USOO9278134B2

(12) United States Patent (10) Patent No.: US 9.278,134 B2 Rogers et al. (45) Date of Patent: Mar. 8, 2016

(54) DUAL FUNCTIONING IONIC LIQUIDS AND 4,891.386 A * 1/1990 Gasparotti ...... 514,555 SALTS THEREOF 4,970,156 A 11/1990 Avrameas et al. 5,221,758 A 6/1993 Maynard 5,246,716 A 9, 1993 Sedun et al. (75) Inventors: Robin D. Rogers, Tuscaloosa, AL (US); 5,679,146 A 10/1997 Kalt et al. Daniel T. Daly, Tuscsaloosa, AL (US); 5,683,832 A 1 1/1997 Bonhote et al. Douglas MacFarlane, Victoria (AU); 5,714,536 A 2/1998 Ziolo et al. Janet L. Scott, Port Sunlight (GB); 37:6 A SE May, 1 Kenneth R. Seddon, Donaghadee (E), 5,827.602 A 10/1998 KochSC et al.ca. Gabriela Gurau, Tuscaloosa, AL (US); 5,856,513 A 1/1999 Ueet al. Katharina Bica, Vienna (AT); Jelena 6,001,342 A 12/1999 Forestier et al. Turanjanin, Victoria (AU); Pamela M. 6,376,712 B2 4/2002 Narizuka et al. Dean, Victoria (AU) 6,451,220 B1 9, 2002 Ziolo et al. s 6,613,310 B1 9/2003 Campbell et al. 6,808,557 B2 10/2004 Holbrey et al. (73) Assignees: The Board of Trustees of the 6,824,599 B2 11/2004 Swatloski et al. University of Alabama, Tuscaloosa, AL 6,967,074 B2 11/2005 Duffy et al. (US); Monash University, Melbourne 2002/0010291 A1 1/2002 Murphy (AU); Queen's University Belfast, 2003/0059604 A1 3/2003 Hattori et al. Belfast (GB) 2003. O157351 A1 8, 2003 Swatloski et al. 2003. O165445 A1 9, 2003 Malnou et al. 2003/0233742 A1 12/2003 J tal. (*) Notice: Subject to any disclaimer, the term of this 2004/OO38031 A1 2/2004 ify al. patent is extended or adjusted under 35 2005, 0123851 A1 6, 2005 Shinbori et al. U.S.C. 154(b) by 156 days. 2005, 0194561 A1 9, 2005 Davis 2005/O196671 A1 9, 2005 Paonessa et al. 2005/0285073 A1 12/2005 Singh et al. (21) Appl. No.: 13/142.559 2006/0090271 A1 5.2006 Price et al. 2006/0090777 A1 5, 2006 Hecht et al. (22) PCT Filed: Dec. 29, 2009 2006/00946.17 A1 5.2006 Price et al. 2006/01 18755 A1 6/2006 Fujioka et al. (86). PCT No.: PCT/US2O09/069652 2006/O128996 A1 6/2006 Vaultier et al. S371 (c)(1), (Continued) (2), (4) Date: Nov. 3, 2011 FOREIGN PATENT DOCUMENTS (87) PCT Pub. No.: WO2010/078300 CA 2479941 10, 2003 PCT Pub. Date: Jul. 8, 2010 CH 153446 6, 1932 (Continued) (65) Prior Publication Data US 2012/0046244A1 Feb. 23, 2012 OTHER PUBLICATIONS International Search Report and Written Opinion for Application No. Related U.S. Application Data PCT/US2011/047619 dated Apr. 9, 2012. (60) Eyal application No. 61/141,168, filed on Dec. WassercheidE.N.E.E. et al., Ionic liquids—new “solutions”"S.S.S. for transition s Weckstrometal. Entrapment of Whole Cell Yeast B-Galactosidase in 51) Int. C Precipated Cellulose Derivatives, Food Process Eng., vol. 2, Applied (51) Int. Cl. Science Publishers Ltd., pp. 148-151 (1979). A6 IK3I/66 (2006.01) Welton, Room-temperature ionic liquids. Solvents for synthesis and A6 IK3I/205 (2006.01) catalysis, Chem. Rev. 99:2071-2083 (1999). (52) ti 7/248 (2006.01) (Continued) CPC ...... A61K 47/4803 (2013.01) (58) Field of Classification Search Primary Examiner — Tigabu Kassa None (74) Attorney, Agent, or Firm — Meunier Carlin & Curfman See application file for complete search history. LLC (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS Disclosed herein are ionic liquid compositions comprising 1943,176 A 1/1934 Graenacher active pharmaceutical, biological, and nutritional com 2,004,891 A 6/1935 Goldberg et al. pounds, and methods of use. Further disclosed are composi 4,063,017 A 12/1977 Tsao et al. 4,097.666 A 6, 1978 Johnson et al. tions of matter including liquid ion pairs alone or in Solution 4,171,352 A 10/1979 Wolgemuth et al. and their use; compositions of ionic liquids that are solvated. 4,188,263. A 2, 1980 Hulsmann et al. for example, hydrated and their uses. 4.421,547 A 12/1983 Prisbylla 4,520,105 A 5, 1985 Sinner et al. 4,522,934 A 6, 1985 Shum et al. 14 Claims, 7 Drawing Sheets US 9.278,134 B2 Page 2

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Fig. 1 U.S. Patent Mar. 8, 2016 Sheet 2 of 7 US 9.278,134 B2

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Fig. 2 U.S. Patent Mar. 8, 2016 Sheet 3 of 7 US 9.278,134 B2

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Fig. 3 U.S. Patent Mar. 8, 2016 Sheet 4 of 7 US 9.278,134 B2

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Fig. 4 U.S. Patent Mar. 8, 2016 Sheet 5 of 7 US 9.278,134 B2

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Fig. 5 U.S. Patent Mar. 8, 2016 Sheet 6 of 7 US 9.278,134 B2

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Fig. 6 U.S. Patent Mar. 8, 2016 Sheet 7 of 7 US 9.278,134 B2

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log inviscosity(Polse'

Fig. 7 US 9,278,134 B2 1. 2 DUAL FUNCTIONING IONIC LIQUIDS AND compound determines its physical properties such as disso SALTS THEREOF lution rate, solubility, bioavailability, crystal habit, mechani cal strength, etc. (Datta et al., Nature Reviews—Drug Discov CROSS REFERENCE TO RELATED ery, 2004, 3:42-57). The delivery of an exact dosage in APPLICATIONS manufacture and the manufacturing process itself often depend on which of several possible polymorphs or pseudo This application is a 371 U.S. National Phase of Interna polymorphs are present. tional Application PCT/US2009/069652, filed Dec. 29, 2009, The variation in properties among different polymorphs (or which claims the benefit of priority to Provisional Applica pseudo-polymorphs) usually means that one crystalline form tion Ser. No. 61/141,168 filed on Dec. 29, 2008, the entire 10 is desired or preferred over other forms. Obtaining a particu disclosure of which is incorporated herein by reference. lar form can be difficult, however. Typically, researchers have to experiment with a multitude of variables in crystallization FIELD conditions, such as aqueous solvent mixtures, amount of water, amount of target compound, relative humidity, tem Disclosed herein are ionic liquid compositions comprising 15 perature of incubation, incubation time, etc., in a process active pharmaceutical, biological, and nutritional com characterized by trial and error. Further, the search for salts of pounds, and methods of use. Further disclosed are composi crystalline forms (usually sought after to control dissolution tions of matter including liquid ion pairs alone or in Solution rate and solubility) can require extensive experimentation. and their use; compositions of ionic liquids that are solvated. Each salt of a drug or each different solvent used to crystallize for example, hydrated and their uses. the drug or a salt of the drug may lead to polymorphs or pseudo-polymorphs that have to be fully investigated and that BACKGROUND have different properties (see e.g., Reutzel-Edens et al., Anhydrates and hydrates of olanzapine: Crystallization, Polymorphism is the ability of a substance to exist in two or Solid-state characterization, and structural relationships.” more crystalline forms that have a different arrangement and/ 25 Crystal Growth & Design, 2003, 3:897-907). or conformation of molecules in a crystalline lattice (see e.g., Another common problem that exists with many pharma Chawla and Bansal, CRIPS 2004, 5(1):9-12: Bernstein, ceuticals, agrochemicals, nutraceuticals etc. is low solubility. “Polymorphism in Molecular Crystals.” IUCR Monographs Low solubility can make formulating a particular compound on Crystallography 14, Oxford Science Publications, 2002, difficult, and generally low solubility translates into low bio pp. 1-28, 240-256). It has been estimated that a large number 30 availability. Much research is conducted on finding ways to of pharmaceuticals exhibit polymorphism. For example, 70% improve a compounds solubility and availability. Typically of barbiturates, 60% of sulfonamides, and 23% of steroids are methods include complex delivery devices and chemical believed to exist in different polymorphic forms or “polymor modifications of the drug. phs” (Haleblian et al., J Pharm Sci 1975, 64:1269-1288). Polymorphism and pseudo-polymorphism is difficult to In some cases, when crystals of a compound are forming 35 predict, i.e., there is a relationship between the crystalline (e.g., crystallizing from a solution), solvent molecules may state of a compound and its chemical properties (e.g., disso become entrapped or bound within the crystal lattice. The lution rate, solubility), biological properties (e.g., bioavail presence of the entrapped solvent molecules may affect the ability, pharmacokinetics), mechanical and physical proper three-dimensional crystal lattice that eventually crystallizes. ties, and manufacturing processes. In some instances The occurrence of a compound (target molecule) crystalliz 40 polymorphs and pseudo-polymorphs can interconvert. More ing in different three-dimensional lattices based upon the over, there is a need for compositions that can manifest their presence of solvent molecules has been termed “pseudo base property, for example, their pharmacological properties, polymorphism.” Akin to polymorphs, such “pseudo-poly while having controllable and/or adjustable chemical, bio morphs,” also known as “solvates” (or “hydrates' when the logical, and physical properties, that the formulator can Solvent is water), are crystalline solids containing either sto 45 “tune' to the desired properties while at the same time avoid ichiometric (i.e., whole number ratios of target molecules to ing any undesirable polymorphism. In addition, there is a Solvent molecules) or non-stoichiometric (i.e., non-whole need for compounds having these properties which have number ratios of target molecules to solvent molecules) modifiable dissolution and solubility properties. As such, amounts of a solvent incorporated within the crystal structure. there is further needed methods of preparing and using com In general, different crystalline forms of molecules (e.g., 50 positions having these controllable properties. Further, there pharmaceutical compounds) can exist in the same or different is a need for methods of converting compounds that are dif hydrated or solvated states. ficult to solubilize into a form that allows for increased solu The existence of various polymorphs or pseudo-polymor bility. Disclosed herein are compositions and methods that phs can greatly affect a pharmaceutical's performance since provide for the above compounds, compositions, and meth each form can have different physical and chemical proper 55 ods. ties. For example, one particular polymorph pseudo-poly morph may be more bioavailable, more stable (e.g., longer SUMMARY shelflife), or more easily formulated or tableted than another polymorph. Similarly, one polymorph pseudo-polymorph In accordance with the purposes of the disclosed materials, may be more active or less toxic than another. Some specific 60 compounds, compositions, devices, and methods, as embod examples of the dramatic difference that can exist between ied and broadly described herein, the disclosed subject mat various pharmaceutical polymorphs are described in, e.g., ter, in one aspect, relates to compounds and compositions and Brittain et al., J Pharm Sci 2002, 91: 1573-1580 and Moris methods for preparing and using such compounds and com sette et al., Proc Natl AcadSci USA 2003, 100:2180-2184. positions. In a further aspect, the disclosed subject matter The effects of polymorphism and pseudo-polymorphism 65 relates to ionic liquid compositions that can be used for or in on quality and performance of a drug is widely recognized. biological, pharmaceutical, nutritional, cosmetic, industrial, The exact solid state polymorph (or pseudo-polymorph) of a and commercial compositions. Methods for making the dis US 9,278,134 B2 3 4 closed ionic liquid compositions are also disclosed. Also FIG. 4 depicts the depression of glass transition and satu disclosed are methods of preparing ionic liquid compositions ration of double functional co-ionic liquids based on of active pharmaceutical, biological, nutritional, and ener lidocainium salicylate. getic ingredients. Also the disclosed are methods of using the FIG. 5 depicts the decomposition of the prodrug ionic compositions described herein to overcome polymorphism, liquids 1-2-(4-acetamidophenoxy)-2-oxoethyl-3-methyl overcome solubility and delivery problems, to control release 1H-imidazol-3-ium chloride (O) and 2-(4-acetamidophe rates, add functionality, enhance efficacy, and improve ease of noxy)-2-oxoethyltributylphosphonium chloride () versus use and manufacture. Also disclosed is the use of multiple time in phosphate buffer pH 7.4 at 37° C. functional co-ionic liquids with excess of any free base or any FIG. 6 depicts the decomposition of (E)-4-(3,7-dimethy 10 locta-2,6-dienyloxy)-4-OXobutanoic acid versus on tempera free acid in equilibrium with cation or anion that are com ture. The first decomposition step represents the release of the posed of active pharmaceutical, biological, nutritional, or Volatile fragrance geraniol. energetic ingredients. The present disclosure is based upon FIG. 7 depicts the Walden plot for various propantheline the discovery that the physico-chemical properties of com p-toluenesulfonates. mon pharmaceutical salts can be modified by addition of the 15 corresponding protic acid or base to form new ionic liquid DETAILED DESCRIPTION species of the type B"HBA or BIA'HA. Also disclosed is a process for preparation via solvent-free The materials, compounds, compositions, articles, and methods, e.g. grinding or reaction in molten state. The pro methods described herein may be understood more readily by cess can include addition of a acid or base to a common reference to the following detailed description of specific pharmaceutical active salt or by direct solvent-free reaction of aspects of the disclosed subject matter and the Examples acid with base in a ratio other than 1:1 to form co-ionic liquids included therein. of the type B"HBA or BAHA). Before the present materials, compounds, compositions, Additional advantages will be set forth in part in the articles, devices, and methods are disclosed and described, it description that follows, and in part will be obvious from the 25 is to be understood that the aspects described below are not description, or may be learned by practice of the aspects limited to specific synthetic methods or specific reagents, as described below. The advantages described below will be Such may, of course, vary. It is also to be understood that the realized and attained by means of the elements and combina terminology used herein is for the purpose of describing tions particularly pointed out in the appended claims. It is to particular aspects only and is not intended to be limiting. be understood that both the foregoing general description and 30 Also, throughout this specification, various publications are referenced. The disclosures of these publications in their the following detailed description are exemplary and entireties are hereby incorporated by reference into this appli explanatory only and are not restrictive. cation in order to more fully describe the state of the art to Further disclosed is the use of ionic liquids for immobili which the disclosed matter pertains. The references disclosed Zation, delivery, and controlled release of pharmaceutically 35 are also individually and specifically incorporated by refer active neutral compounds. This use is based upon the discov ence herein for the material contained in them that is dis ery that neutral active compounds, especially pharmaceuti cussed in the sentence in which the reference is relied upon. cals, can be covalently linked with ionic structural moiety and In this specification and in the claims that follow, reference turned into an ionic liquid by appropriate choice of the will be made to a number of terms, which shall be defined to counter ion. The ionic liquid acts not only as Support for the 40 have the following meanings: active compounds, being able to store pharmaceuticals in Throughout the description and claims of this specification inactive form but also allow a simple tuning of physical the word “comprise' and other forms of the word, such as properties like solubility, bioavailability, lipophilicity or con “comprising and "comprises.” means including but not lim trol over polymorphism as well as the control over release ited to, and is not intended to exclude, for example, other kinetics of the active compound. 45 additives, components, integers, or steps. Yet further discloses is a synthetic methodology to transfer As used in the description and the appended claims, the neutral compounds into salts, wherein the active compound singular forms “a” “an.” and “the include plural referents can be of either positive or negative charge, with the possi unless the context clearly dictates otherwise. Thus, for bility to form dual functioning salts by introduction of a example, reference to “a composition' includes mixtures of second, pharmaceutically or biologically active counterion. 50 two or more such compositions, reference to “an ionic liquid Further described herein is a method for the immobiliza includes mixtures of two or more such ionic liquids, reference tion of volatile fragrance and flavor compounds in the form of to “the compound” includes mixtures of two or more such ionic liquids of neglible volatility for storage as well for compounds, and the like. controlled and prolonged release of the fragrance- or flavor “Optional' or “optionally’ means that the subsequently compounds under defined conditions such as temperature, or 55 described event or circumstance can or cannot occur, and that pH value. the description includes instances where the event or circum stance occurs and instances where it does not. BRIEF DESCRIPTION OF THE FIGURES Ranges can be expressed herein as from “about one par ticular value, and/or to “about another particular value. FIG. 1 depicts the binary phase diagram for choline DPP as 60 When Such a range is expressed, another aspect includes from example for ionic liquid diluates. the one particular value and/or to the other particular value. FIG. 2 depicts the depression and elimination of the melt Similarly, when values are expressed as approximations, by ing point of P(Bu)Sal H, in a series of co-ionic liquids use of the antecedent “about it will be understood that the comprising oligomeric anions. particular value forms another aspect. It will be further under FIG. 3 depicts the conductivity and viscosity of various 65 stood that the endpoints of each of the ranges are significant P(Bu)Sal H. compositions in a series of co-ionic liquids both in relation to the other endpoint, and independently of comprising oligomeric anions. the other endpoint. It is also understood that there are a US 9,278,134 B2 5 6 number of values disclosed herein, and that each value is also imply any particular order, amount, preference, or impor herein disclosed as “about that particular value in addition to tance to the components or steps modified by these terms. the value itself. For example, if the value “10 is disclosed, References in the specification and concluding claims to then “about 10' is also disclosed. It is also understood that parts by weight of a particular element or component in a when a value is disclosed, then “less than or equal to the composition denotes the weight relationship between the ele value, “greater than or equal to the value.” and possible ranges ment or component and any other elements or components in between values are also disclosed, as appropriately under the composition or article for which a part by weight is stood by the skilled artisan. For example, if the value “10 is expressed. Thus, in a compound containing 2 parts by weight disclosed, then “less than or equal to 10” as well as “greater of component X and 5 parts by weight component Y. X and Y than or equal to 10” is also disclosed. It is also understood that 10 are present at a weight ratio of 2:5, and are present in Such throughout the application data are provided in a number of ratio regardless of whether additional components are con different formats and that this data represent endpoints and tained in the compound. starting points and ranges for any combination of the data A weight percent (wt.%) of a component, unless specifi points. For example, if a particular data point “10 and a 15 cally stated to the contrary, is based on the total weight of the particular data point “15” are disclosed, it is understood that formulation or composition in which the component is greater than, greater than or equal to, less than, less than or included. equal to, and equal to 10 and 15 are considered disclosed as The term “ion, as used herein, refers to any molecule, well as between 10 and 15. It is also understood that each unit portion of a molecule, cluster of molecules, molecular com between two particular units are also disclosed. For example, plex, moiety, or atom that contains a charge (positive, nega if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also tive, or both (e.g., Zwitterions) or that can be made to contain disclosed. a charge. Methods for producing a charge in a molecule, As used herein, by a “subject' is meant an individual. Thus, portion of a molecule, cluster of molecules, molecular com the “subject' can include domesticated animals (e.g., cats, plex, moiety, or atom are disclosed herein and can be accom dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, 25 plished by methods known in the art, e.g., protonation, depro etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, tonation, oxidation, reduction, alkylation, etc. etc.), and birds. "Subject' can also include a mammal. Such as The term “anion' is a type of ion and is included within the a primate or a human. meaning of the term “ion'. An "anion' is any molecule, By “reduce' or otherforms of the word, such as “reducing portion of a molecule (e.g., Zwitterion), cluster of molecules, or “reduction is meant lowering of an event or characteristic 30 (e.g., microorganism growth or Survival). It is understood that molecular complex, moiety, or atom that contains a net nega this is typically in relation to some standard or expected value, tive charge or that can be made to contain a net negative in other words it is relative, but that it is not always necessary charge. The term "anion precursor is used herein to specifi for the standard or relative value to be referred to. For cally refer to a molecule that can be converted to an anion via example, “reduces bacteria growth' means lowering the 35 a chemical reaction (e.g., deprotonation). amount of bacteria relative to a standard or a control. The term “cation is a type of ion and is included within the By "prevent' or other forms of the word, such as “prevent meaning of the term “ion'. A "cation' is any molecule, por ing’ or “prevention, is meant to stop a particular event or tion of a molecule (e.g., Zwitterion), cluster of molecules, characteristic, to stabilize or delay the development or pro molecular complex, moiety, or atom, that contains a net posi gression of a particular event or characteristic, or to minimize 40 tive charge or that can be made to contain a net positive the chances that a particular event or characteristic will occur. charge. The term “cation precursor is used herein to specifi Prevent does not require comparison to a control as it is cally refer to a molecule that can be converted to a cation via typically more absolute than, for example, reduce. As used a chemical reaction (e.g., protonation or alkylation). herein, something could be reduced but not prevented, but As used herein, the term “substituted” is contemplated to Something that is reduced could also be prevented. Likewise, 45 include all permissible Substituents of organic compounds. In Something could be prevented but not reduced, but something a broad aspect, the permissible Substituents include acyclic that is prevented could also be reduced. It is understood that and cyclic, branched and unbranched, carbocyclic and het where reduce or prevent are used, unless specifically indi erocyclic, and aromatic and nonaromatic Substituents of cated otherwise, the use of the other word is also expressly organic compounds. Illustrative Substituents include, for disclosed. 50 example, those described below. The permissible substituents By “treat' or other forms of the word, such as “treated' or can be one or more and the same or different for appropriate “treatment, is meant to administer a composition or to per organic compounds. For purposes of this disclosure, the het form a method in order to reduce, prevent, inhibit, break eroatoms, such as nitrogen, can have hydrogen Substituents down, or eliminate a particular characteristic or event (e.g., and/or any permissible Substituents of organic compounds microorganism growth or survival). The term “control is 55 described herein which satisfy the valencies of the heteroat used synonymously with the term “treat.” oms. This disclosure is not intended to be limited in any By “antimicrobial is meant the ability to treat or control manner by the permissible Substituents of organic com (e.g., reduce, prevent, inhibit, break-down, or eliminate) pounds. Also, the terms “substitution” or “substituted with microorganism growth or Survival at any concentration. Simi include the implicit proviso that Such substitution is in accor larly, the terms “antibacterial.” “antiviral.” and “antifungal' 60 dance with permitted valence of the substituted atom and the respectively mean the ability to treat or control (e.g., reduce, substituent, and that the substitution results in a stable com prevent, inhibit, break-down, or eliminate) bacterial, viral, pound, e.g., a compound that does not spontaneously undergo and fungal growth or Survival at any concentration. transformation Such as by rearrangement, cyclization, elimi It is understood that throughout this specification the identi nation, etc. fiers “first and “second are used solely to aid in distinguish 65 “D’.” “D’.” “D,” and “D' are used herein as generic ing the various components and steps of the disclosed subject symbols to represent various specific Substituents. These matter. The identifiers “first and 'second are not intended to symbols can be any Substituent, not limited to those disclosed US 9,278,134 B2 7 8 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 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 benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, unbranched saturated hydrocarbon group of 1 to 24 carbon and the like. The term “aryl also includes "heteroaryl.” atoms, such as methyl, ethyl, n-propyl, isopropyl. n-butyl, which is defined as a group that contains an aromatic group isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl. 10 dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the that has at least one heteroatom incorporated within the ring like. The alkyl group can also be substituted or unsubstituted. of the aromatic group. Examples of heteroatoms include, but The alkyl group can be substituted with one or more groups are not limited to, nitrogen, oxygen, Sulfur, and phosphorus. including, but not limited to, alkyl, halogenated alkyl, alkoxy, Likewise, the term “non-heteroaryl, which is also included alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxy 15 in the term “aryl. defines a group that contains an aromatic lic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, group that does not contain a heteroatom. The aryl group can sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described be substituted or unsubstituted. The aryl group can be substi below. tuted with one or more groups including, but not limited to, Throughout the specification “alkyl is generally used to alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, het refer to both unsubstituted alkyl groups and substituted alkyl eroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, groups; however, Substituted alkyl groups are also specifi hydroxy, ketone, nitro, silyl, Sulfo-oxo, Sulfonyl, Sulfone, cally referred to herein by identifying the specific sulfoxide, or thiol as described herein. The term “biary1' is a Substituent(s) on the alkyl group. For example, the term specific type of aryl group and is included in the definition of "halogenated alkyl specifically refers to an alkyl group that aryl. Biaryl refers to two aryl groups that are bound together is Substituted with one or more halide, e.g., fluorine, chlorine, 25 via a fused ring structure, as in naphthalene, or are attached bromine, or iodine. The term “alkoxyalkyl specifically refers via one or more carbon-carbon bonds, as in biphenyl. to an alkyl group that is substituted with one or more alkoxy The term “cycloalkyl as used herein is a non-aromatic groups, as described below. The term “alkylamino” specifi carbon-based ring composed of at least three carbon atoms. cally refers to an alkyl group that is substituted with one or Examples of cycloalkyl groups include, but are not limited to, more amino groups, as described below, and the like. When 30 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The “alkyl is used in one instance and a specific term Such as term "heterocycloalkyl is a cycloalkyl group as defined “alkylalcohol is used in another, it is not meant to imply that above where at least one of the carbon atoms of the ring is the term “alkyl does not also refer to specific terms such as substituted with a heteroatom such as, but not limited to, “alkylalcohol and the like. nitrogen, oxygen, Sulfur, or phosphorus. The cycloalkyl This practice is also used for other groups described herein. 35 That is, while a term such as “cycloalkyl refers to both group and heterocycloalkyl group can be substituted or unsubstituted and substituted cycloalkyl moieties, the substi unsubstituted. The cycloalkyl group and heterocycloalkyl tuted moieties can, in addition, be specifically identified group can be substituted with one or more groups including, herein; for example, a particular Substituted cycloalkyl can be but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, het referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substi 40 eroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, tuted alkoxy can be specifically referred to as, e.g., a "halo hydroxy, ketone, nitro, silyl, Sulfo-oxo, Sulfonyl, Sulfone, genated alkoxy, a particular Substituted alkenyl can be, e.g., sulfoxide, or thiol as described herein. an “alkenylalcohol and the like. Again, the practice of using The term “cycloalkenyl as used herein is a non-aromatic a general term, such as “cycloalkyl and a specific term, Such carbon-based ring composed of at least three carbon atoms as “alkylcycloalkyl is not meant to imply that the general 45 and containing at least one double bound, i.e., C=C. term does not also include the specific term. Examples of cycloalkenyl groups include, but are not limited The term “alkoxy” as used herein is an alkyl group bound to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopenta through a single, terminal ether linkage; that is, an “alkoxy” dienyl, cyclohexenyl, cyclohexadienyl, and the like. The term group can be defined as —OD' where D'' is alkyl as defined "heterocycloalkenyl is a type of cycloalkenyl group as above. 50 defined above, and is included within the meaning of the term The term “alkenyl' as used herein is a hydrocarbon group “cycloalkenyl, where at least one of the carbon atoms of the of from 2 to 24 carbon atoms with a structural formula con ring is substituted with a heteroatom such as, but not limited taining at least one carbon-carbon double bond. Asymmetric to, nitrogen, oxygen, Sulfur, or phosphorus. The cycloalkenyl structures such as (DD)C=C(DD) are intended to group and heterocycloalkenyl group can be substituted or include both the E and Z isomers. This may be presumed in 55 unsubstituted. The cycloalkenyl group and heterocycloalk structural formulae herein wherein an asymmetric alkene is enyl group can be substituted with one or more groups includ present, or it may be explicitly indicated by the bond symbol ing, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, C=C. The alkenyl group can be substituted with one or more heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, groups including, but not limited to, alkyl, halogenated alkyl, halide, hydroxy, ketone, nitro, silyl, Sulfo-oxo, Sulfonyl, Sul alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, 60 fone, sulfoxide, or thiol as described herein. carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, The term “cyclic group' is used hereinto refer to eitheraryl silyl, Sulfo-oxo, Sulfonyl, Sulfone, Sulfoxide, or thiol, as groups, non-aryl groups (i.e., cycloalkyl, heterocycloalkyl, described below. cycloalkenyl, and heterocycloalkenyl groups), or both. The term “alkynyl' as used herein is a hydrocarbon group Cyclic groups have one or more ring systems that can be of 2 to 24 carbon atoms with a structural formula containing 65 Substituted or unsubstituted. A cyclic group can contain one at least one carbon-carbon triple bond. The alkynyl group can or more aryl groups, one or more non-aryl groups, or one or be substituted with one or more groups including, but not more aryl groups and one or more non-aryl groups. US 9,278,134 B2 9 10 The term "aldehyde' as used herein is represented by the alkyl group, one of the hydrogenatoms of the alkyl group can formula—C(O)H. Throughout this specification “C(O) is a optionally be substituted with a hydroxyl group, an alkoxy short hand notation for C=O. group, an amine group, an alkyl group, a halide, and the like. The terms “amine' or "amino” as used herein are repre Depending upon the groups that are selected, a first group can sented by the formula NDDD, where D, D, and D can be incorporated within second group or, alternatively, the first be, independently, hydrogen, an alkyl, halogenated alkyl, group can be pendant (i.e., attached) to the second group. For alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, example, with the phrase “an alkyl group comprising an heterocycloalkyl, or heterocycloalkenyl group described amino group, the amino group can be incorporated within above. the backbone of the alkyl group. Alternatively, the amino The term “carboxylic acid as used herein is represented by 10 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. 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)ID' or - C(O)OD', where D' can be an alkyl, biological, physiological, or therapeutic effect in a biological halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, 15 system. For example, the bioactive property can be the control cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy of infection or inflammation, enhancement or Suppression of cloalkenyl group described above. growth, action as an analgesic, anti-viral, pesticidal, herbi The term “ether as used herein is represented by the for cidal, or nutrientional action, etc. Many examples of bioactive mula D'OD, where D'' and D can be, independently, an properties are disclosed herein. alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, Unless stated to the contrary, a formula with chemical cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy bonds shown only as Solid lines and not as wedges or dashed cloalkenyl group described above. lines contemplates each possible isomer, e.g., each enanti The term “ketone' as used herein is represented by the omer, diastereomer, and meso compound, and a mixture of formula D'C(O)ID, where D'' and D' can be, independently, isomers, such as a racemic or scalemic mixture. an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, 25 Reference will now be made in detail to specific aspects of cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy the disclosed materials, compounds, compositions, articles, cloalkenyl group described above. and methods, examples of which are illustrated in the accom The term “halide' as used herein refers to the halogens panying Examples. fluorine, chlorine, bromine, and iodine. Materials and Compositions The term “hydroxyl as used herein is represented by the 30 Certain materials, compounds, compositions, and compo formula—OH. nents disclosed herein can be obtained commercially or The term "nitro” as used herein is represented by the for readily synthesized using techniques generally known to mula - NO. those of skill in the art. For example, the starting materials and The term “silyl as used herein is represented by the for reagents used in preparing the disclosed compounds and mula - SiD' DD, where D, D, and D can be, indepen 35 compositions are either available from commercial Suppliers dently, hydrogen, alkyl, halogenated alkyl, alkoxy, alkenyl, such as Aldrich Chemical Co., (Milwaukee, Wis.). Acros alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocy Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, cloalkyl, or heterocycloalkenyl group described above. Pa.), Sigma (St. Louis, Mo.), or are prepared by methods The term “sulfo-oxo' as used herein is represented by the known to those skilled in the art following procedures set formulas-S(O)D', -S(O),D', OS(O),D', or - OS(O), 40 forth in references such as Fieser and Fieser’s Reagents for OD', where D' can be hydrogen, an alkyl, halogenated alkyl, Organic Synthesis, Volumes 1-17 (John Wiley and Sons, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 1991); Rodd's Chemistry of Carbon Compounds, Volumes heterocycloalkyl, or heterocycloalkenyl group described 1-5 and Supplementals (Elsevier Science Publishers, 1989); above. Throughout this specification “S(O) is a short hand Organic Reactions, Volumes 1-40 (John Wiley and Sons, notation for S=O. 45 1991); March's Advanced Organic Chemistry, (John Wiley The term “sulfonyl is used herein to refer to the sulfo-oxo and Sons, 4th Edition); and Larock’s Comprehensive Organic group represented by the formula—S(O),D', where D' can Transformations (VCH Publishers Inc., 1989). Other materi be hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, als, such as the active pharmaceutical ingredients, pesticides, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, herbicides, and other biological agents disclosed herein can or heterocycloalkenyl group described above. 50 be obtained from commercial sources. The term "sulfonylamino” or “sulfonamide' as used herein In one aspect, disclosed herein are ionic liquid composi is represented by the formula—S(O)NH-. tions. The term "ionic liquid” has many definitions in the art, The term “sulfone' as used herein is represented by the but is used herein to refer to Salts (i.e., compositions compris formula D'S(O).D., where D'' and D can be, independently, ing cations and anions) that are liquidata temperature of at or an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, 55 below about 150° C. That is, at one or more temperature cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy ranges or points at or below about 150° C. the disclosed ionic cloalkenyl group described above. liquid compositions are liquid; although, it is understood that The term “sulfoxide’ as used herein is represented by the they can be solids at other temperature ranges or points. Since formula D'S(O)D, where D'' and D can be, independently, the disclosed ionic liquid compositions are liquid, and thus an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, 60 not crystalline Solids, at a given temperature, the disclosed cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy compositions do not suffer from the problems of polymor cloalkenyl group described above. phism associated with crystalline solids. The term “thiol as used herein is represented by the for The use of the term “liquid to describe the disclosed ionic mula—SH. liquid compositions is meant to describe a generally amor “R” “R” “R” “R”,” etc., where n is some integer, as 65 phous, non-crystalline, or semi-crystalline State. For used herein can, independently, possess one or more of the example, while Some structured association and packing of groups listed above. For example, if R is a straight chain cations and anions can occurat the atomic level, the disclosed US 9,278,134 B2 11 12 ionic liquid compositions have minor amounts of Such kinds of anions). Likewise, it is contemplated that the dis ordered structures and are therefore not crystalline solids. The closed ionic liquid compositions can comprise one kind of compositions disclosed herein can be fluid and free-flowing anion with more than one kind of cation (e.g., 2, 3, 4, 5, 6, 7, liquids or amorphous Solids such as glasses or waxes at a 8, 9, 10, or more different kinds of cations). Further, the temperature at or below about 150°C. In particular examples disclosed ionic liquids can comprise more than one kind of disclosed herein, the disclosed ionic liquid compositions are anion (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different kinds of liquid at the body temperature of a subject. anions) with more than one kind of cation (e.g., 2, 3, 4, 5, 6, Further, the disclosed ionic liquid compositions are mate 7, 8, 9, 10 or more different kinds of cations). Specific rials composed of at least two different ions; each of which examples include, but are not limited to, one kind of cation can independently and simultaneously introduce a specific 10 with 1,2,3,4,5,6,7,8,9, 10, or more kinds of anions, 2 kinds characteristic to the composition not easily obtainable with of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of traditional dissolution and formulation techniques. Thus, by anions, 3 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or providing different ions and ion combinations, one can more kinds of anions, 4 kinds of cations with 1, 2, 3, 4, 5, 6, change the characteristics or properties of the disclosed ionic 7, 8, 9, 10, or more kinds of anions, 5 kinds of cations with 1, liquid compositions in a way not seen by simply preparing 15 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of anions, 6 kinds of various crystalline salt forms. Examples of characteristics cations with 1,2,3,4,5,6,7,8,9, 10, or more kinds of anions, that can be controlled in the disclosed compositions include, 7 kinds of cations with 1,2,3,4,5,6,7,8,9, 10, or more kinds but are not limited to, melting, solubility control, and rate of ofanions, 8 kinds of cations with 1, 2,3,4,5,6,7,8,9, 10, or dissolution. It is this multi-nature/functionality of the dis more kinds of anions, 9 kinds of cations with 1, 2, 3, 4, 5, 6, closed ionic liquid compositions which allows one to fine 7, 8, 9, 10, or more kinds of anions, 10 kinds of cations with tune or design in very specific desired material properties. 1,2,3,4,5,6,7,8,9, 10, or more kinds of anions, or more than It is further understood that the disclosed ionic liquid com 10 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more positions can include solvent molecules (e.g., water); how kinds of anions. ever, these solvent molecules should not be present in excess Other specific examples include, but are not limited to, one in the sense that the disclosed ionic liquid compositions are 25 kind of anion with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of dissolved in the Solvent, forming a solution. That is, the cations, 2 kinds of anions with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or disclosed ionic liquid compositions contain no or minimal more kinds of cations, 3 kinds of anions with 1, 2, 3, 4, 5, 6, amounts of solvent molecules that are free and not bound or 7, 8, 9, 10, or more kinds of cations, 4 kinds of anions with 1, associated with the ions present in the ionic liquid composi 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of cations, 5 kinds of tion. Thus, the disclosed ionic liquid compositions can be 30 anions with 1,2,3,4,5,6,7,8,9, 10, or more kinds of cations, liquid hydrates or Solvates, but not solutions. 6 kinds of anions with 1, 2,3,4,5,6,7,8,9, 10, or more kinds Ionic liquids have been of general interest because they are of cations, 7 kinds of anions with 1, 2,3,4,5,6,7,8,9, 10, or environmentally-friendly alternatives to organic solvents for more kinds of cations, 8 kinds of anions with 1, 2, 3, 4, 5, 6, various chemical processes, e.g., liquid/liquid extractions, 7, 8, 9, 10, or more kinds of cations, 9 kinds of anions with 1, catalysis, separations, and electrochemistry. Ionic liquids 35 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of cations, 10 kinds of have also become popular alternative media for chemical anions with 1,2,3,4,5,6,7,8,9, 10, or more kinds of cations, synthesis because of their low volatility and low toxicity. See or more than 10 kinds of anions with 1,2,3,4,5,6,7,8,9, 10, e.g., Wasserscheid and Keim, Angew Chem Int Ed Engl, 2000, or more kinds of cations. 39:3772; and Wasserscheid, “Ionic Liquids in Synthesis,” 1 In addition to the cations and anions, the ionic liquid com Ed., Wiley-VCH, 2002. Further, ionic liquids can reduce 40 positions disclosed herein can also contain nonionic species, costs, disposal requirements, and hazards associated with Such as solvents, preservatives, dyes, colorants, thickeners, Volatile organic compounds. Other exemplary properties of Surfactants, viscosity modifiers, mixtures and combinations ionic liquids are high ionic conductivity, non-volatility, non thereof and the like. However, the amount of such nonionic flammability, high thermal stability, wide temperature for species is typically low (e.g., less than about 10,9,8,7,6, 5, liquid phase, highly Solvability, and non-coordinating. For a 45 4, 3, 2, or 1 wt.% based on the total weight of the composi review of ionic liquids see, for example, Welton, Chem. Rev. tion). In some examples described herein, the disclosed ionic 1999,99:2071-2083; and Carlinet al., Advances in Nonague liquid compositions are neat; that is, the only materials ous Chemistry, Mamantov et al. Eds. VCH Publishing, New present in the disclosed ionic liquids are the cations and York, 1994. anions that make up the ionic liquid compositions. It is under The specific physical properties (e.g., melting point, vis 50 stood, however, that with neat compositions, some additional cosity, density, water solubility, etc.) of ionic liquids are materials or impurities can sometimes be present, albeit at determined by the choice of cation and anion, as is disclosed low to trace amounts (e.g., less than about 10,9,8,7,6, 5, 4, more fully herein. As an example, the melting point for an 3, 2, or 1 wt.% based on the total weight of the composition). ionic liquid can be changed by making structural modifica The disclosed ionic liquid compositions are liquid at some tions to the ions or by combining differentions. Similarly, the 55 temperature range or point at or below about 150° C. For particular chemical properties (e.g., bioactivity, toxicity, example, the disclosed ionic liquids can be a liquid at or pharmacokinetics, etc.), can be selected by changing the con below about 150, 149,148,147,146,145,144, 143, 142,141, stituent ions of the ionic liquid. 140, 139, 138, 137, 136, 135, 134, 133, 132, 131, 130, 129, The ionic liquid compositions disclosed herein are com 128, 127, 126, 125, 124, 123, 122, 121, 120, 119, 118, 117, prised of at least one kind of anion and at least one kind of 60 116, 115, 114, 113, 112, 111, 110, 109, 108, 107, 106, 105, cation. The at least one kind of cation, the at least one kind of 104, 103, 102,101,100, 99,98, 97,96, 95, 94.93, 92,91,90, anion, or both can be a pharmaceutical active, a pesticidal 89, 88,87, 86, 85, 84, 83,82, 81,80, 79,78, 77,76, 75, 74,73, active, a herbicidal active, a food additive, a nutraceutical, or 72, 71, 70, 69,68, 67, 66, 65, 64, 63, 62,61, 60, 59,58, 57,56, the like, including any combination thereof, as is disclosed 55, 54,53, 52, 51, 50,49, 48,47, 46, 45, 44, 43,42, 41, 40, 39, herein. It is contemplated that the disclosed ionic liquid com 65 38, 37, 36,35, 34,33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, positions can comprise one kind of cation with more than one 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10,9,8,7,6, 5, 4, 3, kind of anion (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different 2, 1, 0, -1, -2, -3, -4, -5,-6, -7, -8, -9, -10, -11, -12, -13, US 9,278,134 B2 13 14 -14, -15, -16, -17, -18, -19, -20, -21, -22, -23, -24, -25, neutral species: an anion precursor (e.g., in the form of an -26, -27, -28, -29, or -30°C., where any of the stated values inorganic acid, carboxylic organic acid, non-carboxylic acid, can form an upper or lower endpoint when appropriate. In or Zwitterion species) and a cation precursor (e.g., inorganic further examples, the disclosed ionic liquids can be liquid at base, organic base, Zwitterion species) are combined result any point from about -30°C. to about 150° C., from about ing in ionic liquid compositions as disclosed herein. -20°C. to about 140°C., -10°C. to about 130°C., from about Providing ions used to prepare the disclosed ionic liquids 0° C. to about 120° C., from about 10° C. to about 110° C., depends, in one aspect, on the desired properties of the result from about 20°C. to about 100° C., from about 30°C. to about ing ionic liquid composition. As described herein, the dis 90°C., from about 40°C. to about 80°C., from about 50° C. closed ionic liquid compositions can have multiple desired to about 70° C., from about -30° C. to about 50° C., from 10 properties, which, at least in part, come from the properties of about -30° C. to about 90° C., from about -30° C. to about the cation(s) and/or anion(s) used to prepare the ionic liquid. 110° C., from about -30° C. to about 130° C., from about Thus, to prepare the disclosed ionic liquids, one or more kinds -30°C. to about 150° C., from about 30° C. to about 90° C., of cations with a desired property(ies) are provided. One or from about 30°C. to about 110°C., from about 30°C. to about more kinds of anions with a desired property(ies) that is 130°C., from about 30° C. to about 150° C., from about 0°C. 15 similar or different to that of the cation(s) can likewise be to about 100°C., from about 0°C. to about 70° C., from about provided. Of course, providing a desired anion(s) and 0° to about 50° C., and the like. cation(s) can be done in any order, depending on the prefer Further, in some examples the disclosed ionic liquid com ence and aims of the practitioner. For example, a particular positions can be liquid over a wide range oftemperatures, not cation(s) can be provided and then aparticular anion(s) can be just a narrow range of, say, 1-2 degrees. For example, the provided. Alternatively, a particular anion(s) can be provided disclosed ionic liquid compositions can be liquids over a and then a particular cation(s) can be provided. Further, the range of at least about 4, 5, 6, 7, 8, 9, 10, or more degrees. In cation(s) and anion(s) can be provided simultaneously. other example, the disclosed ionic liquid compositions can be As noted, providing a suitable ion can be based on selecting liquid over at least about a 11, 12, 13, 14, 15, 16, 17, 18, 19. an ion that possesses a property that is desired (e.g., the ion 20, or more degree temperature range. Such temperature 25 has a property that is desired to be possessed by the resulting ranges can begin and/or end at any of the temperature points ionic liquid). Examples of properties that could be desired in disclosed in the preceding paragraph. a suitable cation and/or anion (and thus the ionic liquid made In many examples disclosed herein the disclosed ionic therefrom) include, but are not limited to, biological, thera liquid compositions are liquid at the temperature at which peutic, prophylactic, nutritional, pesticidal, and/or herbicidal they will be used or processed. For example, many of the 30 activity. Inertness, taste, viscosity modulation, Solubility disclosed ionic liquid compositions can be used for therapeu modulation, stability, and toxicity are other properties of a tic or nutritional purposes in a subject. In this case, the dis given ion that could be desired and considered. While more closed ionic liquid compositions can be liquid at the Subjects specific properties are disclosed elsewhere herein, the dis body temperature (e.g., about 37° C. for a human). Other closed methods and compositions are not limited to any par examples include compositions that can be used as herbicides 35 ticular combination of properties, as such will depend on the or pesticides, which are liquid at the temperature of their use preferences and goals of the practitioner. (e.g., ambient temperature). In still other examples, the dis Typically, the desired properties of the cation(s) and closed compositions can be liquid at the temperature at which anion(s) will be different or complimentary to one another. In they are formulated or processed. this way, the resulting ionic liquid can possess multiple It is understood, however, that the disclosed ionic liquid 40 desired properties: those properties imparted by the cation(s) compositions can, though need not, be solubilized, and solu and those imparted by the anion(s). In other words, some or tions of the disclosed ionic liquids are contemplated herein. all of the ions present in the disclosed ionic liquids can inde Further, the disclosed ionic liquid compositions can be for pendently and simultaneously introduce a specific function mulated in an extended or controlled release vehicle, for ality or property to the disclosed ionic liquid compositions. It example, by encapsulating the ionic liquids in microspheres 45 is this multiple functionality characteristic that can allow one or microcapsules using methods known in the art. Still fur to fine-tune or design very specific physical, chemical, and ther, the disclosed ionic liquid compositions can themselves bioactive properties in the disclosed ionic liquid composi be solvents for other solutes. For example, the disclosed ionic tions. Additional functionality can be obtained by using the liquids can be used to dissolve a particular nonionic or ionic disclosed ionic liquid compositions as solvents to dissolve a pharmaceutical active. These and other formulations of the 50 Solute(s) with another desired property, thus resulting in a disclosed ionic liquids are disclosed elsewhere herein. solution where the ions of the ionic liquid as well as the solute In some examples, the disclosed ionic liquids are not solu contribute desired properties to the composition. General and tions where ions are dissolved in a solute. In other examples, specific examples of various combinations of ions and their the disclosed ionic liquid compositions do not contain ionic associated properties are disclosed herein. exchange resins. In still other examples, the disclosed ionic 55 In some particular examples, one or more ions in the dis liquids are substantially free of water. By substantially free is closed ionic liquid composition (e.g., the anions, cations, or meant that water is present at less than about 10,9,8,7,6, 5, both) can be a pharmaceutical active, e.g., an existing drug 4, 3, 2, 1, 0.5, 0.25, or 0.1 wt.%, based on the total weight of that is ionic or that can be made ionic. Many drugs exist the composition. naturally or at physiological conditions as an ion, or they can The disclosed ionic liquid compositions can be prepared by 60 be converted to ions via simple chemical transformations methods described herein. Generally, the particular cation(s) (e.g., alkylation, protonation, deprotonation, etc.). As such, and anion(s) used to prepare the disclosed ionic liquids are these drugs can be used to prepare anionic liquid composition selected as described herein. Then, with the particular as disclosed herein. Such drugs can possess any therapeutic or cation(s) and anion(s) in hand, they can be combined, result prophylactic activity, many of which are described herein. ing in ionic liquid compositions as disclosed herein. Addi 65 Combining Such drugs with other ions to prepare an ionic tionally, the method for the preparation of the disclosed ionic liquid, as is disclosed herein, can result in the modification liquid compositions can include the reaction in which two and/or enhancement of the drugs properties. For example, a US 9,278,134 B2 15 16 first drug ion with a given property can be combined with an The use of ionic liquid in fragrance and flavor industry is oppositely charged second ion with another property to effect mainly dealing with solvent applications for the synthesis of the controlled release, controlled delivery, biological impact, fragrance and flavor materials in ionic liquids or with the taste, physical properties (stability, Solubility, toxicity, melt extraction of naturals (Sullivan, N. Innovations in Pharma ing point, etc.), or to overcome polymorphism in the first drug ceutical Technology 2006, 20:75-77). ion. In this way, new drug compositions can be created by For example, Forsyth et al. investigated the utilization of forming ionic liquids with functionality crafted into the com ionic liquid solvents for the synthesis of lily-of-the-valley bination of the ions, as disclosed herein. fragrance and fragrance intermediate Lilial (Forsyth et al., J. As another example, the first drug ion may be combined Mol. Cat. A. 2005, 231:61-66). The role of ionic liquids in 10 consumer products and fragrances is comparingly less with a second drug ion that has properties complimentary to explored (Davey, Perf Flav. 2008, 33:34-35; Liu, Flav. Frag. the first. Examples of this can include, but are not limited to, Cosm. (Xiangliao Xiangjing Huazhuangpin) 2004, 29:30 an ion having anesthetic properties being combined with an 36). Creavis noted that the rate of evaporation of a perfume ion having antibacterial properties, an ion having anesthetic could be slowed using an ionic liquid as fixative (Petrat et al. properties being combined with an ion having coagulation 15 US 2006/0166856; Creavis AG DE 10337579 A1). Examples properties, or an ion having coagulation properties being include a chypre accord, a musk base and a rose composition combined with an ion having antibacterial properties. Ionic with increased fiber Substantivity compared to the same com liquids resulting from Such combinations could find uses in position without the ionic liquid. The modification of textile wound repair, for example. Still other examples of desirable Surfaces, optionally adding a benefit agent which includes a combination include ions having therapeutic or prophylactic perfume followed by removal of the ionic liquid was efficacy being combined with ions having taste enhancement described by Procter and Gamble. (US 20060090271, US properties (i.e., taste modifiers). Ionic liquids resulting from 20060090777, EP 1807497). Benefit agent delivery systems this combination can be useful in enhancing the taste and comprising ionic liquids and their uses in detergent compo palatability of medicines. Still further examples can include sitions have also been reported. (Price et al. US2006094617) two differently charged ions each with similar uses but with 25 Delivery devices or storage media for fragrances and fla different mechanisms of action. Specific examples of Such Vors based on ionic liquids that include a covalent attachment combinations can include, but are not limited to, combina of the active compound and immobilization as a salt and there tions of ions with antineoplastic properties or antiviral prop application for storage as well as for prolonged and controlled erties. Ionic liquids prepared from Suchion combinations can triggered release not mentioned in any form in prior literature. be useful as drug “cocktails, where two or more bioactive 30 Ions agents are present in a single ionic liquid combination. The disclosed ionic liquids contain at least one kind of According to the methods and compositions disclosed cation and at least one kind of anion. Examples of suitable herein, ion identification and combination, as disclosed cations and anions are disclosed herein. It should be under herein, can involve any ion, not justionic drugs, as long as the stood that when a particular compound is disclosed as being combination results in an ionic liquid. For example, ions that 35 a cation, for example, it can also, in other circumstances, be have pesticidal properties can be combined with oppositely an anion and Vice versa. Many compounds are known to exist charged ions having pesticidal, herbicidal, antimicrobial as cations in Some environments and anions in other environ properties, and the like. In other examples, ions with antibac ments. Further, many compounds are known to be convertible terial properties can be combined with oppositely charges to cations and anions through various chemical transforma ions that have preservative properties, taste modifiers, etc. In 40 tions. Examples of Such compounds are disclosed herein. still other examples, an ion with one therapeutic or prophy The materials, compounds, compositions, and components lactic property can be combined with another therapeutic or that can be used for, can be used in conjunction with, can be prophylactic ion. As should be appreciated, the various com used in preparation for, or are products of the disclosed meth binations of ions according to the disclosed methods are ods and compositions are disclosed herein. It is understood numerous, and depend only on the desired combination of 45 that when combinations, Subsets, interactions, groups, etc. of properties and whether the resulting ion combination is an these materials are disclosed that while specific reference of ionic liquid as defined herein. each various individual and collective combinations and per Specific examples of properties that can be exhibited by the mutation of these compounds may not be explicitly disclosed, disclosed compositions include antibacterial, FDA approved each is specifically contemplated and described herein. For dyes, anti-acne, antibiotic, UV blocker, wetting agents, pre 50 example, if an ionic liquid composition is disclosed and a servative, emollient, anti-inflammatory, and vitamin. number of modifications that can be made to a number of components of the ionic liquid composition are discussed, Ionic Liquid Immobilized Fragrances each and every combination and permutation that are possible are specifically contemplated unless specifically indicated to Fragrance and flavor formulations suffer from limited life 55 the contrary. Thus, if a class of cations A, B, and C are time because their constituents evaporate, are degrading or disclosed as well as a class of anions D, E, and F and an lost during storage. Perfumes in consumer products tend to example of a ionic liquid A-D is disclosed, then even if each fade by evaporation, oxidation, chemical degradation or inter is not individually recited, each is individually and collec action with other ingredients. The flavor industry has tively contemplated. Thus, in this example, each of the ionic addresses the issue of performance loss of flavors by devel 60 liquids A-E, A-F. B-D, B-E, B-F, C-D, C-E, and C-F are oping specific delivery systems. At the present time, Sustained specifically contemplated and should be considered disclosed release techniques for flavor and fragrance delivery present in from disclosure of A, B, and C: D, E, and F; and the example literature are usually based on encapsulation either in hydro ionic liquid A-D. Likewise, any Subset or combination of philic matrices, via spray drying, granulation and spray-coat these is also specifically contemplated and disclosed. Thus, ing, encapsulation by coacervation and interfacial polymer 65 for example, the sub-group of A-E, B-F, and C-E are specifi ization and the use of colloidal carriers for the application in cally contemplated and should be considered disclosed from aqueous products (Quellet et al. Chimia 2001, 55:421-428). disclosure of A, B, and C, D, E, and F. and the example US 9,278,134 B2 17 18 combination A-D. This concept applies to all aspects of this facilities. In pharmacological preparations they are used Such disclosure including, but not limited to, steps in methods of as mouth rinses, lozenges, sprays and gels. making and using the disclosed compositions. Thus, if there In humans and animals QACs have been considered too are a variety of additional steps that can be performed it is toxic for systematic applications, but are accepted to be safe understood that each of these additional steps can be per 5 for topical applications. Furthermore, QACs have recently formed with any specific aspect or combination of aspects of been used as penetration enhancers for transnasal and trans the disclosed methods, and that each Such combination is buccal drug delivery, as well as in nasal vaccination (Klinguer specifically contemplated and should be considered dis et al., Vaccine, 2001, 19:4236). This ability to penetrate and closed. 10 open cell membrane has been widely used in drug delivery via Cations liposomes (mainly QACs with two long alkyl chains) and Particular examples of cationic compounds that can be non-viral gene delivery (Liu and Huang, J. Contr Rel, 2002, present in the disclosed ionic liquid compositions are com 78:259). Many examples of compounds having nitrogen pounds that contain nitrogenatoms. Nitrogenatoms can exist atoms, which exist as quaternary ammonium species or can or can be converted to positively-charged quaternary ammo 15 be converted into quaternary ammonium species, are dis nium species, for example, through alkylation or protonation closed herein. of the nitrogen atom. Thus compounds that possess a quater nary nitrogen atom (known as quaternary ammonium com In some examples, when the cation is a quaternary ammo pounds (QACs)) are typically cations. According to the meth nium compound, the anion is not an inorganic anion, ods and compositions disclosed herein, any compound that examples of which are disclosed herein. In other examples, contains a quaternary nitrogen atom or a nitrogen atom that where the cation is a quaternary ammonium compound, the can be converted into a quaternary nitrogen atom can be a anion is not a halide. Suitable cation for the disclosed ionic liquid compositions. Aliphatic Heteroaryls QACs can have numerous biological properties that one Some specific QACs suitable for use herein are aliphatic may desire to be present in the disclosed ionic liquid compo 25 heteroaryls. An aliphatic heteroaryl cation is a compound that sitions. For example, many QACs are known to have antibac terial properties. The antibacterial properties of QACs were comprises an aliphatic moiety bonded to a heteroaryl moiety. first observed toward the end of the 19" century among the In the aliphatic heteroaryl cation, the aliphatic moiety can be carbonium dyestuffs, such as auramin, methyl violet, and any alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl group, malachite green. These types of compounds are effective 30 as described herein. Generally, the aliphatic moiety can com chiefly against the Gram-positive organisms. Jacobs and prise at least 10, at least 12, at least 14, at least 16, at least 18, Heidelberger first discovered QACs antibacterial effect in or at least 20 carbon atoms. In other examples, the aliphatic 1915 studying the antibacterial activity of substituted hexam ethylene-tetrammonium salts (Jacobs and Heidelberger, Proc moiety can comprise a mixture of aliphatic groups having a Nat AcadSci USA, 1915, 1:226: Jacobs and Heidelberger, J 35 range of carbon atoms. For example, the aliphatic moiety can Biol Chem, 1915, 20:659; Jacobs and Heidelberger, J Exptl comprise from 10 to 40, from 12 to 38, from 14 to 36, from 16 Med, 1916, 23:569). to 34, from 18 to 32, from 14 to 18, or from 20 to 30 carbon Browning et al. found great and somewhat less selective atoms. In some specific examples, the aliphatic moiety can bactericidal powers among quaternary derivatives of pyri contain 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, dine, quinoline, and phenazine (Browning et al., Proc Roy Soc 40 25, 26, 27, 28, 29, 30, 31, 32,33, 34,35, 36, 37,38, 39, 40, 41, London, 1922, 93B:329; Browning et al., Proc Roy Soc Lon don, 1926, 100B:293). Hartman and Kagi observed antibac 42, 43, 44, or 45 carbonatoms, where any of the stated values terial activity in QACs of acylated alkylene diamines (Hart can form an upper or lower endpoint when appropriate. man and Kagi, ZAngew Chem, 1928, 4:127). Examples of specific aliphatic moieties that can be used In 1935, Domagk synthesized long-chain QACs, including 45 include, but are not limited to, decyl, dodecyl (lauryl), tet benzalkonium chloride, and characterized their antibacterial radecyl (myristyl), hexadecyl (palmityl or cetyl), octadecyl activities (Domagk, Deut Med Wochenschr, 1935, 61:829). (Stearyl), eicosyl (arachidyl), and linolenyl groups, including He showed that these salts are effective against a wide variety branched derivatives thereof and any mixtures thereof. In the of bacterial strains. This study of the use of QACs as germi aliphatic heteroaryl cations, the aliphatic moiety is bonded to cides was greatly stimulated. 50 a heteroatom in the heteroaryl moiety. Many scientists have focused their attention on water soluble QACs because they exhibit a range of properties: they In the aliphatic heteroaryl cation, the heteroaryl moiety can are surfactants, they destroy bacteria and fungi, they serve as be any heteroaryl moiety as described herein. For example, a catalyst in phase-transfer catalysis, and they show anti the heteroaryl moiety can be an aryl group having one or more electrostatic and anticorrosive properties. They exertantibac 55 heteroatoms (e.g., nitrogen, oxygen, Sulfur, phosphorous, or terial action against both Gram-positive and Gram-negative halonium). Examples of specific heteroaryl moieties that can bacterial as well as against Some pathogen species of fungi be used in the aliphatic heteroaryl cations include, but are not and protozoa. These multifunctional salts have also been used limited to, pyrazole, pyridine, pyrazine, pyrimidine, pry in wood preservation, their application promoted in the idazine, indolizine, isoindole, indole, indazole, imidazole, papers of Oertel and Butcher et al. (Oertel, Holztechnologie, 60 oxazole, triazole, thiazole, purine, isoquinoline, quinoline, 1965, 6:243; Butcher et al., For Prod.J., 1977, 27:19: Butcher phthalazine, quinooxaline, phenazine, and the like, including et al., J. For Sci, 1978, 8:403). QACs are also widely used as skin antiseptics, disinfec substituted derivatives and mixtures thereof. In the aliphatic tants, fabric softeners, antistatic agents, cleaning agents, and heteroaryl cations, a heteroatom in the heteroaryl moiety is preservatives. Detergent properties and antimicrobial activi 65 bonded to the aliphatic moiety. When the heteroatom of the ties of QACs have made them useful for general environmen heteroaryl is nitrogen, this forms a quaternary ammonium tal sanitations, for examples, in hospitals and food production cation, as described herein. US 9,278,134 B2 19 20 Further examples of aliphatic heteroaryl cations are those C-C alkyl groups and C-C alkyl groups include methyl, having the following structures: ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl, pentyl, iso-pentyl, hexyl, 2-ethylbutyl, 2-methylpentyl, and the like. Corresponding C-C alkoxy groups contain the above C-C, R4 alkyl group bonded to an oxygen atom that is also bonded to the cation ring. An alkoxyalkyl group contains an ether group R3 R5 bonded to an alkyl group, and here contains a total of up to six carbon atoms. It is to be noted that there are two isomeric 1,2,3-triazoles. In some examples, all R groups not required R7 R6 10 for cation formation can be H. The phrase “when present is often used herein in regard to R1 substituent R group because not all cations have all of the PYRIDINIUM PYRIDAZINIUM numbered R groups. All of the contemplated cations contain R4 at least four R groups, which can be H, although R need not 15 be present in all cations. R3 R3 N R4 In one example, all R groups that are not required for cation formation; i.e., those other than R' and R for compounds other than the imidazolium, pyrazolium, and triazolium cat R6 R5 R6DIOC R5 ions shown above, are H. A cation that contains a single five-membered ring that is R1 RI free offusion to other ring structures is suitable for use herein. PYRIMIDINIUM PYRAZINIUM Exemplary cations are illustrated below wherein R', R, and R4 R5 R3 R4 R5 R3 R-R, when present, are as defined before.

25 Go)\, Go) O. R4 R3 R4 R3 R11 Y NR2 R21 N R5 R11 )-N R3 R2

R3 R1 R4 Y N N Y N (e) N \ IMIDAZOLIUM PYRAZOLIUM OXAZOLIUM 30 N R4 R3 R4 R3 R2 11N N R4 R3 R2 1,2,3-TRIAZOLIUM 1,2,4-TRIAZOLIUM

R11 N%C. NR2 R11 N%G. \ 35 R2 R1-N N. R4 Y O. R11 YO. NR2 R21 NO. R5 1,2,3-TRIAZOLIUM 1,2,4-TRIAZOLIUM R1 Y R4 R4 R3 RI R5 R3 R5 R4 40 R3 R5 THIAZOLIUM IMIDAZOLIUM PYRAZOLIUM Go), R11 R7 N R6 R6 N R 3 A V w V 45 R4 R1 R2 R1 R2 THIAZOLIUM PIPERIDINIUM PYRROLIDINIUM

R4 R5 R4 OXAZOLIUM R R3 50 Of the cations that contain a single five-membered ring free of fusion to other ring structures, an imidazolium cation that R7 R9 corresponds in structure to Formula A is also suitable, R8 RI 55 wherein R', R, and R-R, are as defined before. QUINOLIUM ISOQUINOLIUM (A) wherein R' and Rare, independently, a C-C alkyl group or a C-C alkoxyalkyl group, and R. R. R. R. R. R. and 60 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 nitro, alkyl amino, alkyl cyano, alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, and alkoxy azido. In other 65 examples, both R" and R groups are C-C alkyl, with one In a further example, an N,N-1,3-di-(C-C alkyl)-substi being methyl, and R-R, when present, are H. Exemplary tuted-imidazolium ion can be used; i.e., an imidazolium cat US 9,278,134 B2 21 22 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 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 Aare 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 disclosed ionic liquid compositions are dialiphatic dialkyl (B) ammonium cations. A dialiphatic dialkyl ammonium cation 10 is a compound that comprises two aliphatic moieties and two Y N(e) N alkyl moieties bonded to a nitrogen atom. The aliphatic moi RI N2 CH3 eties can be the same or different and can be any aliphatic group as described above. The alkyl moieties can be the same Aliphatic Benzylalkyl Ammonium or different can be any alkyl group as described above. In the The disclosed ionic liquid compositions can also comprise 15 disclosed dialiphatic dialkyl ammoniums cations, the two an aliphatic benzylalkyl ammonium cation. An aliphatic ben aliphatic moieties can have 10 or more carbon atoms and the Zylalkyl ammonium cation is a cation that comprises an ali two alkyl moieties can have less than 10 carbon atoms. In phatic moiety bonded to the nitrogen atom of a benzylalkyl another alternative, the two aliphatic moieties can have less amine moiety. The aliphatic moiety can be as described than 10 carbon atoms and the two alkyl moieties can have 10 herein. The benzylalkyl amine moiety can be a benzyl amine or more carbon atoms. One or more types of dialiphatic where the amine is bonded to an alkyl or cyclic alkyl group, as dialkyl ammonium cations can be used in the ionic liquid described herein. One or more types of aliphatic benzylalkyl compositions disclosed herein. ammonium cation can be used in the ionic liquid composi In Some particular examples, the dialiphatic dialkyl ammo tions disclosed herein. The aliphatic benzylalkyl ammonium nium cation can be di-dodecyl dimethyl ammonium, di-tet cation suitable for use herein can be prepared by methods 25 radecyl dimethyl ammonium, dihexadecyl dimethyl ammo known in the art or can be obtained from commercial sources. nium, and the like, including combinations thereof. In one aspect, the aliphatic benzylalkyl ammonium cation Tetraalkyl Ammonium can be represented by the following formula: The disclosed ionic liquid compositions can also comprise a tetraalkyl ammonium cation. Suitable tetraalkyl ammonium 30 cations comprise four alkyl moieties, as disclosed herein. In one example, a tetraalkyl ammonium cation can comprise one R11 o long chain alkyl moiety (e.g., 10 or more carbon atoms in N-R12 length) and three short chain alkyl moieties (e.g., less than 10 V carbon atoms in length). R10 35 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 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 40 ammonium, or mixtures thereof. Other examples include, but (e.g., the number of carbon atoms is 10 or greater). In other are not limited to, cetyl dimethylethyl ammonium, lauryl examples, one or more of the “R” substituents can be a short dimethylethyl ammonium, myristyl dimethylethyl ammo chain alkyl group (e.g., the number of carbon atoms is less nium, Stearyl dimethylethyl ammonium, arachidyl dimethyl than 10). In still other examples, one of the “R” substituents is ethyl ammonium, or mixtures thereof. a long chain alkyl group and the other two “R” substituents 45 Other Cations are short chain alkyl groups. Other cations that are suitable for use in the disclosed In one aspect, the aliphatic benzylalkyl ammonium cation methods and compositions are compounds that contain met can have any of the aliphatic moieties disclosed herein als. According to the methods and compositions disclosed bonded to any benzylalkyl amine moieties disclosed herein. herein, any compound that contains a metal atom can be a In some specific examples, R' in the formula of aliphatic 50 Suitable cation. Organometallic compounds or metal com benzylalkyl ammonium cation can be an aliphatic group of plexes commonly have one or more metal atom in a positive from 10 to 40 carbon atoms, e.g., a decyl, dodecyl (lauryl), oxidation state. Examples of metals that can be present in a tetradecyl (myristyl), hexadecyl (palmitylor cetyl), octadecyl suitable cation include, but are not limited to, lithium, (stearyl), or eicosyl (arachidyl) group, and R'' and R' can Sodium, potassium beryllium, magnesium, calcium, stron each be, independent of one another, a methyl, ethyl, propyl. 55 tium, chromium, manganese, iron, cobalt, nickel, copper, and butyl, pentyl, or hexyl group. Zinc. Silver nanoparticles can also be used. Examples of In another aspect, the aliphatic benzylalkyl ammonium Suitable organometallic cations include, but are not limited to, cation can include, but are not limited to, alkyl dimethyl metallocenium, alkylgermanyl, alkyltin, or alkylsilyl (e.g., benzyl ammonium cations. Specific examples of alkyl dim trimethylsilylium, triethylsilylium, tris(trimethylsilyl)sily ethylbenzyl ammonium cations include, but are not limited 60 lium, tribenzylsilylium, triphenylsilylium, tricyclohexylsily to, cetyl dimethylbenzyl ammonium, lauryl dimethylbenzyl lium, and dimethyloctadecylsilylium). ammonium, myristyl dimethyl benzyl ammonium, Stearyl Another Suitable group of quaternary ammonium cations dimethylbenzyl ammonium, and arachidyl dimethylbenzyl are those that have been prepared by esterifying a compound ammonium. containing a carboxylic acid moiety or transesterifying a In yet another aspect, the aliphatic benzylalkyl ammonium 65 compound with an ester moiety with a choline moiety. Such cation can include, but are not limited to, alkyl methylethyl choline esters can be biofriendly, permanent ions that are benzyl ammonium cations. Specific examples of alkyl meth amenable to being added to various compounds while still US 9,278,134 B2 23 being easily cleavable under physiological conditions. The choline esters can be used to increase the solubility and bio R13 R13 R 14 availability of many neutral compounds. N N Further examples of cations include (2-hydroxyethyl)- / > ( \, ( \, dimethylundecyloxymethyl-ammonium, (2-acetoxyethyl)- R 14 N R 15 R 14 N1 R 15 N1 heptyloxymethyldimethylammonium, and (2-acetoxyethyl)- O G) O dodecyloxymethyldimethylammonium, mepenZolate, Sulfathiazole, thimerosal, and valproic acid. imidazolate 1,2,3-triazolate 1,2,4-triazolate R13 R13 In other examples, the cation can be an energetic cation as 10 14 C) 14 9 disclosed in Katritzky et al., “ILs Based on Energetic Imida R N R N Zolium Cations: Nitro- and Nitrile-substituted N,N'Dialky limidazolium Salts' New J Chem 30:349, 2006, which is AX- R17 MY incorporated by reference herein at least for its teachings of R 15 N R15 N 15 energetic ions. R 16 R 16 Anions Particular examples of anionic compounds that can be benzimidazolate benz-1,2,3-triazolate present in the disclosed ionic liquids are compounds that contain oxygen atoms. Oxygen atoms can exist or can be wherein R. R. R. R. (R''7), when present, are inde converted to negatively charged, anionic species, for pendently H, a C-C alkyl, a C-C alkoxyalkyl group, a example, through deprotonation of alcohols or acids, through C-C alkoxy group, or energetic Substituents like nitro, saponification of esters, or through alkylation of ketones. amino, cyano, azido, alkyl nitro, alkyl amino, alkyl cyano, Likewise, compounds that contain Sulfur atoms can also exist alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, and or be converted to anionic species through similar reactions. 25 alkoxyazido. Exemplary C-C alkyl groups and C-C alkyl Still further, compounds that contain nitrogen atoms, espe groups include methyl, ethyl, propyl, iso-propyl, butyl, sec cially nitrogen atoms adjacent to electron withdrawing butyl, iso-butyl, pentyl, iso-pentyl, hexyl, 2-ethylbutyl, 2-me groups or resonance stabilizing structures, can be converted thylpentyl, and the like. Corresponding C-C alkoxy groups to anions through deprotonation. According to the methods contain the above C-C alkyl group bonded to an oxygen 30 atom that is also bonded to the cation ring. An alkoxyalkyl and compositions disclosed herein, any compound that con group contains an ether 10 group bonded to an alkyl group, tains an oxygen, Sulfur, or nitrogen atom can be a suitable and here contains a total of up to six carbon atoms. It is to be anion for the disclosed ionic liquid compositions. noted that there are two isomeric 1,2,3-triazoles. In some Other suitable anions include, but are not limited to, halides examples, all R groups not required for anion formation can (e.g., fluoride, chloride, bromide, and iodide), Sulfates 35 be H. (SO), carbonates, bicarbonates, phosphates, phosphates, Further examples of suitable energetic anions are disclosed nitrates (NO), nitrites (NO), acetates (CHCO), and the in Katritzky et al., “ILs Based on Energetic Azolate Anions.” like. Other examples of anions include, but are not limited to Chem Eur J 12:4630, 2006, which is incorporated by refer PF, that is immiscible in water and BF that is miscible in ence herein at least for its teachings of energetic anions. water depending on the ratio of ionic liquid to water, system 40 Compound that can Exist that as Both: Anion or Cation temperature, and alkyl chain length of cation. Other anions Examples of compounds that exist as cations in Some envi include triflate (TfG); CFSO), nonaflate (NfO; CF (CF). ronments and anions in other environments include, but are SO), bis(triflyl)amide (Tf.N. (CFSO)N), trifluoroac not limited to, 1,3-dimethylimidazolium, 1-butyl-3-meth etate (TFA; CFCO), and heptafluororobutanoate (HB; CF ylimidazolium, 1,2,3-triazolium, tetrazolium, 1,2,4-triaZo (CF)SO). Other types of ionic liquids include haloalumi 45 lium, 1,3-dimethyl-1,2,3-triazolium, and 1,3-dimethyl-4-ni nates, such as chloroaluminate. troimidazolium, which exist as a cations, and Other Suitable anions contemplated herein are saccharin 4-nitroimidazolate, 4,5-dinitroimidazolate, 3,5-dinitro-1,2, and acesulfame. Saccharin, as an alkali metal salt, and 4-triazolate, tetraZolate, 5-aminotetraZolate, 2-nitroimida acesulfame (6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one Zolate, which exist as an anion. Those separate ions can still 2,2-dioxide), which has previously only been offered as 50 form single productionic liquids. potassium salt, are in widespread use in foodstuffs as non Examples of compounds that can change from an anion in nutritive Sweeteners. Such anions can be used when one one environment to a cation in another environment due to desires to prepare an ionic liquid composition that has Sweet chemical modifications are the Sulfurylides through the reac ness as one of its desired properties. For example, saccharin tion of a sulfide with methyliodide to form the sulfonium ion. and acesulfame can be combined with pharmaceutically 55 Specific Examples of Pharmaceutical Actives active cations to prepare Sweet tasting ionic liquids that have When pharmaceutical activity is a desired property of the pharmaceutical activity. disclosed ionic liquids, one or more of the ions in the dis closed ionic liquid compositions can be a pharmaceutical Specific examples of other anions include piperacillin, active. Pharmaceutical actives that exist as ions or can be folic acid, ibuprofen, fast green FCF, docusate, acesulfamate, 60 converted to ions, and which are suitable for use in preparing penicillin G, Colawet MA-80, salicylic acid, saccharinate, the disclosed ionic liquid compositions, include the following Sulfacetamide, naproxen, benzoate, diclofenac, and trans-cin categories and specific examples. It is not intended that the namic acid. category be limited by the specific examples. Those of ordi Other suitable anions include, but are not limited to, Sub nary skill in the art will be able to readily identify those stituted and un-Substituted imidazolates, 1,2,3-triazolates, 65 pharmaceutical actives that can be used in the disclosed meth and 1,2,4-triazolates, benzimidazolates, benz-1.2.3-triaz ods and compositions. For example, one can identify a com olates, as shown below: pound with a given property or activity by consulting various US 9,278,134 B2 25 26 sources, such as the Merck Index (13" Edition, Wiley, 2001), flutamide, nilutamide, nicorandil, oZagrel, bunitrolol, iprat The United States Pharmacopeia National Formulary ropium bromide, pyridinol carbamate, bucillamine, (USP-NF), and the FDA's Orange book, which are each diacerein, amlexanox, cromolyn, azidamfenicol, thiampheni incorporated by reference herein at least for their teachings of col, brodimoprim, tetroXoprim, acetosulfone sodium, dap pharmaceutical actives. Once a compound with a desired 5 Sone, benzoylpas, cyamelide, picotamide, acetylpheneturide, property is identified, the skilled artisan can determine albutoin, caroXaZone, indalpine, calcium mesoxalate, whether the compound is ionic or can be made ionic. Such buformin, alkofanone, metformin, edrophomium chloride, determinations can be performed based on the compounds neostigmine, p-aminopro-piophenon, methylene blue, folinic structure, which can readily be determined by consulting the acid, tiopronin, fomepizole, asOxime chloride, obidoxime Sources mentioned herein or experimentally. Knowing a com 10 pound's structure can readily reveal if the compound is ionic. chloride, chlonidine, tiapride, alizapride, bromopride, potas In fact, many pharmaceutical actives exist as salts and are thus sium p-aminobenzoate, chlordantoin, bromosalicylchloranil Suitable for use in preparing the disclosed ionic liquid com ide, acetazolamide, benfunolol, allopurinol, carprofen, acriv positions. Further, if a compound is notionic, but contains an astine, Metron S, Acifran, Benfluorex, Chlorisoncl-amine ion forming moiety (e.g., nitrogen, oxygen, Sulfur, or metal 15 chloride, Pentamethon-ium bromide, 2-Aminothiazole, atoms, as described herein), the compound can be converted Methylthio-uracil, Amexinium Methyl Sulfate, Dopamine to an ion and then combined with a Suitable counterion to Hydrochloride, Balsalazide, Mesalamine, Enfenamic Acid, prepare the disclosed ionic liquid compositions. Those of Menfenamic Acid, Flufenamic Acid Aluminum Salt, Ber ordinary skill in the art will recognize numerous other com berine, Chloguanide, Valproic Acid, Lisuride, Naratriptan, pounds that fall within the categories and that are useful Ambutonium Bromide, Benzilonium Bromide, 9-Amino according to the disclosed compositions and methods. camptothecin, TenuaZonic Acid, Clometocillin, Fluoxetine Some specific examples of pharmaceutical actives that can Hydrochloride, Pamidronic Acid, Risedronate Sodium, be used in the disclosed ionic liquids include, but are not Benserazide Hydrochloride, Carbidopa, Metyrosine, Phento limited to, aspirin, LIBRIUMTM, isoniazid, penicillin, lamine, Elformithine Hydrochloride monohydrate, Sul PRONTOSILTM, cisplatin, 6-mercaptopurine, RITUXANTM, 25 famethox-azole, Tamsulosin Hydrochloride, Terazosin, Nita TAXOLTM, phenobarbital, PROZACTM, ALLEGRATM, Zoxanide, Acranil, Hydroxy stil-bamidine, Pentamidine, VIOXXTM, quinine, ivermectin, L-dopa, THORAZINETM, Pyrimethamine, AcetarSone, Aminitrozole, BenZnidazole, salvarsan, TAGAMETTM, AZT, crixivan, salbutamol, Eflornithine Hydrochlo-ride, Acitretin, 6-AZauridine, digoxin, fluride, LOVASTATINTM, erythropoietin, hydrocor Amisulpride, Remoxipride Hydrochloride Monohydrate, tisone, insulin, oral contraceptives, oxytocin, PRE 30 Bufe-Xamac, Bumadizon, Chloram-phenicol, BenZOxonium, MARINTM, RU-486, thyroxine, thalidomide, cyclosporine, Chloride, Cetalkonium Chloride, Aliben-dol, Ambutonium fentanyl, methadone, morphine, botox, vitamins, FOSA Bromide, Arshpenamine, Sodium Arsanilate, Anagrelide, MAXTM, RITALINTM, and VIAGRATM, including ionic Beraprost, Cilostazol, Bibenzonium Bromide, Sodium Dibu derivatives thereof. Other examples of pharmaceutical active nate, Aldioxa, Cimetidine, Allopurinol, Succinimide, Foscar ions orpharmaceutical actives that can be made ionic include, 35 net Sodium, Efavirenz, Etifoxine, Valnoctamide, Cannabinol, but are not limited to, pantoprazole, sold under the trade Oxitropium Bromide, Tiotropium Bromide, Fendiline names PROTONIXTM and PANTOZOLTM, and rabeprazole, Hydrochloride, Prenylamine, Acetazolamide, Flumethiazide, sold under the trade names ACIPHEXTM and PARIETTM, Acadesine, Cariporide, Levosimendan, Pimobendan Hydro which are used to treat gastrointestinal disorders. Risedr chloride, Ursodiol, Chenodiol, Cholic Acid Monohydrate, onate, sold under the trade name ACTONELTM, and alendr 40 Clanobutin, Echothiophate Iodide, Edrophonium Chloride, onate, sold under the trade name FOSAMAXTM, are used to Ambenonium, hloride, Distigmine Bromide, Asoxime Chlo treat osteoporosis and are further examples of Suitable com ride, Obidoxime Chloride, Pemoline, Phenmetrazine, Cele pounds that can be used to prepare the disclosed ionic liquid coxib, Cetraxate, Irsogladine, Naphazoline Hydrochloride, compositions. Further examples include losartan, Sold under Nordefrin Hydrochloride, Dapsone, Sulfapyridine Sodium the trade names NU-LOTANTM, COZAARTM, and HYZ 45 Salt, Mercapto-merin Sodium, Mercumatilin Sodium, Per AARTM, and fosinopril, sold under the trade name MONO golid, Pramipexole, Dihydro-chloride, Amisulpride, PRILTM, which are used to treat hypertension and are other Sulpiride, Cephaeline, Bromhexine, Ambroxol Hydrochlo examples of Suitable compounds that can be used to prepare ride, Carnitine, Cinitapride, Cisapride, Cortivazol, Enox the disclosed ionic liquid compositions. Atorvastatin, sold olone, Clomiphene, Pentoxifylline, Adrenalone, Carbazo under the trade name LIPITORTM, and pravastatin, sold under 50 chrome, odium Sulfonate. Thioctic Acid, Timonacid, the trade name PRAVACHOLTM, are used to treat cholesterol Pidotimod, Bucillamine, 6-Mercapto-purine, Brequinar, Ret and are further examples of Suitable compounds that can be inoic Acid, Salicylic Acid, Docusate Calcium (Sodium), used to prepare the disclosed ionic liquid compositions. A Picosolfate Sodium, Ibudilast, Zafirlukast, Choline Chloride, further example is montelukast, which is used to treat asthma Methionine, Bismuth Sodium Triglycollam-ate, Chloro and is sold under the trade name SINGULAIRTM. Further 55 quine, Prinomastat, Carbachol, Neostigmine, Acetylcysteine, examples of pharmaceutical actives that are ionic or can be Bromhexine, Tetrazepam, Tizanidine, Tropicamide, Phenyle made ionic and combined with other ions to form the dis phrine, Hydrochloride, Cyclazocine, Amiphenazole, Zan closed ionic liquid compositions are: prostaglandin E, pros amivir. Succinyl-choline Bromide/Chloride?, Iodide, Faza taglandin F2, Sulprostone, cetapril, benzaepril, captopril, dinium Bromide, Omapatrilat, Riluzole, Repinotan, methylhexaneamine, Synephrine, isoetharine, methoxyphe 60 Indeloxazine Hydrochloride, Donepezil, Carboprost, Pinaci namine, tamsulosin, tolaZoline, bufuralol, nadoxolol, acetyl dil, Nicorandil, Fampridine, Tedisamil, Cabergoline, Bera salicylsalicylic acid, ammonium salicylate, buthalital prost, Dimefline, Fominoben, 2-Hexyl-decanoic Acid, Sodium, thiopental Sodium, isobutyl p-aminobenzoate, phe Sodium Tetradecyl Sulfate, Flurazepam, Etodroxizine, nol, clortermine, fenproporex, dermatol, niclosamide, pelle Hexafluor-enium, romide, Ritodrine, Terbutaline. p-Amino tierine, dithiazanine iodide, thiabendazole, antimony Sodium 65 benzoic Acid, Solisobenzone, Ticrynafen, Orotic Acid, thioglycolate, niridazole, isotretinoin, lodoxamide, rama Nafronyl, Nicametate, Perhexyline, Cloricromen, Cicloni troban, finasteride, minoxidil, carbarSone, diphetarSone, cate, Cinepazide, Chromocarb, Dobesilate Calcium, Thia US 9,278,134 B2 27 28 mine (Vit. B), Pyridoxine Hydrochloride (Vit. Bs), dol, lomoxicam, magnesium salicylate, mefenamic acid, Oxaceprol, Acetylcysteine, Penicillamine, Allopurinol, menabitan hydrochloride, meperidine hydrochloride, Further examples of pharmaceutical actives that are ionic meptazinol hydrochloride, methadone hydrochloride, meth or can be made ionic and combined with other ions to form the adyl acetate, methopholine, methotrimeprazine, metkepha disclosed ionic liquid compositions are detailed below, along 5 mid acetate, mimbane hydrochloride, mirfentanil hydrochlo with their typically pharmaceutical use. ride, molinaZone, morphine Sulfate, moxazocine, nabitan Adrenergic: adrenalone, amidephrine mesylate, apracloni hydrochloride, nalbuphine hydrochloride, nalmexone hydro dine hydrochloride, brimonidine tartrate, dapiprazole hydro chloride, namoxyrate, nantradol hydrochloride, naproxen, chloride, deterenol hydrochloride, diplivefrin, dopamine naproxen Sodium, naproxol, nefopam hydrochloride, nexeri hydrochloride, ephedrine Sulfate, epinephrine, epinephrine 10 dine hydrochloride, noracymethadol hydrochloride, ocfenta bitartrate, epinephryl borate, esproquin hydrochloride, nil hydrochloride, octaZamide, olvanil, oxetorone fumarate, etafedrine hydrochloride, hydroxyamphetamine hydrobro oxycodone, oxycodone hydrochloride, oxycodone terephtha mide, levonordefrin, mephentermine Sulfate, metaraminol late, oxymorphone hydrochloride, pemedolac, pentamor bitartrate, metizoline hydrochloride, naphazoline hydrochlo phone, pentazocine, pentazocine hydrochloride, pentazocine ride, norepinephrine bitartrate, oxidopamine, oxymetazoline 15 lactate, phenazopyridine hydrochloride, phenyramidol hydrochloride, phenylephrine hydrochloride, phenylpro hydrochloride, picenadol hydrochloride, pinadoline, pirfeni panolamine hydrochloride, phenylpropanolamine polistirex, done, piroxicam olamine, pravadoline maleate, prodilidine prenalterol hydrochloride, propylhexedrine, pseudoephe hydrochloride, profadol hydrochloride, propirarn fumarate, drine hydrochloride, tetrahydrozoline hydrochloride, trama propoxyphene hydrochloride, propoxyphene napsylate, Zoline hydrochloride, Xylometazoline hydrochloride. proxazole, proxazole citrate, proXorphan tartrate, pyrro Adrenocortical steroid: ciprocinonide, desoxycorticoster liphene hydrochloride, remifentanil hydrochloride, salcolex, one acetate, desoxycortico-sterone pivalate, dexamethasone Salethamide maleate, salicylamide, Salicylate meglumine, acetate, fludrocortisone acetate, flumoxonide, hydrocorti Salsalate, Sodium salicylate, spiradoline mesylate, Sufentanil, Sone hemisuccinate, methylprednisolone hemisuccinate, Sufentanil citrate, talmetacin, talniflumate, talosalate, tazad naflocort, procinonide, timobesone acetate, tipredane. 25 olene Succinate, tebufelone, tetrydamine, tifurac sodium, tili Adrenocortical Suppressant: aminoglutethimide, trilos dine hydrochloride, tiopinac, tonazocine mesylate, tramadol tane. hydrochloride, trefentanil hydrochloride, trolamine, Verado Alcohol deterrent: disulfuram. line hydrochloride, verilopam hydrochloride, volazocine, Aldosterone antagonist: canrenoate potassium, canrenone, Xorphanol mesylate, Xylazine hydrochloride, Zenazocine dicirenone, mexrenoate potassium, prorenoate potassium, 30 mesylate, Zomepirac sodium, Zucapsaicin. spironolactone. Androgen: fluoxymesterone, mesterolone, methyltest Amino acid: alanine, aspartic acid, cysteine hydrochloride, osterone, nandrolone decanoate, nandrolonephenpropionate, cystine, histidine, isoleucine, leucine, lysine, lysine acetate, nisterime acetate, Oxandrolone, oxymetholone, silandrone, lysine hydrochloride, methionine, phenylalanine, proline, stanozolol, testosterone, testosterone cypionate, testosterone serine, threonine, tryptophan, tyrosine, Valine. 35 enanthate, testosterone ketolaurate, testosterone phenylac Ammonia detoxicant: arginine: arginine glutamate, argin etate, testosterone propionate, trestolone acetate. ine hydrochloride. Anesthesia, adjunct to: Sodium oxybate. Anabolic: bolandiol dipropionate, bolasterone, boldenone Anesthetic: alliflurane, benoximate hydrochloride, ben undecylenate, bolenol, bolnantalate, ethylestrenol, meth Zocaine, biphenamine hydrochloride, bupivacaine hydro enolone acetate, methenolone enanthate, mibolerone, nan 40 chloride, butamben, butamben picrate, chloroprocaine hydro drolone cyclotate, norbolethone, pizotyline, quinbolone, chloride, cocaine, cocaine hydrochloride, cyclopropane, Stenbolone acetate, tibolone, Zeranol. desflurane, dexivacaine, diamocaine cyclamate, dibucaine, Analeptic: modafinil. dibucaine hydrochloride, dyclonine hydrochloride, enflu Analgesic: acetaminophen, alfentanil hydrochloride, ami rane, ether, ethyl chloride, etidocaine, etoxadrol hydrochlo nobenzoate potassium, aminobenzoate sodium, anidoxime, 45 ride, euprocin hydrochloride, fluoroxene, halothane, isob anileridine, anileridine hydrochloride, anilopam hydrochlo utamben, isoflurane, ketamine hydrochloride, levoxadrol ride, anirolac, antipyrine, aspirin, benoxaprofen, benzy hydrochloride, lidocaine, lidocaine hydrochloride, mepiv damine hydrochloride, bici fadine hydrochloride, brifentanil acaine hydrochloride, methohexital sodium, methoxyflurane, hydrochloride, bromadoline maleate, bromfenac sodium, midazolam hydrochloride, midazolam maleate, minaxolone, buprenorphine hydrochloride, butacetin, butixirate, butor 50 nitrous oxide, norflurane, octodrine, oxethazaine, phencycli phanol, butorphanol tartrate, carbamazepine, carbaspirin cal dine hydrochloride, pramoxine hydrochloride, prilocalne cium, carbiphene hydrochloride, carfentanil citrate, ciprefa hydrochloride, procaine hydrochloride, propanidid, propara dol Succinate, ciramadol, ciramadol hydrochloride, caine hydrochloride, propofol, propoxycaine hydrochloride, clonixeril, clonixin, codeine, codeine phosphate, codeine Sul pyrrocaine, risocaine, rodocaine, roflurane, Salicyl alcohol, fate, conorphone hydrochloride, cyclazocine, dexoxadrol 55 sevoflurane, teflurane, tetracaine, tetracaine hydrochloride, hydrochloride, dexpemedolac, dezocine, diflunisal, dihydro thiamylal, thiamylal Sodium, thiopental sodium, tiletamine codeine bitartrate, dimefadane, dipyrone, doXpicomine hydrochloride, Zolamine hydrochloride. hydrochloride, drinidene, enadoline hydrochloride, epirizole, Anorectic compounds including dexfenfluramine. ergotamine tartrate, ethoxazene hydrochloride, etofenamate, Anorexic: a minorex, amphecloral, chlorphentermine eugenol, fenoprofen, fenoprofen calcium, fentanyl citrate, 60 hydrochloride, clominorex, clortermine hydrochloride, floctafenine, flufenisal, fluniXin, flunixin meglumine, flupir diethylpropion hydrochloride, fenfluramine hydrochloride, tine maleate, fluproduaZone, fluradoline hydrochloride, flur fenisorex, fluidorex, fluminorex, levamfetamine Succinate, biprofen, hydromorphone hydrochloride, ibufenac, indopro mazindol, mefenorex hydrochloride, phenmetrazine hydro fen, ketazocine, ketorfanol, ketorolac tromethamine, letimide chloride, phentermine, sibutramine hydrochloride. hydrochloride, levomethadyl acetate, levomethadyl acetate 65 Antagonist: atipamezole, atosiban, bosentan, cimetidine, hydrochloride, levonantradol hydrochloride, levorphanol tar cimetidine hydrochloride, clentiazem maleate, detirelix trate, lofemizole hydrochloride, lofentanil oxalate, lorcina acetate, devaZepide, donetidine, etintidine hydrochloride, US 9,278,134 B2 29 30 famotidine, fenmetozole hydrochloride, flumazenil, icatibant hydrochloride, panadiplon, pancopride, paZinaclone, Seraza acetate, icotidine, isradipine, metiarnide, nadide, nalmefene, pine hydrochloride, tandospirone citrate, Zalospirone hydro nalmexone hydrochloride, naloxone hydrochloride, naltrex chloride. one, nilvadipine, oxilorphan, oxmetidine hydrochloride, Anti-arthritic: lodelaben. oXimetidine mesylate, quadazocine mesylate, ranitidine, ran Anti-asthmatic: ablukast, ablukast Sodium, azelastine itidine bismuth citrate, ranitidine hydrochloride, sufotidine, hydrochloride, bunaprolast, cinalukast, crornitrile Sodium, teludipine hydrochloride, tiapamil hydrochloride, tiotidine, cromolyn Sodium, enofelast, isamoxole, ketotifen fumarate, vapiprost hydrochloride, Zaltidine hydrochloride. levcromakalim, lodoxamide ethyl, lodoxamide Anterior pituitary activator: epimestrol. tromethamine, montelukast sodium, Ontazolast, oxarbazole, 10 oXatomide, piriprost, piriprost potassium, pirolate, pobi Anterior pituitary Suppressant: danazol. lukastedamine, quaZolast, repirinast, ritolukast, Sulukast, tet Anthelmintic: albendazole, anthelmycin, bromoxanide, razolast meglumine, tiaramide hydrochloride, tibenelast bunamidine hydrochloride, butonate, cambendazole, carban Sodium, tomelukast, tranilast, Verlukast, Verofylline, Zar tel lauryl Sulfate, clioxanide, closantel, cyclobendazole, irlukast. dichlorvos, diethylcarbamazine citrate, dribendazole, 15 Anti-atherosclerotic: mifobate, timefuronc. dymanthine hydrochloride, etibendazole, fenbendazole, Anticholelithic: monoctanoin. furodazole, hexylresorcinol, mebendazole, morantel tartrate, Anticholelithogenic: chenodiol, ursodiol. niclosamide, nitramisole hydrochloride, nitrodan, oxantel Anticholinergic: alverinc citrate, anisotropine methylbro pamoate, Oxfendazole, Oxibendazole, parbendazole, pipera mide, atropine, atropine oxide hydrochloride, atropine Sul mide maleate, piperazine, piperazine citrate, piperazine ede fate, belladonna, benapryzine hydrochloride, benzetimide tate calcium, proclonol, pyrantel pamoate, pyrantel tartrate, hydrochloride, benzilonium bromide, biperiden, biperiden pyrvinium pamoate, rafoxanide, stilbazium iodide, tetrami hydrochloride, biperiden lactate, clidinium bromide, cyclo sole hydrochloride, thiabendazole, ticarbodine, tioxidazole, pentolate hydrochloride, dexetimide, dicyclomine hydro triclofenol piperazine, Vincofos, Zilantel. chloride, dihexyverine hydrochloride, domazoline fumarate, Anti-acne: adapalene, erythromycin Salnacedin, inocoter 25 elantrine, elucaine, ethybenztropine, eucatropine hydrochlo One acetate, acCutane. ride, glycopyrrolate, heteronium bromide, homatropine Anti-adrenergic: acebutolol, alprenolol hydrochloride, hydrobromide, homatropine methylbromide, hyoscyamine, atenolol, bretylium tosylate, bunolol hydrochloride, carteolol hyoscyamine hydrobromide, hyoscyamine Sulfate, isopropa hydrochloride, celiprolol hydrochloride, cetamolol hydro mide iodide, mepenZolate bromide, methylatropine nitrate, chloride, cicloprolol hydrochloride, dexpropranolol hydro 30 metoquizine, oxybutynin chloride, parapenzolate bromide, chloride, diacetolol hydrochloride, dihydroergotamine mesy pentapiperium methylsulfate, phencarbamide, poldine meth late, dilevalol hydrochloride, esmolol hydrochloride, ylsulfate, proglumide, propantheline bromide, propenzolate exaprolol hydrochloride, fenspiride hydrochloride, flestolol hydrochloride, Scopolamine hydrobromide, tematropium sulfate, labetalol hydrochloride, levobetaxolol hydrochlo methylsulfate, tiquinamide hydrochloride, tofenacin hydro ride, levobunolol hydrochloride, metalol hydrochloride, 35 chloride, toguizine, triampyZine Sulfate, trihexyphenidyl metoprolol, metoprolol tartrate, nadolol, pamatolol Sulfate, hydrochloride, tropicamide. penbutolol Sulfate, phentolamine mesylate, practolol, propra Anticoagulant: ancrod, anticoagulant citrate dextrose solu nolol hydrochloride, proroxanhydrochloride, solypertine tai tion, anticoagulant citrate phosphate dextrose adenine solu trate, Sotalol hydrochloride, timolol, timolol maleate, tipre tion, anticoagulant citrate phosphate dextrose solution, anti nolol hydrochloride, tolamolol, Zollertine hydrochloride. 40 coagulant heparin Solution, anticoagulant sodium citrate Anti-allergic: amlexanox, astemizole, azelastine hydro Solution, ardeparin Sodium, bivalirudin, bromindione, dalte chloride, eclaZolast, minocromil, nedocromil, nedocromil parin Sodium, desirudin, dicumnarol, heparin calcium, hep calcium, nedocromil sodium, nivimedone sodium, pemiro arin Sodium, lyapolate sodium, nafamo.stat mesylate, phen last potassium, pentigetide, pirquinozol, poisonoak extract, procoumon, tinzaparin Sodium, warfarin Sodium. probicromil calcium, proXicromil, repirinast, tetraZolast 45 Anticoccidal: maduramicin. meglumine, thiazinamium chloride, tiacrilast, tiacrilast Anticonvulsant: albutoin, ameltolide, atolide, buramate, Sodium, tiprinast meglumine, tixanoX. carbamazepine, cinromide, citenamide, clonazepam, cyhep Anti-amebic: berythromycin, bialamicol hydrochloride, tamide, dezinamide, dimethadione, divalproex sodium, eter chloroquine, chloroquine hydrochloride, chloroquine phos obarb, ethosuximide, ethotoin, flurazepam hydrochloride, phate, clamoxyquin hydrochloride, clioquinol, emetine 50 fluzinamide, fosphenyloin Sodium, gabapentin, ilepcimide, hydrochloride, iodoquinol, paromomycin Sulfate, quinfa lamotrigine, magnesium sulfate, mephenyloin, mephobar mide, Symetime hydrochloride, teclozan, tetracycline, tetra bital, methetoin, methSuximide, millacemide hydrochloride, cycline hydrochloride. nabazenil, nafimidone hydrochloride, nitrazepam, phenace anti-androgen: benorterone, cioteronel, cyproterone mide, phenobarbital, phenobarbital Sodium, phensuximide, acetate, delmadinone acetate, oxendolone, topterone, Zanot 55 phenyloin, phenyloin Sodium, primidone, progabide, ralito COC. line, remacemide hydrochloride, ropizine, sabeluzole, stirip Anti-anemic: epoetin alfa, epoetin beta, ferrous Sulfate, entol, Sulthiame, thiopental sodium, tiletamine hydrochlo dried, leucovorin calcium. ride, topiramate, trimethadione, Valproate sodium, Valproic Anti-anginal: amlodipine besylate, amlodipine maleate, acid, vigabatrin, ZonicleZole hydrochloride, Zonisamide. betaxolol hydrochloride, bevantolol hydrochloride, buto 60 Antidepressant: adatanserin hydrochloride, adinazolam, prozine hydrochloride, carvedilol, cinepazet maleate, meto adinazolam mesylate, alaproclate, aletamine hydrochloride, prolol Succinate, molsidomine, monatepil maleate, primi amedalin hydrochloride, amitriptyline hydrochloride, amox dolol, ranolazine hydrochloride, tosifen, Verapamil apine, aptazapine maleate, azaloxan fumarate, azepindole, hydrochloride. azipramine hydrochloride, bipenamol hydrochloride, bupro Anti-anxiety agent: adatanserin hydrochloride, alpidem, 65 pion hydrochloride, butacetin, butriptyline hydrochloride, binospirone mesylate, bretazenil, glemanserin, ipsapirone caroxazone, cartazolate, ciclazindol, cidoxepin hydrochlo hydrochloride, mirisetron maleate, Ocinaplon, ondansetron ride, cilobamine mesylate, clodazon hydrochloride, clomi US 9,278,134 B2 31 32 pramine hydrochloride, cotinine fumarate, cyclindole, cype rperazine maleate, promethazine hydrochloride, namine hydrochloride, cyprolidol hydrochloride, thiethylperazine, thiethylperazine malate, thiethylperazine cyproximide, daledalin tosylate, dapoxetine hydrochloride, maleate, trimethobenzamide hydrochloride, Zacopride daZadrol maleate, dazepinil hydrochloride, desipramine hydrochloride. hydrochloride, dexamisole, deximafen, dibenzepin hydro Anti-epileptic: felbamate, loreclezole, tolgabide. chloride, dioxadrol hydrochloride, dothiepin hydrochloride, Anti-estrogen: clometherone, delmadinone acetate, doxepin hydrochloride, dulloxetine hydrochloride, eclan nafoxidine hydrochloride, nitromifene citrate, raloxifene amine maleate, encyprate, etoperidone hydrochloride, fantri hydrochloride, tamoxifen citrate, toremifene citrate, triox done hydrochloride, fehmetozole hydrochloride, fenmetra ifene mesylate. mide, fezolamine fumarate, fluotracen hydrochloride, 10 Antifibrinolytic: nafamo.stat mesylate. fluoxetine, fluoxetine hydrochloride, fluparoxan hydrochlo Antifungal: acrisorcin, ambruticin, amphotericin b, aza ride, gamfexine, guanoxyfen Sulfate, imafen hydrochloride, conazole, azaserine, basifungin, bifonazole, biphenamine imiloxan hydrochloride, imipramine hydrochloride, indelox hydrochloride, bispyrithione magSulfex, butoconazole azine hydrochloride, intriptyline hydrochloride, iprindole, nitrate, calcium undecylenate, candicidin, carbol-fuchsin, isocarboxazid, ketipramine fumarate, lofepramine hydro 15 chlordantoin, ciclopiroX, ciclopiroX olamine, cillofungin, chloride, lortalamine, maprotiline, maprotiline hydrochlo cisconazole, clotrimazole, cuprimyxin, denofungin, dipy ride, melitracen hydrochloride, millacemide hydrochloride, rithione, doconazole, econazole, econazole nitrate, enilcona minaprine hydrochloride, mirtazapine, moclobemide, moda Zole, ethonam nitrate, fenticonazole nitrate, filipin, flucona line Sulfate, napactadine hydrochloride, napamezole hydro Zole, flucytosine, fungimycin, griseofulvin, hamycin, chloride, nefazodone hydrochloride, nisoxetine, nitrafudam isoconazole, itraconazole, kalafungin, ketoconazole, hydrochloride, nomifensine maleate, nortriptyline hydro lomofimgin, lydimycin, mepartricin, miconazole, micona chloride, octriptyline phosphate, opipramol hydrochloride, Zole nitrate, monensin, monensin Sodium, naftifine hydro oxaprotiline hydrochloride, oxypertine, paroxetine, chloride, neomycin undecylenate, nifuratel, nifurmerone, phenelZine Sulfate, pirandamine hydrochloride, pizotyline, nitralamine hydrochloride, nystatin, octanoic acid, orcona pridefine hydrochloride, prolintane hydrochloride, protrip 25 Zole nitrate, oxiconazole nitrate, oxifungin hydrochloride, tyline hydrochloride, quipazine maleate, rolicyprine, seproX parconazole hydrochloride, partricin, potassium iodide, pro etine hydrochloride, sertraline hydrochloride, sibutramine clonol, pyrithione Zinc, pyrrolnitrin, rutamycin, sangui hydrochloride, Sulpiride, Suritozole, tametraline hydrochlo narium chloride, Saperconazole, scopafungin, selenium Sul ride, tampramine fumarate, tandamine hydrochloride, thiaz fide, sinefungin, Sulconazole nitrate, terbinafine, terconazole, esim hydrochloride, thozalinone, tomoxetine hydrochloride, 30 thiram, ticlatone, tioconazole, tolciclate, tolindate, tolnaftate, trazodone hydrochloride, trebenzomine hydrochloride, trimi triacetin, triafungin, undecylenic acid, viridofulvin, Zinc pramine, trimipramine maleate, venlafaxine hydrochloride, undecylenate, Zinoconazole hydrochloride. One specific anti viloxazine hydrochloride, Zimeldine hydrochloride, fungal that is Suitable is itraconazole. Zometapine. Antiglaucoma agent: alprenoXime hydrochloride, col Antidiabetic: acetohexamide, buformin, butoxamine 35 forsin, dapiprazole hydrochloride, diplivefrin hydrochloride, hydrochloride, camiglibose, chlorpropamide, ciglitaZone, naboctate hydrochloride, pilocarpine, pimabine. englitaZone sodium, etoformin hydrochloride, gliamilide, Antihemophilic: antihemophilic factor. glibornuride, glicetanile Sodium, gliflumide, glipizide, gluca Antihemorrhagic: poliglusam. gon, glyburide, glyhexamide, glymidine sodium, glyocta Antihistaminic: acrivastine, antazoline phosphate, astemi mide, glyparamide, insulin, insulin, dalanated, insulin 40 Zole, azatadine maleate, barmastine, bromodiphenhydramine human, insulin human, isophane, insulin human Zinc, insulin hydrochloride, brompheniramine maleate, carbinoxamine human Zinc, extended, insulin, isophane, insulin lispro, insu maleate, cetirizine hydrochloride, chlorpheniramine maleate, lin, neutral, insulin Zinc, insulin Zinc, extended, insulin Zinc, chlorpheniramine polistirex, cinnarizine, clemastine, clemas prompt, linogliride, linogliride fumarate, metformin, methyl tine fumarate, closiramine aceturate, cycliramine maleate, palmoxirate, palmoxirate Sodium, pioglitaZone hydrochlo 45 cyclizine, cyproheptadine hydrochloride, dexbromphe ride, pirogliride tartrate, proinsulin human, Seglitide acetate, niramine maleate, dexchlorpheniramine maleate, dimethin tolaZamide, tolbutamide, tolpyrramide, troglitaZone, Zopolr dene maleate, diphenhydramine citrate, diphenhydramine estat, and Sitagliptin. hydrochloride, dorastine hydrochloride, doxylamine Succi Antidiarrheal: rolgamidine, diphenoxylate hydrochloride nate, ebastine, levocabastine hydrochloride, loratadine, (lomotil), metronidazole (flagyl), methylprednisolone 50 mianserin hydrochloride, noberastine, orphenadrine citrate, (medrol), Sulfasalazine (aZulfidine). pyrabrom, pyrilamine maleate, pyroxamine maleate, rocas Antidiuretic: argipressin tannate, desmopressin acetate, tine hydrochloride, rotoxamine, tazifylline hydrochloride, lypressin. temelastine, terfenadine, tripelennamine citrate, tripelen Antidote: dimercaprol, edrophonium chloride, fomepi namine hydrochloride, triprolidine hydrochloride, Zolamine Zole, leucovorin calcium, levoleucovorin calcium, methylene 55 hydrochloride. blue, protamine Sulfate. Antihyperlipidemic: cholestyramine resin, clofibrate, Antidyskinetic: selegiline hydrochloride. colestipol hydrochloride, crilvastatin, dalvastatin, dextrothy Anti-emetic: alosetron hydrochloride, batanopride hydro roxine sodium, fluvastatin Sodium, gemfibrozil, lecimibide, chloride, bemesetron, benzquinamide, chlorpromazine, chlo lovastatin, niacin, pravastatin Sodium, probucol, simvastatin, rpromazine hydrochloride, clebopride, cyclizine hydrochlo 60 tiqueside, Xenbucin. ride, dimenhydrinate, diphenidol, diphenidol hydrochloride, Antihyperlipoproteinemic: acifran, beloxamide, beZafi diphenidol pamoate, dolasetron mesylate, domperidone, brate, boxidine, butoxamine hydrochloride, cetaben sodium, dronabinol, fluidorex, flumeridone, galdansetron hydrochlo ciprofibrate, gemcadiol, halofenate, lifibrate, meglutol, ride, granisetron, granisetron hydrochloride, lurosetron nafenopin, pimetime hydrochloride, theofibrate, tibric acid, mesylate, meclizine hydrochloride, metoclopramide hydro 65 treloxinate. chloride, metopimazine, ondansetron hydrochloride, panco Antihypertensive: alfuZosin hydrochloride, alipamide, pride, prochlorperazine, prochlorperazine edisylate, prochlo althiazide, amiquinsin hydrochloride, amlodipine besylate, US 9,278,134 B2 33 34 amlodipine maleate, anaritide acetate, atiprosin maleate, bel parachlorophenol, camphorated, potassium permanganate, fosdil, bemitradine, bendacalol mesylate, bendroflumethiaz poVidone-iodine, sepazonium chloride, silver nitrate, Sulfa ide, benzthiazide, betaxolol hydrochloride, bethanidine sul diazine, silver, Symclosene, thimerfonate sodium, thimero fate, bevantolol hydrochloride, biclodil hydrochloride, sal: troclosene potassium. bisoprolol, bisoprolol fumarate, bucindolol hydrochloride, Anti-inflammatory: acetominophen, alclofenac, alclom bupicomide, buthiazide: candoXatril, candoxatrilat, captopril, etaSone dipropionate, algestone acetonide, alpha amylase, carvedilol, ceronapril, chlorothiazide Sodium, cicletanine, amcinafal, amcinafide, amfenac sodium, amiprilose hydro cilaZapril, clonidine, clonidine hydrochloride, clopamide, chloride, anakinra, anirolac, anitraZafen, apaZone, bal cyclopenthiazide, cyclothiazide, darodipine, debrisoquin Sul Salazide disodium, bendazac, benoxaprofen, benzydamine fate, delapril hydrochloride, diapamide, diazoxide, dilevalol 10 hydrochloride, bromelains, broperamole, budesonide, car hydrochloride, diltiazem malate, ditekiren, doxazosin mesy profen, cicloprofen, cintaZone, cliprofen, clobetasol propi late, ecadotril, enalapril maleate, enalaprilat, enalkiren, onate, clobetaSone butyrate, clopirac, cloticaSone propionate, endralazine mesylate, epithiazide, eprosartan, eprosartan cormethasone acetate, cortodoxone, deflazacort, desonide, mesylate, fenoldopam mesylate, flavodilol maleate, flo desoximetaSone, dexamethasone dipropionate, diclofenac rdipine, floseduinan, fosinopril sodium, fosinoprilat, guana 15 potassium, diclofenac sodium, diflorasone diacetate, diflumi benz, guanabenZ acetate, guanacline Sulfate, guanadrel Sul done sodium, diflunisal, difluprednate, diftalone, dimethyl fate, guancydine, guanethidine monosulfate, guanethidine Sulfoxide, drocinonide, endrysone, enlimomab, enolicam Sulfate, guanfacine hydrochloride, guanisoquin Sulfate, gua Sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, noclor Sulfate, guanoctine hydrochloride, guanoxabenz, gua fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fen noxan Sulfate, guanoxyfen Sulfate, hydralazine hydrochlo tiazac, flazalone, fluazacort, flufenamic acid, flumizole, ride, hydralazine polistirex, hydroflumethiazide, flunisolide acetate, flunixin, flunixin meglumine, fluocortin indacrinone, indapamide, indolaprif hydrochloride, butyl, fluorometholone acetate, fluguaZone, flurbiprofen, indoramin, indoramin hydrochloride, indorenate hydrochlo fluretofen, fluticasone propionate, furaprofen, furobufen, hal ride, lacidipine, leniquinsin, levcromakalim, lisinopril, cinonide, halobetasol propionate, halopredone acetate, lofexidine hydrochloride, losartan potassium, losulazine 25 ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, hydrochloride, mebutamate, mecamylamine hydrochloride, ilonidap, indomethacin, indomethacin Sodium, indoprofen, medroxalol, medroxalol hydrochloride, methalthiazide, indoxole, intrazole, isoflupredone acetate, isoxepac, isoxi methyclothiazide, methyldopa, methyldopate hydrochloride, cam, ketoprofen, lofemizole hydrochloride, lornoxicam, metipranolol, metolaZone, metoprolol fumarate, metoprolol loteprednol etabonate, meclofenamate sodium, meclofe Succinate, metyrosine, minoxidil, monatepil maleate, 30 namic acid, meclorisone dibutyrate, mefenamic acid, muZolimine, nebivolol, nitrendipine, oftormine, pargyline mesalamine, meseclaZone, methylprednisolone Suleptanate, hydrochloride, pazoxide, pelanserin hydrochloride, perin morniflumate, nabumetone, naproxen, naproxen sodium, dopril erbumine, phenoxybenzamine hydrochloride, pinaci naproXol, nimaZone, olSalazine sodium, orgotein, orpanoxin, dil, pivopril, polythiazide, praZosin hydrochloride, primi oxaprozin, oxyphenbutaZone, paranyline hydrochloride, pen dolol, prizidilol hydrochloride, quinapril hydrochloride, 35 tosan polysulfate Sodium, phenbutaZone sodium glycerate, quinaprilat, quinaZosin hydrochloride, quinelorane hydro pirfenidone, piroXicam, piroxicam cinnamate, piroxicamola chloride, quinpirole hydrochloride, quinuclium bromide, mine, pirprofen, prednazate, prifelone, prodolic acid, produa ramipril, rauwolfia serpentina, reserpine, saprisartan potas Zone, proxazole, proxazole citrate, rimexolone, romazarit, sium, Saralasin acetate, sodium nitroprusside, Sulfinalol salcolex, Salnacedin, Salsalate, sanguinarium chloride, secla hydrochloride, tasosartan, teludipine hydrochloride, temoca 40 Zone, Sermetacin, Sudoxicam, Sulindac, Suprofen, talmetacin, pril hydrochloride, terazosin hydrochloride, terlakiren, tia talniflumate, talosalate, tebufelone, tenidap, tenidap Sodium, menidine, tiamenidine hydrochloride, ticrynafen, tinabinol, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tiXocor tiodazosin, tipentosin hydrochloride, trichlormethiazide, tri tol pivalate, tolmetin, tolmetin Sodium, triclonide, triflumi maZosin hydrochloride, trimethaphan camsylate, trimoxam date, Zidometacin, Zomepirac sodium. ine hydrochloride, tripamide, Xipamide, Zankiren hydrochlo 45 Antikeratinizing agent: doretinel, linarotene, pelretin. ride, Zofenoprilat arginine. Antimalarial: acedapsone, amodiaquine hydrochloride, Antihypotensive: ciclafrine hydrochloride, midodrine amduinate, arteflene, chloroquine, chloroquine hydrochlo hydrochloride. ride, chloroquine phosphate, cycloguanil pamoate, enpiroline Anti-infective: difloxacin hydrochloride, lauryl isoquino phosphate, halofantrine hydrochloride, hydroxychloroquine linium bromide, moxalactam disodium, omidazole, pentiso 50 Sulfate, mefloquine hydrochloride, menoctone, mirincamy micin, Sarafloxacin hydrochloride, protease inhibitors of hiv cin hydrochloride, primaquine phosphate, pyrimethamine, and other retroviruses, integrase inhibitors of hiv and other quinine Sulfate, tebuquine. retroviruses, cefaclor (CECLORTM), acyclovir (ZOVI Antimicrobial: aztreonam, chlorhexidine gluconate, imi RAXTM), norfloxacin (NOROXINTM), cefoxitin (ME durea, lycetamine, nibroxane, piraZmonam sodium, propi FOXINTM), cefuroxime axetil (CEFTINTM), ciprofloxacin 55 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 ride, Sergolexole maleate, Sumatriptan Succinate, Zatosetron renone, carbamide peroxide, cetalkonium chloride, cetylpy maleate. ridinium chloride: chlorhexidine hydrochloride, clioquinol, 60 Antimitotic: podofilox. domiphen bromide, fenticlor, fludazonium chloride, fuchsin, Antimycotic: amorolfine. basic, furazolidone, gentian violet, haiquinols, hexachlo Antinauseant: buclizine hydrochloride, cyclizine lactate, rophene: hydrogen peroxide, ichthammol, imidecyl iodine, naboctate hydrochloride. iodine, isopropyl alcohol, mafenide acetate, meralein Antineoplastic: acivicin, aclarubicin, acodazole hydro Sodium, mercufenol chloride, mercury, ammoniated, methyl 65 chloride, acronine, adoZelesin, aldesleukin, altretamine, benzethonium chloride, nitrofuraZone, nitromersol, octeni ambomycin, ametantrone acetate, aminoglutethimide, amsa dine hydrochloride, oxychlorosene, oxychlorosene Sodium, crine, anastroZole, anthramycin, asparaginase, asperlin, aza US 9,278,134 B2 35 36 citidine, azetepa, azotomycin, batimastat, benzodepa, ABL antagonists, benzochlorins, benzoylstaurosporine, beta bicalutamide, bisantrene hydrochloride, bisnafide dimesy lactam derivatives, beta-alethine, betaclamycin B, betulinic late, bizelesin, bleomycin Sulfate, brequinar Sodium, bropir acid, bFGF inhibitor, bicalutamide, bisantrene, bisaziridinyl imine, buSulfan, cactinomycin, calusterone, caracemide, car spermine, bisnafide, bistratene A, bizelesin, breflate, bropir betimer, carboplatin, carmustine, carubicin hydrochloride, imine, budotitane, buthionine Sulfoximine, calcipotriol, carzelesin, cedefingol, chlorambucil, cirolemycin, cisplatin, calphostin C, camptothecin derivatives, canarypox IL-2, cladribine, crisinatol mesylate, cyclophosphamide, cytara capecitabine, carboxamide-amino-triazole, carboxyamidot bine, dacarbazine, dactinomycin, daunorubicin hydrochlo riazole, CaRest M3, CARN 700, cartilage derived inhibitor, ride, decitabine, dexormaplatin, deZaguanine, deZaguanine carzelesin, casein kinase inhibitors (ICOS), castanospermine, mesylate, diaziquone, docetaxel, doxorubicin, doxorubicin 10 cecropin B. cetrorelix, chlorins, chloroquinoxaline Sulfona hydrochloride, droloxifene, droloxifene citrate, dromo mide, cicaprost, cis-porphyrin, cladribine, clomifene ana stanolone propionate, duaZomycin, edatrexate, eflomithine logues, clotrimazole, collismycin A, collismycin B, combre hydrochloride, elsamitrucin, enloplatin, enpromate, epipro tastatin A4, combretastatin analogue, conagenin, pidine, epirubicin hydrochloride, erbulozole, esorubicin crambescidin 816, crisinatol, cryptophycin 8, cryptophycin A hydrochloride, estramustine, estramustine phosphate 15 derivatives, curacin A, cyclopentanthraquinones, cyclo Sodium, etanidazole, ethiodized oil I 131, etoposide, etopo platam, cypemycin, cytarabine ocfosfate, cytolytic factor, side phosphate, etoprine, fadrozole hydrochloride, faZara cytostatin, dacliximab, decitabine, dehydrodidemnin B, bine, fenretinide, floxuridine, fludarabine phosphate, fluo deslorelin, dexifosfamide, dexraZoxane, dexVerapamil, diazi rouracil, fluorocitabine, fosquidone, fostriecin Sodium, quone, didemnin B, didox, diethylnorspermine, dihydro-5- gemcitabine, gemcitabine hydrochloride, gold au 198, azacytidine, dihydrotaxol. 9-dioxamycin, diphenyl spiro hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofos mustine, docosanol, dolasetron, doxifluridine, droloxifene, ine, interferon alfa-2a, interferon alfa-2b, interferon alfa-N1, dronabinol, duocannycin SA, ebselen, ecomustine, edelfos interferon alfa-N3, interferon beta-la, interferon gamma-Ib, ine, edrecolomab, eflornithine, elemene, emitefur, epirubicin, iproplatin, irinotecan hydrochloride, lanreotide acetate, letro epristeride, estramustine analogue, estrogen agonists, estro Zole, leuprolide acetate, liarozole hydrochloride, lometrexol 25 gen antagonists, etanidazole, etoposide phosphate, exemes Sodium, lomustine, losoxantrone hydrochloride, masoprocol, tane, fadrozole, faZarabine, fenretinide, filgrastim, finas maytansine, mechlorethamine hydrochloride, megestrol teride, flavopiridol, flezelastine, fluasterone, fludarabine, acetate, melengestrol acetate, melphalan, menogaril, mercap fluorodaunorunicin hydrochloride, forfenimex, formestane, topurine, methotrexate, methotrexate Sodium, metoprine, fostriecin, fotemustine, gadolinium texaphyrin, gallium meturedepa, mitindomide, mitocarcin, mitocromin, mitogil 30 nitrate, galocitabine, ganirelix, gelatinase inhibitors, gemcit lin, mitomalcin, mitomycin, mitosper, mitotane, mitox abine, glutathione inhibitors, hepsulfam, heregulin, hexam antrone hydrochloride, mycophenolic acid, nocodazole, ethylene bisacetamide, hypericin, ibandronic acid, idarubi nogalamycin, Ormaplatin, oxiSuran, paclitaxel, pegaspargase, cin, idoxifene, idramantone, ilmofosine, illomastat, peliomycin, pentamustine, peplomycin Sulfate, perfosfa imidazoacridones, imiquimod, immunostimulant peptides, mide, pipobroman, piposulfan, piroXantrone hydrochloride, 35 insulin-like growth factor-1 receptor inhibitor, interferon plicamycin, plomestane, porfimer Sodium, porfiromycin, agonists, interferons, interleukins, iobenguane, iododoxoru prednimustine, procarbazine hydrochloride, puromycin, bicin, ipomeanol, 4-irinotecan, iroplact, irsogladine, isoben puromycin hydrochloride, pyrazofurin, riboprine, rogletim gazole, isohomohalicondrin B, itasetron, jasplakinolide, ide, safmgol, Safingol hydrochloride, Semustine, simtraZene, kahalalide F, lamellarin-N triacetate, lanreotide, leinamycin, sparfosate Sodium, sparsomycin, spirogermanium hydro 40 lenograstim, lentinan Sulfate, leptolstatin, letrozole, leukemia chloride, Spiromustine, spiroplatin, streptonigrin, StreptoZo inhibiting factor, leukocyte alpha interferon, leuprolide--es cin, strontium chloride Sr 89, Sulofenur, talisomycin, taxane, trogen-progesterone, leuprorelin, levamisole, liarozole, lin taxoid, tecogalan Sodium, tegafur, teloxantrone hydrochlo ear polyamine analogue, lipophilic disaccharide peptide, ride, temoporfin, teniposide, teroxirone, testolactone, thiami lipophilic platinum compounds, lissoclinamide 7, lobaplatin, prine, thioguanine, thiotepa, tiazofurin, tirapazamine, topo 45 lombricine, lometrexol, lonidamine, losoxantrone, lovasta tecan hydrochloride, toremifene citrate, trestolone acetate, tin, loxoribine, lurtotecan, lutetium texaphyrin, lysofylline, triciribine phosphate, trimetrexate, trimetrexate glucuronate, lytic peptides, maitansine, mannostatin A, marimastat, maso triptorelin, tubulozole hydrochloride, uracil mustard, ure procol, maspin, matrilysin inhibitors, matrix metalloprotein depa, Vapreotide, Verteporfin, vinblastine Sulfate, Vincristine ase inhibitors, menogaril, merbarone, meterelin, methioni Sulfate, vindesine, Vindesine Sulfate, vinepidine Sulfate, Ving 50 nase, metoclopramide, MIF inhibitor, mifepristone, lycinate sulfate, vinleurosine sulfate, vinorelbine tartrate, miltefosine, 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 55 chorionic gonadotrophin, monophosphoryl lipid A+myobac cin, acylfulvene, adecypenol, adoZelesin, aldesleukin, ALL terium cell wall sk, mopidamol, multiple drug resistance TKantagonists, altretamine, ambamustine, amidox, amifos genie inhibitor, multiple tumor Suppressor 1-based therapy, tine, aminolevulinic acid, amrubicin, atrsacrine, anagrelide, mustard anticancer agent, mycaperoxide B, mycobacterial anastroZole, andrographolide, angiogenesis inhibitors, cell wall extract, myriaporone, N-acetyldinaline, N-substi antagonist D, antagonist G, antarelix, anti-dorsalizing mor 60 tuted benzamides, nafarelin, nagrestip, naloxone-pentaZo phogenetic protein-1, antiandrogen, prostatic carcinoma, cine, napavin, naphterpin, nartograstim, nedaplatin, nemoru antiestrogen, antineoplaston, antisense oligonucleotides, bicin, neridronic acid, neutral endopeptidase, nilutamide, aphidicolin glycinate, apoptosis gene modulators, apoptosis nisamycin, nitric oxide modulators, nitroxide antioxidant, regulators, apurinic acid, ara-CDP-DL-PTBA, arginine nitrullyn, O6-benzylguanine, octreotide, okicenone, oligo deaminase, asulacrine, atamestane, atrimustine, axinastatin 65 nucleotides, onapristone, ondansetron, ondansetron, oracin, 1, axinastatin 2, axinastatin 3, aZasetron, azatoxin, azaty oral cytokine inducer, ormaplatin, osaterone, Oxaliplatin, rosine, baccatin III derivatives, balanol, batimastat, BCR/ oxaunomycin, paclitaxel analogues, paclitaxel derivatives, US 9,278,134 B2 37 38 palauamine, palmitoylrhizoxin, pamidronic acid, panax chloride, lazabemide, levodopa, lometraline hydrochloride, ytriol, panomifene, parabactin, paZelliptine, pegaspargase, mofegiline hydrochloride, naxagolide hydrochloride, parep peldesine, pentosan polysulfate sodium, pentostatin, pentro tide Sulfate, procyclidine hydrochloride, quinetorane hydro Zole, perflubron, perfosfamide, perillyl alcohol, phenazino chloride, ropinirole hydrochloride, selegiline hydrochloride, mycin, phenylacetate, phosphatase inhibitors, picibanil, pilo tolcapone, trihexyphenidyl hydrochloride, antiperistaltic: carpine hydrochloride, pirarubicin, piritrexim, placetin A, difenoximide hydrochloride, difenoxin, diphenoxylate placetin B, plasminogen activator inhibitor, platinum com hydrochloride, fluperamide, lidamidine hydrochloride, lop plex, platinum compounds, platinum-triamine complex, por eramide hydrochloride, malethamer, nufenoXole, paregoric. fimer Sodium, porfiromycin, propyl bis-acridone, prostaglan Antipneumocystic: atovaquone. din J2, proteasome inhibitors, protein A-based immune 10 Antiproliferative agent: piritreximisethionate. modulator, protein kinase Cinhibitor, protein kinase Cinhibi Antiprostatic hypertrophy: sitogluside. tors, microalgal, protein tyrosine phosphatase inhibitors, Antiprotozoal: amodiaquine, azanidazole, bamidazole, purine nucleoside phosphorylase inhibitors, purpurins, pyra camidazole, chlortetracycline bisulfate, chlortetracycline Zoloacridine, pyridoxylated hemoglobin polyoxyethylene hydrochloride, flubendazole, flunidazole, halofuginone conjugate, rafantagonists, raltitrexed, ramosetron, ras farne 15 hydrobromide, imidocarb hydrochloride, ipronidazole, met syl protein transferase inhibitors, ras inhibitors, ras-GAP ronidazole, misonidazole, moXnidazole, nitarSone, partricin, inhibitor, retelliptine demethylated, rhenium Re 186 etidr puromycin, puromycin hydrochloride, ronidazole, Sulnida onate, rhizoxin, ribozymes, RII retinamide, rogletimide, rohi Zole, tinidazole. tukine, romurtide, roquinimex, rubiginone B1, ruboxyl, saf Antipruritic: cyproheptadine hydrochloride, methdilazine, ingol, Saintopin, SarCNU, sarcophytol A, SargramoStim, Sdi methdilazine hydrochloride, trimeprazine tartrate. 1 mimetics, semustine, Senescence derived inhibitor 1, sense Antipsoriatic: acitretin, anthralin, azaribine, calcipotriene, oligonucleotides, signal transduction inhibitors, signal trans cycloheximide, enaZadrem phosphate, etretinate, liaroZole duction modulators, single chain antigen binding protein, fumarate, lonapalene, tepoxalin. sizofuran, Sobuzoxane, Sodium borocaptate, sodium pheny Antipsychotic: acetophenazine maleate, alentemol hydro lacetate, Solverol. Somatomedin binding protein, Sonermin, 25 bromide, alpertine, azaperone, batelapine maleate, benperi sparfosic acid, Spicamycin D, Spiromustine, splenopentin, dol, benzindopyrine hydrochloride, brofbxine, bromperidol, spongistatin 1, squalamine, stem cell inhibitor, stem-cell divi bromperidol decanoate, butaclamol hydrochloride, butapera sion inhibitors, stipiamide, Stromelysin inhibitors, sulfi Zine, butaperazine maleate, carphenazine maleate, carvotro nosine, Superactive vasoactive intestinal peptide antagonist, line hydrochloride, chlorpromazine, chlorpromazine hydro Suradista, Suramin, Swainsonine, synthetic glycosaminogly 30 chloride, chlorprothixene, cinperene, cintriamide, clomacran cans, tallimustine, tamoxifen methiodide, tauromustine, taZ phosphate, clopenthixol, clopimozide, clopipazan mesylate, arotene, tecogalan sodium, tegafur, tellurapyrylium, telom cloroperone hydrochloride, clothiapine, clothixamide male erase inhibitors, temoporfin, temozolomide, teniposide, ate, clozapine, cyclophenazine hydrochloride, droperidol. tetrachlorodecaoxide, tetrazomine, thaliblastine, thalido etazolate hydrochloride, fenimide, flucindole, flumezapine, mide, thiocoraline, thrombopoietin, thrombopoietin mimetic, 35 fluphenazine decanoate, fluiphenazine enanthate, fluphena thymalfasin, thymopoietin receptor agonist, thymotrinan, Zine hydrochloride, fluspiperone, fluspirilene, flutroline, gev thyroid stimulating hormone, tin ethyl etiopurpurin, tira otroline hydrochloride, halopemide, haloperidol, haloperidol paZamine, titanocene dichloride, topotecan, top sentin, decanoate, illoperidone, imidoline hydrochloride, lenperone, toremifene, totipotent stem cell factor, translation inhibitors, maZapertine Succinate, mesoridazine, mesoridazine besylate, tretinoin, triacetyluridine, triciribine, trimetrexate, triptore 40 metiapine, milemperone, millipertine, molindone hydrochlo lin, tropisetron, turosteride, tyrosine kinase inhibitors, tyr ride, naranol hydrochloride, neflumozidehydrochloride, oca phostins, UBC inhibitors, ubenimex, urogenital sinus-de peridone, olanzapine, oxiperomide, penfluridol, pentiapine rived growth inhibitory factor, urokinase receptor maleate, perphenazine, pimozide, pinoxepin hydrochloride, antagonists, vapreotide, variolin B. vector system, erythro pipamperone, piperacetazine, pipotiazine palniitate, piquin cyte gene therapy, Velaresol, Veramine, Verdins, verteporfin, 45 done hydrochloride, prochlorperazine edisylate, prochlor Vinorelbine, Vinxaltine, vitaxin, Vorozole, Zanoterone, Zeni perazine maleate, promazine hydrochloride, remoxipride, platin, Zilascorb, Zinostatin stimalamer. remoxipride hydrochloride, rimcazole hydrochloride, seperi Anti-cancer Supplementary potentiating agents: tricyclic dol hydrochloride, sertindole, Setoperone, spiperone, thior anti-depressant drugs (e.g., imipramine, desipramine, amit idazine, thioridazine hydrochloride, thiothixene, thiothixene ryptyline, clomiprainine, trimipramine, doxepin, nortrip 50 hydrochloride, tioperidone hydrochloride, tiospirone hydro tyline, protriptyline, amoxapine and maprotiline), non-tricy chloride, trifluoperazine hydrochloride, trifluperidol, triflu clic anti-depressant drugs (e.g., Sertraline, traZodone and promazine, triflupromazine hydrochloride, Ziprasidone citalopram), Ca' antagonists (e.g., Verapamil, nifedipine, hydrochloride. nitrendipine and caroverine), calmodulin inhibitors (e.g., pre Antirheumatic: auranofin, aurothioglucose, bindarit, nylamine, trifluoroperazine and clomipramine), amphoteri 55 lobenzarit Sodium, phenylbutaZone, piraZolac, prinomide cin B, triparanol analogues (e.g., tamoxifen), antiarrhythmic tromethamine, Seprilose. drugs (e.g., quinidine), antihypertensive drugs (e.g., reser Antischistosomal: becanthone hydrochloride, hycanthone, pine), thiol depleters (e.g., buthionine and Sulfoximine) and lucanthone hydrochloride, niridazole, oxamniquine, pararo Multiple Drug Resistance reducing agents such as Crema saniline pamoate, teroxalene hydrochloride. phor EL. 60 Antiseborrheic: chloroxine, piroctone, piroctone olamine, Antineutropenic: filgrastim, lenograstim, molgramostim, resorcinol monoacetate, antisecretory: arbaprostil, deprostil, regramos tim, Sargramostim. fenoctimine Sulfate, octreotide, octreotide acetate, omepra Antiobsessional agent: fluvoxamine maleate. Zole Sodium, rioprostil, trimoprostil. Antiparasitic: abamectin, clorSulon, ivermectin. Antispasmodic: stilonium iodide, tizanidine hydrochlo Antiparkinsonian: benztropine mesylate, biperiden, 65 ride. biperiden hydrochloride, biperiden lactate, carmantadine, Antithrombotic: anagrelide hydrochloride, bivalirudin, ciladopa hydrochloride, dopamantine, ethopropazine hydro dalteparin Sodium, danaparoid sodium, daZOXiben hydro US 9,278,134 B2 39 40 chloride, efegatran Sulfate, enoxaparin Sodium, ifetroban, hydrochloride, sematilide hydrochloride, Suricamide male ifetroban Sodium, tinzaparin sodium, trifenagrel. ate, tocamide, tocamide hydrochloride, transcamide. Antitussive: benzonatate, butamirate citrate, chlophedi Cardioprotectant: dexraZOxane, draflazine. anol hydrochloride, codeine polistirex, codoxime, dex Cardiotonic: actodigin, aminone, bemoradan, butopamine, tromethorphan, dextromethorphan hydrobromide, dex carbazeran, carsatirin Succinate, deslanoside, digitalis, digi tromethorphan polistirex, ethyl dibunate, guaiapate, toxin, digoxin, dobutamine, dobutamine hydrochloride, dob hydrocodone bitartrate, hydrocodone polistirex, levopro utamine lactobionate, dobutamine tartrate, enoXimone, ima poxyphene napsylate, noscapine, pemerid nitrate, Zodan hydrochloride, indolidan, isomazole hydrochloride, pipazethate, SuXemerid Sulfate. levdobutamine lactobionate, lixazinone sulfate, medorinone, 10 milrinone, pelrinone hydrochloride, pimobendan, piroxi Anti-ulcerative: aceglutamide aluminum, cadexomer mone, prinoXodan, proscillaridin, quaZinone, tazolol hydro iodine, cetraxate hydrochloride, enisoprost, isotiquimide, chloride, Vesnarinone. lansoprazole, lavoltidine Succinate, misoprostol, nizatidine, Cardiovascular agent: dopexamine, dopexamine hydro nolinium bromide, pantoprazole, pifarnine, pirenzepine chloride. hydrochloride, rabeprazole sodium, remiprostol, roXatidine 15 Choleretic: dehydrocholic acid, fencibutirol, hymec acetate hydrochloride, Sucralfate. Sucrosofate potassium, romone, piprozolin, sincalide, tocamphyl. tolimidone. Cholinergic: aceclidine, bethanechol chloride, carbachol, Anti-urolithic: cysteamine, cysteamine hydrochloride, demecarium bromide, dexpanthenol, echothiophate iodide, tricitrates. isofluorophate, methacholine chloride, neostigmine bromide, Appetite Suppressant: dexfenfluramine hydrochloride, neostigmine methylsulfate, physostigmine, physostigmine phendimetrazine tartrate, phentermine hydrochloride. salicylate, physostigmine Sulfate, pilocarpine, pilocarpine Benign prostatic hyperplasia therapy agent: tamsulosin hydrochloride, pilocarpine nitrate, pyridostigmine bromide. hydrochloride. Cholinergic agonist: Xanomeline, Xanomeline tartrate. Blood glucose regulators: human insulin, glucagon, tolaza Cholinesterase deactivator obidoxime chloride, prali mide, tolbutamide, chloropropamide, acetohexamide and 25 doXime chloride, pralidoxime iodide, pralidoxime mesylate. glipizide. Coccidiostat: arprinocid, narasin, semduramicin, semdu Bone resorption inhibitor: alendronate sodium, etidronate ramicin Sodium. disodium, pamidronate disodium. Dognition adjuvant: ergoloid mesylates, piracetam, Bronchodilator: albuterol, albuterol sulfate, azanator male pramiracetam hydrochloride, pramiracetam Sulfate, tacrine ate, bamifylline hydrochloride, bitolterol mesylate, butap 30 hydrochloride. rost, carbuterol hydrochloride, clorprenaline hydrochloride, Cognition enhancer: besipirdine hydrochloride, linopird colterol mesylate, doxaprost, doxofylline, dyphylline, ine, sibopirdine. enprofylline, ephedrine, ephedrine hydrochloride, fenoterol, Depressant: omeprazole. fenprinast hydrochloride, guaithylline, hexoprenaline Sul Diagnostic aid: aminohippurate sodium, anazolene fate, hoquizil hydrochloride, ipratropium bromide, isoet 35 Sodium, arclofenin, arginine, bentiromide, benzylpenicilloyl harine, isoetharine hydrochloride, isoetharine mesylate, iso polylysine, butedronate tetrasodium, butilfenin, coccidioidin, proterenol hydrochloride, isoproterenol Sulfate, corticorelin ovine triflutate, corticotropin, repository, corti metaproterenol polistirex, metaproterenol Sulfate, nisbuterol cotropin Zinc hydroxide, diatrizoate meglumine, diatrizoate mesylate, oxtriphylline, picumeterol fumarate, piquizil Sodium, diatrizoic acid, diphtheria toxin for Schick test, dis hydrochloride, pirbuterol acetate, pirbuterol hydrochloride, 40 ofenin, edrophonium chloride, ethiodized oil, etifenin, exam procaterol hydrochloride, pseudoephedrine Sulfate, quaZod etazime, ferristenc, ferumoxides, ferumoXsil, fluorescein, ine, quinterenol Sulfate, racepinephrine, racepinephrine fluorescein Sodium, gadobenate dimeglumine, gadoteridol. hydrochloride, reproterol hydrochloride, rimiterol hydrobro gadodiamide, gadopentetate dimeglumine, gadoversetamide, mide, Salmeterol, Salmeterol Xinafoate, Soterenol hydrochlo histoplasmin, impromidine hydrochloride, indigotindisul ride, sulfonterol hydrochloride, Suloxifen oxalate, terbutaline 45 fonate Sodium, indocyanine green, lobenguane sulfate I'', Sulfate, theophylline, Xanoxate sodium, Zindotrine, Zinterol iobenzamic acid, iocarmate meglumine, locarmic acid, ioc hydrochloride. etamic acid, iodamide, lodamide megiumine, iodipamide Carbonic anhydrase inhibitor: acetazolamide, acetazola meglumine, iodixanol, iodoxamate meglumine, iodoxamic mide sodium, dichlorphenamide, dorzolamide hydrochlo acid, ioglicic acid, ioglucol, ioglucomide, ioglycamic acid, ride, methazolamide, seZolamide hydrochloride. 50 iogulamide, lohexyl, iomeprol, iopamidol, iopanoic acid, Cardiac depressant: acecamide hydrochloride, acetylcho iopentol, iophendylate, iprofenin, iopronic acid, ioprocemic line chloride, actisomide, adenosine, amiodarone, aprindine, acid, iopydol, iopydone, iosefamic acid, io.seric acid, ioSula aprindine hydrochloride, artilide fumarate, azimilide mide meglumine, ioSumetic acid, iotasul, iotetric acid, Dihydrochloride, bidisomide, bucamide maleate, bucro iothalamate meglumine, iothalamate sodium, iothalamic marone, butoprozine hydrochloride, capobenate Sodium, 55 acid, iotrolan, iotroxic acid, ioversol, ioxaglate meglumine, capobenic acid, cifenline, cifenline Succinate, clofilium phos ioxagiate Sodium, ioxaglic acid, ioxilan, ioxotrizoic acid, ipo phate, disobutamide, disopyramide, disopyramide phos date calcium, ipodate sodium, isosulfan blue, leukocyte typ phate, dofetilide, drobuline, edifolone acetate, emilium tosy ing serum, lidofenin, mebrofenin, meglumine, metrizamide, late, encamide hydrochloride, flecamide acetate, ibutilide metrizoate sodium, metyrapone, metyrapone tartrate, mumps fumarate, indecamide hydrochloride, ipazilide fumarate, 60 skin test antigen, pentetic acid, propyliodone, quinaldine lorajmine hydrochloride, lorcamide hydrochloride, meoben blue, sermorelin acetate, sodium iodide I'', sprodiamide, tine Sulfate, mexiletine hydrochloride, modecamide, mori Stannous pyrophosphate, Stannous Sulfur colloid. Succimer, cizine, oxiramide, pirmenol hydrochloride, pirolazamide, teriparatide acetate, tetrofosmin, tolbutamide Sodium, tuber pranolium chloride, procainamide hydrochloride, pro culin, tyropanoate sodium, Xylose. pafenone hydrochloride, pyrinoline, quindonium bromide, 65 Diuretic: ambuphylline, ambuside, amiloride hydrochlo quinidine gluconate, quinidine Sulfate, recainam hydrochlo ride, azolimine, azosemide, brocrinat, bumetanide, chlorothi ride, recainam tosylate, risotilide hydrochloride, ropitoin azide, chlorthalidone, clazolimine, clorexolone, ethacrynate US 9,278,134 B2 41 42 Sodium, ethacrynic acid, etoZolin, fenduizone, furosemide, dihydroequilenin, 17 alpha estradiol, 17 beta estradiol, leu hydrochlorothiazide, isosorbide, mannitol, mefruside, oZoli prolide (LUPRONTM), glucagon, testolactone, clomiphene, none, piretanide, spiroXasone, torsemide, triamterene, triflo human menopausal gonadotropins, human chorionic gona cin, urea. dotropin, urofollitropin, bromocriptine, gonadorelin, lutein Dopaminergic agent: ibopamine. izing hormone releasing hormone and analogs, gonadotro Ectoparasiticide: nifluridide, permethrin. pins, danazol, testosterone, dehydroepiandrosterone, Emetic: apomorphine hydrochloride. androstenedione, dihydroestosterone, relaxin, oxytocin, Enzyme inhibitor: acetohydroxamic acid, alrestatin vasopressin, folliculostatin, follicle regulatory protein, gona Sodium, aprotinin, benazepril hydrochloride, benazeprilat, doctrinins, oocyte maturation inhibitor, insulin growth factor, benurestat, bromocriptine, bromocriptine mesylate, cilastatin 10 follicle stimulating hormone, luteinizing hormone, tamox Sodium, fluorofamide, lergotrile, lergotrile mesylate, levcy ifen, corticorelinovine triftutate, coSyntropin, metogest, pitu closerine, libenzapril, pentopril, pepstatin, perindopril, polig itary, posterior, seractide acetate, Somalapor, somatrem, nate Sodium, Sodium amylosulfate, Sorbinil, spirapril hydro Somatropin, somenopor, somidobove. chloride, spiraprilat, taleranol, teprotide, tolfamide, Hypocholesterolemic: lifibrol. Zofenopril calcium. 15 Hypoglycemic: darglitaZone sodium: glimepiride. Estrogen: chlorotrianisene, dienestrol, diethylstilbestrol, Hypolipidemic: azalanstat dihydrochloride, colestolone, diethylstilbestrol diphosphate, equilin, estradiol, estradiol Surfomer, Xenalipin. cypionate, estradiolenanthate, estradiol undecylate, estradiol Hypotensive: viprostol. Valerate, estraZinol hydrobromide, estriol, estrofurate, estro Hmgcoa reductase inhibitors: lovastatin (MEVACORTM), gens, conjugated, estrogens, esterified, estrone, estropipate, simvastatin (ZOCORTM), pravastatin (PRAVACHOLTM), flu ethinyl estradiol, fenestrel, mestranol, nylestriol, quinestrol. vasatin (LESCOLTM). Fibrinolytic: anistreplase, bisobrin lactate, brinolase. Immunizing agent: antirabies serum, antivenin (latrodec Free oxygen radical scavenger: pegorgotein. tus mactans), antivenin (micrurus fulvius), antivenin (crotal Gastrointestinal motility agents: cisapride (PROPUL idae) polyvalent, BCG vaccine, botulism antitoxin, cholera SIDTM), metoclopramide (REGLANTM), hyoscyamine 25 vaccine, diphtheria antitoxin, diphtheria toxoid, diphtheria (LEVSINTM). toxoid adsorbed, globulin, immune, hepatitis b immune Glucocorticoid: amcinonide, beclomethasone dipropi globulin, hepatitis B virus vaccine inactivated, influenza virus onate, betamethasone, betamethasone acetate, betametha vaccine, measles virus vaccine live, meningococcal polysac Sone benzoate, betamethasone dipropionate, betamethasone charide vaccine group A, meningococcal polysaccharide vac Sodium phosphate, betamethasone Valerate, carbenoXolone 30 cine group C, mumps virus vaccine live, pertussis immune Sodium, clocortolone acetate, clocortolone pivalate, clopred globulin, pertussis vaccine, pertussis vaccine adsorbed, nol, corticotropin, corticotropin, repository, corticotropin plague vaccine, poliovirus vaccine inactivated, poliovirus Zinc hydroxide, cortisone acetate, cortivaZol, descinolone vaccine live oral, rabies immune globulin, rabies vaccine, Rh acetonide, dexamethasone, dexamethasone sodium phos (D) immune globulin, rubella virus vaccine live, Smallpox phate, diflucortolone, diflucortolone pivalate, flucloronide, 35 vaccine, tetanus antitoxin, tetanus immune globulin, tetanus flumethasone, flumethasone pivalate, flunisolide, fluocino toxoid, tetanus toxoid adsorbed, typhoid vaccine, yellow lone acetonide, fluocinonide, fluocortolone, fluocortolone fever vaccine, Vaccinia immune globulin, varicella-Zoster caproate, fluorometholone, fluperolone acetate, flupredniso immune globulin. lone, fluprednisolone Valerate, flurandrenolide, formocortal, Immunomodulator: dimepranol acedoben, imiquimod, hydrocortisone, hydrocortisone acetate, hydrocortisone 40 interferon beta-Ib, lisofylline, mycophenolate mofetil, preza buteprate, hydrocortisone butyrate, hydrocortisone sodium tide copper acetate. phosphate, hydrocortisone sodium Succinate, hydrocortisone Immunoregulator: azarole, fanetizole mesylate, frentizole, Valerate, medrysone, methylprednisolone, methylpredniso oxamisole hydrochloride, ristianol phosphate, thymopentin, lone acetate, methylprednisoloime sodium phosphate, meth tilomisole. ylprednisolone sodium Succinate, nivaZol, paramethasone 45 Immunostimulant: loxoribine, teceleukin. acetate, prednicarbate, prednisolone, prednisolone acetate, Immunosuppressant: azathioprine, azathioprine Sodium, prednisolone hemisuccinate, prednisolone sodium phos cyclosporine, daltroban, gusperimus trihydrochloride, siroli phate, prednisolone sodium Succinate, prednisolone tebutate, mus, tacrolimus. prednisone, prednival, ticabesone propionate, tralonide, tri Impotence therapy adjunct: deleguamine hydrochloride. amcinolone, triamcinolone acetonide, triamcinolone 50 Inhibitor: acarbose, atorvastatin calcium, benserazide, bro acetonide Sodium, triamcinolone diacetate, triamcinolone cresine, carbidopa, clavulanate potassium, daZmegrel, doce hexacetonide. benone, epoprostenol, epoprostenol Sodium, epristeride, fin Gonad-stimulating principle: buserelin acetate, clomi asteride, flurbiprofen sodium, furegrelate sodium, lufironil, phene citrate, ganirelix acetate, gonadorelin acetate, gona miglitol, orlistat, pimagedine hydrochloride, pirmagrel, dorelin hydrochloride, gonadotropin, chorionic, menotro 55 ponalrestat, ridogrel, Sulbactam benzathine, Sulbactampiv pins. oxil, Sulbactam Sodium, Suronacrine maleate, taZobactam, Hair growth stimulant: minoxidil. taZobactam Sodium, ticlopidine hydrochloride, tirilazad Hemostatic: aminocaproic acid, oXamarin hydrochloride, mesylate, tolrestat, Velnacrine maleate, Zifrosilone, Zileuton. Sulmarin, thrombin, tranexarnic acid. Keratolytic: alcloxa, aldioxa, benzoyl peroxide, diben Histamine H2 receptor antagonists: ranitidine (ZAN 60 Zothiophene, etarotene, isotretinoin, motretinide, picotrin TACTM), famotidine (PEPCIDTM), cimetidine (TAGA diolamine, resorcinol, resorcinol monoacetate, Salicylic acid, METTM), nizatidine (AXIDTM). Sumarotene, tazarotene, tetroquinone, tretinoin. Hormone: diethylstilbestrol, progesterone, 17 hydroxy LHRL agonist: deslorelin, goserelin, histrelin, lutrelin progesterone, medroxyprogesterone, norgestrel, norethyno acetate, nafarelin acetate. drel, estradiol, megestrol (megace), norethindrone, levonorg 65 Liver disorder treatment: malotilate. estrel, ethyndiol, ethinyl estradiol, mestranol, estrone, equi Luteolysin: femprostalene. lin, 17 alpha dihydroequilin, equilenin, 17 alpha Memory adjuvant: dimoxamine hydrochloride, ribaminol. US 9,278,134 B2 43 44 Mental performance enhancer: aniracetam. teboroxime, technetium Tc" tetrofosmin, technetium Mood regulator: fengabine. Tc'"tiatide, thyroxine I'', thyroxine I'', tolpovidone I'', Mucolytic: acetylcysteine, carbocysteine, domiodol. triolein I?, triolein I. Mucosal protective agents: misoprostol (CYTOTECTM). Regulator: calcifediol, calcitonin, calcitriol, clodronic Mydriatic: berefrine. acid, dihydrotachysterol, etidronic acid, oxidronic acid, piri Nasal decongestant: nemaZoline hydrochloride, pseu dronate Sodium, risedronate Sodium, Secalciferol. doephedrine polistirex. Relaxant: adiphenine hydrochloride, alcuronium chloride, Neuroleptic: duoperone fumarate, risperidone. aminophylline, azumolene sodium, baclofen, benzoctamine Neuromuscular blocking agent: atracurium besylate, cisa hydrochloride, carisoprodol, chlorphenesin carbamate, chlo tracurium besylate, doxacurium chloride, gallamine triethio 10 dide, metocurine iodide, mivacurium chloride, pancuronium rZoxazone, cinflumide, cinnamedrine, clodanolene, bromide, pipecuronium bromide, rocuronium bromide, suc cyclobenzaprine hydrochloride, dantrolene, dantrolene cinylcholine chloride, tubocurarine chloride, vecuronium sodium, femalamide, fenyripol hydrochloride, fetoxylate bromide. hydrochloride, flavoxate hydrochloride, fletazepam, flume Neuroprotective: dizocilpine maleate. 15 tramide-flurazepam hydrochloride, hexafluorenium bromide, NMDA antagonist: selfotel. isomylamine hydrochloride, lorbamate, mebeverine hydro Non-hormonal sterol derivative: pregnenolone succinate. chloride, meSuprine hydrochloride, metaxalone, methocar Oxytocic: carboprost, carboprost methyl, carboprost bamol, methixene hydrochloride, nafomine malate, neleZa tromethamine, dinoprost, dinoprost tromethamine, dinopro prine maleate, papaverine hydrochloride, pipoxolan. stone, ergonovine maleate, meteneprost, methylergonovine Hydrochloride, quinctolate, ritodrine, ritodrine hydrochlo maleate, oxytocin, Sparteine Sulfate. ride, rolodine, theophylline sodium glycinate, thiphenamil Plasminogen activator: alteplase, urokinase. hydrochloride, xilobam. Platelet activating factor antagonist: lexipafant. Repartitioning agent: cimaterol. Platelet aggregation inhibitor: acadesine, beraprost, bera Scabicide: amitraz, crotamiton. prost sodium, ciprostene calcium, itaZigrel, lifarizine, 25 Sclerosing agent: ethanolamine oleate, morrhuate Sodium, OXagrelate. tribenoside. Post-stroke and post-head trauma treatment: citicoline Sedative: propiomazine. Sodium. Sedative-hypnotic: allobarbital, alonimid, alprazolam, Potentiator: pentostatin, talopram hydrochloride. amobarbital sodium, bentazepam, brotizolam, butabarbital, Progestin: algestone acetophenide, amadinone acetate, 30 butabarbital sodium, butalbital, capuride, carbocloral, chloral anagestone acetate, chlormadinone acetate, cingestol, cloge betaine, chloral hydrate, chlordiazepoxide hydrochloride, stone acetate, clomegestone acetate, desogestrel, dimethister cloperidone hydrochloride, clorethate, cyprazepam, dex one, dydrogesterone, ethynerone, ethynodiol diacetate, clamol hydrochloride, diazepam, dichloralphenaZone, esta etonogestrel, fluorogestone acetate, gestaclone, gestodene, Zolam, ethchlorVynol, etomidate, fenobam, flunitrazepam, gestonorone caproate, gestrinone, haloprogesterone, hydrox 35 fosazepam, glutethimide, halazepam, lormetazepam, meclo yprogesterone caproate, levonorgestrel, lynestrenol, qualone, meprobamate, methaqualone, midaflur, paralde medrogestone, medroxyprogesterone acetate, methynodiol hyde, pentobarbital, pentobarbital sodium, perlapine, diacetate, norethindrone, norethindrone acetate, norethyno prazepam, quazepam, reclazepam, roletamide, secobarbital, drel, norgestimate, norgestomet, norgestrel, oxogestone secobarbital Sodium, Suproclone, thalidomide, tracazolate, phenpropionate, progesterone, quingestanol acetate, 40 trepipam maleate, triazolam, tricetamide, triclofos Sodium, quingestrone, tigestol. trimetozine, uldazepam, Zaleplon, Zolazepam hydrochloride, Prostaglandin: cloprostenol Sodium, fluprostenol Sodium, Zolpidem tartrate. gemeprost, prostalene, Sulprostone. Selective adenosine alantagonist: apaxifylline. Prostate growth inhibitor: pentomone. Serotonin antagonist: altanserin tartrate, amesergide, ket Prothyrotropin: protirelin. 45 anserin, ritanserin. Psychotropic: minaprine. Serotonin inhibitor: cinanserin hydrochloride, fenclonine, Pulmonary surface: beractant, colfosceril palmitate. fonazine mesylate, Xylamidine tosylate. Radioactive agent: fibrinogen I'', fludeoxyglucose F, Serotonin receptor antagonist: tropanserin hydrochloride. fluorodopa F, insulin I'', insulin I'', iobenguane I'', Steroid: dexamethasone aceflirate, mometasone furoate. iodipamide sodium I'', iodoantipyrine I'', iodocholesterol 50 Stimulant: amfonelic acid, amphetamine Sulfate, ampyZine I'', iodohippurate sodium I', iodohippurate sodium I'', Sulfate, arbutamine hydrochloride, azabon, caffeine, ceru iodohippurate sodium I'', iodopyracet I', iodopyracet letide, ceruletide diethylamine, cisapride, dazopride fuma I'', iofetamine hydrochloride I'', iomethin I', iomethin rate, dextroamphetamine, dextroamphetamine Sulfate, 131 , iothalamate sodium I', iothalamate sodium I'', ioty difluanine hydrochloride, dimefline hydrochloride, dox rosine I'', liothyronine I'', liothyronine I'', merisoprol 55 apram hydrochloride, etryptamine acetate, ethamivan, fen acetate Hg', merisoprol acetate Hg' , merisoprol Hg",197 ethylline hydrochloride, flubanilate hydrochloride, fluo selenomethionine Se', technetium Tc'"antimony trisulfide rothyl, histamine phosphate, indriline hydrochloride, colloid, technetium Tc'" bicisate, technetium Tc'" disofe mefexamide, methamphetamine hydrochlo ride, meth nin, technetium Tc'" etidronate, technetium Tc" exameta ylphenidate hydrochloride, pemoline, pyrovalerone hydro zime, technetium Tc'" furifosmin, technetium Tc" glu 60 chloride, Xamoterol. Xamoterol fumarate. ceptate, technetium Tc" lidofenin, technetium Tc'" Suppressant: amfhutizole, coXchicine, taZofelone. mebrofenin, technetium Tc" medronate, technetium Tc’" Symptomatic multiple Sclerosis: fampiridine. medronate disodium, technetium Tc" mertiatide, techne Synergist: proadifen hydrochloride. tium Tc'" oxidronate, technetium Tc'" pentetate, techne Thyroid hor move: levothyroxine sodium, liothyronine tium Tc"99. pentetate calcium trisodium, technetium Tc'" 65 Sodium, liotrix. sestamibi, technetium Tc" siboroxime, technetium Tc 99. Thyroid inhibitor: methimazole, propylthiouracil. succimer, technetium Tc'" sulfur colloid, technetium Tc99. Thyromimetic: thyromedan hydrochloride. US 9,278,134 B2 45 46 Tranquilizer: bromazepam, buspirone hydrochloride, azadirachtine, azasetron, azatyrosine, azelaic acid, azelas chlordiazepoxide, claZolam, clobazam, cloraZepate dipotas tine, azelnidipine, azimilide, azithromycin, aZosemide, aztre sium, cloraZepate monopotassium, demoxepam, dexmedeto onam, baccatin III, bacoside A, bacoside B, bactobolamine, midine, enciprazine hydrochloride, gepirone hydrochloride, balaZipone, balhimycin, balofloxacin, balsalazide, bam hydroxyphenamate, hydroxy Zine buterol, baohuoside 1, bamidipine, basifungin, batebulast, Hydrochloride, hydroxy Zine pamoate, ketazolam, batimastat, beauvericin, becaplermin, becliconazole, lorazepam, lorZafone, loxapine, loxapine Succinate, befloxatone, belfosdil, bellenamine, benflumetol, benidipine, medazepam hydrochloride, nabilone, nisobamate, benzisoxazole, benzochlorins, benzoidazoxan, benzoylstau oxazepam, pentabamate, piremperone, ripazepam, rolipram, rosporine, benztropine, bepridil, beractant, beraprost, ber Sulazepam, taciamine hydrochloride, temazepam, trifluba 10 lafenone, bertosamil, besipirdine, beta-alethine, betaclamy Zam, tybamate, Valnoctamide. cin B, betamipron, betaxolol, betulinic acid, bevantolol, Amyotrophic lateral Sclerosis agents: riluzole. bicalutamide, bifemelane, bimakalim, bimithil, binospirone, Cerebral ischemia agents: dextrorphan hydrochloride. bioxalomycin alpha2, biriperone, bis-benzimidazole A, bis Paget’s disease agents: tiludronate disodium. benzimidazole B, bisantrene, bisaramil, bisaziridinylsper Unstable angina agents: tirofiban hydrochloride. 15 mine, bisnafide, bisoprolol, bistramide D, bistramide K, bis UricoSuric: benzbromarone, irtemazole, probenecid, tratene A, boldine, bopindolol, brefeldin, breflate, Sulfinpyrazone. brimonidine, bromfenac, bromperidol, bropirimine, bucin Vasoconstrictor: angiotensin amide, fely pressin, methy dolol, budesonide, budlpine, budotitane, bunaprolast, Sergide, methysergide maleate. bunaZosin, butenafine, buthionine Sulfoximine, butiXocort Vasodilator: alprostadil, azaclorzine hydrochloride, bam propionate, cadexomer iodine, calanolide A, calcipotriol, ethan sulfate, bepridil hydrochloride, buterizine, cetiedil cit calphostin C, camonagrel, candesartan, candesartancilexetil, rate, chromonar hydrochloride, clonitrate, diltiazem hydro candoXatril, candoXatrilat, capecitabine, capromab, capsai chloride, dipyridamole, droprenilamine, erythrityl cin, captopril, carbazomycin C, carbetocin, carbovir, car tetranitrate, felodipine, flunarizine hydrochloride, fostedil, boxamide-amino-triazole, carboxyamidotriazole, carboxym hexobendine, inositol niacinate, iproxamine hydrochloride, 25 ethylated B-1,3-glucan, carperitide, carteolol, carumonam, isosorbide dinitrate, isosorbide mononitrate, isoXSuprine carvedilol, carvotroline, carZelesin, castanospermine, hydrochloride, lidoflazine, mefenidil, mefenidil fumarate, cebaracetam, cecropin B, cefcapene pivoxil, cefdaloXime mibefradil dihydrochloride, mioflazine hydrochloride, mixi pentexiltosilate, cefdinir, cefditoren pivoxil, cefepime, cefe dine, nafronyl oxalate, nicardipine hydrochloride, nicer tamet, cefetamet pivoxil, cefixime, cefluprenam, cefimneta goline, nicorandil, nicotinyl alcohol, nifedipine, nimodipine, 30 Zole, cefimninox, cefodizime, cefoselis, cefotetan, cefotiam, nisoldipine, Oxfenicine, oXprenolol hydrochloride, pen cefotiam hexetil, cefoZopran, cefpimizole, ce?piramide, cef taerythritol tetranitrate, pentoxifylline, pentrinitrol, perhexy pirome, cefpodoxime proxetil, cefprozil, cefsulodin, line maleate, pindolol, pirsidomine, prenylamine, propatyl cefteram, ceftibuten, cefiriaxone, cefuroxime axetil, cellas nitrate, Suloctidil, terodiline hydrochloride, tipropidil hydro trol, celikalim, celiprolol, cepacidine A, cericlamine, ceriv chloride, tolazoline hydrochloride, Xanthinol niacinate. 35 astatin, ceronapril, certoparin Sodium, cetiedil, cetirizine, Vulnerary: allantoin. chloroorienticin A, chloroorienticin B, chloroquinoxaline Wound healing agent: erSofermin. Sulfonamide, cibenzoline, cicaprost, ciclesonide, cicletanine, Xanthine oxidase inhibitor: allopurinol, oxypurinol. cicloprolol, cidofovir, cilansetron, cilaZapril, cilnidipine, Other pharmaceutical agents include: 1-decpyrrolidinone, cilobradine, cilostazol, cimetropium bromide, cinitapride, 1-dodecpyrrolidinone, 16C.-fluoroestradiol, 16-epiestriol, 40 cinolazepam, cioteronel, ciprofibrate, ciprofloxacin, cipros 16C.-gitoxin, 17C. estradiol, 17 Bestradiol. 1 alpha-hydroxyvi tene, cis-porphyrin, cisapride, cisatracurium besilate, cistin tamin D2,2'-nor-cGMP, 20-epi-1.25 dihydroxyvitamin D3, exine, citalopram, citicoline, citreamicin alpha, cladribine, 22-oxacalcitriol, 20VV, 3-isobutyl GABA, 6-FUDCA, clarithromycin, clausenamide, clebopride, clinafloxacin, clo 7-methoxytacrine, abamectin, abanoquil, abecamil, abirater bazam, clobetaSone butyrate, clodronic acid, clomethiazole, one, acadesine, acamprosate, acarbose, aceclofenac, aceman 45 clopidogrel, clotrimazole, colestimide, colfosceril palmitate, nan, acetomepregenol, acetyl-L-carnitine, acetylcysteine, collismycin A, collismycin B, combretastatin A4, complesta N-acetylmethadol, acifran, acipimoX, acitemate, acitretin, tin, conagenin, contignasterol, contortrostatin, cosalane, cos aclarubicin, aclatonium, napadisilate, aconiazide, acrivasti tatolide, cotinine, coumermycin A1, cucumariosid, curacin net, adafenoxate, adapalene, adatanserin, adecypenol, ade A, curdlan sulfate, curiosin, cyclazosin, cyclic HPMPC, fovir dipivoxil, adelmidrol, ademetionine, adinazolam, adi 50 cyclobenzaprine, cyclobut A, cyclobut G, cyclocapron, cyclo posin, adoZelesin, adrafinil, 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, daidzein, daidzin, dalfopristin, dalte alinastine, alosetron, alpha idoSone, alprostadil, altretamine, parin Sodium, danaparoid, daphnodorin A, dapiprazole, dapi altromycin B. ambamustine, amelometaSone, ameSergide, 55 tant, darifenacin, 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, ampiroxicam, aminone, amrubicin, Zine, delmopinol, delphinidin, deoxypyridinoline, depro amsacrine, amylin, amythiamicin, anagrelide, anakinra, done, depsidomycin, deramciclane, dermatan Sulfate, desflu ananain, anaritide, anastroZole, andrographolide, anordrin, 60 rane, desirudin, deslorelin, desmopressin, desogestrel, apadoline, apafant, apaxifylline, aphidicolin glycinate, apra desoxoarniodarone, detajmium bitartrate, dexifosfamide, clonidine, aprosulate Sodium, aptiganel, apurinic acid, arani dexketoprofen, dexloxiglumide, dexmedetomidine, dex dipine, arbekacin, arbidol, arbutamine, ardeparin Sodium, pemedolac, dexraZoxane, dexSotalol, dextrin2-Sulphate, dex arecatannin B1, argatroban, aripiprazol, arotinolol, asimado Verapamil, dezinamide, dezocine, diaziquone, diclofenac line, aspalatone, asperfuran, aspoxicillin, astemizole, asula 65 digolil, diclofenac potassium, dicranin, didemnin B, didox, crine, atamestanie, atenolol, S-atevirdine, atosiban, atova dienogest, diethylhomospermine, diethylnorspermine, dihy quone, atpenin B, atrimustine, atrinositol, aureobasidin A, drexidine, dihydro-5-azacytidine, dimethyl prostaglandin US 9,278,134 B2 47 48 A1, dimethylhomospermine, dimiracetam, dioxamycin, dipine, leminoprazole, lenercept, lenograstim, lentinan Sul diphency prone, diphenyl spiromustine, diprafenone, dipro fate, leptin, leptolstatin, lercanidipine, lerisetron, lesopitron, pylnorspermine, dirithromycin, discodermolide, disulfuram, letraZuril, letrozole, leucomyzin, leuprorelin, levcromakalim, ditekiren, docarpamine, docosanol. 1-dofetilide, dolasetron, levetiracetam, levobetaxolol, levobunolol, levobupivacaine, domitroban, dopexamine, dorzolamide, doSmalfate, dotariz levocabastine, levocamitine, levodropropizine, levofloxacin, ine, doxacurium chloride, doxazosin, doxifluridine, doxofyl levomoprolol, levonorgestrel, leVormeloxifene, levosimen line, draculin, draflazine, droloxifene, dronabinol, drosperi dan, levoSulpiride, linotroban, linsidomine, lintitript, linto done, drotaverine acephyllinate, droxicam, ebiratide, pride, liothyronine sodium, lirexapride, lisinopril, lobaplatin, ebrotidine, ebselen, ecabapide, ecabet, ecadotril, ecdlisteron, lobucavir, lodoxamide, lombricine, lomefloxacin, lomeriZ echicetin, echistatin, ecomustine, ecteinascidin 722, ectein 10 ine, lometrexol, lonazolac, lonidamine, loracarbef, lorata ascidin 729, ecteinascidin 743, edaravone, edelfosine, edoba dine, lorglumide, lomoxicam, losartan, losigamone, losox comab, edrecolomab, efegatran, eflornithine, efonidipine, antrone, loteprednol, loviride, loxoribine, lubeluzole, egualen, elcatonin, eletriptan, elgodipine, eliprodil, eltenac, lurtotecan, luteinizing hormone, lutetium, luzindole, lydica emakalim, emedastine, emiglitate, emitefur, emoctakin, ena mycin, lysofylline, lysostaphin, magainin2 amide, magnolol. doline hydrochloride, enalapril, enaZadrem, englitaZone, 15 mallotochromene, mallotojaponin, malotilate, mangafodipir, enlimomab, enoxacin, enoxaparin sodium, enoXimone, enta manidipine, maniwamycin A, mannostatin A, manumycin E, capone, enterostatin, epoprostenol, epoxymexrenone, epris manumycin F. mapinastine, marimastat, masoprocol, teride, eprosartan, eptastigmine, erdosteine, ersentilide, erso maspin, massetolide, meterelin, methoxatone, methylhista fermin, erytlritol, esuprone, etanidazole, etanterol, ethacizin, mine, R-alpha, methylinosine monophosphate, methylpred ethinylestradiol, etizolam, etodolac, etoposide phosphate, nisolone aceponate, methylprednisolone Suleptanate, metipa etrabamine, everninomicin, examorelin, exemestane, fadro mide, metoclopramide, metoprolol. S-metrifonate, Zole, faerieflungin, famciclovir, fampiridine, fantofarone, faro mibefradil, michellamine B, microcolin A, midodrine, mife penem, fasidotril, fasudil, faZarabine, fedotozine, felbamate, pristone, miglitol, millacemide, milameline, mildronate, mil fenofibrate, fenoldopam, fenretinide, fenspiride, fenticona nacipran, milrinone, miltefosine, minaprine, miokamycin, Zole, fepradinol, ferpifosate sodium, ferristene, ferrixan, 25 mipragoside, mirfentanil, mirimostim, mirtazapine, miso ferumoxsil, fexofenadine, flavopiridol, flecamide, fle prostol, mitoguaZone, mitolactol, mitonafide, mitoxantrone, robuterol, fleroxacin, flesinoxan, flezelastine, flobufen, flo mivacurium chloride, mivaZerol, mixanpril, mizolastine, moxef, florfenicol, florifenine, flosatidil, fluasterone, flu mizoribine, moclobemide, modafinil, moexipril, mofarotene, conazole, fludarabine, flumazenil, flumecinol, flumequine, mofeZolac, molgramoStim, mometasone, montirelin, mopi flunarizine, fluocalcitriol, fluorodaunorunicin hydrochloride, 30 damol, moracizine, mosapramine, mosapride, motilide, mox fluoxetine, R-fluoxetine, S-fluparoxan, flupirtine, flurbipro iraprine, moxonidine, nadifloxacin, nadroparin calcium, fen axetil, flurithromycin, fluticasone propionate, flutrima nafadotride, nafamostat, nafarelin, naftopidil, naglivan, Zole, fluvastatin, fluvoxamine, forasartan, forfenimex, form nagrestip, nalmefene, naphterpin, napsagatran, naratriptan, estane, formoterol, formoterol, R.R-fosfomycin, trometamol. nartograstim, nasaruplase, nateplase, niperotidine, nirav fosinopril, fosphenyloin, fostriecin, fotemustine, gabapentin, 35 oline, nisamycin, nisin, nisoldipine, nitazoxanide, niteca gadobenic acid, gadobutrol, gadodiamide, gadodiamide pone, nitrendipine, nitrendipine, S-nitrofurantoin monohy EOB-DTPA, gadolinium texaphyrin, gadoteric acid, gadot drate, nitrullyn, nizatidine, ofloxacin, okicenone, olanzapine, eridol, gadoversetamide, galantamine, galdansetron, gallo olopatadine, olprinone, olSalazine, omeprazole, onapristone, pamil, galocitabine, gamolenic acid, ganirelix, gepirone, ondansetron, ondansetron, R-OntaZolast, oracin, otenZepad, gestrinone, girisopam, glaspimod, glaucocalyxin A, glutapy 40 oxaliplatin, oxamisole, Oxandrolone, Oxaprozin, oxaunomy rone, glycopine, glycopril, granisetron, grepafloxacin, hali cin, oXcarbazepine, oxiconazole, oxiracetam, oxodipine, oza chondrin B, halofantrine, halomon, halopredone, hatomami grel, palauamine, palinavir, palmitoylrhizoxin, pamaqueside, cin, hatomarubigin A, hatomarubigin B, hatomarubigin C, pamicogrel, pamidronic acid, panamesine, panaxytriol, hatomarubigin D, ibogaine, ibopamine, ibudilast, illi panipenem, panipenum, pannorin, panomifene, pantethine, maquinone, ilmofosine, illomastat, illoperidone, iloprost, imi 45 pantoprazole, parabactin, pamaparin Sodium, paroxetine, dapril, imidazenil, indinavir, indolidan, indometacin farnesil, parthenolide, paZelliptine, paZufloxacin, pefloxacin, pegas indometacin, tropine ester, indoramin, inocoterone, inogat pargase, peldesine, pemedolac, pemirolast, penciclovir, pen ran, inolimomab, interferon alfa, interferon alfa-2a, inter tafuside, pentamidine, pentamorphone, pentigetide, pen feron alfa-2B, interferon alfa-N 1, interferon alfa-N3, inter tosan, pentostatin, pentroZole, perflubron, perfosfamide, feron B, interferon B-1 A1, interferon B-1B, interferon 50 pergolide, perindoprilat, peroSpirone, phenaridine, 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-1B, 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, 55 cidil, pinocebrin, pioglitaZone, pipecuronium bromide, iobenguane, iobitridol, iodoamiloride, iododoxorubicin, iof pirarubicin, piretanide, pirfenidone, piritrexim, pirlindole, ratol, iomeprol, iopentol, iopromide, iopyrol, iotriside, iover pirmagrel, pirmenol, pirodavir, pirodomast, piroXicam cin Sol, ioxilan, ipazilide, IpdR, ipenoxaZone, ipidacrine, namate, propagermanium, propentofylline, propionylcam ipomeanol, 4-ipriflavone, ipsapirone, irbesartan, irinotecan, itine, L-propiram, propiram-paracetamol, propiverine, pro irloxacin, irsogladine, irtemazole, isalsteine, isbogrel, isepa 60 pyl bis-acridone, prostaglandin J2, prostratin, protegrin, micin, isobengaZole, isofloxythepin, isohomohalicondrin B, protoSufloxacin, prulifloxacin, pyrazoloacridine, quazepam, isopropyl unoprostone, isradipine, itameline, itasetron, ito quetiapine, quiflapon, quinagolide, quinapril, quinfamide, pride, itraconazole, ketoprofen, R-ketoprofen, S-ketorolac, quinupristin, raloxifene, raltitrexed, ramatroban, ramipril, lacidipine, lactitol, lactivicin, laennec, lafutidine, lamel ramosetron, ranelic acid, ranitidine bismuth citrate, ranola rarin-N triacetate, lamifiban, lamivudine, lamotrigine, lano 65 Zine, recainam, regavirumab, relaxin, repirinast, resinfera conazole, lanperisone, lanreotide, lanSoprazole, latanoprost, toxin, reticulon, reviparin sodium, revizinone, ricasetron, lateritin, laurocapram, lazabemide, lemefloxacin, lemil ridogrel, rifabutin, rifapentine, rifaximin, rilopiroX, riluzole, US 9,278,134 B2 49 50 rimantadine, rimexolone, rimoprogin, riodipine, ripisartan, Sodium, apramycin, aspartocin, astromicin Sulfate, avilamy risedronic acid, rispenzepine, risperidone, ritanserin, riti cin, avoparcin, azithromycin, azlocillin, azlocillin Sodium, penem, ritipenemacoxil, ritolukast, ritonavir, rizatriptan ben bacampicillin hydrochloride, bacitracin, bacitracin methyl Zoate, rohitukine, rokitamycin, ropinirole, ropivacaine, ene disalicylate, bacitracin Zinc, bambermycins, benzoylpas roquinimex, roXatidine, roXindole, roXithromycin, rubigi calcium, berythromycin, betamicin Sulfate, biapenem, binira none B1, ruboxyl, rufloxacin, rupatidine, ruzadolane, Safin mycin, biphenamine hydrochloride, bispyrithione mag gol, Safironil, Saintopin, salbutamol, R-Salmeterol, Salme Sulfex, butikacin, butirosin Sulfate, capreomycin Sulfate, car terol, R-Sainacedin, sameridine, Sampatrilat, Sanfetrinem, badox, carbenicillin disodium, carbenicillin indanyl Sodium, Saprisartan, sapropterin, saquinavir, sarcophytol A Sargra carbenicillin phenyl sodium, carbenicillin potassium, caru mostim, Sarpogrelate, Saruplase, Saterinone, satigrel, Satumo 10 monam sodium, cefaclor, cefadroxil, cefamandole, cefaman mab pendetide, selegiline, selenium thiosemicarbazone, dole nafate, cefamandole sodium, cefaparole, cefatrizine, sematilide, semduramicin, Semotiadil, Semustine, sermore cefazaflur Sodium, cefazolin, cefazolin Sodium, cefbupera lin, Sertaconazole, sertindole, Sertraline, setiptiline, Zone, cefdinir, cefepime, cefepime hydrochloride, cefetecol, Sevirumab, sevoflurane, seZolamide, silipide, silteplase, sim cefixime, cefimenoXime hydrochloride, cefimetazole, endan, simvastatin, sinitrodil, sinnabidol, sipatrigine, siroli 15 cefnetazole sodium, cefonicid monosodium, cefonicid mus, sizofuran, Somatomedin B, Somatomedin C. Somatrem, Sodium, cefoperaZone sodium, ceforanide, cefotaxime Somatropin, Sonermin, Stalol, staurosporine, stavudine, Sodium, cefotetan, cefotetan disodium, cefotiam hydrochlo stepronin, stipiamide, Stiripentol, Stobadine, Succibun, ride, cefoxitin, cefoxitin Sodium, cefpimizole, ce?pimizole Sucralfate, Sulfasalazine, Sulfmosine, Sulfoxamine, Sodium, cefpiramide, ce?piramide sodium, cefpirome Sulfate, Sulopenem, Sultamicillin, Sultopride, Sulukast, Sumatriptan, cefpodoxime proxetil, cefprozil, cefroxadine, cefsulodin Symakalim, tandospirone, tapgen, taprostene, tasosartan, Sodium, ceftazidime, ceftibuten, ceftizoxime Sodium, ceftri taZanolast, tazarotene, teicoplanin, telenzepine, tellurapyry aXone sodium, cefuroxime, cefuroxime axetil, cefuroxime lium, telmesteine, telmisartan, temocapril, temoporfin, temo pivoxetil, cefuroxime Sodium, cephacetrile sodium, cephal Zolomide, tenidap, teniposide, tenosal, tenoxicam, tepirin exin, cephalexin hydrochloride, cephaloglycin, cephalori dole, tepoxalin, teraZosin, terbinafine, terfenadine, 25 dine, cephalothin Sodium, cephapirin Sodium, cephradine, terflavoxate, terguride, terlakiren, terlipressin, terodiline, ter cetocycline hydrochloride, cetophenicol, chloramphenicol, tatolol, testosterone buciclate, tetrachlorodecaoxide, tetra chloramphenicol palmitate, chloramphenicol pantothenate Zomine, thaliblastine, thalidomide, thiocoraline, thiofedrine, complex, chloramphenicol sodium Succinate, chlorhexidine thiomarinol, thioperamide, thyroid stimulating hormone, phosphanilate, chloroxylenol, chlortetracycline bisulfate, tiagabine, tianeptine, tiapafant, tibolone, ticlopidine, tienox 30 chlortetracycline hydrochloride, cinoxacin, ciprofloxacin, olol, tilisolol, tilnoprofen arbamel, tiludronic acid, tinzaparin ciprofloxacin hydrochloride, cirolemycin, clarithromycin, sodium, tiotropium bromide, tipredane, tiqueside, tirandaly clinafloxacin hydrochloride, clindamycin, clindamycin digin, tirapazamine, tirilazad, tirofiban, tiropramide, topsen hydrochloride, clindamycin palmitate hydrochloride, clinda tin, torasemide, toremifene, to Sufloxacin, trafermin, trandola mycin phosphate, clofazimine, cloxacillin benZathine, clox pril, traXanox, tretinoin, tretinoin tocoferil, triacetyluridine, 35 acillin Sodium, cloxyquin, colistimethate sodium, colistin tricaprilin, trichohyalin, trichosanthin, alpha, triciribine, tri Sulfate, coumermycin, coumermycin Sodium, cyclacillin, entine, triflavin, trimegestone, triptorelin, troglitaZone, trom cycloserine, dalfopristin, dapsone, daptomycin, demeclocy bodipine, tropisetron, trospectomycin, trovafloxacin, troVir cline, demeclocycline hydrochloride, demecycline, denofun dine, tucaresol, tulobuterol, tylogenin, urapidil, uridine gin, diaveridine, dicloxacillin, dicloxacillin Sodium, dihy triphosphate, Valaciclovir, Valproate magnesium, valproate 40 drostreptomycin Sulfate, dipyrithione, dirithromycin, semisodium, Valsartan, Vamicamide, Vanadeine, Vaminolol. doxycycline, doxycycline calcium, doxycycline fosfatex, Vapreotide, variolin B. Velaresol, Venlafaxine, Veramine, doxycycline hyclate, droxacin sodium, enoxacin, epicillin, Verapamil, S-Verdins, Veroxan, Verteporfin, Vesnarinone, epitetracycline hydrochloride, erythromycin, erythromycin Vexibinol, vigabatrin, vinbumine citrate, vinbumine resinate, acistrate, erythromycin estolate, erythromycin ethylsucci Vinconate, Vinorelbine, Vinpocetine, Vinpocetine citrate, Vin 45 nate, erythromycin gluceptate, erythromycin lactobionate, toperol, Vinxaltine, Voriconazole, Vorozole, Voxergolide, erythromycin propionate, erythromycin Stearate, ethambutol Xemilofiban, Ximoprofen, yangambin, Zabicipril, Zacopride, hydrochloride, ethionamide, fleroxacin, floxacillin, fludala Zacopride, R-Zafirlukast, Zalcitabine, Zaleplon, Zalospirone, nine, flumequine, fosfomycin, fosfomycin tromethamine, Zaltoprofen, Zanamivir, Zankiren, Zanoterone, Zatebradine, fumoxicillin, furazolium chloride, furazolium tartrate, fusi Zatosetron, Zenarestat, Zeniplatin, Zifrosilone, Zilascorb, 50 date Sodium, fusidic acid, gentamicin Sulfate, gloXimonam, Zileuton, Zinostatin stimalamer, Ziprasidone, Zoledronic acid, gramicidin, haloprogin, hetacillin, hetacillin potassium, Zolmitriptan, Zolpidem, Zonisamide, Zopiclone, Zopiclone, hexedine, ibafloxacin, imipenem, isoconazole, isepamicin, S-Zopolrestat, Zotepine. isoniazid, josamycin, kanamycin Sulfate, kitasamycin, levo Specific Examples of Antibacterials furaltadone, levopropylcillin potassium, lexithromycin, lin When antibacterial activity is a desired property of the 55 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 lomicin potassium phosphate, medulidox, meropenem, 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 60 enamine hippurate, methenamine mandelate, methicillin QACs have antibacterial properties). Further examples of Sodium, metioprim, metronidazole hydrochloride, metron Suitable antibacterial agents include, but are not limited to, idazole phosphate, mezlocillin, meZlocillin Sodium, minocy acedapsone, acetosulfone sodium, alamecin, alexidine, amdi cline, minocycline hydrochloride, mirincamycin hydrochlo nocillin, amdinocillin pivoxil, amicycline, amifloxacin, ami ride, monensin, monensin Sodiumr, nafcillin Sodium, floxacin meSylate, amikacin, amikacin Sulfate, aminosali 65 nalidixate sodium, nalidixic acid, natainycin, nebramycin, cylic acid, aminosalicylate Sodium, amoxicillin, neomycin palmitate, neomycin Sulfate, neomycin unde amphomycin, amplicillin, amplicillin Sodium, apalcillin cylenate, netilmicin Sulfate, neutramycin, nifuiradene, US 9,278,134 B2 51 52 nifuraldezone, nifuratel, nifuratrone, nifurdazil, nifurimide, hydrochloride, delavirdine mesylate, desciclovir, didanosine, nifiupirinol, nifurquinazol, nifurthiazole, nitrocycline, nitro disoxaril, edoxudine, enviradene, enviroXime, famciclovir, furantoin, nitromide, norfloxacin, novobiocin Sodium, famotine hydrochloride, fiacitabine, fialuridine, fosarilate, ofloxacin, onnetoprim, oxacillin sodium, oximonam, oxi foscarnet sodium, foSfonet Sodium, ganciclovir, ganciclovir monam Sodium, oxolinic acid, oxytetracycline, oxytetracy Sodium, idoxuridine, kethoxal, lamivudine, lobucavir, memo cline calcium, oxytetracycline hydrochloride, paldimycin, tine hydrochloride, methisaZone, nevirapine, penciclovir, parachlorophenol, paulomycin, pefloxacin, pefloxacin mesy pirodavir, ribavirin, rimantadine hydrochloride, saquinavir late, penamecillin, penicillin G benzathine, penicillin G mesylate, Somantadine hydrochloride, Sorivudine, statolon, potassium, penicilling procaine, penicilling sodium, peni stavudine, tillorone hydrochloride, trifluridine, Valacyclovir cillin V, penicillin V benzathine, penicillin V hydrabamine, 10 hydrochloride, vidarabine, Vidarabine phosphate, vidarabine penicillin V potassium, pentizidone sodium, phenyl ami Sodium phosphate, Viroxime, Zalcitabine, Zidovudine, Zin nosalicylate, piperacillin Sodium, pirbenicillin Sodium, piri viroxime, and Tamiflu. dicillin Sodium, pirlimycin hydrochloride, pivampicillin These and other suitable antivirals can be identified based hydrochloride, pivampicillin pamoate, pivampicillin on the desired properties of the antiviral and whether the probenate, polymyxin B sulfate, porfiromycin, propikacin, 15 antiviral is or can be converted into an ion. As noted, identi pyrazinamide, pyrithione Zinc, quindecamine acetate, quinu fication of whether an antiviral is an ion or can be converted pristin, racephenicol, ramoplanin, ranimycin, relomycin, into an ion can be done by a skilled artisan inspecting the repromicin, rifabutin, rifametane, rifamexil, rifamide, chemical structure of the antiviral. rifampin, rifapentine, rifaximin, rollitetracycline, rollitetracy Specific Examples of Pesticidal Actives cline nitrate, rosaramicin, rosaramicin butyrate, rosaramicin When pesticidal activity is a desired property of the dis propionate, rosaramicin Sodium phosphate, rosaramicin closed ionic liquids, one or more of the ions in the disclosed Stearate, rosoxacin, roXarsone, roXithromycin, Sancycline, ionic liquids can be a pesticide. Included within the meaning Sanfetrinem Sodium, Sarmoxicillin, Sarpicillin, scopafungin, of "pesticide' are insecticides and fungicides. Examples of Sisomicin, sisomicin Sulfate, sparfloxacin, spectinomycin suitable pesticides include, but are not limited to, carfentra hydrochloride, spiramycin, stallimycin hydrochloride, Steffi 25 Zone-ethyl, SulfentraZone, clomaZone, diclofop-methyl, mycin, Streptomycin Sulfate, streptonicozid, Sulfabenz, Sul oxamyl propargite, prosulfuron, pyridate, pyriftalid, S-meto fabenzamide, Sulfacetamide, Sulfacetamide Sodium, Sulfacy lachlor, simazine, terbuthylazine, terbutryn, triasulfuron, tri tine, Sulfadiazine, Sulfadiazine sodium, Sulfadoxine, floxysulfuron, trinexapac-ethyl, ametryn, atrazine, benoxa Sulfalene, Sulfamerazine, Sulfameter, Sulfamethazine, Sul cor, bifenthrin, butafenacil, choline azide, chlortoluron, famethizole, Sulfamethoxazole, Sulfamonomethoxine, Sulfa 30 cinosulfuron, clodinafop, cloquintocet, DEET, desmetryn, moXole, Sulfanilate Zinc, Sulfanitran, Sulfasalazine, Sulfa dicamba, dimethachlor, dimethametryn, DTPA NaFe, somizole, sulfathiazole, sulfazamet, sulfisoxazole, EDDHA NaFe, fenclorim, flumetralin, fluometuron, fluthi Sulfisoxazole acetyl, Sulfisboxazole diolamine, Sulfomyxin, acetmethyl, halosulfuron, isoproturon, metobromuron, meto Sulopenem, Sultamricillin, Suncillin Sodium, talampicillin lachlor, norflurazon, oxasulfuron, piperophos, pretilachlor, hydrochloride, teicoplanin, temafloxacin hydrochloride, 35 primisulfuron, prometryn, propaquizafop, acilbenzolar-s-me temocillin, tetracycline, tetracycline hydrochloride, tetracy thyl, chlorothalonil, cyproconazole, cyprodinil, difenocona cline phosphate complex, tetroXoprim, thiamphenicol, Zole, fenpropidin, fenpropimorph, furalaxyl, metalaxyl, thiphencillin potassium, ticarcillin cresyl Sodium, ticarcillin metalaxyl-m, oxadixyl, penconazole, propiconazole, disodium, ticarcillin monosodium, ticlatone, tiodonium chlo pyrifenox, thiabendaZol, abamectin, bromopropylate, cyper ride, tobramycin, tobramycin Sulfate, to Sufloxacin, trimetho 40 methrin, cypermethrin high-cis, cyromazine, diafenthiuron, prim, trimethoprim Sulfate, trisulfapyrimidines, troleando diazinon, dichlorvos, disulfoton, emamectinbenzoate, mycin, trospectomycin Sulfate, tyrothricin, Vancomycin, fenoxycarb, formothion, furathiocarb, lufenuron, methi Vancomycin hydrochloride, Virginiamycin, and Zorbamycin. dathion, permethrine, codilemone, phosphamidon, profeno Penicillin G, which is used as an antibacterial agent for infec fos, pymetrozine, quinalphos, terrazole, thiamethoxam, thio tions including pneumonia, meningitis, and skin, bone, joint, 45 cyclam, thiometon, triallate, trifloxystrobin, VincloZolin, stomach, blood, and heart valve infections, is a particular Zetacypermethrin, and the like. Prohexadione is a FDA example suitable for use herein. tazobactum, sold under the approved reduced risk fungicide and is also useful for the trade names ZOSYNTM and TAZOCINTM, ceftrioxone, sold disclosed ionic liquids. Further examples of suitable pesti under the trade name ROCEPHINTM, and metronidazol, sold cides can be found in The Pesticide Manual, 11" Edition, under the trade name FLAGYLTM, are also used to treat 50 British Crop Protection Council, 1997, which is incorporated bacterial infections and are further examples of suitable com by reference herein at least for its teaching of pesticides. pounds that can be used to prepare the disclosed ionic liquids. These and other suitable pesticides can be identified based These and other suitable antibacterials can be identified on the desired properties of the pesticide and whether the based on the desired properties of the antibacterial and pesticide is or can be converted into an ion. As noted, identi whether the antibacterial active is or can be converted into an 55 fication of whether a pesticide is an ion or can be converted ion. As noted, identification of whetheran antibacterial active into an ion can be done by a skilled artisan inspecting the is an ion or can be converted into an ion can be done by a chemical structure of the pesticide. skilled artisan inspecting the chemical structure of the anti Specific Examples of Herbicidal Actives bacterial. When herbicidal activity is a desired property of the dis Specific Examples of Antiviral 60 closed ionic liquids, one or more of the ions in the disclosed When antiviral activity is a desired property of the dis ionic liquids can be a herbicide. Examples of suitable herbi closed ionic liquids, one or more of the ions in the disclosed cides include, but are not limited to, carfentraZone, imazapyr, ionic liquids can be an antiviral. Examples of Suitable antivi benefin, acifluorfen, and 2-2-chloro-3-(2.2.2-trifluoroet ral actives include, but are not limited to, acemannan, acyclo hoxymethyl)-4-methylsulfonylbenzoylcyclohexane-1. Vir, acyclovir Sodium, adefovir, alovudine, alvircept Sudotox, 65 Other suitable herbicides include inhibitors of the biosyn amantadine hydrochloride, aranotin, arildone, atevirdine thesis of branched amino acids such as ethoxysulfuron, flu mesylate, pyridine, cidofovir, cipamfylline, cytarabine metSulam, halosulfuron, imaZamox, imazapyr, imaZaquin, US 9,278,134 B2 53 54 imazethapyr, metoSulam, nicosulfuron, primisulfuron, pro The concept of specific Stoichiometric salts—note that this sulfuron, rimsulfuron, thifensulfuron-methyl, triflusulfuron, Sort of clustering may also be of import. N-(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl-2-dim The activity of drugs in the body is not the only consider ethylaminocar-bonyl-5-formylaminobenzenesulfonamide ation, but also the formulation advantages that may (Foramsulfuron), and the like. Still further, suitable herbi accrue from having an ion-pairing or ion-clustering salt. cides include inhibitors of the photosynthesis electron trans In applications other than drugs (though also applies here, port Such as ametryne, atrazine, bromoxynil, cyanazine, diu particularly to pro-drugs that hydrolyze or easily ron, hexaZinone, metribuzin, pyridate, terbuthylazine, and the degraded drugs—analogous to protection against UV like. In yet further examples, suitable herbicides for the dis degradation by formulation as inclusion complexes), closed ionic liquids include synthetic auxins such as copy 10 some of the advantages will be in the ability to create a ralid, dicamba, diflufenZopyr, fluoroxypyr, and the like. Inhibitors offatty acid biosynthesis, such as butylate, EPTC, liquid formulation that DOES NOT require water ad fenoxaprop-P-ethyl, and the like, can also be used in the Vantages are a) stabilization; b) ease of dispersion/dis disclosed ionic liquid compositions. In other examples, Suit Solution upon introduction into an aqueous system and able herbicides can include inhibitors of cell division such as 15 c) possibilities to dissolve other substances in these acetochlor, alachlor, dimethenamid, flufenacet, mefenacet, salts—for example “edible IL to dissolve drugs' the metolachlor, S-metolachlor, thenylchlor, and the like. In still liquid salts could be used to dissolve other solid actives. other examples, the herbicide can be an inhibitor of protopor Many examples of liquid organic salts are far from fully phyrinogen oxidase, Such as fluthiacet-methyl, carfentra ionized. Instead, they form ion pairs and aggregates of ions in Zone-ethyl, and the like. Inhibitors of hydroxyphenylpyruvate the liquid state and are better described as Liquid Ion Pairs dioxygenase, Such as isoxaflutole, mesotrione, Sulcotrione, than “Ionic Liquids'. The distinction between these states can 4-(4-trifluoromethyl-2-methylsulfonylbenzoyl)-5-hydroxy be made on the basis of the behavior of the transport property 1-methyl-3-methylpyrazole, and the like, can also be used. data when plotted in a Walden plot. The Walden plot is a graph Further examples of suitable herbicides include, but are not of log equivalent conductivity (corrected for molar volume) limited to, glyphosate, pendimethalin, trifluralin, asulam, tri 25 vs. log fluidity and thus may be used to estimate the degree of aziflam, diflufenican, glufosinate-ammonium, and the like. association cations and anions (as correlated motion of cation Clofencet, fluoroxpyr, mesosulfuron, diflufenzopyr are fur and anion clusters). Ionic Liquids typically lie within one ther examples of suitable herbicides and they are FDA order of magnitude of the “Ideal Ionic Liquid line (that line approved. on which salts which exhibit no correlated motion of cation Specific Examples of Other Ions 30 and anion lie) meaning that they are between 10 and 100% In addition to the pharmaceutical, antibacterial, antiviral, ionic. Liquid Ion Pairs lie beyond this region, i.e., more than pesticidal, and herbicidal actives disclosed herein, other com one order of magnitude away from the Ideal line. Such liquid pounds that are ions or can be converted to ions can be used in salts are less than 10% ionized. Examples of such liquid salts the disclosed ionic liquid compositions. Specific examples of of therapeutic ions include propanthaline tosylate which is these include, but are not limited to, the food additives Allura 35 about 1% ionized, as estimated from the Walden plot (FIG. 7). Red AC (FD&C Red No. 40), Tartrazine (FD&C Yellow No. This degree of association of cations and anions (as ion 5), Indigotine (FD&C Blue No. 2), Erythrosine (FD&C Red pairs or larger clusters) will affect various physico-chemical No. 3), and Sunset Yellow (FD&C Yellow No. 6), which are properties of the salts; for example, greater “ion-pairing FDA-approved color additives for food use. Further, nutra (which should be understood to mean clustering of any num ceuticals such as fatty acids, cholesterols, vitamins, minerals, 40 ber of cations and anions) will yield a more fluid and more and trace elements can be suitable ions for the disclosed ionic Volatile salt as ion pairs (or clusters) move as single entities liquid compositions. SEA-NIN-211 is an antifoulant that can and may be vaporized as uncharged clusters which thus more be used as an ionid the disclosed compositions. readily escape the liquid due to decreased coloumbic interac tions with the bulk. Liquid Ion Pairs 45 If Suchion-pairing, or clustering, persists in Solution cation oranion interactions with the environment, e.g., the body, will Dual functioning organic salts that do not behave as free not simply be additive and the salt will not behave in the same ions either neator in a solvent (including water) will retain the way as a 1:1 molar mixture of salts containing the same cation functionality of each ion in close enough proximity to lead to and anion. In addition, such ion-pairing, or ion-clustering, synergistic effects. The degree of association (or conversely 50 salts may form a separate phase in certain solvent systems and dissociation) will affect the physical, chemical, and impor may thus be utilized as emulsions or other dispersed phases. tantly, the biological properties. The non-additive effect of cation and anion in ion-paired, or Ion pairing/clustering which imparts some extra (other clustered, salts may be either synergistic (enhanced efficacy) than merely additive) effect in operation, e.g., enhances or antagonistic (decreased efficacy) and this allows modula the therapeutic effect or increases the activity of the 55 tion of properties by judicious choice of cation/anion pairs in individual ions OR decreases the activity. While this salt formation. latter may often seem to be unimportant there are cases Opportunities exist for the preparation of: where it would be desirable, e.g., in slow release formu Enhanced therapeutic salt Substances which combine: lations (activity here may refer to solubility or rate of 2 API ions chosen for specific activity diffusion from the reservoir). 60 an API ion and second active which alters physico The ability to “design a liquid salt that is the thermody chemical properties such as lipophilicity, thus chang namically most stable state AT a specific temperature, ing, for example, membrane or transdermal transport i.e., NOT a quenched amorphous phase that may crys an API ion and second ion which serves to mask unpleas tallize, is important as this offers opportunities in for ant taste and/or Smell mulation of, e.g., emulsions and will almost always pro 65 animal therapeutic Substances vide a more soluble or dispersible form than a crystalline Enhanced agrochemical Substances which may have simi form. lar effects to those above and US 9,278,134 B2 55 56 yields a material easily dispersible in a second carrier, that the remaining water is involved in direct solvation inter for example, as an emulsion, which nonetheless actions with the ions. This marks the beginning of region C, retains its lipophilicity and thus is not easily removed which we refer to as the hydrate ionic liquid region. In this from Surfaces, e.g. leaves region the ionic liquid should be considered to be the solvent. Note that it is possible that the melting point of the pure salt Solvates/Hydrates may be higher than room temperature, or even higher than 100°C. If the addition of the soluteamount of water to the salt Liquid salts can existina defined intermediate stage where to form a mixture of composition in region C is sufficient to they are Solvated, but not in Solution. This stage is charac lower the melting point of the salt to below room temperature terized by all solvent present in the liquid salt being bound 10 rather than free as demonstrated by DSC and other data. (or other temperature of interest) then the mixture can still be A convenient method of determining the point where an considered to be a hydrate ionic liquid. The important prop ionic liquid containing dissolved water becomes an aqueous erties of such mixtures is that they are still (in common with solution, in which water is the solvent rather than the solute, single component ionic liquids) liquids comprised solely of is low temperature thermal analysis. By this means we can 15 ions, in this case hydrated ions. determine the point, with increasing water content, at which The use of the term “hydrate here is justified by its use in the crystallization and melting of bulk ice first appears in the solid state chemistry to describe salts which contain water mixtures. The low temperature phase behaviour of aqueous molecules in their crystal structures. In many cases eg salt solutions has been extensively studied in the context of Ca(NO), .4H2O, there is a well understood metal solvation cryobiology (Angell, C. A. D. R. MacFarlane et al., Journal involved such that one could consider this salt to be Ca(H2O) of Physical Chemistry, 1981. 85 p. 1461-1464; MacFarlane, (NO). Indeed it melts congruently at 65° C. to a fluid, D. R. R. K. Kadiyala, and C. A. Angell, Journal of Chemical conductive liquid state. Such hydrate salt ionic liquids have Physics, 1983. 79 p. 3921-3927, Journal of Physical Chem been studied in detail (MacFarlane, D. R. and D. K. Y. Wong, istry, 1983. 87 p. 1094-1095; MacFarlane, D., Cryobiology, Journal of Physical Chemistry, 1985. 89 p. 5849-5855; Mac 1985. 22 p. 601-602; MacFarlane, D. R., Cryobiology, 1986. 25 Farlane, D. R. and C. A. Angell, Journal of Physical Chem 23 p. 559-560; MacFarlane, D. R., Cryobiology, 1986. 23 p. istry, 1984.88 p. 4779-4781). The solid hydrate salts often 230-244; MacFarlane, D. R., Cryobiology, 1987. 24 p. 181 contain a variable number of water molecules Suggesting a 195). Typical binary phase diagrams have been established Solid solution situation exists in some cases. Nonetheless and show the characteristics illustrated in FIG. 1. these salts are still referred to as hydrates. We therefore pro At high water contents (Region A of the diagram) the 30 sample will crystallize ice during cooling in the DSC and pose that the parallel situation in which a liquid salt-water exhibit a subsequent melting peak during warming. This peak mixture containing a variable amount of solute water be is more precisely described as the ice liquidus peak, corre referred to as a hydrate ionic liquid as long as it exists in sponding to the process of ice dissolution into the solution. Region C of the binary phase diagram. The liquidus line of ice in these solutions is denoted TL. 35 At lower water contents, corresponding to the middle of Intermediate Partially Ionized Liquid Phases this diagram, Region B, the ice crystalisation during cooling, or at low temperatures during Subsequent warming, becomes Without wishing to be bound by theory, for the purposes of less extensive and more sluggish, since less bulk water is the present disclosure, when a disclosed acid (HA) is com available to freeze into ice. Annealing experiments can be 40 bined with a disclosed base (B), an equilibrium can exist as used to allow the ice to form and one observes the liquidus follows: line falling rapidly in Region B. In the absence of a fully formed eutectic, which is common in many aqueous—Salt HA+B (P BHA binaries, part of the Solution remains unfrozen during the AS Such, the combination of a functional acid, HA, and a cooling or annealing treatment. This part contains all of the 45 functional base, B, can produce liquid compositions having a salt and some water. The composition of the unfrozen part can dual function or capacity, i.e., the properties of each indi be estimated from the phase diagram and the lever rule. Evi vidual component. Disclosed herein are examples of an acid dence for this can also be seen via the appearance of a glass that is a solidat room temperature which when combined with transition at temperature denoted Tg in the partially frozen a base that is a solid at room temperature, leads to a liquid that solution. Since the composition of the unfrozen fraction is 50 independent of starting concentration, Tg is almost compo is a partially ionized composition. Therefore, the formulator, sition independent through regions A and B as seen in the by controlling the equilibrium, can also adjust or modify the diagram. physical, chemical, and biological properties of the final com At some point in region B, depending on the cooling rate pound. applied, it will be possible to quench the sample into the 55 glassy State without the crystallisation of any ice. The warm Multiple Functional Co-Ionic Liquids ing DSC trace then will show the true Tg for that composition (marked as Tg in FIG. 1). Typically Tg is a strong function of Disclosed herein are pharmaceutically active, multiply composition through regions B and C. Despite the ability to functional co-ionic liquids comprising oligomeric cations or quench into a fully glassy state, the sample can still crystallize 60 anions and wherein the co-ionic liquids provide a method for ice during warming in region B, indicating that solvent water the modification of physico-chemical properties of pharma still exists in the solution. ceutically active salts. Used here, the term “co-ionic liquids' However, in region BTL is rapidly approaching Tg and, at includes ionic liquids with excess of any free base in equilib the composition where it falls below Tg, formation of ice rium with the cation or excess of any free acid anion in becomes an insignificant event on any measurable timescale. 65 equilibrium with the anion; thus it is possible to prepare At that point it can be said that the solution shows no evi pharmaceutically active ionic liquids with dimeric or oligo dence, on any measurable timescale, of “solvent' water and meric ions of the type: US 9,278,134 B2 57 58 temperature. A permanent proton exchange between anion XHA and corresponding acid is present in these coionic liquids B.A(HA), making both species undistinguishable on a NMR time scale. The degree of additional acid or base does therefore affect various physico-chemical properties of the salts; for example, These compositions differ from conventional mixture of ionic the formation of a “super-anion' or “super-cation” (which is liquids with neutral compounds by the fact that a proton is a result of a proton exchange between the ion and the corre shared between anion and any acid or between cation and any sponding acid or base) will lead to a permanent delocalization base and all components are therefore present as ions. of charge and depress the melting point or completely elimi These compositions also differ from conventional mixtures 10 nate crystallization. The presence of distinct oligomeric spe of ionic liquids by the fact that the total amount of cationic cies, e.g. dimeric or trimeric anions can be demonstrated via compounds is not balanced by the total amount of anionic conductivity measurements: The presence of local maxima compounds anymore, although an overall cation:anion ratio for conductivity of P(Bu)(Sal), H for the species P(Bu). of 1:1 is obtained. Sal-H and P(Bu) Sal-H strongly indicates the presence of For example, whereas a conventional ionic liquid would 15 hydrogen-bonded oligomericanions (FIG. 3). have been 1 part cation, 0.5 part first anion, and 0.5 part Current strategies for reduction of melting point of phar second anion, the co-ionic liquids disclosed in this invention maceutical active salts mainly rely on the formation of con can be 1 part cation, 1 part first anionic unit and 1 part of a ventional eutectics, however, this includes the addition of a second anionic unit that are in proton exchanged to form one third and different compound that could completely alter the mixed anion with a total charge of -1. When the disclosed chemical properties of the salt. Our invention differs by the ionic liquid compositions have two or more ions with a bio absence of an eutectic point: Addition of acid or base elimi active property (e.g., pharmaceutical active ingredients, pes nates the melting point or drives it below the glass transition ticidal actives, herbicidal actives, and the like), these compo temperature and will eventually lead to a point of saturation at sitions can be particularly desired because each of the active a certain Stoichiometry. Higher concentrations result in the ingredients in the composition would have the same solubility 25 precipitation of excess acid and in a suspension of solid acid and would dissolve together when formulated or adminis in a co-ionic liquid with a dimericanion. The identity of the tered. cation or of the anion is not critical to the scope of this The present invention provides in a first aspect a method to invention: Independently of the cation, a depression of elimi transform solid salts into liquid mixtures by simply changing nation of the melting point or in case of salts that appear as the stoichiometry of the active pharmaceutical salts without 30 glasses—a decrease of the glass transition temperature was addition of a new compound that might completely alter the observed was observed with different pharmaceutically biological properties. This can be particularly useful when active acids with 2- or 3-fold excess. Some specific examples overcoming formulation, Solubility, bioavailability, size, and of co-ionic liquids include, but are not limited to the pharma polymorphism issues. ceutically active anions salicylate and ibuprofenate as well as In the current invention, it is not even necessary to add an 35 to the biological active cations cetylpyridinium, lidocainium, additional equivalent of acid or base to form dimericanions or ephedrinium, choline or caffeine. cations. For example, an co-ionic liquid composition dis Salicylate is chiefly used in anti-acne formulation, but also closed herein can eliminate the melting point of a solid salt by in various skin-care products. Ibuprofen is used as an anti addition of Sub-stoichiometric amounts of acid, as it is dem inflammatory and available as over-the-counter analgesic. onstrated in the example with tetrabutylphosphonium salicy 40 Lidocaine is a common local anesthetic. Cetylpyridinium is late: an excess of 0.1 equivalent of salicylic acid does already used as an antiseptic agent alone or in combination with other reduce the melting point of the conventional salt from 57 to drugs for oral and throat care. It is essentially nontoxic and 39° C., and a 0.3 molar excess completely eliminates the can be applied to the skin or mucous membranes. Besides melting point to yield a free flowing liquid (FIG. 2), despite their pharmaceutical activity, caffeine and ephedrine are also the fact that both ionic liquid and free acid are solid at room common in dietary Supplement.

II

O O O O 1 P(Bu)" C r N O- - - H- O OH HO 1. Y OH HO

III IV

O O s1n-1-- O---H-O

HO US 9,278,134 B2 59 60 -continued

OH P(Bu)"

VI

VII VIII

OH --

By example, an elimination of melting point or a reduction of -continued melting point or glass transition with excess acid was 25 obtained for tetrabutylphosphonium salicylate I, tributylm ethylammonium salicylate II choline salicylate III, cetylpy ridinium salicylate IV, tetrabutylphoshonium lactate V. tet rabutylphoshonium ibuprofenate VI, lidocaine salicylate VII 1. and caffeine salicylate VIII for tetrabutylphosphonium lac 30 tate.

N OH 35 In further examples, the disclosed co-ionic liquid compo sitions are not limited to higher anionic species, but can be observed almost in the same manner when excess base is added: An excess of lidocaine to the parent salt lidocaine salicylate results not only in a decreased glass transition tem 40 In the present invention, the concept double functional co perature, but also in a notable reduction of viscosity until at a ionic liquids is not limited to mixtures of a neutral salt with certain excess of lidocaine a point of Saturation is obtained the corresponding acid or base, but can be also applied to the and a solid sample results (FIG. 4). Specific examples of such addition of different solid acids or bases other than the parent protic compositions include, but are not limited to, composi compounds to obtain liquids type BIA'HA or B'HBA. It tions where the cation is a local anesthetic likelidocaine IX or 45 is therefore possible to expand the scope of ionic liquids to a decongestant like ephedrine X or one of its diastereomers more than two compounds that are none the less all involved and are shown below. in proton-exchange process and therefore differ from a simple Solution of a third compound in a conventional ionic liquid. 50 Some specific examples of co-ionic liquids include, but are not limited to the pharmaceutically active anions salicylate IX and ibuprofenate, or the vitamin niacine. Examples also include chiral species, as it was demonstrated with camphor 55 Sulfonic acid.

XI

60 O P(Bu)" C OH O 65 US 9,278,134 B2 61 62 -continued -continued XIV XII N a 5 P(Bu)" on-O O O OH 10 XIII It is notable in all cases a liquid product is obtained with a glass transition temperature at around -50° C. only, although both starting materials tetrabutyl phosphonium salicylate and the shown acids are solid at room temperature. This elimina O---H-OS 15 tion of melting point is most likely related to a formation of a mixed “super-anion' that is derived from proton delocatiza tion as it was observed in the tetrabutylphosphonium salicy OH late-salicylic acid dimer. A reasonable difference in pKa of about 2 units is therefore necessary to allow a permanent hydrogen exchange between the acids A" and A and the inhibition of crystallization.

XV O

O- - - H - O S.

OH O

XVI O

O---H-O

OH O

XVII O C

s, 1-1 O- - - H- O O

OH O US 9,278,134 B2 63 64 Other therapeutic useful combinations of 3 or more active -continued compounds include the antibacterial cation cetylpyridinium in combination with various pharmaceutically active anions: XXI Salicylate is chiefly used in anti-acne formulation, but also in -- various skin-care products. Ibuprofen is used as an anti-in flammatory and available as over-the-counter analgesic, and $1H clofibric acid is used as lipid-lowering agent. Some specific O examples of triple functional ionic liquids that show a melting OH depression compared to the common dual functional co-ionic H liquids include, but are not limited to the combinations N^^ O cetylpyridinium salicylate-cinammate XV cetylpyridinium O salicylate-ibuprofenate XVI and cetylpyridinium salicylate clofibrate XVII.

XVIII

XIX

O -H O HO E

OH

Other examples include co-ionic liquids comprising three 35 -continued analgesics compounds, as demonstrated in the compounds XXII lidocaine salicylate-ibuprofenate XVIII and tramadolium salicylate-ibuprofenate XIX. -- 40 On s In another embodiment of the disclosed co-ionic liquids HN O relates to ionic liquids comprising two or more biologically O functional compound sharing one proton with the total charge HOa O of +1 and one biological functional anion. Non-limiting examples of this embodiment include combinations of the 45 r -it decongestant ephedrine with two analgesic or anaesthetic compounds, as present in ephedrinium-lidocainium salicy XXIII late XX or ephedrinium-lidocainium ibuprofenate XXI. Similarly to dimeric anions, triple functional painkillers can -- be prepared from 3 analgesic compounds like tramadolium 50 lidocainium ibuprofenate XXII or tramadolium-lidocainium On O

salicylate XXIII. HN O 55 OH

1. 60 OH O Despite the fact that lidocaine, tramadole hydrate, ibupro 1n fene and even the conventional salt tramadolium ibuprofenate OH are solid at room temperature the co-ionic liquid of the type 65 BHBA was obtained as clear liquid with a glass transition r N temperature at -37° C. Synergistic (enhanced efficiency) as previously described for API ionic liquids, e.g. in lidocainium US 9,278,134 B2 65 66 docusate are very likely in these multiple-compound ionic salicylate salt of the type BIA'HA). Similarly, if the melting liquids and allow modulation of properties by judicious points of at least one of the starting materials or the product choice of cation/anions with the desired activities. are below the decomposition temperature of the API-IL, the Other therapeutically useful combinations include ionic pharmaceutically active co-ionic liquids can be prepared in liquids comprised of the decongestant ephedrine and the molten state from the acid-base precursors, as it was demon common antiemetic and antihistaminic promethazine, a com strated with the system ephedrinium-salicylate 3:1. bination of promethazine and ephedrine that is established against e.g. seasickness. Triple functional ionic liquids can be obtained in combination with an emollient anion like docu Ionic Liquid Prodrugs sate XXIV or with salicylicylate XXV. It notable that these 10 triple-functional ionic liquids are not limited to stoichiomet This invention relates to the use of ionic liquids for immo ric mixtures of the three active compounds in the ratio 1:1:1, bilization, delivery, and controlled release of pharmaceuti but allow individual dosing of a selected compounds, as cally active liquid or low melting salt compositions. The would be present in the co-ionic liquid promethazine-ephe present invention is based upon the discovery that active drinium docusate in the ratio 0.5:1:1. compounds, especially pharmaceuticals, can be covalently

XXIV

OS

OH N-H- N

XXV

OCON

OH N-H->NN OH

In a further aspect, this invention relates to solvent-free linked with ionic structural moiety and turned into an ionic methods of preparation for co-ionic liquids. The synthesis of 5 liquid by appropriate choice of the counterion. double- or multiple functional co-ionic liquids can be easily achieved by stirring additional acid or base with the conven tional API IL in an appropriate solvent that dissolves both active starting materials, e.g. reaction of cetylpyridinium salicylate compound and salicylic acid in acetone. Alternatively, if the cation is 50 available as hydroxide salt, direct reaction with the appropri ate excess of one or more acids in a co-solvent will directly give rise to co-ionic liquids of the type BIA'HA), as dem onstrated with tetrabutylphosphonium salicylate-salicylic 55 Current methods for the modification of the physical prop acid. erties of Solid drugs rely mainly on its transformation into a However, methods of preparation also include solvent-free salt; however, this is limited to acidic or basic pharmaceuti techniques, e.g. grinding or reaction in molten state. Solid cally active compounds. The term “active compound is used tetrabutylphoshonium salicylate and salicylic acid can be eas to include any pharmaceutically or biologically active com ily liquefied by simple grinding in a mortar or by melting the 60 pound, but also nutritional, fragrance or flavour compound, as Solid tetrabutylphoshonium salicylate and Salicylic acid to long as a functional group, typically a hydroxy or amine obtain the liquid tetrabutylphosphonium salicylate-salicylic group, is present to covalently attach this compound on the acid. This solvent-free preparation technique can be even ionic structure. Thus the neutral compound can be transferred expanded to the preparation of triple-functional co-ionic liq into salts, wherein the active compound is immobilized as uids directly from the acid/base precursors: Grinding of solid 65 part of the ionic liquid in either positive or negative charge. lidocaine, ibuprofenic acid and salicylic acid for 15 minutes at The term “linking unit comprises a spacer to attach the room temperature gave the liquid lidocainium-ibuprofenate neutral active compound to the charged moiety, thus it must US 9,278,134 B2 67 68 possess two reactive positions. In the present invention, link liquidionused for immobilization but also on the counterion. ing is achieved by esterification of the neutral active com Anappropriate choice of the counterion can therefore be used pound with a halogenated acid chloride, e.g. chloroacetyl to dramatically change solubility of the parent compound or chloride that can be further alkylated with any cation precur turn hydrophilic salts into hydrophobic salts. Sor to transfer the neutral compound into a charged species. This ionic liquid prodrug approach provides an opportu The labile ester bond allows cleaving the prodrug and liber nity to model release kinetics of the active compound on the ating the active compound under defined conditions that structure. The choice of linking unit, the covalently attached include, but are not limited to hydrolysis, pH-dependent ionic moiety and the counter ion can all be used to design a cleavage, enzymatic hydrolysis, thermical cleavage or photo prodrug that is labile under defined conditions only. For cleavage. 10 example, in the present invention it has been demonstrated However, the linking unit is not limited to ester function- that a change of ionic liquid unit covalently attached to the alities; basically, any functional group that can be cleaved active compound can dramatically influence drug release. Xamplesle le?s 1nclude, inbut are ca,not 11m1tedN", to aS esters, sing am1des, E. VersatileStill liquid ES delivery liquid systems Pitts with a wide rangecosts of tuneaS acetals, diorthoesters, vinylethers, dithiols or azo conjugates. able properties for neutral compounds. The term "ionic moiety' can include both cationic or The invention also provides the possibility to form dual anionic groups covalently attached to the active compound. In functioning salts by introduction of a second, pharmaceuti case of cations, conventional ionic liquids structural motives cally or biologically active counter ion or a second, charged phosphon1umE. but are compounds not s 11Ke to,1m1daZOl1um, E. pyr1d1n1um, A. pyr- or neutralactive compound. and a charged Prodrug active decomposition compound in will exactly than providethe same a rolidinium. Special emphasis has to be put pharmaceutically dosage. acceptable cations that will leave approved materials after This invention also includes triple-functional salts, Sri St. E. trisits will s wherein a neutral active compound is covalently attached to a E"S"SE"R"ENE,Ca1 a WCOTWS1S all CleaS OaC1V COOUC. as EN, ESPN conventional ionic liquid cations, it is also possible to attach dazolium cations. The constitution of which, can then be the stral active compound to a second, charged active com- paired with a third charged active compounds, which will pound. result in the delivery of 3 active compounds in the same Alternatively, in case of immobilization of the neutral com- dosage. pound on the anion, any functional group bearing a negative ' charge can be chosen. Examples include, but are not limited

to carboxylates, Sulphates, Sulphonates or phosphonates. The term “counter ion’ can include both cations and charged

anions, including pharmaceutical or biological active com- active pounds. The role of the counterion is to control the physilogi- compoun compound II cal properties of the ionic liquid composition, such as liquid range, hydrophobicity and lipophilicity, melting point, etc. In the current invention, the ionic liquid acts not only as Support counterion for the active compounds, being able to store pharmaceuticals active compound III in inactive form but also allow a simple tuning of physical " properties of compounds that cannot be directly transferred into salts. Specific examples in the current invention include ionic This invention provides in a first aspect a synthetic meth- liquids prodrugs based on acetaminophen, a widely used odology to transfer neutral compounds into liquid salts to analgesic and antipyretic drug used for the relief of fever, overcome polymorphism, overcome solubility and delivery headaches, and other minor aches and pains. The phenol problems, to control release rates, add functionality, enhance proton is not acidic enough to form a stable anion and pair it efficacy (synergy), and improve ease of use and manufacture. with appropriate cations; however, we demonstrated that our It has been discovered that the physical properties of the ionic liquid prodrug strategy can be used to transfer acetami active compound are depending both on the type of ionic nophen in a stable liquid salt.

OH O O O na

us N -- C C Hepyridine us N O H acetone, H 0° C. tort, 2h 1 O 69% 2

N-methylpyrrollidine pyridine

N-Methylimidazole EE, rf, 2d EE, rf, 2d EE, rf, 2d 79% 97% 83% US 9,278,134 B2 69 70 -continued Geno N1V+N O O Cl O s/ c O Cl O GerryO 3 Paracet-Melm-Cl 4 Paracet-Mepyr-Cl 5 Paracet-Py-Cl 6 Paracet-P(Bu)-CI

AgDoc AgLac MeOH MeOH rt, 15 min rt, 15 min

anion exchange to hydrophobic docusates 7, 8, 9, 10 anion exchange to hydrophilic lactates

15 Ionic Liquid Supported Fragrances attach this compound on the ionic structure. Thus the neutral compound can be transferred into a low-volatile salt, wherein This invention relates to the use of ionic liquids for storage the active compound is immobilized as part of the ionic liquid and controlled release of Volatile compounds, especially fra- in either positive or negative charge. Examples include, but grances and flavors as liquid salt compositions. The present '' are not limited to fragrance alcohols like geraniol, menthol, invention is based upon the discovery that volatile com- prenol, citronellol or farnesol. The term “linker comprises a pounds can be covalently linked with ionic structural moiety spacing unit to attach the neutral active compound to the and turned into an ionic liquid by appropriate choice of the charged moiety, thus it must possess two reactive positions. counter ion. 25 For specific examples in the present invention, linking is achieved by esterification of a fragrance alcohol with a halo genated acid chloride, e.g. chloroacetyl chloride that can be further alkylated with any cation precursor to transfer the neutral compound into a charged species. The labile ester 30 bond allows cleaving the prodrug and liberating the neutral active compound under defined conditions that include, but are not limited to hydrolysis, pH-dependent cleavage, enzy matic hydrolysis, thermical cleavage, photo cleavage or elec trodecomposition. Current methods to issue the loss of volatile frangance or 35 However, the linking unit is not limited to ester function alities; basically, any functional group that can be cleaved flavour compounds address specific delivery systems like under defined conditions can be used as linking- 0 unit. microcapsules and carriers for long-lasting ScentS. Examples include, but are not limited to esters, amides, In the current invention, the ionic liquid acts not only as acetals, diorthoesters, vinylethers, dithiols orazo conjugates. Support for the active compounds, being able to store fra- The selection of a particular linker, ionic group and coun grances and flavors or, in general volatile compounds in non- "terion depends on the nature of the product in which the Volatile form but also allows a simple tuning of release con- delivery system is to be used as well as on the kind of release ditions. mechanism required. For example, in the present invention it This invention provides in a first aspect a synthetic meth- has been demonstrated that a change of linking unit can lead odology to transfer neutral Volatile compounds into liquid as to different release systems. Specifically, the ionic liquid salts to modify physical properties, avoid evaporation, over- compositions can be considered as Smart retention and deliv come solubility and delivery problems, to control release ery devices for triggered release of fragrance, flavour or any rates, add functionality, and improve ease of use, storage and other volatile compound. manufacture. It has been discovered that the physical proper- By example, the typical fragrance alcohol geraniol can be ties of the active compound are depending both on the type of 50 reacted with chloroacetyl chloride as linking unit and further ionic liquid ion used for immobilization, the linking unit but alkylated with N-methylimidazol to the quaternary imidazo also on the counterion. The term “active compound is used lium salt 3, which provides, as any ionic liquid neglible Vola to include any active compound, but especially nutritional, tility. Further ion exchange to docusate 4 can dramatically fragrance or flavor compound, as long as a functional group, change physical properties, e.g. solubility and turn a hydro typically a hydroxy or amine group, is present to covalently philic chloride salt 3 into a hydrophobic liquid.

OH C pyridine He --~~ -- cry CHCl2, O C. tort, 24h O Nr-r-rO 9996 1 2

N-methylimidazole neat, rt, on 67% US 9,278,134 B2 71 72 -continued 21 21 O N 1N1N

C O Sodium docusate ar ar O 1s -- 1. acetone/H2O, OS rt, 24h O \=/ O > 99% 3

O N-- 4

Ionic liquid-supported hydrophobic fragrance 4 shows, as ion or a second, charged active compound. Ionic liquid typically for any ionic liquid, neglible volatility but can be decomposition will than provide a neutral and a charged decomposed by means of heat only to liberate geraniol (FIG. active fragrance or flavour in exactly the same dosage. 6). Food and pharmaceutical regulations restrict the palette of material used for Sustained release. The invention also includes example for immobilization of the active compound This invention also includes triple-functional salts, on the anion of the ionic liquid delivery system, which can be wherein a neutral active compound is covalently attached to a completely composed of GRAS (Generally Recognized As 25 second, charged active compounds, replace to the typical Safe) compounds. A typical example of this type of ionic structural elements that are present in ionic liquids, e.g. imi liquid delivery system includes the immobilization of fra dazolium cations. The constitution of which, can then be grance alcohols as hemisuccinates that can be further depro paired with a third charged active compounds, which will tonated with any basic component, e.g. hydroxides of quater result in the delivery of 3 active compounds in the same rate nary amines to give an ionic liquid. and dosage.

O O OH pyridine, 4-DMAP O -- ar ar --~~ O CHCl2,92% rt, 24h N-- O OH 1 O 5

choline hydroxide MeOH, 5 min 9996

N 2N-1\on O

O

N-- O O 6

60 Cleavage of ionic liquid immobilized fragrance 6 by the EXAMPLES process of acidic, basic or enzymatic ester hydrolysis will release the fragrance and leave only choline (a vitamine) and The following examples are set forth below to illustrate the Succinic acid, a compound that is generally recognized as safe methods and results according to the disclosed subject matter. (GRAS). 65 These examples are not intended to be inclusive of all aspects The invention also provides the possibility to form dual of the subject matter disclosed herein, but rather to illustrate functioning salts by introduction of a second active counter representative methods and results. All chemicals used were US 9,278,134 B2 73 ofanalytical grade, purchased from Sigma-Aldrich (UK), and TABLE I-continued used without further purification unless otherwise noted. Commercially available solutions of hydroxides were titrated Water prior to use to determine the exact concentration. Composition mp content Multiple Functional Co-Ionic Liquids P(Bu):Sal Appearance C. Tso., C. 90 m/m) 1:30 Liquid -43) 164 Example 1 1:31 Suspension -43 1:3.5 Suspension -45°l Tetrabutylphosphonium Salicylate-Salicylic Acid 1:3.7 Suspension -43 150 O.1033 10 Salicylic acid Solid 158 (lit) 136 determined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C. min and cooling with -2.5°C. minto -80°C. for 3 cycles. Plglass transition temperature, eldetermined on a Mettler Toledo Star TGADSC unit by heating from 25° C. to 600° C. with 5°C.min under nitrogen. OH 15 Table I shows thermal data and water content of different / tetrabutylphosphonium salicylate-salicylic acid co-ionic liq uids. FIG. 2 is a plot of the melting point depression and melting ? -- point elimination curves for the data depicted in Table I. O FIG.3 depicts the conductivity of different P(Bu)Sal H compositions in a series of co-ionic liquids comprising oli -e- gomeric anions. C acetone/H2O 25 OH Example 2

Tetrabutylphosphonium Salicylate-salicylic 30 s -- - O - O O P O- -H-O Acid-solvent-free Synthesis Via Grinding ? OH OH 35 OH Salicylic acid (5-20 mmol) and tetrabutylphosphonium hydroxide (~40% sol. in HO) (3.414 g, 5 mmol) were dis solved in 20 ml of acetone stirred for 15 min at room tem -- / perature. The solvent was evaporated and the remaining vis 40 cous liquid was dried under reduced pressure (0.01 mbar, 50° C.) with stirring for 24 hrs. 'H-NMR (300 MHz, d-DMSO) ? -- 8(ppm)=7.74 (dd, J=7.7 Hz, J–1.9 Hz, 1H), 7.32 (dt, J–7.6 Hz, J-1.8 Hz, 1H), 6.8 (m, 2H), 2.20 (m, 4H), 1.41 (m, 8H), O 0.9 (t, J=7.1 Hz, 6 H). 'P-NMR (121.5 MHz, d-DMSO) 45 8(ppm)=35.1. C-NMR (75 MHz, d-DMSO) 8(ppm)= He 171.9(s), 163.1(s), 131.1 (d), 129.8(d), 120.6 (s), 115.7 (d), C acetone/H2O 115.6 (d), 23.3 (d. J=16.4 Hz), 22.6 (d. J–4.8 Hz), 17.3 (d. OH J=47.3 Hz), 13.2 (s). 50 TABLE I s - O O -- O- - H - O Water P Composition mp content P(Bu):Sal Appearance C. Tso., C. 90 m/m) OH OH 55 :1 Solid 57 312 O.O766 :1.1 Solid 52 297 O.1359 :1.2 Solid -54 211 O.1283 :13 Liquid -54 2O7 O.228O :1.4 Liquid -51 209 O.1308 Solid tetrabutylphosphonium salicylate (3.963 g, 10 :1.5 Liquid -52(b 2O6 0.1587 mmol) and Salicylic acid (1.601 g, 10 mmol) were grinded for :1.6 Liquid -50 2OO O.3210 60 2 minutes in a mortar until a colorless, free-flowing liquid was :1.7 Liquid -48 194 O.1807 :18 Liquid -47 198 O.1529 obtained. Physical data were similar to those obtained with :19 Liquid -46 198 O.2462 conventional synthesis (example 1). :2 Liquid -46 192 O.1924 :2.4 Liquid -45 184 0.1517 'H-NMR (300 MHz, d-DMSO)8(ppm)=7.74 (dd, J=7.7 :2.7 Liquid -43 173 O.1412 65 Hz, J–1.87 Hz), 7.32 (dt, J =7.6 Hz, J-1.80 Hz, 1H), 6.77 :28 Liquid -43 169 O.1127 (m. 2H), 2.20 (m, 4H), 1.41 (m, 8 H), 0.9 (t, J=7.1 Hz, 6H). 'C-NMR (75 MHz, d-DMSO)8(ppm)=172.0 (s), 162.3 (s), US 9,278,134 B2 75 76 133.8 (d), 130.5 (d), 117.9 (d), 117.1 (s), 116.8 (d), 23.30 (d. Table II shows thermal data of different tributylmethylam J=15.94 Hz), 22.61 (d. J=5.31 Hz), 17.31 (d. J=47.82 Hz), monium salicylate-salicylic acid co-ionic liquids. 13.73 (s). Example 4 Example 3 Choline Salicylate-salicylic Acid Methyltributylammonium Salicylate-salicylic Acid

10 O

OH OH N -- -- -7N-1sOH methanol 15 OH h -- O O 2n-1-ohN O- -H-O OH OH

O Salicylic acid (5 or 10 mmol) and choline hydroxide (5 mmol. 40% solution in MeOH) were dissolved in 20 ml of -e- methanol and stirred for 15 min at room temperature. The OH acetone/H2O 25 Solvent was evaporated and the remaining viscous liquid was dried at 0.1 mbar with stirring for 24 hrs. OH H-NMR (300 MHz, de-DMSO) 8(ppm)=7.64 (dd, J=7.4 HZ, J–1.9 HZ, 1H), 7.3 (m. 1H), 6.6 (m, 2H), 3.8 (m, 2H), 3.4 30 (m. 2H), 3.1 (s, 9H). TABLE III

O O Ratio Cho:Sal Appearance mp Cl Tso. ase I C. 35 1:1 solid 48 (lit) 2O3 N e O--H-O 1:2 liquid -41bl 173 determined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C. min and cooling with -2.5°C. minto -80°C. for 3 cycles. Plglass transition temperature, ? - OH OH determined on a Mettler Toledo Star TGADSC unit by heating from 25° C. to 600° C. 40 with 5°C.min under nitrogen. Table III shows thermal data of different choline salicylate Salicylic acid (5-20 mmol) and tributylmethylammonium salicylic acid co-ionic liquids. hydroxide (5 mmol, 40% solution in HO) were dissolved in 20 ml of acetone stirred for 15 min at room temperature. The Example 5 Solvent was evaporated and the remaining viscous liquid was 45 dried at 0.1 mbar with stirring for 24 hrs. Cetylpyridinium Salicylate-salicylic Acid 'H-NMR (300 MHz, d-DMSO)8(ppm)=7.63 (dd, J–7.7 Hz, J–1.9 Hz, 1H), 7.10 (m. 1H), 6.57 (m, 2H), 3.19 (m, 6H), 2.94 (s.3H), 1.59 (m, 6H), 1.29 (sext, J–7.4 Hz, 6H), 0.9 (t, J=7.4 Hz, 9H). 'C-NMR (75 MHz, d-DMSO) 8(ppm)= 50 O 1719, 1620, 133.4, 130.1, 117.5, 116.9, 60.4, 47.5, 23.4, -- 19.2, 13.5.

TABLE II 21 OH 55 O

Ratio N(Bu)Me:Sal Appearance mp Cl Tso. ase I C. Hip OH acetOne 1:1 solid 83 193 1:2 liquid -37 (b) 196 60 OH 1:3 liquid –41(T) 177 O O

ldetermined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C.min and cooling with -2.5°C. minto -80°C. for 3 cycles, Plglass transition temperature, 65 21 OH OH eldetermined on a Mettler Toledo Star TGADSC unit by heating from 25°C. to 600° C. Cra Cro with 5°C.min under nitrogen. US 9,278,134 B2 77 Salicylic acid (5-15 mmol) and cetylpyridinium salicylate TABLEV (5 mmol) were dissolved in 20 ml of acetone and stirred for 15 minat room temperature. The solvent was evaporated and the remaining viscous liquid was dried at 0.1 mbar with stirring Ratio P(Bu) Ibu Appearance T. Clel Tso. ase (C.' for 24 hrs. 5 'H-NMR (300 MHz, d-DMSO) 8(ppm)=9.12 (d. J=6.1 1:1 liquid -43 234 Hz, 2H), 8.59 (t, J=8.3 Hz, 1H), 8.16 (t, J=7.3 Hz, 2H), 7.64 1:2 liquid -40 264 (d. 7.5 Hz, 1H), 7.12 (t, J=7.5, 1H), 6.57 (m, 2H), 4.59 (t, 1:3 liquid -39 189 J–7.4 Hz, 2H), 1.88 (m, 2H), 1.22 (s. 27H), 0.84 (t, J=7.1 Hz, 10 ldetermined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C. min and 3H). 'C-NMR (75 MHz, d-DMSO)8(ppm)=171.8, 163.4, cooling with -2.5°C. minto -80°C. for 3 cycles. 145.8, 145.2, 1314, 130.2, 128.4, 121.1, 116.1, 160.0, 61.2, Pldetermined on a Mettler Toledo Star TGADSC unit by heating from 25°C. to 600° C. 31.7, 31.2, 29.4, 29.3, 29.2, 29.1, 28.8, 25.8, 22.5, 14.2. with 5°C.min under nitrogen.

TABLE IV Table V shows thermal data of different tetrabutylphospho 15 nium ibuprofenate-ibuprofenic co-ionic liquids. Ratio CetPy:Sal Appearance mpo C.) (al Tso. ase, C.) Example 7 1:1 solid 71 2O6 1:2 solid S4 184 1:3 solid -21bl 162 Tetrabutylphosphonium Lactate-lactic Acid

ldetermined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C.min and cooling with -2.5°C. minto -80°C. for 3 cycles, Plglass transition temperature, 25 eldetermined on a Mettler Toledo Star TGADSC unit by heating from 25°C. to 600° C. with 5°C.min under nitrogen. OH / OH Table IV shows thermal data of different cetylpyridinium -- P -- OH Hos salicylate-salicylic acid co-ionic liquids. 30 acetone HO Example 6 O

Tetrabutylphosphonium Ibuprofenate-ibuprofenic 35 Acid / OH OH -- O- -H-O P P(Bu)"OH 40 ? O O OH acetone/H2O Lactic acid (5-15 mmol) and tetrabutylphosphonium O 45 hydroxide (~40% sol. in HO) (3.414 g, 5 mmol) were dis solved in 20 ml of acetone and stirred for 15 min at room O--H-O temperature. The Solvent was evaporated and the remaining viscous liquid was dried at 0.1 mbar with stirring for 24 hrs. O O 50 H-NMR (300 MHz, d-DMSO) 8(ppm)=3.84 (bris, 1H), 3.44 (q, J=6.7 Hz, 1H), 2.18 (m, 8H), 1.41 (m, 16H), 1.05 (d. P(Bu)" J=7.2 Hz, 3H), 0.91 (t, J=6.7 Hz, 12H). 'P-NMR (121.5 MHz, d-DMSO) 8(ppm)=35.0. 'C-NMR (75 MHz, Ibuprofenic acid (5-15 mmol) and tetrabutylphosphonium d-DMSO)8(ppm)=176.8, 67.3, 23.72 (d. J=15.5 Hz), 23.01 hydroxide (~40% sol. in HO) (3.414 g, 5 mmol) were dis 55 (d. J=4.7 Hz), 21.91, 17.70 (d. J=47.9 Hz), 13.62 (s). solved in 20 ml of acetone and stirred for 15 min at room temperature. The Solvent was evaporated and the remaining TABLE VI viscous liquid was dried at 0.1 mbar with stirring for 24 hrs. Ratio P(Bu). Lac Appearance T C.|al Ts, onse." H-NMR (300 MHz, d-DMSO)8(ppm)=7.13 (d. J=8.1 Hz, 60 2H), 6.94 (d. 8.1 Hz, 2H), 3.21 (q, 7.7 Hz, 1H), 2.48 (m, 2H), 1:1 liquid 1.78 (mp) 262 2.36 (d. 7.3 Hz, 2H), 2.14 (m, 8H), 1.77 (sept, 6.2 Hz, 1H), 1:2 liquid -56 215 1.40 (m, 16 H), 1.18 (d. J=70 Hz, 3H), 0.91 (t, 7.0 Hz, 12H), 1:3 liquid -SS 176 0.84 (d. J=7.0 Hz, 6H). 'C-NMR (75 MHz, d-DMSO) ldetermined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C. min and 8(ppm)=174.8, 144.2, 136.9, 127.8, 127.2, 49.3, 44.4, 29.7, 65 cooling with -2.5°C. minto -80°C. for 3 cycles. Pldetermined on a Mettler Toledo Star TGADSC unit by heating from 25°C. to 600° C. 23.4 (d. J=15.8 Hz), 22.7 (d. J=4.7 Hz), 22.2, 20.5, 17.3 (d. with 5°C,imin, under nitrogen. J=48.1 Hz), 13.3. US 9,278,134 B2 79 80 Table VI shows thermal data of different tetrabutylphos FIG. 4 depicts the depression of glass transition and satu phonium lactate-lactic acid co-ionic liquids. ration of double functional co-ionic liquids based on lidocainium salicylate. Example 8 Example 9 Lidocaine Salicylates Ephedrine Salicylate

10

OH -- O OH H N r OH 15 C'r N OH OH O OH

OH O N

OH

n1

25 OH 1-1 O 6H O OH H 30 OH O O NN N lah N^^ O--H-O l OH OH 35 O OH O O Salicylic acid or lidocaine free base (0.5, 1, 1.5 or 2 eq.) and H lidocaine Salicylate were suspended in acetone (20 ml) and NN O--H-O stirred at room temperature until a clear Solution was 40 obtained. The solvent was evaporated and remaining Volatile OH HO material removed under vacuum (0.01 mbar, 40° C.). 'H-NMR (300 MHz, d-DMSO)8(ppm)=10.05 (brs, 1H), Salicylic acid or ephedrine free base (0.5, 1, 1.5 or 2 eq.) 7.72 (dd, J–7.8 Hz, J-1.8 Hz, 1H), 7.24 (m, 1H), 7.09 (s. 3H), 6.70 (m, 2H), 3.98 (s. 2H), 3.10 (q, J=7.3 Hz, 4H), 2.16 and ephedrinium salicylate were suspended in acetone (20 (s, 6H), 1.22 (t, J=7.3 Hz, 6H). 'C-NMR (75 MHz, 45 ml) and stirred at room temperature until a clear Solution was d-DMSO)8(ppm)=171.9, 164.6, 1619, 135.0, 134.0, 133.4, obtained. The solvent was evaporated and remaining Volatile material removed under vacuum (0.01 mbar, 40° C.). 130. 1, 127.8, 126.9, 117.6, 116.9, 116.4, 53.3, 48.3, 18.1, 9.5. 'H-NMR (300 MHz, d-DMSO) 8(ppm)=9.30 (brs, 2H), TABLE VII 7.76 (dd, J=7.7 Hz, J-1.8 Hz, 1H), 7.38 (m, 4H), 7.24 (m, 50 2H), 6.70 (m, 2H), 6.48 (brs, 1H), 5.21 (s, 1H), 3.41 (m, 1H), Lid Sal Appearance T.I. Clel Tase, so, C.' 2.69 (s.3H), 0.95 (d. J=6.8 Hz, 3H). 'C-NMR (75 MHz, 3 1 solid -32 161 d-DMSO)8(ppm)=172.9, 162.1, 141.4, 132.0, 130.3, 128.2, 2.5 1 solid -25 137 127.2, 125.8, 119.6, 11.6.8, 116.0, 69.6, 59.3, 30.6, 9.1. 2 1 glass -15 154 1.5 1 glass -1 169 55 1 1 glass 19 161 TABLE VIII 1 1.5 viscous liquid 13 142 1 2 viscous liquid 3 138 Ratio Eph:Sal Appearance mpo C.) (al Tase, so, C.J.' 1 2.5 solid -4 132 1:3 solid 61 1 3 solid -3 128 1:2 solid 61 130 1 solid 69 (mp) 152 60 1:1 solid 97 161 1 solid 160 (mp) 134 2:1 glass 2(b) 127 3:1 liquid 5(b) 123 determined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C.min and cooling with -2.5°C. minto -80°C. for 3 cycles, Pldetermined on a Mettler Toledo Star TGADSC unit by heating from 25° C. to 600° C. ldetermined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C. min and with 5°C. min. under nitrogen. cooling with 5°C/min to -80°C, for 3 cycles. 65 Plglass transition temperature eldetermined on a Mettler Toledo Star TGADSC unit by heating from 25° C. to 600° C. Table VII shows thermal data of different lidocaine salicy with 5°C,imin, under nitrogen. lateco-ionic liquids. US 9,278,134 B2 81 82 Table VIII shows thermal data of different ephedrinium Table IX shows thermal data of different ephedrinium sali salicylate co-ionic liquids. cylate co-ionic liquids prepared by grinding.

Example 10 Example 11 Ephedrine Salicylate-solvent-free Synthesis Via Grinding Ephedrine Salicylate-solvent-free Synthesis in Molten State

10 O

OH -- OH H N 15 OH OH C'r N O H N O O H N

-- OH

C O H 1 25 O O H N OH O N OH HN OH OH

O OH | O O 35 H O NS OH | O O H N- O- -H-O 40 Salicylic acid or ephedrine free base (0.5, 1, 1.5 or 2 eq.) OH HO and ephedrinium salicylate were grinded for 15 minutes in a mortar. Analytical data were similar to those obtained in conventional synthesis. H-NMR (300 MHz, d-DMSO) Salicylic acid and ephedrine free base (1, 2 or 3 eq.) were 8(ppm)=9.30 (brs, 2H), 7.76 (dd, J–7.7 Hz, J-1.8 Hz, 1H), 45 molten in a hot mortar until a free-flowing clear liquid was 7.38 (m, 4H), 7.24 (m, 2H), 6.70 (m, 2H), 6.48 (brs, 1H), 5.21 obtained. The mixture was cooled to room temperature and, (s, 1H), 3.41 (m, 1H), 2.69 (s.3H), 0.95 (d. J=6.8 Hz, 3H). in case of Solid products grinded to obtain colourless pow 'C-NMR (75 MHz, d-DMSO) 8(ppm)=172.9, 162.1, ders. 'H-NMR (300 MHz, d-DMSO) 8(ppm)=9.30 (brs, 1414, 132.0, 130.3, 128.2, 127.2, 125.8, 119.6, 116.8, 116.0, 2H), 7.76 (dd, J=7.66 Hz, J–1.80 Hz, 1H), 7.38 (m, 4H), 69.6, 59.3, 30.6, 9.1. 50 7.24 (m, 2H), 6.70 (m, 2H), 6.48 (brs, 1H), 5.21 (s, 1H), 3.41 TABLE IX (m. 1H), 2.69 (s.3H), 0.95 (d. J=6.76 Hz, 3H). 'C-NMR (75 MHz, d-DMSO) 8(ppm)=172.9, 162.1, 1414, 132.0, 130.3, Ratio Eph:Sal Appearance mpo C.) (al Tase, so, C.) 128.2, 127.2, 125.8, 119.6, 116.8, 116.0, 69.6, 59.3, 30.6, 9.1. 1:4 solid 61 124 55 1:3 solid 61 122 TABLE X 1:2 solid 61 131 1:1.4 solid 61 153 Ratio Eph:Sal Appearance mpo C.) (al Tase, so, C.J.' 1:1.3 solid 60 147 1:1-2 solid 60 154 1:3 solid 61 135 1:1.1 solid 91 163 1:2 solid 61 133 1:1 solid 97 161 60 1:1 solid 97 161 2:1 glass s(b) 118 2:1 glass 7(b) 144 3:1 liquid 4l 115 3:1 liquid 2(b) 128 ldetermined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C.min and ldetermined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C. min and cooling with 5°C.fminto -80°C, for 3 cycles. cooling with 5°C/min to -80°C, for 3 cycles. Plglass transition temperature 65 Plglass transition temperature eldetermined on a Mettler Toledo Star TGADSC unit by heating from 25°C. to 600° C. eldetermined on a Mettler Toledo Star TGADSC unit by heating from 25° C. to 600° C. with 5°C. min. under nitrogen. with 5°C.min under nitrogen. US 9,278,134 B2 83 84 Table X shows thermal data of different ephedrinium sali Table XI shows thermal data of different ephedrinium clofi cylate co-ionic liquids prepared by melting. brate co-ionic liquids prepared by melting.

Example 12 Example 13 Caffeine Salicylate-solvent-free Synthesis Via Ephedrinium Clofibrate-solvent-free Synthesis Via Grinding Melting

10

O N OH C

n -- mXO -e- 15 -N v O O

-- O O

H C 1. O---H-O 6H H HO OH O OH HO N O Ha 25 Caffeine salicylate (19.40 mg, 0.058 mmol) and salicylic acid (8.06 mg 0.058 mmol) were grinded for 15 minutes in a mortar at room temperature. A colorless powder was O obtained. OH -- 30 H 'H-NMR (300 MHz, d-DMSO)8(ppm)=11.29 (brs, 1H), N 8.01 (s, 1H), 7.90 (dd, J–8.1 Hz, J-1.4 Hz, 2H), 7.51 (t, N J–7.83 Hz, 2H), 6.94 (m, 4H), 3.07 (s.3H), 3.41 (s.3H), 3.21 (S. 3H). mp 122°C., Tso, 111° C. 35 O Cl Example 14 O- - - H- O O Tetrabutylphosphonium Salicylate-ibuprofenic Acid O P(Bu)SalIbuH OH O 40

Clofibric acid (1 or 2 eq.) and ephedrine free base (1 or 2 eq.) were molten in a hot mortar until a free-flowing clear liquid was obtained. The mixture was cooled to room tem 45 perature and, in case of Solid products, grinded to obtain yellow powders. 'H-NMR (300 MHz, d-DMSO)8(ppm)= 9.36 (brs, 2H), 7.30 (m, 5H), 7.19 (d. J=8.8 Hz, 2H), 6.82 (d. J=8.8 Hz, 2H), 5.10 (s, 1H), 3.12 (m. 1H), 2.52 (s.3H), 1.41 (s, 6H), 0.85 (d. J=6.6 Hz, 3H). 'C-NMR (75 MHz, 50 d-DMSO)8(ppm)=176.8, 155.5, 141.8, 128.5, 128.0, 126.9, 125.8, 123.4, 119.2, 80.2, 69.8, 59.5, 30.7, 25.8, 9.6.

TABLE XI 55 Ratio Tonset 5% Eph:Clofib Appearance mp C. o Clel

1:2 glass 12(b) 182 Ibuprofenic acid (1.032 g, 5 mmol), salicylic acid (0.6909 1:1 solid 131 169 60 g, 5 mmol) and tetrabutylphosphonium hydroxide (~40% sol. 2:1 glass 7(b) 135 in HO)(3.414 g. 5 mmol) were dissolved in 20 ml of acetone and stirred for 15 min at room temperature. The solvent was determined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C.min and evaporated and the remaining viscous liquid was dried at 0.01 cooling with 5°C.fminto -80°C, for 3 cycles. Plglass transition temperature mbar with stirring for 24 hrs. The desired compound is iso 65 eldetermined on a Mettler Toledo Star TGADSC unit by heating from 25°C. to 600° C. lated as a colourless liquid. 'H-NMR (300 MHz, d-DMSO) with 5°C. min. under nitrogen. Ö(ppm)=7.65 (dd, J=7.6 Hz, J-1.8 Hz, 1H), 7.18 (d. 8.0 Hz, 2H), 7.11 (m, 3H), 6.59 (m, 2H), 3.63 (q, J=7.2 Hz, 2H), 2.41 US 9,278,134 B2 85 86 (d. 7.2 Hz, 2H), 2.17 (m, 8H), 1.80 (sept, J=6.70, 1H), 1.42 -continued (m. 16H), 1.34 (s, J=7.1 Hz, 3H), 0.9 (t, J=6.9 HZ, 12H), 0.85 (d. 6.7 Hz, 6H). 'C-NMR (75 MHz, d-DMSO) 8(ppm)= O 175.4, 1712, 162.9, 139.5, 138.5, 131.3, 129.9, 128.9, 127.1, OH 115.9, 115.8, 44.3, 44.2, 29.6, 23.3 (d. J=15.8 Hz), 22.6 (d. 5 4.8 Hz), 22.2, 18.5, 17.3 (47.6 Hz), 13.7.

T-45° C. T5%osef 181o C. OH rt O

Example 15 10 Lactic acid (0.4504g, 5 mmol), salicylic acid (0.6909 g, 5 mmol) and tetrabutylphosphonium hydroxide (~40% sol. in Tetrabutylphosphonium Salicylate-camphorsulfonic HO) (3.414 g. 5 mmol) were dissolved in 20 ml of acetone Acid P(Bu)SalCSAH and stirred for 15 min at room temperature. The solvent was 15 evaporated and the remaining viscous liquid was dried at 0.01 mbar with stirring for 24 hrs. The desired compound is iso lated as a colourless liquid: 'H-NMR (300 MHz, d-DMSO) Ö(ppm)=7.63 (dd, J–7.6 Hz, J–1.9 Hz), 7.11 (m, 1H), 6.58 (m,3H), 4.03 (q, J=6.9 Hz, 1H), 2.17 (m, 8H), 1.42 (m, 16H), 1.23 (d, 7.0 Hz, 3H), 0.90 (t, J=7.3 Hz, 12 H). 'P-NMR (121.5 MHz, d-DMSO)8(ppm)=35.0. 'C-NMR (75 MHz, - d-DMSO)8(ppm)=176.3, 171.1, 163.0, 131.2, 129.9, 120.5, 117.8, 115,767.3, 23.4 (d. J=15.8 Hz), 22.6 (d. J=4.3 Hz), 25 20.5, 17.3 (d. J=47.7 Hz), 13.3 (s). T-53°C., Tso, 178° C.

Example 17 30 Tetrabutylphosphonium Salicylate-cinnamic Acid P(Bu)SalCinn H Camphorsulphonic acid (5 mmol), salicylic acid (0.6909 g, 35 5 mmol) and tetrabutylphosphonium hydroxide (~40% sol. in HO) (3.414 g. 5 mmol) were dissolved in 20 ml of acetone and stirred for 15 min at room temperature. The solvent was evaporated and the remaining viscous liquid was dried at 0.01 mbar with stirring for 24 hrs. The desired compound is iso 40 lated as a colourless liquid: 'H-NMR (300 MHz, d-DMSO) - 8(ppm)=7.79 (dd, J–7.9 Hz, J-1.8 Hz), 7.52 (m. 1H), 6.94 (m,3H), 2.97 (d. J=14.8 Hz, 1H), 2.71 (quin, J=10.8 Hz, 1H), 2.36 (d. J=14.8 Hz, 1H), 2.19 (m,9H), 1.93 (t, J=4.5 Hz, 1H), 45 1.84 (m, 2H), 1.42 (m, 16 H), 1.26 (m, 2H), 1.05 (s.3H), 0.91 (t, J=6.9 Hz, 12H), 0.74 (s.3H). T-33°C., Tso., 203° C. Example 16 50 Tetrabutylphosphonium Salicylate-lactic Acid P(Bu)SalLacH Cinnamic acid (0.7408g, 5 mmol), salicylic acid (0.6909 g, 55 5 mmol) and tetrabutylphosphonium hydroxide (~40% sol. in HO) (3.414 g. 5 mmol) were dissolved in 20 ml of acetone stirred and for 15 min at room temperature. The solvent was evaporated and the remaining viscous liquid was dried at 0.1 mbar with stirring for 24 hrs. Identity and purity was con - 60 firmed via "H NMR. The desired compound is isolated as a colourless liquid; "H-NMR (300 MHz, d-DMSO)8(ppm)= 7.67 (m, 3H), 7.57 (d. J=19.1 Hz, 1H), 7.41 (m, 3H), 7.12 (m, 1H), 6.56(m,3H), 2.17 (m,8H), 14.1 (m, 16.H), 0.91 (t, J=6.9 -- 65 Hz, 12 H). "P-NMR (121.5 MHz, d-DMSO)8(ppm)=35.1. 'C-NMR (75 MHz, d-DMSO) 8(ppm)=17.1.2, 167.6, 163.0, 143.3, 1344, 131.1, 130.0, 129.9, 128.9, 128.1,

US 9,278,134 B2 91 92 Lidocaine (270.13 mg, 1.15 mmol) and tramadolium ibu -continued profenate (541.4 mg, 1.153 mmol) were dissolved in 20 ml of acetone and stirred for 15 min at room temperature. The Solvent was evaporated and the remaining viscous liquid was dried at 0.01 mbar with stirring for 24 hrs. The desired com pound is isolated as a colourless liquid. 'H-NMR (300 MHz, d-DMSO)8(ppm)=9.17 (brs, 1H), 7.19 (m, 3H), 7.06 (m, 7H), 6.73 (dd, J1=8.1 Hz, J2=2.3 Hz, 1H), 4.42 (brs, 2H), 3.74 (s, 3H), 3.61 (q, J–7.0 Hz, 1H), 3.13 (s. 2H), 2.61 (q, J–7.2 Hz, 4H), 2.50 (s. 2H), 2.41 (d. J=7.4 Hz, 2H), 2.13 (s, 10 7H), 1.94 (s, 6H), 1.89-141 (m, 8H), 1.33 (d. J=7.1 Hz, 3H), Promethazine (2 mmol) was added to ephedrinium docu 1.07 (t, J–7.1 Hz, 6H), 0.86 (d. J–6.6 Hz, 6H). T-20° C., T 1540 C. sate (2 mmol) and stirred for 15 minutes at 50° C. to obtain a 5%osef light yellow viscous oil. Identity and purity were confirmed Example 26 15 via "H and 'C NMR. 'H-NMR (300 MHz, d-DMSO) Ö(ppm)=7.39 (d. J=4.5 Hz, 3H), 7.29 (m. 1H), 7.19 (m, 4H), Tramadolium-lidocaine Salicylate HTramLidSal 7.08 (d. J=8.1 Hz, 2H), 6.95 (t, 7.4 Hz, 2H), 5.04 (d.J=2.7 Hz, 1H), 4.05 (dd, J1=13.81 Hz, J2=5.0 Hz, 1H), 3.89 (m, 4H), 3.68 (m, 2H), 3.35 (m, 1H), 2.87(m,3H), 12.63 (s.3H), 2.24 (s, 6H), 1.49 (m, 2H), 1.23 (m. 16H), 0.84 (m. 18H). 'C- NMR (75 MHz, d-DMSO) 8(ppm)=1710, 168.3, 145.1, 1410, 128. 1, 127.6, 1227.3, 127.2, 125.8, 124.4, 122.6,

116.2, 69.9, 66.2, 66.1, 61.5, 59.0, 55.6, 49.7, 40.6, 38.2, 38.2, 34.1, 30.8, 29.7, 29.6, 29.5, 28.3, 23.2, 23.0, 22.4, 13.9, 12.2, 25 10.8, 9.5. T-19°C., Tso, 164° C.

OH Example 28 30 Promethazine-ephedrinium Docusate 0.5:1:1

Lidocaine (5 mmol) and tramadolium salicylate (5 mmol) 35 were dissolved in 20 ml of acetone and stirred for 15 min at room temperature. The solvent was evaporated and the remaining viscous liquid was dried at 0.01 mbar with stirring for 24hrs and solidified after into a colourless solid. 'H-NMR OC S DO -- (300 MHz, d-DMSO)8(ppm)=10.32 (brs, 1H), 7.672 (dd. N J=7.8 Hz, 1H), 7.26 (t, J=8.2 Hz, 1H), 7.15 (t, J–7.2 Hz, 1H), 40 7.06 (m, 5H), 6.79 (d. J–8.7 Hz, 1H), 6.62 (m, 2H), 3.76 (s, 3H), 3.39 (brs, OH), 2.69 (m, 4H), 2.51 (m, 6H), 2.14 (m,

9H), 1.61 (m, 7H), 1.09 (t, J=7.0 Hz, 6 H). 'C-NMR (75 0.5 MHz, d-DMSO)8(ppm)=171.7, 1622, 159.1, 150.2, 135.1, 45 135.0, 1316, 130.0, 129.0, 127.6, 126.4, 119.9, 117.2, 116.2, 115.8, 111.4, 111.1, 73.9, 59.6, 56.2, 54.9, 48.1, 40.8, 4.0.2, 25.7, 24.6, 21.2, 18.1, 11.7. mp 64° C., T5%osef 181o C. Example 27 50 Promethazine-ephedrinium Docusate 1:1:1

55 Promethazine (1 mmol) was added to ephedrinium docu sate (2 mmol) and stirred for 15 minutes in acetone. The Solvent was evaporated and remaining volatile material was removed under reduced pressure (0.01 mbar, 50° C.). 60 'H-NMR (300 MHz, d-DMSO)8(ppm)=7.39 (d. J=4.5 Hz), OH 7.29(m), 7.19 (m), 7.08 (d. J=8.1 Hz), 6.95 (t, 7.4 Hz), 5.04 (d. J=2.7 Hz), 4.05 (dd, J=13.81 Hz, J-5.0 Hz), 3.89 (m, 4H), 3.68 (m), 3.35 (m), 2.87 (n), 12.63 (s), 2.24 (s), 1.49 (m, 65 2H), 1.23 (m, 16H), 0.84 (m. 18H). 'C-NMR (75 MHz, d-DMSO)8(ppm)=1710, 168.3, 145.1, 141.0, 128. 1, 127.6, 1227.3, 127.2, 125.8, 124.4, 122.6, 116.2, 69.9, 66.2, 66.1, US 9,278,134 B2 93 94 61.5, 59.0, 55.6, 49.7, 40.6, 38.2, 38.2, 34.1, 30.8, 29.7, 29.6, was collected via filtration, washed with water and dried 29.5, 28.3, 23.2, 23.0, 22.4, 13.9, 12.2, 10.8, 9.5. under reduced pressure (0.01 mbar, 50° C.) to yield 2 as colourless needles in 72% yield. The product was pure Example 29 according to "H NMR and directly subjected to the next step without further purification. Promethazine-ephedrinium Salicylate 'H-NMR (300 MHz, d-DMSO) 8(ppm)=10.05 (s, 1H), 7.62 (d. J=9.01 Hz, 2H), 7.10 (d. J=9.01 Hz, 2H), 4.67 (s. 2H), 3.38 (s, 3H), 2.05 (s, 3H). 'C-NMR (75 MHz, d-DMSO) 10 Ö(ppm)=168.7, 166.9, 145.6, 137.2, 122.0, 120.3, 41.6, 24.3. S mp 186°C.

N Example 31

15 OH Synthesis of 1-(2-(4-acetamidophenoxy)-2-oxoet OH hyl)-3-methyl-1H-imidazol-3-ium Chloride 3

O N-methylimidazole O na Her Promethazine (2 mmol) and ephedrinium salicylate (2 ethylacetate, rf, us N O 48 h. mmol) were dissolved in 25 ml of acetone and stirred for 15 H 79% min at room temperature, the solvent was evaporated and 25 remaining Volatile material was removed under vacuum (0.01 2 mbar, 50°C.) to yield the product as colourless viscous glass. C10H10CINO3 'H-NMR (300 MHz, d-DMSO)8(ppm)=7.72 (dd, J=7.7 227.64 Hz, J-1.8 Hz, 1H), 7.42-7.15 (m, 10H), 7.0 (m, 1H), 7.01 (d. J=7.9 Hz, 1H), 6.96 (t, J=7.2 Hz, 2H), 6.65 (m, 2H), 5.13 (d. 30 J=2.5 Hz, 1H), 4.10 (dd, J=14.0 Hz, J-5.0 Hz, 1H), 3.72 (dd, J=14.2 Hz, J-8.6Hz), 3.37 (m, 1H), 3.01 (m, 1H), 2.65 (s.3H), 2.2.9 (s, 6H), 0.99 (d. J=6.6 Hz, 3H), 0.92 (d. 6.8 Hz, 3H). T 14°C., Tsoi, 151° C. Ionic Liquid Prodrugs 35 Example 30 Synthesis of 4-Acetamidophenyl 2-chloroacetate 2 40

OH O "Sr- "- O O -- C Cl Herpyridine O C. to rt 45 N O s JOrci H 2h 3. 1. C8HoNO 151.16 50 O 4-Acetamidophenyl 2-chloroacetate 2 (1.138g, 5 mmol) O ^c and N-methylimidazol (0.492 g. 6 mmol) were suspended in us N O 50 ml of anhydrous ethyl acetate and refluxed for 48 hrs. After H cooling to room temperature the white precipitate was fil 2 55 tered, washed with ethylacetate and diethylether and dried C10H10CINO3 under reduced pressure to give 3 in 79% yield. The product 227.64 was pure according to H NMR and was directly subjected to the next step without further purification. Paracetamol 1 (15.117 g. 50 mmol) and pyridine (7.910 60 The desired compound is isolated as a colourless powder. g, 50 mmol) were suspended in anhydrous acetone (200 ml) 'H-NMR (300 MHz, d-DMSO)8(ppm)=10.08 (s, 1H), 9.28 and chilled to 0°C. under an atmosphere of dry nitrogen. (s, 1H), 7.86 (s, 1H), 7.78 (s, 114), 7.68 (d. J=9.01 Hz, 2H), Chloroacetylchloride (11.29 g, 50 mmol) was added drop 7.13 (d. J=9.01 Hz, 2H), 5.57 (s. 2H), 3.93 (s.3H), 2.05 (s, wise (violent reaction) and the resulting solution was stirred 3H). 'C-NMR (75 MHz, d-DMSO)8(ppm)=168.4, 166.1, for additional 2 hours at room temperature. Water (300 ml) 65 144.9, 137.9, 137.7, 123.8, 123.5, 121.4, 119.9, 49.7, 36.0, was added and the mixture was heated until a clear Solution 23.9. was obtained. The product 2 precipitated upon cooling and mp 206°C. (dec), Tsoi, 200° C. US 9,278,134 B2 95 Example 32 -continued O 1-(2-(4-acetamidophenoxy)-2-oxoethyl)-1-meth O O 1. N ylpyrrolidinium Chloride 4 ul N O "| 21 H C 5)

O 306.74 N-methylpyrrollidine 10 -e- O ra ethylacetate, rf, us N O 48 h. 4-Acetamidophenyl 2-chloroacetate 2 (1.138g, 5 mmol) H 7996 and pyridine (0.475 g, 6 mmol) were suspended in 50 ml of 2 anhydrous ethyl acetate and refluxed for 48 hrs. After cooling C10H10CINO3 15 to room temperature the white precipitate was filtered, 227.64 washed with ethylacetate and diethylether and dried under reduced pressure to give 5 in 97% yield. The product was pure according to H NMR and was directly subjected to the next step without further purification. The desired compound is isolated as a colourless powder. 'H-NMR (300 MHz, d-DMSO) 8(ppm)=10.31 (s, 1H), 9.27 (d. J=6.5 Hz, 2H), 8.76 (t, 7.9 Hz, 1H), 8.29 (t, 7.2 Hz, 2H), 7.71 (d. J=9.7 Hz, O 2H), 7.11 (d. J=9.7 Hz, 2H), 4.69 (s. 2H), 2.08 (s, 3H). mp ul rt) 25 199° C. (dec), T 5%osef 1980 C. N Example 34 4) C15H2CINO3 30 (2-(4-acetamidophenoxy)-2-oxoethyl)tributylphos 312.79 phonium Chloride 6

4-Acetamidophenyl 2-chloroacetate 2 (1.138 g. 5 mmol) and N-methylpyrrolidine (0.511 g, 6 mmol) were suspended 35 O in 50 ml of anhydrous ethyl acetate and refluxed for 48 hrs. O na tributylphosphine After cooling to room temperature the white precipitate was us O Heethylacetate, rf, filtered, washed with ethylacetate and diethylether and dried N 48 h. under reduced pressure to give 4 in 97% yield. The product H 65.9% was pure according to H NMR and was directly subjected to 40 2 the next step without further purification. The desired com C10H10CINO3 pound is isolated as a colourless powder. H-NMR (300 MHz, 227.64 d-DMSO)8(ppm)=10.48 (s, 1H), 7.72 (d. J=8.90 Hz, 2H), O 7.17 (d. J=8.90 Hz, 2H), 4.91 (s. 2H), 3.75 (m, 4H), 3.26 (s, O ^-- P(Bu)3 3H), 2.13 (m, 4H), 2.06 (s, 3H). 'C-NMR (75 MHz, 45 us N O C d-DMSO)8(ppm)=168.8, 164.8, 1444, 138.2, 121.9, 120.2, H 65.5, 62.0, 49.7, 24.3, 21.7. mp 186°C. (dec), Ts, 197° C. 6 CH3CINOP 50 429.96 Example 33 4-Acetamidophenyl 2-chloroacetate 2 (1.138g, 5 mmol) 1-(2-(4-acetamidophenoxy)-2-oxoethyl)pyridinium and tributylphosphine (0.475 g, 6 mmol) were suspended in Chloride 5 55 50 ml of anhydrous ethyl acetate and refluxed for 48 hrs. After cooling to room temperature the white precipitate was fil tered, washed with ethylacetate and diethylether and dried under reduced pressure to give 6. The crude product was O crystallized twice from acetonitrile to give pure 6 in 65% 60 O ra Hepyridine yield. Identity and purity was confirmed via H and 'C us O ethylacetate, rf, NMR. The desired compound is isolated as colourless N 48 h. needles. H-NMR (300 MHz, d-DMSO)8(ppm)=10.49 (s. H 83% 1H), 7.71 (d.J=8.95 Hz, 2H), 7.12 (d. J=8.95 Hz, 2H), 4.18 (d. 2 J=14.33, 2H), 2.41 (m, 3H), 2.06 (s.3H), 1.55 (m, 6H), 1.41 C10H10CINO3 65 (m, 6H), 0.91 (t, J=7.17). 'P-NMR (121.5 MHz, d-DMSO) 227.64 Ö(ppm)=34.8. 'C-NMR (75 MHz, d-DMSO) 8(ppm)= 168.4, 164.7, 144.8, 137.8, 1214, 119.9, 25.8 (d. J=47.9 US 9,278,134 B2 97 98 Hz), 23.9, 23.3 (d. J=16.77 Hz), 22.6 (d. J–4.43 Hz), 18.2 (d. -continued J=47.7 Hz), 13.2. mp 199° C. (dec), T5%osef 1970 C. Example 35

Synthesis of 1-(2-(4-acetamidophenoxy)-2-oxoet hyl)-3-methyl-1H-imidazol-3-ium Docusate 7

10 Prepared according to example 35 in quantitative yield. O silver The desired compound is isolated as a yellow oil. H-NMR (300 MHz, d-DMSO)8(ppm)=10.011 (s, 1H), 7.66 (d. J=8.7 O r N ~\ N'- docusate e 15 Hz, 2H), 7.17 (d. J=8.7 Hz, 2H), 4.82 (s. 2H), 3.88 (m, 2H), us | U Morn15 min C 3.72 (m, 5H), 3.25 (s.3H), 2.88 (m, 2H), 2.14 (m, 4H), 2.05 N >99% (s, 3H), 1.47 (m. 2H), 1.23 (m, 16H), 0.82 (m. 12H). C NMR (75 MHz, d-DMSO) 8(ppm)=168.4, 166.1, 144.9, 137.9, 137.7, 123.8, 123.5, 1214, 119.9, 49.7, 36.0, 23.9. 'C-NMR (75 MHz, d-DMSO) 8(ppm)=1710, 1684, 164.4,144.5, 137.7, 121.6, 119.8, 66.1, 65.1, 61.6, 49.4, 38.1, 34.1, 29.7, 29.6, 28.3, 23.9, 23.2, 23.0, 22.4, 21.4, 13.8, 10.7.

T5%osef 233 C.

25 OS Example 37

1-(2-(4-acetamidophenoxy)-2-oxoethyl)pyridinium 30 Docusate 9

Chloride 3 (309.1 mg, 1 mmol) and silver docusate 35 (529.4 mg, 1 mmol) were suspended in 50 ml of anhydrous methanol and stirred in the dark at room temperature for 15 min. The suspension was filtered over celite and the filtrate Oro was evaporated <40° C. Remaining volatile material was removed under reduced pressure (0.01 mbar, 40°C.) to yield 40 product 7 in quantitative yield. The desired compound is isolated as a yellow oil. H-NMR (300 MHz, d-DMSO) 8(ppm)=10.07 (s, 1H), 9.16 (s, 1H), 7.82 (s, 1H), 7.77(s, 1H), 7.64 (d. J=9.2 Hz, 2H), 7.14 (d. J–9.2 Hz, 2H), 5.51 (s. 2H), 3.93 (s.3H), 3.88 (m, 4H), 3.65 (dd, J=11.5 Hz, J-3.8 Hz, 45 1H), 2.85 (m, 2H), 2.04 (s.3H), 1.49 (m, 2H), 1.23 (m, 16H), 0.86 (m, 12H). 'C-NMR (75 MHz, d-DMSO) 8(ppm)= 1710, 168.4, 166.0, 144.9, 137.8, 137.5, 123.8, 123.5, 121.5, O 119.9, 66.1, 61.5, 49.7, 38.1, 36.0, 34.1, 29.7, 29.6, 28.3, 23.9, 50 23.2, 22.4, 13.9, 10.8, 10.7. Ts 217° C. OS O~1- Example 36

55 1-(2-(4-acetamidophenoxy)-2-oxoethyl)-1-meth O N-- ylpyrrolidinium Docusate 8 Prepared according to example 35 in quantitative yield. 60 The desired compound is isolated as a yellow glass. H-NMR (300 MHz, d-DMSO) 8(ppm)=10.13 (s, 1H), 9.21 (d. J=6.2 Hz, 2H), 8.82 (t, 7.8 Hz, 1H), 8.36 (t, 7.2 Hz, 2H), 7.72 (d. J=9.0 Hz, 2H), 7.25 (d. J=9.0 Hz, 2H), 6.00 (s. 2H), 3.96 (m, 4H), 3.71 (dd, J = 11.3 Hz, J-3.7 Hz, 1H), 2.94 (m, 2H), 2.12 65 (s, 3H), 1.56 (m, 2H), 1.00 (m, 16 H), 0.93 (m, 12H). C Crb NMR (75 MHz, d-DMSO) 8(ppm)=7.1.0, 168.4, 165.6, 147.0, 146.5, 144.9, 137.6, 127.9, 121.5, 119.9, 66.2, 66.1, US 9,278,134 B2 99 100 61.5, 60.4, 38.1, 34.1, 29.7, 29.6, 28.3, 23.2, 23.1, 23.0, 22.4, 2H), 7.32 (d. J=8.1 Hz, 2H), 6.68 (d. J=8.1 Hz, 2H), 5.29 (s.

13.9, 10.8, 10.7. T3. 25°C., T.238°C.oOS 8. 2H), 3.90 (s.3H), 3.57 (q, J=6.8 Hz, 1H), 1.98 (s.3H), 1.11 (d. J=6.6 Hz, 3H). Example 38 5 Example 40 1-(2-(4-acetamidophenoxy)-2-oxoethyl)-1-meth (2-(4-acetamidophenoxy)-2-oxoethyl)tributylphos2-(4-acetamidorbh -2- thvl)tributvlphos ylpyrrolidinium Lactate 12 phonium Docusate 10

10

12 10 O OH

O 1Sri 15 O O N O us N O O r H N O O H OS ~1- 20 Prepared according to example 39 in quantitative yield. Identity and purity were confirmed via Hand 'CNMR. The S1- desired'H-NMR compound (300 MHz,is isolated d-DMSO) as a yellow 8(ppm)=9.82 oil. (s, 1H), O 7.33 (d. J=8.8 Hz, 2H), 6.69 (d. J=88 Hz, 2H), 4.55 (s. 2H), 25 3.76 (s, 3H), 3.66 (m, 4H), 3.54 (q, J=6.7 Hz, 1H), 2.09 (m, 4H), 1.97 (s.3H), 1.09 (d. J=6.8 Hz, 3H). T 166° C. Prepared according to example 35 in quantitative yield. The desired compound is isolated as a yellow oil. H-NMR Example 41 (300 MHz, d-DMSO) 8(ppm)=10.07 (s, 1H), 7.64 (s. 2H), 7.14 (s. 2H), 4.07 (d. J–146 Hz, 2H), 3.88 (s, 4H), 3.62 (s. ' Prodrug Hydrolysis—General Procedure 1H), 2.84 (m, 2H), 2.36 (s, 6H), 2.04 (s.3H), 1.49 (m. 14H), 1.23 (m, 16H), 0.89 (m, 21 H). 'C-NMR (75 MHz, Acetaminophen prodrug (0.5 mmol) was dissolved in 5 ml phosphate buffer pH 7.4. The resulting 0.1 M solutions were d-DMSO)8(ppm)=168.4, 166. 1, 144.9, 137.9, 137.7, 123.8, stirred in a preheated oil bath at 37° C. Sample of 0.05 ml 123.5, 121.4, 119.9, 49.7, 36.0, 23.9. T-17° C., Tso, 35 were withdrawn at intervals, diluted with DO to 0.5 ml and 227O C. "H NMR spectra was immediately measured. Decomposition could be monitored via integration of representing aromatic Example 39 signals of prodrug and of free acetaminophen. 40 Ionic Liquid Immobilized Fragrances Synthesis of 1-(2-(4-acetamidophenoxy)-2-oxoet hyl)-3-methyl-1H-imidazol-3-ium Lactate 11 Example 42 Synthesis of (E)-3,7-dimethylocta-2,6-dienyl 45 2-chloroacetate 2 O silver O N 1\ lactate N"- --> O S. MeOH, rt, N 15 min OH

H 3) C >99% 50 N-- -- O OH 1. O 1. \, o C us O S. C pyridine N 55 CHCl2, 0°C. O O to rt, 24h 11 9996 O 21 21 ^a Chloride(3)(309.1 mg, 1 mmol) and racemic silver lactate O (196.4 mg, 1 mmol) were suspended in 25 ml of anhydrous methanol and stirred in the dark at room temperature for 15 2 min. The suspension was filtered over celite and the filtrate was evaporated at <40° C. Remaining volatile material was Geraniol 1 (7.711 g, 50 mmol) and pyridine (3.955g, 50 removed under reduced pressure (0.01 mbar, 40°C.) to yield 65 mmol) were suspended in anhydrous dichloromethane (200 product 11 as yellow oil in quantitative yield. 'H-NMR (300 ml) and chilled to 0°C. under an atmosphere of dry nitrogen. MHz, d-DMSO) 8(ppm)=9.85 (s, 1H), 9.18 (s, 1H), 7.75 (s, Chloroacetylchloride (5.647 g, 50 mmol) was added drop US 9,278,134 B2 101 102 wise (violent reaction) and the resulting solution was stirred -continued for 24hrs at room temperature. Water (100 ml) was added, the organic layer was separated and the aqueous layer extracted with dichloromethane. The combined organic layers were r "- successively washed with 2N HCl, saturated NaHCO, solu tion and brine, dried over MgSO and the solvent was evapo rated. Remaining Volatile material was removed under reduced pressure (0.01 mbar) to yield product 2 as yellow liquid. The product was pure according to "H NMR and directly subjected to the next step without further purification. 10 'H-NMR (300 MHz, d-DMSO) 8(ppm)—5.31 (t, J–7.4 HZ, 1H), 5.06 (m, 1H), 4.64 (d. J–7.4 Hz, 2H), 4.38 (s. 2H), rocO N-- 2.03 (m, 4H), 1.68 (s, 3H), 1.64 (s, 3H), 1.56 (s, 3H). C 4) NMR (75 MHz, d-DMSO) 8(ppm)=167.3, 1424, 131.1, 123.7, 117.8, 62.2, 41.1, 38.9, 25.7, 25.4, 17.5, 16.2. 15 Imidazolium chloride 3 (312.8 mg, 1 mmol) and sodium Example 43 docusate (444.6 mg, 1 mmol) were dissolved in 20 ml of acetone/HO 1:1 and stirred overnight at room temperature. Synthesis of (E)-1-(2-(3,7-dimethylocta-2,6-dieny The remaining suspension was diluted with 50 ml of HO and loxy)-2-oxoethyl)-3-methyl-1H-imidazol-3-ium extracted with dichloromethane. The organic layer was Chloride 3 washed successively with water until no more chloride ions could be detected in the washings (checked by addition of AgNO, solution), dried over MgSO and the solvent was evaporated. Remaining volatile material was removed under O 25 reduced pressure (0.01 mbar) to give imidazolium docusate --~~ N^c HipN-methylimidazol 4 in quantitative yield as yellow oil. H-NMR (300 MHz, O neat, 40°C., 2 24h d-DMSO) 8(ppm)=9.07 (s, 1H), 7.71 (s. 2H), 5.33 (t, J–7.3 67% HZ, 1H), 5.24 (s. 2H), 5.07 (m, 1H), 4.69 (d. J–7.3 Hz, 2H), O C 30 3.91 (s.3H), 3.90 (m, 4H), 3.62 (dd, J=11.39 Hz, J-3.88 Hz, 21 21 -- 1H), 2.86 (m, 2H), 2.04 (m, 4H), 1.68 (s, 3H), 1.65 (s.3H), 1.57 (s, 3H), 1.49 (m, 2H), 1.24 (m, 16 H), 0.84 (m, 12H). --~~ O 1\N/ 'C-NMR (75 MHz, d-DMSO) 8(ppm)=171.1, 168.1, 3. 166.9, 142.7, 137.7, 131.2, 123.7, 123.6, 123.4, 117.6, 66.2, 35 66.1, 62.4, 61.4, 49.5, 38.1,356.0, 34.1, 29.8, 29.6, 28.3, 25.8, 25.5, 23.2, 23.0, 22.4, 17.6, 16.2, 13.9, 10.8. Ts 170° C. Geraniol ester 2 (2.307 g. 10 mmol) and N-methylimida Thermocleavage of the immobilized fragrance Geraniol Zole (0.821 g, 10 mmol) were mixed in and stirred in a sealed 4 was demonstrated with TGA (FIG. 6). Mass loss of the vessel at 40° C. for 24 hrs. A light-brown solid was formed first decomposition step obtained corresponds to mass per and suspended in anhydrous diethylether. The solid precipi 40 centage of Geraniol 1 in the prodrug 4. tate was filtered, washed with diethylether and dried under reduced pressure (0.01 mbar) to give imidazolium chloride Example 45 3 in 67% yield as light-yellow hygroscopic solid. The prod uct was pure according to H NMR and directly subjected to Synthesis of (E)-4-(3,7-dimethylocta-2,6-dienyloxy)- the next step without further purification. 'H-NMR (300 45 MHz, d-DMSO) 8(ppm)=9.36 (s, 1H), 7.82 (s. 2H), 5.37 (s, 4-oxobutanoic Acid 5 2H), 5.33 (t, J=7.0 Hz, 1H), 5.07 (s, 1H), 4.68 (d. J=7.1 Hz, 2H), 3.93 (s.3H), 2.03 (m, 4H), 1.66 (s.3H), 1.64 (s.3H), 1.56 (s, 3H). 'C-NMR (75 MHz, d-DMSO) 8(ppm)=166.9, 142.6, 137.8, 131.1, 123.7, 123.6, 123.3, 117.8, 62.4, 49.4, 35.9, 25.8, 25.5, 17.6, 16.1. mp 160° C. (dec), T 125° C. Example 44 55 Synthesis of (E)-1-(2-(3,7-dimethylocta-2,6-dieny O pyridine, 4-DMAP -- loxy)-2-oxoethyl)-3-methyl-1H-imidazol-3-ium CH2Cl2, rt, 24h Docusate 4 9996 O 60 O O O C Sodium a a Yr- docusate --~~ O OH O N/S. 800 tone/HO s rt, 24h 65 5) US 9,278,134 B2 103 104 Geraniol 1 (1.542g, 10 mmol), succinic anhydride (1.201 140.7, 131.1, 123.8, 119.0, 67.3, 60.2, 55.0, 53.1, 39.3, 32.8, g, 12 mmol) and 4-DMAP (10 mg, cat) were suspended in 31.2, 25.8, 25.5, 17.6, 16.2. T-65° C., T., 170° C. anhydrous dichloromethane (50 ml) under an atmosphere of dry nitrogen. Pyridine (0.791 g, 10 mmol) was added and the New API ILS reaction mixture was stirred for 24 hrs at room temperature. The reaction mixture was successively washed with 2N HCl Example 47 and H2O, dried over NaSO and the solvent was evaporated. Remaining Volatile material was removed under reduced Tramadolium Salicylate 1 pressure (0.01 mbar) to yield product 2 as yellow liquid in 99% yield. The product was pure according to H NMR and 10 directly subjected to the next step without further purification. H-NMR (300 MHz, d-DMSO) 8(ppm)=12.24 (brs, 1H), 5.29 (t, J=7.0 Hz, 1H), 5.08 (t, 6.7, 1H), 4.55 (d. J=7.1 Hz, 2H), 2.49 (m, 2H), 2.03 (m, 4H), 1.67 (s, 3H), 1.66 (s, 3H), NH 1.59 (s.3H). 'C-NMR (75 MHz, d-DMSO)8(ppm)=173.3, 15 172.2, 1412, 131.1, 123.7, 118.5, 60.7, 38.9, 28.7, 28.6, 25.8, 25.5, 17.5, 16.1. HO

OH Example 46

Synthesis of 2-Hydroxy-N,N,N-trimethyletha naminium (E)-4-(3,7-dimethylocta-2,6-dienyloxy)-4- oxobutanoate 6 25 Tramadolium hydrochloride (1.499 g, 5 mmol) and sodium salicylate (0.801 g, 5 mmol) were dissolved in 50 ml of acetone/HO 1:1 and stirred overnight at room temperature. O 30 The obtained suspension was chilled to 0°C., the precipitate was collected via filtration, washed with HO and dried under -e- MeOH, reduced pressure (0.01 mbar) to isolate tramadolium salicy --~~~O late as colourless solid in 79% yield. H-NMR (300 MHz, 0° C., 5 min 5) 9996 d-DMSO) 8(ppm)=7.69 (dd, J=7.6 Hz, J-1.8 Hz, 1H), 35 7.27 (t, J=8.1 Hz, 1H), 7.19 (m, 1H), 7.08 (m, 2H), 6.79 (m, 1H), 6.66 (m, 2H), 3.76 (s.3H), 3.56(brs, 1H), 2.83 (t, J=11.9 HZ, 1H), 2.52 (s, 6H), 2.33 (d. 13.0 Hz, 1H), 2.24 (m. 1H), 1.89 (m. 1H), 1.64 (m, 7H). 'C-NMR (75 MHz, d-DMSO) 8(ppm)=1720, 262.3, 159.2, 150.0, 1319, 120.1, 129.1, 40 119.5, 117.2, 116.5, 117.2, 116.5, 115.9, 111.5, 111.1, 73.9, 59.4, 55.0, 43.0, 40.5, 40.4, 25.7, 24.6, 21.2. mp 183° C., T5% osef 2200 C. Example 48 OH 45 Tramadolium rac-ibuprofenate 121

50

Hemisuccinate 5 (1.0173 g, 4 mmol) was dissolved in 10 ml of methanol and chilled to 0° C. Choline hydroxide in 55 HO (1.13 ml, 40% sol. in methanol, 4 mmol) was added dropwise and the reaction mixture was stirred for 5 min at 0°C. The Solvent was evaporated and remaining Volatile material was removed under reduced pressure (0.01 mbar) to yield product 6 as yellow liquid in quantitative yield. The product was 60 pure according to 'H NMR without further purification. H-NMR (300 MHz, d-DMSO)8(ppm)=5.28 (t, J=7.0 Hz, 1H), 5.07 (t, J=6.8 Hz, 1H), 4.49 (d. J=7.0 Hz, 2H), 3.85 (m, Tramdolium hydrochloride (1.499 g, 5 mmol) and racemic 2H), 3.44 (m, 2H), 3.13 (s.9H), 2.36 (t, J=7.2 Hz, 2H), 2.10 65 sodium ibuprofenate (1.1441 g, 5 mmol) were dissolved in 50 (t, J=7.2 Hz, 2H), 2.03 (m, 4H, 1.65 (s, 6H), 1.57 (s, 3H). ml of acetone/HO 1:1 and stirred overnight at room tempera 'C-NMR (75 MHz, d-DMSO) 8(ppm)=174.0, 173.6, ture. The remaining suspension was diluted with 50 ml of US 9,278,134 B2 105 106 H2O and extracted with dichloromethane. The organic layer layer was washed Successively with water until no more chlo was washed successively with water until no more chloride ride ions could be detected in the washings (checked by ions could be detected in the washings (checked by addition addition of AgNO solution), dried over MgSO and the sol of AgNO solution), dried over MgSO and the solvent was vent was evaporated. Remaining Volatile material was evaporated. Remaining volatile material was removed under removed under reduced pressure (0.01 mbar) to give trama reduced pressure (0.01 mbar) to give tramadolium rac-ibu dolium meclofenamate 3 in 95% yield as colourless solid profenate 2 in 89% yield as viscous glass that solidified after foam. Identity and purity of the obtained product were con 2 weeks. 'H-NMR (300 MHz, d-DMSO)8(ppm)=7.19 (m, firmed via HNMR. 'H-NMR (300 MHz, d-DMSO)8(ppm) 3H), 7.08 (m, 2H), 7.00 (m, 2H), 6.72 (dd, J=8.1, J–2.3 Hz, =10.62 (brs, 1H), 7.95 (dd, J=7.9 Hz, J=1.2 Hz, 1H), 7.50 1H)), 3.73 (s.3H), 3.58 (q, J–7.0 Hz, 1H), 2.40 (d. J–7.0 Hz, 10 (d. J=8.3, 1H), 7.3 (d. J=7.9 Hz, 1H), 7.28 (d. J–7.9 Hz, 1H), 2H), 2.11 (m, 1H), 1.91 (s, 6H), 1.85-1.35 (m, 9H), 1.31 (d. 7.18 (t, J=7.7 Hz, 1H), 7.10 (m, 2H), 6.80 (dd, J =8.1 Hz, J=7.1 Hz, 3H), 0.85 (d. J=7.7 Hz, 6H) ppm. mp 75° C., J–2.2 Hz, 1H), 6.71 (t, J=7.5 Hz, 1H), 5.82 (brs, 1H), 3.78 (s, T5%osef 1750 C. 3H), 2.60 (m, 1H, 2.40 (s, 3H), 2.32 (s, 6H), 2.11 (m, 2H), 15 1.99 (d. 11.9 Hz, 1H), 1.61 (m, 7H). 'C-NMR (75 MHz, Example 49 d-DMSO)8(ppm)=1713, 159.1, 150.7, 146.3, 136.3, 135.8, 133.2, 131.7, 131.6, 130.1, 128.9, 128.4,128.0, 117.3, 116.7, Tramadolium (S)-ibuprofenate 3 112.3, 74.2, 59.7, 54.9, 43.9, 41.6, 40.7, 26.2, 25.0, 21.4, 20.2. T38°C., Tsoi, 172°C. Example 51

Tramadolium Docusate 5 25

HO

30 5

NHS O Prepared according to example 48 in 76% yield. 'H-NMR 35 (300 MHz, d-DMSO)8(ppm)=7.19 (m, 3H), 7.08 (m, 2H), HO OS O ~1- 7.00 (m, 2H), 6.72 (dd, J=8.1, J–2.3 Hz, 1H)), 3.73 (s.3H), 3.58 (q, J=7.0 Hz, 1H), 2.40 (d. J=7.0 Hz, 2H), 2.11 (m, 1H), 1.91 (s, 6H), 1.85-1.35 (m, 9H), 1.31 (d. J=7.1 Hz, 3H), 0.85 40 (d. J=7.7 Hz, 6H) ppm. O N-- O Example 50

Tramadolium Meclofenamate 4 45

Tramadolium hydrochloride (0.5997 g, 2 mmol) and sodium docusate (0.8892g, 2 mmol) were dissolved in 20 ml 50 of acetone/HO 1:1 and stirred overnight at room tempera ture. The remaining suspension was diluted with 50 ml of H2O and extracted with dichloromethane. The organic layer HO was washed successively with water until no more chloride NH 55 ions could be detected in the washings (checked by addition of AgNO solution), dried over MgSO and the solvent was C evaporated. Remaining volatile material was removed under reduced pressure (0.01 mbar) to give tramadolium docusate 3 in quantitative yield as yellow oil. H-NMR (300 MHz, 60 d-DMSO)8(ppm)=7.26 (t, 1H, J=8.0Hz), 7.06(m,2H), 6.79 (dd. 1H, J,-8.1, J–2.3 Hz), 5.17 (bs, 1H, OH), 3.88 (m. 2H), 3.74 (s.3H), 3.64 (dd. 1H, J–3.7 Hz, J-11.1 Hz), 2.86 (m, Tramadolium hydrochloride (0.492 g, 1.64 mmol) and 3H), 2.38 (d. 2H), 2.22 (m, 2H), 1.9-1.5 (m, 4H), 1.5 (m, 2H), sodium meclofenamate (0.522g, 1.64 mmol) were dissolved 1.3-1.1 (m, 16H), 0.8 (m, 12H). 'C-NMR (75 MHz, in 20 ml of acetone/HO 1:1 and stirred overnight at room 65 d-DMSO)8(ppm)=171.36, 168.62, 159.54, 150.11, 129.52, temperature. The remaining suspension was diluted with 50 117.48, 111.88, 111.43, 74.15, 66.60, 66.53, 66.49, 66.44, ml of H2O and extracted with dichloromethane. The organic 61.80, 59.89, 55.29, 40.68, 38.49, 34.40, 30.08, 29.97, 29.91, US 9,278,134 B2 107 108 28.69, 25.79, 24.68, 23.52, 23.36, 22.76, 22.73, 21.45, 14.24, reduced pressure (0.01 mbar) to give benzethonium salicylate 14.21, 11.14, 11.11, 11.07. T-6° C. T 5%osef 226 C. 6 as yellow glass. "H-NMR (300 MHz, d-DMSO)8(ppm) =7.65 (m. 1H), 7.53 (m, 5H), 7.26 (d. J=8.9 Hz, 2H), 7.10 (s, Example 52 1H), 6.82 (d. J=8.9 Hz, 2H), 6.57 (m, 2H), 4.61 (s. 2H), 4.11 (s. 2H), 4.00 (m, 2H), 3.82 (s.2H), 3.39 (m, 2H), 3.02 (s, 6H), Cetylpyridinium Salicylate 6 1.67 (s. 2H), 1.28 (s, 6 H), 0.66 (s, 9H). 'C-NMR (75 MHz, d-DMSO)8(ppm)=1710, 168.3, 141.0, 128.2, 127.4,125.8, 69.7, 66.2, 61.5, 59.1, 38.2, 34.1, 30.7, 29.8, 29.6, 28.4, 23.2, 23.0, 22.5, 13.9, 10.8, 9.2. T-149 C., T5% osef 180° C. 10 Example 54 S1-1 o Lidocainium Salicylate 8

15 21 OH

Cetylpyridinium chloride monohydrate (20.64 g. 56 O mmol) and sodium salicylate (8.96 g. 56 mmol) were dis solved in 100 ml of acetone/HO 1:1 and stirred overnight at Nti-N O room temperature. The remaining Suspension was diluted with 100 ml of HO and extracted with dichloromethane. The organic layer was washed Successively with water until no r OH more chloride ions could be detected in the washings (checked by addition of AgNO solution), dried over MgSO 25 Lidocaine hydrochloride monohydrate (23.105 g, 80 and the solvent was evaporated. Remaining Volatile material mmol) and sodium salicylate (8.962 g, 80 mmol) were dis was removed under reduced pressure (0.01 mbar) to give solved in 10 ml of acetone/HO 1:1 and stirred overnight at cetylpyridinium salicylate 6 in 56% yield as colourless room temperature. The remaining Suspension was diluted waxy solid. 'H-NMR (300 MHz, de-DMSO) 8(ppm)=9.12 with 100 ml of HO and extracted with dichloromethane. The (d. J=6.08 Hz, 2H), 8.59 (t, J=8.29 Hz, 1H), 8.16 (t, J=7.27 30 organic layer was washed Successively with water until no Hz, 2H), 7.64 (d. 7.54 Hz, 1H), 7.12 (t, J=7.54, 1H), 6.57 (m, more chloride ions could be detected in the washings 2H), 4.59 (t, J–7.44 Hz, 2H), 1.88 (m, 2H), 1.22 (s.27H), 0.84 (checked by addition of AgNO, solution), dried over MgSO (t, J=7.14 Hz, 3H). 'C-NMR (75 MHz, d-DMSO)8(ppm)= and the solvent was evaporated. Remaining Volatile material 171.8, 1634, 145.8, 145.2, 131.4, 130.2, 128.4,121.1, 116.1, was removed under reduced pressure (0.01 mbar) to give 160.0, 61.2, 31.7, 31.2, 29.4, 29.3, 29.2, 29.1, 28.8, 25.8, 22.5, 35 lidocainium salicylate 8 in 54% yield as pale yellow viscous 14.2. mp 57°C., Tso. 206° C. oil. Solvent-Free Procedure: Example 53 Salicylic acid (5 mmol) and lidocaine free base (5 mmol) were molten in a hot mortar until a free-flowing clear liquid Benzethonium Salicylate 7 40 was obtained. The mixture was cooled to room temperature and formed a viscous glass. H-NMR (300 MHz, d-DMSO) Ö(ppm)=10.05 (brs, 1H), 7.72 (dd, J–7.75 Hz, J–1.80 Hz, 1H), 7.24 (m. 1H), 7.09 (s.3H), 6.70 (m, 2H), 3.98 (s. 2H), 3.10(q, J–7.28 Hz, 4H), 2.16 (s, 6H), 1.22 (t, J–7.34 Hz, 6H). 45 'C-NMR (75 MHz, d-DMSO) 8(ppm)=1719, 164.6, 1619, 135.0, 134.0, 133.4, 130. 1, 127.8, 126.9, 117.6, 116.9, 1164, 53.3, 48.3, 18.1, 9.5. T., 19°C., T 5%osef 161o C. Example 55 Tetrabutylphosphonium Salicylate 9 O

OH

Benzethonium chloride (4.481 g, 10 mmol) and sodium salicylate (1.601 g, 10 mmol) were dissolved in 50 ml of 60 u? acetone/HO 1:1 and stirred overnight at room temperature. The remaining suspension was diluted with 50 ml of HO and extracted with dichloromethane. The organic layer was ? OH washed successively with water until no more chloride ions could be detected in the washings (checked by addition of 65 AgNO solution), dried over MgSO and the solvent was Salicylic acid (0.691 g, 5 mmol) and tetrabutylphospho evaporated. Remaining volatile material was removed under nium hydroxide (~40% sol. in HO) (3.414 g. 5 mmol) were US 9,278,134 B2 109 110 dissolved in 20 ml of acetone stirred for 15 min at room 142.4, 140.9, 138.5, 128.5, 127.9, 127.1, 126.7, 125.9, 70.6, temperature. The Solvent was evaporated and the remaining 59.8, 46.6, 44.3, 31.5, 29.7, 22.2, 19.5, 10.7. mp 110° C., viscous liquid was dried at 0.1 mbar with stirring for 24hrs to T5% osef 238 C. obtain tetrabutylphosphonium salicylate 9 in quantitative yield as colourless crystals. 'H-NMR (300 MHz, d-DMSO) Example 58 8(ppm)=7.74 (dd, J–7.73 Hz, J-1.87 Hz, 1H), 7.32 (dt, J–7.59 Hz, J-1.80 Hz, 1H), 6.77 (m, 2H), 2.20 (m, 8 H), Ephedrinium Clofibrate 12 1.41 (m, 16 H), 0.9 (t, J–7.06 Hz, 12 H). "P-NMR (121.5 MHz, d-DMSO) 8(ppm)=35.1. C-NMR (75 MHz, d-DMSO) 8(ppm)=171.9(s), 163.1(s), 131.1 (d), 129.8(d), 10 120.6 (s), 115.7 (d), 115.6 (d), 23.31 (d. J=16.36 Hz), 22.62 12 (d. 4.84 Hz), 17.30 (47.27 Hz), 13.19 (s). mp57°C.; Tso OH 312°C.; water content (KF) 0.076% (m/m). N C Example 56 15 Ephedrinium Salicylate 10

Clofibric acid (1.073 g, 5 mmol) and ephedrine (0.826 g. 5 10 OH -- O mmol) were molten in a hot mortar until a free-flowing clear H liquid was obtained. The mixture solidified at room tempera N ture and was grinded to obtain a yellow powder in quantitative N O 25 yield. 'H-NMR (300 MHz, de-DMSO) 8(ppm)=9.36 (brs, 2H), 7.30 (m, 5H), 7.19 (d. J=8.8 Hz, 2H), 6.82 (d. J=8.75 Hz, OH 2H), 5.10 (s, 1H), 3.12 (m. 1H), 2.52 (s.3H), 1.41 (s, 6H), 0.85 (d. J=6.58 Hz), 3H). 'C-NMR (75 MHz, d-DMSO) 8(ppm)= 176.8, 155.5, 141.8, 128.5, 128.0, 126.9, 125.8, Salicylic acid (0.691 g, 5 mmol) and ephedrine (0.826g, 5 30 123.4, 119.2, 80.2, 69.8, 59.5, 30.7, 25.8, 9.6. mp 131° C., mmol) were molten in a hot mortar until a free-flowing clear T 166° C. liquid was obtained. The mixture was cooled to room tem 5% osef perature Solidified and was grinded to obtain a colourless Example 59 powder in quantitative yield. 'H-NMR (300 MHz, d-DMSO) 8(ppm)=9.30 (brs, 2H), 7.76 (dd, J–7.66 Hz, 35 Ephedrinium Docusate 13 J–1.80 Hz, 1H), 7.38 (m, 4H), 7.24 (m, 2H), 6.70 (m, 2H), 6.48 (brs, 1H), 5.21 (s, 1H), 3.41 (m, 1H), 2.69 (s.3H), 0.95 (d. J=6.76 Hz,3H). 'C-NMR (75 MHz, d-DMSO)8(ppm)= 172.9, 162.1, 1414, 132.0, 130.3, 128.2, 127.2, 125.8, 119.6, 13 116.8, 116.0, 69.6, 59.3, 30.6, 9.1. mp 97° C., T 161° 40 OH C. Example 57 Ephedrinium Ibuprofenate 11 45

11 50 co Ephedrinium hydrochloride (2.017 g. 10 mmol) and 55 sodium docusate (4.446 g, 10 mmol) were dissolved in 50 ml of acetone/HO 1:1 and stirred overnight at room tempera ture. The remaining suspension was diluted with 50 ml of Ibuprofenic acid (0.691 g, 5 mmol) and ephedrine (0.826 g. H2O and extracted with dichloromethane. The organic layer 5 mmol) were molten in a hot mortar until a free-flowing clear was washed successively with water until no more chloride liquid was obtained. The mixture was cooled to room tem 60 ions could be detected in the washings (checked by addition perature, Solidified and was grinded to obtain a colourless of AgNO, solution), dried over MgSO and the solvent was powder in quantitative yield. 'H-NMR (300 MHz, evaporated. Remaining volatile material was removed under d-DMSO) 8(ppm)=7.34 (m, 4H), 7.19 (m, 3H), 7.03 (d. reduced pressure (0.01 mbar) to give ephedrinium docusate J=7.89 Hz, 2H), 5.80 (brs, 1H), 4.97 (d. J=2.8 Hz, 1H), 3.45 13 in 98% yield as colourless viscous oil. H-NMR (300 (q, J=7.1 Hz, 1H), 3.04 (m, 1H), 2.45 (s.3H), 2.38 (d. J=7.15 65 MHz, d-DMSO) 8(ppm)=8.45 (brs, 2H), 7.34 (m, 5H), 6.13 Hz, 2H), 1.78 (sept, J=6.8 Hz, 1H), 1.30 (d. J=7.17, 3 H), 0.83 (d. J–4.24 Hz, 1H), 5.06 (t, J=3.22 Hz, 1H), 3.89 (m, 4H), (m, 9H). 'C-NMR (75 MHz, d-DMSO) 8(ppm)=1779, 3.65 (dd, J = 11.47 Hz, J-3.91 Hz, 1H), 2.86 (m,2H), 2.64 (s, US 9,278,134 B2 111 112 3H), 1.49 (m, 2H), 1.23 (m, 16 H), 0.86 (m, 15 H). 'C-NMR ture. The clear solution was evaporated and the residue dis (75 MHz, d-DMSO) 8(ppm)=1710, 168.3, 141.0, 128.2, Solved in anhydrous acetone. The Suspension was filtered 127.4, 125.8, 69.6, 66.2, 61.5, 59.0, 38.2, 34.1, 30.7, 29.8, over celite and the filtrate was evaporated. Remaining volatile 29.6, 28.4, 23.2, 23.0, 22.5, 13.9, 10.8, 9.2. T-25° C., material was removed under reduced pressure (0.01 mbar) to T5%osef 238 C. give procainamide Salicylate 15 as pale yellow viscous oil. 'H-NMR (300 MHz, d-DMSO) 8(ppm)=8.47 (t, J=5.6 Hz, Example 60 1H), 7.72 (dd, J=7.7 Hz, J–19 Hz, 1H), 7.60 (d. J=8.7 Hz, 2H), 7.23 (m, 1H), 6.71 (m, 2H), 6.54 (d. J=8.6 Hz, 2H), 3.60 Promethazine Docusate 14 (s. 2H), 3.19 (m, 6H), 1.23 (t, J=7.1 Hz, 6H). 'C-NMR (75 10 MHz, d-DMSO) 8(ppm)=172.5, 166.9, 162.2, 152.0, 132.2, 130.2, 128.8, 120.4, 119.1, 11.6.8, 1160.0, 112.5, 50.0, 46.7, 14 34.3, 8.6. Tso 199°C. OC S O 15 Example 62 Procainamide Ibuprofenate 16

NH- 1+N 16 HN

H -- 25 N-1a1a. l roc 30 Promethazine hydrochloride (3.209 g, 10 mmol) and sodium docusate (4.446 g. 10 mmol) were dissolved in 50 ml of acetone/HO 1:1 and stirred overnight at room tempera ture. The remaining suspension was diluted with 50 ml of H2O and extracted with dichloromethane. The organic layer 35 was washed successively with water until no more chloride ions could be detected in the washings (checked by addition of AgNO solution), dried over MgSO and the solvent was evaporated. Remaining volatile material was removed under reduced pressure (0.01 mbar) to give promethazine docusate 40 14 in 99% yield as light yellow oil. H-NMR (300 MHz, d-DMSO) 8(ppm)=9.59 (brs, 1H), 7.26 (m, 6H), 7.04 (t, J=7.3 Hz, 2H), 4.37 (dd, J=14.3 Hz, J-4.8 Hz, 1H), 4.05 (dd, J=14.6 Hz, J–8.1 Hz, 1H), 3.89 (m, 4H), 3.66 (m, 2H), 2.91 (m, 2H), 2.82 (s, 6H), 1.49 (m, 2H), 1.28 (d. J=6.5 Hz, 45 3H), 1.22 (m, 16 H), 0.83 (m. 12 H). Tsoi, 24.6°C. Example 61 Procainamide hydrochloride (2.718g. 10 mmol) and race Procainamide Salicylate 15 50 mic sodium ibuprofenate (2.283 g, 10 mmol) were dissolved in 50 ml of acetone/HO 1:1 and stirred overnight at room temperature. The remaining suspension was diluted with 50 ml of H2O and extracted with dichloromethane. The organic 15) layer was washed Successively with water until no more chlo 55 ride ions could be detected in the washings (checked by addition of AgNO solution), dried over MgSO and the sol HN vent was evaporated. Remaining Volatile material was O removed under reduced pressure (0.01 mbar) to give -- procainamide ibuprofenate 16 in as Viscous yellow liquid. N-1a1a. OH 60 'H-NMR (300 MHz, d-DMSO) 8(ppm)=7.96 (t, J=5.7 HZ, 1H), 7.56 (d. J=8.6 Hz, 2H), 7.20 (d. J=8.8 Hz, 2H), 6.69 O N (d. 8.8 Hz, 2H), 6.54 (d. J=8.6 Hz, 2H), 5.60 (brs, 2H), 3.61 (q, 7.2 Hz, 1H), 3.29(m, 2H), 2.56 (m, 6H), 2.42 (d. J–7.2 Hz, Procainamide hydrochloride (2.718 g, 10 mmol) and 65 2H), 1.82 (sept, 6.9 HZ, 1H), 1.35 (d. J=6.9 Hz, 3H), 0.99 (t, sodium salicylate (1.601 g, 10 mmol) were dissolved in 10 ml 7.1 Hz, 6H), 0.86 (d. J=6.8 Hz, 6H). 'C-NMR (75 MHz, of acetone/HO 1:1 and stirred overnight at room tempera d-DMSO)8(ppm)=175.7, 166.1, 151.5, 139.4, 138.9, 128.9, US 9,278,134 B2 113 114 128.6, 127.1, 121.3, 112.5, 51.6, 46.7, 44.6, 44.2, 37.0, 29.6, der in quantitative yield. 1H-NMR (300 MHz, d-DMSO) 22.2, 18.7, 11.6. Tso, 182°C. Ö(ppm)=7.20 (d. J=8.1 Hz, 2H), 7.1 (d. 8.1 Hz, 2H), 5.77 (br s, 3H), 3.61 (q, 7.2 Hz, 1H), 3.45 (t, J–6.1, 6H), 2.61 (t, J=6.1 Example 63 HZ, 6H), 2.42 (d. J–7.2 Hz, 2H), 2.42 (d. 7.2 Hz, 2H), 1.82 (sept, 6.8 Hz, 1H), 1.35 (d. J=7.1 Hz, 3H), 0.87 (d. J=6.6 Hz, Procainamide Docusate 17 6H). 'C-NMR (75 MHz, d-DMSO)8(ppm)=175.7, 139.4, 138.8, 128.9, 127.1, 59.0, 57.1, 44.6, 44.3, 29.6, 22.2, 18.7. mp 90° C., Tso 163°C.

17 10 Example 65 HN Tetrabutylphosphonium Ibuprofenate 19 N-1a1nH -- 15 O O N 19

rocO N-- P 25 Procainamide hydrochloride (2.718 g, 10 mmol) and sodium docusate (4.4456 g. 10 mmol) were dissolved in 20 ml of acetone/HO 1:1 and stirred overnight at room tempera Ibuprofenic acid (1.032 g, 5 mmol) and tetrabutylphospho ture. The remaining suspension was diluted with 50 ml of nium hydroxide (~40% sol. in HO) (3.414 g. 5 mmol) were HO and extracted with dichloromethane. The organic layer 30 dissolved in 20 ml of acetone stirred for 15 min at room was washed successively with water until no more chloride temperature. The Solvent was evaporated and the remaining ions could be detected in the washings (checked by addition viscous liquid was dried at 0.1 mbar with stirring for 24hrs to of AgNO, solution), dried over MgSO and the solvent was obtain tetrabutylphosphonium ibuprofenate 19 in quantita evaporated. Remaining volatile material was removed under tive yield as colourless viscous liquid. 'H-NMR (300 MHz, reduced pressure (0.01 mbar) to give procainamide docusate 35 d-DMSO) 8(ppm)=7.13 (d. J=8.08 Hz, 2H), 6.94 (d. 8.08 17 in quantitative yield as yellow oil. H-NMR (300 MHz, Hz, 2H), 3.21 (q, 7.74 Hz, 1H), 2.48 (m, 2H), 2.36 (d. 7.28 Hz, d-DMSO)8(ppm)=9.08 (brs, 1H), 8.27 (t, J=5.6 Hz, 1H), 2H), 2.14 (m, 8H), 1.77 (sept, 6.15 Hz, 1H), 1.40 (m, 16 H), 7.52 (d. J=8.6 Hz, 2H), 6.55 (d. J=8.6 Hz, 2H), 5.71 (brs, 2H), 1.18 (d. J=7.03 Hz, 3H), 0.91 (t, 7.02 Hz, 12H), 0.84 (d. 3.89 (m, 4H), 3.65 (dd, J=11.5 Hz, J-38 Hz, 1H), 3.53 (q, J=7.02 Hz, 6H). 'C-NMR (75 MHz, d-DMSO) 8(ppm) 6.1 Hz, 2H), 3.2 (m, 6H), 2.87(m, 4H), 1.49 (m, 2H), 1.22 (m, 40 =174.8, 144.2, 136.9, 127.8, 127.2, 49.3, 44.4, 29.7, 23.4 (d. J=15.8 Hz), 22.7 (d. J=4.7 Hz), 22.2, 20.5, 17.3 (d. J=48.1 22H), 0.84 (m, 12H). Hz), 13.3. mp-43°C., T 234° C. T5%osef 2310 C. 5% osef Example 64 Example 66 45 Triethanolammonium Ibuprofenate 18 Tributylhydroxyethylphosphonium Docusate 20

18 50 20

55 OH

Ibuprofenic acid (1.032 g, 5 mmol) and triethanolamine (0.746 g. 5 mmol) were molten in a hot mortar until a free 65 flowing clear liquid was obtained. The mixture solidified at room temperature and was grinded to obtain colourless pow US 9,278,134 B2 115 116 Tributylhydroxyethylphosphonium chloride (10.019 g, acetonitrile and two spatulas of activated charcoal (6-12 35.5 mmol) and sodium docusate (15.770 g., 35.5 mmol) were Mesh) were added to the solution. The mixture was left stir dissolved in 100 ml of acetone/HO 1:1 and stirred overnight ring overnight and then filtered through activated aluminum at room temperature. The remaining Suspension was diluted oxide (basic, Brockmann I). The solvent was removed leaving with 100 ml of HO and extracted with dichloromethane. The a clear viscous oily residue. The product was dried under organic layer was washed Successively with water until no vacuum on a Shlenk line at 55° C. for 3 hours. (crude yield: more chloride ions could be detected in the washings 91%) (checked by addition of AgNO solution), dried over MgSO and the solvent was evaporated. Remaining Volatile material was removed under reduced pressure (0.01 mbar) to give 10

tributylhydroxyethylphosphonium docusate 20 in 92% yield as colourless liquid. 'H-NMR (300 MHz, d-DMSO) 8(ppm)=5.77 brs, 1H), 3.82 (m, 6H), 3.63 (dd, J=11.3 Hz, J–3.8 Hz, 1H), 2.85 (m. 2H), 2.42 (m. 2H), 2.20 (m, 6H), 1.43 (m, 14H), 0.92 (t, J=7.1 Hz, 9H), 0.84 (m, 12H). 'P- 15 NMR (121.5 MHz, d-DMSO)8(ppm)=34.5. C-NMR (75 MHz, d-DMSO) 8(ppm)=1710, 163.3, 66.1, 66.0, 61.4, 544, 54.3, 38.1, 34.1, 29.7, 28.6, 29.5, 28.3, 23.6 (d. J=15.9 Hz), 23.2, 23.0, 22.7 (d. 4.9 Hz), 22.4, 22.3, 18.1 (d. 48.5), O 29 30 13.9, 13.8, 13.2, 10.7. T-45° C.T.s 280° C. Example 67 o- 2 25 24 O 27 26 Choline Docusate 21 25 Propantheline p-Toluenesulfonate "H NMR (300 MHz, d-DMSO): & 1.13-118 (qJ3.9, 12H: H19, H20, H22, H23), 2.28 (s.3H: H24), 2.66 (s.3H: H17), 3.41-3.46 (t(b), J47,2H: H16), 3.71-3.77 (m, 2H: H18, H21), 4.34-4.39 (t(b), J 4.7, 30 2H: H15), 5.31 (s, 1H: H7), 7.09-7.12 (m, 2H: H26, H30), 7.12-722 (m, 4H; H2, H4, H10, H12), 7.39-7.40 (m, 4H; H3, H5, H9, H11), 7.46-7.49 (m, 2H; H27, H29). 'C NMR (75 MHz, d-DMSO): & 16.13-16.20 (C19, C20, C22, C23): 20.70 (C24); 40.81 (C17); 44.07 (C7): 54.18 (C16): 59.72 35 (C15): 63.84 (C18, C21): 116.54(C2, C12): 118.22 (C6, C8); 123.62 (C4, C10): 125.44 (C27, C29); 127.95 (C26, C30): 129.35 (C3, C11): 129.53 (C5, C9); 137.46 (C28); 145.85 Choline chloride (1.396 g. 10 mmol) and sodium docusate (C25): 150.86 (C1, C13): 170.32 (C14). MS (ESI): ES+ m/z: (4.4456 g, 10 mmol) were dissolved in 50 ml of acetone/HO 368.0 (propantheline"), ES- m/z. 171.0 (p-toluene 1:1 and stirred overnight at room temperature. The remaining 40 sulfonate). ISE: The bromide concentration was determined suspension was diluted with 50 ml of HO and extracted with by dissolving 0.205.6 g of propantheline p-toluenesulfonate in dichloromethane. The organic layer was washed Successively 10 mL of methanol, indicating <100 ppm bromide. DSC: A with water until no more chloride ions could be detected in the reproducible Tg at 7+ C. washings (checked by addition of AgNO solution), dried over MgSO and the solvent was evaporated. Remaining 45 Compositions volatile material was removed under reduced pressure (0.01 mbar) to give choline docusate 21 in quantitative yield as Viscosity, conductivity and AW values for various propan yellow very viscous liquid. 'H-NMR (300 MHz, d-DMSO) theline p-toluenesulfonate (PtTos)/water composites. Ö(ppm)-4,88 (t, J=5.4 Hz, 1H), 4.21 (dd, J = 10.6 Hz, J-4.32 HZ, 1H), 4.02 (m, 6H), 3.63 (m, 2H), 3.8 (s.9H), 3.2 (m, 4H), 50 TABLE X 1.57 (m, 2H), 1.27 (m, 16H), 0.87(m, 12H).T.s, 189° C. Viscosity Conductivity Compositions (mPa is) + 1% (Scm)** AW Ionic Liquid Solvates PtTos pure >2000: 5.41 x 107 2.0 Water:PTTos (25 wt %) 3 30.1 x 10 O.69 Example 68 55 Water:PTTos (20 wt %) 3 26.1 x 10 0.77 Propantheline p-Toluenesulfonate Water:PTTos (4.8 wt %) 1 15.2 x 10 O.63 instrument limit **conductivity error does not exceed the data point in all cases A mixture of propantheline bromide (3.32 g, 7.41 mmol) AW–distance form the ideal line and silverp-toluenesulfonate (2.07 g., 7.41 mmol) in acetoni 60 trile (100 mL) was protected from light and stirred overnight The low ionicity nature of the ionic liquid is demonstrated at room temperature. A yellow precipitate formed instanta via the Walden plot according to the discussion of Fraser etal neously. The reaction mixture was filtered through Celite to (Chem Commun2007). Data for this compound are plotted in remove AgBr. The filtrate was then re-filtered through micro FIG. 7 which shows that it lies 2 log units below the reference filters (0.20 um). The solvent was evaporated to leave a clear 65 line, Suggesting the degree of ionicity is only approximately yellow viscous residue. To remove any colour from the 1%. With addition of 25 weight% water, AW value decreased. sample, propantheline p-toluenesulfonate was re-dissolved in This is true for all of the propantheline p-toluenesulfonate/ US 9,278,134 B2 117 118 water systems studied. With the increasing water content the 5. The method according to claim 1, wherein combining AW seems to become approximately constant perhaps indi two cations or cation precursors, represented as B and B, cating that full dissociation had been reached. with one anion, represented as A, is by adding base B to an What is claimed is: ionic liquid having the formula (BHA. 1. A method for preparing a bioactive co-ionic ionic liquid 6. The method according to claim 1, wherein combining composition comprising: the two cation precursor with one anion or two anion precur combining two pharmaceutical actives selected from Sor with one cation is accomplished by an acid-base neutral single charged cations, cation precursors, and combina ization reaction. tions thereof, represented as B' and B, with one anion 7. The method according to claim 1, wherein the cation B having a single negative charge, represented as A, or 10 combining two pharmaceutical actives selected from comprises tetrabutylphosphonium and the anion A comprises single charged anions, anion precursors, and combina salicylate and ibuprofenate, cinnamate, camphorsulfonate, tions thereof, represented as A' and A, with one cation lactate or thiosalicylate. having a single positive charge, represented as B. 8. The method according to claim 1, wherein the cation B thereby producing a co-ionic liquid (BHBA or 15 is tetrabutylphosphonium and the anions A" and A are ibu BAHA), where H is hydrogen, that is liquid at a profenate or niacinate. temperature at or below about 150° C. 9. The method according to claim 1, wherein the cation B wherein B' and B are selected from choline, lidocaine, is cetylpyridinium and the anions A" and A are salicylate and tramadolium, caffeine, cetylpyridinium, ephedrinium, ibuprofenate, cinnamate, or clofibrate. propantheline, acetaminophen derivative, procaina 10. The method according to claim 1, wherein the cation B mide, promethazine, and combinations thereof, and is lidocaine and the anions A" and A are salicylate and Ibu wherein A' and A are selected from salicylate, ibupro profenate. fenate, lactate, camphorsulfonate, trans-cinnamate, 11. The method according to claim 1, wherein the cation B docusate, niacinate, clofibrate, and combinations is tramadolium and the anions A" and A are salicylate and thereof. 25 ibuprofenate. 2. The method of claim 1 wherein from about 75% to about 12. The method according to claim 1, wherein the cations 100% of the composition comprises an ion pair. B' and B are ephedrinium and lidocaine and the anion A is 3. The method of claim 1, wherein the cations and anions or ibuprofenate. the cation precursors and anion precursors are combined in 13. The method according to claim 1, wherein the cations the presence of one or more solvents, thereby producing a 30 B' and B are tramadolium and lidocaine and the anion A is solvated ionic liquid; wherein at least a portion of the solvent salicylate or ibuprofenate. provides direct solvation. 4. The method according to claim 1, wherein combining 14. The method according to claim 1, wherein the cations two anions or anion precursors, represented as A' and A. B' and B are promethazine and ephedrine and the anion A is with one cation, represented as B, is by adding acid HA to a 35 docusate or salicylate. non-protic ionic liquid having the formula BA". k k k k k