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(12) Patent Application Publication (10) Pub. No.: US 2012/0046244 A1 Rogers Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2012/0046244 A1 Rogers Et Al 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.
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