6; of AgNO. Afterwards chloroform was distilled off (evapo 22.0: 21.6; 13.8; anion: 167.7: 145.2: 1348; 131.3, 130.8; rated) and the residue (remains) wax was dried at 50° C. in 122.3; 118.9. 15 vacuum. Synthesized benzalkonium saccharinate was obtained with 98% yield. It is very sweet in taste. Obtained TABLE 2 wax is poorly dissolvable in cold and warm water. Crystalline benzalkonium saccharinate, with the melting point of 80-82° Thermal stability data of synthesized salts C., was obtained form the mixture of dry (no water) and diethylether in the volume ratio of 10:1. Temperature BASac DDA)Sac (BAAce DDAAce "H NMR (DMSO-d) 7.59 (m, 9H), 4.53 (s, 2H), 3.24 (m, g -52.5 -58 2H), 2.95 (s, 6H), 1.77 (m, 2H), 1.24 (m, 20H), 0.85 (t, J=7 ?e 21.5 18.0 26.4 -45.5 Hz, 3H); 'C NMR cation: 132.8, 130.1, 128.8, 128.0, 66.1, s-s 65.5 63.4, 49.0, 31.2, 28.9, 28.85, 28.7, 28.6, 28.4, 25.7, 22.0, 21.7, m 82.5 22.5 89 -29 25 13.8, anion: 167.7, 145.2, 134.8, 1314, 130.8, 122.3, 118.9. Tonser(5%) 176 184 186 182 onset 2O6 211 (203)258 2O1 Example III T. 227 221 (225)273 245 Benzalkonium Acesulfamate BAAce T. glass transition. T-crystallization temperature recorded by the DSC. 30 To the reactor the water solution of 1 mol of benzalkonium T-solid-solid transitions recorded by the DSC. chloride (alkyl substituent is the mixture of the following To melting point recorded by the DSC, groups: octyl, decyl, dodecyl, tetradecyl, hexadecyl and octy Teso-onset temperature for 5% of the decomposition, decyl) and water solution of 1.5 mol of acesulfamate sodium Tse onset temperature of the decomposition, were put in (placed). The mixture was stirred for 1 h at the T-temperature of total decomposition, 35 temperature of 60°C. After the mixture was cooled down to the room temperature. Formed wax was dissolved in chloro form and separated water phase was removed. Chloroform TABLE 3 phase was washed with fresh distilled water (so many times) MIC values for investigated salts until all chloride ions were washed out (removed). The 40 progress was monitored by using water solution of AgNO. BA) DDA) (BA) DDA) Chloroform was distilled off (evaporated) and the product culture Sac Sac Ace Ace BAC** DDAC*** dried at 60°C. in vacuum. Obtained wax, with the 95% yield, S. airetts 4 4 4 8 2 2 was crystallized out (re-crystallized) from the mixture of E. faecium 8 8 8 8 4 4 THF, acetone and diethylether in the volume ratio of 10:10:1. E. coi 16 16 31.2 16 8 8 45 Crystalline benzalkonium acesulfamate, which has Sweet C. albicans 16 16 16 16 8 8 Average 11 11 14.8 12 5.5 5.5 taste, melts between 90 and 91°C. The melting point recorded value on the by the DSC (diffraction scanning calorimeter) was 89° C. This salt is poorly dissolvable in cold and warm water. *in ppm. Measured thermal decomposition temperature of obtained benzalkonium chloride. 50 salt are placed in Table 2, while biological activity data in ***didecyldimethylammonium chloride Table 3 and Table 4. Calculated average values for MIC and MBC indicate high activity of the salt, slightly lower than that TABLE 4 of the starting benzalkonium chloride H NMR (DMSO-d) cation: 7.52 (m, 5H), 4.53 (s. 2H), MBC values for investigated Salts. 55 3.24 (m, 2H), 2.95 (s, 6H), 1.78 (m, 2H), 1.25 (m, 20H), 0.85 BA) DDA) (BA) DDA) (t, J=7 Hz, 3H), anion: 5.28 (s, 1H), 1.90 (s.3H); C NMR Culture Sac Sac Ace Ace BAC** DDAC*** cation: 132.8, 130.1, 128.8, 128.0, 66.1, 63.4, 49.0, 31.2, 28.9, 28.87, 28.7, 28.6, 28.4, 25.7, 22.0, 21.7, 13.8, anion: S. airetts 31.2 62.5 31.2 16 62.5 31.2 E. faecium 16 16 31.2 31.2 31.2 31.2 167.6, 159.5, 102.0, 19.3. E. coi 62.5 16 125 62.5 62.5 31.2 60 C. albicans 31.2 16 31.2 16 16 16 Example IV Average 35.2 27.6 54.7 31.4 43.1 27.4 value Didecyldimethylammonium Acesulfamate *in ppm. DDAAce benzalkonium chloride. 65 ***didecyldimethylammonium chloride 0.03 mol of didecyldimethylammonium bromide, in form of gel (75%) in water, and water solution of 0.03 mol (6.04 g) US 8,802,596 B2 161 162 of acesulfamate potassium salt were put in (placed) into the nitrate test. A rotary evaporator removed the chloroform and reactor. The mixture was stirred for 1 h at the room tempera a yellowish gel was obtained in 76.99% yield. "H and 'C ture. Afterwards 50 mL of chloroform was added. Water NMR (DMSO) were obtained. Melting point (hot plate appa phase was separated and chloroform phase was washed with ratus)=35-40°C. Thermal data determined by thermalgravi fresh distilled water (so many times) util all chloride ions metric analysis (TGA): T =164° C. and T = 181° C. were washed out (removed). The progress was monitored by orses-6 dasei using water solution of AgNO. After the chloroform was Example VI evaporated, the liquid (fluid) was obtained with 94% yield, and dried at 65° C. in vacuum. Didecyldimethylammonium Sulfacetamide The hydrophobic, sweet liquid, with high viscosity, lighter 10 than water and thermally stable was obtained (Table 2). Cal Didceyldimethylammonium bromide (0.001 mol) was dis culated MIC and MBC values are shown in the Table 3 and solved in 60 mL of distilled water by gentle heating and Table 4. Comparing average values of MIC and MBC for the stirring. Sodium sulfacetamide (0.001 mol) was dissolved in synthesized salt with the values for didecyldimethylammo 60 mL of distilled water by gentle heating and stirring. The nium chloride the only slight difference in the biological 15 two solutions were combined and the reaction mixture was activity is seen (recorded). heated and stirred for 30 minutes. The reaction mixture Elemental analysis: CHN: CHNOS (488.77) calcu cooled to room temperature and then 60 mL of chloroform lated values C=63.89%, H=10.72% iN=5.73%; experimental was added. The reaction mixture was stirred for an additional values C=64.09%, H=10.99%, N=5.41%. "H NMR (DMSO 30 minutes. The two phases were separated and the chloro d) cation: 3.22 (m, 4H), 2.99 (s. 6H), 1.63 (m, 4H), 1.26 (m, form phase was washed several times with cool distilled water 28H), 0.86 (t, J–7 Hz, 6H), anion: 5.26 (q, J=1 Hz, 1H), 1.89 to remove any inorganic salt. The presence of chloride anions (d, J-2 Hz,3H); CNMR cation: 62.7, 49.8, 31.2, 28.8, 28.7, was monitored by silver nitrate test. A rotary evaporator 28.6, 28.4, 25.7, 22.0, 21.6, 13.8, anion: 167.6, 159.4, 102.0, removed the chloroform and a yellowish gel was obtained in 19.3. 87.74% yield. H and 'C NMR (DMSO) were obtained. In the biological activity measurements (tests) following 25 Melting point (hot plate apparatus)=25-30°C. Thermal data bacteria were used: Staphylococcus aureus ATCC 6538, determined by thermalgravimetric analysis (TGA): Tso Enterococcus faecium ATCC 49474, Escherichia coli ATCC 183.3° C. and T=200.2°dasei C. 25922 and fungi Candida albicans ATCC 10231. Microbiological activity tests were performed using disso Example VII lution method. Determinations were performed on liquid 30 base (background): Mueller-Hinton for bacteria and Sab Hexadecylpyridinium Sulfacetamide ouraud for fungi. Starting solution had the concentration of 1 g/cm. From this solution, all other Solutions (lower concen Hexadecylpyridinium chloride (0.001 mol) was dissolved trations) were prepared. To those solutions, 0.1 cm of the in 60 mL of distilled water by gentle heating and stirring. Suspensions of standard microorganisms at a concentration of 35 Sodium sulfacetamide (0.001 mol) was dissolved in 60 mL of 10° cfu cm were added. The samples with bacteria were distilled water by gentle heating and stirring. The two solu incubated for 24hat the temperature of 37°C., and with fungi tions were combined and the reaction mixture was heated and there were incubated for 48 h at the temperature of 22°C. stirred for 30 minutes. The reaction mixture cooled to room After incubation time the MIC, Minimal Inhibitory Concen temperature and then 60 mL of chloroform was added. The tration, minimal concentration of the investigated compound 40 reaction mixture was stirred for an additional 30 minutes. The at which the growth of the microorganisms is stopped (visu two phases were separated and the chloroform phase was ally), was specified (recorded) for every sample. To define the washed several times with cool distilled water to remove any MBC, Minimal Bactericidal Concentration, additionally to inorganic salt. The presence of chloride anions was monitored each solution the 10 cm of the inactivator was added on the by silver nitrate test. A rotary evaporator removed the chlo base (background) (0.3% lecithin, 3% polysorbate 80 and 45 roform and an orange wax was obtained in 99.22% yield. "H 0.1% L-cysteine). The samples with bacteria were incubated and 'C NMR (DMSO) were obtained. Melting point (hot for 48 h in the temperature of 37°C. The fungi samples were plate apparatus)-30-40°C. Thermal data determined by ther incubated for 5 days at the temperature of 22°C. MBC values malgravimetric analysis (TGA): Tso.OS8 211° C. and were defined (specified) as the concentration at which the T=2199dasei C. level of the reduction of the microorganisms was not lower 50 than 99.99%. Example VIII Example V Benzalkonium Ibuprofen

Benzalkonium Sulfacetamide 55 Benzalkonium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. Ibuprofen Benzalkonium chloride (0.001 mol) was dissolved in 60 (0.001 mol) was dissolved in 60 mL of distilled water by mL of distilled water by gentle heating and stirring. Sodium gentle heating and stirring. The two solutions were combined sulfacetamide (0.001 mol) was dissolved in 60 mL of distilled and the reaction mixture was heated and stirred for 30 min water by gentle heating and stirring. The two solutions were 60 utes. The reaction mixture cooled to room temperature and combined and the reaction mixture was heated and stirred for then 60 mL of chloroform was added. The reaction mixture 30 minutes. The reaction mixture cooled to room temperature was stirred for an additional 30 minutes. The two phases were and then 60 mL of chloroform was added. The reaction mix separated and the chloroform phase was washed several times ture was stirred for an additional 30 minutes. The two phases with cool distilled water to remove any inorganic salt. The were separated and the chloroform phase was washed several 65 presence of chloride anions was monitored by silver nitrate times with cool distilled water to remove any inorganic salt. test. A rotary evaporator removed the chloroform and a % The presence of chloride anions was monitored by silver yield. H and 'C NMR (DMSO) were obtained. Melting US 8,802,596 B2 163 164 point (hot plate apparatus)=C. Thermogravimetric analysis: stirring. The two solutions were combined and the reaction T -41.1° C., Tso-133° C. and T -153° C. mixture was heated and stirred for 30 minutes. The reaction mixture cooled to room temperature and then 60 mL of chlo Example IX roform was added. The reaction mixture was stirred for an additional 30 minutes. The two phases were separated and the Didecyldimethylammonium Ibuprofen chloroform phase was washed several times with cool dis tilled water to remove any inorganic salt. The presence of chloride anions was monitored by silver nitrate test. A rotary Didecyldimethylammonium bromide (0.001 mol) was dis evaporator removed the chloroform and a yellowish viscous solved in 60 mL of distilled water by gentle heating and liquid was obtained in 96.93% yield. H and 'C NMR stirring. Ibuprofen (0.001 mol) was dissolved in 60 mL of 10 (DMSO) were obtained. Melting point (hot plate apparatus)= distilled water by gentle heating and stirring. The two solu liquid at room temperature. Thermal data determined by ther tions were combined and the reaction mixture was heated and malgravimetric analysis (TGA): Tso. 248° C. and stirred for 30 minutes. The reaction mixture cooled to room Tdasei =262° C. temperature and then 60 mL of chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The 15 Example XIII two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any Didecyldimethylammonium Colawet MA-80 inorganic salt. The presence of chloride anions was monitored by silver nitrate test. A rotary evaporator removed the chlo Decyldimethylammonium bromide (0.001 mol) was dis roform and a % yield. "H and 'C NMR (DMSO) were solved in 60 mL of distilled water by gentle heating and obtained. Melting point (hot plate apparatus)= C. Thermo stirring. Sodium dihexylsulfosuccinate (Colawet MA-80 gravimetric analysis: T. 57.1° C., Torses-6 =153° C. and from Colonial Chemicals, South Pittsburg, Tenn., 0.001 mol) T =1720 C. was dissolved in 60 mL of distilled water by gentle heating dasei and stirring. The two solutions were combined and the reac Example X 25 tion mixture was heated and stirred for 30 minutes. The reac tion mixture cooled to room temperature and then 60 mL of Didecyldimethylammonium Trans-Cinnamate chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The two phases were separated and Didecyldimethylammonium bromide (0.001 mol) was dis the chloroform phase was washed several times with cool solved in 50 mL of hot distilled water. trans-Cinnamic acid 30 distilled water to remove any inorganic salt. The presence of (0.001 mol) was added to the didecyldimethylammonium chloride anions was monitored by silver nitrate test. A rotary solution. The reaction solution was stirred at 90° C. for 4 h. evaporator removed the chloroform and a yellowish viscous The reaction Solution was cooled to room temperature and liquid was obtained in 96.93% yield. H and 'C NMR then 60 mL of chloroform was added. The two phases were (DMSO) were obtained. Melting point (hot plate apparatus)= separated and the chloroform phase was washed several times 35 liquid at room temperature. Thermal data determined by ther with cool distilled water to remove any inorganic salt. The malgravimetric analysis (TGA): Torses-6 =2.18° C. and presence of chloride anions was monitored by silver nitrate T=226°dasei C. test. A rotary evaporator removed the chloroform and a wax was obtained in 93% yield. Hand 'C NMR (DMSO) were Example XIV obtained. Melting point (hot plate apparatus)=54-55° C. 40 Benzalkonium Colawet MA-80 Example XI Benzalkonium chloride (0.001 mol) was dissolved in 60 Benzalkonium Trans-Cinnamate mL of distilled water by gentle heating and stirring. Sodium 45 dihexylsulfosuccinate (Colawet MA-80 from Colonial Benzalkonium chloride (0.001 mol) was dissolved in warm Chemicals, South Pittsburg, Tenn., 0.001 mol) was dissolved distilled water. trans-Cinnamic acid (0.001 mol) was added to in 60 mL of distilled water by gentle heating and stirring. The the benzalkonium solution. The reaction solution was stirred two solutions were combined and the reaction mixture was at 90° C. for 4 hours. The reaction solution was cooled to heated and stirred for 30 minutes. The reaction mixture room temperature then 60 mL of chloroform was added. The cooled to room temperature and then 60 mL of chloroform two phases were separated and the chloroform phase was was added. The reaction mixture was stirred for an additional washed several times with cool distilled water to remove any 30 minutes. The two phases were separated and the chloro inorganic salt. The presence of chloride anions was monitored form phase was washed several times with cool distilled water by silver nitrate test. A rotary evaporator removed the chlo to remove any inorganic salt. The presence of chloride anions roform and an orange viscous liquid was obtained in 90% 55 was monitored by silver nitrate test. A rotary evaporator yield. H and 'C NMR (DMSO) were obtained. Melting removed the chloroform and a clear viscous liquid was point (hot plate apparatus) liquid at room temperature. obtained in 75.56% yield. H and 'C NMR (DMSO) were obtained. Melting point (hot plate apparatus) liquid at room Example XII temperature. Thermal data determined by thermalgravimetric 60 analysis (TGA): Tso. 223°C. and T-262dasei C. Hexadecylpyridinium Colawet MA-80 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 dihexylsulfosuccinate (Colawet MA-80 from Colo 65 nial Chemicals, South Pittsburg, Tenn., 0.001 mol) was dis Didecyldimethylammonium bromide (0.003 mol) was dis solved in 60 mL of distilled water by gentle heating and solved in 100 mL of distilled water by gentle heating and US 8,802,596 B2 165 166 stirring. Fast Green FCF (0.001 mol) was dissolved in 60 mL temperature, and then 60 mL of chloroform was added. The of distilled water by gentle heating and stirring. The two reaction mixture was stirred for an additional 30 minutes. The Solutions were combined and the reaction mixture was heated two phases were separated and the chloroform phase was and stirred for 30 minutes. The reaction mixture cooled to washed several times with cool distilled water to remove any room temperature and then 60 mL of chloroform was added. inorganic salt. The presence of chloride anions was monitored The reaction mixture was stirred for an additional 30 minutes. by silver nitrate test. A rotary evaporator removed the chlo The two phases were separated and the chloroform phase was roform and a soft orange solid was obtained in 58.66% yield. washed several times with cool distilled water to remove any Melting 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 10 Example XX roform and a dark blue liquid was obtained in 65.54% yield. Melting point (hot plate apparatus) liquid at room tempera Didecyldimethylammonium Piperacillin ture. Thermal data determined by thermalgravimetric analy sis (TGA): Tso-194° C. and Tdasei 200° C. Didceyldimethylammonium bromide (0.001 mol) was dis 15 solved in 60 mL of distilled water by gentle heating and Example XVII stirring. Sodium piperacillin (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. The two Hexadecylpyridinium Fast Green FCF Solutions were combined and the reaction mixture was heated and stirred for 30 minutes. The reaction mixture cooled to Hexadecylpyridinium chloride (0.003 mol) was dissolved room temperature and then 60 mL of chloroform was added. in 100 mL of distilled water by gentle heating and stirring. The reaction mixture was stirred for an additional 30 minutes. Fast Green FCF (0.001 mol) was dissolved in 60 mL of The two phases were separated and the chloroform phase was distilled water by gentle heating and stirring. The two solu washed several times with cool distilled water to remove any tions were combined and the reaction mixture was heated and inorganic salt. The presence of chloride anions was monitored stirred for 30 minutes. The reaction mixture cooled to room 25 by silver nitrate test. A rotary evaporator removed the chlo temperature and then 60 mL of chloroform was added. The roform and a clear gel was obtained in 50.65% yield. "Hand reaction mixture was stirred for an additional 30 minutes. The 'C NMR (DMSO) were obtained. Melting point (hot plate two phases were separated and the chloroform phase was apparatus)=25-30°C. Thermal data determined by thermal washed several times with cool distilled water to remove any gravimetric analysis (TGA): T orses-6 =181° C. and T= inorganic salt. The presence of chloride anions was monitored 30 2050 C. by silver nitrate test. A rotary evaporator removed the chlo roform and a dark blue solid was obtained in 28.14% yield. Example XXI Melting point (hot plate apparatus)=40-50°C. Thermal data determined by thermalgravimetric analysis (TGA): Benzalkonium Piperacillin Tso. 21.6°C. and T-218°C./307 C./504°C. 35 Benzalkonium chloride (0.001 mol) was dissolved in 60 Example XVIII mL of distilled water by gentle heating and stirring. Sodium piperacillin (0.001 mol) was dissolved in 60 mL of distilled Benzalkonium Fast Green FCF water by gentle heating and stirring. The two solutions were 40 combined and the reaction mixture was heated and stirred for Benzalkonium chloride (0.003 mol) was dissolved in 100 30 minutes. The reaction mixture cooled to room temperature mL of distilled water by gentle heating and stirring. Fast and then 60 mL of chloroform was added. The reaction mix Green FCF (0.001 mol) was dissolved in 60 mL of distilled ture was stirred for an additional 30 minutes. The two phases water by gentle heating and stirring. The two solutions were were separated and the chloroform phase was washed several combined and the reaction mixture was heated and stirred for 45 times with cool distilled water to remove any inorganic salt. 30 minutes. The reaction mixture cooled to room temperature The presence of chloride anions was monitored by silver and then 60 mL of chloroform was added. The reaction mix nitrate test. A rotary evaporator removed the chloroform and ture was stirred for an additional 30 minutes. The two phases a cloudy solid was obtained in 26.12% yield. H and 'C were separated and the chloroform phase was washed several NMR (DMSO) were obtained. Melting point (hot plate appa times with cool distilled water to remove any inorganic salt. 50 ratus)-30-40°C. Thermal data determined by thermalgravi The presence of chloride anions was monitored by silver metric analysis (TGA): TsoOS8 165° C. and T=177°C.dasei nitrate test. A rotary evaporator removed the chloroform and a dark bluegel was obtained in 91.52% yield. Melting point Example XXII (hot plate apparatus)=35-45°C. Thermal data determined by thermalgravimetric analysis (TGA): Tso-136° C. and 55 Benzalkonium Penicillin G Tdasei =195o C. Benzalkonium chloride (0.001 mol) was dissolved in 60 Example XIX mL of distilled water by gentle heating and stirring. Potas sium penicillin G (0.001 mol) was dissolved in 60 mL of Hexadecylpyridinium Piperacillin 60 distilled water by gentle heating and stirring. The two solu tions were combined and the reaction mixture was heated and Hexadecylpyridinium chloride (0.001 mol) was dissolved stirred for 30 minutes. The reaction mixture cooled to room in 60 mL of distilled water by gentle heating and stirring. temperature and then 60 mL of chloroform was added. The Sodium piperacillin (0.001 mol) was dissolved in 60 mL of reaction mixture was stirred for an additional 30 minutes. The distilled water by gentle heating and stirring. The two solu 65 two phases were separated and the chloroform phase was tions were combined and the reaction mixture was heated and washed several times with cool distilled water to remove any stirred for 30 minutes. The reaction mixture cooled to room inorganic salt. The presence of chloride anions was monitored US 8,802,596 B2 167 168 by silver nitrate test. A rotary evaporator removed the chlo washed with distilled water until chloride ions were no longer roform and a yellowish soft solid was obtained in 93.60% detected using AgNO. Organic solvent was removed and the yield. H and 'C NMR (DMSO) were obtained. Melting residue was dried in vacuum. Benzalkonium salicylate was point (hot plate apparatus)-30-40°C. obtained with 90% yield as wax at room temperature; it is soluble in hot water. Thermogravimetric analysis: T-43.5° Example XXIII C., Tso-150° C., and T-180° C. "Hand i3C NMR (DMSO) were obtained. Didecyldimethylammonium Penicillin G Example XXVII Didecyldimethylammonium bromide (0.001 mol) was dis- 0 solved in 60 mL of distilled water by gentle heating and (2-hydroxyethyl)dimethylundecyloxymethylammonium stirring. Potassium penicillin G (0.001 mol) was dissolved in Benzoate 60 mL of distilled water by gentle heating and stirring. The two solutions were combined and the reaction mixture was 2-(dimethylamino)ethanol (0.05 mol) was dissolved in heated and stirred for 30 minutes. The reaction mixture 15 anhydrous hexane (20 mL) and a solution of chloromethyl cooled to room temperature and then 60 mL of chloroform undecyl ether (0.05 mol) was added dropwise at room tem was added. The reaction mixture was stirred for an additional perature. The reaction mixture was stirred for 15 minutes. The 30 minutes. The two phases were separated and the chloro obtained precipitate was washed with dry hexane (40 mL). form phase was washed several times with cool distilled water The material was used in the next step, without further puri to remove any inorganic salt. The presence of chloride anions fication. The prepared was dissolved in was monitored by silver nitrate test. A rotary evaporator water and an aqueous solution of (0.07 mol) removed the chloroform and an orange gel was obtained in was added. The solution was stirring for 15 min. After 10 h. 76% yield. "Hand 'C NMR (DMSO) were obtained. Melt the reaction mixture was concentrated using a rotary evapo ing point (hot plate apparatus)=25-30°C. rator. To a dry crude product, anhydrous acetone (30 mL) was 25 added. The solid product was filtered and acetone was Example XXIV removed. The product was dried for 10 hat 50° C. in vacuum to obtain (2-hydroxyethyl)dimethylundecyloxymethylam Hexadecylpyridinium Penicillin G monium benzoate as a grease in 80% yield. Thermogravimet ric analysis: TF127° C. "Hand 'C NMR (DMSO) were Hexadecylpyridinium chloride (0.001 mol) was dissolved 30 obtained. in 60 mL of distilled water by gentle heating and stirring. Potassium penicillin G (0.001 mol) was dissolved in 60 mL of Example XXVIII distilled water by gentle heating and stirring. The two solu tions were combined and the reaction mixture was heated and (2-acetoxyethyl)heptyloxymethyldimethylammonium stirred for 30 minutes. The reaction mixture cooled to room 35 Benzoate temperature and then 60 mL of chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The In a two-necked, round bottomed flask, equipped with a two phases were separated and the chloroform phase was condenser and addition funnel, 2-(dimethylamino)ethyl washed several times with cool distilled water to remove any acetate (0.1 mol) was mixed with 150 mL of anhydrous hex inorganic salt. The presence of chloride anions was monitored 40 ane. Chloromethylhexyl ether (0.1 mol) was slowly added by silver nitrate test. A rotary evaporator removed the chlo over 15 minutes. After 30 minutes, the reaction mixture was roform and an orange gel was obtained in about 99% yield. cooled to the temperature of minus 18° C. and the crude Melting point (hot plate apparatus)=35-40°C. product was separated. The crude product was washed with 100 mL of hexane and used in the next step without further Example XXV 45 purification. The material was dissolved in 100 mL of water and aqueous Solution of sodium benzoate was added in sto Didecyldimethylammonium Salicylate ichiometric amount. After 30 minutes, two phases were sepa rated. The water phase was removed and 100 mL of anhy Didecyldimethylammonium bromide (0.03 mol) (tech., drous acetone was added to the residue. Precipitated NaCl 75% gel in water) was dissolved in 50 mL hot, distilled water. 50 was filtered off and the obtained liquid product, (2-acetoxy Salicylic acid (0.03 mol) was added to the solution. The ethyl)heptyloxymethyldimethylammonium benzoate, was mixture was stirred vigorously at 90° C. for 4 h. After cooling dried for 12 hat 60°C. in vacuum. The product was obtained to room temperature, 60 mL of chloroform was added. Chlo as Viscous liquid in 65% yield. Thermogravimetric analysis: roform phase was washed with distilled water until bromide T-120°dasei C. Hand 'C NMR (DMSO) were obtained. ions were no longer detected using AgNO. The obtained wax 55 (93% yield) was dried in vacuum. Thermogravimetric analy Example XXIX sis: T=-1.0°C., T-30.4° C., T onsetS9% =169° C. and T onset= 200° C. Hand 'C NMR (DMSO) were obtained. (2-acetoxyethyl)dodecyloxymethyldimethylammonium Benzoate Example XXVI 60 In a two-necked, round bottomed flask, equipped with a Benzalkonium Salicylate condenser and addition funnel, the 2-(dimethylamino)ethyl acetate (0.05 mol) was mixed with 30 mL of anhydrous hex Benzalkonium chloride (0.03 mol) was dissolved in warm ane. Chloromethyl dodecyl ether (0.055 mol) was slowly distilled water and stechiometric amount of salicylic acid was 65 added over 5 minutes. After 15 minutes, the reaction mixture added. The reaction mixture was stirred at 90° C. for 4 h. After was cooled to the temperature of minus 18°C. and the crude cooling, chloroform was added. The organic phase was product was separated. The precipitate was washed with 30 US 8,802,596 B2 169 170 mL of hexane and used in the next step without further puri benzeneacetate (100% yield), was obtained as a grease that is fication. The crude (2-acetooxyethyl)-dodecyloxymeth soluble in chloroform, acetone, and DMSO. The product yldimethylammonium chloride was dissolved in 30 mL of lacks miscibility with water and hexane. Thermogravimetric water and aqueous solution of potassium benzoate (0.065 analysis: Tso-162°C., and T-183° C. "H and 'C mol) was added. After 30 min, 30 mL of chloroform was 5 NMR (DMSO) were obtained. added. The chloroform phase was separated and washed with Example XXXIV distilled water until chloride ions were no longer detected using AgNO. The obtained grease was dried under vacuum. Didecyldimethylammonium The product was obtained as grease in 67% yield. Thermo 2-(2,6-dichlorophenyl)amino-benzeneacetate gravimetric analysis: T-122° C. "H and 'C NMR 10 (Alternative Synthesis) (DMSO) were obtained. A solution of didecyldimethylammonium acesulfamate Example XXX (0.01 mol) in acetone was prepared. The aqueous solution of sodium diclofenac (0.02 mol) was added and the reaction Didecyldimethylammonium Salicylate 15 mixture was stirred at 60° C. for 2 h. The solution was extracted with ethyl acetate. Organic phase was separated and Didecyldimethylammonium chloride (0.03 mol) was dis evaporated. The product, didecyldimethylammonium 2-(2, solved in 50 mL distilled water and sodium salicylate (0.04 6-dichlorophenyl)aminobenzeneacetate (88% yield), was mol) was added to solution. The mixture was stirred at 40°C. dried under vacuum. H and 'C NMR (DMSO) were ifor 1 h. After cooling to room temperature, 60 mL of chlo obtained. roform was added. The chloroform phase was separated and washed with distilled water until chloride ions were no longer Example XXXV detected using AgNO. The didecyldimethylammonium sali cylate was obtained in 95% yield. The product is insoluble in Didecyldimethylammonium N-4-(2-amino-1,4- water and was dried under vacuum. 25 dihydro-4-oxo-6-pteridinyl)methylaminobenzoyl L-glutamate Example XXXI Didecyldimethylammonium chloride (0.025 mol) was dis Didecyldimethylammonium Salicylate (Alternative solved in 40 mL distilled water and the folic acid sodium salt Synthesis) 30 (0.01 mol) was added. The solution was stirred at room tem perature for 30 min. After separation of the phases, the The stechiometric amounts of didecyldimethylammonium organic phase was washed with distilled, cold water until saccharinate and Sodium salicylate were mixed in distilled chloride ions were no longer detected using AgNO. The water and stirred at 60° C. for 2 h. After that time the solution organic phase was separated and solvent was evaporated. The was cooled to room temperature. The product was extracted 35 product (90% yield), didecyldimethylammonium N-4-(2- from the aqueous solution with chloroform. The chloroform amino-1,4-dihydro-4-OXO-6-pteridinyl)methylaminoben phase was removed and solvent was evaporated. Synthesized Zoyl-L-glutamate, was dried at 50° C. under vacuum. Prod didecyldimethylammonium salicylate (90% yield) was dried uct is soluble in chloroform, acetone, DMSO. It lacks under vacuum. miscibility with water and hexane.' Hand 'CNMR (DMSO) 40 were obtained. Thermogravimetric analysis: Tso-153° Example XXXII C., and T-201°dasei C. "H and 'C NMR (DMSO) were obtained. Benzalkonium Salicylate Example XXXVI Benzalkonium saccharinate (0.01 mol) and benzoic acid 45 (0.01 mol) were dissolved in 25 mL of hot acetone. The Didecyldimethylammonium mixture was stirred at room temperature for 5 h. Distilled (S)-6-methoxy-O-methyl-2-naphthaleneacetate water was added. The organic phase was separated and washed with distilled water. Organic phase was evaporated The stoichiometric mixture (0.025 mol) of didecyldim and the product, benzalkonium salicylate, was dried under 50 ethylammonium chloride and naproxen Sodium salt were dis vacuum. "Hand 'C NMR (DMSO) were obtained. solved in distilled water and stirred at room temperature for 1 h. The product was extracted by ethyl acetate and organic Example XXXII phase was separated and then washed with distilled water. Ethyl acetate phase was removed and solvent evaporated. The Didecyldimethylammonium 55 product, didecyldimethylammonium (S)-6-methoxy-O-me 2-(2,6-dichlorophenyl)amino-benzeneacetate thyl-2-naphthaleneacetate (95% yield), was dried under vacuum. The product is soluble in chloroform, acetone, and Didecyldimethylammonium chloride (0.03 mol) was dis DMSO. It lacks miscibility with water and hexane. Thermo solved in 40 mL distilled water and diclofenac sodium salt gravimetric analysis: Tso 156°C., and T-190° C. (0.04 mol) was added to the solution. The solution was stirred 60 'Hand 'C NMR (DMSO) were obtained. at room temperature for 30 min. Chloroform (40 mL) was added to the reaction mixture and the mixture was stirred. Example XXXVII After separation of the phases, the organic phase was washed with 40 mL distilled, cold water until chloride ions were no Lidocaine Docusate longer detected using AgNO. Chloroform was removed and 65 the residue was dried at 50° C. in vacuum. The product, Lidocaine hydrochloride (0.0188 mol) was dissolved in 50 didecyldimethylammonium 2-(2,6-dichlorophenyl)amino mL methanol and Sodium docusate bis(2-ethylhexyl)sulfos US 8,802,596 B2 171 172 uccinate sodium salt (0.0188 mol) was dissolved in 50 mL. was stirred at 60° C. for 2 hand then cooled to room tempera The two solutions were combined and stirred for two hours, ture. The aqueous solution was extracted by chloroform. during this time a white precipitate (NaCl) formed. The Chloroform was removed and prepared didecyldimethylam methanol was removed by rotary evaporation which leaves a monium 2-acetoxybenzoate with 90% yield was dried in white sticky solid. To this solid, 150 mL of chloroform was added. A portion of the product dissolved the chloroform WaCUU. while the byproduct (NaCl) remained as a suspended solid. The NaCl was removed by filtration, and the solvent was Example XLIII removed by rotary evaporation. The product, lidocaine docu sate, is a colorless syrup and is dried under high vacuum. "H Didecyldimethylammonium p-toluenesulfonate and 'C NMR (CDC1) were obtained. 10 0.015 mol of didecyldimethylammonium chloride, 0.01 Example XXXVIII mol of p-toluenesulfonic acid, 0.01 mol of NaOH and 100 mL of distilled water were charged to a round bottomed flaskand Didecyldimethylammonium Benzoate 15 heated. The mixture was stirred for 2 hat 40°C., whence the Didecyldimethylammonium chloride (0.02 mol) was dis phases were allowed to separate. The organic layer was then solved in distilled water and 0.015 mol of benzoic acid washed three times with distilled water. The aqueous phases sodium salt was added. The solution was stirred at 80°C. for were tested for the presence of chloride ion using silver nitrate 7h. The reaction mixture was extracted by chloroform. Chlo Solution. Finally, the organic layer was vacuum stripped to roform phase was removed and washed with distilled, cold remove water. The obtained didecyldimethylammonium water until chloride ions were no longer detected using p-toluenesulfonate with 95% yield is soluble in chloroform, AgNO. Then chloroform was removed. Obtained benzoate acetone, DMSO, and insoluble in water and hexane. in 85% yield was dried in vacuum. "H NMR and 'C NMR (CDC1) were obtained. Example XLIV Example XXXIX 25 Didecyldimethylammonium nicotinate Benzalkonium Benzoate To 0.002 mol of didecyldimethylammonium bromide (tech. 75% gel in water) dissolved in 60 mL hot, distilled 10g of benzalkonium chloride (in which alkyl represents a 30 water was added 0.002 mol of nicotinic acid. The mixture was mixture of the alkyls from CH, to CH-7) was soluble in stirred vigorously at 90° C. for 4 h. After cooling to room distilled water and 7.2 g of sodium benzoate was added. The temperature 60 mL of chloroform was added. Chloroform reaction mixture was stirred at 90° C. for 6h. After cooling, 50 phase was washed with distilled water until bromide ions mL of chloroform was added. The organic phase was washed were no longer detected using AgNO. The obtained waxy, with distilled water until chloride ions were detected using white solid was dried in vacuum. AgNO. Chloroform was removed and the residue was dried 35 in vacuum. Benzoate was obtained with 84% yield. Example XLV Example XL MultiComponent Ionic Liquids (2-hydroxyethyl)cyclododecyloxymethyldimethy 40 lammonium Benzoate Multicomponent ionic liquids containing 3 or more differ entions were prepared to show the tenability of the disclosed 0.1 mol of (2-hydroxyethyl)cyclododecyloxymethyldim compositions and methods. Three ionic liquids were prepared ethylammonium chloride was dissolved in 100 mL of anhy 1. benzalkonium, acesulfamate, and saccharinate drous acetone and sodium benzoate was added. After 5 h of 2. benzalkonium, mepenZolate, and docusate stirring, NaCl was filtered and the reaction mixture was con 3. hexadecylpyridinium, acesulfamate, and saccharinate centrated using a rotary evaporator. The obtained was dried The ionic liquids were prepared by dissolving each com for 10 h at 50° C. in vacuum. pound in a common solvent such as water, methanol, or ethanol. The solutions were combined and stirred. The sol Example XLI vent was then evaporated to reveal the ionic liquid and the 50 inorganic salt. The ionic liquid was purified by dissolving it in Didecyldimethylammonium Mandelate a solvent, such as hexane, methanol, or ethanol. The inorganic To 0.03 mol of didecyldimethylammonium chloride dis salt was filtered off. The solvent was evaporated to produce solved in 50 mL distilled water was added 0.03 mol of man the pure ionic liquid. delic acid and 0.03 mol of NaOH. The mixture was stirred at 55 50° C. for 2 h. After cooling to room temperature, 60 mL of Ionic Ratio of chloroform was added. Chloroform phase was washed with Liquid ions Form Melting Point (C.) 9% Yield distilled water until chloride ions were no longer detected 1 2:1:1 Brownish solid 40-45 75.4% using AgNO. The obtained mandelate with 96% yield is 1 3:1:2 White Solid 30-40 82.7% insoluble in water and was dried in vacuum. 60 1 3:2:1 Orange solid 35-45 72.2% 3 2:1:1 Yellow Solid 30-35 95.8% Example XLII 3 3:1:2 Yellow Solid 30-40 76.8% 3 3:2:1 Orange solid 30-35 87.3% 2 2:1:3 Colorless gel Didecyldimethylammonium 2-acetoxybenzoate 2 1:2:3 Clear wax 65 2 1:1:2 Whitish gel A stoichiometric mixture of didecyldimethylammonium chloride, acetylsalicyclic acid, and NaOH in distilled water US 8,802,596 B2 173 174 Example XLVI white solid (presumed to be NaNO) did not. The mixture was filtered and evaporated under reduced pressure to give a soft Lidocaine Complex of Ag+ mass of slightly off-white final product (which should be stored away from light because it is photosensitive). This In a reaction vessel charged with a magnetic stirbar and material was soluble in lidocaine docusate, Some organic shielded from light, 1.0 g (5.9 mmol) AgNO was dissolved in Solvents, and was relatively slow to dissolve in water, doing approximately 25 mL of deionized water. In a separate reac so to only a limited degree. The two ions have known antimi tion vessel, similarly chared with a stirbar and shielded from crobial and emollient properties, respectively. light, 5.51 g (0.024 mol) of lidocaine (free-base form) was dissolved/suspended in 25 mL of deionized water. To the 10 latter solution was added in one portion the aqueous solution Example XLIX of silver nitrate. A copious white precipitate forms quickly, which (all the while protected from light) was quickly iso lated by suction filtration. The recovered solid was dried in Benzalkonium Sulfathiazole vacuum, and Subsequently recrystallized by slow evaporation 15 of a methanol/acetonitrile solution to give well-formed col orless crystals that are moderately light-stable. Example XLVII Ranitidine Docusate In a reaction vessel charged with a magnetic stirbar, 2.50 g (7.12 mmol) of Ranitidine hydrochloride was dissolved in approximately 25 mL of deionized water. In a separate reac 25 tion vessel, similarly charged with a stirbar, 3.17 g (7.12 mmol) of sodium docusate was dissolved/suspended in 25 mL of warm, deionized water. To the latter solution was added NH2 in one portion the aqueous solution of Sodium docusate. The deep orange-brown milieu was stirred overnight, after which 30 n = 5 to 15 time the aqueous system was repeatedly extracted with 100 mL portions of chloroform. Emulsification of the two phases was quite pronounced, so each time the system was heated to Benzalkonium chloride (0.003 mol) was dissolved in 100 about 60°C., then allowed to cool and settle for 5-7 days, after mL of distilled water by gentle stirring and heating. Sulfathia which point the dark chloroform phase was separated, dried 35 Zole sodium (0.003 mol) was dissolved in 60 mL of distilled over anhydrous MgSO, filtered, and rotary evaporated to water by gentle stirring and heating. The two solutions were yield a viscous, deep brown-orange oil (Ranitidine docusate). combined and the reaction mixture was stirred and heated for The two ions have known histamine H2-receptor antagonist 1 h. The reaction mixture was cooled to room temperature and and an emollient properties, respectively. 60 mL of chloroform was added to the reaction mixture. The 40 Example XLVIII two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any Silver Docusate inorganic salt. The presence of chloride ions was monitored by silver nitrate test. A rotary evaporator removed the chlo roformandan orange wax was obtained in a 50.04% yield. "H 45 and 'C NMR (DMSO) were obtained. Melting point (hot plate apparatus)=40-50° C. Thermal data was determined by thermalgravimetric analysis: Tso-156° C. and T 173° C. The benzalkonium ion is a known antibacterial and 50 the other ion is used to treat, for example, gonorrhea and other bacterial infections.

Example L 55 In a reaction vessel charged with a magnetic stirbar and Benzalkonium Docusate protected from light, 5.0 g (29 mmol) of silver nitrate was 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 60 Solution became gradually gelatinous with attendant difficul ties in stirring that were remedied by gently heating the Solu tion. After addition of the final portion of sodium docusate, the warmed solution/suspension was stirred overnight, after which point it was rotary evaporated to yield a slightly tan 65 mass. The mass was extracted with a chloroform-acetonitrile mixture, into which much of the material dissolved but some US 8,802,596 B2 175 176 -continued Valproic acid sodium salt (0.003 mol) was dissolved in 60 mL of distilled water by gentle stirring and heating. The two Solutions were combined and the reaction mixture was stirred at room temperature for 1 h. A rotary evaporator was used to remove the 95% ethanol and produced the ionic liquid and NaCl salt. Tetrahydrofuran (THF) was used to dissolve the ionic liquid while the NaCl salt precipitated. The NaCl salt was filtered from the reaction solution. A rotary evaporator n = 5 to 15 was used to remove the THF and a dark yellow liquid was 10 obtained in a 77.14% yield. Melting point (hot plate appara Benzalkonium chloride (0.003 mol) was dissolved in 100 tus) liquid at room temperature. The two ions are used as an mL of 95% ethanol by gentle stirring and heating. Docusate antibacterial and an anti-convulsant and mood stabilizer in sodium (0.003 mol) was dissolved in 100 mL of 95% ethanol bipolar disorder, respectively. by gentle stirring and heating. The two solutions were com bined and the reaction mixture was stirred at room tempera 15 Example LIII ture for 1 h. A rotary evaporator was used to remove the 95% ethanol and produced the ionic liquid and NaCl salt. Hexane Hexadecylpyridinium Sulfathiazole was used to dissolve the ionic liquid while the NaCl salt precipitated. The NaCl salt was filtered from the reaction Solution. A rotary evaporator was used to remove the hexane and a white solid was obtained in a 78.32% yield. H(DMSO) was obtained. Melting point (hot plate apparatus)=25-30°C. y The two ions have known antibacterial and emollient proper ties, respectively. -- Example LI 25 o Yi o=54–0 Benzalkonium Thimerosal \ / Nt

30

35 Hexadecylpyridinium chloride (0.003 mol) was dissolved in 100 mL of distilled water by gentle stirring and heating. Benzalkonium chloride (0.003 mol) was dissolved in 100 Sulfathiazole sodium (0.003 mol) was dissolved in 60 mL of mL of 95% ethanol by gentle stirring and heating. Thimerosal distilled water by gentle stirring and heating. The two solu sodium (0.003 mol) was dissolved in 100 mL of 95% ethanol 40 tions were combined and the reaction mixture was stirred at by gentle stirring and heating. The two solutions were com room temperature for 1 h. A rotary evaporator was used to bined and the reaction mixture was stirred at room tempera remove the distilled water and produced the ionic liquid and ture for 1 h. A rotary evaporator was used to remove the 95% ethanol and produced the ionic liquid and NaCl salt. Chloro NaCl salt. Benzene was used to dissolve the ionic liquid while form was used to dissolve the ionic liquid while the NaCl salt the NaCl salt precipitated. The NaCl salt was filtered from the precipitated. The NaCl salt was filtered from the reaction 45 reaction solution. A rotary evaporator was used to remove the Solution. A rotary evaporator was used to remove the chloro benzene and a yellow solid was obtained in a 77.22% yield. form and a clear gel was obtained in a 72.92% yield. Melting NMR (DMSO) was obtained. Melting point (hot plate appa point (hot plate apparatus) liquid at room temperature. The ratus)=40-50° C. The hexadecylpyridinium ion is known to benzalkonium ion has known antibacterial properties and the have antibacterial properties and the sulfathiazole is known thimerosal ion is a known preservative in vaccines, oph 50 for the treatment of gonorrhea and other bacterial infections. thalmic and nasal products, and tattoo inks. Example LII Example LIV

Hexadecylpyridinium Valproic Acid 55 Mepenzolate Docusate

(). T 60 n = 14 65 Hexadecylpyridinium chloride (0.003 mol) was dissolved in 100 mL of distilled water by gentle stirring and heating. US 8,802,596 B2 177 178 -continued Example LVI Benzalkonium Mepenzolate Docusate Ratio (2:1:3) Benzalkonium chloride (0.002 mol) was dissolved in 100 mL 95% ethanol by gentle stirring and heating. Mepenzolate bromide (0.001 mol) was dissolved in 100 mL 99% methanol by gentle stirring and heating. Docusate sodium (0.003 mol) was dissolved in 60 mL 95% ethanol by gentle stirring and 10 heating. The three solutions were combined and the reaction Mepenzolate bromide (0.003 mol) was dissolved in 100 mixture was stirred at room temperature for 2 h. A rotary mL 99% methanol by gentle stirring and heating. Docusate evaporator was used to remove the 95% ethanol and the 99% sodium (0.003 mol) was dissolved in 60 mL 99% methanol by methanol. It produced the ionic liquid and NaBrand NaCl gentle stirring and heating. The two solutions were combined salt. Hexane was used to dissolve the ionic liquid while the and the reaction mixture was stirred at room temperature for 15 NaBrand NaCl salt precipitated. The NaBrand NaCl salt was 1 h. A rotary evaporator was used to remove the 99% metha filtered from the reaction solution. A rotary evaporator was nol and produced the ionic liquid and NaBr salt. Hexane was used to remove the hexane and a whitish gel was obtained in used to dissolve the ionic liquid while the NaBr salt precipi a 68.84% yield. Melting point (hot plate apparatus) liquid at tated. The NaBr salt was filtered from the reaction solution. A room temperature. rotary evaporator was used to remove the hexane and a white wax was obtained in a 62.75% yield. Melting point (hot plate Example LVII apparatus)=50–55°C. The two ions are know to have anticho linergic and emollient properties, respectively. Benzalkonium Mepenzolate Docusate Ratio (1:2:3) 25 Benzalkonium chloride (0.001 mol) was dissolved in 100 Example LV mL 95% ethanol by gentle stirring and heating. Mepenzolate bromide (0.002 mol) was dissolved in 100 mL 99% methanol by gentle stirring and heating. Docusate sodium (0.003 mol) Benzalkonium Mepenzolate Docusate Ratio (1:1:2) was dissolved in 60 mL 95% ethanol by gentle stirring and 30 heating. The three solutions were combined and the reaction mixture was stirred at room temperature for 2 h. A rotary evaporator was used to remove the 95% ethanol and the 99% methanol. It produced the ionic liquid and NaBrand NaCl salt. Hexane was used to dissolve the ionic liquid while the NaBrand NaCl salt precipitated. The NaBrand NaCl salt was 35 filtered from the reaction solution. A rotary evaporator was used to remove the hexane and a clear gel was obtained in a 53.68% yield. Melting point (hot plate apparatus)=liquid at room temperature. 40 Example LVIII Benzalkonium Sulfathiazole Saccharinate Ratio (2:1:1)

45 n = 5 to 15 y - N l S 50 M OESEO Benzalkonium chloride (0.0015 mol) was dissolved in 100 mL 95% ethanol by gentle stirring and heating. Mepenzolate NaCH3 bromide (0.003 mol) was dissolved in 100 mL 99% methanol by gentle stirring and heating. Docusate sodium (0.003 mol) 55 was dissolved in 60 mL 95% ethanol by gentle stirring and heating. The three solutions were combined and the reaction NH2 mixture was stirred at room temperature for 2 h. A rotary O evaporator was used to remove the 95% ethanol and the 99% methanol. It produced the ionic liquid and NaBrand NaCl 60 salt. Hexane was used to dissolve the ionic liquid while the N NaBrand NaCl salt precipitated. The NaBrand NaCl salt was M filtered from the reaction solution. A rotary evaporator was O7\ O used to remove the hexane and a clear viscous liquid was n = 5 to 15 obtained in a 44.09% yield. Melting point (hot plate appara 65 tus) liquid at room temperature. The three ions have known antibacterial, anticholinergic, and emollient properties. US 8,802,596 B2 179 180 Benzalkonium chloride (0.003 mol) was dissolved in 100 A rotary evaporator was used to remove the distilled water. It mL of distilled water by gentle stirring and heating. Sulfathia produced the ionic liquid and KCl and NaCl salt. 95% ethanol Zole sodium (0.0015 mol) was dissolved in 50 mL of distilled was used to dissolve the ionic liquid while the KCl and NaCl water by gentle stirring and heating. Acesulfamate potassium salt precipitated. The KCl and NaCl salt was filtered from the (0.0015 mol) was dissolved in 50 mL of distilled water by reaction solution. A rotary evaporator was used to remove the gentle stirring and heating. The three solutions were com 95% ethanol and a white solid was obtained in an 82.70% bined and the reaction mixture was stirred and heated for 1 h. yield. Melting point (hot plate apparatus)-30-40°C. A rotary evaporator was used to remove the distilled water. It produced the ionic liquid and NaCl salt. 99% methanol was Example LXI used to dissolve the ionic liquid while the NaCl salt precipi 10 tated. The NaCl salt was filtered from the reaction solution. A rotary evaporator was used to remove the 99% methanol and Benzalkonium Saccharinate Acesulfamate Ratio an orange gel was obtained in a 97.02% yield. Melting point (3:2:1) (hot plate apparatus) liquid at room temperature. The first two ions have known antibacterial properties and the third ion 15 Benzalkonium chloride (0.003 mol) was dissolved in 100 is a known artificial Sweetener. mL of distilled water by gentle stirring and heating. Saccha rinate sodium (0.002 mol) was dissolved in 50 mL of distilled Example LIX water by gentle stirring and heating. Acesulfamate potassium (0.001 mol) was dissolved in 50 mL of distilled water by Benzalkonium Saccharinate Acesulfamate Ratio gentle stirring and heating. The three solutions were com (2:1:1) bined and the reaction mixture was stirred and heated for 1 h. A rotary evaporator was used to remove the distilled water. It produced the ionic liquid and KCl and NaCl salt. 95% ethanol was used to dissolve the ionic liquid while the KCl and NaCl 25 salt precipitated. The KCl and NaCl salt was filtered from the reaction solution. A rotary evaporator was used to remove the 95% ethanol and a white solid was obtained in a 72.16% yield. Melting point (hot plate apparatus)=35-45° C.

30 Example LXII

Hexadecylpyridinium Saccharinate Acesulfamate Ratio (2:1:1) 35 n = 5 to 15 O |- N Benzalkonium chloride (0.003 mol) was dissolved in 100 40 mL of distilled water by gentle stirring and heating. Saccha \ / le. rinate sodium (0.0015 mol) was dissolved in 50 mL of dis H3C 1so tilled water by gentle stirring and heating. Acesulfamate O potassium (0.0015 mol) was dissolved in 50 mL of distilled water by gentle stirring and heating. The three solutions were 45 combined and the reaction mixture was stirred and heated for N 1 h. A rotary evaporator was used to remove the distilled M water. It produced the ionic liquid and NaCl and KCl salt. 7\ 95% ethanol was used to dissolve the ionic liquid while the O O NaCl and KCl salt precipitated. The NaCl and KCl salt was 50 filtered from the reaction solution. A rotary evaporator was used to remove the 95% ethanol and a brown solid was obtained in a 75.41% yield. Melting point (hot plate appara Hexadecylpyridinium chloride (0.003 mol) was dissolved tus)=40-45° C. The first ion has known antibacterial proper in 100 mL of distilled water by gentle stirring and heating. ties and the next two ions are known artificial Sweeteners. Saccharinate sodium (0.0015 mol) was dissolved in 50 mL of 55 distilled water by gentle stirring and heating. Acesulfamate Example LX potassium (0.0015 mol) was dissolved in 50 mL of distilled water by gentle stirring and heating. The three solutions were Benzalkonium Saccharinate Acesulfamate Ratio combined and the reaction mixture was stirred and heated for (3:1:2) 1 h. A rotary evaporator was used to remove the distilled 60 water. It produced the ionic liquid and KCl and NaCl salt. Benzalkonium chloride (0.003 mol) was dissolved in 100 99% methanol was used to dissolve the ionic liquid while the mL of distilled water by gentle stirring and heating. Saccha KCl and NaCl salt precipitated. The KCl and NaCl salt was rinate sodium (0.001 mol) was dissolved in 50 mL of distilled filtered from the reaction solution. A rotary evaporator was water by gentle stirring and heating. Acesulfamate potassium used to remove the 99% methanol and a yellow solid was (0.002 mol) was dissolved in 50 mL of distilled water by 65 obtained in a 95.78% yield. Melting point (hot plate appara gentle stirring and heating. The three solutions were com tus)-30-35°C. The first ion has known antibacterial proper bined and the reaction mixture was stirred and heated for 1 h. ties and the next two ions are known artificial Sweeteners. US 8,802,596 B2 181 182 Example LXIII stirring. Potassium acesulfamate (0.001 mol) was dissolved in 7 mL of distilled water by gentle heating and stirring. The Hexadecylpyridinium Saccharinate Acesulfamate two solutions were combined and the reaction mixture was Ratio (3:1:2) heated and stirred for 90 minutes. The reaction mixture was 5 cooled to room temperature and then 7 mL of chloroform was Hexadecylpyridinium chloride (0.003 mol) was dissolved added. The reaction mixture was stirred for an additional 20 in 100 mL of distilled water by gentle stirring and heating. minutes. The two phases were separated and the chloroform Saccharinate sodium (0.001 mol) was dissolved in 50 mL of phase was washed several times with cool distilled water to distilled water by gentle stirring and heating. Acesulfamate remove any inorganic salt. The presence of bromide anions potassium (0.002 mol) was dissolved in 50 mL of distilled 10 was monitored by silver nitrate test. Chloroform was removed water by gentle stirring and heating. The three solutions were on a rotary evaporator and remaining product was dried combined and the reaction mixture was stirred and heated for removed at 60° C. under vacuum. Product, as viscous liquid, 1 h. A rotary evaporator was used to remove the distilled was obtained in 92% yield. Hand 'C NMR (DMSO) were water. It produced the ionic liquid and KCl and NaCl salt. obtained. The two ions have known antimicrobial and sweet 99% methanol was used to dissolve the ionic liquid while the 15 ener properties, respectively. KCl and NaCl salt precipitated. The KCl and NaCl salt was filtered from the reaction solution. A rotary evaporator was used to remove the 99% methanol and a yellowish solid was Example LXVI obtained in a 76.76% yield. Melting point (hot plate appara tus)-30-40° C. Didecyldimethylammonium Docusate Example LXIV Didecyldimethylammonium bromide (0.005 mol) was dis Diundecyldimethlammonium Saccharinate solved 100 mL of 95% ethanol by gentle stirring. Docusate sodium was dissolved in 50 mL of 95% ethanol by gentle 25 stirring. The two solutions were combined and the reaction mixture was stirred for 1 hour at room temperature. A rotary O evaporator removed the ethanol to give the ionic liquid and NaBr. The ionic liquid was dissolved in hexane and the NaBr was filtered off. A rotary evaporator removed the hexane to N-4 r. 30 give a white solid obtained in a 78.00% yield. "H and 'C / s/ NMR (DMSO) were obtained. Melting point (hot plate appa 8 / \, ratus)=25-30° C. Diundecyldimethlammonium bromide (0.0023 mol) was 35 Example LXVII dissolved in 7 mL of distilled water by gentle heating and stirring. Sodium saccharinate (0.001 mol) was dissolved in 7 Lidocaine Docusate Rat Tail Flick Test mL of distilled water by gentle heating and stirring. The two Solutions were combined and the reaction mixture was heated and stirred for 90 minutes. The reaction mixture was cooled to 40 The rat tail flick test is used to determine the local anes room temperature and then 7 mL of chloroform was added. thetic ability of lidocaine docusate compared with lidocaine The reaction mixture was stirred for an additional 30 minutes. hydrochloride. The rat is immobilized in a restraining sock, so The two phases were separated and the chloroform phase was that the tail is only exposed. The tail is dipped into hot water washed several times with cool distilled water to remove any and the number of times the rat flicks its tail is recorded. When inorganic salt. The presence of bromide anions was moni 45 the anesthetic is applied, the rats tail should be numb there tored by silver nitrate test. Chloroform was removed on a fore it will not feel the hot water and the number of tail flicks rotary evaporator and remaining product was dried removed should decrease. at 60° C. under vacuum. Product, as viscous liquid, was obtained in 81.00% yield. H and 'C NMR (DMSO) were For this test Swiss-Webster male mice were used. They obtained. The two ions have known antimicrobial and Sweet were habituated in a restraining sock 3 times during a 10 day ener properties, respectively. 50 period. A baseline tail flick was determined for each rat in 47.5°C. water bath. The rats tail was then dipped into a Example LXV solution of dimethylsulfoxide (DMSO) and lidocaine hydro chloride or lidocaine docusate for 60 seconds. The number of Diundecyldimethylammonium Acesulfamate tail flicks was determined at 15, 30, 60, and 120 minutes in the 55 47.5°C. water bath. FIGS. 4A and B are two graphs with the results at concentrations of DMSO lidocaine hydrochloride solution and lidocaine docusate of 1 mM and 100 mM. Using O the following equation, one can determine the '% MPE at each time for the two compounds in question. N/ 8 N 60 / & HC o1so TF—latency to withdraw tail from hot water O BL-baseline withdrawal time without the drug 65 One can see from the graphs that lidocaine docusate has a Diundecyldimethlammonium bromide (0.0023 mol) was higher and longeranesthetic ability than lidocaine hydrochlo dissolved in 7 mL of distilled water by gentle heating and ride in DMSO. This is likely due to the synergistic effects.