US 20120046244A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0046244 A1 Rogers et al. (43) Pub. Date: Feb. 23, 2012

(54) DUAL FUNCTIONING IONIC LIQUIDS AND (86). PCT No.: PCT/USO9/69652 SALTS THEREOF S371 (c)(1), (75) Inventors: Robin D. Rogers, Tuscaloosa, AL (2), (4) Date: Nov. 3, 2011 (US); Daniel T. Daly, Tuscaloosa, AL (US); Douglas MacFarlane, Related U.S. Application Data SG (KSR,kiSt. Port (60) Eyal application No. 61/141,168, filed on Dec. Seddon, Donaghadee (IE): s Gabriela Gurau, Tuscaloosa, AL O O (US); Katharina Bica, Vienna Publication Classification (AT); Jelena Turanjanin, Victoria (51) Int. Cl. (AU); Pamela M. Dean, Victoria A6II 3/66 (2006.01) (AU) A6II 3L/205 (2006.01) A6II 3/545 (2006.01) (73) Assignees: THE BOARD OF TRUSTEES OF A613/606 (2006.01) THE UNIVERSITY OF (52) U.S. Cl...... 514/75; 514/166; 514/555; 514/226.2 ALABAMA, Tuscaloosa, AL (US); QUEENS UNIVERSITY (57) ABSTRACT BELFAST, Belfast (UK); MONASH UNIVERSITY, Disclosed herein are ionic liquid compositions comprising Melbourne (AU) active pharmaceutical, biological, and nutritional com pounds, and methods of use. Further disclosed are composi (21) Appl. No.: 13/142.559 tions of matter including liquid ion pairs alone or in Solution and their use; compositions of ionic liquids that are solvated. (22) PCT Filed: Dec. 29, 2009 for example, hydrated and their uses. Patent Application Publication Feb. 23, 2012 Sheet 1 of 7 US 2012/0046244 A1

O 20 40 SO 8) O) Wit% Choline DPP

Fig. 1 Patent Application Publication Feb. 23, 2012 Sheet 2 of 7 US 2012/0046244 A1

CN- P(Busal H,

Vam 4. T

P(Bu)4SalHis P(Bu)Sal.Hoa P(Bu),Salih É P(Bu),Salih P(Bu)SaHol P(Bu)Sal

-50 O SO 100 150 Temperature C

Fig. 2 Patent Application Publication Feb. 23, 2012 Sheet 3 of 7 US 2012/0046244 A1

0.35 0.20 E. 9 0.30 0.18 m - 0.16. 0.25 g 0.14 S 2 0.20 0.12 C O 0.15 H 0.10 0.0 0.2 0.4 0.6 0.8 mol fraction salicylic acid XsalH

Fig. 3 Patent Application Publication Feb. 23, 2012 Sheet 4 of 7 US 2012/0046244 A1

1.0

0. 5 N- |HLidjSal,H, HLidSal His Y- HLidSal Nu --- (HLidissal - s-N HLid, Sal "l N- HLid, lSal N-1\- HLidSal

-50 O SO 100 150 Temperature C

Fig. 4 Patent Application Publication Feb. 23, 2012 Sheet 5 of 7 US 2012/0046244 A1

1 OO Š, 80 is5 60 5. 40- E S O - r O O SO 100 150 2 OO 25O 3 OO 350 time min

Fig.5 Patent Application Publication Feb. 23, 2012 Sheet 6 of 7 US 2012/0046244 A1

Onset 688 Step S.29.5% -i.7487 ag Residue 78.262.7% 7.489 mg

Inflect. Pt. 178.59 °C Midpoint 179.43 °C Onset 2SS.45 °C

Step -66.825.3%

-6,3885 mg Residue 11530.2% 1.102.3 mg infect. Pt. 33.95 °C Midpoint 296.78 °C

Fig. 6 Patent Application Publication Feb. 23, 2012 Sheet 7 of 7 US 2012/0046244 A1

3 4. Water:Pt.Tos (25wt.%) at 25 oc at Water:PTTos (20w) at 25 cc 2 WateriPTTos (4.8wie at 25 oc PTTos(pure) at 90 oC

-2O.

o 3.

log firwiscosity(Polse'

Fig. 7 US 2012/0046244 A1 Feb. 23, 2012

DUAL FUNCTIONING IONIC LIQUIDS AND morph) of a compound determines its physical properties SALTS THEREOF such as dissolution rate, solubility, bioavailability, crystal habit, mechanical strength, etc. (Datta et al., Nature PRIORITY Reviews—Drug Discovery, 2004, 3:42-57). The delivery of an exact dosage in manufacture and the manufacturing pro 0001. This application claims the benefit of Provisional cess itself often depend on which of several possible poly Application Ser. No. 61/141,168 filed on Dec. 29, 2008, the morphs or pseudo-polymorphs are present. entire disclosure of which is incorporated herein by reference. 0007. The variation in properties among different poly morphs (orpseudo-polymorphs) usually means that one crys FIELD talline form is desired or preferred over other forms. Obtain 0002 Disclosed herein are ionic liquid compositions com ing a particular form can be difficult, however. Typically, prising active pharmaceutical, biological, and nutritional researchers have to experiment with a multitude of variables compounds, and methods of use. Further disclosed are com in crystallization conditions, such as aqueous solvent mix positions of matter including liquid ion pairs alone or in tures, amount of water, amount of target compound, relative Solution and their use; compositions of ionic liquids that are humidity, temperature of incubation, incubation time, etc., in solvated, for example, hydrated and their uses. a process characterized by trial and error. Further, the search for salts of crystalline forms (usually sought after to control BACKGROUND dissolution rate and solubility) can require extensive experi mentation. Each salt of a drug or each different solvent used 0003 Polymorphism is the ability of a substance to existin to crystallize the drug or a salt of the drug may lead to two or more crystalline forms that have a different arrange polymorphs or pseudo-polymorphs that have to be fully ment and/or conformation of molecules in a crystalline lattice investigated and that have different properties (see e.g., (see e.g., Chawla and Bansal, CRIPS 2004, 5(1):9-12; Bern Reutzel-Edens et al., “Anhydrates and hydrates of olanzap stein, “Polymorphism in Molecular Crystals.” IUCR Mono ine: Crystallization, Solid-state characterization, and struc graphs on Crystallography 14, Oxford Science Publications, tural relationships. Crystal Growth & Design, 2003, 3:897 2002, pp. 1-28, 240-256). It has been estimated that a large 907). number of pharmaceuticals exhibit polymorphism. For 0008 Another common problem that exists with many example, 70% of barbiturates, 60% of sulfonamides, and 23% pharmaceuticals, agrochemicals, nutraceuticals etc. is low of steroids are believed to exist in different polymorphic solubility. Low solubility can make formulating a particular forms or “polymorphs” (Haleblian et al., J Pharm Sci 1975, compound difficult, and generally low solubility translates 64:1269-1288). into low bioavailability. Much research is conducted on find 0004. In some cases, when crystals of a compound are ing ways to improve a compound's solubility and availability. forming (e.g., crystallizing from a solution), Solvent mol Typically methods include complex delivery devices and ecules may become entrapped or bound within the crystal chemical modifications of the drug. lattice. The presence of the entrapped solvent molecules may 0009 Polymorphism and pseudo-polymorphism is diffi affect the three-dimensional crystal lattice that eventually cult to predict, i.e., there is a relationship between the crys crystallizes. The occurrence of a compound (target molecule) talline State of a compound and its chemical properties (e.g., crystallizing in different three-dimensional lattices based dissolution rate, solubility), biological properties (e.g., bio upon the presence of Solvent molecules has been termed availability, pharmacokinetics), mechanical and physical “pseudo-polymorphism.” Akin to polymorphs, such properties, and manufacturing processes. In some instances “pseudo-polymorphs.” also known as “solvates” (or polymorphs and pseudo-polymorphs can interconvert. More “hydrates' when the solvent is water), are crystalline solids over, there is a need for compositions that can manifest their containing either stoichiometric (i.e., whole number ratios of base property, for example, their pharmacological properties, target molecules to solvent molecules) or non-stoichiometric (i.e., non-whole number ratios of target molecules to solvent while having controllable and/or adjustable chemical, bio molecules) amounts of a solvent incorporated within the crys logical, and physical properties, that the formulator can tal structure. In general, different crystalline forms of mol “tune' to the desired properties while at the same time avoid ecules (e.g., pharmaceutical compounds) can exist in the ing any undesirable polymorphism. In addition, there is a same or different hydrated or solvated states. need for compounds having these properties which have 0005. The existence of various polymorphs or pseudo modifiable dissolution and solubility properties. As such, polymorphs can greatly affect a pharmaceutical's perfor there is further needed methods of preparing and using com mance since each form can have different physical and chemi positions having these controllable properties. Further, there cal properties. For example, one particular polymorph is a need for methods of converting compounds that are dif pseudo-polymorph may be more bioavailable, more stable ficult to solubilize into a form that allows for increased solu (e.g., longer shelf life), or more easily formulated or tableted bility. Disclosed herein are compositions and methods that than another polymorph. Similarly, one polymorph pseudo provide for the above compounds, compositions, and meth polymorph may be more active or less toxic than another. ods. Some specific examples of the dramatic difference that can exist between various pharmaceutical polymorphs are SUMMARY described in, e.g., Brittain et al., J Pharm Sci 2002, 91:1573 0010. In accordance with the purposes of the disclosed 1580 and Morissette et al., Proc Natl AcadSci USA 2003, materials, compounds, compositions, devices, and methods, 100: 2180-2184. as embodied and broadly described herein, the disclosed sub 0006. The effects of polymorphism and pseudo-polymor ject matter, in one aspect, relates to compounds and compo phism on quality and performance of a drug is widely recog sitions and methods for preparing and using Such compounds nized. The exact solid State polymorph (or pseudo-poly and compositions. In a further aspect, the disclosed subject US 2012/0046244 A1 Feb. 23, 2012 matter relates to ionic liquid compositions that can be used for 0017 FIG. 2 depicts the depression and elimination of the or in biological, pharmaceutical, nutritional, cosmetic, indus melting point of P(Bu) Sal H. in a series of co-ionic liq trial, and commercial compositions. Methods for making the uids comprising oligomeric anions. disclosed ionic liquid compositions are also disclosed. Also 0018 FIG. 3 depicts the conductivity and viscosity of disclosed are methods of preparing ionic liquid compositions various P(Bu)Sal H. compositions in a series of co-ionic of active pharmaceutical, biological, nutritional, and ener liquids comprising oligomeric anions. getic ingredients. Also the disclosed are methods of using the 0019 FIG. 4 depicts the depression of glass transition and compositions described herein to overcome polymorphism, saturation of double functional co-ionic liquids based on overcome solubility and delivery problems, to control release lidocainium salicylate. rates, add functionality, enhance efficacy, and improve ease of 0020 FIG. 5 depicts the decomposition of the prodrug use and manufacture. Also disclosed is the use of multiple ionic liquids 1-2-(4-acetamidophenoxy)-2-oxoethyl-3-me functional co-ionic liquids with excess of any free base or any thyl-1H-imidazol-3-ium chloride (O) and 2-(4-acetami free acid in equilibrium with cation or anion that are com dophenoxy)-2-oxoethyltributylphosphonium chloride () posed of active pharmaceutical, biological, nutritional, or versus time in phosphate buffer pH 7.4 at 37°C. energetic ingredients. The present disclosure is based upon 0021 FIG. 6 depicts the decomposition of (E)-4-(3,7-dim the discovery that the physico-chemical properties of com ethylocta-2,6-dienyloxy)-4-oxobutanoic acid versus on tem mon pharmaceutical salts can be modified by addition of the perature. The first decomposition step represents the release corresponding protic acid or base to form new ionic liquid of the Volatile fragrance geraniol. species of the type B"HBA or BAHA). 0022 FIG. 7 depicts the Walden plot for various propan 0011. Also disclosed is a process for preparation via sol theline p-toluenesulfonates. Vent-free methods, e.g. grinding or reaction in molten state. The process can include addition of a acid or base to a com DETAILED DESCRIPTION mon pharmaceutical active salt or by direct solvent-free reac 0023 The materials, compounds, compositions, articles, tion of acid with base in a ratio other than 1:1 to form co-ionic and methods described herein may be understood more liquids of the type B"HBA or BIA'HA. readily by reference to the following detailed description of 0012. Additional advantages will be set forth in part in the specific aspects of the disclosed subject matter and the description that follows, and in part will be obvious from the Examples included therein. description, or may be learned by practice of the aspects 0024. Before the present materials, compounds, composi described below. The advantages described below will be tions, articles, devices, and methods are disclosed and realized and attained by means of the elements and combina described, it is to be understood that the aspects described tions particularly pointed out in the appended claims. It is to below are not limited to specific synthetic methods or specific be understood that both the foregoing general description and reagents, as such may, of course, vary. It is also to be under the following detailed description are exemplary and stood that the terminology used herein is for the purpose of explanatory only and are not restrictive. describing particular aspects only and is not intended to be 0013 Further disclosed is the use of ionic liquids for limiting. immobilization, delivery, and controlled release of pharma 0025. Also, throughout this specification, various publica ceutically active neutral compounds. This use is based upon tions are referenced. The disclosures of these publications in the discovery that neutral active compounds, especially phar their entireties are hereby incorporated by reference into this maceuticals, can be covalently linked with ionic structural application in order to more fully describe the state of the art moiety and turned into an ionic liquid by appropriate choice to which the disclosed matter pertains. The references dis of the counterion. The ionic liquidacts not only as Support for closed are also individually and specifically incorporated by the active compounds, being able to store pharmaceuticals in reference herein for the material contained in them that is inactive form but also allow a simple tuning of physical discussed in the sentence in which the reference is relied properties like solubility, bioavailability, lipophilicity or con upon. trol over polymorphism as well as the control over release 0026. In this specification and in the claims that follow, reference will be made to a number of terms, which shall be kinetics of the active compound. defined to have the following meanings: 0014. Yet further discloses is a synthetic methodology to 0027. Throughout the description and claims of this speci transfer neutral compounds into salts, wherein the active fication the word “comprise' and other forms of the word, compound can be of either positive or negative charge, with Such as "comprising” and "comprises.” means including but the possibility to form dual functioning salts by introduction not limited to, and is not intended to exclude, for example, of a second, pharmaceutically or biologically active counte other additives, components, integers, or steps. 1O. 0028. As used in the description and the appended claims, 0.015. Further described herein is a method for the immo the singular forms “a,” “an and “the' include plural referents bilization of volatile fragrance and flavor compounds in the unless the context clearly dictates otherwise. Thus, for form of ionic liquids of neglible volatility for storage as well example, reference to “a composition' includes mixtures of for controlled and prolonged release of the fragrance- or two or more such compositions, reference to “an ionic liquid flavor compounds under defined conditions such as tempera includes mixtures of two or more such ionic liquids, reference ture, or pH value. to “the compound” includes mixtures of two or more such compounds, and the like. BRIEF DESCRIPTION OF THE FIGURES (0029 “Optional” or “optionally” means that the subse quently described event or circumstance can or cannot occur, 0016 FIG. 1 depicts the binary phase diagram for choline and that the description includes instances where the event or DPP as example for ionic liquid diluates. circumstance occurs and instances where it does not. US 2012/0046244 A1 Feb. 23, 2012

0030) Ranges can be expressed hereinas from “about one (e.g., microorganism growth or Survival). The term “control particular value, and/or to “about another particular value. is used synonymously with the term “treat.” When Such a range is expressed, another aspect includes from 0035. By “antimicrobial” is meant the ability to treat or the one particular value and/or to the other particular value. control (e.g., reduce, prevent, inhibit, break-down, or elimi Similarly, when values are expressed as approximations, by nate) microorganism growth or Survival at any concentration. use of the antecedent “about it will be understood that the Similarly, the terms “antibacterial.” “antiviral and “antifun particular value forms another aspect. It will be further under gal' respectively mean the ability to treat or control (e.g., stood that the endpoints of each of the ranges are significant reduce, prevent, inhibit, break-down, or eliminate) bacterial, both in relation to the other endpoint, and independently of viral, and fungal growth or Survival at any concentration. the other endpoint. It is also understood that there are a 0036. It is understood that throughout this specification number of values disclosed herein, and that each value is also the identifiers “first and “second are used solely to aid in herein disclosed as “about that particular value in addition to distinguishing the various components and steps of the dis the value itself. For example, if the value “10 is disclosed, closed subject matter. The identifiers “first and “second are then “about 10' is also disclosed. It is also understood that not intended to imply any particular order, amount, prefer when a value is disclosed, then “less than or equal to the ence, or importance to the components or steps modified by value, “greater than or equal to the value.” and possible ranges these terms. between values are also disclosed, as appropriately under 0037 References in the specification and concluding stood by the skilled artisan. For example, if the value “10 is claims to parts by weight of a particular element or compo disclosed, then “less than or equal to 10” as well as “greater nent in a composition denotes the weight relationship than or equal to 10” is also disclosed. It is also understood that between the element or component and any other elements or throughout the application data are provided in a number of components in the composition or article for which a part by different formats and that this data represent endpoints and weight is expressed. Thus, in a compound containing 2 parts starting points and ranges for any combination of the data by weight of component X and 5 parts by weight component points. For example, if a particular data point “10 and a Y,X and Y are presentata weight ratio of 2:5, and are present particular data point “15” are disclosed, it is understood that in Such ratio regardless of whether additional components are greater than, greater than or equal to, less than, less than or contained in the compound. equal to, and equal to 10 and 15 are considered disclosed as 0038 A weight percent (wt.%) of a component, unless well as between 10 and 15. It is also understood that each unit specifically stated to the contrary, is based on the total weight between two particular units are also disclosed. For example, of the formulation or composition in which the component is if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also included. disclosed. 0039. The term “ion, as used herein, refers to any mol 0031. As used herein, by a “subject' is meant an indi ecule, portion of a molecule, cluster of molecules, molecular vidual. Thus, the “subject' can include domesticated animals complex, moiety, or atom that contains a charge (positive, (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, negative, or both (e.g., Zwitterions) or that can be made to sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, contain a charge. Methods for producing a charge in a mol rat, guinea pig, etc.), and birds. "Subject' can also include a ecule, portion of a molecule, cluster of molecules, molecular mammal. Such as a primate or a human. complex, moiety, or atom are disclosed herein and can be 0032. By “reduce” or other forms of the word, such as accomplished by methods known in the art, e.g., protonation, “reducing or “reduction is meant lowering of an event or deprotonation, oxidation, reduction, alkylation, etc. characteristic (e.g., microorganism growth or Survival). It is 0040. The term “anion' is a type of ion and is included understood that this is typically in relation to some standard or within the meaning of the term “ion'. An “anion' is any expected value, in other words it is relative, but that it is not molecule, portion of a molecule (e.g., Zwitterion), cluster of always necessary for the standard or relative value to be molecules, molecular complex, moiety, or atom that contains referred to. For example, “reduces bacteria growth' means a net negative charge or that can be made to contain a net lowering the amount of bacteria relative to a standard or a negative charge. The term "anion precursor is used herein to control. specifically refer to a molecule that can be converted to an 0033. By “prevent” or other forms of the word, such as anion via a chemical reaction (e.g., deprotonation). “preventing or “prevention is meant to stop a particular 0041. The term “cation' is a type of ion and is included event or characteristic, to stabilize or delay the development within the meaning of the term “ion'. A “cation' is any or progression of a particular event or characteristic, or to molecule, portion of a molecule (e.g., Zwitterion), cluster of minimize the chances that a particular event or characteristic molecules, molecular complex, moiety, or atom, that contains will occur. Prevent does not require comparison to a control as a net positive charge or that can be made to contain a net it is typically more absolute than, for example, reduce. As positive charge. The term “cation precursor is used herein to used herein, something could be reduced but not prevented, specifically refer to a molecule that can be converted to a but something that is reduced could also be prevented. Like cation via a chemical reaction (e.g., protonation or alkyla wise, something could be prevented but not reduced, but tion). Something that is prevented could also be reduced. It is under 0042. As used herein, the term “substituted” is contem stood that where reduce or prevent are used, unless specifi plated to include all permissible Substituents of organic com cally indicated otherwise, the use of the other word is also pounds. In a broad aspect, the permissible Substituents expressly disclosed. include acyclic and cyclic, branched and unbranched, car 0034. By “treat” or other forms of the word, such as bocyclic and heterocyclic, and aromatic and nonaromatic “treated' or “treatment is meant to administer a composition Substituents of organic compounds. Illustrative Substituents or to perform a method in order to reduce, prevent, inhibit, include, for example, those described below. The permissible break-down, or eliminate a particular characteristic or event substituents can be one or more and the same or different for US 2012/0046244 A1 Feb. 23, 2012 appropriate organic compounds. For purposes of this disclo 0048. The term “alkoxy” as used herein is an alkyl group Sure, the heteroatoms, such as nitrogen, can have hydrogen bound through a single, terminal ether linkage; that is, an Substituents and/or any permissible Substituents of organic “alkoxy” group can be defined as —OD' where D'' is alkyl as compounds described herein which satisfy the valencies of defined above. the heteroatoms. This disclosure is not intended to be limited 0049. The term “alkenyl as used herein is a hydrocarbon in any manner by the permissible Substituents of organic group of from 2 to 24 carbon atoms with a structural formula compounds. Also, the terms “substitution' or “substituted containing at least one carbon-carbon double bond. Asym with include the implicit proviso that such substitution is in metric structures such as (D'D)C=C(DD) are intended to accordance with permitted valence of the substituted atom include both the E and Z isomers. This may be presumed in and the substituent, and that the substitution results in a stable structural formulae herein wherein an asymmetric alkene is compound, e.g., a compound that does not spontaneously present, or it may be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more undergo transformation Such as by rearrangement, cycliza groups including, but not limited to, alkyl, halogenated alkyl, tion, elimination, etc. alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, 0043 “D',” “D’.” “D and “D are used herein as carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, generic symbols to represent various specific Substituents. silyl, Sulfo-oxo, Sulfonyl, Sulfone, Sulfoxide, or thiol, as These symbols can be any substituent, not limited to those described below. disclosed herein, and when they are defined to be certain 0050. The term “alkynyl as used herein is a hydrocarbon Substituents in one instance, they can, in another instance, be group of 2 to 24 carbon atoms with a structural formula defined as some other Substituents. containing at least one carbon-carbon triple bond. The alky 0044) The term “aliphatic' as used herein refers to a non nyl group can be substituted with one or more groups includ aromatic hydrocarbon group and includes branched and ing, but not limited to, alkyl, halogenated alkyl, alkoxy, alk unbranched, alkyl, alkenyl, or alkynyl groups. enyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, Sulfo 0045. The term “alkyl as used herein is a branched or oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below. unbranched saturated hydrocarbon group of 1 to 24 carbon 0051. The term “aryl as used herein is a group that con atoms, such as methyl, ethyl, n-propyl, isopropyl. n-butyl, tains any carbon-based aromatic group including, but not isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl. limited to, benzene, naphthalene, phenyl, biphenyl, phenoxy dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the benzene, and the like. The term “aryl also includes "het like. The alkyl group can also be substituted or unsubstituted. eroaryl, which is defined as a group that contains an aromatic The alkyl group can be substituted with one or more groups group that has at least one heteroatom incorporated within the including, but not limited to, alkyl, halogenated alkyl, alkoxy, ring of the aromatic group. Examples of heteroatoms include, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxy but are not limited to, nitrogen, oxygen, Sulfur, and phospho lic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, rus. Likewise, the term “non-heteroaryl, which is also sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described included in the term “aryl. defines a group that contains an below. aromatic group that does not contain a heteroatom. The aryl 0046 Throughout the specification “alkyl is generally group can be substituted or unsubstituted. The aryl group can used to refer to both unsubstituted alkyl groups and substi be substituted with one or more groups including, but not tuted alkyl groups; however, Substituted alkyl groups are also limited to, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, specifically referred to herein by identifying the specific sub aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, stituent(s) on the alkyl group. For example, the term "halo ether, halide, hydroxy, ketone, nitro, silyl, Sulfo-oxo, Sulfo genated alkyl specifically refers to an alkyl group that is nyl, sulfone, sulfoxide, or thiol as described herein. The term Substituted with one or more halide, e.g., fluorine, chlorine, “biaryl is a specific type of aryl group and is included in the bromine, or iodine. The term “alkoxyalkyl specifically refers definition of aryl. Biaryl refers to two aryl groups that are to an alkyl group that is substituted with one or more alkoxy bound together via a fused ring structure, as in naphthalene, or groups, as described below. The term “alkylamino” specifi are attached via one or more carbon-carbon bonds, as in cally refers to an alkyl group that is substituted with one or biphenyl. more amino groups, as described below, and the like. When 0.052 The term “cycloalkyl as used herein is a non-aro “alkyl is used in one instance and a specific term Such as matic carbon-based ring composed of at least three carbon “alkylalcohol is used in another, it is not meant to imply that atoms. Examples of cycloalkyl groups include, but are not the term “alkyl does not also refer to specific terms such as limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, “alkylalcohol and the like. etc. The term "heterocycloalkyl is a cycloalkyl group as 0047. This practice is also used for other groups described defined above where at least one of the carbon atoms of the herein. That is, while a term such as “cycloalkyl refers to ring is substituted with a heteroatom such as, but not limited both unsubstituted and substituted cycloalkyl moieties, the to, nitrogen, oxygen, Sulfur, or phosphorus. The cycloalkyl substituted moieties can, in addition, be specifically identified group and heterocycloalkyl group can be substituted or herein; for example, a particular Substituted cycloalkyl can be unsubstituted. The cycloalkyl group and heterocycloalkyl referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substi group can be substituted with one or more groups including, tuted alkoxy can be specifically referred to as, e.g., a "halo but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, het genated alkoxy, a particular Substituted alkenyl can be, e.g., eroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, an “alkenylalcohol and the like. Again, the practice of using hydroxy, ketone, nitro, silyl, Sulfo-oxo, Sulfonyl, Sulfone, a general term, such as “cycloalkyl and a specific term, Such sulfoxide, or thiol as described herein. as “alkylcycloalkyl is not meant to imply that the general 0053. The term "cycloalkenyl as used herein is a non term does not also include the specific term. aromatic carbon-based ring composed of at least three carbon US 2012/0046244 A1 Feb. 23, 2012

atoms and containing at least one double bound, i.e., C=C. nated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, Examples of cycloalkenyl groups include, but are not limited cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopenta described above. Throughout this specification “S(O) is a dienyl, cyclohexenyl, cyclohexadienyl, and the like. The term short hand notation for S=O. "heterocycloalkenyl is a type of cycloalkenyl group as 0066. The term “sulfonyl' is used herein to refer to the defined above, and is included within the meaning of the term sulfo-oxo group represented by the formula S(O),D', “cycloalkenyl, where at least one of the carbon atoms of the where D' can be hydrogen, an alkyl, halogenated alkyl, alk ring is substituted with a heteroatom Such as, but not limited enyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, het to, nitrogen, oxygen, Sulfur, or phosphorus. The cycloalkenyl erocycloalkyl, or heterocycloalkenyl group described above. group and heterocycloalkenyl group can be substituted or 0067. The term “sulfonylamino” or “sulfonamide' as used unsubstituted. The cycloalkenyl group and heterocycloalk herein is represented by the formula—S(O)NH-. enyl group can be substituted with one or more groups includ 0068. The term "sulfone' as used herein is represented by ing, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, the formula D'S(O),D', where D'' and D can be, indepen heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, dently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, halide, hydroxy, ketone, nitro, silyl, Sulfo-oxo, Sulfonyl, Sul heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or fone, sulfoxide, or thiol as described herein. heterocycloalkenyl group described above. 0054 The term “cyclic group' is used herein to refer to 0069. The term “sulfoxide’ as used herein is represented either aryl groups, non-aryl groups (i.e., cycloalkyl, hetero by the formula D'S(O)D, where D'' and D can be, indepen cycloalkyl, cycloalkenyl, and heterocycloalkenyl groups), or dently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, both. Cyclic groups have one or more ring systems that can be heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or Substituted or unsubstituted. A cyclic group can contain one heterocycloalkenyl group described above. or more aryl groups, one or more non-aryl groups, or one or (0070. The term “thiol” as used herein is represented by the more aryl groups and one or more non-aryl groups. formula—SH. 0055. The term “aldehyde' as used herein is represented (0071. “R',” “R” “R” “R”,” etc., where n is some integer, by the formula —C(O)H. Throughout this specification as used hereincan, independently, possess one or more of the “C(O) is a short hand notation for C=O. groups listed above. For example, if R is a straight chain 0056. The terms “amine' or “amino” as used herein are alkyl group, one of the hydrogenatoms of the alkyl group can represented by the formula NDDD, where D', D, and D optionally be substituted with a hydroxyl group, an alkoxy can be, independently, hydrogen, an alkyl, halogenated alkyl, group, an amine group, an alkyl group, a halide, and the like. alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, Depending upon the groups that are selected, a first group can heterocycloalkyl, or heterocycloalkenyl group described be incorporated within second group or, alternatively, the first above. group can be pendant (i.e., attached) to the second group. For 0057 The term “carboxylic acid as used herein is repre example, with the phrase “an alkyl group comprising an sented by the formula —C(O)OH. A “carboxylate” as used amino group, the amino group can be incorporated within herein is represented by the formula—C(O)O. the backbone of the alkyl group. Alternatively, the amino 0058. The term “ester” as used herein is represented by the group can be attached to the backbone of the alkyl group. The formula –OC(O)ID" or - C(O)CD', where D' can be an nature of the group(s) that is (are) selected will determine if alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, the first group is embedded or attached to the second group. cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy 0072 The term “bioactive property” is any local or sys cloalkenyl group described above. temic biological, physiological, or therapeutic effect in a 0059. The term “ether” as used herein is represented by the biological system. For example, the bioactive property can be formula D'OD, where D'' and D can be, independently, an the control of infection or inflammation, enhancement or alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, Suppression of growth, action as an analgesic, anti-viral, pes cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocy ticidal, herbicidal, or nutrientional action, etc. Many cloalkenyl group described above. examples of bioactive properties are disclosed herein. 0060. The term “ketone' as used herein is represented by 0073. Unless stated to the contrary, a formula with chemi the formula D'C(O)ID, where D'' and D' can be, indepen cal bonds shown only as solid lines and not as wedges or dently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, dashed lines contemplates each possible isomer, e.g., each heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or enantiomer, diastereomer, and meso compound, and a mix heterocycloalkenyl group described above. ture of isomers, such as a racemic or scalemic mixture. 0061. The term “halide' as used herein refers to the halo 0074 Reference will now be made in detail to specific gens fluorine, chlorine, bromine, and iodine. aspects of the disclosed materials, compounds, compositions, 0062. The term “hydroxyl as used herein is represented articles, and methods, examples of which are illustrated in the by the formula —OH. accompanying Examples. 0063. The term "nitro” as used herein is represented by the formula - NO. Materials and Compositions 0064. The term “silyl as used herein is represented by the 0075 Certain materials, compounds, compositions, and formula—SiDDD, where D', D, and D can be, indepen components disclosed herein can be obtained commercially dently, hydrogen, alkyl, halogenated alkyl, alkoxy, alkenyl, or readily synthesized using techniques generally known to alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocy those of skill in the art. For example, the starting materials and cloalkyl, or heterocycloalkenyl group described above. reagents used in preparing the disclosed compounds and 0065. The term "sulfo-oxo' as used herein is represented compositions are either available from commercial Suppliers by the formulas - S(O)D', S(O),D', OS(O),D', or such as Aldrich Chemical Co., (Milwaukee, Wis.). Acros —OS(O).OD', where D' can be hydrogen, an alkyl, haloge Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, US 2012/0046244 A1 Feb. 23, 2012

Pa.), Sigma (St. Louis, Mo.), or are prepared by methods extractions, catalysis, separations, and electrochemistry. known to those skilled in the art following procedures set Ionic liquids have also become popular alternative media for forth in references such as Fieser and Fieser’s Reagents for chemical synthesis because of their low volatility and low Organic Synthesis, Volumes 1-17 (John Wiley and Sons, toxicity. See e.g., Wasserscheid and Keim, Angew Chen Int 1991); Rodd's Chemistry of Carbon Compounds, Volumes Ed Engl, 2000, 39:3772; and Wasserscheid, “Ionic Liquids in 1-5 and Supplementals (Elsevier Science Publishers, 1989); Synthesis,” 1 Ed., Wiley-VCH, 2002. Further, ionic liquids Organic Reactions, Volumes 1-40 (John Wiley and Sons, can reduce costs, disposal requirements, and hazards associ 1991); March's Advanced Organic Chemistry, (John Wiley ated with Volatile organic compounds. Other exemplary prop and Sons, 4th Edition); and Larock's Comprehensive Organic erties of ionic liquids are high ionic conductivity, non-vola Transformations (VCH Publishers Inc., 1989). Other materi tility, non-flammability, high thermal stability, wide als. Such as the active pharmaceutical ingredients, pesticides, temperature for liquid phase, highly Solvability, and non herbicides, and other biological agents disclosed herein can coordinating. For a review of ionic liquids see, for example, be obtained from commercial sources. Welton, Chem. Rev. 1999, 99:2071-2083; and Carlin et al., 0076. In one aspect, disclosed herein are ionic liquid com Advances in Nonacqueous Chemistry, Mamantov et al. Eds. positions. The term "ionic liquid' has many definitions in the VCH Publishing, New York, 1994. art, but is used herein to refer to salts (i.e., compositions 0081. The specific physical properties (e.g., melting point, comprising cations and anions) that are liquid at a tempera Viscosity, density, water Solubility, etc.) of ionic liquids are ture of at or below about 150° C. That is, at one or more determined by the choice of cation and anion, as is disclosed temperature ranges or points at or below about 150° C. the more fully herein. As an example, the melting point for an disclosed ionic liquid compositions are liquid; although, it is ionic liquid can be changed by making structural modifica understood that they can be solids at other temperature ranges tions to the ions or by combining differentions. Similarly, the or points. Since the disclosed ionic liquid compositions are particular chemical properties (e.g., bioactivity, toxicity, liquid, and thus not crystalline Solids, at a given temperature, pharmacokinetics, etc.), can be selected by changing the con the disclosed compositions do not suffer from the problems of stituentions of the ionic liquid. polymorphism associated with crystalline solids. I0082. The ionic liquid compositions disclosed herein are 0077. The use of the term “liquid” to describe the dis comprised of at least one kind of anion and at least one kind closed ionic liquid compositions is meant to describe a gen of cation. The at least one kind of cation, the at least one kind erally amorphous, non-crystalline, or semi-crystalline state. of anion, or both can be a pharmaceutical active, a pesticidal For example, while some structured association and packing active, a herbicidal active, a food additive, a nutraceutical, or of cations and anions can occur at the atomic level, the dis the like, including any combination thereof, as is disclosed closed ionic liquid compositions have minor amounts of Such herein. It is contemplated that the disclosed ionic liquid com ordered structures and are therefore not crystalline solids. The positions can comprise one kind of cation with more than one compositions disclosed herein can be fluid and free-flowing kind of anion (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different liquids or amorphous Solids such as glasses or waxes at a kinds of anions). Likewise, it is contemplated that the dis temperature at or below about 150°C. In particular examples closed ionic liquid compositions can comprise one kind of disclosed herein, the disclosed ionic liquid compositions are anion with more than one kind of cation (e.g., 2, 3, 4, 5, 6, 7, liquid at the body temperature of a subject. 8, 9, 10, or more different kinds of cations). Further, the 0078. Further, the disclosed ionic liquid compositions are disclosed ionic liquids can comprise more than one kind of materials composed of at least two different ions; each of anion (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different kinds of which can independently and simultaneously introduce a spe anions) with more than one kind of cation (e.g., 2, 3, 4, 5, 6, cific characteristic to the composition not easily obtainable 7, 8, 9, 10 or more different kinds of cations). Specific with traditional dissolution and formulation techniques. examples include, but are not limited to, one kind of cation Thus, by providing different ions and ion combinations, one with 1,2,3,4,5,6,7,8,9, 10, or more kinds of anions, 2 kinds can change the characteristics or properties of the disclosed of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of ionic liquid compositions in a way not seen by simply pre anions, 3 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or paring various crystalline salt forms. Examples of character more kinds of anions, 4 kinds of cations with 1, 2, 3, 4, 5, 6, istics that can be controlled in the disclosed compositions 7, 8, 9, 10, or more kinds of anions, 5 kinds of cations with 1, include, but are not limited to, melting, solubility control, and 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of anions, 6 kinds of rate of dissolution. It is this multi-nature/functionality of the cations with 1,2,3,4,5,6,7,8,9, 10, or more kinds of anions, disclosed ionic liquid compositions which allows one to fine 7 kinds of cations with 1,2,3,4,5,6,7,8,9, 10, or more kinds tune or design in very specific desired material properties. ofanions, 8 kinds of cations with 1, 2,3,4,5,6,7,8,9, 10, or 0079. It is further understood that the disclosed ionic liq more kinds of anions, 9 kinds of cations with 1, 2, 3, 4, 5, 6, uid compositions can include solvent molecules (e.g., water); 7, 8, 9, 10, or more kinds of anions, 10 kinds of cations with however, these solvent molecules should not be present in 1,2,3,4,5,6,7,8,9, 10, or more kinds of anions, or more than excess in the sense that the disclosed ionic liquid composi 10 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more tions are dissolved in the solvent, forming a solution. That is, kinds of anions. the disclosed ionic liquid compositions contain no or minimal I0083. Other specific examples include, but are not limited amounts of solvent molecules that are free and not bound or to, one kind of anion with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more associated with the ions present in the ionic liquid composi kinds of cations, 2 kinds of anions with 1, 2, 3, 4, 5, 6, 7, 8, 9, tion. Thus, the disclosed ionic liquid compositions can be 10, or more kinds of cations, 3 kinds of anions with 1, 2, 3, 4, liquid hydrates or Solvates, but not solutions. 5, 6, 7, 8, 9, 10, or more kinds of cations, 4 kinds of anions 0080) Ionic liquids have been of general interest because with 1,2,3,4,5,6,7,8,9, 10, or more kinds of cations, 5 kinds they are environmentally-friendly alternatives to organic Sol of anions with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of vents for various chemical processes, e.g., liquid/liquid cations, 6 kinds of anions with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or US 2012/0046244 A1 Feb. 23, 2012

more kinds of cations, 7 kinds of anions with 1, 2, 3, 4, 5, 6, peutic or nutritional purposes in a Subject. In this case, the 7, 8, 9, 10, or more kinds of cations, 8 kinds of anions with 1, disclosed ionic liquid compositions can be liquid at the Sub 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of cations, 9 kinds of ject's body temperature (e.g., about 37° C. for a human). anions with 1,2,3,4,5,6,7,8,9, 10, or more kinds of cations, Other examples include compositions that can be used as herbicides or pesticides, which are liquid at the temperature 10 kinds of anions with 1,2,3,4,5,6,7,8,9, 10, or more kinds of their use (e.g., ambient temperature). In still other of cations, or more than 10 kinds of anions with 1, 2, 3, 4, 5, examples, the disclosed compositions can be liquid at the 6, 7, 8, 9, 10, or more kinds of cations. temperature at which they are formulated or processed. 0084. In addition to the cations and anions, the ionic liquid 0088. It is understood, however, that the disclosed ionic compositions disclosed herein can also contain nonionic spe liquid compositions can, though need not, be solubilized, and cies, such as solvents, preservatives, dyes, colorants, thick Solutions of the disclosed ionic liquids are contemplated eners, Surfactants, viscosity modifiers, mixtures and combi herein. Further, the disclosed ionic liquid compositions can nations thereof and the like. However, the amount of such beformulated in an extended or controlled release vehicle, for nonionic species is typically low (e.g., less than about 10,9,8, example, by encapsulating the ionic liquids in microspheres 7, 6, 5, 4, 3, 2, or 1 wt.% based on the total weight of the or microcapsules using methods known in the art. Still fur composition). In some examples described herein, the dis ther, the disclosed ionic liquid compositions can themselves closed ionic liquid compositions are neat; that is, the only be solvents for other solutes. For example, the disclosed ionic materials present in the disclosed ionic liquids are the cations liquids can be used to dissolve a particular nonionic or ionic and anions that make up the ionic liquid compositions. It is pharmaceutical active. These and other formulations of the understood, however, that with neat compositions, some disclosed ionic liquids are disclosed elsewhere herein. additional materials or impurities can sometimes be present, I0089. In some examples, the disclosed ionic liquids are not albeit at low to trace amounts (e.g., less than about 10,9,8,7, solutions where ions are dissolved in a solute. In other 6, 5, 4, 3, 2, or 1 wt.% based on the total weight of the examples, the disclosed ionic liquid compositions do not composition). contain ionic exchange resins. In still other examples, the 0085. The disclosed ionic liquid compositions are liquidat disclosed ionic liquids are substantially free of water. By some temperature range or point at or below about 150° C. Substantially free is meant that water is present at less than For example, the disclosed ionic liquids can be a liquid at or about 10,9,8,7,6, 5, 4, 3, 2, 1, 0.5, 0.25, or 0.1 wt.%, based below about 150, 149,148,147,146,145,144, 143, 142,141, on the total weight of the composition. 140, 139, 138, 137, 136, 135, 134, 133, 132, 131, 130, 129, 0090 The disclosed ionic liquid compositions can be pre 128, 127, 126, 125, 124, 123, 122, 121, 120, 119, 118, 117, pared by methods described herein. Generally, the particular 116, 115, 114, 113, 112, 111, 110, 109, 108, 107, 106, 105, cation(s) and anion(s) used to prepare the disclosed ionic 104,103,102, 101,100,99,98, 97,96, 95, 94, 93, 92,91,90, liquids are selected as described herein. Then, with the par 89, 88,87, 86, 85, 84, 83,82, 81,80, 79,78, 77,76, 75, 74,73, ticular cation(s) and anion(s) in hand, they can be combined, 72, 71, 70, 69,68, 67, 66, 65, 64, 63, 62,61, 60, 59,58, 57,56, resulting in ionic liquid compositions as disclosed herein. 55, 54,53, 52, 51, 50,49, 48,47, 46, 45, 44, 43,42, 41, 40, 39, Additionally, the method for the preparation of the disclosed 38, 37, 36,35, 34,33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, ionic liquid compositions can include the reaction in which 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10,9,8,7,6, 5, 4, 3, two neutral species: an anion precursor (e.g., in the form of an 2, 1, 0, -1, -2, -3, -4, -5,-6, -7, -8, -9, -10, -11, -12, -13, inorganic acid, carboxylic organic acid, non-carboxylic acid, -14, -15, -16, -17, -18, -19, -20, -21, -22, -23, -24, -25, or Zwitterion species) and a cation precursor (e.g., inorganic -26, -27, -28, 29, or -30°C., where any of the stated values base, organic base, Zwitterion species) are combined result can form an upper or lower endpoint when appropriate. In ing in ionic liquid compositions as disclosed herein. further examples, the disclosed ionic liquids can be liquid at 0091 Providing ions used to prepare the disclosed ionic any point from about -30°C. to about 150° C., from about liquids depends, in one aspect, on the desired properties of the -20°C. to about 140°C., -10°C. to about 130°C., from about resulting ionic liquid composition. As described herein, the 0° C. to about 120° C., from about 10° C. to about 110° C., disclosed ionic liquid compositions can have multiple desired from about 20°C. to about 100° C., from about 30°C. to about properties, which, at least in part, come from the properties of 90°C., from about 40°C. to about 80°C., from about 50° C. the cation(s) and/or anion(s) used to prepare the ionic liquid. to about 70° C., from about -30° C. to about 50° C., from Thus, to prepare the disclosed ionic liquids, one or more kinds about -30° C. to about 90° C., from about -30° C. to about of cations with a desired property(ies) are provided. One or 110° C., from about -30° C. to about 130° C., from about more kinds of anions with a desired property(ies) that is -30°C. to about 150° C., from about 30° C. to about 90° C., similar or different to that of the cation(s) can likewise be from about 30°C. to about 110°C., from about 30°C. to about provided. Of course, providing a desired anion(s) and cation 130°C., from about 30° C. to about 150° C., from about 0°C. (s) can be done in any order, depending on the preference and to about 100°C., from about 0°C. to about 70° C., from about aims of the practitioner. For example, a particular cation(s) 0° to about 50° C., and the like. can be provided and then a particular anion(s) can be pro I0086. Further, in some examples the disclosed ionic liquid vided. Alternatively, a particular anion(s) can be provided and compositions can be liquid over a wide range oftemperatures, then a particular cation(s) can be provided. Further, the cation not just a narrow range of say, 1-2 degrees. For example, the (s) and anion(s) can be provided simultaneously. disclosed ionic liquid compositions can be liquids over a 0092. As noted, providing a suitable ion can be based on range of at least about 4, 5, 6, 7, 8, 9, 10, or more degrees. In selecting an ion that possesses a property that is desired (e.g., other example, the disclosed ionic liquid compositions can be the ion has a property that is desired to be possessed by the liquid over at least about a 11, 12, 13, 14, 15, 16, 17, 18, 19. resulting ionic liquid). Examples of properties that could be 20, or more degree temperature range. Such temperature desired in a suitable cation and/or anion (and thus the ionic ranges can begin and/or end at any of the temperature points liquid made therefrom) include, but are not limited to, bio disclosed in the preceding paragraph. logical, therapeutic, prophylactic, nutritional, pesticidal, and/ 0087. In many examples disclosed herein the disclosed or herbicidal activity. Inertness, taste, viscosity modulation, ionic liquid compositions are liquid at the temperature at solubility modulation, stability, and toxicity are other prop which they will be used or processed. For example, many of erties of a given ion that could be desired and considered. the disclosed ionic liquid compositions can be used for thera While more specific properties are disclosed elsewhere US 2012/0046244 A1 Feb. 23, 2012

herein, the disclosed methods and compositions are not lim example, ions that have pesticidal properties can be combined ited to any particular combination of properties, as Such will with oppositely charged ions having pesticidal, herbicidal, depend on the preferences and goals of the practitioner. antimicrobial properties, and the like. In other examples, ions 0093. Typically, the desired properties of the cation(s) and with antibacterial properties can be combined with oppositely anion(s) will be different or complimentary to one another. In charges ions that have preservative properties, taste modifi this way, the resulting ionic liquid can possess multiple ers, etc. In still other examples, anion with one therapeutic or desired properties: those properties imparted by the cation(s) prophylactic property can be combined with another thera and those imparted by the anion(s). In other words, some or peutic or prophylactic ion. As should be appreciated, the all of the ions present in the disclosed ionic liquids can inde various combinations of ions according to the disclosed meth pendently and simultaneously introduce a specific function ods are numerous, and depend only on the desired combina ality or property to the disclosed ionic liquid compositions. It tion of properties and whether the resulting ion combination is this multiple functionality characteristic that can allow one is an ionic liquid as defined herein. to fine-tune or design very specific physical, chemical, and 0097 Specific examples of properties that can be exhib bioactive properties in the disclosed ionic liquid composi ited by the disclosed compositions include antibacterial, FDA tions. Additional functionality can be obtained by using the approved dyes, anti-acne, antibiotic, UV blocker, wetting disclosed ionic liquid compositions as solvents to dissolve a agents, preservative, emollient, anti-inflammatory, and Vita Solute(s) with another desired property, thus resulting in a 1. solution where the ions of the ionic liquid as well as the solute contribute desired properties to the composition. General and Ionic Liquid Immobilized Fragrances specific examples of various combinations of ions and their 0.098 Fragrance and flavor formulations suffer from lim associated properties are disclosed herein. ited lifetime because their constituents evaporate, are degrad 0094. In some particular examples, one or more ions in the ing or lost during storage. Perfumes in consumer products disclosed ionic liquid composition (e.g., the anions, cations, tend to fade by evaporation, oxidation, chemical degradation or both) can be a pharmaceutical active, e.g., an existing drug or interaction with other ingredients. The flavor industry has that is ionic or that can be made ionic. Many drugs exist addresses the issue of performance loss of flavors by devel naturally or at physiological conditions as an ion, or they can oping specific delivery systems. At the present time, Sustained be converted to ions via simple chemical transformations release techniques for flavor and fragrance delivery present in (e.g., alkylation, protonation, deprotonation, etc.). As such, literature are usually based on encapsulation either in hydro these drugs can be used to prepare anionic liquid composition philic matrices, via spray drying, granulation and spray-coat as disclosed herein. Such drugs can possess any therapeutic or ing, encapsulation by coacervation and interfacial polymer prophylactic activity, many of which are described herein. ization and the use of colloidal carriers for the application in Combining Such drugs with other ions to prepare an ionic aqueous products (Quellet et al. Chimia 2001, 55:421-428). liquid, as is disclosed herein, can result in the modification 0099. The use of ionic liquid in fragrance and flavor indus and/or enhancement of the drug's properties. For example, a try is mainly dealing with solvent applications for the synthe first drug ion with a given property can be combined with an sis of fragrance and flavor materials in ionic liquids or with oppositely charged second ion with another property to effect the extraction of naturals (Sullivan, N. Innovations in Phar the controlled release, controlled delivery, biological impact, maceutical Technology 2006, 20:75-77). taste, physical properties (stability, Solubility, toxicity, melt 0100 For example, Forsyth et al. investigated the utiliza ing point, etc.), or to overcome polymorphism in the first drug tion of ionic liquid solvents for the synthesis of lily-of-the ion. In this way, new drug compositions can be created by Valley fragrance and fragrance intermediate Lilial (Forsyth et forming ionic liquids with functionality crafted into the com al., J. Mol. Cat. A. 2005, 231:61-66). The role of ionic liquids bination of the ions, as disclosed herein. in consumer products and fragrances is comparingly less 0095. As another example, the first drug ion may be com explored (Davey, Perf Flav. 2008, 33:34-35; Liu, Flav. Frag. bined with a second drug ion that has properties complimen Cosm. (Xiangliao Xiangjing Huazhuangpin) 2004, 29:30 tary to the first. Examples of this can include, but are not limited to, an ion having anesthetic properties being com 36). Creavis noted that the rate of evaporation of a perfume bined with an ion having antibacterial properties, an ion hav could be slowed using an ionic liquid as fixative (Petrat et al. ing anesthetic properties being combined with an ion having US 2006/0166856; Creavis AG DE 10337579 A1). Examples coagulation properties, or an ion having coagulation proper include a chypre accord, a musk base and a rose composition ties being combined with an ion having antibacterial proper with increased fiber Substantivity compared to the same com ties. Ionic liquids resulting from Such combinations could position without the ionic liquid. The modification of textile find uses in wound repair, for example. Still other examples of Surfaces, optionally adding a benefit agent which includes a desirable combination include ions having therapeutic or pro perfume followed by removal of the ionic liquid was phylactic efficacy being combined with ions having taste described by Procter and Gamble. (US 20060090271, US enhancement properties (i.e., taste modifiers). Ionic liquids 20060090777, EP 1807497). Benefit agent delivery systems resulting from this combination can be useful in enhancing comprising ionic liquids and their uses in detergent compo the taste and palatability of medicines. Still further examples sitions have also been reported. (Price et al. US2006094617) can include two differently charged ions each with similar 0101 Delivery devices or storage media for fragrances uses but with different mechanisms of action. Specific and flavors based on ionic liquids that include a covalent examples of such combinations can include, but are not lim attachment of the active compound and immobilization as a ited to, combinations of ions with antineoplastic properties or salt and there application for storage as well as for prolonged antiviral properties. Ionic liquids prepared from Such ion and controlled triggered release not mentioned in any form in combinations can be useful as drug “cocktails, where two or prior literature. more bioactive agents are present in a single ionic liquid Ions combination. 0096. According to the methods and compositions dis 0102 The disclosed ionic liquids contain at least one kind closed herein, ion identification and combination, as dis of cation and at least one kind of anion. Examples of Suitable closed herein, can involve any ion, not just ionic drugs, as cations and anions are disclosed herein. It should be under long as the combination results in an ionic liquid. For stood that when a particular compound is disclosed as being US 2012/0046244 A1 Feb. 23, 2012

a cation, for example, it can also, in other circumstances, be Nat AcadSci USA, 1915, 1:226: Jacobs and Heidelberger, J an anion and Vice versa. Many compounds are known to exist Biol Chem, 1915, 20:659; Jacobs and Heidelberger, J Exptl as cations in some environments and anions in other environ Med, 1916, 23:569). ments. Further, many compounds are known to be convertible 0106 Browning et al. found great and somewhat less to cations and anions through various chemical transforma selective bactericidal powers among quaternary derivatives tions. Examples of Such compounds are disclosed herein. of pyridine, quinoline, and phenazine (Browning et al., Proc 0103 The materials, compounds, compositions, and com Roy Soc London, 1922, 93B:329; Browning et al., Proc Roy ponents that can be used for, can be used in conjunction with, Soc London, 1926, 100B:293). Hartman and Kagi observed can be used in preparation for, or are products of the disclosed antibacterial activity in QACs of acylated alkylene diamines methods and compositions are disclosed herein. It is under (Hartman and Kagi, ZAngew Chem, 1928, 4:127). stood that when combinations, Subsets, interactions, groups, 0107. In 1935, Domagk synthesized long-chain QACs, etc. of these materials are disclosed that while specific refer including benzalkonium chloride, and characterized their ence of each various individual and collective combinations antibacterial activities (Domagk, Deut Med Wochenschr, and permutation of these compounds may not be explicitly 1935, 61:829). He showed that these salts are effective against disclosed, each is specifically contemplated and described a wide variety of bacterial strains. This study of the use of herein. For example, if an ionic liquid composition is dis QACs as germicides was greatly stimulated. closed and a number of modifications that can be made to a 0108. Many scientists have focused their attention on number of components of the ionic liquid composition are water soluble QACs because they exhibit a range of proper discussed, each and every combination and permutation that ties: they are Surfactants, they destroy bacteria and fungi, they are possible are specifically contemplated unless specifically serve as a catalyst in phase-transfer catalysis, and they show indicated to the contrary. Thus, if a class of cations A, B, and Care disclosed as well as a class of anions D, E, and F and an anti-electrostatic and anticorrosive properties. They exert example of a ionic liquid A-D is disclosed, then even if each antibacterial action against both Gram-positive and Gram is not individually recited, each is individually and collec negative bacterial as well as against Some pathogen species of tively contemplated. Thus, in this example, each of the ionic fungi and protozoa. These multifunctional salts have also liquids A-E, A-F B-D, B-E, B-F, C-D, C-E, and C-F are been used in wood preservation, their application promoted in specifically contemplated and should be considered disclosed the papers of Oertel and Butcher et al. (Oertel, Holztechnolo from disclosure of A, B, and C: D, E, and F; and the example gie, 1965, 6:243; Butcher et al., For Prod J, 1977, 27:19; ionic liquid A-D. Likewise, any Subset or combination of Butcher et al., J. For Sci, 1978, 8:403). these is also specifically contemplated and disclosed. Thus, 0109 QACs are also widely used as skin antiseptics, dis for example, the sub-group of A-E, B-F, and C-E are specifi infectants, fabric softeners, antistatic agents, cleaning agents, cally contemplated and should be considered disclosed from and preservatives. Detergent properties and antimicrobial disclosure of A, B, and C, D, E, and F; and the example combination A-D. This concept applies to all aspects of this activities of QACs have made them useful for general envi disclosure including, but not limited to, steps in methods of ronmental sanitations, for examples, in hospitals and food making and using the disclosed compositions. Thus, if there production facilities. In pharmacological preparations they are a variety of additional steps that can be performed it is are used Such as mouth rinses, lozenges, sprays and gels. understood that each of these additional steps can be per 0110. In humans and animals QACs have been considered formed with any specific aspect or combination of aspects of too toxic for systematic applications, but are accepted to be the disclosed methods, and that each Such combination is safe for topical applications. Furthermore, QACs have specifically contemplated and should be considered dis recently been used as penetration enhancers for transnasal closed. and transbuccal drug delivery, as well as in nasal vaccination (Klinguer et al., Vaccine, 2001, 19:4236). This ability to pen Cations etrate and open cell membrane has been widely used in drug delivery via liposomes (mainly QACs with two long alkyl 0104 Particular examples of cationic compounds that can be present in the disclosed ionic liquid compositions are chains) and non-viral gene delivery (Liu and Huang, J. Contr compounds that contain nitrogen atoms. Nitrogen atoms can Rel, 2002, 78:259). Many examples of compounds having exist or can be converted to positively-charged quaternary nitrogenatoms, which exist as quaternary ammonium species ammonium species, for example, through alkylation or pro or can be converted into quaternary ammonium species, are tonation of the nitrogen atom. Thus compounds that possess disclosed herein. a quaternary nitrogenatom (known as quaternary ammonium 0111. In some examples, when the cation is a quaternary compounds (QACs)) are typically cations. According to the ammonium compound, the anion is not an inorganic anion, methods and compositions disclosed herein, any compound examples of which are disclosed herein. In other examples, that contains a quaternary nitrogen atom or a nitrogen atom where the cation is a quaternary ammonium compound, the that can be converted into a quaternary nitrogen atom can be anion is not a halide. a suitable cation for the disclosed ionic liquid compositions. 0112 Aliphatic Heteroaryls 0105 QACs can have numerous biological properties that one may desire to be present in the disclosed ionic liquid 0113 Some specific QACs suitable for use herein are ali compositions. For example, many QACs are known to have phatic heteroaryls. An aliphatic heteroaryl cation is a com antibacterial properties. The antibacterial piperties of QACs pound that comprises an aliphatic moiety bonded to a het were first observed toward the end of the 19' century among eroaryl moiety. In the aliphatic heteroaryl cation, the aliphatic the carbonium dyestuffs, such as auramin, methyl violet, and moiety can be any alkyl, alkenyl, alkynyl, cycloalkyl, or malachite green. These types of compounds are effective cycloalkenyl group, as described herein. Generally, the ali chiefly against the Gram-positive organisms. Jacobs and phatic moiety can comprise at least 10, at least 12, at least 14, Heidelberger first discovered QACs antibacterial effect in at least 16, at least 18, or at least 20 carbon atoms. In other 1915 studying the antibacterial activity of substituted hexam examples, the aliphatic moiety can comprise a mixture of ethylene-tetrammonium salts (Jacobs and Heidelberger, Proc aliphatic groups having a range of carbon atoms. For US 2012/0046244 A1 Feb. 23, 2012 example, the aliphatic moiety can comprise from 10 to 40, from 12 to 38, from 14 to 36, from 16 to 34, from 18 to 32, -continued from 14 to 18, or from 20 to 30 carbonatoms. In some specific R4 R3 R4 R3 examples, the aliphatic moiety can contain 10, 11, 12, 13, 14. R3 R2 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43,44, or 45 carbon O. na R11 N%O. \ N atoms, where any of the stated values can form an upper or NS lower endpoint when appropriate. Examples of specific ali R2 11N, R4 phatic moieties that can be used include, but are not limited to, 1,2,3-TRIAZOLIUM 1,2,4-TRIAZOLIUM decyl, dodecyl (lauryl), tetradecyl (myristyl), hexadecyl R4 R5 R3 R5 R4 (palmityl or cetyl), octadecyl (Stearyl), eicosyl (arachidyl), R3 R5 and linolenyl groups, including branched derivatives thereof and any mixtures thereof. In the aliphatic heteroaryl cations, (Go), the aliphatic moiety is bonded to a heteroatom in the het R11 R7 N R6 R6 N R 3 eroaryl moiety. / V M V R4 R1 R2 R1 R2 0114. In the aliphatic heteroaryl cation, the heteroaryl moiety can be any heteroaryl moiety as described herein. For THIAZOLIUM PIPERIDINIUM PYRROLIDINIUM example, the heteroaryl moiety can be an aryl group having R5 R4 R4 R3 one or more heteroatoms (e.g., nitrogen, oxygen, Sulfur, phos R R3 phorous, or halonium). Examples of specific heteroaryl moi eties that can be used in the aliphatic heteroaryl cations include, but are not limited to, pyrazole, pyridine, pyrazine, R7 R9 pyrimidine, pryidazine, indolizine, isoindole, indole, inda Zole, imidazole, oxazole, triazole, thiazole, purine, isoquino R8 R1 line, quinoline, phthalazine, quinooxaline, phenazine, and the QUINOLIUM ISOQUINOLIUM like, including substituted derivatives and mixtures thereof. In the aliphatic heteroaryl cations, a heteroatom in the het eroaryl moiety is bonded to the aliphatic moiety. When the wherein R' and Rare, independently, a C-C alkyl group or heteroatom of the heteroaryl is nitrogen, this forms a quater a C-C alkoxyalkyl group, and R. R. R. R. R. R. and nary ammonium cation, as described herein. R(R-R), when present, are independently H, a C-C alkyl, 0115 Further examples of aliphatic heteroaryl cations are a C-C alkoxyalkyl group, a C-C alkoxy group, or an ener those having the following structures: 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 R4 examples, both R" and R groups are C-C alkyl, with one R3 R5 being methyl, and R-R, when present, are H. Exemplary C-C alkyl groups and C-C alkyl groups include methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl, pentyl, R7 R6 iso-pentyl, hexyl, 2-ethylbutyl, 2-methylpentyl, and the like. Corresponding C-C alkoxy groups contain the above C-C, R1 alkyl group bonded to an oxygen atom that is also bonded to PYRIDINIUM PYRIDAZINIUM the cation ring. An alkoxyalkyl group contains an ether group R4 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 R3 R3 N R4 1,2,3-triazoles. In some examples, all R groups not required for cation formation can be H. GO DIOC 0116. The phrase “when present is often used herein in R6 2. R5 R6 R5 regard to Substituent R group because not all cations have all R1 RI of the numbered R groups. All of the contemplated cations PYRIMIDINIUM PYRAZINIUM contain at least four R groups, which can be H, although R R4 R5 R3 R4 R5 R3 need not be present in all cations. 0117. In one example, all R groups that are not required for cation formation; i.e., those other than R' and R for com pounds other than the imidazolium, pyrazolium, and triaZo R11 (G)\,Y NR, R21 Go)N. R5 R11 O. lium cations shown above, are H. R3 R1 R4 0118. A cation that contains a single five-membered ring that is free of fusion to other ring structures is suitable for use IMIDAZOLIUM PYRAZOLIUM OXAZOLIUM herein. Exemplary cations are illustrated below wherein R', R, and R-R, when present, are as defined before. US 2012/0046244 A1 Feb. 23, 2012

described herein. The benzylalkyl amine moiety can be a benzyl amine where the amine is bonded to an alkyl or cyclic alkyl group, as described herein. One or more types of ali phatic benzylalkyl ammonium cation can be used in the ionic liquid compositions disclosed herein. The aliphatic benzyla lkyl ammonium cation Suitable for use herein can be prepared by methods known in the art or can be obtained from com mercial Sources. I0123. In one aspect, the aliphatic benzylalkyl ammonium 1,2,4-TRIAZOLIUM cation can be represented by the following formula: R5 R3 R4 R5 R3 R4

R11 CS Go)\, Go) o R11 Y R11 Y YR2 R21 N R5 N-R12 V R4 R3 R1 R10 THIAZOLIUM IMIDAZOLIUM PYRAZOLIUM R5 R3 wherein R' is analiphatic group, as described above, R'' and R" are, independent of one another, alkyl groups or cyclic alkyl groups as described herein. In some examples, one or (Go), more of the “R” substituents can be a long chain alkyl group (e.g., the number of carbon atoms is 10 or greater). In other R11 Y examples, one or more of the “R” substituents can be a short R4 chain alkyl group (e.g., the number of carbon atoms is less OXAZOLIUM than 10). In still other examples, one of the “R” substituents is a long chain alkyl group and the other two “R” substituents are short chain alkyl groups. 0119. Of the cations that contain a single five-membered 0.124. In one aspect, the aliphatic benzylalkyl ammonium ring free of fusion to other ring structures, an imidazolium cation can have any of the aliphatic moieties disclosed herein cation that corresponds in structure to Formula A is also bonded to any benzylalkyl amine moieties disclosed herein. suitable, wherein R', R, and R-R, are as defined before. In some specific examples, R' in the formula of aliphatic benzylalkyl ammonium cation can be an aliphatic group of from 10 to 40 carbon atoms, e.g., a decyl, dodecyl (lauryl), (A) tetradecyl (myristyl), hexadecyl (palmitylor cetyl), octadecyl (stearyl), or eicosyl (arachidyl) group, and R'' and R' can each be, independent of one another, a methyl, ethyl, propyl. butyl, pentyl, or hexyl group. 0.125. In another aspect, the aliphatic benzylalkyl ammo nium cation can include, but are not limited to, alkyl dimethyl benzyl ammonium cations. Specific examples of alkyl dim ethylbenzyl ammonium cations include, but are not limited 0120 In a further example, an NN-1,3-di-(C-C alkyl)- to, cetyl dimethylbenzyl ammonium, lauryl dimethylbenzyl Substituted-imidazolium ion can be used; i.e., animidazolium ammonium, myristyl dimethyl benzyl ammonium, Stearyl cation wherein R-R of Formula A are each H, and RandR dimethylbenzyl ammonium, and arachidyl dimethylbenzyl are independently each a C-C alkyl group or a C-C, ammonium. alkoxyalkyl group. In yet another example, the cation illus I0126. In yet another aspect, the aliphatic benzylalkyl trated by a compound that corresponds in structure to For ammonium cation can include, but are not limited to, alkyl mula B, below, wherein R-R of Formula A are each hydro methylethylbenzyl ammonium cations. Specific examples of gen and R' is a C1-Co-alkyl group or a C-C alkoxyalkyl alkyl methylethylbenzyl ammonium cations include, but are group. not limited to, cetyl methylethyl benzyl ammonium, lauryl methylethylbenzyl ammonium, myristyl methylethylbenzyl ammonium, Stearyl methylethyl benzyl ammonium, and (B) arachidyl methylethylbenzyl ammonium. I0127 Dialiphatic Dialkyl Ammonium 11 N2 CH3 I0128. Still further examples of QACs that can be used in the disclosed ionic liquid compositions are dialiphatic dialkyl ammonium cations. A dialiphatic dialkyl ammonium cation 0121 Aliphatic Benzylalkyl Ammonium is a compound that comprises two aliphatic moieties and two 0122) The disclosed ionic liquid compositions can also alkyl moieties bonded to a nitrogen atom. The aliphatic moi comprise an aliphatic benzylalkyl ammonium cation. An ali eties can be the same or different and can be any aliphatic phatic benzylalkyl ammonium cation is a cation that com group as described above. The alkyl moieties can be the same prises an aliphatic moiety bonded to the nitrogen atom of a or different can be any alkyl group as described above. In the benzylalkyl amine moiety. The aliphatic moiety can be as disclosed dialiphatic dialkyl ammoniums cations, the two US 2012/0046244 A1 Feb. 23, 2012

aliphatic moieties can have 10 or more carbon atoms and the N,N' Dialkylimidazolium Salts' New J Chem 30:349, 2006, two alkyl moieties can have less than 10 carbon atoms. In which is incorporated by reference herein at least for its another alternative, the two aliphatic moieties can have less teachings of energetic ions. than 10 carbon atoms and the two alkyl moieties can have 10 or more carbon atoms. One or more types of dialiphatic Anions dialkyl ammonium cations can be used in the ionic liquid compositions disclosed herein. 0.138 Particular examples of anionic compounds that can 0129. In some particular examples, the dialiphatic dialkyl be present in the disclosed ionic liquids are compounds that contain oxygen atoms. Oxygen atoms can exist or can be ammonium cation can be di-dodecyl dimethyl ammonium, converted to negatively charged, anionic species, for di-tetradecyl dimethyl ammonium, dihexadecyl dimethyl example, through deprotonation of alcohols or acids, through ammonium, and the like, including combinations thereof. saponification of esters, or through alkylation of ketones. 0130 Tetraalkyl Ammonium Likewise, compounds that contain Sulfur atoms can also exist 0131 The disclosed ionic liquid compositions can also or be converted to anionic species through similar reactions. comprise a tetraalkyl ammonium cation. Suitable tetraalkyl Still further, compounds that contain nitrogen atoms, espe ammonium cations comprise four alkyl moieties, as disclosed cially nitrogen atoms adjacent to electron withdrawing herein. In one example, a tetraalkyl ammonium cation can groups or resonance stabilizing structures, can be converted comprise one long chain alkyl moiety (e.g., 10 or more carbon to anions through deprotonation. According to the methods atoms in length) and three short chain alkyl moieties (e.g., and compositions disclosed herein, any compound that con less than 10 carbon atoms in length). tains an oxygen, Sulfur, or nitrogen atom can be a Suitable 0132) Some specific examples of tetraalkyl ammonium anion for the disclosed ionic liquid compositions. cations that can be included in the disclosed ionic liquid 0.139. Other suitable anions include, but are not limited to, compositions include, but are not limited to, cetyl trimethyl halides (e.g., fluoride, chloride, bromide, and iodide), Sulfates ammonium, lauryl trimethyl ammonium, myristyl trimethyl (SO), carbonates, bicarbonates, phosphates, phosphates, ammonium, Stearyl trimethyl ammonium, arachidyl trim nitrates (NO), nitrites (NO), acetates (CHCO), and the ethyl ammonium, or mixtures thereof. Other examples like. Other examples of anions include, but are not limited to include, but are not limited to, cetyl dimethylethyl ammo PF, that is immiscible in water and BF, that is miscible in nium, lauryl dimethylethyl ammonium, myristyl dimethyl water depending on the ratio of ionic liquid to water, system ethyl ammonium, Stearyl dimethylethyl ammonium, temperature, and alkyl chain length of cation. Other anions arachidyl dimethylethyl ammonium, or mixtures thereof. include triflate (TfG); CFSO), nonaflate (NfO; CF (CF) 0133. Other Cations SO), bis(triflyl)amide (Tf.N. (CFSO)N), trifluoroac 0134. Other cations that are suitable for use in the dis etate (TFA; CFCO), and heptafluororobutanoate (HB; CF closed methods and compositions are compounds that con (CF)SO). Other types of ionic liquids include tain metals. According to the methods and compositions dis haloaluminates, such as chloroaluminate. closed herein, any compound that contains a metal atom can 0140. Other suitable anions contemplated herein are sac be a Suitable cation. Organometallic compounds or metal charin and acesulfame. Saccharin, as an alkali metal salt, and complexes commonly have one or more metal atom in a acesulfame (6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one positive oxidation state. Examples of metals that can be 2,2-dioxide), which has previously only been offered as present in a suitable cation include, but are not limited to, potassium salt, are in widespread use in foodstuffs as non lithium, Sodium, potassium beryllium, magnesium, calcium, nutritive Sweeteners. Such anions can be used when one strontium, chromium, manganese, iron, cobalt, nickel, cop desires to prepare an ionic liquid composition that has Sweet per, and zinc. Silver nanoparticles can also be used. Examples ness as one of its desired properties. For example, Saccharin of suitable organometallic cations include, but are not limited and acesulfame can be combined with pharmaceutically to, metallocenium, alkylgermanyl, alkyltin, oralkylsilyl (e.g., active cations to prepare Sweet tasting ionic liquids that have trimethylsilylium, triethylsilylium, tris(trimethylsilyl)sily pharmaceutical activity. lium, tribenzylsilylium, triphenylsilylium, tricyclohexylsily 0141 Specific examples of otheranions include piperacil lium, and dimethyloctadecylsilylium). lin, folic acid, ibuprofen, fast green FCF, docusate, acesulfa 0135 Another suitable group of quaternary ammonium mate, penicillin G, Colawet MA-80, salicylic acid, sacchari cations are those that have been prepared by esterifying a nate, Sulfacetamide, naproxen, benzoate, diclofenac, and compound containing a carboxylic acid moiety or transesteri trans-cinnamic acid. fying a compound with an ester moiety with a choline moiety. 0142. Other suitable anions include, but are not limited to, Such choline esters can be biofriendly, permanent ions that Substituted and un-Substituted imidazolates, 1,2,3-triaz are amenable to being added to various compounds while still olates, and 1,2,4-triazolates, benzimidazolates, benz-1.2.3- being easily cleavable under physiological conditions. The triazolates, as shown bellow: choline esters can be used to increase the solubility and bio availability of many neutral compounds. 0.136 Further examples of cations include (2-hydroxy R13 R13 R 14 ethyl)-dimethylundecyloxymethyl-ammonium, (2-acetoxy ethyl)-heptyloxymethyldimethylammonium, and (2-ac N N etoxyethyl)-dodecyloxymethyldimethylammonium, R 14 J N > R 15 R 14 R N1\ R 15 CN1 mepenZolate, Sulfathiazole, thimerosal, and valproic acid. O O O 0.137 In other examples, the cation can be an energetic cation as disclosed in Katritzky et al., “ILs Based on Ener imidazolate 1,2,3-triazolate 1,2,4-triazolate getic Imidazolium Cations: Nitro- and Nitrile-substituted US 2012/0046244 A1 Feb. 23, 2012 13

sources, such as the Merck Index (13" Edition, Wiley, 2001), -continued The United States Pharmacopeia National Formulary R13 R13 (USP-NF), and the FDA's Orange book, which are each incor porated by reference herein at least for their teachings of R3 e R3 & pharmaceutical actives. Once a compound with a desired X- R17 / property is identified, the skilled artisan can determine R15 N R15 N whether the compound is ionic or can be made ionic. Such determinations can be performed based on the compound's R 16 R 16 structure, which can readily be determined by consulting the Sources mentioned herein or experimentally. Knowing a com benzimidazolate benz-1,2,3-triazolate pound's structure can readily reveal if the compound is ionic. In fact, many pharmaceutical actives exist as salts and are thus wherein R. R. R. R. (R''7), when present, are inde Suitable for use in preparing the disclosed ionic liquid com pendently H, a C-C alkyl, a C-C alkoxyalkyl group, a positions. Further, if a compound is notionic, but contains an C-C alkoxy group, or energetic Substituents like nitro, ion forming moiety (e.g., nitrogen, oxygen, Sulfur, or metal amino, cyano, azido, alkyl nitro, alkyl amino, alkyl cyano, atoms, as described herein), the compound can be converted alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, and to an ion and then combined with a suitable counterion to alkoxyazido. Exemplary C-C alkyl groups and C-C alkyl prepare the disclosed ionic liquid compositions. Those of groups include methyl, ethyl, propyl, iso-propyl, butyl, sec ordinary skill in the art will recognize numerous other com butyl, iso-butyl, pentyl, iso-pentyl, hexyl, 2-ethylbutyl, 2-me pounds that fall within the categories and that are useful thylpentyl, and the like. Corresponding C-C alkoxy groups according to the disclosed compositions and methods. contain the above C-C alkyl group bonded to an oxygen 0147 Some specific examples of pharmaceutical actives atom that is also bonded to the cation ring. An alkoxyalkyl that can be used in the disclosed ionic liquids include, but are group contains an ether 10 group bonded to an alkyl group, not limited to, aspirin, LIBRIUMTM, isoniazid, penicillin, and here contains a total of up to six carbon atoms. It is to be PRONTOSILTM, cisplatin, 6-mercaptopurine, RITUXANTM, noted that there are two isomeric 1,2,3-triazoles. In some TAXOLTM, phenobarbital, PROZACTM, ALLEGRATM, examples, all R groups not required for anion formation can VIOXXTM, quinine, ivermectin, L-dopa, THORAZINETM, be H. salvarsan, TAGAMETTM, AZT, crixivan, salbutamol, 0143 Further examples of suitable energetic anions are digoxin, fluride, LOVASTATINTM, erythropoietin, hydrocor disclosed in Katritzky et al., “ILs Based on Energetic Azolate tisone, insulin, oral contraceptives, oxytocin, PRE Anions.” Chem Eur) 12:4630, 2006, which is incorporated MARINTM, RU-486, thyroxine, thalidomide, cyclosporine, by reference herein at least for its teachings of energetic fentanyl, methadone, morphine, botox, vitamins, FOSA anions. MAXTM, RITALINTM, and VIAGRATM, including ionic Compound that can Exist that as Both: Anion or Cation derivatives thereof. Other examples of pharmaceutical active 0144. Examples of compounds that exist as cations in ions orpharmaceutical actives that can be made ionic include, Some environments and anions in other environments but are not limited to, pantoprazole, sold under the trade include, but are not limited to, 1,3-dimethylimidazolium, names PROTONIXTM and PANTOZOLTM, and rabeprazole, 1-butyl-3-methylimidazolium, 1,2,3-triazolium, tetrazolium, sold under the trade names ACIPHEXTM and PARIETTM, 1,2,4-triazolium, 1,3-dimethyl-1,2,3-triazolium, and 1,3- which are used to treat gastrointestinal disorders. Risedr dimethyl-4-nitroimidazolium, which exist as a cations, and onate, sold under the trade name ACTONELTM, and alendr 4-nitroimidazolate, 4,5-dinitroimidazolate, 3,5-dinitro-1,2, onate, sold under the trade name FOSAMAXTM, are used to 4-triazolate, tetraZolate, 5-aminotetraZolate, 2-nitroimida treat osteoporosis and are further examples of Suitable com Zolate, which exist as an anion. Those separate ions can still pounds that can be used to prepare the disclosed ionic liquid form single productionic liquids. compositions. Further examples include losartan, Sold under 0145 Examples of compounds that can change from an the trade names NU-LOTANTM, COZAARTM, and HYZ anion in one environment to a cation in another environment AARTM, and fosinopril, sold under the trade name MONO due to chemical modifications are the sulfur ylides through PRILTM, which are used to treat hypertension and are other the reaction of a sulfide with methyliodide to form the sulfo examples of Suitable compounds that can be used to prepare nium ion. the disclosed ionic liquid compositions. Atorvastatin, sold under the trade name LIPITORTM, and pravastatin, sold under the trade name PRAVACHOLTM, are used to treat cholesterol Specific Examples of Pharmaceutical Actives and are further examples of Suitable compounds that can be 0146 When pharmaceutical activity is a desired property used to prepare the disclosed ionic liquid compositions. A of the disclosed ionic liquids, one or more of the ions in the further example is montelukast, which is used to treat asthma disclosed ionic liquid compositions can be a pharmaceutical and is sold under the trade name SINGULAIRTM. Further active. Pharmaceutical actives that exist as ions or can be examples of pharmaceutical actives that are ionic or can be converted to ions, and which are Suitable for use in preparing made ionic and combined with other ions to form the dis the disclosed ionic liquid compositions, include the following closed ionic liquid compositions are: prostaglandin E, pros categories and specific examples. It is not intended that the taglandin F2, Sulprostone, cetapril, benzaepril, captopril, category be limited by the specific examples. Those of ordi methylhexaneamine, Synephrine, isoetharine, methoxyphe nary skill in the art will be able to readily identify those namine, tamsulosin, tolaZoline, bufuralol, nadoxolol, acetyl pharmaceutical actives that can be used in the disclosed meth salicylsalicylic acid, ammonium salicylate, buthalital ods and compositions. For example, one can identify a com Sodium, thiopental Sodium, isobutyl p-aminobenzoate, phe pound with a given property or activity by consulting various nol, clortermine, fenproporex, dermatol, niclosamide, pelle US 2012/0046244 A1 Feb. 23, 2012

tierine, dithiazanine iodide, thiabendazole, antimony Sodium Sodium Tetradecyl Sulfate, Flurazepam, Etodroxizine, thioglycolate, niridazole, isotretinoin, lodoxamide, rama Hexafluor-enium, romide, Ritodrine, Terbutaline. p-Amino troban, finasteride, minoxidil, carbarSone, diphetarSone, benzoic Acid, Solisobenzone, Ticrynafen, Orotic Acid, flutamide, nilutamide, nicorandil, oZagrel, bunitrolol, iprat Nafronyl, Nicametate, Perhexyline, Cloricromen, Cicloni ropium bromide, pyridinol carbamate, bucillamine, cate, Cinepazide, Chromocarb, Dobesilate Calcium, Thia diacerein, amlexanox, cromolyn, azidamfenicol, thiampheni mine (Vit. B), Pyridoxine Hydrochloride (Vit. Bs), col, brodimoprim, tetroXoprim, acetosulfone sodium, dap Oxaceprol, Acetylcysteine, Penicillamine, Allopurinol, Sone, benzoylpas, cyamelide, picotamide, acetylpheneturide, 0.148. Further examples of pharmaceutical actives that are albutoin, caroXaZone, indalpine, calcium mesoxalate, ionic or can be made ionic and combined with other ions to buformin, alkofanone, metformin, edrophomium chloride, form the disclosed ionic liquid compositions are detailed neostigmine, p-aminopro-piophenon, methylene blue, folinic below, along with their typically pharmaceutical use. 0149 Adrenergic: adrenalone, amidephrine mesylate, acid, tiopronin, fomepizole, asOxime chloride, obidoxime apraclonidine hydrochloride, brimonidine tartrate, dapipra chloride, chlonidine, tiapride, alizapride, bromopride, potas Zole hydrochloride, deterenol hydrochloride, diplivefrin, sium p-aminobenzoate, chlordantoin, bromosalicylchloranil dopamine hydrochloride, ephedrine Sulfate, epinephrine, epi ide, acetazolamide, benfunolol, allopurinol, carprofen, acriv nephrine bitartrate, epinephrylborate, esproquin hydrochlo astine, Metron S, Acifran, Benfluorex, Chlorisoncl-amine ride, etafedrine hydrochloride, hydroxyamphetamine hydro chloride, Pentamethon-ium bromide, 2-Aminothiazole, bromide, levonordefrin, mephentermine Sulfate, Methylthio-uracil, Amexinium Methyl Sulfate, Dopamine metaraminol bitartrate, metizoline hydrochloride, naphazo Hydrochloride, Balsalazide, Mesalamine, Enfenamic Acid, line hydrochloride, norepinephrine bitartrate, oxidopamine, Menfenamic Acid, Flufenamic Acid Aluminum Salt, Ber oxymetazoline hydrochloride, phenylephrine hydrochloride, berine, Chloguanide, Valproic Acid, Lisuride, Naratriptan, phenylpropanolamine hydrochloride, phenylpropanolamine Ambutonium Bromide, Benzilonium Bromide, 9-Amino polistirex, prenalterol hydrochloride, propylhexedrine, pseu camptothecin, TenuaZonic Acid, Clometocillin, Fluoxetine doephedrine hydrochloride, tetrahydrozoline hydrochloride, Hydrochloride, Pamidronic Acid, Risedronate Sodium, Benserazide Hydrochloride, Carbidopa, Metyrosine, Phento tramazoline hydrochloride, Xylometazoline hydrochloride. lamine, Elformithine Hydrochloride monohydrate, Sul 0150 Adrenocortical steroid: ciprocinonide, desoxycorti famethox-azole, Tamsulosin Hydrochloride, Terazosin, Nita costerone acetate, desoxycortico-sterone pivalate, dexam Zoxanide, Acranil, Hydroxy stil-bamidine, Pentamidine, ethasone acetate, fludrocortisone acetate, flumoxonide, Pyrimethamine, Acetarsone, Aminitrozole, BenZinidazole, hydrocortisone hemisuccinate, methylprednisolone Eflornithine Hydrochlo-ride, Acitretin, 6-AZauridine, hemisuccinate, naflocort, procinonide, timobesone acetate, Amisulpride, Remoxipride Hydrochloride Monohydrate, tipredane. Bufe-Xamac, Bumadizon, Chloram-phenicol, BenZOxonium, 0151. Adrenocortical suppressant: aminoglutethimide, Chloride, Cetalkonium Chloride, Aliben-dol, Ambutonium triloStane. Bromide, Arshpenamine, Sodium Arsanilate, Anagrelide, 0152 Alcohol deterrent: disulfuram. Beraprost, Cilostazol, Bibenzonium Bromide, Sodium Dibu 0153 Aldosterone antagonist: canrenoate potassium, can nate, Aldioxa, Cimetidine, Allopurinol, Succinimide, Foscar renone, dicirenone, mexrenoate potassium, prorenoate potas net Sodium, Efavirenz, Etifoxine, Valnoctamide, Cannabinol, sium, Spironolactone. Oxitropium Bromide, Tiotropium Bromide, Fendiline 0154 Amino acid: alanine, aspartic acid, cysteine hydro Hydrochloride, Prenylamine, Acetazolamide, Flumethiazide, chloride, cystine, histidine, isoleucine, leucine, lysine, lysine Acadesine, Cariporide, Levosimendan, Pimobendan Hydro acetate, lysine hydrochloride, methionine, phenylalanine, chloride, Ursodiol, Chenodiol, Cholic Acid Monohydrate, proline, serine, threonine, tryptophan, tyrosine, Valine. Clanobutin, Echothiophate Iodide, Edrophonium Chloride, O155 Ammonia detoxicant: arginine: arginine glutamate, Ambenonium, hloride, Distigmine Bromide, Asoxime Chlo arginine hydrochloride. ride, Obidoxime Chloride, Pemoline, Phenmetrazine, Cele 0156 Anabolic: bolandiol dipropionate, bolasterone, coxib, Cetraxate, Irsogladine, Naphazoline Hydrochloride, boldenone undecylenate, bolenol, bolnantalate, ethylestre Nordefrin Hydrochloride, Dapsone, Sulfapyridine Sodium nol, methenolone acetate, methenolone enanthate, mibole Salt, Mercapto-merin Sodium, Mercumatilin Sodium, Per rone, nandrolone cyclotate, norbolethone, pizotyline, quin golid, Pramipexole, Dihydro-chloride, Amisulpride, bolone, Stenbolone acetate, tibolone, Zeranol. Sulpiride, Cephaeline, Bromhexine, Ambroxol Hydrochlo (O157 Analeptic: modafinil. ride, Carnitine, Cinitapride, Cisapride, Cortivazol, Enox 0158 Analgesic: acetaminophen, alfentanil hydrochlo olone, Clomiphene, Pentoxifylline, Adrenalone, Carbazo ride, aminobenzoate potassium, aminobenzoate Sodium, ani chrome, odium Sulfonate. Thioctic Acid, Timonacid, doXime, anilleridine, anilleridine hydrochloride, anilopam Pidotimod, Bucillamine, 6-Mercapto-purine, Brequinar, Ret hydrochloride, anirolac, antipyrine, aspirin, benoxaprofen, inoic Acid, Salicylic Acid, Docusate Calcium (Sodium), benzydamine hydrochloride, bici fadine hydrochloride, Picosolfate Sodium, Ibudilast, Zafirlukast, Choline Chloride, brifentanil hydrochloride, bromadoline maleate, bromfenac Methionine, Bismuth Sodium Triglycollam-ate, Chloro Sodium, buprenorphine hydrochloride, butacetin, butixirate, quine, Prinomastat, Carbachol, Neostigmine, Acetylcysteine, butorphanol, butorphanol tartrate, carbamazepine, carbaspi Bromhexine, Tetrazepam, Tizanidine, Tropicamide, Phenyle rin calcium, carbiphene hydrochloride, carfentanil citrate, phrine, Hydrochloride, Cyclazocine, Amiphenazole, Zan ciprefadol Succinate, ciramadol, ciramadol hydrochloride, amivir. Succinyl-choline Bromide/Chloride/, Iodide, Faza clonixeril, clonixin, codeine, codeine phosphate, codeine Sul dinium Bromide, Omapatrilat, Riluzole, Repinotan, fate, conorphone hydrochloride, cyclazocine, dexoxadrol Indeloxazine Hydrochloride, Donepezil, Carboprost, Pinaci hydrochloride, dexpemedolac, dezocine, diflunisal, dihydro dil, Nicorandil, Fampridine, Tedisamil, Cabergoline, Bera codeine bitartrate, dimefadane, dipyrone, doXpicomine prost, Dimefline, Fominoben, 2-Hexyl-decanoic Acid, hydrochloride, drinidene, enadoline hydrochloride, epirizole, US 2012/0046244 A1 Feb. 23, 2012 ergotamine tartrate, ethoxazene hydrochloride, etofenamate, thiamylal, thiamylal Sodium, thiopental sodium, tiletamine eugenol, fenoprofen, fenoprofen calcium, fentanyl citrate, hydrochloride, Zolamine hydrochloride. floctafenine, flufenisal, fluniXin, flunixin meglumine, flupir 0162 Anorectic compounds including dexfenfluramine. tine maleate, fluproduaZone, fluradoline hydrochloride, flur 0163 Anorexic: a minorex, amphecloral, chlorphenter biprofen, hydromorphone hydrochloride, ibufenac, indopro mine hydrochloride, clominorex, clortermine hydrochloride, fen, ketazocine, ketorfanol, ketorolac tromethamine, letimide diethylpropion hydrochloride, fenfluramine hydrochloride, hydrochloride, levomethadyl acetate, levomethadyl acetate fenisorex, fluidorex, fluminorex, levamfetamine Succinate, hydrochloride, levonantradol hydrochloride, levorphanol tar mazindol, mefenorex hydrochloride, phenmetrazine hydro trate, lofemizole hydrochloride, lofentanil oxalate, lorcina chloride, phentermine, sibutramine hydrochloride. dol, lomoxicam, magnesium salicylate, mefenamic acid, 0.164 Antagonist: atipamezole, atosiban, bosentan, cime menabitan hydrochloride, meperidine hydrochloride, tidine, cimetidine hydrochloride, clentiazem maleate, detire meptazinol hydrochloride, methadone hydrochloride, meth lix acetate, devaZepide, donetidine, etintidine hydrochloride, adyl acetate, methopholine, methotrimeprazine, metkepha famotidine, fenmetozole hydrochloride, flumazenil, icatibant mid acetate, mimbane hydrochloride, mirfentanil hydrochlo acetate, icotidine, isradipine, metiarnide, nadide, nalmefene, ride, molinaZone, morphine Sulfate, moxazocine, nabitan nalmexone hydrochloride, naloxone hydrochloride, naltrex hydrochloride, nalbuphine hydrochloride, nalmexone hydro one, nilvadipine, OXilorphan, oxmetidine hydrochloride, chloride, namoxyrate, nantradol hydrochloride, naproxen, oXmetidine mesylate, quadazocine mesylate, ranitidine, ran naproxen Sodium, naproXol, nefopam hydrochloride, nexeri itidine bismuth citrate, ranitidine hydrochloride, sufotidine, dine hydrochloride, noracymethadol hydrochloride, ocfenta teludipine hydrochloride, tiapamil hydrochloride, tiotidine, nil hydrochloride, octaZamide, olvanil, oxetorone fumarate, vapiprost hydrochloride, Zaltidine hydrochloride. oxycodone, oxycodone hydrochloride, oxycodone terephtha 0.165 Anterior pituitary activator: epimestrol. late, oxymorphone hydrochloride, pemedolac, pentamor 0166 Anterior pituitary suppressant: danazol. phone, pentazocine, pentazocine hydrochloride, pentazocine 0.167 Anthelmintic: albendazole, anthelmycin, bromox lactate, phenazopyridine hydrochloride, phenyramidol anide, bunamidine hydrochloride, butonate, cambendazole, hydrochloride, picenadol hydrochloride, pinadoline, pirfeni carbantel lauryl Sulfate, clioxanide, closantel, cyclobenda done, piroxicam olamine, pravadoline maleate, prodilidine Zole, dichlorvos, diethylcarbamazine citrate, dribendazole, hydrochloride, profadol hydrochloride, propirarn fumarate, dymanthine hydrochloride, etibendazole, fenbendazole, propoxyphene hydrochloride, propoxyphene napsylate, furodazole, hexylresorcinol, mebendazole, morantel tartrate, proxazole, proxazole citrate, proXorphan tartrate, pyrro niclosamide, nitramisole hydrochloride, nitrodan, oxantel liphene hydrochloride, remifentanil hydrochloride, salcolex, pamoate, Oxfendazole, oxibendazole, parbendazole, pipera Salethamide maleate, Salicylamide, Salicylate meglumine, mide maleate, piperazine, piperazine citrate, piperazine ede Salsalate, Sodium salicylate, spiradoline mesylate, Sufentanil, tate calcium, proclonol, pyrantel pamoate, pyrantel tartrate, Sufentanil citrate, talmetacin, talniflumate, talosalate, tazad pyrvinium pamoate, rafoxanide, stilbazium iodide, tetrami olene Succinate, tebufelone, tetrydamine, tifurac sodium, tili sole hydrochloride, thiabendazole, ticarbodine, tioxidazole, dine hydrochloride, tiopinac, tonazocine mesylate, tramadol triclofenol piperazine, Vincofos, Zilantel. hydrochloride, trefentanil hydrochloride, trolamine, Verado 0168 Anti-acne: adapalene, erythromycin Salnacedin, line hydrochloride, verilopam hydrochloride, volazocine, inocoterone acetate, accutane. Xorphanol mesylate, Xylazine hydrochloride, Zenazocine 0169. Anti-adrenergic: acebutolol, alprenolol hydrochlo mesylate, Zomepirac sodium, Zucapsaicin. ride, atenolol, bretylium tosylate, bunolol hydrochloride, car 0159 Androgen: fluoxymesterone, mesterolone, methylt teolol hydrochloride, celiprolol hydrochloride, cetamolol estosterone, nandrolone decanoate, nandrolone phenpropi hydrochloride, cicloprolol hydrochloride, dexpropranolol onate, nisterime acetate, Oxandrolone, oxymetholone, silan hydrochloride, diacetolol hydrochloride, dihydroergotamine drone, stanozolol, testosterone, testosterone cypionate, mesylate, dilevalol hydrochloride, esmolol hydrochloride, testosterone enanthate, testosterone ketolaurate, testosterone exaprolol hydrochloride, fenspiride hydrochloride, flestolol phenylacetate, testosterone propionate, trestolone acetate. sulfate, labetalol hydrochloride, levobetaxolol hydrochlo (0160 Anesthesia, adjunct to: Sodium oxybate. ride, levobunolol hydrochloride, metalol hydrochloride, 0161 Anesthetic: alliflurane, benoximate hydrochloride, metoprolol, metoprolol tartrate, nadolol, pamatolol Sulfate, benzocaine, biphenamine hydrochloride, bupivacaine hydro penbutolol Sulfate, phentolamine mesylate, practolol, propra chloride, butamben, butamben picrate, chloroprocaine hydro nolol hydrochloride, proroxanhydrochloride, solypertine tai chloride, cocaine, cocaine hydrochloride, cyclopropane, des trate, Sotalol hydrochloride, timolol, timolol maleate, tipre flurane, dexivacaine, diamocaine cyclamate, dibucaine, nolol hydrochloride, tolamolol, Zollertine hydrochloride. dibucaine hydrochloride, dyclonine hydrochloride, enflu 0170 Anti-allergic: amlexanox, astemizole, azelastine rane, ether, ethyl chloride, etidocaine, etoxadrol hydrochlo hydrochloride, eclaZolast, minocromil, nedocromil, nedocro ride, euprocin hydrochloride, fluoroxene, halothane, isob mil calcium, nedocromil sodium, nivimedone sodium, utamben, isoflurane, ketamine hydrochloride, levoxadrol pemirolast potassium, pentigetide, pirquinozol, poisonoak hydrochloride, lidocaine, lidocaine hydrochloride, mepiv extract, probicromil calcium, proxicromil, repirinast, tetraZo acaine hydrochloride, methohexital sodium, methoxyflurane, last meglumine, thiazinamium chloride, tiacrilast, tiacrilast midazolam hydrochloride, midazolam maleate, minaxolone, Sodium, tiprinast meglumine, tixanoX. nitrous oxide, norflurane, octodrine, oxethazaine, phencycli 0171 Anti-amebic: berythromycin, bialamicol hydro dine hydrochloride, pramoxine hydrochloride, prilocalne chloride, chloroquine, chloroquine hydrochloride, chloro hydrochloride, procaine hydrochloride, propanidid, propara quine phosphate, clamoxyquin hydrochloride, clioquinol, caine hydrochloride, propofol, propoxycaine hydrochloride, emetine hydrochloride, iodoquinol, paromomycin Sulfate, pyrrocaine, risocaine, rodocaine, roflurane, Salicyl alcohol, quinfamide, Symetine hydrochloride, teclozan, tetracycline, sevoflurane, teflurane, tetracaine, tetracaine hydrochloride, tetracycline hydrochloride. US 2012/0046244 A1 Feb. 23, 2012

(0172 anti-androgen:benorterone, cioteronel, cyproterone ride, fluzinamide, fosphenyloin sodium, gabapentin, ilepcim acetate, delmadinone acetate, oxendolone, topterone, Zanot ide, lamotrigine, magnesium sulfate, mephenyloin, eOle. mephobarbital, methetoin, methsuximide, millacemide 0173 Anti-anemic: epoetin alfa, epoetin beta, ferrous sul hydrochloride, nabazenil, nafimidone hydrochloride, fate, dried, leucovorin calcium. nitrazepam, phenacemide, phenobarbital, phenobarbital (0174 Anti-anginal: amlodipine besylate, amlodipine Sodium, phensuXimide, phenyloin, phenyloin sodium, primi maleate, betaxolol hydrochloride, bevantolol hydrochloride, done, progabide, ralitoline, remacemide hydrochloride, rop butoprozine hydrochloride, carvedilol, cinepazet maleate, izine, sabeluzole, stiripentol, Sulthiame, thiopental sodium, metoprolol succinate, molsidomine, monatepil maleate, tiletamine hydrochloride, topiramate, trimethadione, val primidolol, ranolazine hydrochloride, tosifen, verapamil proate sodium, Valproic acid, vigabatrin, Zoniclezole hydro hydrochloride. chloride, Zonisamide. (0175 Anti-anxiety agent: adatanserinhydrochloride, alpi 0185. Antidepressant: adatanserin hydrochloride, adina dem, binospirone mesylate, bretazenil, glemanserin, ipsa Zolam, adinazolam mesylate, alaproclate, aletamine hydro pirone hydrochloride, mirisetron maleate, ocinaplon, chloride, amedalin hydrochloride, amitriptyline hydrochlo ondansetron hydrochloride, panadiplon, pancopride, pazina ride, amoxapine, aptazapine maleate, azaloxan fumarate, clone, Serazapine hydrochloride, tandospirone citrate, aZepindole, azipramine hydrochloride, bipenamol hydro Zalospirone hydrochloride. chloride, bupropion hydrochloride, butacetin, butriptyline 0176 Anti-arthritic: lodelaben. hydrochloride, caroxazone, cartazolate, ciclazindol, cidox 0177 Anti-asthmatic: ablukast, ablukast sodium, azelas epin hydrochloride, cilobamine mesylate, clodazon hydro tine hydrochloride, bunaprolast, cinalukast, crornitrile chloride, clomipramine hydrochloride, cotinine fumarate, Sodium, cromolyn sodium, enofelast, isamoxole, ketotifen cyclindole, cypenamine hydrochloride, cyprolidol hydro fumarate, levcromakalim, lodoxamide ethyl, lodoxamide chloride, cyproximide, daledalin tosylate, dapoxetine hydro tromethamine, montelukast sodium, ontazolast, oxarbazole, chloride, dazadrol maleate, dazepinil hydrochloride, Oxatomide, piriprost, piriprost potassium, pirolate, pobi desipramine hydrochloride, dexamisole, deximafen, diben lukastedamine, quaZolast, repirinast, ritolukast, sulukast, tet Zepin hydrochloride, dioxadrol hydrochloride, dothiepin raZolast meglumine, tiaramide hydrochloride, tibenelast hydrochloride, doxepin hydrochloride, dulloxetine hydro Sodium, tomelukast, tranilast, Verlukast, Verofylline, Zar chloride, eclanamine maleate, encyprate, etoperidone hydro irlukast. chloride, fantridone hydrochloride, fehmetozole hydrochlo 0178 Anti-atherosclerotic: mifobate, timefuronc, ride, fenmetramide, fezolamine fumarate, fluotracen 0179 Anticholelithic: monoctanoin. hydrochloride, fluoxetine, fluoxetine hydrochloride, flupar 0180 Anticholelithogenic: chenodiol, ursodiol. oxan hydrochloride, gamfexine, guanoxyfen sulfate, imafen 0181 Anticholinergic: alverinc citrate, anisotropine hydrochloride, imiloxan hydrochloride, imipramine hydro methylbromide, atropine, atropine oxide hydrochloride, atro chloride, indeloxazine hydrochloride, intriptyline hydrochlo pine sulfate, belladonna, benapryzine hydrochloride, ben ride, iprindole, isocarboxazid, ketipramine fumarate. Zetimide hydrochloride, benzilonium bromide, biperiden, lofepramine hydrochloride, lortalamine, maprotiline, mapro biperiden hydrochloride, biperiden lactate, clidinium bro tiline hydrochloride, melitracen hydrochloride, millacemide mide, cyclopentolate hydrochloride, dexetimide, dicyclom hydrochloride, minaprine hydrochloride, mirtazapine, ine hydrochloride, dihexyverine hydrochloride, domazoline moclobemide, modaline sulfate, napactadine hydrochloride, fumarate, elantrine, elucaine, ethybenztropine, eucatropine napamezole hydrochloride, nefazodone hydrochloride, hydrochloride, glycopyrrolate, heteronium bromide, homat nisoxetine, nitrafudam hydrochloride, nomifensine maleate, ropine hydrobromide, homatropine methylbromide, hyos nortriptyline hydrochloride, octriptyline phosphate, cyamine, hyoscyamine hydrobromide, hyoscyamine sulfate, opipramol hydrochloride, oxaprotiline hydrochloride, isopropamide iodide, mepenzolate bromide, methylatropine oxypertine, paroxetine, phenelzine sulfate, pirandamine nitrate, metoquizine, oxybutynin chloride, parapenzolate hydrochloride, pizotyline, pridefine hydrochloride, prolin bromide, pentapiperium methylsulfate, phencarbamide, pol tane hydrochloride, protriptyline hydrochloride, quipazine dine methylsulfate, proglumide, propantheline bromide, pro maleate, rolicyprine, seproxetine hydrochloride, sertraline penzolate hydrochloride, scopolamine hydrobromide, temat hydrochloride, sibutramine hydrochloride, sulpiride, Surito ropium methylsulfate, tiquinamide hydrochloride, tofenacin Zole, tametraline hydrochloride, tampramine fumarate, tan hydrochloride, toquizine, triampyzine sulfate, trihex damine hydrochloride, thiazesimhydrochloride, thozalinone, yphenidyl hydrochloride, tropicamide. tomoxetine hydrochloride, trazodone hydrochloride, treben 0182 Anticoagulant: ancrod, anticoagulant citrate dex Zomine hydrochloride, trimipramine, trimipramine maleate, trose solution, anticoagulant citrate phosphate dextrose Venlafaxine hydrochloride, viloxazine hydrochloride, Zimel adenine solution, anticoagulant citrate phosphate dextrose dine hydrochloride, Zometapine. Solution, anticoagulant heparin solution, anticoagulant 0186 Antidiabetic: acetohexamide, buformin, butoxam Sodium citrate solution, ardeparin sodium, bivalirudin, bro ine hydrochloride, camiglibose, chlorpropamide, ciglitazone. mindione, dalteparin sodium, desirudin, dicumnarol, heparin englitaZone sodium, etoformin hydrochloride, gliamilide. calcium, heparin sodium, lyapolate sodium, nafamostat glibornuride, glicetanile sodium, gliflumide, glipizide, gluca meSylate, phenprocoumon, tinzaparin sodium, warfarin gon, glyburide, glyhexamide, glymidine sodium, glyocta sodium. mide, glyparamide, insulin, insulin, dalanated, insulin 0183 Anticoccidal: maduramicin. human, insulin human, isophane, insulin human zinc, insulin 0184 Anticonvulsant: albutoin, ameltolide, atolide, bura human Zinc, extended, insulin, isophane, insulin lispro, insu mate, carbamazepine, cinromide, citenamide, clonazepam, lin, neutral, insulin Zinc, insulin zinc, extended, insulin zinc, cyheptamide, dezinamide, dimethadione, divalproex sodium, prompt, linogliride, linogliride fumarate, metformin, methyl eterobarb, ethosuximide, ethotoin, flurazepam hydrochlo palmoxirate, palmoxirate sodium, pioglitazone hydrochlo US 2012/0046244 A1 Feb. 23, 2012 ride, pirogliride tartrate, proinsulin human, Seglitide acetate, niramine maleate, chlorpheniramine polistirex, cinnarizine, tolaZamide, tolbutamide, tolpyrramide, troglitaZone, Zopolr clemastine, clemastine fumarate, closiramine aceturate, cyc estat, and Sitagliptin. liramine maleate, cyclizine, cyproheptadine hydrochloride, 0187 Antidiarrheal: rolgamidine, diphenoxylate hydro dexbrompheniramine maleate, dexchlorpheniramine male chloride (lomotil), metronidazole (flagyl), methylpredniso ate, dimethindene maleate, diphenhydramine citrate, diphen lone (medrol), Sulfasalazine (aZulfidine). hydramine hydrochloride, dorastine hydrochloride, doxy 0188 Antidiuretic: argipressin tannate, desmopressin lamine Succinate, ebastine, levocabastine hydrochloride, acetate, lypressin. loratadine, mianserin hydrochloride, noberastine, 0189 Antidote: dimercaprol, edrophonium chloride, orphenadrine citrate, pyrabrom, pyrilamine maleate, pyrox fomepizole, leucovorin calcium, levoleucovorin calcium, amine maleate, rocastine hydrochloride, rotoxamine, tazifyl methylene blue, protamine Sulfate. line hydrochloride, temelastine, terfenadine, tripelennamine 0.190 Antidyskinetic: selegiline hydrochloride. citrate, tripelennamine hydrochloride, triprolidine hydro 0191 Anti-emetic: alosetron hydrochloride, batanopride chloride, Zolamine hydrochloride. hydrochloride, bemesetron, benzquinamide, chlorprom 0200 Antihyperlipidemic: cholestyramine resin, clofi azine, chlorpromazine hydrochloride, clebopride, cyclizine brate, colestipol hydrochloride, crilvastatin, dalvastatin, dex hydrochloride, dimenhydrinate, diphenidol, diphenidol trothyroxine sodium, fluvastatin Sodium, gemfibrozil, lecimi hydrochloride, diphenidol pamoate, dolasetron mesylate, bide, lovastatin, niacin, pravastatin Sodium, probucol, domperidone, dronabinol, fluidorex, flumeridone, simvastatin, tiqueside, Xenbucin. galdansetron hydrochloride, granisetron, granisetron hydro 0201 Antihyperlipoproteinemic: acifran, beloxamide, chloride, lurosetron meSylate, meclizine hydrochloride, bezafibrate, boxidine, butoxamine hydrochloride, cetaben metoclopramide hydrochloride, metopimazine, ondansetron Sodium, ciprofibrate, gemcadiol, halofenate, lifibrate, meglu hydrochloride, pancopride, prochlorperazine, prochlorpera tol, nafenopin, pimetine hydrochloride, theofibrate, tibric Zine edisylate, prochlorperazine maleate, promethazine acid, treloxinate. hydrochloride, thiethylperazine, thiethylperazine malate, thi 0202 Antihypertensive: alfuzosin hydrochloride, alipam ethylperazine maleate, trimethobenzamide hydrochloride, ide, althiazide, amiquinsin hydrochloride, amlodipine besy Zacopride hydrochloride. late, amlodipine maleate, anaritide acetate, atiprosin maleate, 0.192 Anti-epileptic: felbamate, loreclezole, tolgabide. belfosdil, bemitradine, bendacalol mesylate, bendroflume 0193 Anti-estrogen: clometherone, delmadinone acetate, thiazide, benzthiazide, betaxolol hydrochloride, bethanidine nafoxidine hydrochloride, nitromifene citrate, raloxifene sulfate, bevantolol hydrochloride, biclodil hydrochloride, hydrochloride, tamoxifen citrate, toremifene citrate, triox bisoprolol, bisoprolol fumarate, bucindolol hydrochloride, ifene mesylate. bupicomide, buthiazide: candoXatril, candoxatrilat, captopril, 0194 Antifibrinolytic: na?amostat mesylate. carvedilol, ceronapril, chlorothiazide Sodium, cicletanine, 0.195 Antifungal: acrisorcin, ambruticin, amphotericinb, cilaZapril, clonidine, clonidine hydrochloride, clopamide, aZaconazole, azaserine, basifungin, bifonazole, biphenamine cyclopenthiazide, cyclothiazide, darodipine, debrisoquin Sul hydrochloride, bispyrithione magSulfex, butoconazole fate, delapril hydrochloride, diapamide, diazoxide, dilevalol nitrate, calcium undecylenate, candicidin, carbol-fuchsin, hydrochloride, diltiazem malate, ditekiren, doxazosin mesy chlordantoin, ciclopiroX, ciclopiroX olamine, cillofungin, late, ecadotril, enalapril maleate, enalaprilat, enalkiren, cisconazole, clotrimazole, cuprimyxin, denofungin, dipy endralazine mesylate, epithiazide, eprosartan, eprosartan rithione, doconazole, econazole, econazole nitrate, enilcona mesylate, fenoldopam mesylate, flavodilol maleate, flo Zole, ethonam nitrate, fenticonazole nitrate, filipin, flucona rdipine, floseduinan, fosinopril sodium, fosinoprilat, guana Zole, flucytosine, fungimycin, griseofulvin, hamycin, benz, guanabenZ acetate, guanacline Sulfate, guanadrel Sul isoconazole, itraconazole, kalafungin, ketoconazole, fate, guancydine, guanethidine monosulfate, guanethidine lomofimgin, lydimycin, mepartricin, miconazole, micona Sulfate, guanfacine hydrochloride, guanisoquin Sulfate, gua Zole nitrate, monensin, monensin Sodium, naftifine hydro noclor Sulfate, guanoctine hydrochloride, guanoxabenz, gua chloride, neomycin undecylenate, nifuratel, nifurmerone, noxan Sulfate, guanoxyfen Sulfate, hydralazine hydrochlo nitralamine hydrochloride, nystatin, octanoic acid, orcona ride, hydralazine polistirex, hydroflumethiazide, Zole nitrate, oxiconazole nitrate, oxifungin hydrochloride, indacrinone, indapamide, indolaprif hydrochloride, parconazole hydrochloride, partricin, potassium iodide, pro indoramin, indoramin hydrochloride, indorenate hydrochlo clonol, pyrithione Zinc, pyrrolnitrin, rutamycin, sangui ride, lacidipine, leniquinsin, levcromakalim, lisinopril, narium chloride, Saperconazole, scopafungin, selenium Sul lofexidine hydrochloride, losartan potassium, losulazine fide, sinefungin, Sulconazole nitrate, terbinafine, terconazole, hydrochloride, mebutamate, mecamylamine hydrochloride, thiram, ticlatone, tioconazole, tolciclate, tolindate, tolnaftate, medroxalol, medroxalol hydrochloride, methalthiazide, triacetin, triafungin, undecylenic acid, viridofulvin, Zinc methyclothiazide, methyldopa, methyldopate hydrochloride, undecylenate, Zinoconazole hydrochloride. One specific anti metipranolol, metolaZone, metoprolol fumarate, metoprolol fungal that is Suitable is itraconazole. Succinate, metyrosine, minoxidil, monatepil maleate, 0196. Antiglaucoma agent: alprenoxime hydrochloride, muZolimine, nebivolol, nitrendipine, oftormine, pargyline colforsin, dapiprazole hydrochloride, dipivefrin hydrochlo hydrochloride, paZoxide, pelanserin hydrochloride, perin ride, naboctate hydrochloride, pilocarpine, pimabine. dopril erbumine, phenoxybenzamine hydrochloride, pinaci 0.197 Antihemophilic: antihemophilic factor. dil, pivopril, polythiazide, prazosin hydrochloride, primi 0198 Antihemorrhagic: poliglusam. dolol, prizidilol hydrochloride, quinapril hydrochloride, 0199 Antihistaminic: acrivastine, antazoline phosphate, quinaprilat, quinaZosin hydrochloride, quinelorane hydro astemizole, azatadine maleate, barmastine, bromodiphenhy chloride, quinpirole hydrochloride, quinuclium bromide, dramine hydrochloride, brompheniramine maleate, carbi ramipril, rauwolfia serpentina, reserpine, Saprisartan potas noxamine maleate, cetirizine hydrochloride, chlorphe sium, Saralasin acetate, Sodium nitroprusside, Sulfinalol US 2012/0046244 A1 Feb. 23, 2012 hydrochloride, tasosartan, teludipine hydrochloride, temoca mine, pirprofen, prednazate, prifelone, prodolic acid, produa pril hydrochloride, terazosin hydrochloride, terlakiren, tia Zone, proxazole, proxazole citrate, rimexolone, romazarit, menidine, tiamenidine hydrochloride, ticrynafen, tinabinol, salcolex, Salnacedin, Salsalate, sanguinarium chloride, secla tiodazosin, tipentosin hydrochloride, trichlormethiazide, tri Zone, Sermetacin, Sudoxicam, Sulindac, Suprofen, talmetacin, maZosin hydrochloride, trimethaphan camsylate, trimoxam talniflumate, talosalate, tebufelone, tenidap, tenidap Sodium, ine hydrochloride, tripamide, Xipamide, Zankiren hydrochlo tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tiXocor ride, Zofenoprilat arginine. tol pivalate, tolmetin, tolmetin Sodium, triclonide, triflumi 0203 Antihypotensive: ciclafrine hydrochloride, mido date, Zidometacin, Zomepirac sodium. drine hydrochloride. 0207 Antikeratinizing agent: doretinel, linarotene, pelre 0204 Anti-infective: difloxacin hydrochloride, lauryl iso tin. quinolinium bromide, moxalactam disodium, omidazole, 0208 Antimalarial: acedapsone, amodiaquine hydrochlo pentisomicin, Sarafloxacin hydrochloride, protease inhibitors ride, amguinate, arteflene, chloroquine, chloroquine hydro of hiv and other retroviruses, integrase inhibitors of hiv and chloride, chloroquine phosphate, cycloguanil pamoate, other retroviruses, cefaclor (CECLORTM), acyclovir (ZOVI empiroline phosphate, halofantrine hydrochloride, hydroxy RAXTM), norfloxacin (NOROXINTM), cefoxitin (ME chloroquine Sulfate, mefloquine hydrochloride, menoctone, FOXINTM), cefuroxime axetil (CEFTINTM), ciprofloxacin mirincamycin hydrochloride, primaquine phosphate, (CIPROTM). pyrimethamine, quinine Sulfate, tebuquine. 0205 Anti-infective, topical: alcohol, aminacrine hydro 0209 Antimicrobial: aztreonam, chlorhexidine glucon chloride, benzethonium chloride: bithionolate sodium, bro ate, imidurea, lycetamine, nibroxane, piraZmonam Sodium, mchlorenone, carbamide peroxide, cetalkonium chloride, propionic acid, pyrithione sodium, Sanguinarium chloride, cetylpyridinium chloride: chlorhexidine hydrochloride, clio tigemonam dicholine. quinol, domiphen bromide, fenticlor, fludazonium chloride, 0210 Antimigraine: dolasetron mesylate, naratriptan fuchsin, basic, furazolidone, gentian violet, haiquinols, hydrochloride, Sergolexole maleate, Sumatriptan Succinate, hexachlorophene: hydrogen peroxide, ichthammol, imidecyl Zatosetron maleate. iodine, iodine, isopropyl alcohol, mafenide acetate, meralein 0211 Antimitotic: podofilox. Sodium, mercufenol chloride, mercury, ammoniated, methyl 0212 Antimycotic: amorolfine. benzethonium chloride, nitrofuraZone, nitromersol, octeni 0213 Antinauseant: buclizine hydrochloride, cyclizine dine hydrochloride, oxychlorosene, oxychlorosene Sodium, lactate, naboctate hydrochloride. parachlorophenol, camphorated, potassium permanganate, 0214) Antineoplastic: acivicin, aclarubicin, acodazole poVidone-iodine, sepazonium chloride, silver nitrate, Sulfa hydrochloride, acronine, adoZelesin, aldesleukin, altre diazine, silver, Symclosene, thimerfonate Sodium, thimero tamine, ambomycin, ametantrone acetate, aminoglutethim sal: troclosene potassium. ide, amsacrine, anastroZole, anthramycin, asparaginase, 0206 Anti-inflammatory: acetominophen, alclofenac, asperlin, azacitidine, azetepa, azotomycin, batimastat, ben alclometasone dipropionate, algestone acetonide, alpha amy Zodepa, bicalutamide, bisantrene hydrochloride, bisnafide lase, amcinafal, amcinafide, amfenac sodium, amiprilose dimesylate, bizelesin, bleomycin Sulfate, brequinar Sodium, hydrochloride, anakinra, anirolac, anitraZafen, apaZone, bal bropirimine, buSulfan, cactinomycin, calusterone, carace Salazide disodium, bendazac, benoxaprofen, benzydamine mide, carbetimer, carboplatin, carmustine, carubicin hydro hydrochloride, bromelains, broperamole, budesonide, car chloride, carzelesin, cedefingol, chlorambucil, cirolemycin, profen, cicloprofen, cintaZone, cliprofen, clobetasol propi cisplatin, cladribine, crisinatol mesylate, cyclophosphamide, onate, clobetasone butyrate, clopirac, cloticaSone propionate, cytarabine, dacarbazine, dactinomycin, daunorubicin hydro cormethasone acetate, cortodoxone, deflazacort, desonide, chloride, decitabine, dexormaplatin, deZaguanine, deZagua desoximetasone, dexamethasone dipropionate, diclofenac nine mesylate, diaziquone, docetaxel, doxorubicin, doxoru potassium, diclofenac sodium, diflorasone diacetate, diflumi bicin hydrochloride, droloxifene, droloxifene citrate, done sodium, diflunisal, difluprednate, diftalone, dimethyl dromostanolone propionate, duaZomycin, edatrexate, eflo Sulfoxide, drocinonide, endrysone, enlimomab, enolicam mithine hydrochloride, elsamitrucin, enloplatin, empromate, Sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, epipropidine, epirubicin hydrochloride, erbulozole, esorubi fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fen cin hydrochloride, estramustine, estramustine phosphate tiazac, flazalone, fluazacort, flufenamic acid, flumizole, Sodium, etanidazole, ethiodized oil I 131, etoposide, etopo flunisolide acetate, flunixin, flunixin meglumine, fluocortin side phosphate, etoprine, fadrozole hydrochloride, faZara butyl, fluorometholone acetate, fluguaZone, flurbiprofen, bine, fenretinide, floxuridine, fludarabine phosphate, fluo fluretofen, fluticasone propionate, furaprofen, furobufen, hal rouracil, fluorocitabine, fosquidone, fostriecin Sodium, cinonide, halobetasol propionate, halopredone acetate, gemcitabine, gemcitabine hydrochloride, gold au 198, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofos ilonidap, indomethacin, indomethacin Sodium, indoprofen, ine, interferon alfa-2a, interferon alfa-2b, interferon alfa-N1, indoxole, intrazole, isoflupredone acetate, isoxepac, isoxi interferon alfa-N3, interferon beta-la, interferon gamma-Ib, cam, ketoprofen, lofemizole hydrochloride, lornoxicam, iproplatin, irinotecan hydrochloride, lanreotide acetate, letro loteprednol etabonate, meclofenamate sodium, meclofe Zole, leuprolide acetate, liarozole hydrochloride, lometrexol namic acid, meclorisone dibutyrate, mefenamic acid, Sodium, lomustine, losoxantrone hydrochloride, masoprocol, mesalamine, meseclaZone, methylprednisolone Suleptanate, maytansine, mechlorethamine hydrochloride, megestrol morniflumate, nabumetone, naproxen, naproxen Sodium, acetate, melengestrol acetate, melphalan, menogaril, mercap naproxol, nimaZone, olSalazine sodium, orgotein, orpanoxin, topurine, methotrexate, methotrexate sodium, metoprine, oxaprozin, oxyphenbutaZone, paranyline hydrochloride, pen meturedepa, mitindomide, mitocarcin, mitocromin, mitogil tosan polysulfate sodium, phenbutaZone sodium glycerate, lin, mitomalcin, mitomycin, mitosper, mitotane, mitox pirfenidone, piroxicam, piroxicam cinnamate, piroxicamola antrone hydrochloride, mycophenolic acid, nocodazole, US 2012/0046244 A1 Feb. 23, 2012 nogalamycin, Ormaplatin, oxiSuran, paclitaxel, pegaspargase, nitrate, galocitabine, ganirelix, gelatinase inhibitors, gemcit peliomycin, pentamustine, peplomycin Sulfate, perfosfa abine, glutathione inhibitors, hepsulfam, heregulin, hexam mide, pipobroman, piposulfan, piroXantrone hydrochloride, ethylene bisacetamide, hypericin, ibandronic acid, idarubi plicamycin, plomestane, porfimer Sodium, porfiromycin, cin, idoxifene, idramantone, ilmofosine, illomastat, prednimustine, procarbazine hydrochloride, puromycin, imidazoacridones, imiquimod, immunostimulant peptides, puromycin hydrochloride, pyrazofurin, riboprine, rogletim insulin-like growth factor-1 receptor inhibitor, interferon ide, safmgol, Safingol hydrochloride, Semustine, simtraZene, agonists, interferons, interleukins, iobenguane, iododoxoru sparfosate Sodium, sparsomycin, spirogermanium hydro bicin, ipomeanol, 4-irinotecan, iroplact, irsogladine, isoben chloride, Spiromustine, spiroplatin, streptonigrin, StreptoZo gazole, isohomohalicondrin B, itasetron, jasplakinolide, cin, strontium chloride Sr 89, Sulofenur, talisomycin, taxane, kahalalide F, lamellarin-N triacetate, lanreotide, leinamycin, taxoid, tecogalan Sodium, tegafur, teloxantrone hydrochlo lenograstim, lentinan Sulfate, leptolstatin, letrozole, leukemia ride, temoporfin, teniposide, teroxirone, testolactone, thiami inhibiting factor, leukocyte alpha interferon, leuprolide--es prine, thioguanine, thiotepa, tiazofurin, tirapazamine, topo trogen-progesterone, leuprorelin, levamisole, liarozole, lin tecan hydrochloride, toremifene citrate, trestolone acetate, ear polyamine analogue, lipophilic disaccharide peptide, triciribine phosphate, trimetrexate, trimetrexate glucuronate, lipophilic platinum compounds, lissoclinamide 7, lobaplatin, triptorelin, tubulozole hydrochloride, uracil mustard, ure lombricine, lometrexol, lonidamine, losoxantrone, lovasta depa, Vapreotide, Verteporfin, vinblastine Sulfate, Vincristine tin, loxoribine, lurtotecan, lutetium texaphyrin, lysofylline, Sulfate, vindesine, Vindesine Sulfate, vinepidine Sulfate, Ving lytic peptides, maitansine, mannostatin A, marimastat, maso lycinate sulfate, vinleurosine sulfate, vinorelbine tartrate, procol, maspin, matrilysin inhibitors, matrix metalloprotein Vinrosidine Sulfate, Vinzolidine Sulfate, Vorozole, Zeniplatin, ase inhibitors, menogaril, merbarone, meterelin, methioni Zinostatin, Zorubicin hydrochloride. nase, metoclopramide, MIF inhibitor, mifepristone, 0215. Other anti-neoplastic compounds include: 20-epi-1, miltefosine, mirimostim, mismatched double stranded RNA, 25 dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, acla mitoguaZone, mitolactol, mitomycin analogues, mitonafide, rubicin, acylfulvene, adecypenol, adoZelesin, aldesleukin, mitotoxin fibroblast growth factor-Saporin, mitoxantrone, ALL-TK antagonists, altretamine, ambamustine, amidox, mofarotene, molgramostim, monoclonal antibody, human amifostine, aminolevulinic acid, amrubicin, atrsacrine, chorionic gonadotrophin, monophosphoryl lipid A+myobac anagrelide, anastrozole, andrographolide, angiogenesis terium cell wall sk, mopidamol, multiple drug resistance inhibitors, antagonist D, antagonist G, antarelix, anti-dorsal genie inhibitor, multiple tumor Suppressor 1-based therapy, izing morphogenetic protein-1, antiandrogen, prostatic carci mustard anticancer agent, mycaperoxide B, mycobacterial noma, antiestrogen, antineoplaston, antisense oligonucle cell wall extract, myriaporone, N-acetyldinaline, N-substi otides, aphidicolin glycinate, apoptosis gene modulators, tuted benzamides, nafarelin, nagrestip, naloxone-pentaZo apoptosis regulators, apurinic acid, ara-CDP-DL-PTBA, cine, napavin, naphterpin, nartograstim, nedaplatin, nemoru arginine deaminase, asulacrine, atameStane, atrimustine, axi bicin, neridronic acid, neutral endopeptidase, nilutamide, nastatin 1, axinastatin 2, axinastatin 3, aZasetron, azatoxin, nisamycin, nitric oxide modulators, nitroxide antioxidant, aZatyrosine, baccatin III derivatives, balanol, batimastat, nitrullyn, 06-benzylguanine, octreotide, okicenone, oligo BCR/ABL antagonists, benzochlorins, benzoylstaurospo nucleotides, onapristone, ondansetron, ondansetron, oracin, rine, beta lactam derivatives, beta-alethine, betaclamycin B, oral cytokine inducer, ormaplatin, osaterone, Oxaliplatin, betulinic acid, bFGF inhibitor, bicalutamide, bisantrene, oxaunomycin, paclitaxel analogues, paclitaxel derivatives, bisaziridinylspermine, bisnafide, bistratene A, bizelesin, palauamine, palmitoylrhizoxin, pamidronic acid, panax breflate, bropirimine, budotitane, buthionine sulfoximine, ytriol, panomifene, parabactin, paZelliptine, pegaspargase, calcipotriol, callphostin C, camptothecin derivatives, canary peldesine, pentosan polysulfate sodium, pentostatin, pentro poX IL-2, capecitabine, carboxamide-amino-triazole, car Zole, perflubron, perfosfamide, perillyl alcohol, phenazino boxyamidotriazole, CaRest M3, CARN 700, cartilage mycin, phenylacetate, phosphatase inhibitors, picibanil, pilo derived inhibitor, carzelesin, casein kinase inhibitors (ICOS). carpine hydrochloride, pirarubicin, piritrexim, placetin A, castanospermine, cecropin B, cetrorelix, chlorins, chloroqui placetin B, plasminogen activator inhibitor, platinum com noxaline Sulfonamide, cicaprost, cis-porphyrin, cladribine, plex, platinum compounds, platinum-triamine complex, por clomifene analogues, clotrimazole, collismycin A, collismy fimer Sodium, porfiromycin, propyl bis-acridone, prostaglan cin B, combretastatin A4, combretastatin analogue, conage din J2, proteasome inhibitors, protein A-based immune nin, crambescidin 816, crisinatol, cryptophycin 8, cryptophy modulator, protein kinase Cinhibitor, protein kinase Cinhibi cin A derivatives, curacin A, cyclopentanthraquinones, tors, microalgal, protein tyrosine phosphatase inhibitors, cycloplatam, cypemycin, cytarabine ocfosfate, cytolytic fac purine nucleoside phosphorylase inhibitors, purpurins, pyra tor, cytostatin, dacliximab, decitabine, dehydrodidemnin B, Zoloacridine, pyridoxylated hemoglobin polyoxyethylene deslorelin, dexifosfamide, dexraZOxane, dexVerapamil, diazi conjugate, rafantagonists, raltitrexed, ramosetron, ras farne quone, didemnin B, didox, diethylnorspermine, dihydro-5- syl protein transferase inhibitors, ras inhibitors, ras-GAP azacytidine, dihydrotaxol. 9-dioxamycin, diphenyl spiro inhibitor, retelliptine demethylated, rhenium Re 186 etidr mustine, docosanol, dolasetron, doxifluridine, droloxifene, onate, rhizoxin, ribozymes, RII retinamide, rogletimide, rohi dronabinol, duocannycin SA, ebselen, ecomustine, edelfos tukine, romurtide, roquinimex, rubiginone B1, ruboxyl, saf ine, edrecolomab, eflornithine, elemene, emitefur, epirubicin, ingol, Saintopin, SarCNU, sarcophytol A, SargramoStim, Sdi epristeride, estramustine analogue, estrogen agonists, estro 1 mimetics, semustine, Senescence derived inhibitor 1, sense gen antagonists, etanidazole, etoposide phosphate, exemes oligonucleotides, signal transduction inhibitors, signal trans tane, fadrozole, faZarabine, fenretinide, filgrastim, finas duction modulators, single chain antigen binding protein, teride, flavopiridol, flezelastine, fluasterone, fludarabine, sizofuran, Sobuzoxane, sodium borocaptate, sodium pheny fluorodaunorunicin hydrochloride, forfenimex, formestane, lacetate, Solverol. Somatomedin binding protein, Sonermin, fostriecin, fotemustine, gadolinium texaphyrin, gallium sparfosic acid, Spicamycin D, Spiromustine, splenopentin, US 2012/0046244 A1 Feb. 23, 2012 20 spongistatin 1, squalamine, stem cell inhibitor, stem-cell divi 0227 Antipsychotic: acetophenazine maleate, alentemol sion inhibitors, stipiamide, Stromelysin inhibitors, sulfi hydrobromide, alpertine, azaperone, batelapine maleate, ben nosine, Superactive vasoactive intestinal peptide antagonist, peridol, benzindopyrine hydrochloride, brofbxine, bromperi Suradista, Suramin, Swainsonine, synthetic glycosaminogly dol, bromperidol decanoate, butaclamol hydrochloride, cans, tallimustine, tamoxifen methiodide, tauromustine, taZ butaperazine, butaperazine maleate, carphenazine maleate, arotene, tecogalan Sodium, tegafur, tellurapyrylium, telom carvotroline hydrochloride, chlorpromazine, chlorpromazine erase inhibitors, temoporfin, temozolomide, teniposide, hydrochloride, chlorprothixene, cinperene, cintriamide, clo tetrachlorodecaoxide, tetrazomine, thaliblastine, thalido macran phosphate, clopenthixol, clopimozide, clopipazan mide, thiocoraline, thrombopoietin, thrombopoietin mimetic, mesylate, cloroperone hydrochloride, clothiapine, clothixa thymalfasin, thymopoietin receptor agonist, thymotrinan, mide maleate, clozapine, cyclophenazine hydrochloride, dro thyroid stimulating hormone, tin ethyl etiopurpurin, tira peridol, etazolate hydrochloride, fenimide, flucindole, paZamine, titanocene dichloride, topotecan, top sentin, flumeZapine, fluiphenazine decanoate, fluiphenazine enan toremifene, totipotent stem cell factor, translation inhibitors, thate, fluphenazine hydrochloride, fluspiperone, fluspirilene, tretinoin, triacetyluridine, triciribine, trimetrexate, triptore flutroline, gevotroline hydrochloride, halopemide, haloperi lin, tropisetron, turosteride, tyrosine kinase inhibitors, tyr dol, haloperidol decanoate, illoperidone, imidoline hydro phostins, UBC inhibitors, ubenimex, urogenital sinus-de chloride, lenperone, mazapertine Succinate, mesoridazine, rived growth inhibitory factor, urokinase receptor mesoridazine besylate, metiapine, milemperone, millipertine, antagonists, vapreotide, variolin B. vector system, erythro molindone hydrochloride, naranol hydrochloride, neflu cyte gene therapy, Velaresol, Veramine, Verdins, verteporfin, mozide hydrochloride, ocaperidone, olanzapine, oxipero Vinorelbine, Vinxaltine, vitaxin, Vorozole, Zanoterone, Zeni mide, penfluridol, pentiapine maleate, perphenazine, platin, Zilascorb, Zinostatin stimalamer. pimozide, pinoxepin hydrochloride, pipamperone, piperac 0216 Anti-cancer Supplementary potentiating agents: tri etazine, pipotiazine palniitate, piquindone hydrochloride, cyclic anti-depressant drugs (e.g., imipramine, desipramine, prochlorperazine edisylate, prochlorperazine maleate, pro amitryptyline, clomiprainine, trimipramine, doxepin, mazine hydrochloride, remoxipride, remoxipride hydrochlo nortriptyline, protriptyline, amoxapine and maprotiline), ride, rimcazole hydrochloride, seperidol hydrochloride, non-tricyclic anti-depressant drugs (e.g., Sertraline, traZ sertindole, Setoperone, spiperone, thioridazine, thioridazine odone and citalopram), Ca' antagonists (e.g., Verapamil, hydrochloride, thiothixene, thiothixene hydrochloride, tio nifedipine, nitrendipine and caroverine), calmodulin inhibi peridone hydrochloride, tiospirone hydrochloride, trifluop tors (e.g., prenylamine, trifluoroperazine and clomipramine), erazine hydrochloride, trifluperidol, triflupromazine, triflu amphotericin B, triparanol analogues (e.g., tamoxifen), anti promazine hydrochloride, Ziprasidone hydrochloride. arrhythmic drugs (e.g., quinidine), antihypertensive drugs 0228 Antirheumatic: auranofin, aurothioglucose, bin (e.g., reserpine), thiol depleters (e.g., buthionine and Sulfox darit, lobenzarit Sodium, phenylbutaZone, piraZolac, prino imine) and Multiple Drug Resistance reducing agents such as mide tromethamine, Seprilose. Cremaphor EL. 0229 Antischistosomal: becanthone hydrochloride, 0217 Antineutropenic: filgrastim, lenograstim, molgra hycanthone, lucanthone hydrochloride, niridazole, oxam mostim, regramos tim, sargramostim. niquine, pararosaniline pamoate, teroxalene hydrochloride. 0218 Antiobsessional agent: fluvoxamine maleate. 0230 Antiseborrheic: chloroxine, piroctone, piroctone 0219 Antiparasitic: abamectin, clorsulon, ivermectin. olamine, resorcinol monoacetate, antisecretory: arbaprostil, 0220 Antiparkinsonian: benztropine mesylate, biperiden, deprostil, fenoctimine Sulfate, octreotide, octreotide acetate, biperiden hydrochloride, biperiden lactate, carmantadine, omeprazole Sodium, rioprostil, trimoprostil. ciladopa hydrochloride, dopamantine, ethopropazine hydro 0231. Antispasmodic: stilonium iodide, tizanidine hydro chloride, lazabemide, levodopa, lometraline hydrochloride, chloride. mofegiline hydrochloride, naxagolide hydrochloride, parep 0232 Antithrombotic: anagrelide hydrochloride, bivaliru tide Sulfate, procyclidine hydrochloride, quinetorane hydro din, dalteparin Sodium, danaparoid sodium, daZOXiben chloride, ropinirole hydrochloride, selegiline hydrochloride, hydrochloride, efegatran Sulfate, enoxaparin Sodium, tolcapone, trihexyphenidyl hydrochloride, antiperistaltic: ifetroban, ifetroban sodium, tinzaparin Sodium, trifenagrel. difenoximide hydrochloride, difenoxin, diphenoxylate 0233 Antitussive: benzonatate, butamirate citrate, chlo hydrochloride, fluperamide, lidamidine hydrochloride, lop phedianol hydrochloride, codeine polistirex, codoxime, dex eramide hydrochloride, malethamer, nufenoXole, paregoric. tromethorphan, dextromethorphan hydrobromide, dex 0221) Antipneumocystic: atovaquone. tromethorphan polistirex, ethyl dibunate, guaiapate, 0222 Antiproliferative agent: piritreximisethionate. hydrocodone bitartrate, hydrocodone polistirex, levopro 0223) Antiprostatic hypertrophy: sitogluside. poxyphene napsylate, noscapine, pemerid nitrate, 0224 Antiprotozoal: amodiaquine, azanidazole, bamida pipazethate, SuXemerid Sulfate. Zole, camidazole, chlortetracycline bisulfate, chlortetracy 0234 Anti-ulcerative: aceglutamide aluminum, cadex cline hydrochloride, flubendazole, flunidazole, halofuginone omer iodine, cetraxate hydrochloride, enisoprost, isotiquim hydrobromide, imidocarb hydrochloride, ipronidazole, met ide, lanSoprazole, lavoltidine Succinate, misoprostol, nizati ronidazole, misonidazole, moXnidazole, nitarSone, partricin, dine, nolinium bromide, pantoprazole, pifarnine, pirenzepine puromycin, puromycin hydrochloride, ronidazole, Sulnida hydrochloride, rabeprazole sodium, remiprostol, roXatidine Zole, tinidazole. acetate hydrochloride, Sucralfate. Sucrosofate potassium, 0225. Antipruritic: cyproheptadine hydrochloride, meth tolimidone. dilazine, methdilazine hydrochloride, trimeprazine tartrate. 0235 Anti-urolithic: cysteamine, cysteamine hydrochlo 0226 Antipsoriatic: acitretin, anthralin, azaribine, calci ride, tricitrates. potriene, cycloheximide, enazadrem phosphate, etretinate, 0236. Appetite suppressant: dexfenfluramine hydrochlo liaroZole fumarate, lonapalene, tepoxalin. ride, phendimetrazine tartrate, phentermine hydrochloride. US 2012/0046244 A1 Feb. 23, 2012

0237 Benign prostatic hyperplasia therapy agent: tamsu 0248 Cholinergic: aceclidine, bethanechol chloride, car losin hydrochloride. bachol, demecarium bromide, dexpanthenol, echothiophate 0238 Blood glucose regulators: human insulin, glucagon, iodide, isofluorophate, methacholine chloride, neostigmine tolaZamide, tolbutamide, chloropropamide, acetohexamide bromide, neostigmine methylsulfate, physostigmine, physos and glipizide. tigmine salicylate, physostigmine Sulfate, pilocarpine, pilo 0239 Bone resorption inhibitor: alendronate sodium, carpine hydrochloride, pilocarpine nitrate, pyridostigmine etidronate disodium, pamidronate disodium. bromide. 0240 Bronchodilator: albuterol, albuterol sulfate, azana 0249 Cholinergic agonist. Xanomeline, Xanomeline tar tor maleate, bamifylline hydrochloride, bitolterol mesylate, trate. butaprost, carbuterol hydrochloride, clorprenaline hydro (0250 Cholinesterase deactivator: obidoxime chloride, chloride, colterol mesylate, doxaprost, doxofylline, dyphyl pralidoxime chloride, pralidoxime iodide, pralidoxime mesy line, enprofylline, ephedrine, ephedrine hydrochloride, late. fenoterol, fenprinast hydrochloride, guaithylline, hexoprena 0251 Coccidiostat: arprinocid, narasin, semduramicin, line Sulfate, hoquizil hydrochloride, ipratropium bromide, semduramicin Sodium. isoetharine, isoetharine hydrochloride, isoetharine mesylate, 0252) Dognition adjuvant: ergoloid mesylates, piracetam, isoproterenol hydrochloride, isoproterenol sulfate, metapro pramiracetam hydrochloride, pramiracetam Sulfate, tacrine terenol polistirex, metaproterenol Sulfate, nisbuterol mesy hydrochloride. late, oxtriphylline, picumeterol fumarate, piquizil hydrochlo 0253 Cognition enhancer: besipirdine hydrochloride, ride, pirbuterol acetate, pirbuterol hydrochloride, procaterol linopirdine, Sibopirdine. hydrochloride, pseudoephedrine Sulfate, quaZodine, quinter 0254. Depressant: omeprazole. enol Sulfate, racepinephrine, racepinephrine hydrochloride, 0255 Diagnostic aid: aminohippurate sodium, anazolene reproterol hydrochloride, rimiterol hydrobromide, salme Sodium, arclofenin, arginine, bentiromide, benzylpenicilloyl terol, salmeterol Xinafoate, soterenol hydrochloride, sul polylysine, butedronate tetrasodium, butilfenin, coccidioidin, fonterol hydrochloride, Suloxifen oxalate, terbutaline sulfate, corticorelin ovine triflutate, corticotropin, repository, corti theophylline, Xanoxate sodium, Zindotrine, Zinterol hydro cotropin Zinc hydroxide, diatrizoate meglumine, diatrizoate chloride. Sodium, diatrizoic acid, diphtheria toxin for Schick test, dis 0241 Carbonic anhydrase inhibitor: acetazolamide, ofenin, edrophonium chloride, ethiodized oil, etifenin, exam acetazolamide Sodium, dichlorphenamide, dorzolamide etazime, ferristenc, ferumoxides, ferumoXsil, fluorescein, hydrochloride, methazolamide, sezolamide hydrochloride. fluorescein Sodium, gadobenate dimeglumine, gadoteridol. 0242 Cardiac depressant: acecamide hydrochloride, ace gadodiamide, gadopentetate dimeglumine, gadoversetamide, tylcholine chloride, actisomide, adenosine, amiodarone, histoplasmin, impromidine hydrochloride, indigotindisul aprindine, aprindine hydrochloride, artilide fumarate, azimil fonate sodium, indocyanine green, lobenguane sulfate I'', iobenzamic acid, iocarmate meglumine, locarmic acid, ioc ide etamic acid, iodamide, lodamide megiumine, iodipamide 0243 Dihydrochloride, bidisomide, bucamide maleate, meglumine, iodixanol, iodoxamate meglumine, iodoxamic bucromarone, butoprozine hydrochloride, capobenate acid, ioglicic acid, ioglucol, ioglucomide, ioglycamic acid, Sodium, capobenic acid, cifenline, cifenline Succinate, clofi iogulamide, lohexyl, iomeprol, iopamidol, iopanoic acid, lium phosphate, disobutamide, disopyramide, disopyramide iopentol, iophendylate, iprofenin, iopronic acid, ioprocemic phosphate, dofetilide, drobuline, edifolone acetate, emilium acid, iopydol, iopydone, iosefamic acid, io.seric acid, ioSula tosylate, encamide hydrochloride, flecamide acetate, ibutil mide meglumine, ioSumetic acid, iotasul, iotetric acid, ide fumarate, indecamide hydrochloride, ipazilide fumarate, iothalamate meglumine, iothalamate sodium, iothalamic lorajmine hydrochloride, lorcamide hydrochloride, meoben acid, iotrolan, iotroxic acid, ioversol, ioxaglate meglumine, tine Sulfate, mexiletine hydrochloride, modecamide, mori ioxagiate Sodium, ioxaglic acid, ioxilan, ioxotrizoic acid, ipo cizine, oxiramide, pirmenol hydrochloride, pirolazamide, date calcium, ipodate sodium, isosulfan blue, leukocyte typ pranolium chloride, procainamide hydrochloride, pro ing serum, lidofenin, mebrofenin, meglumine, metrizamide, pafenone hydrochloride, pyrinoline, quindonium bromide, metrizoate sodium, metyrapone, metyrapone tartrate, mumps quinidine gluconate, quinidine Sulfate, recainam hydrochlo skin test antigen, pentetic acid, propyliodone, quinaldine ride, recainam tosylate, risotilide hydrochloride, ropitoin blue, sermorelin acetate, sodium iodide I'', sprodiamide, hydrochloride, sematilide hydrochloride, Suricamide male Stannous pyrophosphate, Stannous Sulfur colloid. Succimer, ate, tocamide, tocamide hydrochloride, transcamide. teriparatide acetate, tetrofosmin, tolbutamide Sodium, tuber 0244 Cardioprotectant: dexraZOxane, draflazine. culin, tyropanoate sodium, Xylose. 0245 Cardiotonic: actodigin, aminone, bemoradan, buto 0256 Diuretic: ambuphylline, ambuside, amiloride pamine, carbazeran, carsatirin Succinate, deslanoside, digi hydrochloride, azolimine, azosemide, brocrinat, bumetanide, talis, digitoxin, digoxin, dobutamine, dobutamine hydrochlo chlorothiazide, chlorthalidone, clazolimine, clorexolone, ride, dobutamine lactobionate, dobutamine tartrate, ethacrynate Sodium, ethacrynic acid, etoZolin, fenduizone, enoXimone, imaZodan hydrochloride, indolidan, isomazole furosemide, hydrochlorothiazide, isosorbide, mannitol, hydrochloride, levdobutamine lactobionate, lixazinone sul mefruside, oZolinone, piretanide, SpiroXasone, torsemide, tri fate, medorinone, milrinone, pelrinone hydrochloride, amterene, triflocin, urea. pimobendan, piroXimone, prinoXodan, proscillaridin, quazi 0257 Dopaminergic agent: ibopamine. none, tazolol hydrochloride, Vesnarinone. 0258 Ectoparasiticide: nifluridide, permethrin. 0246 Cardiovascular agent: dopexamine, dopexamine 0259 Emetic: apomorphine hydrochloride. hydrochloride. 0260 Enzyme inhibitor: acetohydroxamic acid, alrestatin 0247 Choleretic: dehydrocholic acid, fencibutirol, hyme Sodium, aprotinin, benazepril hydrochloride, benazeprilat, cromone, piprozolin, sincalide, tocamphyl. benurestat, bromocriptine, bromocriptine mesylate, cilastatin US 2012/0046244 A1 Feb. 23, 2012 22

Sodium, fluorofamide, lergotrile, lergotrile mesylate, levcy pins, danazol, testosterone, dehydroepiandrosterone, closerine, libenzapril, pentopril, pepstatin, perindopril, polig androstenedione, dihydroestosterone, relaxin, oxytocin, nate Sodium, Sodium amylosulfate, Sorbinil, spirapril hydro vasopressin, folliculostatin, follicle regulatory protein, gona chloride, spiraprilat, taleranol, teprotide, tolfamide, doctrinins, oocyte maturation inhibitor, insulin growth factor, Zofenopril calcium. follicle stimulating hormone, luteinizing hormone, tamox 0261) Estrogen: chlorotrianisene, dienestrol, diethylstill ifen, corticorelinovine triftutate, coSyntropin, metogest, pitu bestrol, diethylstilbestrol diphosphate, equilin, estradiol, itary, posterior, seractide acetate, Somalapor, somatrem, estradiol cypionate, estradiolenanthate, estradiol undecylate, Somatropin, somenopor, somidobove. estradiol Valerate, estraZinol hydrobromide, estriol, estrofu (0271 Hypocholesterolemic: lifibrol. rate, estrogens, conjugated, estrogens, esterified, estrone, 0272 Hypoglycemic: dargilitaZone sodium: glimepiride. estropipate, ethinyl estradiol, fenestrel, mestranol, nylestriol, 0273 Hypolipidemic: azalanstat dihydrochloride, colles quinestrol. tolone, Surfomer, Xenalipin. 0262 Fibrinolytic: anistreplase, bisobrin lactate, brino 0274) Hypotensive: viprostol. lase. 0275 Hmgcoa reductase inhibitors: lovastatin (MEVA 0263 Free oxygen radical Scavenger: pegorgotein. CORTM), simvastatin (ZOCORTM), pravastatin (PRAVA 0264 Gastrointestinal motility agents: cisapride (PRO CHOLTM), fluvasatin (LESCOLTM). PULSIDTM), metoclopramide (REGLANTM), hyoscyamine 0276. Immunizing agent: antirabies serum, antivenin (la (LEVSINTM). trodectus mactans), antivenin (micrurus fulvius), antivenin 0265. Glucocorticoid: amcinonide, beclomethasone (crotalidae) polyvalent, BCG vaccine, botulism antitoxin, dipropionate, betamethasone, betamethasone acetate, cholera vaccine, diphtheria antitoxin, diphtheria toxoid, diph betamethasone benzoate, betamethasone dipropionate, theria toxoid adsorbed, globulin, immune, hepatitis b immune betamethasone sodium phosphate, betamethasone Valerate, globulin, hepatitis B virus vaccine inactivated, influenza virus carbenoXolone sodium, clocortolone acetate, clocortolone vaccine, measles virus vaccine live, meningococcal polysac pivalate, cloprednol, corticotropin, corticotropin, repository, charide vaccine group A, meningococcal polysaccharide vac corticotropin Zinc hydroxide, cortisone acetate, cortivaZol. cine group C, mumps virus vaccine live, pertussis immune descinolone acetonide, dexamethasone, dexamethasone globulin, pertussis vaccine, pertussis vaccine adsorbed, Sodium phosphate, diflucortolone, diflucortolone pivalate, plague vaccine, poliovirus vaccine inactivated, poliovirus flucloronide, flumethasone, flumethasone pivalate, vaccine live oral, rabies immune globulin, rabies vaccine, Rh flunisolide, fluocinolone acetonide, fluocinonide, fluocor (D) immune globulin, rubella virus vaccine live, smallpox tolone, fluocortolone caproate, fluorometholone, fluperolone vaccine, tetanus antitoxin, tetanus immune globulin, tetanus acetate, fluprednisolone, fluprednisolone Valerate, flurandre toxoid, tetanus toxoid adsorbed, typhoid vaccine, yellow nolide, formocortal, hydrocortisone, hydrocortisone acetate, fever vaccine, Vaccinia immune globulin, varicella-Zoster hydrocortisonebuteprate, hydrocortisone butyrate, hydrocor immune globulin. tisone sodium phosphate, hydrocortisone sodium Succinate, hydrocortisone Valerate, medrysone, methylprednisolone, 0277 Immunomodulator: dimepranolacedoben, imiqui methylprednisolone acetate, methylprednisoloime sodium mod, interferon beta-Ib, lisofylline, mycophenolate mofetil, phosphate, methylprednisolone sodium Succinate, nivaZol. prezatide copper acetate. paramethasone acetate, prednicarbate, prednisolone, pred 0278 Immunoregulator: azarole, fanetizole mesylate, nisolone acetate, prednisolone hemisuccinate, prednisolone frentizole, oxamisole hydrochloride, ristianol phosphate, thy Sodium phosphate, prednisolone sodium Succinate, predniso mopentin, tilomisole. lone tebutate, prednisone, prednival, ticabesone propionate, 0279 Immunostimulant: loxoribine, teceleukin. tralonide, triamcinolone, triamcinolone acetonide, triamci 0280 Immunosuppressant: azathioprine, azathioprine nolone acetonide Sodium, triamcinolone diacetate, triamci Sodium, cyclosporine, daltroban, gusperimus trihydrochlo nolone hexacetonide. ride, sirolimus, tacrolimus. 0266 Gonad-stimulating principle: buserelin acetate, clo 0281 Impotence therapy adjunct: deleduanine hydro miphene citrate, ganirelix acetate, gonadorelin acetate, gona chloride. dorelin hydrochloride, gonadotropin, chorionic, menotro 0282. Inhibitor: acarbose, atorvastatin calcium, benser pins. azide, brocresine, carbidopa, clavulanate potassium, 0267 Hair growth stimulant: minoxidil. daZmegrel, docebenone, epoprostenol, epoprostenol Sodium, 0268 Hemostatic: aminocaproic acid, oxamarin hydro epristeride, finasteride, flurbiprofen sodium, furegrelate chloride, Sulmarin, thrombin, tranexarnic acid. Sodium, lufironil, miglitol, orlistat, pimagedine hydrochlo 0269. Histamine H2 receptor antagonists: ranitidine ride, pirmagrel, ponalrestat, ridogrel, Sulbactam benzathine, (ZANTACTM), famotidine (PEPCIDTM), cimetidine (TAGA Sulbactampivoxil, Sulbactam Sodium, Suronacrine maleate, METTM), nizatidine (AXIDTM). taZobactam, taZobactam Sodium, ticlopidine hydrochloride, 0270 Hormone: diethylstilbestrol, progesterone, 17 tirilazad mesylate, tolrestat, Velnacrine maleate, Zifrosilone, hydroxy progesterone, medroxyprogesterone, norgestrel, Zileuton. norethynodrel, estradiol, megestrol (megace), norethindrone, 0283 Keratolytic: alcloxa, aldioxa, benzoyl peroxide, levonorgestrel, ethyndiol, ethinyl estradiol, mestranol, dibenzothiophene, etarotene, isotretinoin, motretinide, picot estrone, equilin, 17alpha dihydroequilin, equilenin, 17alpha rin diolamine, resorcinol, resorcinol monoacetate, salicylic dihydroequilenin, 17 alpha estradiol, 17 beta estradiol, leu acid, Sumarotene, tazarotene, tetroquinone, tretinoin. prolide (LUPRONTM), glucagon, testolactone, clomiphene, 0284. LHRL agonist: deslorelin, goserelin, histrelin, lutre human menopausal gonadotropins, human chorionic gona lin acetate, nafarelin acetate. dotropin, urofollitropin, bromocriptine, gonadorelin, lutein 0285 Liver disorder treatment: malotilate. izing hormone releasing hormone and analogs, gonadotro 0286 Luteolysin: femprostalene. US 2012/0046244 A1 Feb. 23, 2012

0287 Memory adjuvant: dimoxamine hydrochloride, rib netium Tc'" exametazime, technetium Tc'" furifosmin, aminol. technetium Tc’" gluceptate, technetium Tc" lidofenin, 0288 Mental performance enhancer: aniracetam. technetium Tc’"mebrofenin, technetium Tc’" medronate, 0289 Mood regulator: fengabine. technetium Tc’" medronate disodium, technetium Tc'" 0290 Mucolytic: acetylcysteine, carbocysteine, domi mertiatide, technetium Tc'" oxidronate, technetium Tc 99. odol. pentetate, technetium Tc’” pentetate calcium trisodium, 0291. Mucosal protective agents: misoprostol (CYTO technetium Tc'" sestamibi, technetium Tc'" siboroxime, TECTM). technetium Tc’" succimer, technetium Tc" sulfur colloid, 0292 Mydriatic: berefrine. technetium Tc'"teboroxime, technetium Tc'"tetrofosmin, 0293 Nasal decongestant: nemazoline hydrochloride, technetium Tc’" tiatide, thyroxine I'', thyroxine I'', pseudoephedrine polistirex. tolpovidone I'', triolein I'', triolein I''. 0294 Neuroleptic: duoperone fumarate, risperidone. 0312 Regulator: calcifediol, calcitonin, calcitriol, clo 0295 Neuromuscular blocking agent: atracurium besy dronic acid, dihydrotachysterol, etidronic acid, oxidronic late, cisatracurium besylate, doxacurium chloride, gallamine acid, piridironate Sodium, risedronate sodium, Secalciferol. triethiodide, metocurine iodide, mivacurium chloride, pancu 0313 Relaxant: adiphenine hydrochloride, alcuronium ronium bromide, pipecuronium bromide, rocuronium bro chloride, aminophylline, azumolene sodium, baclofen, ben mide, Succinylcholine chloride, tubocurarine chloride, Vecu Zoctamine hydrochloride, carisoprodol, chlorphenesin car ronium bromide. bamate, chlorZoxazone, cinflumide, cinnamedrine, 0296 Neuroprotective: dizocilpine maleate. clodanolene, cyclobenzaprine hydrochloride, dantrolene, 0297 NMDA antagonist: selfotel. dantrolene sodium, femalamide, fenyripol hydrochloride, 0298) Non-hormonal sterol derivative: pregnenolone suc fetoxylate hydrochloride, flavoxate hydrochloride, fle cinate. tazepam, flumetramide-flurazepam hydrochloride, hexafluo 0299 Oxytocic: carboprost, carboprost methyl, carbo renium bromide, isomylamine hydrochloride, lorbamate, prost tromethamine, dinoprost, dinoprost tromethamine, mebeverine hydrochloride, mesuprine hydrochloride, dinoprostone, ergonovine maleate, meteneprost, methyler metaxalone, methocarbamol, methixene hydrochloride, gonovine maleate, oxytocin, Sparteine Sulfate. nafomine malate, neleZaprine maleate, papaverine hydro 0300 Plasminogen activator: alteplase, urokinase. chloride, pipoxolan. 0301 Platelet activating factor antagonist: lexipafant. 0314 Hydrochloride, quinctolate, ritodrine, ritodrine 0302 Platelet aggregation inhibitor: acadesine, beraprost, hydrochloride, rolodine, theophylline sodium glycinate, beraprost sodium, ciprostene calcium, itaZigrel, lifarizine, thiphenamil hydrochloride, xilobam. OXagrelate. 0315 Repartitioning agent: cimaterol. 0303 Post-stroke and post-head trauma treatment: citi 0316 Scabicide: amitraz, crotamiton. coline Sodium. 0317 Sclerosing agent: ethanolamine oleate, morrhuate 0304 Potentiator: pentostatin, talopram hydrochloride. Sodium, tribenoside. 0305 Progestin: algestone acetophenide, amadinone 0318 Sedative: propiomazine. acetate, anagestone acetate, chlormadinone acetate, cinges 0319 Sedative-hypnotic: allobarbital, alonimid, alpra tol, clogestone acetate, clomegestone acetate, desogestrel, Zolam, amobarbital Sodium, bentazepam, brotizolam, but dimethisterone, dydrogesterone, ethynerone, ethynodiol abarbital, butabarbital sodium, butalbital, capuride, carboclo diacetate, etonogestrel, fluorogestone acetate, gestaclone, ral, chloral betaine, chloral hydrate, chlordiazepoxide gestodene, gestonorone caproate, gestrinone, haloprogester hydrochloride, cloperidone hydrochloride, clorethate, one, hydroxyprogesterone caproate, levonorgestrel, lynestre cyprazepam, dexclamol hydrochloride, diazepam, dichloral nol, medrogestone, medroxyprogesterone acetate, methyno phenaZone, estaZolam, ethchlorVynol, etomidate, fenobam, diol diacetate, norethindrone, norethindrone acetate, flunitrazepam, fosazepam, glutethimide, halazepam, norethynodrel, norgestimate, norgestomet, norgestrel, lormetazepam, mecloqualone, meprobamate, methaqualone, OXogestone phenpropionate, progesterone, quingestanol midaflur, paraldehyde, pentobarbital, pentobarbital sodium, acetate, quingestrone, tigestol. perlapine, prazepam, quazepam, reclazepam, roletamide, 0306 Prostaglandin: cloprostenol sodium, fluprostenol secobarbital, secobarbital Sodium, Suproclone, thalidomide, Sodium, gemeprost, prostalene, Sulprostone. tracazolate, trepipam maleate, triazolam, tricetamide, triclo 0307 Prostate growth inhibitor: pentomone. fos Sodium, trimetozine, uldazepam, Zaleplon, Zolazepam 0308 Prothyrotropin: protirelin. hydrochloride, Zolpidem tartrate. 0309 Psychotropic: minaprine. 0320 Selective adenosineal antagonist: apaxifylline. 0310 Pulmonary surface: beractant, colfosceril palmitate. 0321 Serotonin antagonist: altanserin tartrate, ameser 0311 Radioactive agent: fibrinogen I'', fludeoxyglucose gide, ketanserin, ritanserin. F', fluorodopa F, insulin I', insulin I'', iobenguane 0322 Serotonin inhibitor: cinanserin hydrochloride, fen I', iodipamide sodium I'', iodoantipyrine I'', iodocho clonine, fonazine mesylate, Xylamidine tosylate. lesterol I'', iodohippurate sodium I'', iodohippurate 0323 Serotonin receptor antagonist: tropanserin hydro sodium I'', iodohippurate sodium I'', iodopyracet I'', chloride. iodopyracet I'', iofetamine hydrochloride I'', iomethin 0324 Steroid: dexamethasone aceflrate, mometaSone I', iomethin I'', iothalamate sodium I', iothalamate furoate. sodium I'', iotyrosine I'', liothyronine I'', liothyronine 0325 Stimulant: amfonelic acid, amphetamine sulfate, I'', merisoprol acetate Hg', merisoprol acetate Hg", ampyZine Sulfate, arbutamine hydrochloride, azabon, caf merisoprol Hg', selenomethionine Se', technetium Tc’" feine, ceruletide, ceruletide diethylamine, cisapride, dazo antimony trisulfide colloid, technetium Tc" bicisate, tech pride fumarate, dextroamphetamine, dextroamphetamine netium Tc'" disofenin, technetium Tc" etidronate, tech sulfate, difluanine hydrochloride, dimefline hydrochloride, US 2012/0046244 A1 Feb. 23, 2012 24 doxapram hydrochloride, etryptamine acetate, ethamivan, tionine, adinazolam, adiposin, adoZelesin, adrafinil, alace fenethylline hydrochloride, flubanilate hydrochloride, fluo pril, aladapcin, alaptide, albendazole, albolabrin, rothyl, histamine phosphate, indriline hydrochloride, aldecalmycin, aldesleukin, alendronic acid, alentemol, alfa mefexamide, methamphetamine hydrochlo ride, meth calcidol, alfuizosin, alglucerase, alinastine, alosetron, alpha ylphenidate hydrochloride, pemoline, pyrovalerone hydro idosone, alprostadil, altretamine, altromycin B. ambamus chloride, Xamoterol. Xamoterol fumarate. tine, amelometasone, ameSergide, amezinium metilsulfate, 0326 Suppressant: amfhutizole, coxchicine, tazofelone. 0327 Symptomatic multiple sclerosis: fampridine. amfebutamone, amidox, amifloxacin, amifostine, amio 0328 Synergist: proadifen hydrochloride. darone, amisulpride, amlexanox, amlodipine, amlodipine, 0329. Thyroid hor move: levothyroxine sodium, liothyro ampiroXicam, aminone, amrubicin, amsacrine, amylin, nine Sodium, liotrix. amythiamicin, anagrelide, anakinra, ananain, anaritide, anas 0330. Thyroid inhibitor: methimazole, propylthiouracil. trozole, andrographolide, anordrin, apadoline, apafant, 0331 Thyromimetic: thyromedan hydrochloride. apaxifylline, aphidicolin glycinate, apraclonidine, aprosulate 0332 Tranquilizer: bromazepam, buspirone hydrochlo Sodium, aptiganel, apurinic acid, aranidipine, arbekacin, arbi ride, chlordiazepoxide, claZolam, clobazam, cloraZepate dol, arbutamine, ardeparin Sodium, arecatannin B1, arga dipotassium, cloraZepate monopotassium, demoXepam, troban, aripiprazol, arotinolol, asimadoline, aspalatone, dexmedetomidine, enciprazine hydrochloride, gepirone asperfuran, aspoxicillin, astemizole, asulacrine, atameStanie, hydrochloride, hydroxyphenamate, hydroxy Zine atenolol, S-atevirdine, atosiban, atovaquone, atpenin B, atri 0333 Hydrochloride, hydroxyzine pamoate, ketazolam, mustine, atrinositol, aureobasidin A. azadirachtine, aza lorazepam, lorZafone, loxapine, loxapine Succinate, setron, azatyrosine, azelaic acid, azelastine, azelnidipine, azi medazepam hydrochloride, nabilone, nisobamate, milide, azithromycin, azosemide, aztreonam, baccatin III, oxazepam, pentabamate, piremperone, ripazepam, rolipram, bacoside A, bacoside B, bactobolamine, balazipone, balhi mycin, balofloxacin, balsalazide, bambuterol, baohuoside 1. Sulazepam, taciamine hydrochloride, temazepam, trifluba bamidipine, basifungin, batebulast, batimastat, beauvericin, Zam, tybamate, Valnoctamide. becaplermin, becliconazole, befloxatone, belfosdil, bellena 0334 Amyotrophic lateral sclerosis agents: riluzole. mine, benflumetol, benidipine, benzisoxazole, benzochlor 0335 Cerebral ischemia agents: dextrorphan hydrochlo ins, benzoidazoxan, benzoylstaurosporine, benztropine, ride. bepridil, beractant, beraprost, berlafenone, bertosamil, 0336 Paget’s disease agents: tiludronate disodium. besipirdine, beta-alethine, betaclamycin B, betamipron, 0337 Unstable angina agents: tirofiban hydrochloride. betaxolol, betulinic acid, bevantolol, bicalutamide, bife 0338. Uricosuric: benzbromarone, irtemazole, melane, bimakalim, bimithil, binospirone, bioxalomycin probenecid, Sulfinpyrazone. alpha2, biriperone, bis-benzimidazole A, bis-benzimidazole 0339 Vasoconstrictor: angiotensin amide, felypressin, B, bisantrene, bisaramil, bisaziridinylspermine, bisnafide, methysergide, methysergide maleate. bisoprolol, bistramide D, bistramide K, bistratene A, boldine, 0340 Vasodilator: alprostadil, azaclorzine hydrochloride, bopindolol, brefeldin, breflate, brimonidine, bromfenac, bro bamethan sulfate, bepridil hydrochloride, buterizine, cetiedil mperidol, bropirimine, bucindolol, budesonide, budipine, citrate, chromonar hydrochloride, clonitrate, diltiazem budotitane, bunaprolast, bunaZosin, butenafine, buthionine hydrochloride, dipyridamole, droprenilamine, erythrityl tet Sulfoximine, butiXocort propionate, cadexomer iodine, cal ranitrate, felodipine, flunarizine hydrochloride, fostedil, hex anolide A, calcipotriol, calphostin C, camonagrel, cande obendine, inositol niacinate, iproxamine hydrochloride, isos Sartan, candesartan cilexetil, candoXatril, candoxatrilat, orbide dinitrate, isosorbide mononitrate, isoXSuprine capecitabine, capromab, capsaicin, captopril, carbazomycin hydrochloride, lidoflazine, mefenidil, mefenidil fumarate, C, carbetocin, carbovir, carboxamide-amino-triazole, car mibefradil dihydrochloride, mioflazine hydrochloride, mixi boxyamidotriazole, carboxymethylated glucan, carperitide, dine, nafronyl oxalate, nicardipine hydrochloride, nicer carteolol, carumonam, carvedilol, carvotroline, carZelesin, goline, nicorandil, nicotinyl alcohol, nifedipine, nimodipine, castanospermine, cebaracetam, cecropin B, cefcapene piv nisoldipine, Oxfenicine, oXprenolol hydrochloride, pen oxil, cefdaloxime pentexil tosilate, cefdinir, cefditoren piv taerythritol tetranitrate, pentoxifylline, pentrinitrol, perhexy oxil, cefepime, cefetamet, cefetamet pivoxil, cefixime, ceflu line maleate, pindolol, pirsidomine, prenylamine, propatyl prenam, cefimnetazole, cefimninox, cefodizime, cefoselis, nitrate, Suloctidil, terodiline hydrochloride, tipropidil hydro cefotetan, cefotiam, cefotiam hexetil, cefoZopran, ce?pimi chloride, tolazoline hydrochloride, Xanthinol niacinate. Zole, cefpiramide, cefpirome, cefpodoxime proxetil, cef 0341 Vulnerary: allantoin. prozil, cefsulodin, cefteram, ceftibuten, cefiriaxone, 0342. Wound healing agent: ersofermin. cefuroxime axetil, celastrol, celikalim, celiprolol, cepacidine 0343 Xanthine oxidase inhibitor: allopurinol, oxypurinol. A, cericlamine, cerivastatin, ceronapril, certoparin Sodium, 0344) Other pharmaceutical agents include: 1-decpyrroli cetiedil, cetirizine, chloroorienticin A, chloroorienticin B, dinone, 1-dodecpyrrolidinone, 16C.-fluoroestradiol, 16-epi chloroquinoxaline Sulfonamide, cibenzoline, cicaprost, estriol, 16C.-gitoxin, 17C. estradiol, 17 B estradiol. 1 alpha ciclesonide, cicletanine, cicloprolol, cidofovir, cilansetron, hydroxyvitamin D2,2'-nor-cGMP 20-epi-1,25 cilaZapril, cilnidipine, cilobradine, cilostaZol, cimetropium dihydroxyvitamin D3, 22-oxacalcitriol, 2CVV, 3-isobutyl bromide, cinitapride, cinolazepam, cioteronel, ciprofibrate, GABA, 6-FUDCA, 7-methoxytacrine, abamectin, abanoquil, ciprofloxacin, ciprostene, cis-porphyrin, cisapride, cisatracu abecamil, abiraterone, acadesine, acamprosate, acarbose, rium besilate, cistinexine, citalopram, citicoline, citreamicin aceclofenac, acemannan, acetomepregenol, acetyl-L-car alpha, cladribine, clarithromycin, clausenamide, clebopride, nitine, acetylcysteine, N-acetylmethadol, acifran, acipimox, clinafloxacin, clobazam, clobetaSone butyrate, clodronic acitemate, acitretin, aclarubicin, aclatonium, napadisilate, acid, clomethiazole, clopidogrel, clotrimazole, colestimide, aconiazide, acrivastinet, adafenoxate, adapalene, ada colfosceril palmitate, collismycin A, collismycin B, combre tanserin, adecypenol, adefovir dipivoxil, adelmidrol, ademe tastatin A4, complestatin, conagenin, contignasterol, contor US 2012/0046244 A1 Feb. 23, 2012

trostatin, cosalane, costatolide, cotinine, coumermycin A1, ibogaine, ibopamine, ibudilast, illimaquinone, ilmofosine, cucumariosid, curacin A, curdlan Sulfate, curiosin, cycla ilomastat, illoperidone, iloprost, imidapril, imidazenil, indi Zosin, cyclic HPMPC, cyclobenzaprine, cyclobut A, cyclobut navir, indolidan, indometacin farnesil, indometacin, tropine G. cyclocapron, cycloplatam, cyclosin, cyclothialidine, ester, indoramin, inocoterone, inogatran, inolimomab, inter cyclothiazomycin, cypemycin, cyproterone, cytarabine feron alfa, interferon alfa-2a, interferon alfa-2B, interferon ocfosfate, cytochalasin B, dacliximab, dactimicin, daidzein, alfa-N 1, interferon alfa-N3, interferon B, interferon B-1 A1, daidzin, dalfopristin, dalteparin Sodium, danaparoid, daph interferon B-1B, interferon gamma-1A, interferon gamma nodorin A, dapiprazole, dapitant, darifenacin, darlucin A, 1B, interferon omega, interferon, consensus, interleukin-1, darsidomine, dduTP decitabine, deferiprone, deflazacort, interleukin-1 alpha, interleukin-1B, interleukin-10, interleu dehydrodidemnin B, dehydroepiandrosterone, delapril, kin-11, interleukin-12, interleukin-12, interleukin-15, inter deleduanine, delfaprazine, delmopinol, delphinidin, deoxy leukin-2, interleukin-3, interleukin-4, interleukin-5, interleu pyridinoline, deprodone, depsidomycin, deramciclane, der kin-7, interleukin-8, iobenguane, iobitridol, iodoamiloride, matan Sulfate, desflurane, desirudin, deslorelin, desmo iododoxorubicin, iofratol, iomeprol, iopentol, iopromide, pressin, desogestrel, desoxoarniodarone, detajmium iopyrol, iotriside, ioVersol, ioxilan, ipazilide, IpdR, ipenox bitartrate, dexifosfamide, dexketoprofen, dexloxiglumide, aZone, ipidacrine, ipomeanol, 4-ipriflavone, ipsapirone, irbe dexmedetomidine, dexpemedolac, dexraZoxane, dexSotalol, Sartan, irinotecan, irloxacin, irsogladine, irtemazole, isal dextrin 2-Sulphate, dexVerapamil, dezinamide, dezocine, Steine, isbogrel, isepamicin, isobengaZole, isofloxythepin, diaziquone, diclofenac digolil, diclofenac potassium, dicra isohomohalicondrin B, isopropyl unoprostone, isradipine, nin, didemnin B, didox, dienogest, diethylhomospermine, itameline, itasetron, itopride, itraconazole, ketoprofen, R-ke diethylnorspermine, dihydrexidine, dihydro-5-azacytidine, toprofen, S-ketorolac, lacidipine, lactitol, lactivicin, laennec, dimethyl prostaglandin A1, dimethylhomospermine, lafutidine, lamelrarin-N triacetate, lamifiban, lamivudine, dimiracetam, dioxamycin, diphency prone, diphenyl spiro lamotrigine, lanoconazole, lanperisone, lanreotide, lanSopra mustine, diprafenone, dipropylnorspermine, dirithromycin, Zole, latanoprost, lateritin, laurocapram, lazabemide, leme discodermolide, disulfuram, ditekiren, docarpamine, floxacin, lemildipine, leminoprazole, lenercept, lenograstim, docosanol. 1-dofetilide, dolasetron, domitroban, dopexam lentinan Sulfate, leptin, leptolstatin, lercanidipine, lerisetron, ine, dorzolamide, doSmalfate, dotarizine, doxacurium chlo lesopitron, letraZuril, letrozole, leucomyzin, leuprorelin, ride, doxazosin, doxifluridine, doxofylline, draculin, drafla levcromakalim, levetiracetam, levobetaxolol, levobunolol, Zine, droloxifene, dronabinol, drosperidone, drotaverine levobupivacaine, levocabastine, levocamitine, levodro acephyllinate, droxicam, ebiratide, ebrotidine, ebselen, propizine, levofloxacin, levomoprolol, levonorgestrel, ecabapide, ecabet, ecadotril, ecdlisteron, echicetin, echistatin, levormeloxifene, levosimendan, levoSulpiride, linotroban, ecomustine, ecteinascidin 722, ecteinascidin 729, ecteinasci linsidomine, lintitript, lintopride, liothyronine Sodium, lirex din 743, edaravone, edelfosine, edobacomab, edrecolomab, apride, lisinopril, lobaplatin, lobucavir, lodoxamide, lombri efegatran, eflornithine, efonidipine, egualen, elcatonin, elet cine, lomefloxacin, lomerizine, lometrexol, lonazolac, riptan, elgodipine, eliprodil, eltenac, emakalim, emedastine, lonidamine, loracarbef, loratadine, lorglumide, lomoxicam, emiglitate, emitefur, emoctakin, enadoline hydrochloride, losartan, losigamone, losoxantrone, loteprednol, loviride, enalapril, enaZadrem, englitaZone, enlimomab, enoxacin, loxoribine, lubeluzole, lurtotecan, luteinizing hormone, lute enoxaparin Sodium, enoXimone, entacapone, enterostatin, tium, luZindole, lydicamycin, lysofylline, lysostaphin, epoprostenol, epoxymexrenone, epristeride, eprosartan, magainin 2 amide, magnolol, mallotochromene, malloto eptastigmine, erdosteine, ersentilide, erSofermin, erytlritol, japonin, malotilate, mangafodipir, manidipine, maniwamy esuprone, etanidazole, etanterol, ethacizin, ethinylestradiol. cinA, mannostatin A, manumycin E, manumycin F. mapinas etizolam, etodolac, etoposide phosphate, etrabamine, everni tine, marimastat, masoprocol, maspin, massetolide, nomicin, examorelin, exemestane, fadrozole, faerieflungin, meterelin, methoxatone, methylhistamine, R-alpha, methyli famciclovir, fampiridine, fantofarone, faropenem, fasidotril, nosine monophosphate, methylprednisolone aceponate, fasudil, fazarabine, fedotozine, felbamate, fenofibrate, methylprednisolone Suleptanate, metipamide, metoclopra fenoldopam, fenretinide, fenspiride, fenticonazole, fepradi mide, metoprolol. S-metrifonate, mibefradil, michellamine nol, ferpifosate Sodium, ferristene, ferrixan, ferumoxsil, fex B, microcolin A, midodrine, mifepristone, miglitol, millace ofenadine, flavopiridol, flecamide, flerobuterol, fleroxacin, mide, milameline, mildronate, milnacipran, milrinone, milte flesinoxan, flezelastine, flobufen, flomoxef, florfenicol, flo fosine, minaprine, miokamycin, mipragoside, mirfentanil, rifenine, flosatidil, fluasterone, fluconazole, fludarabine, flu mirimoStim, mirtazapine, misoprostol, mitoguaZone, mito mazenil, flumecinol, flumequine, flunarizine, fluocalcitriol, lactol, mitonafide, mitoxantrone, mivacurium chloride, fluorodaunorunicin hydrochloride, fluoxetine, R-fluoxetine, mivaZerol, mixanpril, mizolastine, mizoribine, moclobe S-fluparoxan, flupirtine, flurbiprofen axetil, flurithromycin, mide, modafinil, moexipril, mofarotene, mofeZolac, molgra fluticasone propionate, flutrimazole, fluvastatin, fluvoxam mostim, mometasone, montirelin, mopidamol, moracizine, ine, forasartan, forfenimex, formestane, formoterol, formot mosapramine, mosapride, motilide, moxiraprine, moxoni erol, R.R-fosfomycin, trometamol, fosinopril, fosphenyloin, dine, nadifloxacin, nadroparin calcium, nafadotride, nafamo fostriecin, fotemustine, gabapentin, gadobenic acid, stat, nafarelin, naftopidil, naglivan, nagrestip, nalmefene, gadobutrol, gadodiamide, gadodiamide-EOB-DTPA, gado naphterpin, napsagatran, naratriptan, nartograstim, nasaru linium texaphyrin, gadoteric acid, gadoteridol, gadoverseta plase, nateplase, niperotidine, niravoline, nisamycin, nisin, mide, galantamine, galdansetron, gallopamil, galocitabine, nisoldipine, nitazoxanide, nitecapone, nitrendipine, nitren gamolenic acid, ganirelix, gepirone, gestrinone, girisopam, dipine, S-nitrofurantoin monohydrate, nitrullyn, nizatidine, glaspimod, glaucocalyxin A, glutapyrone, glycopine, glyco ofloxacin, okicenone, olanzapine, olopatadine, olprinone, pril, granisetron, grepafloxacin, halichondrin B, halofantrine, olsalazine, omeprazole, onapristone, ondansetron, halomon, halopredone, hatomamicin, hatomarubigin A, ondansetron, R-Ontazolast, oracin, otenZepad, oxaliplatin, hatomarubigin B, hatomarubigin C, hatomarubigin D, oxamisole, Oxandrolone, oxaprozin, oxaunomycin, oXcarba US 2012/0046244 A1 Feb. 23, 2012 26

Zepine, oxiconazole, oxiracetam, oxodipine, oZagrel, palaua bodipine, tropisetron, trospectomycin, trovafloxacin, troVir mine, palinavir, palmitoylrhizoxin, pamaqueside, pam dine, tucaresol, tulobuterol, tylogenin, urapidil, uridine icogrel, pamidronic acid, panamesine, panaxytriol, triphosphate, Valaciclovir, Valproate magnesium, valproate panipenem, panipenum, pannorin, panomifene, pantethine, semisodium, Valsartan, Vamicamide, Vanadeine, Vaminolol. pantoprazole, parabactin, pamaparin Sodium, paroxetine, Vapreotide, variolin B. velaresol, Venlafaxine, Veramine, parthenolide, paZelliptine, paZufloxacin, pefloxacin, pegas Verapamil, S-Verdins, Veroxan, Verteporfin, Vesnarinone, pargase, peldesine, pemedolac, pemirolast, penciclovir, pen Vexibinol, vigabatrin, vinbumine citrate, vinbumine resinate, tafuside, pentamidine, pentamorphone, pentigetide, pen Vinconate, Vinorelbine, Vinpocetine, Vinpocetine citrate, Vin tosan, pentostatin, pentroZole, perflubron, perfosfamide, toperol, Vinxaltine, Voriconazole, Vorozole, Voxergolide, pergolide, perindoprilat, peroSpirone, phenaridine, phenazi Xemilofiban, Ximoprofen, yangambin, Zabicipril, Zacopride, nomycin, phenserine, phensuccinal, phentolamine mesilate, Zacopride, R-Zafirlukast, Zalcitabine, Zaleplon, Zalospirone, phenylacetate, phenylalanylketoconazole, picenadol, piciba Zaltoprofen, Zanamivir, Zankiren, Zanoterone, Zatebradine, nil, picroliv, picumeterol, pidotimod, pilocarpine hydrochlo Zatosetron, Zenarestat, Zeniplatin, Zifrosilone, Zilascorb, ride, pilsicamide, pimagedine, pimilprost, pimobendan, pina Zileuton, Zinostatin stimalamer, Ziprasidone, Zoledronic acid, cidil, pinocebrin, pioglitaZone, pipecuronium bromide, Zolmitriptan, Zolpidem, Zonisamide, Zopiclone, Zopiclone, pirarubicin, piretanide, pirfenidone, piritrexim, pirlindole, S-Zopolrestat, Zotepine. pirmagrel, pirmenol, pirodavir, pirodomast, piroXicam cin 0345 Specific Examples of Antibacterials namate, propagermanium, propentofylline, propionylcam 0346 When antibacterial activity is a desired property of itine, L-propiram, propiram-paracetamol, propiverine, pro the disclosed ionic liquids, one or more of the ions in the pyl bis-acridone, prostaglandin J2, prostratin, protegrin, disclosed ionic liquids can be an antibacterial. That is the one protoSufloxacin, prulifloxacin, pyrazoloacridine, quazepam, or more kinds of cations, one or more kinds of anions, or both quetiapine, quiflapon, quinagolide, quinapril, quinfamide, cations and anions can be an antibacterial. Many of Suitable quinupristin, raloxifene, raltitrexed, ramatroban, ramipril, antibacterial have already been disclosed herein (e.g., many ramosetron, ranelic acid, ranitidine bismuth citrate, ranola QACs have antibacterial properties). Further examples of Zine, recainam, regavirumab, relaxin, repirinast, resinfera Suitable antibacterial agents include, but are not limited to, toxin, reticulon, reviparin sodium, revizinone, ricasetron, acedapsone, acetosulfone sodium, alamecin, alexidine, amdi ridogrel, rifabutin, rifapentine, rifaximin, rilopiroX, riluzole, nocillin, amdinocillin pivoxil, amicycline, amifloxacin, ami rimantadine, rimexolone, rimoprogin, riodipine, ripisartan, floxacin meSylate, amikacin, amikacin Sulfate, aminosali risedronic acid, rispenzepine, risperidone, ritanserin, riti cylic acid, aminosalicylate sodium, amoxicillin, penem, ritipenemacoxil, ritolukast, ritonavir, rizatriptan ben amphomycin, amplicillin, amplicillin Sodium, apalcillin Zoate, rohitukine, rokitamycin, ropinirole, ropivacaine, Sodium, apramycin, aspartocin, astromicin Sulfate, avilamy roquinimex, roXatidine, roXindole, roXithromycin, rubigi cin, avoparcin, azithromycin, azlocillin, azlocillin Sodium, none B1, ruboxyl, rufloxacin, rupatidine, ruzadolane, Safin bacampicillin hydrochloride, bacitracin, bacitracin methyl gol, Safironil, Saintopin, salbutamol, R-Salmeterol, Salme ene disalicylate, bacitracin Zinc, bambermycins, benzoylpas terol, R-Sainacedin, sameridine, Sampatrilat, Sanfetrinem, calcium, berythromycin, betamicin Sulfate, biapenem, binira Saprisartan, sapropterin, saquinavir, sarcophytol A Sargra mycin, biphenamine hydrochloride, bispyrithione mag mostim, Sarpogrelate, Saruplase, Saterinone, satigrel, Satumo Sulfex, butikacin, butirosin Sulfate, capreomycin Sulfate, car mab pendetide, selegiline, selenium thiosemicarbazone, badox, carbenicillin disodium, carbenicillin indanyl Sodium, sematilide, semduramicin, Semotiadil, Semustine, sermore carbenicillin phenyl sodium, carbenicillin potassium, caru lin, Sertaconazole, sertindole, Sertraline, setiptiline, monam sodium, cefaclor, cefadroxil, cefamandole, cefaman Sevirumab, sevoflurane, seZolamide, silipide, silteplase, sim dole nafate, cefamandole sodium, cefaparole, cefatrizine, endan, simvastatin, sinitrodil, sinnabidol, sipatrigine, siroli cefazaflur Sodium, cefazolin, cefazolin Sodium, cefbupera mus, sizofuran, Somatomedin B, Somatomedin C. Somatrem, Zone, cefdinir, cefepime, cefepime hydrochloride, cefetecol, Somatropin, Sonermin, Stalol, staurosporine, stavudine, cefixime, cefimenoXime hydrochloride, cefimetazole, stepronin, stipiamide, Stiripentol, Stobadine, Succibun, cefnetazole sodium, cefonicid monosodium, cefonicid Sucralfate, Sulfasalazine, Sulfmosine, Sulfoxamine, Sodium, cefoperaZone sodium, ceforanide, cefotaxime Sulopenem, Sultamicillin, Sultopride, Sulukast, Sumatriptan, Sodium, cefotetan, cefotetan disodium, cefotiam hydrochlo Symakalim, tandospirone, tapgen, taprostene, tasosartan, ride, cefoxitin, cefoxitin Sodium, cefpimizole, ce?pimizole taZanolast, tazarotene, teicoplanin, telenzepine, tellurapyry Sodium, cefpiramide, ce?piramide sodium, cefpirome Sulfate, lium, telmesteine, telmisartan, temocapril, temoporfin, temo cefpodoxime proxetil, cefprozil, cefroxadine, cefsulodin Zolomide, tenidap, teniposide, tenosal, tenoxicam, tepirin Sodium, ceftazidime, ceftibuten, ceftizoxime Sodium, ceftri dole, tepoxalin, teraZosin, terbinafine, terfenadine, aXone sodium, cefuroxime, cefuroxime axetil, cefuroxime terflavoxate, terguride, terlakiren, terlipressin, terodiline, ter pivoxetil, cefuroxime Sodium, cephacetrile sodium, cephal tatolol, testosterone buciclate, tetrachlorodecaoxide, tetra exin, cephalexin hydrochloride, cephaloglycin, cephalori Zomine, thaliblastine, thalidomide, thiocoraline, thiofedrine, dine, cephalothin Sodium, cephapirin Sodium, cephradine, thiomarinol, thioperamide, thyroid stimulating hormone, cetocycline hydrochloride, cetophenicol, chloramphenicol, tiagabine, tianeptine, tiapafant, tibolone, ticlopidine, tienox chloramphenicol palmitate, chloramphenicol pantothenate olol, tilisolol, tilnoprofen arbamel, tiludronic acid, tinzaparin complex, chloramphenicol sodium Succinate, chlorhexidine Sodium, tiotropium bromide, tipredane, tiqueside, tirandaly phosphanilate, chloroxylenol, chlortetracycline bisulfate, digin, tirapazamine, tirilazad, tirofiban, tiropramide, topsen chlortetracycline hydrochloride, cinoxacin, ciprofloxacin, tin, torasemide, toremifene, to Sufloxacin, trafermin, trandola ciprofloxacin hydrochloride, cirolemycin, clarithromycin, pril, traXanox, tretinoin, tretinoin tocoferil, triacetyluridine, clinafloxacin hydrochloride, clindamycin, clindamycin tricaprilin, trichohyalin, trichosanthin, alpha, triciribine, tri hydrochloride, clindamycin palmitate hydrochloride, clinda entine, triflavin, trimegestone, triptorelin, troglitaZone, trom mycin phosphate, clofazimine, cloxacillin benZathine, clox US 2012/0046244 A1 Feb. 23, 2012 27 acillin Sodium, cloxyquin, colistimethate sodium, colistin Somizole, Sulfathiazole, Sulfazamet, Sulfisoxazole, Sulfate, coumermycin, coumermycin Sodium, cyclacillin, Sulfisoxazole acetyl, Sulfisboxazole diolamine, Sulfomyxin, cycloserine, dalfopristin, dapsone, daptomycin, demeclocy Sulopenem, Sultamricillin, Suncillin sodium, talampicillin cline, demeclocycline hydrochloride, demecycline, denofun hydrochloride, teicoplanin, temafloxacin hydrochloride, gin, diaveridine, dicloxacillin, dicloxacillin Sodium, dihy temocillin, tetracycline, tetracycline hydrochloride, tetracy drostreptomycin Sulfate, dipyrithione, dirithromycin, cline phosphate complex, tetroXoprim, thiamphenicol, doxycycline, doxycycline calcium, doxycycline fosfatex, thiphencillin potassium, ticarcillin cresyl Sodium, ticarcillin doxycycline hyclate, droxacin Sodium, enoxacin, epicillin, disodium, ticarcillin monosodium, ticlatone, tiodonium chlo epitetracycline hydrochloride, erythromycin, erythromycin ride, tobramycin, tobramycin Sulfate, to Sufloxacin, trimetho acistrate, erythromycin estolate, erythromycin ethylsucci prim, trimethoprim Sulfate, trisulfapyrimidines, troleando nate, erythromycin gluceptate, erythromycin lactobionate, mycin, trospectomycin Sulfate, tyrothricin, Vancomycin, erythromycin propionate, erythromycin Stearate, ethambutol Vancomycin hydrochloride, Virginiamycin, and Zorbamycin. hydrochloride, ethionamide, fleroxacin, floxacillin, fludala Penicillin G, which is used as an antibacterial agent for infec nine, flumequine, fosfomycin, fosfomycin tromethamine, tions including pneumonia, meningitis, and skin, bone, joint, fumoxicillin, furazolium chloride, furazolium tartrate, fusi stomach, blood, and heart valve infections, is a particular date sodium, fusidic acid, gentamicin Sulfate, gloXimonam, example suitable for use herein. tazobactum, sold under the gramicidin, haloprogin, hetacillin, hetacillin potassium, trade names ZOSYNTM and TAZOCINTM, ceftrioxone, sold hexedine, ibafloxacin, imipenem, isoconazole, isepamicin, under the trade name ROCEPHINTM, and metronidazol, sold isoniazid, josamycin, kanamycin Sulfate, kitasamycin, levo under the trade name FLAGYLTM, are also used to treat furaltadone, levopropylcillin potassium, lexithromycin, lin bacterial infections and are further examples of suitable com comycin, lincomycin hydrochloride, lomefloxacin, lom pounds that can be used to prepare the disclosed ionic liquids. efloxacin hydrochloride, lomefloxacin mesylate, loracarbef, 0347 These and other suitable antibacterials can be iden mafenide, meclocycline, meclocycline Sulfosalicylate, mega tified based on the desired properties of the antibacterial and lomicin potassium phosphate, medulidox, meropenem, meth whether the antibacterial active is or can be converted into an acycline, methacycline hydrochloride, methenamine, meth ion. As noted, identification of whetheran antibacterial active enamine hippurate, methenamine mandelate, methicillin is an ion or can be converted into an ion can be done by a Sodium, metioprim, metronidazole hydrochloride, metron skilled artisan inspecting the chemical structure of the anti idazole phosphate, mezlocillin, meZlocillin Sodium, minocy bacterial. cline, minocycline hydrochloride, mirincamycin hydrochlo (0348 Specific Examples of Antiviral ride, monensin, monensin Sodiumr, nafcillin Sodium, 0349 When antiviral activity is a desired property of the nalidixate sodium, nalidixic acid, natainycin, nebramycin, disclosed ionic liquids, one or more of the ions in the dis neomycin palmitate, neomycin Sulfate, neomycin unde closed ionic liquids can be an antiviral. Examples of Suitable cylenate, netilmicin Sulfate, neutramycin, nifuiradene, antiviral actives include, but are not limited to, acemannan, nifuraldezone, nifuratel, nifuratrone, nifurdazil, nifurimide, acyclovir, acyclovir Sodium, adefovir, alovudine, alvircept nifiupirinol, nifurquinazol, nifurthiazole, nitrocycline, nitro Sudotox, amantadine hydrochloride, aranotin, arildone, furantoin, nitromide, norfloxacin, novobiocin Sodium, atevirdine mesylate, pyridine, cidofovir, cipamfylline, cyt ofloxacin, onnetoprim, oxacillin sodium, oximonam, oxi arabine hydrochloride, delavirdine mesylate, desciclovir, monam Sodium, oxolinic acid, oxytetracycline, oxytetracy didanosine, disoxaril, edoxudine, enviradene, enviroXime, cline calcium, oxytetracycline hydrochloride, paldimycin, famciclovir, famotine hydrochloride, fiacitabine, fialuridine, parachlorophenol, paulomycin, pefloxacin, pefloxacin mesy fosarilate, foScarnet Sodium, fosfonet Sodium, ganciclovir, late, penamecillin, penicillin G benzathine, penicillin G ganciclovir Sodium, idoxuridine, kethoxal, lamivudine, lobu potassium, penicilling procaine, penicilling sodium, peni cavir, memotine hydrochloride, methisaZone, nevirapine, cillin V, penicillin V benzathine, penicillin V hydrabamine, penciclovir, pirodavir, ribavirin, rimantadine hydrochloride, penicillin V potassium, pentizidone sodium, phenyl ami saquinavir meSylate, Somantadine hydrochloride, Sorivudine, nosalicylate, piperacillin Sodium, pirbenicillin Sodium, piri statolon, stavudine, tillorone hydrochloride, trifluridine, Vala dicillin Sodium, pirlimycin hydrochloride, pivampicillin cyclovir hydrochloride, Vidarabine, Vidarabine phosphate, hydrochloride, pivampicillin pamoate, pivampicillin Vidarabine Sodium phosphate, viroXime, Zalcitabine, Zidovu probenate, polymyxin B sulfate, porfiromycin, propikacin, dine, Zinviroxime, and Tamiflu. pyrazinamide, pyrithione Zinc, quindecamine acetate, quinu 0350. These and other suitable antivirals can be identified pristin, racephenicol, ramoplanin, ranimycin, relomycin, based on the desired properties of the antiviral and whether repromicin, rifabutin, rifametane, rifamexil, rifamide, the antiviral is or can be converted into an ion. As noted, rifampin, rifapentine, rifaximin, rollitetracycline, rollitetracy identification of whether an antiviral is an ion or can be cline nitrate, rosaramicin, rosaramicin butyrate, rosaramicin converted into an ion can be done by a skilled artisan inspect propionate, rosaramicin Sodium phosphate, rosaramicin ing the chemical structure of the antiviral. Stearate, rosoxacin, roXarsone, roXithromycin, Sancycline, 0351 Specific Examples of Pesticidal Actives Sanfetrinem Sodium, Sarmoxicillin, Sarpicillin, scopafungin, 0352. When pesticidal activity is a desired property of the Sisomicin, sisomicin Sulfate, sparfloxacin, spectinomycin disclosed ionic liquids, one or more of the ions in the dis hydrochloride, spiramycin, stallimycin hydrochloride, Steffi closed ionic liquids can be a pesticide. Included within the mycin, Streptomycin Sulfate, streptonicozid, Sulfabenz, Sul meaning of "pesticide' are insecticides and fungicides. fabenzamide, Sulfacetamide, Sulfacetamide Sodium, Sulfacy Examples of suitable pesticides include, but are not limited to, tine, Sulfadiazine, Sulfadiazine sodium, Sulfadoxine, carfentraZone-ethyl, SulfentraZone, clomaZone, diclofop-me Sulfalene, Sulfamerazine, Sulfameter, Sulfamethazine, Sul thyl, oxamyl propargite, prosulfuron, pyridate, pyriftalid, famethizole, Sulfamethoxazole, Sulfamonomethoxine, Sulfa S-metolachlor, simazine, terbuthylazine, terbutryn, triasulfu moXole, Sulfanilate Zinc, Sulfanitran, Sulfasalazine, Sulfa ron, trifloxysulfuron, trinexapac-ethyl, ametryn, atrazine, US 2012/0046244 A1 Feb. 23, 2012 28 benoxacor, bifenthrin, butafenacil, choline azide, chlortolu limited to, glyphosate, pendimethalin, trifluralin, asulam, tri ron, cinosulfuron, clodinafop, cloquintocet, DEET, desm aziflam, diflufenican, glufosinate-ammonium, and the like. etryn, dicamba, dimethachlor, dimethametryn, DTPA NaFe, Clofencet, fluoroxpyr, mesosulfuron, diflufenzopyr are fur EDDHA NaFe, fenclorim, flumetralin, fluometuron, fluthi ther examples of suitable herbicides and they are FDA acetmethyl, halosulfuron, isoproturon, metobromuron, meto approved. lachlor, norflurazon, oxasulfuron, piperophos, pretilachlor, 0357 Specific Examples of Other Ions primisulfuron, prometryn, propaquizafop, acilbenzolar-s-me 0358. In addition to the pharmaceutical, antibacterial, thyl, chlorothalonil, cyproconazole, cyprodinil, difenocona antiviral, pesticidal, and herbicidal actives disclosed herein, Zole, fenpropidin, fempropimorph, furalaxyl, metalaxyl, other compounds that are ions or can be converted to ions can metalaxyl-m, oxadixyl, penconazole, propiconazole, be used in the disclosed ionic liquid compositions. Specific pyrifenox, thiabendaZol, abamectin, bromopropylate, cyper examples of these include, but are not limited to, the food methrin, cypermethrin high-cis, cyromazine, diafenthiuron, additives Allura Red AC (FD&C Red No. 40), Tartrazine diazinon, dichlorvos, disulfoton, emamectinbenzoate, (FD&C Yellow No. 5), Indigotine (FD&C Blue No. 2), Eryth fenoxycarb, formothion, furathiocarb, lufenuron, methi rosine (FD&C Red No. 3), and SunsetYellow (FD&C Yellow dathion, permethrine, codilemone, phosphamidon, profeno No. 6), which are FDA-approved color additives for food use. fos, pymetrozine, quinalphos, terrazole, thiamethoxam, thio Further, nutraceuticals such as fatty acids, cholesterols, Vita cyclam, thiometon, triallate, trifloxystrobin, VincloZolin, mins, minerals, and trace elements can be suitable ions for the Zetacypermethrin, and the like. Prohexadione is a FDA disclosed ionic liquid compositions. SEA-NIN-211 is an anti approved reduced risk fungicide and is also useful for the foulant that can be used as an ionid the disclosed composi disclosed ionic liquids. Further examples of suitable pesti tions. cides can be found in The Pesticide Manual, 11" Edition, British Crop Protection Council, 1997, which is incorporated Liquid Ion Pairs by reference herein at least for its teaching of pesticides. 0359 Dual functioning organic salts that do not behave as 0353. These and other suitable pesticides can be identified free ions either neat or in a solvent (including water) will based on the desired properties of the pesticide and whether retain the functionality of eachion in close enough proximity the pesticide is or can be converted into an ion. As noted, to lead to synergistic effects. The degree of association (or identification of whether a pesticide is an ion or can be con conversely dissociation) will affect the physical, chemical, Verted into an ion can be done by a skilled artisan inspecting and importantly, the biological properties. the chemical structure of the pesticide. 0360 Ion pairing/clustering which imparts some extra 0354) Specific Examples of Herbicidal Actives (other than merely additive) effect in operation, e.g., 0355. When herbicidal activity is a desired property of the enhances the therapeutic effect or increases the activity disclosed ionic liquids, one or more of the ions in the dis of the individual ions OR decreases the activity. While closed ionic liquids can be a herbicide. Examples of suitable this latter may often seem to be unimportant there are herbicides include, but are not limited to, carfentraZone, cases where it would be desirable, e.g., in slow release imazapyr, benefin, acifluorfen, and 2-2-chloro-3-(2.2.2-trif formulations (activity here may refer to solubility or rate luoroethoxymethyl)-4-methylsulfonylbenzoylcyclohexane of diffusion from the reservoir). 1 0361. The ability to “design a liquid salt that is the thermodynamically most stable state AT a specific tem 0356. Other suitable herbicides include inhibitors of the perature, i.e., NOT a quenched amorphous phase that biosynthesis of branched amino acids Such as ethoxysulfu may crystallize, is important as this offers opportunities ron, flumetSulam, halosulfuron, imaZamox, imazapyr, imaza informulation of, e.g., emulsions and will almost always quin, imazethapyr, metoSulam, nicosulfuron, primisulfuron, provide a more soluble or dispersible form than a crys prosulfuron, rimsulfuron, thifensulfuron-methyl, triflusulfu talline form. ron, N-(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl-2- 0362. The concept of specific stoichiometric salts— dimethylaminocar-bonyl-5-formylaminobenzenesulfona note that this sort of clustering may also be of import. mide (Foramsulfuron), and the like. Still further, suitable 0363 The activity of drugs in the body is not the only herbicides include inhibitors of the photosynthesis electron consideration, but also the formulation advantages that transport Such as ametryne, atrazine, bromoxynil, cyanazine, may accrue from having an ion-pairing or ion-clustering diuron, hexazinone, metribuzin, pyridate, terbuthylazine, and salt. the like. In yet further examples, suitable herbicides for the 0364. In applications other than drugs (though also disclosed ionic liquids include synthetic auxins such as copy applies here, particularly to pro-drugs that hydrolyze or ralid, dicamba, diflufenZopyr, fluoroxypyr, and the like. easily degraded drugs—analogous to protection against Inhibitors offatty acid biosynthesis, such as butylate, EPTC, UV degradation by formulation as inclusion com fenoxaprop-P-ethyl, and the like, can also be used in the plexes), some of the advantages will be in the ability to disclosed ionic liquid compositions. In other examples, Suit create a liquid formulation that DOES NOT require water—advantages are a) stabilization; b) ease of dis able herbicides can include inhibitors of cell division such as persion/dissolution upon introduction into an aqueous acetochlor, alachlor, dimethenamid, flufenacet, mefenacet, system and c) possibilities to dissolve other Substances metolachlor, S-metolachlor, thenylchlor, and the like. In still in these salts—for example "edible IL to dissolve other examples, the herbicide can be an inhibitor of protopor drugs’ the liquid salts could be used to dissolve other phyrinogen oxidase, Such as fluthiacet-methyl, carfentra Solid actives. Zone-ethyl, and the like. Inhibitors of hydroxyphenylpyruvate 0365. Many examples of liquid organic salts are far from dioxygenase, Such as isoxaflutole, mesotrione, Sulcotrione, fully ionized. Instead, they form ion pairs and aggregates of 4-(4-trifluoromethyl-2-methylsulfonylbenzoyl)-5-hydroxy ions in the liquid State and are better described as Liquid Ion 1-methyl-3-methylpyrazole, and the like, can also be used. Pairs than “Ionic Liquids'. The distinction between these Further examples of suitable herbicides include, but are not states can be made on the basis of the behavior of the transport US 2012/0046244 A1 Feb. 23, 2012 29 property data when plotted in a Walden plot. The Walden plot al., Journal of Physical Chemistry, 1981. 85 p. 1461-1464: is a graph of log equivalent conductivity (corrected for molar MacFarlane, D. R. R. K. Kadiyala, and C. A. Angell, Journal Volume) vs. log fluidity and thus may be used to estimate the of Chemical Physics, 1983. 79 p. 3921-3927, Journal of degree of association cations and anions (as correlated Physical Chemistry, 1983.87 p. 1094-1095; MacFarlane, D., motion of cation and anion clusters). Ionic Liquids typically Cryobiology, 1985. 22 p. 601-602; MacFarlane, D. R. Cryo lie within one order of magnitude of the “Ideal Ionic Liquid biology, 1986. 23 p. 559-560; MacFarlane, D. R., Cryobiol line (that line on which salts which exhibit no correlated ogy, 1986. 23 p. 230-244: MacFarlane, D. R., Cryobiology, motion of cation and anion lie) meaning that they are between 1987. 24 p. 181-195). Typical binary phase diagrams have 10 and 100% ionic. Liquid Ion Pairs lie beyond this region, been established and show the characteristics illustrated in i.e., more than one order of magnitude away from the Ideal FIG 1. line. Such liquid salts are less than 10% ionized. Examples of 0378. At high water contents (Region A of the diagram) Such liquid salts of therapeutic ions include propanthaline the sample will crystallize ice during cooling in the DSC and tosylate which is about 1% ionized, as estimated from the exhibit a Subsequent melting peak during warming. This peak Walden plot (FIG. 7). is more precisely described as the ice liquidus peak, corre 0366. This degree of association of cations and anions (as sponding to the process of ice dissolution into the solution. ion pairs or larger clusters) will affect various physico-chemi The liquidus line of ice in these solutions is denoted TL. cal properties of the salts; for example, greater “ion-pairing 0379 At lower water contents, corresponding to the (which should be understood to mean clustering of any num middle of this diagram, Region B, the ice crystalisation dur ber of cations and anions) will yield a more fluid and more ing cooling, or at low temperatures during Subsequent warm Volatile salt as ion pairs (or clusters) move as single entities ing, becomes less extensive and more sluggish, since less bulk and may be vaporized as uncharged clusters which thus more water is available to freeze into ice. Annealing experiments readily escape the liquid due to decreased coloumbic interac can be used to allow the ice to form and one observes the tions with the bulk. liquidus line falling rapidly in Region B. In the absence of a 0367 If such ion-pairing, or clustering, persists in solution fully formed eutectic, which is common in many aqueous— cation or anion interactions with the environment, e.g., the salt binaries, part of the Solution remains unfrozen during the body, will not simply be additive and the salt will not behave cooling or annealing treatment. This part contains all of the in the same way as a 1:1 molar mixture of salts containing the salt and some water. The composition of the unfrozen part can same cation and anion. In addition, such ion-pairing, or ion be estimated from the phase diagram and the lever rule. Evi clustering, salts may form a separate phase in certain solvent dence for this can also be seen via the appearance of a glass systems and may thus be utilized as emulsions or other dis transition at temperature denoted Tg in the partially frozen persed phases. The non-additive effect of cation and anion in solution. Since the composition of the unfrozen fraction is ion-paired, or clustered, salts may be either synergistic (en independent of starting concentration, Tg is almost compo hanced efficacy) or antagonistic (decreased efficacy) and this sition independent through regions A and B as seen in the allows modulation of properties by judicious choice of cation/ diagram. anion pairs in Salt formation. 0380 At some point in region B, depending on the cooling 0368. Opportunities exist for the preparation of: rate applied, it will be possible to quench the sample into the 0369 Enhanced therapeutic salt substances which com glassy State without the crystallisation of any ice. The warm bine: ing DSC trace then will show the true Tg for that composition 0370 2API ions chosen for specific activity (marked as Tg in FIG. 1). Typically Tg is a strong function of 0371 an API ion and second active which alters composition through regions B and C. Despite the ability to physicochemical properties such as lipophilicity, thus quench into a fully glassy state, the sample can still crystallize changing, for example, membrane or transdermal ice during warming in region B, indicating that solvent water transport still exists in the solution. 0372 an API ion and second ion which serves to 0381. However, in region BTL is rapidly approaching Tg mask unpleasant taste and/or Smell and, at the composition where it falls below Tg, formation of 0373 animal therapeutic substances ice becomes an insignificant event on any measurable times 0374 Enhanced agrochemical substances which may cale. At that point it can be said that the solution shows no have similar effects to those above and evidence, on any measurable timescale, of “solvent' water 0375 yields a material easily dispersible in a second and that the remaining water is involved in direct Solvation carrier, for example, as an emulsion, which nonethe interactions with the ions. This marks the beginning of region less retains its lipophilicity and thus is not easily C, which we refer to as the hydrate ionic liquid region. In this region the ionic liquid should be considered to be the removed from Surfaces, e.g. leaves solvent. Solvates/Hydrates 0382. Note that it is possible that the melting point of the pure salt may be higher than room temperature, or even higher 0376 Liquid salts can existina defined intermediate stage than 100° C. If the addition of the solute amount of water to where they are solvated, but not in solution. This stage is the salt to form a mixture of composition in region C is characterized by all solvent present in the liquid Salt being sufficient to lower the melting point of the salt to below room bound rather than free as demonstrated by DSC and other temperature (or other temperature of interest) then the mix data. ture can still be considered to be a hydrate ionic liquid. The 0377. A convenient method of determining the point important properties of such mixtures is that they are still (in where an ionic liquid containing dissolved water becomes an common with single component ionic liquids) liquids com aqueous solution, in which water is the solvent rather than the prised solely of ions, in this case hydrated ions. Solute, is low temperature thermal analysis. By this means we (0383. The use of the term “hydrate” here is justified by its can determine the point, with increasing water content, at use in Solid state chemistry to describe salts which contain which the crystallization and melting of bulk ice first appears water molecules in their crystal structures. In many cases eg in the mixtures. The low temperature phase behaviour of Ca(NO), .4H2O, there is a well understood metal solvation aqueous salt Solutions has been extensively studied in the involved such that one could consider this salt to be Ca(H2O) context of cryobiology (Angell, C. A. D. R. MacFarlane et (NO). Indeed it melts congruently at 65° C. to a fluid, US 2012/0046244 A1 Feb. 23, 2012 30 conductive liquid state. Such hydrate salt ionic liquids have ingredients in the composition would have the same solubility been studied in detail (MacFarlane, D. R. and D. K.Y. Wong, and would dissolve together when formulated or adminis Journal of Physical Chemistry, 1985. 89 p. 5849-5855; Mac tered. Farlane, D. R. and C. A. Angell, Journal of Physical Chem istry, 1984.88 p. 4779-4781). The solid hydrate salts often 0388. The present invention provides in a first aspect a contain a variable number of water molecules Suggesting a method to transform Solid salts into liquid mixtures by simply Solid solution situation exists in some cases. Nonetheless changing the Stoichiometry of the active pharmaceutical salts these salts are still referred to as hydrates. We therefore pro without addition of a new compound that might completely pose that the parallel situation in which a liquid salt-water alter the biological properties. This can be particularly useful mixture containing a variable amount of Solute water be when overcoming formulation, solubility, bioavailability, referred to as a hydrate ionic liquid as long as it exists in size, and polymorphism issues. Region C of the binary phase diagram. 0389. In the current invention, it is not even necessary to add an additional equivalent of acid or base to form dimeric Intermediate Partially Ionized Liquid Phases anions or cations. For example, an co-ionic liquid composi tion disclosed hereincan eliminate the melting point of a solid 0384 Without wishing to be bound by theory, for the salt by addition of sub-stoichiometric amounts of acid, as it is purposes of the present disclosure, when a disclosed acid demonstrated in the example with tetrabutylphosphonium (HA) is combined with a disclosed base (B), an equilibrium salicylate: an excess of 0.1 equivalent of Salicylic acid does can exist as follows: already reduce the melting point of the conventional salt from 57 to 39°C., and a 0.3 molar excess completely eliminates the HA+B (). A melting point to yield a free flowing liquid (FIG. 2), despite AS Such, the combination of a functional acid, HA, and a the fact that both ionic liquid and free acid are solid at room functional base, B, can produce liquid compositions having a temperature. A permanent proton exchange between anion dual function or capacity, i.e., the properties of each indi and corresponding acid is present in these coionic liquids vidual component. Disclosed herein are examples of an acid making both species undistinguishable on a NMR time scale. that is a solidat room temperature which when combined with The degree of additional acid or base does therefore affect a base that is a solid at room temperature, leads to a liquid that various physico-chemical properties of the salts; for example, is a partially ionized composition. Therefore, the formulator, the formation of a “super-anion' or “super-cation” (which is by controlling the equilibrium, can also adjust or modify the a result of a proton exchange between the ion and the corre sponding acid or base) will lead to a permanent delocalization physical, chemical, and biological properties of the final com of charge and depress the melting point or completely elimi pound. nate crystallization. The presence of distinct oligomeric spe cies, e.g. dimeric or trimeric anions can be demonstrated via Multiple Functional Co-Ionic Liquids conductivity measurements: The presence of local maxima 0385 Disclosed herein are pharmaceutically active, mul for conductivity of P(Bu)(Sal), H for the species P(Bu) tiply functional co-ionic liquids comprising oligomeric cat Sal-H and P(Bu)Sal-H strongly indicates the presence of ions or anions and wherein the co-ionic liquids provide a hydrogen-bonded oligomericanions (FIG. 3). method for the modification of physico-chemical properties 0390 Current strategies for reduction of melting point of of pharmaceutically active salts. Used here, the term “co pharmaceutical active salts mainly rely on the formation of ionic liquids' includes ionic liquids with excess of any free conventional eutectics, however, this includes the addition of base in equilibrium with the cation or excess of any free acid a third and different compound that could completely alter the anion in equilibrium with the anion; thus it is possible to chemical properties of the salt. Our invention differs by the prepare pharmaceutically active ionic liquids with dimeric or absence of an eutectic point: Addition of acid or base elimi oligomeric ions of the type: nates the melting point or drives it below the glass transition temperature and will eventually lead to a point of saturation at yB' XHA a certain Stoichiometry. Higher concentrations result in the (BHB) A- - - HB"A - B"AHA"). precipitation of excess acid and in a suspension of solid acid in a co-ionic liquid with a dimericanion. The identity of the cation or of the anion is not critical to the scope of this These compositions differ from conventional mixture of ionic invention: Independently of the cation, a depression of elimi liquids with neutral compounds by the fact that a proton is nation of the melting point or in case of salts that appear as shared between anion and any acid or between cation and any glasses—a decrease of the glass transition temperature was base and all components are therefore present as ions. observed was observed with different pharmaceutically 0386 These compositions also differ from conventional active acids with 2- or 3-fold excess. Some specific examples mixtures of ionic liquids by the fact that the total amount of of co-ionic liquids include, but are not limited to the pharma cationic compounds is not balanced by the total amount of ceutically active anions salicylate and ibuprofenate as well as anionic compounds anymore, although an overall cation:an to the biological active cations cetylpyridinium, lidocainium, ion ratio of 1:1 is obtained. ephedrinium, choline or caffeine. 0387 For example, whereas a conventional ionic liquid would have been 1 part cation, 0.5 part first anion, and 0.5 part 0391 Salicylate is chiefly used in anti-acne formulation, second anion, the co-ionic liquids disclosed in this invention but also in various skin-care products. Ibuprofen is used as an can be 1 part cation, 1 part first anionic unit and 1 part of a anti-inflammatory and available as over-the-counter analge second anionic unit that are in proton exchanged to form one sic. Lidocaine is a common local anesthetic. Cetylpyridinium mixed anion with a total charge of -1. When the disclosed is used as an antiseptic agent alone or in combination with ionic liquid compositions have two or more ions with a bio other drugs for oral and throat care. It is essentially nontoxic active property (e.g., pharmaceutical active ingredients, pes and can be applied to the skin or mucous membranes. Besides ticidal actives, herbicidal actives, and the like), these compo their pharmaceutical activity, caffeine and ephedrine are also sitions can be particularly desired because each of the active common in dietary Supplement. US 2012/0046244 A1 Feb. 23, 2012 31

II

O O

-- N1 O---H-O OH HO ? Y OH HO

III IV

O O O O

O- - - H- O s1N-1 O- - - H - O 2n-1-on 21 OH HO OH HO V OH OH P(Bu)" - t O O VI

O- - - H- O P(Bu)" O O

VII VIII

OH + O O O O O N N n O---H-O N O- - - H - O 1 N. OH HO H OH HO O

By example, an elimination of melting point or a reduction of melting point or glass transition with excess acid was obtained for tetrabutylphosphonium salicylate I, tributylm IX ethylammonium salicylate II choline salicylate III, cetylpy ridinium salicylate IV, tetrabutylphoshonium lactate V. tet rabutylphoshonium ibuprofenate VI, lidocaine salicylate VII and caffeine salicylate VIII for tetrabutylphosphonium lac tate. 0392. In further examples, the disclosed co-ionic liquid compositions 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 1n OH salicylate results not only in a decreased glass transition tem perature, but also in a notable reduction of viscosity until at a certain excess of lidocaine a point of Saturation is obtained and a solid sample results (FIG. 4). Specific examples of such protic compositions include, but are not limited to, composi tions where the cation is a local anesthetic likelidocaine IX or a decongestant like ephedrine X or one of its diastereomers and are shown below. US 2012/0046244 A1 Feb. 23, 2012 32

-continued -continued

XII -- O

1 O P(Bu)" O- - - H-O N

O H OH O XIII N OH O

P(Bu)" O---H-OS

In the present invention, the concept double functional co OH O ionic liquids is not limited to mixtures of a neutral salt with the corresponding acid or base, but can be also applied to the addition of different solid acids or bases other than the parent compounds to obtain liquids type BIA'HA or B'HBA. It XIV is therefore possible to expand the scope of ionic liquids to N more than two compounds that are none the less all involved 2 in proton-exchange process and therefore differ from a simple P(Bu)" Solution of a third compound in a conventional ionic liquid. 0393. Some specific examples of co-ionic liquids include, O O but are not limited to the pharmaceutically active anions salicylate and ibuprofenate, or the vitamin niacine. Examples also include chiral species, as it was demonstrated with cam It is notable in all cases a liquid product is obtained with a phorsulfonic acid. glass transition temperature at around -50° C. only, although both starting materials tetrabutyl phosphonium salicylate and XI the shown acids are solid at room temperature. This elimina tion of melting point is most likely related to a formation of a O mixed “super-anion' that is derived from proton delocatiza tion as it was observed in the tetrabutylphosphonium salicy late-salicylic acid dimer. A reasonable difference in pKa of P(Bu)" C -- about 2 units is therefore necessary to allow a permanent OH O hydrogen exchange between the acids A" and A and the inhibition of crystallization.

XV O N 14 2 OH O

XVI O

2 OH O US 2012/0046244 A1 Feb. 23, 2012 33

-continued XVII C ON, 1N-1 O- - - H - O X. O

Other therapeutic useful combinations of 3 or more active compounds include the antibacterial cation cetylpyridinium in combination with various pharmaceutically active anions: XX 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 1. clofibric acid is used as lipid-lowering agent. Some specific examples of triple functional ionic liquids that show a melting OH depression compared to the common dual functional co-ionic liquids include, but are not limited to the combinations 1n OH cetylpyridinium salicylate-cinammate XV cetylpyridinium ^ salicylate-ibuprofenate XVI and cetylpyridinium salicylate N clofibrate XVII.

XVIII

XIX

O -H O HO E

OH

0394 Other examples include co-ionic liquids comprising three analgesics compounds, as demonstrated in the com -continued pounds lidocaine salicylate-ibuprofenate XVIII and tramado lium salicylate-ibuprofenate XIX. 0395. In another embodiment of the disclosed co-ionic liquids relates to ionic liquids comprising two or more bio XXI logically functional compound sharing one proton with the total charge of +1 and one biological functional anion. Non limiting examples of this embodiment include combinations of the decongestant ephedrine with two analgesic or anaes thetic compounds, as present in ephedrinium-lidocainium salicylate XX or ephedrinium-lidocainium ibuprofenate XXI. Similarly to dimericanions, triple functional painkillers can be prepared from 3 analgesic compounds like tramado lium-lidocainium ibuprofenate XXII or tramadolium lidocainium salicylate XXIII. US 2012/0046244 A1 Feb. 23, 2012 34

0396. Despite the fact that lidocaine, tramadole hydrate, -continued ibuprofene and even the conventional salt tramadolium ibu profenate are solid at room temperature the co-ionic liquid of the type B"HBA was obtained as clear liquid with a glass transition temperature at -37° C. Synergistic (enhanced effi ciency) as previously described for API ionic liquids, e.g. in lidocainium docusate are very likely in these multiple-com pound ionic liquids and allow modulation of properties by judicious choice of cation/anions with the desired activities.

XXIII 0397 Other therapeutically useful combinations include ionic liquids comprised of the decongestantephedrine and the common antiemetic and antihistaminic promethazine, a com 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 sate XXIV or with salicylicylate XXV. It notable that these triple-functional ionic liquids are not limited to stoichiomet ric mixtures of the three active compounds in the ratio 1:1:1, but allow individual dosing of a selected compounds, as would be present in the co-ionic liquid promethazine-ephe drinium docusate in the ratio 0.5:1:1.

XXIV S -- O O N OS O ~1-

OH O N-H- - - - N 1N O ---

XXV

OH NS OH US 2012/0046244 A1 Feb. 23, 2012

0398. In a further aspect, this invention relates to solvent chloride that can be further alkylated with any cation precur free methods of preparation for co-ionic liquids. The synthe Sor to transfer the neutral compound into a charged species. sis of double- or multiple functional co-ionic liquids can be The labile ester bond allows cleaving the prodrug and liber easily achieved by stirring additional acid or base with the ating the active compound under defined conditions that conventional API IL in an appropriate solvent that dissolves include, but are not limited to hydrolysis, pH-dependent both starting materials, e.g. reaction of cetylpyridinium sali cleavage, enzymatic hydrolysis, thermical cleavage or photo cylate and salicylic acid in acetone. Alternatively, if the cation cleavage. is available as hydroxide salt, direct reaction with the appro priate excess of one or more acids in a co-solvent will directly 0403. However, the linking unit is not limited to ester give rise to co-ionic liquids of the type BIA'HA), as dem functionalities; basically, any functional group that can be onstrated with tetrabutylphosphonium salicylate-salicylic cleaved under defined conditions can be used as linking unit. acid. Examples include, but are not limited to esters, amides, 0399. However, methods of preparation also include sol acetals, diorthoesters, vinylethers, dithiols orazo conjugates. Vent-free techniques, e.g. grinding or reaction in molten state. 04.04 The term "ionic moiety' can include both cationic Solid tetrabutylphoshonium salicylate and Salicylic acid can oranionic groups covalently attached to the active compound. be easily liquefied by simple grinding in a mortar or by In case of cations, conventional ionic liquids structural melting the Solid tetrabutylphoshonium salicylate and Sali motives include, but are not limited to, quaternary ammonium cylic acid to obtain the liquid tetrabutylphosphonium salicy or phosphonium compounds like imidazolium, pyridinium, late-salicylic acid. This solvent-free preparation technique pyrrolidinium. Special emphasis has to be put pharmaceuti can be even expanded to the preparation of triple-functional cally acceptable cations that will leave approved materials co-ionic liquids directly from the acid/base precursors: after cleavage, e.g. alkylation with trimethylamine will leave Grinding of Solid lidocaine, ibuprofenic acid and salicylic betaine after hydrolysis and release of the active compound. acid for 15 minutes at room temperature gave the liquid The role of this cationic group is, however not limited to lidocainium-ibuprofenate-salicylate salt of the type conventional ionic liquid cations, it is also possible to attach BAHA). Similarly, if the melting points of at least one of the neutral active compound to a second, charged active com the starting materials or the product are below the decompo pound. sition temperature of the API-IL, the pharmaceutically active 04.05 Alternatively, in case of immobilization of the neu co-ionic liquids can be prepared in molten state from the tral compound on the anion, any functional group bearing a acid-base precursors, as it was demonstrated with the system negative charge can be chosen. Examples include, but are not ephedrinium-salicylate 3:1. limited to carboxylates, Sulphates, Sulphonates or phospho nates. Ionic Liquid Prodrugs 0406. The term “counterion' can include both cations and 0400. This invention relates to the use of ionic liquids for anions, including pharmaceutical or biological active com immobilization, delivery, and controlled release of pharma pounds. The role of the counterion is to control the physilogi ceutically active liquid or low melting salt compositions. The cal properties of the ionic liquid composition, such as liquid present invention is based upon the discovery that active range, hydrophobicity and lipophilicity, melting point, etc. In compounds, especially pharmaceuticals, can be covalently the current invention, the ionic liquid acts not only as Support for the active compounds, being able to store pharmaceuticals linked with ionic structural moiety and turned into an ionic in inactive form but also allow a simple tuning of physical liquid by appropriate choice of the counterion. properties of compounds that cannot be directly transferred into salts. 0407. This invention provides in a first aspect a synthetic active ionic methodology to transfer neutral compounds into liquid salts compound linker moiety to overcome polymorphism, overcome solubility and deliv ery problems, to control release rates, add functionality, enhance efficacy (synergy), and improve ease of use and manufacture. It has been discovered that the physical proper ties of the active compound are depending both on the type of 04.01 Current methods for the modification of the physical ionic liquid ion used for immobilization but also on the properties of Solid drugs rely mainly on its transformation counter ion. An appropriate choice of the counter ion can into a salt; however, this is limited to acidic or basic pharma therefore be used to dramatically change solubility of the ceutically active compounds. The term “active compound is parent compound or turn hydrophilic salts into hydrophobic used to include any pharmaceutically or biologically active salts. compound, but also nutritional, fragrance or flavour com 0408. This ionic liquid prodrug approach provides an pound, as long as a functional group, typically a hydroxy or opportunity to model release kinetics of the active compound amine group, is present to covalently attach this compound on on the structure. The choice of linking unit, the covalently the ionic structure. Thus the neutral compound can be trans attached ionic moiety and the counter ion can all be used to ferred into salts, wherein the active compound is immobilized design a prodrug that is labile under defined conditions only. as part of the ionic liquid in either positive or negative charge. For example, in the present invention it has been demon 0402. The term “linking unit comprises a spacer to attach strated that a change of ionic liquid unit covalently attached to the neutral active compound to the charged moiety, thus it the active compound can dramatically influence drug release. must possess two reactive positions. In the present invention, Specifically, the ionic liquid prodrugs can be considered as linking is achieved by esterification of the neutral active com Versatile liquid delivery systems with a wide range of tune pound with a halogenated acid chloride, e.g. chloroacetyl able properties for neutral compounds. US 2012/0046244 A1 Feb. 23, 2012 36

04.09. The invention also provides the possibility to form Ionic Liquid Supported Fragrances dual functioning salts by introduction of a second, pharma ceutically or biologically active counter ion or a second, 0412. This invention relates to the use of ionic liquids for charged active compound. Prodrug decomposition will than storage and controlled release of Volatile compounds, espe provide a neutral and a charged active compound in exactly cially fragrances and flavors as liquid salt compositions. The the same dosage. present invention is based upon the discovery that volatile 0410 This invention also includes triple-functional salts, compounds can be covalently linked with ionic structural wherein a neutral active compound is covalently attached to a moiety and turned into an ionic liquid by appropriate choice second, charged active compounds, replace to the typical of the counter ion. structural elements that are present in ionic liquids, e.g. imi dazolium cations. The constitution of which, can then be paired with a third charged active compounds, which will result in the delivery of 3 active compounds in the same dosage. active compound

charged neutral active compound I active compound II 0413 Current methods to issue the loss of volatile franga

nce or flavour compounds address specific delivery systems counterion like microcapsules and carriers for long-lasting scents. active compound III 0414. In the current invention, the ionic liquid acts not only as Support for the active compounds, being able to store fragrances and flavors or, in general Volatile compounds in 0411 Specific examples in the current invention include non-volatile form but also allows a simple tuning of release ionic liquids prodrugs based on acetaminophen, a widely conditions. used analgesic and antipyretic drug used for the relief offever, 0415. This invention provides in a first aspect a synthetic headaches, and other minor aches and pains. The phenol methodology to transfer neutral volatile compounds into liq proton is not acidic enough to form a stable anion and pair it uid salts to modify physical properties, avoid evaporation, with appropriate cations; however, we demonstrated that our overcome solubility and delivery problems, to control release ionic liquid prodrug strategy can be used to transfer acetami rates, add functionality, and improve ease of use, storage and nophen in a stable liquid salt. manufacture. It has been discovered that the physical proper

OH O O O ^a us + Cl C - PTSridine - ul N O H acetone, H 1 O 0° C. tort, 2h 2

69%

N-methylpyrrollidine pyridine

N-Methylimidazole EE, rf, 2d EE, rf, 2d EE, rf, 2d 79% 97% 83%

Gene)- O O s O Cl C O Cl O G-Sr.O 3 Paracet-Melm-Cl 4 Paracet-Mepyr-Cl 5 Paracet-Py-Cl 6 Paracet-P(Bu)3-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 US 2012/0046244 A1 Feb. 23, 2012 37 ties of the active compound are depending both on the type of delivery system is to be used as well as on the kind of release ionic liquid ion used for immobilization, the linking unit but mechanism required. For example, in the present invention it also on the counterion. The term “active compound is used to include any active compound, but especially nutritional, has been demonstrated that a change of linking unit can lead fragrance or flavor compound, as long as a functional group, to different release systems. Specifically, the ionic liquid typically a hydroxy or amine group, is present to covalently compositions can be considered as Smart retention and deliv attach this compound on the ionic structure. Thus the neutral ery devices for triggered release of fragrance, flavour or any compound can be transferred into a low-volatile salt, wherein other volatile compound. the active compound is immobilized as part of the ionic liquid in either positive or negative charge. Examples include, but 0418. By example, the typical fragrance alcohol geraniol are not limited to fragrance alcohols like geraniol, menthol, can be reacted with chloroacetyl chloride as linking unit and prenol, citronellol or farnesol. The term “linker comprises a further alkylated with N-methylimidazol to the quaternary spacing unit to attach the neutral active compound to the imidazolium salt 3, which provides, as any ionic liquid neg charged moiety, thus it must possess two reactive positions. lible volatility. Further ion exchange to docusate 4 can dra For specific examples in the present invention, linking is matically change physical properties, e.g. solubility and turn achieved by esterification of a fragrance alcohol with a halo a hydrophilic chloride salt 3 into a hydrophobic liquid.

pyridine --- --~~ -- C 1. CH2Cl2, O C. to rt, 24h O --~~O 9996 1 2

N-methylimidazole neat, rt, on 67%

21 21 O N 1N1N

--~~~ o Cl O sodium docusate 21 21 O 1n N1-- acetone/H2O, OS rt, 24h O \=/ O > 999/6 3

O N-- 4 genated acid chloride, e.g. chloroacetyl chloride that can be 0419. Ionic liquid-supported hydrophobic fragrance 4 further alkylated with any cation precursor to transfer the shows, as typically for any ionic liquid, neglible Volatility but neutral compound into a charged species. The labile ester bond allows cleaving the prodrug and liberating the neutral can be decomposed by means of heat only to liberate geraniol active compound under defined conditions that include, but (FIG. 6). are not limited to hydrolysis, pH-dependent cleavage, enzy 0420 Food and pharmaceutical regulations restrict the matic hydrolysis, thermical cleavage, photo cleavage or elec palette of material used for sustained release. The invention trodecomposition. also includes example for immobilization of the active com 0416) However, the linking unit is not limited to ester pound on the anion of the ionic liquid delivery system, which functionalities; basically, any functional group that can be can be completely composed of GRAS (Generally Recog cleaved under defined conditions can be used as linking unit. nized AS Safe) compounds. A typical example of this type of Examples include, but are not limited to esters, amides, ionic liquid delivery system includes the immobilization of acetals, diorthoesters, vinylethers, dithiols orazo conjugates. fragrance alcohols as hemisuccinates that can be further 0417 The selection of a particular linker, ionic group and deprotonated with any basic component, e.g. hydroxides of counterion depends on the nature of the product in which the quaternary amines to give an ionic liquid. US 2012/0046244 A1 Feb. 23, 2012

O

OH pyridine, 4-DMAP O CH2Cl2, rt, 24h N-- -- 92% --~~O 1 O 5

choline hydroxide MeOH, 5 min 9996

0421 Cleavage of ionic liquid immobilized fragrance 6 by Multiple Functional Co-Ionic Liquids the process of acidic, basic or enzymatic ester hydrolysis will Example 1 release the fragrance and leave only choline (a vitamine) and Succinic acid, a compound that is generally recognized as safe Tetrabutylphosphonium Salicylate-Salicylic Acid (GRAS). 0425 0422 The invention also provides the possibility to form dual functioning salts by introduction of a second active counter ion or a second, charged active compound. Ionic liquid decomposition will than provide a neutral and a H charged active fragrance or flavour in exactly the same dos age. P / -- 0423 This invention also includes triple-functional salts, wherein a neutral active compound is covalently attached to a second, charged active compounds, replace to the typical - O structural elements that are present in ionic liquids, e.g. imi dazolium cations. The constitution of which, can then be He paired with a third charged active compounds, which will acetone/H2O result in the delivery of 3 active compounds in the same rate C OH and dosage. O O EXAMPLES s -- H

0424 The following examples are set forth below to illus trate the methods and results according to the disclosed Sub ject matter. These examples are not intended to be inclusive of 0426 Salicylic acid (5-20 mmol) and tetrabutylphospho all aspects of the subject matter disclosed herein, but rather to nium hydroxide (~40% sol. in HO) (3.414 g. 5 mmol) were illustrate representative methods and results. All chemicals dissolved in 20 ml of acetone stirred for 15 min at room used were of analytical grade, purchased from Sigma-Aldrich temperature. The Solvent was evaporated and the remaining viscous liquid was dried under reduced pressure (0.01 mbar, (UK), and used without further purification unless otherwise 50° C.) with stirring for 24 hrs. H-NMR (300 MHz, noted. Commercially available solutions of hydroxides were d-DMSO) 8(ppm)=7.74 (dd, J=7.7 Hz, J–1.9 HZ, 1H), titrated prior to use to determine the exact concentration. 7.32 (dt, J–7.6 Hz, J-1.8 Hz, 1H), 6.8 (m, 2H), 2.20 (m, US 2012/0046244 A1 Feb. 23, 2012 39

4H), 1.41 (m, 8H), 0.9 (t, J=7.1 Hz, 6H). 'P-NMR (121.5 MHz, d-DMSO) 8(ppm)=35.1. C-NMR (75 MHz, -continued d-DMSO) 8(ppm)=171.9(s), 163.1(s), 131.1 (d), 129.8(d), 120.6 (s), 115.7 (d), 115.6 (d), 23.3 (d. J=16.4 Hz), 22.6 (d. J–4.8 Hz), 17.3 (d. J=47.3 Hz), 13.2 (s). s O O -- H TABLE I

Water ? OH OH Composition mp content P(Bu):Sal Appearance C. Tso., C. 90 m/m) :1 Solid 57 312 O.O766 Solid tetrabutylphosphonium salicylate (3.963 g, 10 mmol) :1.1 Solid 52 297 O.1359 :1.2 Solid -54 211 O.1283 and Salicylic acid (1.601 g, 10 mmol) were grinded for 2 :13 Liquid -54 2O7 O.228O minutes in a mortar until a colorless, free-flowing liquid was :1.4 Liquid -51 209 O.1308 obtained. Physical data were similar to those obtained with :1.5 Liquid -52 2O6 0.1587 conventional synthesis (example 1). :1.6 Liquid -50 2OO O.3210 :1.7 Liquid -48 194 O.1807 0431 'H-NMR (300 MHz, d-DMSO)8(ppm)=7.74 (dd, :18 Liquid -47 198 O.1529 J–7.7 Hz, J-1.87 Hz), 7.32 (dt, J=7.6 Hz, J-1.80 Hz, 1H), :19 Liquid -46. 198 O.2462 6.77 (m, 2H), 2.20 (m, 4H), 1.41 (m, 8H), 0.9 (t, J=7.1 Hz, :2 Liquid -46 192 O.1924 6H). 'C-NMR (75 MHz, d-DMSO) 8(ppm)=172.0 (s), :2.4 Liquid -45 184 0.1517 :2.7 Liquid -43 173 O.1412 162.3 (s), 133.8(d), 130.5 (d), 117.9 (d), 117.1 (s), 116.8 (d), :28 Liquid -43 169 O.1127 23.30 (d. J=15.94 Hz), 22.61 (d. J=5.31 Hz), 17.31 (d. J=47. 3.0 Liquid -43 164 82 Hz), 13.73 (s). :31 Suspension -43 :3.5 Suspension -45 Example 3 :3.7 Suspension -43 150 O.1033 Salicylic acid Solid 158 (lit) 136 Methyltributylammonium Salicylate-Salicylic Acid determined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C.min and Qoling with -2.5°C. minto -80°C. for 3 cycles, 0432 glass transition temperature, determined on a Mettler Toledo Star TGA/DSC unit by heating from 25°C. to 600° C. with 5°C.min under nitrogen. 0427 Table I shows thermal data and water content of different tetrabutylphosphonium salicylate-salicylic acid co ionic liquids. 0428 FIG. 2 is a plot of the melting point depression and melting point elimination curves for the data depicted in Table I. 0429 FIG.3 depicts the conductivity of different P(Bu). Sal H compositions in a series of co-ionic liquids compris ing oligomeric anions. O

-e- Example 2 OH acetone/H2O Tetrabutylphosphonium Salicylate-Salicylic Acid Solvent-Free Synthesis Via Grinding OH 0430 O O N e O--H-O

Salicylic acid (5-20 mmol) and tributylmethylammonium hydroxide (5 mmol. 40% solution in HO) were dissolved in 20 ml of acetone stirred 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. 0433 'H-NMR (300 MHz, d-DMSO) 8(ppm)=7.63 (dd,

H J=7.7 Hz, J–19 Hz, 1H), 7.10 (m, 1H), 6.57 (m, 2H), 3.19 OH acetone/H2O (m, 6H), 2.94 (s.3H), 1.59 (m, 6H), 1.29 (sext, J=7.4 Hz, 6H), 0.9 (t, J–74 Hz, 9H). 'C-NMR (75 MHz, d-DMSO)8(ppm) OH =1719, 1620, 133.4, 130.1, 117.5, 116.9, 60.4, 47.5, 23.4, 19.2, 13.5. US 2012/0046244 A1 Feb. 23, 2012 40

Example 5 TABLE II Cetylpyridinium Salicylate-Salicylic Acid Ratio N(Bu)Me:Sal Appearance mpo C.) (al Tso. ase, C.) 0438

1:1 solid 83 193 O 1:2 liquid 37 [Pl 196 -- 1:3 liquid –41(T) 177

ldetermined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C.min and 21 OH cooling with -2.5°C. minto -80°C. for 3 cycles, O Plglass transition temperature, determined on a Mettler Toledo Star TGADSC unit by heating from 25°C. to 600° C. He with 5°C.min under nitrogen. OH acetOne

0434 Table II shows thermal data of different tributylm OH ethylammonium salicylate-Salicylic acid co-ionic liquids. O O Example 4 Choline Salicylate-Salicylic Acid Crs21 OH OH 0435 Salicylic acid (5-15 mmol) and cetylpyridinium salicylate (5 mmol) were dissolved in 20 ml of acetone and stirred for 15 minat room temperature. The solvent was evaporated and the O remaining viscous liquid was dried at 0.1 mbar with stirring for 24 hrs. OH OH 0439 'H-NMR (300 MHz, d-DMSO) 8(ppm)=9.12 (d. -- e J=6.1 Hz, 2H), 8.59 (t, J=8.3 Hz, 1H), 8.16 (t, J=7.3 Hz, 2H), -7N-N OH methanol 7.64 (d. 7.5 Hz, 1H), 7.12 (t, J=7.5, 1H), 6.57 (m, 2H), 4.59 (t, OH J–7.4 Hz, 2H), 1.88 (m, 2H), 1.22 (s. 27H), 0.84 (t, J=7.1 Hz, O O 3H). 'C-NMR (75 MHz, d-DMSO)8(ppm)=171.8, 163.4, 145.8, 145.2, 1314, 130.2, 128.4, 121.1, 116.1, 160.0, 61.2, 2n-1-onN O--H-O 31.7, 31.2, 29.4, 29.3, 29.2, 29.1, 28.8, 25.8, 22.5, 14.2. OH OH TABLE IV Ratio CetPy:Sal Appearance mp Cl Tso. ase I C. Salicylic acid (5 or 10 mmol) and choline hydroxide (5 mmol. 1:1 solid 71 2O6 40% solution in MeOH) were dissolved in 20 ml of methanol 1:2 solid S4 184 and stirred for 15 min at room temperature. The solvent was 1:3 solid 21(b) 162 evaporated and the remaining viscous liquid was dried at 0.1 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. mbar with stirring for 24 hrs. Plglass transition temperature, eldetermined on a Mettler Toledo Star TGADSC unit by heating from 25° C. to 600° C. 0436 'H-NMR (300 MHz, d-DMSO)8(ppm)=7.64 (dd, with 5°C.min under nitrogen. J–74 Hz, J–1.9 HZ, 1H), 7.3 (m, 1H), 6.6 (m, 2H), 3.8 (m, 0440 Table IV shows thermal data of different cetylpyri 2H), 3.4 (m, 2H), 3.1 (s, 9H). dinium salicylate-salicylic acid co-ionic liquids. TABLE III Example 6 Tetrabutylphosphonium Ibuprofenate-Ibuprofenic Ratio Cho:Sal Appearance mpo C.) (al Tso. ase, C.J.' Acid 1:1 solid 48 (lit) 2O3 0441 1:2 liquid -41) 173

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, OH eldetermined on a Mettler Toledo Star TGADSC unit by heating from 25°C. to 600° C. -as with 5°C.min under nitrogen. acetone/H2O 0437. Table III shows thermal data of different choline salicylate-salicylic acid co-ionic liquids. US 2012/0046244 A1 Feb. 23, 2012

viscous liquid was dried at 0.1 mbar with stirring for 24 hrs. -continued '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. 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, d-DMSO)8(ppm)=176.8, 67.3, 23.72 (d. J=15.5 Hz), 23.01 (d. J=4.7 Hz), 21.91, 17.70 (d. J=47.9 Hz), 13.62 (s). TABLE VI 0442. Ibuprofenic acid (5-15 mmol) and tetrabutylphos phonium hydroxide (~40% sol. in HO) (3.414 g. 5 mmol) Ratio P(Bu). Lac Appearance T C.|al T5% onse' were dissolved in 20 ml of acetone and stirred for 15 min at 1:1 liquid 1.78 (mp) 262 room temperature. The solvent was evaporated and the 1:2 liquid -56 215 remaining viscous liquid was dried at 0.1 mbar with stirring 1:3 liquid -SS 176 for 24 hrs. 'H-NMR (300 MHz, d-DMSO) 8(ppm)=7.13 (d. 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. J=8.1 Hz, 2H), 6.94 (d. 8.1 Hz, 2H), 3.21 (q, 7.7 Hz, 1H), 2.48 Pldetermined on a Mettler Toledo Star TGADSC unit by heating from 25°C. to 600° C. (m. 2H), 2.36 (d. 7.3 Hz, 2H), 2.14 (m,8H), 1.77 (sept, 6.2 Hz, with 5°C,imin, under nitrogen. 1H), 1.40 (m, 16H), 1.18 (d. J=7.0 Hz, 3H), 0.91 (t, 7.0 Hz, 0446 Table VI shows thermal data of different tetrabu 12H), 0.84 (d. J–7.0 Hz, 6H), C-NMR (75 MHz, tylphosphonium lactate-lactic acid co-ionic liquids. d-DMSO) 8 (ppm)=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, Example 8 17.3 (d. J=48.1 Hz), 13.3. Lidocaine Salicylates TABLEV 0447 Ratio P(Bu) Ibu Appearance T. Clel Tso. ase (C.' 1:1 liquid -43 234 1:2 liquid -40 264 O 1:3 liquid -39 189 l -- OH 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, Pldetermined on a Mettler Toledo Star TGADSC unit by heating from 25° C. to 600° C. O OH with 5°C.min under nitrogen. O H 0443 Table V shows thermal data of different tetrabu tylphosphonium ibuprofenate-ibuprofenic co-ionic liquids. O N^^O N Example 7 OH Tetrabutylphosphonium Lactate-Lactic Acid O -- 0444 N J-Cn1 O H O H OH N^^ OH l

-- OH -- O acetone / O O HO O N laii ^^ O--H-O - O N OH OH

0448 Salicylic acid or lidocaine free base (0.5, 1, 1.5 or 2 eq.) and lidocaine salicylate were suspended in acetone (20 ml) and stirred at room temperature until a clear Solution was obtained. The solvent was evaporated and remaining Volatile material removed under vacuum (0.01 mbar, 40° C.). 'H-NMR (300 MHz, d-DMSO) 8(ppm)=10.05 (brs, 1H), 7.72 (dd, J–7.8 Hz, J-1.8 Hz, 1H), 7.24 (m. 1H), 7.09 (s. 0445. Lactic acid (5-15 mmol) and tetrabutylphospho 3H), 6.70 (m, 2H), 3.98 (s. 2H), 3.10 (q, J=7.3 Hz, 4H), 2.16 nium hydroxide (~40% sol. in HO) (3.414 g. 5 mmol) were (s, 6H), 1.22 (t, J=7.3 Hz, 6H). 'C-NMR (75 MHz, dissolved in 20 ml of acetone and stirred for 15 min at room d-DMSO)8(ppm)=171.9, 164.6, 161.9, 135.0, 134.0, 133.4, temperature. The Solvent was evaporated and the remaining 130.1, 127.8, 126.9, 117.6, 116.9, 116.4, 53.3, 48.3, 18.1, 9.5. US 2012/0046244 A1 Feb. 23, 2012 42

'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, 2H), 6.70 (m, 2H), 6.48 (brs, 1H), 5.21 (s, 1H), 3.41 (m, 1H), Lid Sal Appearance T. Clel Tase, so I 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 2 1 glass -15 154 127.2, 125.8, 119.6, 11.6.8, 116.0, 69.6, 59.3, 30.6, 9.1. 1.5 1 glass -1 169 1 1 glass 19 161 TABLE VIII 1 1.5 viscous liquid 13 142 1 2 viscous liquid 3 138 1 2.5 solid -4 132 Ratio Eph:Sal Appearance mpo C.) (al Tase, so, C.J.' 1 3 solid -3 128 1 solid 69 (mp) 152 1 solid 160 (mp) 134 1:3 solid 61 ldetermined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C.min and 1:2 solid 61 130 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. 1:1 solid 97 161 with 5°C. min. under nitrogen. 2:1 glass 2(b) 127 Table VII shows thermal data of different lidocaine salicy 3:1 liquid -5&l 123 lateco-ionic liquids. 0449 FIG. 4 depicts the depression of glass transition and ldetermined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C. min and saturation of double functional co-ionic liquids based on cooling with 5°C/min to -80°C, for 3 cycles. lidocainium salicylate. Plglass transition temperature determined on a Mettler Toledo Star TGADSC unit by heating from 25° C. to 600° C. Example 9 with 5°C,imin, under nitrogen. Ephedrine Salicylate 0452 Table VIII shows thermal data of different ephe 0450 drinium salicylate co-ionic liquids. Example 10 OH O -- H N Ephedrine Salicylate-Solvent-Free Synthesis Via O'? N OH Grinding OH 0453 O OH

N OH -- O H2 N N OH OH

OH O O OH NH 1. 6H O N H OH OH N OH C HN

O 1. OH -- O O H NS O- r OH HO OH N 0451 Salicylic acid or ephedrine free base (0.5, 1, 1.5 or 2 eq.) and ephedrinium salicylate were Suspended in acetone (20 ml) and stirred at room temperature until a clear solution O was obtained. The solvent was evaporated and remaining volatile material removed under vacuum (0.01 mbar, 40°C.). US 2012/0046244 A1 Feb. 23, 2012

-continued -continued OH O O

H NN O--H-O

OH HO 1. O

0454 Salicylic acid or ephedrine free base (0.5, 1, 1.5 or 2 OH eq.) and ephedrinium salicylate were grinded for 15 minutes n in a mortar. Analytical data were similar to those obtained in conventional synthesis. "H-NMR (300 MHz, d-DMSO) 8(ppm)=9.30 (brs, 2H), 7.76 (dd, J–7.7 Hz, J-1.8 Hz, 1H), O 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=6.8 Hz, 3H). 'C-NMR (75 MHz, d-DMSO)8(ppm)=1729, 162. 1, 141. 4, 132.0, 130.3, 128.2, 127.2, 125.8, 119.6, 116.8, 116.0, OH -- O O 69.6, 59.3, 30.6, 9.1. H NN O--H-O TABLE IX OH HO Ratio Eph:Sal Appearance mp Cl Tase, so I C. 1:4 solid 61 124 1:3 solid 61 122 1:2 solid 61 131 1:1.4 solid 61 153 1:1.3 solid 60 147 0457 Salicylic acid and ephedrine free base (1, 2 or 3 eq.) 1:1-2 solid 60 154 were molten in a hot mortar until a free-flowing clear liquid 1:1.1 solid 91 163 1:1 solid 97 161 was obtained. The mixture was cooled to room temperature 2:1 glass 5(b) 118 and, in case of Solid products grinded to obtain colourless 3:1 liquid 4&l 115 powders. 'H-NMR (300 MHz, d-DMSO) 8(ppm)=9.30 (br determined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C.min and Qoling with 5°C.fminto -80°C, for 3 cycles. glass transition temperature s, 2H), 7.76 (dd, J–7.66 Hz, J-1.80 Hz, 1H), 7.38 (m, 4H), determined on a Mettler Toledo Star TGADSC unit by heating from 25°C. to 600° C. 7.24 (m, 2H), 6.70 (m, 2H), 6.48 (brs, 1H), 5.21 (s, 1H), 3.41 with 5°C. min. under nitrogen. (m. 1H), 2.69 (s.3H), 0.95 (d. J=6.76 Hz, 3H). 'C-NMR (75 0455 Table IX shows thermal data of different ephe MHz, d-DMSO) 8(ppm)=172.9, 162.1, 1414, 132.0, 130.3, drinium salicylate co-ionic liquids prepared by grinding. 128.2, 127.2, 125.8, 119.6, 116.8, 116.0, 69.6, 59.3, 30.6, 9.1. Example 11

TABLE X Ephedrine Salicylate-Solvent-Free Synthesis in Mol ten State Ratio Eph:Sal Appearance mpo C.) (al Tase, so, C.)

0456 1:3 solid 61 135 1:2 solid 61 133 OH 1:1 solid 97 161 H 2:1 glass 7(b) 144 N N OH 3:1 liquid 2(b) 128

determined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C. min and OH cooling with 5°C/min to -80°C, for 3 cycles. O OH Plglass transition temperature eldetermined on a Mettler Toledo Star TGADSC unit by heating from 25° C. to 600° C. O N with 5°C.min under nitrogen.

0458 Table X shows thermal data of different ephe drinium salicylate co-ionic liquids prepared by melting. US 2012/0046244 A1 Feb. 23, 2012 44

Example 12 Ephedrinium Clofibrate-Solvent-Free Synthesis Via Melting 0459

H 1 C H HO O - O in O

OH C

e O O OH -- N -- nX H O NS

O Cl

O---H-O O O OH O

0460) Clofibric acid (1 or 2 eq.) and ephedrine free base (1 Example 13 or 2 eq.) were molten in a hot mortar until a free-flowing clear Caffeine Salicylate-Solvent-Free Synthesis Via liquid was obtained. The mixture was cooled to room tem Grinding perature and, in case of Solid products, grinded to obtain yellow powders. 'H-NMR (300 MHz, d-DMSO)8(ppm)=9. 0461) 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, O 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. -N V O TABLE XI O O Ratio Tonset 5% Eph:Clofib Appearance mp C. Io Clel O---H-O

1:2 glass 12(b) 182 OH HO 1:1 solid 131 169 2:1 glass 7(b) 135 0462 Caffeine salicylate (19.40 mg, 0.058 mmol) and determined on a Mettler Toledo Star DSC unit by heating to 110°C. with 5°C.min and salicylic acid (8.06 mg, 0.058 mmol) were grinded for 15 cooling with 5°C.fminto -80°C, for 3 cycles. minutes in a mortar at room temperature. A colorless powder Plglass transition temperature was obtained. eldetermined on a Mettler Toledo Star TGADSC unit by heating from 25°C. to 600° C. with 5°C. min. under nitrogen. 0463 'H-NMR (300 MHz, d-DMSO)8(ppm)=11.29 (br s, 1H), 8.01 (s, 1H), 7.90 (dd, J=8.1 Hz, J-1.4 Hz, 2H), 7.51 Table XI shows thermal data of different ephedrinium clofi (t, J=7.83 Hz, 2H), 6.94 (m, 4H), 3.07 (s, 3H), 3.41 (s.3H), brate co-ionic liquids prepared by melting. 3.21 (S. 3H). mp 122°C., Tso, 111° C. US 2012/0046244 A1 Feb. 23, 2012 45

Example 14 0468 Camphorsulphonic acid (5 mmol), salicylic acid Tetrabutylphosphonium Salicylate-Ibuprofenic Acid (0.6909 g, 5 mmol) and tetrabutylphosphonium hydroxide P(Bu)SalIbuIH (~40% sol. in HO)(3.414g, 5mmol) were dissolved in 20 ml of acetone and stirred for 15 min at room temperature. The 0464 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)=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), 1.84 (m, 2H), 1.42 (m, 16H), 1.26 (m, 2H), 1.05 (s, 3H), 0.91 (t. J–6.9 Hz, 12H), 0.74 (s.3H). T-33°C.T.s, 2030 C.

Example 16 Tetrabutylphosphonium Salicylate-Lactic Acid P(Bu) SalLacIH 0469 0465 Ibuprofenic acid (1.032 g, 5 mmol), salicylic acid (0.6909 g, 5 mmol) and tetrabutylphosphonium hydroxide (~40% sol. in HO)(3.414g, 5mmol) 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)=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 (d. 7.2 Hz, 2H), 2.17 (m, 8H), 1.80 (sept, J=6.70, 1H), 1.42 (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)=1754, 171.2, 162.9, 139.5, 138.5, 131.3, 129.9, 128.9, 127.1, 115.9, 115.8, 44.3, 44.2, 29.6, 23.3 (d. J=15.8 Hz), 22.6 (d. 4.8 Hz), 22.2, 18.5, 17.3 (47.6 Hz), 13.7. O 10466 T-45° C., Tsoi, 181° C. OH Example 15

Tetrabutylphosphonium Salicylate-Camphorsulfonic OH rt O Acid P(Bu)SalCSAH 0467

0470 Lactic acid (0.4504 g. 5 mmol), salicylic acid (0.6909 g, 5 mmol) and tetrabutylphosphonium hydroxide (~40% sol. in HO) (3.414g, 5 mmol) were dissolved in 20 ml of acetone and stirred for 15 min at room temperature. The P 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)=7.63 (dd, J=7.6 Hz, J–1.9Hz), 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, 12H). O---H-OS 'P-NMR (121.5 MHz, d-DMSO) 8(ppm)=35.0. 'C-NMR (75 MHz, d-DMSO) 8(ppm)=176.3, 171. 1, 1630, 131.2, OH 129.9, 120.5, 117.8, 115,767.3, 23.4 (d. J=15.8 Hz), 22.6 (d. J–4.3 Hz), 20.5, 17.3 (d. J–47.7 Hz), 13.3 (s). T-53° C., T5% osef 1780 C. US 2012/0046244 A1 Feb. 23, 2012 46

Example 17 0474 Ibuprofenic acid (1.0315 g, 5 mmol), niacine Tetrabutylphosphonium Salicylate-Cinnamic Acid (0.6155 g, 5 mmol) and tetrabutylphosphonium hydroxide P(Bu)SalCinn H (~40% sol. in HO)(3.414g, 5mmol) were dissolved in 20 ml of acetone and stirred for 15 min at room temperature. The 0471) Solvent was evaporated and the remaining viscous liquid was dried at 0.01 mbar with stirring for 24 hrs. Identity and purity was confirmed via "H NMR. The desired compound is iso lated as a colourless liquid: 'H-NMR (300 MHz, d-DMSO) Ö(ppm)=8.97 (s, 1H), 8.50 (dd, J-49 Hz, J–1.7 Hz, 1H), 8.12 (m, 1H), 7.31 (m, 1H), 7.19 (d. 7.9 Hz, 2H), 7.06 (d. 7.9 Hz, 2H), 3.62(q, J–7.3 Hz, 2H), 2.40 (d. 7.1 Hz, 2H), 2.18 (m, 8H), 1.80 (sept, J=6.9, 1H), 1.41 (m, 16H), 1.31 (s, J=7.2 Hz, 3H), 0.9 (t, J=7.2 Hz, 12H), 0.85 (d. 6.6 Hz, 6H). 'P-NMR (121.5 MHz, d-DMSO)8(ppm)=35.1. C-NMR (75 MHz, d-DMSO)8(ppm)=175.7, 166.9, 150.5, 149.7, 139.5, 139.0, 136.2, 134.2, 128.7, 127.1, 122.6, 45.0, 44.2, 29.6, 23.3 (d. J=15.8 Hz), 22.6 (d. 4.8 Hz), 22.1, 18.917.3 (47.6 Hz), 13.2. T-44°C., Tsoi, 201° C.

0472 Cinnamic acid (0.7408 g. 5 mmol), salicylic acid Example 19 (0.6909 g, 5 mmol) and tetrabutylphosphonium hydroxide (~40% sol. in HO) (3.414g, 5 mmol) were dissolved in 20 ml Lidocaine Ibuprofenate-Salicylic Acid Lid IbuSalH of acetone stirred and for 15 min at room temperature. The Solvent-Free Synthesis Solvent was evaporated and the remaining viscous liquid was dried at 0.1 mbar with stirring for 24 hrs. Identity and purity 0475 was confirmed via "H NMR. The desired compound is iso lated 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 Hz, 12H). P-NMR (121.5 MHz, d-DMSO) 8(ppm)=35.1. "C-NMR (75 MHz, d-DMSO) 8(ppm)=171. 2, 167.6, 163.0, 143.3, 1344, 131. 1, 130.0, 129.9, 128.9, r 128. 1, 120.7, 120.0, 115.7, 115.6, 23.3 (d. J=15.9 Hz), 22.6 (d.4.2 Hz), 17.3 (47.8 Hz), 13.2(s). T-43°C. T5%osef 1910 C. Example 18 Tetrabutylphosphonium Ibuprofenate-Niacin P(Bu) IbuNia H 0473

0476 Ibuprofenic acid (206.28 mg, 1 mmol), salicylic acid (160.11 mg, 1 mmol) and lidocaine (234.34 mg, 1 mmol) P were grinded in a mortar for 15 minutes until a clear viscose liquid was obtained. 'H-NMR (300 MHz, d-DMSO)8(ppm) =9.91 (brs, 1H), 7.72 (dd, J =7.7 Hz, J–1.9Hz, 1H), 7.25(m, 1H), 7.19 (d. J=8.0 Hz, 2H), 7.10 (m, 5H), 6.71 (m, 2H), 3.63 N 2 (q, J=7.1 Hz, 1H), 3.06 (q, J–7.4 Hz, 4H), 2.41 (d. J=7.1 Hz, 2H), 2.17 (s, 6H), 1.80 (sept, J=6.8 Hz, 1H), 1.34 (d. J–7.2 Hz, O- - - H- O N 3H), 1.21 (t, J=7.2 Hz, 6H), 0.86 (d. J=7.2 Hz, 6H). 'C-NMR (75 MHz, d-DMSO) 8(ppm)=175.5, 1719, 165.5, 162.2, O O 139.5, 138.5, 135.0, 134.2, 132.8, 130.1, 129.0, 127.8, 127.1, 126.8, 117.9, 117.1, 116.2, 53.9, 48.2, 44.3, 44.2, 29.6, 22.2, 18.5, 18.1, 10.0. T-2°C., Tso, 153°C.

US 2012/0046244 A1 Feb. 23, 2012 48

Example 24 MHz, d-DMSO) 8(ppm)=9.17 (brs, 1H), 7.19 (m, 3H), 7.06 Ephedrinium-Lidocaine Ibuprofenate HEphLidIbu (m,7H), 6.73 (dd, J1=8.1 Hz, J2=2.3 Hz, 1H), 4.42(brs, 2H), 0484 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, 7H), 1.94 (s, 6H), 1.89-1.41 (m, 8H), 1.33 (d. J=7.1 Hz, 3H), 1.07 (t, J–7.1 Hz, 6H), 0.86 (d. J–6.6 Hz, 6H). T-20°C., T5% osef 1540 C. Example 26 Tramadolium-Lidocaine Salicylate HTramlid Sal 0488

0485 Lidocaine (468.67 mg, 2 mmol) and ephedrinium ibuprofenate (743.02 mg, 2 mmol) were dissolved in 20 ml of OH 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 1 week. The desired compound is isolated as a colourless solid. 'H-NMR (300 MHz, d-DMSO) 8(ppm)=9.19 (brs, 1H), 7.32 (m, 5H), 7.20 (d. J=8.1 Hz, 2H), 7.09 (s.3H), 7.05 (d. J–8.2 Hz, 2H), 5.03 (m. 1H), 3.50 (q, J=7.1 Hz, 1H), 3.13 (m,3H), 2.62 (q, J=6.7 Hz, 4H), 2.45 (s.3H), 2.40 (d. J=7.1 0489 Lidocaine (5 mmol) and tramadolium salicylate (5 Hz, 2H), 2.15 (s, 6H), 1.79 (sept, J=6.7 Hz, 1H), 1.32 (d. J–7.0 mmol) were dissolved in 20 ml of acetone and stirred for 15 Hz, 3H), 1.08 (t, J=7.0 Hz, 6H), 0.86 (m, 9H). mp 87° C., minat room temperature. The solvent was evaporated and the T5%onset 1340 C. remaining viscous liquid was dried at 0.01 mbar with stirring Example 25 for 24hrs and solidified after into a colourless solid. 'H-NMR Tramadolium-Lidocaine Ibuprofenate HTramLid (300 MHz, d-DMSO)8(ppm)—10.32 (brs, 1H), 7.672 (dd. Ibu J=7.8 Hz, 1H), 7.26 (t, J=8.2 Hz, 1H), 7.15 (t, J=7.2 Hz, 1H), 7.06 (m, 5H), 6.79 (d. J–8.7 Hz, 1H), 6.62 (m, 2H), 3.76 (s, 0486 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, 6H). 'C-NMR (75 MHz, d-DMSO)8(ppm)=1717, 162.2, 159.1, 150.2, 135.1, 135.0, 1316, 130.0, 129.0, 127.6, 126.4, 119.9, 117.2, 116.2, 115.8, 1114, 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., Tso 181°C. O N HN Example 27 O

Promethazine-Ephedrinium Docusate 1:1:1 r 0490

O

O

0487 Lidocaine (270.13 mg, 1.15 mmol) and tramado Sr lium ibuprofenate (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 compound is isolated as a colourless liquid. 'H-NMR (300 US 2012/0046244 A1 Feb. 23, 2012 49

61.5, 59.0, 55.6, 49.7, 40.6, 38.2, 38.2, 34.1, 30.8, 29.7, 29.6, -continued 29.5, 28.3, 23.2, 23.0, 22.4, 13.9, 12.2, 10.8, 9.5. O Example 29 OS O ~1- Promethazine-Ephedrinium Salicylate

O N-- 0494

0491 Promethazine (2 mmol) was added to ephedrinium S docusate (2 mmol) and stirred for 15 minutes at 50° C. to obtain a light yellow viscous oil. Identity and purity were confirmed via H and 'C NMR. 'H-NMR (300 MHz, N d-DMSO) 8(ppm)=7.39 (d. J–4.5 Hz, 3H), 7.29 (m, 1H), 7.19 (m, 4H), 7.08 (d.J=8.1 Hz, 2H), 6.95 (t, 7.4 Hz, 2H), 5.04 O (d. J=2.7 Hz, 1H), 4.05 (dd, J1=13.81 Hz, J2=5.0 Hz, 1H), OH 3.89 (m, 4H), 3.68 (m, 2H), 3.35 (m, 1H), 2.87(m,3H), 12.63 N-H--N OH (s, 3H), 2.24 (s, 6H), 1.49 (m. 2H), 1.23 (m. 16H), 0.84 (m, 1N 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, 1244, 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, 10.8, 9.5. T-19°C., Tso, 164° C. 0495 Promethazine (2 mmol) and ephedrinium salicylate (2 mmol) were dissolved in 25 ml of acetone and stirred for 15 Example 28 min at room temperature, the solvent was evaporated and remaining Volatile material was removed under vacuum (0.01 Promethazine-Ephedrinium Docusate 0.5:1:1 mbar, 50° C.) to yield the product as colourless viscous glass. 'H-NMR (300 MHz, d-DMSO) 8(ppm)=7.72 (dd, J–7.7 0492 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. 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-8.6 Hz), 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., T5%osef 151 O C. OCN S DO -- Ionic Liquid Prodrugs OH Example 30 N-H--N 1. N 0.5 Synthesis of 4-Acetamidophenyl 2-chloroacetate 2

O 0496

OS ~go OH O O Cl pyridine + Cl Her us Oacetone, C. to rt N O 2h s O N-- 1. C8HoNO 0493 Promethazine (1 mmol) was added to ephedrinium 151.16 docusate (2 mmol) and stirred for 15 minutes in acetone. The O Solvent was evaporated and remaining Volatile material was removed under reduced pressure (0.01 mbar, 50° C.). O ^a 'H-NMR (300 MHz, d-DMSO)8(ppm)=7.39 (d. J–4.5Hz), us N O 7.29(m), 7.19 (m), 7.08 (d. J=8.1 Hz), 6.95 (t, 7.4 Hz), 5.04 H (d. J=2.7 Hz), 4.05 (dd, J=13.81 Hz, J-50 Hz), 3.89 (m, 2 4H), 3.68 (m), 3.35 (m), 2.87(m), 12.63 (s), 2.24 (s), 1.49 (m, C10H10CINO3 2H), 1.23 (m, 16H), 0.84 (m, 18H). 'C-NMR (75 MHz, 227.64 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 2012/0046244 A1 Feb. 23, 2012 50

0497 Paracetamol 1 (15.117 g, 50 mmol) and pyridine Example 32 (7.910 g, 50 mmol) were suspended in anhydrous acetone (200 ml) and chilled to 0°C. under an atmosphere of dry 1-(2-(4-acetamidophenoxy)-2-oxoethyl)-1-meth nitrogen. Chloroacetylchloride (11.29 g, 50 mmol) was ylpyrrolidinium chloride 4 added dropwise (violent reaction) and the resulting Solution was stirred for additional 2 hours at room temperature. Water 0503 (300 ml) was added and the mixture was heated until a clear Solution was obtained. The product 2 precipitated upon cooling and was collected via filtration, washed with water O and dried under reduced pressure (0.01 mbar, 50°C.) to yield O na HeN-methylpyrrollidine us O ethylacetate, rf, 2 as colourless needles in 72% yield. The product was pure N 48 h. according to H NMR and directly subjected to the next step H 79% without further purification. 2 0498 'H-NMR (300 MHz, d-DMSO)8(ppm)=10.05 (s, C10H10CINO3 1H), 7.62 (d.J=9.01 Hz, 2H), 7.10 (d.J=9.01 Hz, 2H), 4.67 (s, 227.64 2H), 3.38 (s, 3H), 2.05 (s, 3H). 'C-NMR (75 MHz, d-DMSO)8(ppm)=168.7, 166.9, 145.6, 137.2, 122.0, 120.3, O 41.6, 24.3. mp 186° C. ul N O Example 31 H C 4) Synthesis of 1-(2-(4-acetamidophenoxy)-2-oxoet C15H2CINO3 hyl)-3-methyl-1H-imidazol-3-ium chloride 3 312.79 0499 0504 4-Acetamidophenyl 2-chloroacetate 2 (1.138 g. 5 O mmol) and N-methylpyrrolidine (0.51 1 g, 6 mmol) were sus He pended in 50 ml of anhydrous ethyl acetate and refluxed for O O ra N-methylimidazoleethylacetate, rf, us N O 48 h. 48 hrs. After cooling to room temperature the white precipi H 79% tate was filtered, washed with ethylacetate and diethylether 2 and dried under reduced pressure to give 4 in 97% yield. The C10H10CINO3 product was pure according to H NMR and was directly 227.64 subjected to the next step without further purification. The O desired compound is isolated as a colourless powder. O N1\ N'- 'H-NMR (300 MHz, d-DMSO)8(ppm)=10.48 (s, 1H), 7.72 O S. (d. J=8.90 Hz, 2H), 7.17 (d. J=8.90 Hz, 2H), 4.91 (s. 2H), 3.75 N C H (m, 4H), 3.26 (s.3H), 2.13 (m, 4H), 2.06 (s, 3H). 'C-NMR (75 MHz, d-DMSO) 8(ppm)=168.8, 164.8, 1444, 138.2, 3. C14H16CIN3O3 121.9, 120.2, 65.5, 62.0, 49.7, 24.3, 21.7. mp 186° C. (dec), 309.75 T5%onset 1970 C. Example 33 0500 4-Acetamidophenyl 2-chloroacetate 2 (1.138 g. 5 mmol) and N-methylimidazol (0.492 g. 6 mmol) were sus 1-(2-(4-acetamidophenoxy)-2-oxoethyl)pyridinium pended in 50 ml of anhydrous ethyl acetate and refluxed for chloride 5 48 hrs. After cooling to room temperature the white precipi tate was filtered, washed with ethylacetate and diethylether 0505 and dried under reduced pressure to give 3 in 79% yield. The product was pure according to H NMR and was directly subjected to the next step without further purification. O

0501. The desired compound is isolated as a colourless O na -e-pyridine powder. 'H-NMR (300 MHz, d-DMSO)8(ppm)=10.08 (s, us O ethylacetate, rf, 1H), 9.28 (s, 1H), 7.86 (s, 1H), 7.78 (s, 114), 7.68 (d. J=9.01 N 48 h. Hz, 2H), 7.13 (d. J=9.01 Hz, 2H), 5.57 (s. 2H), 3.93 (s, 3H), H 83% 2.05 (s.3H). 'C-NMR (75 MHz, d-DMSO)8(ppm)=168.4, 2 166.1, 144.9, 137.9, 137.7, 123.8, 123.5, 1214, 119.9, 49.7, C10H10CINO3 36.0, 23.9. 227.64 0502 mp 20.6°C. (dec), Tsoi, 200° C. US 2012/0046244 A1 Feb. 23, 2012

4, 164.7, 144.8, 137.8, 1214, 119.9, 25.8 (d. J=47.9 Hz), -continued O 23.9, 23.3 (d. J=16.77 Hz), 22.6 (d. J=443 Hz), 18.2 (d. O N1N J=47.7 Hz), 13.2. mp 199° C. (dec), Ts, 197° C. Example 35 N OO2 H C Synthesis of 1-(2-(4-acetamidophenoxy)-2-oxoet 5 hyl)-3-methyl-1H-imidazol-3-ium docusate 7 C15H15CIN2O3 306.74 0507

4-Acetamidophenyl 2-chloroacetate 2 (1.138 g. 5 mmol) O silver and pyridine (0.475 g, 6 mmol) were suspended in 50 ml of O ^ N ~\ N"- -->docusate anhydrous ethyl acetate and refluxed for 48 hrs. After cooling us N O N/ MeOH,15 min rt, to room temperature the white precipitate was filtered, H C washed with ethylacetate and diethylether and dried under >99% reduced pressure to give 5 in 97% yield. The product was 3) 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), JOrc 8.76 (t, 7.9 Hz, 1H), 8.29 (t, 7.2 Hz, 2H), 7.71 (d. J=9.7 Hz, 2H), 7.11 (d. J=9.7 Hz, 2H), 4.69 (s. 2H), 2.08 (s, 3H). mp O 199°C. (dec), Tso 198°C. OS ~1- Example 34 O (2-(4-acetamidophenoxy)-2-oxoethyl)tributylphos phonium chloride 6 r O --- 0506 7

O Chloride 3 (309.1 mg, 1 mmol) and silver docusate (529.4 O ra Hetributylphosphine mg, 1 mmol) were suspended in 50 ml of anhydrous methanol us O ethylacetate, rf, and stirred in the dark at room temperature for 15 min. The N 48 h. H 65.9% suspension was filtered over celite and the filtrate was evapo rated <40° C. Remaining volatile material was removed 2 under reduced pressure (0.01 mbar, 40°C.) to yield product C10H10CINO3 7 in quantitative yield. The desired compound is isolated as 227.64 a yellow oil." H-NMR (300 MHz, d-DMSO) 8(ppm)=10.07 O (s, 1H), 9.16 (s, 1H), 7.82 (s, 1H), 7.77(s, 1H), 7.64 (d. J=9.2 O 1Sri-- Hz, 2H), 7.14 (d. J–9.2 Hz, 2H), 5.51 (s. 2H), 3.93 (s.3H), ul N O C 3.88 (m, 4H), 3.65 (dd, J=11.5 Hz, J-3.8 Hz, 1H), 2.85 (m, H 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. 6 0, 144.9, 137.8, 137.5, 123.8, 123.5, 121.5, 119.9, 66.1, 61.5, CH3CINOP 49.7, 38.1, 36.0, 34.1, 29.7, 29.6, 28.3, 23.9, 23.2, 22.4, 13.9, 429.96 10.8, 10.7. T5%osef 21'70 C.

4-Acetamidophenyl 2-chloroacetate 2 (1.138 g. 5 mmol) Example 36 and tributylphosphine (0.475 g, 6 mmol) were suspended in 1-(2-(4-acetamidophenoxy)-2-oxoethyl)-1-meth 50 ml of anhydrous ethyl acetate and refluxed for 48 hrs. After cooling to room temperature the white precipitate was fil ylpyrrolidinium docusate 8 tered, washed with ethylacetate and diethylether and dried 0508 under reduced pressure to give 6. The crude product was crystallized twice from acetonitrile to give pure 6 in 65% yield. Identity and purity was confirmed via H and 'C NMR. The desired compound is isolated as colourless needles. H-NMR (300 MHz, d-DMSO)8(ppm)=10.49 (s. 1H), 7.71 (d.J=8.95 Hz, 2H), 7.12 (d. J=8.95 Hz, 2H), 4.18 (d. J=14.33, 2H), 2.41 (m, 3H), 2.06 (s.3H), 1.55 (m, 6H), 1.41 (m, 6H), 0.91 (t, J=7.17). 'P-NMR (121.5 MHz, d-DMSO) uCrb 8(ppm)=34.8. 'C-NMR (75 MHz, d-DMSO) 8(ppm)=168. US 2012/0046244 A1 Feb. 23, 2012 52

Example 38 -continued O (2-(4-acetamidophenoxy)-2-oxoethyl)tributylphos phonium docusate 10 OS O ~1- 0512

10 O N-- O O 1Sri us N O H 0509 Prepared according to example 35 in quantitative O yield. The desired compound is isolated as a yellow oil. 'H-NMR (300 MHz, d-DMSO) 8(ppm)=10.011 (s, 1H), OS ~1- 7.66 (d. J=8.7 Hz, 2H), 7.17 (d. J=8.7 Hz, 2H), 4.82 (s. 2H), O 3.88 (m, 2H), 3.72 (m, 5H), 3.25 (s.3H), 2.88 (m, 2H), 2.14 (m, 4H), 2.05 (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, O S--- 144.9, 137.9, 137.7, 123.8, 123.5, 121.4, 119.9, 49.7, 36.0, 23.9. C-NMR (75 MHz, d-DMSO) 8(ppm)=1710, 168.4, 0513 Prepared according to example 35 in quantitative 164.4,144.5, 137.7, 121.6, 119.8, 66.1, 65.1, 61.6, 49.4, 38.1, yield. The desired compound is isolated as a yellow oil. 34.1, 29.7, 29.6, 28.3, 23.9, 23.2, 23.0, 22.4, 21.4, 13.8, 10.7. H-NMR (300 MHz, d-DMSO)8(ppm)=10.07 (s, 1H), 7.64 T 233 C. 5%osef (s. 2H), 7.14 (s. 2H), 4.07 (d. J=14.6 Hz, 2H), 3.88 (s, 4H), 3.62 (s, 1H), 2.84 (m, 2H), 2.36 (s, 6H), 2.04 (s.3H), 1.49 (m, Example 37 14H), 1.23 (m, 16H), 0.89 (m, 21H). 'C-NMR (75 MHz, d-DMSO)8(ppm)=168.4, 166.1,144.9, 137.9, 137.7, 123.8, 1-(2-(4-acetamidophenoxy)-2-oxoethyl)pyridinium 123.5, 1214, 119.9, 49.7, 36.0, 23.9. T-17 C., T5% osef docusate 9 227O C. 0510) Example 39 Synthesis of 1-(2-(4-acetamidophenoxy)-2-oxoet hyl)-3-methyl-1H-imidazol-3-ium lactate 11 0514

Oro O silver O N ~\ lactate N"- --> O us N O N/ MeOH,15 min rt, H C OS O ~1- 3.

O S1 JOO--H O 0511 Prepared according to example 35 in quantitative 11 yield. The desired compound is isolated as a yellow glass. 0515 Chloride 3(309.1 mg, 1 mmol) and racemic silver 'H-NMR (300 MHz, d-DMSO)8(ppm)=10.13 (s, 1H), 9.21 lactate (196.4 mg, 1 mmol) were suspended in 25 ml of (d. J=6.2 Hz, 2H), 8.82 (t, 7.8 Hz, 1H), 8.36 (t, 7.2 Hz, 2H), anhydrous methanol and stirred in the dark at room tempera 7.72 (d. J=9.0 Hz, 2H), 7.25 (d. J=9.0 Hz, 2H), 6.00 (s. 2H), ture for 15 min. The suspension was filtered over celite and 3.96 (m, 4H), 3.71 (dd, J=11.3 Hz, J-3.7 Hz, 1H), 2.94 (m, the filtrate was evaporated at <40° C. Remaining volatile 2H), 2.12 (s.3H), 1.56 (m, 2H), 1.00 (m, 16H), 0.93 (m, 12H). material was removed under reduced pressure (0.01 mbar, 40° C.) to yield product 11 as yellow oil in quantitative 'C-NMR (75 MHz, d-DMSO)8(ppm)=7.1.0, 168.4, 165.6, yield. 'H-NMR (300 MHz, d-DMSO)8(ppm)=9.85 (s, 1H), 147.0, 146.5, 144.9, 137.6, 127.9, 121.5, 119.9, 66.2, 66.1, 9.18 (s, 1H), 7.75 (s. 2H), 7.32 (d. J–8.1 Hz, 2H), 6.68 (d. 61.5, 60.4, 38.1, 34.1, 29.7, 29.6, 28.3, 23.2, 23.1, 23.0, 22.4, J=8.1 Hz, 2H), 5.29 (s. 2H), 3.90 (s.3H), 3.57 (q, J=6.8 Hz, 13.9, 10.8, 10.7. T.25° C.T.s, 238° C. 1H), 1.98 (s.3H), 1.11 (d. J=6.6 Hz, 3H). US 2012/0046244 A1 Feb. 23, 2012

Example 40 2 as yellow liquid. The product was pure according to H 1-(2-(4-acetamidophenoxy)-2-oxoethyl)-1-meth NMR and directly subjected to the next step without further ylpyrrolidinium lactate 12 purification. 0516 0521 '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), 2.03 (m, 4H), 1.68 (s, 3H), 1.64 (s, 3H), 1.56 (s, 3H). 12 'C-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. Example 43 Orb 'r Synthesis of (E)-1-(2-(3,7-dimethylocta-2,6-dieny loxy)-2-oxoethyl)-3-methyl-1H-imidazol-3-ium 0517 Prepared according to example 39 in quantitative chloride 3 yield. Identity and purity were confirmed via H and 'C NMR. The desired compound is isolated as a yellow oil. 'H-NMR (300 MHz, d-DMSO) 8(ppm)=9.82 (s, 1H), 7.33 0522 (d. J=8.8 Hz, 2H), 6.69 (d. J=88 Hz, 2H), 4.55 (s. 2H), 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, 3 H). Tso 166° C. --~~~~ --N-methylimidazol Example 41 O neat, 40°C., Prodrug Hydrolysis—General Procedure 2 3. 0518 Acetaminophen prodrug (0.5 mmol) was dissolved in 5 ml phosphate buffer pH 7.4. The resulting 0.1 M solutions O C were stirred in a preheated oil bath at 37° C. Sample of 0.05 ml were withdrawn at intervals, diluted with DO to 0.5 ml N-- 1-\N and "H NMR spectra was immediately measured. Decompo O N/ sition could be monitored via integration of representing aro 3) matic signals of prodrug and of free acetaminophen. Ionic Liquid Immobilized Fragrances 0523 Geraniolester 2 (2.307 g. 10 mmol) and N-meth Example 42 ylimidazole (0.821 g, 10 mmol) were mixed in and stirred in Synthesis of (E)-3,7-dimethylocta-2,6-dienyl 2-chlo a sealed vessel at 40°C. for 24 hrs. A light-brown solid was roacetate 2 formed and suspended in anhydrous diethylether. The solid 0519 precipitate was filtered, washed with diethylether and dried under reduced pressure (0.01 mbar) to give imidazolium chloride 3 in 67% yield as light-yellow hygroscopic solid. OH The product was pure according to "H NMR and directly subjected to the next step without further purification. --~~ -- 'H-NMR (300 MHz, d-DMSO) 8(ppm)=9.36 (s, 1H), 7.82 1. (s. 2H), 5.37 (s. 2H), 5.33 (t, J=7.0 Hz, 1H), 5.07 (s, 1H), 4.68 C C pyridine (d. J=7.1 Hz, 2H), 3.93 (s, 3H), 2.03 (m, 4H), 1.66 (s, 3H), CH2Cl2, 0°C. 1.64 (s, 3H), 1.56 (s, 3H). 'C-NMR (75 MHz, d-DMSO) O to rt, 24h Ö(ppm)=166.9, 142.6, 137.8, 131.1, 123.7, 123.6, 123.3, 117. 9996 8, 62.4, 49.4, 35.9, 25.8, 25.5, 17.6, 16.1 mp 160° C. (dec), O Tsoonset 1 250 C.

N-- Ora Example 44 2 Synthesis of (E)-1-(2-(3,7-dimethylocta-2,6-dieny loxy)-2-oxoethyl)-3-methyl-1H-imidazol-3-ium 0520 Geraniol 1 (7.711 g, 50 mmol) and pyridine (3.955 docusate 4 g, 50 mmol) were suspended in anhydrous dichloromethane (200 ml) and chilled to 0°C. under an atmosphere of dry nitrogen. Chloroacetylchloride (5.647 g. 50 mmol) was 0524 added dropwise (violent reaction) and the resulting Solution was stirred for 24 hrs at room temperature. Water (100 ml) was added, the organic layer was separated and the aqueous O C Sodium layer extracted with dichloromethane. The combined organic N-- ^ N ~ N- Hosdocusate layers were successively washed with 2N HCl, saturated O S. acetone/H2O, NaHCO solution and brine, dried over MgSO and the sol 3 N/ rt, 24h vent was evaporated. Remaining Volatile material was 3. >99% removed under reduced pressure (0.01 mbar) to yield product US 2012/0046244 A1 Feb. 23, 2012 54

-continued -continued O O 21 21 O N-- O1\,. S. --~~ O ~. O 5) OS O ~~

O 0528 Geraniol 1 (1.542 g, 10 mmol), succinic anhydride (1.201 g, 12 mmol) and 4-DMAP (10 mg, cat) were sus pended in anhydrous dichloromethane (50 ml) under an O --- atmosphere of dry nitrogen. Pyridine (0.791 g, 10 mmol) was 4) added and the reaction mixture was stirred for 24 hrs at room temperature. The reaction mixture was successively washed with 2NHC1 and HO, dried over NaSO and the solvent was 0525 Imidazolium chloride 3 (312.8 mg, 1 mmol) and evaporated. Remaining volatile material was removed under Sodium docusate (444.6 mg, 1 mmol) were dissolved in 20 ml reduced pressure (0.01 mbar) to yield product 2 as yellow of acetone/HO 1:1 and stirred overnight at room tempera liquid in 99% yield. The product was pure according to H ture. The remaining suspension was diluted with 50 ml of NMR and directly subjected to the next step without further H2O and extracted with dichloromethane. The organic layer purification. 'H-NMR (300 MHz, d-DMSO) 8(ppm)=12.24 (brs, 114), 5.29 (t, J=7.0 Hz, 1H), 5.08 (t, 6.7, 1H), 4.55 (d. was washed successively with water until no more chloride J=7.1 Hz, 2H), 2.49 (m, 2H), 2.03 (m, 4H), 1.67 (s.3H), 1.66 ions could be detected in the washings (checked by addition (s.3H), 1.59 (s.3H). 'C-NMR (75 MHz, d-DMSO)8(ppm) of AgNO solution), dried over MgSO and the solvent was =173.3, 172.2, 1412, 131.1, 123.7, 118.5, 60.7, 38.9, 28.7, evaporated. Remaining volatile material was removed under 28.6, 25.8, 25.5, 17.5, 16.1. reduced pressure (0.01 mbar) to give imidazolium docusate 4 in quantitative yield as yellow oil. H-NMR (300 MHz, Example 46 d-DMSO)8(ppm)=9.07 (s, 1H), 7.71 (s. 2H), 5.33 (t, J–7.3 HZ, 1H), 5.24 (s. 2H), 5.07 (m, 1H), 4.69 (d. J=7.3 Hz, 2H), Synthesis of 2-Hydroxy-N,N,N-trimethyletha 3.91 (s.3H), 3.90 (m, 4H), 3.62 (dd, J=11.39 Hz, J-3.88 Hz, naminium (E)-4-(3,7-dimethylocta-2,6-dienyloxy)-4- 1H), 2.86 (m, 2H), 2.04 (m, 4H), 1.68 (s, 3H), 1.65 (s, 3H), oxobutanoate 6 1.57 (s, 3H), 1.49 (m, 2H), 1.24 (m, 16H), 0.84 (m. 12H). 0529) 'C-NMR (75 MHz, d-DMSO)8(ppm)=171.1, 168. 1, 166. 9, 142.7, 137.7, 131.2, 123.7, 123.6, 123.4, 117.6, 66.2, 66.1, 62.4, 61.4, 49.5, 38.1,356.0, 34.1, 29.8, 29.6, 28.3, 25.8, 25.5, O 23.2, 23.0, 22.4, 17.6, 16.2, 13.9, 10.8. Ts 170° C. -e- 0526. Thermocleavage of the immobilized fragrance MeOH, --~~~.O Geraniol 4 was demonstrated with TGA (FIG. 6). Mass loss O°C., 5 min of the first decomposition step obtained corresponds to mass 5) 9996 percentage of Geraniol 1 in the prodrug 4.

Example 45 1.in-son O Synthesis of (E)-4-(3,7-dimethylocta-2,6-dienyloxy)- 4-oxobutanoic acid 5 --~~~O 0527 6

OH 0530 Hemisuccinate 5 (1.0173 g, 4 mmol) was dis solved in 10 ml of methanol and chilled to 0° C. Choline hydroxide in (1.13 ml, 40% sol. in methanol, 4 mmol) was --~~ -- added dropwise and the reaction mixture was stirred for 5 min 1. at 0°C. The solvent was evaporated and remaining volatile O material was removed under reduced pressure (0.01 mbar) to yield product 6 as yellow liquid in quantitative yield. The O pyridine, 4-DMAP Her product was pure according to H NMR without further puri CH2Cl2, rt, 24h fication. 'H-NMR (300 MHz, d-DMSO) 8(ppm)=5.28 (t, 9996 J=7.0 Hz, 1H), 5.07 (t, J=6.8 Hz, 1H), 4.49 (d. J=7.0 Hz, 2H), O 3.85 (m, 2H), 3.44 (m, 2H), 3.13 (s, 9H), 2.36 (t, J=7.2 Hz, 2H), 2.10 (t, J–7.2 Hz, 2H), 2.03 (m, 4H, 1.65 (s, 6H), 1.57 (s, US 2012/0046244 A1 Feb. 23, 2012 55

3H). 'C-NMR (75 MHz, d-DMSO)8(ppm)=174.0, 173.6, 0534 Tramdolium hydrochloride (1.499 g, 5 mmol) and 140.7, 131.1, 123.8, 119.0, 67.3, 60.2, 55.0, 53.1, 39.3, 32.8, racemic sodium ibuprofenate (1.1441 g, 5 mmol) were dis 31.2, 25.8, 25.5, 17.6, 16.2. T-65° C.T.s, 170° C. solved in 50 ml of acetone/HO 1:1 and stirred overnight at room temperature. The remaining Suspension was diluted New API ILS with 50 ml of H2O and extracted with dichloromethane. The organic layer was washed Successively with water until no Example 47 more chloride ions could be detected in the washings Tramadolium Salicylate 1 (checked by addition of AgNO solution), dried over MgSO and the solvent was evaporated. Remaining Volatile material 0531 was removed under reduced pressure (0.01 mbar) to give tramadolium rac-ibuprofenate 2 in 89% yield as viscous glass that solidified after 2 weeks. 'H-NMR (300 MHz, 1. d-DMSO) 8(ppm)=7.19 (m, 3H), 7.08 (m. 2H), 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, NHS 6H), 1.85-1.35 (m,9H), 1.31 (d. J=7.1 Hz, 3H), 0.85 (d. J=7.7 HZ, 6H) ppm. mp 75°C., Ts 175° C. HO O O Example 49 OH Tramadolium (S)-ibuprofenate 3 0535

3.

NH 0532 Tramadolium hydrochloride (1.499 g, 5 mmol) and in sodium salicylate (0.801 g, 5 mmol) were dissolved in 50 ml of acetone/HO 1:1 and stirred overnight at room tempera HO s ture. The obtained suspension was chilled to 0°C., the pre cipitate was collected via filtration, washed with HO and dried under reduced pressure (0.01 mbar) to isolate tramado lium salicylate as colourless solid in 79% yield. 'H-NMR (300 MHz, d-DMSO) 8(ppm)=7.69 (dd, J=7.6 Hz, J-1.8 HZ, 1H), 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, Prepared according to example 48 in 76% yield. 'H-NMR d-DMSO)8(ppm)=1720, 262.3, 159.2, 150.0, 1319, 120.1, (300 MHz, d-DMSO) 8(ppm)=7.19 (m, 3H), 7.08 (m. 2H), 129.1, 119.5, 117.2, 116.5, 117.2, 116.5, 115.9, 111.5, 111.1, 7.00 (m, 2H), 6.72 (dd, J=8.1, J–2.3 Hz, 1H)), 3.73 (s.3H), 73.9, 59.4, 55.0, 43.0, 40.5, 40.4, 25.7, 24.6, 21.2. mp 183°C., 3.58 (q, J=7.0 Hz, 1H), 2.40 (d. J=7.0 Hz, 2H), 2.11 (m, 1H), T 2200 C. 5%osef 1.91 (s, 6H), 1.85-1.35 (m, 9H), 1.31 (d. J=7.1 Hz, 3H), 0.85 (d. J–7.7 Hz, 6H) ppm. Example 48 Example 50 Tramadolium rac-ibuprofenate 121 Tramadolium Meclofenamate 4 0533 0536

2 O NH NH in N

HO HO O C.NH uor C C O O US 2012/0046244 A1 Feb. 23, 2012 56

0537 Tramadolium hydrochloride (0.492 g, 1.64 mmol) 28.69, 25.79, 24.68, 23.52, 23.36, 22.76, 22.73, 21.45, 14.24, and Sodium meclofenamate (0.522 g, 1.64 mmol) were dis 14.21, 11.14, 11.11, 11.07. T-6° C. T., 226°C. solved in 20 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 Example 52 organic layer was washed Successively with water until no more chloride ions could be detected in the washings Cetylpyridinium Salicylate 6 (checked by addition of AgNO solution), dried over MgSO and the solvent was evaporated. Remaining Volatile material (0540 was removed under reduced pressure (0.01 mbar) to give tramadolium meclofenamate 3 in 95% yield as colourless solid foam. Identity and purity of the obtained product were 6 confirmed via "H NMR. 'H-NMR (300 MHz, d-DMSO) O 8(ppm)=10.62 (brs, 1H), 7.95 (dd, J–7.9 Hz, J-1.2 Hz, 1H), 7.50 (d. J=8.3, 1H), 7.3 (d. J=7.9 Hz, 1H), 7.28 (d. J=7.9 S1-1 o Hz, 1H), 7.18 (t, J=7.7 Hz, 1H), 7.10 (m, 2H), 6.80 (dd, J =8.1 Hz, J-2.2 Hz, 1H), 6.71 (t, J–7.5 Hz, 1H), 5.82 (brs, 1H), 21 OH 3.78 (s.3H), 2.60 (m. 1H, 2.40 (s.3H), 2.32 (s, 6H), 2.11 (m, 2H), 1.99 (d. 11.9Hz, 1H), 1.61 (m, 7H). 'C-NMR (75 MHz, d-DMSO)8(ppm)=1713, 159.1, 150.7, 146.3, 136.3, 135.8, 0541 Cetylpyridinium chloride monohydrate (20.64g, 56 133.2, 131.7, 131.6, 130.1, 128.9, 128.4,128.0, 117.3, 116.7, mmol) and sodium salicylate (8.96 g. 56 mmol) were dis 112.3, 74.2, 59.7, 54.9, 43.9, 41.6, 40.7, 26.2, 25.0, 21.4, 20.2. solved in 100 ml of acetone/HO 1:1 and stirred overnight at T38°C. T5%ose 1720 C. room temperature. The remaining Suspension was diluted Example 51 with 100 ml of HO and extracted with dichloromethane. The organic layer was washed Successively with water until no Tramadolium Docusate 5 more chloride ions could be detected in the washings (checked by addition of AgNO solution), dried over MgSO 0538 and the solvent was evaporated. Remaining volatile material was removed under reduced pressure (0.01 mbar) to give 5 cetylpyridinium salicylate 6 in 56% yield as colourless waxy solid. 'H-NMR (300 MHz, de-DMSO) 8(ppm)=9.12 NH (d. J=6.08 Hz, 2H), 8.59 (t, J=8.29 Hz, 1H), 8.16 (t, J=7.27 in O Hz, 2H), 7.64 (d. 7.54 Hz, 1H), 7.12 (t, J=7.54, 1H), 6.57 (m, 2H), 4.59 (t, J–7.44 Hz, 2H), 1.88 (m, 2H), 1.22 (s.27H), 0.84 OS ~1- (t, J=7.14 Hz, 3H). 'C-NMR (75 MHz, d-DMSO)8(ppm) HO O =171.8, 1634, 145.8, 145.2, 1314, 130.2, 128.4, 121.1, 116. 1, 160.0, 61.2, 31.7, 31.2, 29.4, 29.3, 29.2, 29.1, 28.8, 25.8, 22.5, 14.2. mp 57°C., Tso. 206°C. O N-- Example 53 Benzethonium Salicylate 7 0539 Tramadolium hydrochloride (0.5997 g, 2 mmol) (0542 and sodium docusate (0.8892 g, 2 mmol) were dissolved in 20 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 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 tramadolium docusate 3 in quantitative yield as yellow oil. H-NMR (300 MHz, 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), O 3.74 (s.3H), 3.64 (dd. 1H, J–3.7 Hz, J-11.1 Hz), 2.86 (m, 3H), 2.38 (d. 2H), 2.22 (m, 2H), 1.9-1.5 (m, 4H), 1.5 (m, 2H), 1.3-1.1 (m, 16H), 0.8 (m, 12H). 'C-NMR (75 MHz, d-DMSO)8(ppm)=171.36, 168.62, 159.54, 150.11, 129.52, OH 117.48, 111.88, 111.43, 74.15, 66.60, 66.53, 66.49, 66.44, 61.80, 59.89, 55.29, 40.68, 38.49, 34.40, 30.08, 29.97, 29.91, US 2012/0046244 A1 Feb. 23, 2012 57

0543 Benzethonium chloride (4.481 g, 10 mmol) and Example 55 sodium salicylate (1.601 g, 10 mmol) were dissolved in 50 ml of acetone/HO 1:1 and stirred overnight at room tempera Tetrabutylphosphonium Salicylate 9 ture. The remaining suspension was diluted with 50 ml of H2O and extracted with dichloromethane. The organic layer 0547 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 (9) evaporated. Remaining volatile material was removed under reduced pressure (0.01 mbar) to give benzethonium salicylate 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, P - O O 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), 1.67 (s. 2H), 1.28 (s, 6H), 0.66 (s, 9H). 'C-NMR (75 MHz, ? OH d-DMSO)8(ppm)=1710, 168.3, 1410,128.2, 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-14°C., Tsoi, 180° C. 0548 Salicylic acid (0.691 g, 5 mmol) and tetrabutylphos phonium hydroxide (~40% sol. in HO) (3.414 g. 5 mmol) Example 54 were dissolved in 20 ml of acetone stirred for 15 min at room temperature. The Solvent was evaporated and the remaining Lidocainium Salicylate 8 viscous liquid was dried at 0.1 mbar with stirring for 24hrs to obtain tetrabutylphosphonium salicylate 9 in quantitative 0544 yield as colourless crystals. H-NMR (300 MHz, d-DMSO) 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, 8H), 8 O 1.41 (m, 16H), 0.9 (t, J=7.06 Hz, 12H). 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), ^^ o 120.6 (s), 115.7 (d), 115.6 (d), 23.31 (d. J=16.36 Hz), 22.62 (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). 0545 Lidocaine hydrochloride monohydrate (23.105 g, Example 56 80 mmol) and sodium salicylate (8.962 g, 80 mmol) were dissolved in 10 ml of acetone/HO 1:1 and stirred overnight at Ephedrinium Salicylate 10 room temperature. The remaining Suspension was diluted with 100 ml of HO and extracted with dichloromethane. The 0549 organic layer was washed Successively with water until no more chloride ions could be detected in the washings 10 (checked by addition of AgNO, solution), dried over MgSO OH -- O and the solvent was evaporated. Remaining Volatile material H N was removed under reduced pressure (0.01 mbar) to give N O lidocainium salicylate 8 in 54% yield as pale yellow viscous oil. OH Solvent-Free Procedure: 0550 Salicylic acid (0.691 g, 5 mmol) and ephedrine 0546 Salicylic acid (5 mmol) and lidocaine free base (5 (0.826 g, 5 mmol) were molten in a hot mortar until a free mmol) were molten in a hot mortar until a free-flowing clear flowing clear liquid was obtained. The mixture was cooled to liquid was obtained. The mixture was cooled to room tem room temperature Solidified and was grinded to obtain a perature and formed a viscous glass. H-NMR (300 MHz, colourless powder in quantitative yield. H-NMR (300 MHz, d-DMSO)8(ppm)=10.05 (brs, 1H), 7.72 (dd, J–7.75 Hz, d-DMSO) 8(ppm)=9.30 (brs, 2H), 7.76 (dd, J–7.66 Hz, J–1.80 Hz, 1H), 7.24 (m, 1H), 7.09 (s.3H), 6.70 (m, 2H), J–1.80 Hz, 1H), 7.38 (m, 4H), 7.24 (m, 2H), 6.70 (m, 2H), 3.98 (s. 2H), 3.10 (q, J=7.28 Hz, 4H), 2.16 (s, 6H), 1.22 (t, 6.48 (brs, 1H), 5.21 (s, 1H), 3.41 (m, 1H), 2.69 (s.3H), 0.95 J=7.34 Hz, 6H). 'C-NMR (75 MHz, d-DMSO) 8(ppm) (d. J=6.76 Hz, 3H). 'C-NMR (75 MHz, d-DMSO)8(ppm) =171.9, 164.6, 1619, 135.0, 134.0, 133.4, 130.1, 127.8, 126. =172.9, 162.1, 1414, 132.0, 130.3, 128.2, 127.2, 125.8, 119. 9, 117.6, 116.9, 1164, 53.3, 48.3, 18.1, 9.5. T. 19° C., 6, 116.8, 116.0, 69.6, 59.3, 30.6, 9.1. mp 97°C., T 161° T5%osef 161o C. C. US 2012/0046244 A1 Feb. 23, 2012

Example 57 Example 59 Ephedrinium Docusate 13 Ephedrinium Ibuprofenate 11 0555 0551 13 11

OH -- H NS O O

0552. Ibuprofenic acid (0.691 g, 5 mmol) and ephedrine (0.826 g. 5 mmol) were molten in a hot mortar until a free roc flowing clear liquid was obtained. The mixture was cooled to 0556 Ephedrinium hydrochloride (2.017 g. 10 mmol) and room temperature, Solidified and was grinded to obtain a sodium docusate (4.446 g, 10 mmol) were dissolved in 50 ml colourless powder in quantitative yield. H-NMR (300 MHz, of acetone/HO 1:1 and stirred overnight at room tempera ture. The remaining suspension was diluted with 50 ml of d-DMSO) 8(ppm)=7.34 (m, 4H), 7.19 (m, 3H), 7.03 (d. H2O and extracted with dichloromethane. The organic layer J=7.89 Hz, 2H), 5.80 (brs, 1H), 4.97 (d. J=2.8 Hz, 1H), 3.45 was washed successively with water until no more chloride (q, J=7.1 Hz, 1H), 3.04 (m, 1H), 2.45 (s.3H), 2.38 (d. J=7.15 ions could be detected in the washings (checked by addition of AgNO, solution), dried over MgSO and the solvent was Hz, 2H), 1.78 (sept, J=6.8 Hz, 1H), 1.30 (d. J=7.17, 3 H), 0.83 evaporated. Remaining volatile material was removed under (m, 9H). 'C-NMR (75 MHz, d-DMSO) 8(ppm)=1779, reduced pressure (0.01 mbar) to give ephedrinium docusate 142.4, 140.9, 138.5, 128.5, 127.9, 127.1, 126.7, 125.9, 70.6, 13 in 98% yield as colourless viscous oil. H-NMR (300 59.8, 46.6, 44.3, 31.5, 29.7, 22.2, 19.5, 10.7. mp 110° C., MHz, d-DMSO) 8(ppm)=8.45 (brs, 2H), 7.34 (m, 5H), 6.13 T 238 C. (d. J–4.24 Hz, 1H), 5.06 (t, J=3.22 Hz, 1H), 3.89 (m, 4H), 5%osef 3.65 (dd, J = 11.47 Hz, J-3.91 Hz, 1H), 2.86 (m,2H), 2.64 (s, 3H), 1.49 (m, 2H), 1.23 (m, 16H), 0.86 (m, 15 H). 'C-NMR (75 MHz, d-DMSO) 8(ppm)=1710, 168.3, 1410, 128.2, Example 58 127.4, 125.8, 69.6, 66.2, 61.5, 59.0, 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-25° C., Ephedrinium Clofibrate 12 T5%onset 238o C. 0553 Example 60 Promethazine Docusate 14 0557 12

OH -- 14 H C o O'? NN O OC NS DO O X.

NH 0554 Clofibric acid (1.073 g, 5 mmol) and ephedrine 1+N (0.826 g. 5 mmol) were molten in a hot mortar until a free O flowing clear liquid was obtained. The mixture solidified at OS ~go room temperature and was grinded to obtain a yellow powder O in quantitative yield. '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=8.75 Hz, 2H), 5.10 (s, 1H), 3.12 (m, 1H), 2.52 (s.3H), 1.41 O N-- (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, 0558 Promethazine hydrochloride (3.209 g, 10 mmol) 125.8, 123.4, 119.2, 80.2, 69.8, 59.5, 30.7, 25.8, 9.6. mp 131° and sodium docusate (4.446g, 10 mmol) were dissolved in 50 C., Tsos, 166°C. ml of acetone/HO 1:1 and stirred overnight at room tempera US 2012/0046244 A1 Feb. 23, 2012 59 ture. The remaining suspension was diluted with 50 ml of HO and extracted with dichloromethane. The organic layer -continued was washed successively with water until no more chloride ions could be detected in the washings (checked by addition O 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 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, 0562 Procainamide hydrochloride (2.718 g. 10 mmol) J=7.3 Hz, 2H), 4.37 (dd, J=14.3 Hz, J-4.8 Hz, 1H), 4.05 and racemic sodium ibuprofenate (2.283 g, 10 mmol) were (dd, J=14.6 Hz, J–8.1 Hz, 1H), 3.89 (m, 4H), 3.66 (m, 2H), dissolved in 50 ml of acetone/HO 1:1 and stirred overnight at 2.91 (m, 2H), 2.82 (s, 6H), 1.49 (m, 2H), 1.28 (d. J=6.5 Hz, room temperature. The remaining Suspension was diluted 3H), 1.22 (m. 16H), 0.83 (m, 12H). To 246° C. with 50 ml of HO and extracted with dichloromethane. The organic layer was washed Successively with water until no more chloride ions could be detected in the washings Example 61 (checked by addition of AgNO solution), dried over MgSO and the solvent was evaporated. Remaining Volatile material Procainamide Salicylate 15 was removed under reduced pressure (0.01 mbar) to give procainamide ibuprofenate 16 in as Viscous yellow liquid. 0559 0563 '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 (d. 8.8 Hz, 2H), 6.54 (d. J=8.6 Hz, 2H), 5.60 (brs, 2H), 15) 3.61 (q, 7.2 Hz, 1H), 3.29 (m, 2H), 2.56 (m, 6H), 2.42 (d. O J–7.2 Hz, 2H), 1.82 (sept, 6.9 HZ, 1H), 1.35 (d. J=6.9 HZ,3H), HN 0.99 (t, 7.1 Hz, 6H), 0.86 (d. J=6.8 Hz, 6H). 'C-NMR (75 O MHz, d-DMSO)8(ppm)=175.7, 166.1, 151.5, 139.4, 138.9,

-- 128.9, 128.6, 127.1,121.3, 112.5, 51.6, 46.7, 44.6, 44.2, 37.0, N-1 nt OH 29.6, 22.2, 18.7, 11.6. Tso, 182°C. Example 63 Procainamide Docusate 17 0560 Procainamide hydrochloride (2.718 g. 10 mmol) 0564 and sodium salicylate (1.601 g, 10 mmol) were dissolved in 10 ml of acetone/HO 1:1 and stirred overnight at room temperature. The clear Solution was evaporated and the resi 17 due dissolved in anhydrous acetone. The Suspension was HN filtered over celite and the filtrate was evaporated. Remaining H -- volatile material was removed under reduced pressure (0.01 mbar) to give procainamide salicylate 15 as pale yellow N-1a1n viscous oil. "H-NMR (300 MHz, d-DMSO)8(ppm)=8.47 (t, J=5.6 Hz, 1H), 7.72 (dd, J=7.7 Hz, J=1.9 Hz, 1H), 7.60 (d. O O N J=8.7 Hz, 2H), 7.23 (m, 1H), 6.71 (m, 2H), 6.54 (d. J–8.6 Hz, 2H), 3.60 (s. 2H), 3.19 (m, 6H), 1.23 (t, J=7.1 Hz, 6H). 'C-NMR (75 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, 34.3, 8.6. Tse, 199° C. Example 62 rocO N-- Procainamide Ibuprofenate 16 0565 Procainamide hydrochloride (2.718 g, 10 mmol) and sodium docusate (4.4456 g, 10 mmol) were dissolved in 0561 20 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 16 layer was washed Successively with water until no more chlo HN ride ions could be detected in the washings (checked by addition of AgNO solution), dried over MgSO and the sol vent was evaporated. Remaining Volatile material was removed under reduced pressure (0.01 mbar) to give procainamide docusate 17 in quantitative yield as yellow oil. H-NMR (300 MHz, d-DMSO) 8(ppm)=9.08 (brs, 1H), 8.27 (t, J=5.6 Hz, 1H), 7.52 (d. J=8.6 Hz, 2H), 6.55 (d. J=8.6 US 2012/0046244 A1 Feb. 23, 2012 60

Hz, 2H), 5.71 (brs, 2H), 3.89 (m, 4H), 3.65 (dd, J=11.5 Hz, remaining viscous liquid was dried at 0.1 mbar with stirring J–38 Hz, 1H), 3.53 (q, 6.1 Hz, 2H), 3.2 (m, 6H), 2.87 (n, for 24hrs to obtain tetrabutylphosphonium ibuprofenate 19 4H), 1.49 (m, 2H), 1.22 (m, 22H), 0.84 (m, 12H). Tso in quantitative yield as colourless viscous liquid. 'H-NMR 2310 C. (300 MHz, d-DMSO)8(ppm)=7.13 (d. J=8.08 Hz, 2H), 6.94 Example 64 (d. 8.08 Hz, 2H), 3.21 (q, 7.74 Hz, 1H), 2.48 (m, 2H), 2.36 (d. 7.28 Hz, 2H), 2.14 (m, 8H), 1.77 (sept, 6.15 Hz, 1H), 1.40 (m, Triethanolammonium Ibuprofenate 18 16H), 1.18 (d. J=7.03 Hz, 3H), 0.91 (t, 7.02 Hz, 12H), 0.84 (d. 0566 J=7.02 Hz, 6H). 'C-NMR (75 MHz, d-DMSO) 8(ppm) =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 18 HZ), 13.3. mp-43°C., Tso. 234°C. -- HOS-1a 1-N-OH Example 66 Tributylhydroxyethylphosphonium Docusate 20 OH 0570

u? 20

0567 Ibuprofenic acid (1.032 g, 5 mmol) and triethanola mine (0.746g, 5 mmol) were molten in a hot mortar until a - - free-flowing clear liquid was obtained. The mixture solidified at room temperature and was grinded to obtain colourless powder in quantitative yield. 1H-NMR (300 MHz, O d-DMSO) 8(ppm)=7.20 (d. J=8.1 Hz, 2H), 7.1 (d. 8.1 Hz, 2H), 5.77 (brs, 3H), 3.61 (q, 7.2 Hz, 1H), 3.45 (t, J=6.1, 6H), OS ~go 2.61 (t, J=6.1 Hz, 6H), 2.42 (d. J=7.2 Hz, 2H), 2.42 (d. 7.2 Hz, O 2H), 1.82 (sept, 6.8 Hz, 1H), 1.35 (d. J=7.1 Hz, 3H), 0.87 (d. J=6.6 Hz,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. O N-- Example 65 Tetrabutylphosphonium Ibuprofenate 19 0571 Tributylhydroxyethylphosphonium chloride (10.019 g, 35.5 mmol) and sodium docusate (15.770 g., 35.5 0568 mmol) were dissolved in 100 ml of acetone/HO 1:1 and stirred overnight at room temperature. The remaining Suspen 19 sion was diluted with 100 ml of HO and extracted with dichloromethane. The organic layer 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 u? mbar) to give tributylhydroxyethylphosphonium docusate 20 in 92% yield as colourless liquid. 'H-NMR (300 MHz, ? O 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-NMR (121.5 MHz, d-DMSO) 8(ppm)=34.5. C-NMR 0569 Ibuprofenic acid (1.032 g, 5 mmol) and tetrabu (75 MHz, d-DMSO) 8(ppm)=1710, 163.3, 66.1, 66.0, 61.4, tylphosphonium hydroxide (~40% sol. in HO) (3.414 g. 5 544, 54.3, 38.1, 34.1, 29.7, 28.6, 29.5, 28.3, 23.6 (d. J=15.9 mmol) were dissolved in 20 ml of acetone stirred for 15 min Hz), 23.2, 23.0, 22.7 (d. 4.9 Hz), 22.4, 22.3, 18.1 (d. 48.5), at room temperature. The solvent was evaporated and the 13.9, 13.8, 13.2, 10.7. T-45° C., Tsoi, 280° C. US 2012/0046244 A1 Feb. 23, 2012 61

Example 67 -continued Choline Docusate 21 O 29 30 0572 o- 2 25 24 O 27 26 21 O 0575l Propanthelinep pp-Toluenesulfonate "H NMR (300 OS ~1- MHz, d-DMSO): 81.13-1.18 (qJ3.9, 12H: H19, H20, H22, N O H23), 2.28 (s, 3H: H24), 2.66 (s, 3H: H17), 3.41-3.46 (t(b), 2n-1-on O J47, 2H; H16), 3.71-3.77 (m,2H: H18, H21), 4.34-4.39 (t(b), J 4.7, 2H; H15), 5.31 (s, 1H: H7), 7.09-7.12 (m, 2H; H26, O --- 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, 0573 Choline chloride (1.396 g, 10 mmol) and sodium C23); 20.70 (C24); 40.81 (C17); 44.07 (C7); 54.18 (C16); docusate (4.4456 g. 10 mmol) were dissolved in 50 ml of 59.72 (C15): 63.84 (C18, C21): 116.54 (C2, C12): 118.22 acetone/HO 1:1 and stirred overnight at room temperature. (C6, C8): 123.62 (C4, C10): 125.44(C27, C29); 127.95 (C26, The remaining suspension was diluted with 50 ml of HO and C30); 129.35 (C3, C11): 129.53 (C5, C9); 137.46 (C28); extracted with dichloromethane. The organic layer was 145.85 (C25): 150.86 (C1, C13): 170.32 (C14). MS (ESI): washed successively with water until no more chloride ions ES+ m/z. 368.0 (propantheline"), ES-m/z. 171.0 (p-toluene could be detected in the washings (checked by addition of sulfonate). ISE: The bromide concentration was determined AgNO solution), dried over MgSO and the solvent was by dissolving 0.205.6 g of propantheline p-toluenesulfonate in evaporated. Remaining volatile material was removed under 10 mL of methanol, indicating <100 ppm bromide. DSC: A reduced pressure (0.01 mbar) to give choline docusate 21 in reproducible Tg at 7+ C. quantitative yield as yellow very viscous liquid. 'H-NMR (300 MHz, d-DMSO)8(ppm)-4,88 (t, J=5.4 Hz, 1H), 4.21 Compositions (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), 1.57 (m, 2H), 1.27 (m, 16H), 0.87(m, (0576) Viscosity, conductivity and AW values for various 12H). Tso, 189° C. propantheline p-toluenesulfonate (PtTos)/water composites. Ionic Liquid Solvates TABLE X Example 68 Viscosity Conductivity Propantheline p-Toluenesulfonate Compositions (mPa is) + 1% (Scm)** AW PtTos pure >2000: 5.41 x 107 2.0 0574. A mixture of propantheline bromide (3.32 g, 7.41 Water:PTTos (25 wt %) 3 30.1 x 10 O.69 mmol) and silver p-toluenesulfonate (2.07 g., 7.41 mmol) in Water:PTTos (20 wt %) 3 26.1 x 10 0.77 acetonitrile (100 mL) was protected from light and stirred Water:PTTos (4.8 wt %) 1 15.2 x 10 O.63 overnight at room temperature. A yellow precipitate formed instrument limit instantaneously. The reaction mixture was filtered through **conductivity error does not exceed the data point in all cases Celite to remove AgBr. The filtrate was then re-filtered AW–distance form the ideal line through microfilters (0.20 m). The solvent was evaporated to leave a clear yellow viscous residue. To remove any colour 0577. The low ionicity nature of the ionic liquid is dem from the sample, propantheline p-toluenesulfonate was re onstrated via the Walden plot according to the discussion of Fraser et al (Chem Commun 2007). Data for this compound dissolved in acetonitrile and two spatulas of activated char are plotted in FIG. 7 which shows that it lies 2 log units below coal (6-12 Mesh) were added to the solution. The mixture was the reference line, Suggesting the degree of ionicity is only left stirring overnight and then filtered through activated alu approximately 1%. With addition of 25 weight% water, AW minum oxide (basic, Brockmann I). The solvent was removed value decreased. This is true for all of the propantheline leaving a clear Viscous oily residue. The product was dried p-toluenesulfonate/water systems studied. With the increas under vacuum on a Shlenk line at 55° C. for 3 hours. (crude ing water content the AW seems to become approximately yield: 91%) constant perhaps indicating that full dissociation had been reached. 1. A method for preparing a bioactive co-ionic ionic liquid composition, comprising: combining two cations or cation precursors, represented as B' and B, with one anion, represented as A, or combin ing two anions or anion precursors, represented as A' and A, with one cation, represented as B, thereby pro ducing a co-ionic liquid (BHBA or BAHA), where His hydrogen, that is liquid at a temperature at or below about 150° C., wherein B, B'A', and A are pharma ceutical actives. US 2012/0046244 A1 Feb. 23, 2012 62

2. The method of claim 1 62. The method according to claim 1, wherein the cation B wherein from about 75% to about 100% of the composition comprises tetrabutylphosphonium and the anion A comprises comprises an ion pair. salicylate and ibuprofenate, cinnamate, camphorsulfonate, 3-7. (canceled) lactate or thiosalicylate. 8. The method of claim 1, wherein the cations and anions or 63. The method according to claim 1, wherein the cation B the cation precursors and anion precursors are combined in is tetrabutylphosphonium and the anions A" and A are ibu the presence of one or more solvents, thereby producing a profenate or niacinate. 64. The method according to claim 1, wherein the cation B solvated ionic liquid; wherein at least a portion of the solvent is cetylpyridinium and the anions A" and A are salicylate and provides direct solvation. ibuprofenate, cinnamate, or clofibrate. 9-11. (canceled) 65. The method according to claim 1, wherein the cation B 12. The method according to claim 1, wherein acid HA is is lidocaine and the anions A and A are salicylate and ibu added to an non-protic ionic liquid having the formula BA". profenate. 13. The method according to claim 1, wherein base B is 66. The method according to claim 1, wherein the cation B added to an ionic liquid having the formula (BHA. is tramadolium and the anions A" and A are salicylate and 14. (canceled) ibuprofenate. 15. (canceled) 67. The method according to claim 1, wherein the cations 16. The method according to claim 1, wherein combining B' and B are ephedrinium and lidocaine and the anion A is the cation precursor and anion precursor is accomplished by ibuprofenate. an acid-base neutralization reaction wherein the ratio of acid 68. The method according to claim 1, wherein the cations to base used for the neutralization reaction is not 1:1. B' and B are tramadolium and lidocaine and the anion A is 17-59. (canceled) salicylate or ibuprofenate. 60. The method according to claim 1, wherein the cations 69. The method according to claim 1, wherein the cations B' and B are choline, lidocaine, tramadolium, caffeine, B' and B are promethazine and ephedrine and the anion A is cetylpyridinium, ephedrinium or promethazine. docusate or salicylate. 61. The method according to claim 1, wherein the anions A' and A are salicylate, ibuprofenate, lactate, camphorsul 70-164. (canceled) fonate, trans-cinnamate, docusate, niacinate or clofibrate.