CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application Serial No. 61/780,631, filed March 13, 2013, the entire contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

[0002] The invention relates to the field of crystalline polymorphs of gamma secretase modulators, more specifically to novel polymorphic forms of crystalline (R)-2-(5-chloro-6- (2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3 -cyclobutylpropanoic acid or salts thereof.

BACKGROUND OF THE INVENTION

[0003] (R)-2-(5-chloro-6-(2,2,2-trif uoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3- cyclobutylpropanoic acid ("Free Acid") is a gamma secretase modulator, described in U.S. Pat. No. 8,217,064, which is incorporated by reference herein. However, the Free Acid can post challenges for formulation and administration as an active pharmaceutical agent.

[0004] Accordingly, there is a need to develop new salts and polymorphs of (R)-2-(5- chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)bipheny l-3-yl)-3-cyclobutylpropanoate that have acceptable solubility and bioavailability properties for formulation and

administration as active pharmaceutical agents.

SUMMARY OF THE INVENTION

[0005] The present invention is based, in part, upon the surprising discovery that certain crystalline polymorphs of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or salts thereof, such as the crystalline polymorph of the potassium (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate, possess desirable physical and chemical properties for formulation and administration as drugs for human therapy. [0006] It is understood that any of the embodiments described below can be combined in any desired way, and any embodiment or combination of embodiments can be applied to each of the aspects described below, unless the context indicates otherwise.

[0007] These and other aspects and embodiments of the invention will be apparent to one of ordinary skill in the art based upon the following detailed description of the invention.

[0008] In one aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate, which is at least about 95% crystalline, is described.

[0009] In another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)- 4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate, which is at least about 97% crystalline, is described.

[0010] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, which is at least about 99% crystalline, is described.

[0011] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, which is at least about 95%) chemically pure, is described.

[0012] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, which is at least about 98%o chemically pure, is described.

[0013] In some embodiments, the crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4 ' -(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoate ' s purity is determined by HPLC.

[0014] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4 ' -(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoate, having an endothermic onset at about 233-244°C in a differential scanning calorimetry (DSC) profile, is described.

[0015] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4 ' -(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoate, having an endothermic onset at about 243 °C in a differential scanning calorimetry (DSC) profile, is described.

[0016] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4 ' -(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoate, characterized by the differential scanning calorimetry (DSC) profile substantially as shown in Figure 5, is described.

[0017] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, having a peak position at about 5.2 degrees 2-theta in an x-ray powder diffraction pattern obtained using Cu Ka radiation, is described.

[0018] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, having a peak position at about 5.8 degrees 2-theta in an x-ray powder diffraction pattern obtained using Cu Ka radiation, is described.

[0019] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, having a peak position at about 8.4 degrees 2-theta in an x-ray powder diffraction pattern obtained using Cu Ka radiation, is described.

[0020] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, having a peak position at about 10.2 degrees 2-theta in an x-ray powder diffraction pattern obtained using Cu Ka radiation, is described.

[0021] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, having a peak position at about 11.6 degrees 2-theta in an x-ray powder diffraction pattern obtained using Cu Ka radiation, is described.

[0022] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, having a peak position at about 17.2, 18.8, 19.3, 19.8, 22.5, 26.6, or 28.5 degrees 2-theta in an x-ray powder diffraction pattern obtained using Cu Ka radiation, is described.

[0023] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, having a peak position at about 20.5 degrees 2-theta in an x-ray powder diffraction pattern obtained using Cu Ka radiation, is described.

[0024] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, having a peak position at about 21 degrees 2-theta in an x-ray powder diffraction pattern obtained using Cu Ka radiation, is described. [0025] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, having a peak position at about 23.5 degrees 2-theta in an x-ray powder diffraction pattern obtained using Cu Ka radiation, is described.

[0026] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, having a peak position at about 25 degrees 2-theta in an x-ray powder diffraction pattern obtained using Cu Ka radiation, is described.

[0027] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, having a peak position at about 26.8 degrees 2-theta in an x-ray powder diffraction pattern obtained using Cu Ka radiation, is described.

[0028] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, having a peak position at about 29.4 degrees 2-theta in an x-ray powder diffraction pattern obtained using Cu Ka radiation, is described.

[0029] In yet another aspect, crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4 ' -(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoate, characterized, when measured with Cu Ka radiation, by the powder diffraction pattern substantially as shown in Figure 4, is described.

[0030] In yet another aspect, a pharmaceutical composition is described, including the crystalline potassium (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethy l)biphenyl- 3 -yl)-3 -cyclobutylpropanoate of any one of embodiments described herein and a

pharmaceutically acceptable excipient.

[0031] In some embodiments, the crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3 -cyclobutylpropanoate is present in a therapeutically effective amount.

[0032] In some embodiments, the pharmaceutical composition is formulated for oral administration.

[0033] In some embodiments, the pharmaceutical composition is in the form of a unit dosage.

[0034] In some embodiments, the pharmaceutical composition is in the form of a tablet, a capsule or a powder.

[0035] In some embodiments, the pharmaceutical composition is in the form of a tablet. [0036] In yet another aspect, a method of treating or preventing Alzheimer's disease in a patient is described, including administering to the patient in need thereof an effective amount of the crystalline potassium (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate of any one of the embodiments described herein.

[0037] In some embodiments, the patient is a mammal.

[0038] In some embodiments, the mammal is a human.

[0039] In some embodiments, the crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4 ' -(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoate is orally administered.

[0040] In some embodiments, the crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4 ' -(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoate is administered once or twice daily.

[0041] In some embodiments, the crystalline potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4 ' -(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoate is administered as a tablet or a capsule.

[0042] In some embodiments, the effective amount of crystalline potassium (R)-2-(5- chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)bipheny l-3-yl)-3-cyclobutylpropanoate is from about 50 mg to about 500 mg.

[0043] In some embodiments, the effective mount of crystalline potassium (R)-2-(5- chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)bipheny l-3-yl)-3-cyclobutylpropanoate is about 50 mg, 100 mg, 150 mg, 200 mg, 300 mg or 400 mg.

[0044] In some embodiments, the Alzheimer's disease is early onset Alzheimer's disease.

[0045] In yet another aspect, crystalline tromethamine (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3 -cyclobutylpropanoate, which is at least about 95% crystalline, is described.

[0046] In yet another aspect, crystalline tromethamine (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3 -cyclobutylpropanoate, which is at least about 97% crystalline, is described.

[0047] In yet another aspect, crystalline tromethamine (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3 -cyclobutylpropanoate, which is at least about 99% crystalline, is described. [0048] In yet another aspect, crystalline tromethamine (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, which is at least about 95% chemically pure, is described.

[0049] In yet another aspect, crystalline tromethamine (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, which is at least about 98% chemically pure, is described.

[0050] In some embodiments, crystalline tromethamine (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoate, wherein purity is determined by HPLC, is described.

[0051] In yet another aspect, crystalline tromethamine (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4 ' -(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoate, having an endothermic onset at about 47°C in a differential scanning calorimetry (DSC) profile, is described.

[0052] In yet another aspect, crystalline tromethamine (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4 ' -(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoate, characterized by the differential scanning calorimetry (DSC) profile substantially as shown in Figure 3A, is described.

[0053] In yet another aspect, crystalline tromethamine (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4 ' -(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoate, characterized, when measured with Cu Ka radiation, by the powder diffraction pattern shown in Figure 3B, is described.

[0054] In yet another aspect, crystalline (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid, is described.

[0055] In some embodiments, crystalline (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid is described, characterized by respective lattice parameters, a, b, and c of about 13.5859 A, 7.9436 A, and 20.249 A and β of about 95° in the monoclinic crystal system P2i space group, when measured with Μο-Κα radiation at about 120 K.

[0056] In some embodiments, the crystalline (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)- 4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid is at least about 95% crystalline. [0057] In some embodiments, the crystalline (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)- 4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid is at least about 95% chemically pure.

BRIEF DESCRIPTION OF THE FIGURES

[0058] Figure 1 is a graphic representation of XRPD diffractograms of crystalline potassium (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethy l)biphenyl-3-yl)-3- cyclobutylpropanoate crystallized from EtOH and isopropyl alcohol.

[0059] Figure 2 is a graphic representation of a DSC thermogram of the crystalline potassium (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethy l)biphenyl-3-yl)-3- cyclobutylpropanoate.

[0060] Figure 3A is a graphic representation of a DSC thermogram of crystalline tromethamine (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethy l)biphenyl-3-yl)-3- cyclobutylpropanoate crystallized from EtOH and isopropyl alcohol.

[0061] Figure 3B is a graphic representation of a XRPD diffractogram of crystalline tromethamine (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethy l)biphenyl-3-yl)-3- cyclobutylpropanoate crystallized from EtOH and isopropyl alcohol.

[0062] Figure 4 is a graphic representation of a XRPD diffractogram of the crystalline potassium (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethy l)biphenyl-3-yl)-3- cyclobutylpropanoate produced in a scaled-up synthesis.

[0063] Figure 5 is a graphic representation of a DSC thermogram of the crystalline potassium (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethy l)biphenyl-3-yl)-3- cyclobutylpropanoate produced in a scaled-up synthesis.

[0064] Figure 6 is a graphic representation of an HPLC chromatogram of the crystalline potassium (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethy l)biphenyl-3-yl)-3- cyclobutylpropanoate produced in a scaled-up synthesis.

[0065] Figure 7 is a graphic representation of experimental and calculated XRPD traces of a single crystal of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethy l)biphenyl- 3-yl)-3-cyclobutylpropanoic acid. DETAILED DESCRIPTION OF THE INVENTION

1. References and Definitions

[0066] The patent and scientific literature referred to herein establishes knowledge that is available to those of skill in the art. The issued U.S. patents, allowed U.S. applications, published U.S. applications, published foreign applications, foreign patents, and references, including database entries, that are cited herein are hereby incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference.

[0067] As used herein, the term "polymorphs" refer to different polymorphic forms of the same compound and includes, but is not limited to, other solid state molecular forms including solvation products and amorphous forms of the same compound. The term

"polymorph" refers to any one such form. Different polymorphs of a given compound may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, crystal shape, compaction behavior, flow properties, and/or solid state stability. Unstable polymorphs generally convert to the more thermodynamically stable forms at a given temperature after a sufficient period of time. Metastable forms are unstable polymorphs that slowly convert to stable forms. A metastable pharmaceutical solid form can change crystalline structure or solvate/desolvate in response to changes in environmental conditions, processing, or over time. In general, the stable form exhibits the highest melting point and the most chemical stability; however, metastable forms may also have sufficient chemical and physical stability to render them pharmaceutically acceptable. "Chemical stability" refers to stability in chemical properties, such as thermal stability, light stability, and moisture stability.

[0068] The recitation of "about" preceding a range of values is intended to modify both endpoints in the range, e.g., "about 83-89°C" is equivalent to "about 83°C to about 89°C".

[0069] As used herein, the recitation of a numerical range for a variable is intended to convey that the invention may be practiced with the variable equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable can be equal to any integer value within the numerical range, including the end-points of the range. Similarly, for a variable which is inherently continuous, the variable can be equal to any real value within the numerical range, including the end-points of the range. As an example, and without limitation, a variable which is described as having values between 0 and 2 can take the values 0, 1 or 2 if the variable is inherently discrete, and can take the values 0.0, 0.1, 0.01, 0.001, or any other real values > 0 and≤ 2 if the variable is inherently continuous.

[0070] As used herein, unless specifically indicated otherwise, the word "or" is used in the inclusive sense of "and/or" and not the exclusive sense of "either/or."

[0071] As used herein, "Potassium Salt" refers to crystalline potassium (R)-2-(5-chloro-

6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3- yl)-3-cyclobutylpropanoate.

[0072] As used herein, "Tromethamine Salt" refers to crystalline tromethamine (R)-2-(5- chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)bipheny l-3-yl)-3-cyclobutylpropanoate.

As used herein, "tromethamine (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-

(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate" and

"tris(hydroxymethyl)methylamonium (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-

(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate" are used interchangeably.

[0073] As used herein, "Crystalline Salt" refers to Potassium Salt or Tromethamine Salt.

[0074] As used herein, "Free Acid" refers to (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-

(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoic acid.

[0075] Abbreviations: XRD is X-ray diffraction, XRPD is X-Ray Powder Diffraction, SCXRD is Single Crystal X-Ray Diffraction, DSC is Differential Scanning Calorimetry, HPLC is High Performance Liquid Chromatography, DMSO is dimethyl sulfoxide, IPA is isopropyl alcohol, FASSIF is Fasted State Simulated Intestinal Fluid, FESSIF is Fed State Simulated Intestinal Fluid, ee is enantiomeric excess, GVS is Gravimetric Vapor Sorption, n- BuOAc is n-butyl acetate, EtOAc is ethyl acetate, EtOH is ethanol, i-PrOAc is iso-propyl acetate, i-PrOH is iso-propyl alcohol, MeCN is acetonitrile, MEK is methyl ethyl ketone, MeOH is methanol, MIBK is methyl isobutyl ketone, n-BuOH is n-butanol, n-PrOH is n- propanol, PTFE is polytetrafluoroethene, RM is reaction mixture, RT is room temperature, TBME is t-butyl methyl ether, t-BuOH is t-butanol, THF is tetrahydrofuran.

2. (R)-2-(5-chloro-6- ,2,2-trifluoroethoxy)-4 ^, -qrifluoromethyl)biphenyl-3-yl)-3- cyclobutylpropanoic acid

[0076] (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifiuoromethy l)biphenyl-3-yl)-3- cyclobutylpropanoic acid ("Free Acid") is a non-solvated crystalline material having a melting point with an onset at about 91°C. It is sparingly soluble soluble in deionized water. The thermodynamic aqueous solubility of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid was determined to be less than 0.0001 mg/ml.

[0077] Synthesis of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid is described in U.S. Pat. No. 8,217,064, which is incorporated by reference herein.

3. Crystalline Salts

[0078] Crystalline Potassium Salt and Tromethamine Salt were prepared and

characterized as described in the Examples.

[0079] The Potassium Salt is crystallized in a novel crystalline polymorph, which is characterized by a characteristic XRPD diffraction pattern and a well-defined DSC profile. Surprisingly, this polymorph has the requisite chemical and physical properties such as solubility and stability for formulation and administration as an active pharmaceutical ingredient.

[0080] In some embodiments, chemical purity of a Crystalline Salt is determined by HPLC, e.g., by measuring the area under the peak representing the Crystalline Salt and comparing it to the area of non-solvent peaks.

4. Pharmaceutical Compositions of Crystalline Salts or Free Acid and Their

Administration

[0081] Due to their activity, Crystalline Salts and Free Acid are advantageously useful in human medicine. As described above, Crystalline Salts and Free Acid are useful for treating or preventing a neurological disorder in a subject in need thereof. Neurological disorders include, but are not limited to, Alzheimer's disease (including early onset Alzheimer's disease), and schizophrenia.

[0082] Crystalline Salts and Free Acid can be administered in amounts that are effective to treat or prevent a neurological disorder (e.g., Alzheimer's disease) in a subject in need thereof.

[0083] When administered to a subject, a Crystalline Salt or Free Acid can be

administered as a component of a composition that comprises a physiologically acceptable carrier or vehicle. The present compositions, which comprise a Crystalline Salt or Free Acid, can be administered orally. A Crystalline Salt or Free Acid can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, or intestinal mucosa) and can be administered as the sole active pharmaceutical ingredient or together with another biologically active agent. Administration of a Crystalline Salt or Free Acid can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes,

microparticles, microcapsules and capsules.

[0084] Exemplary methods of administration of a Crystalline Salt or Free Acid include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical, specifically to the ears, nose, eyes, or skin. In some instances, administration results in the release of the Crystalline Salt or Free Acid into the bloodstream.

[0085] In one embodiment, Crystalline Salts or Free Acid are administered orally. In other embodiments, it can be desirable to administer Crystalline Salts or Free Acid locally. This can be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository or enema, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.

[0086] In certain embodiments, it can be desirable to introduce Crystalline Salts or Free Acid into the central nervous system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal, and epidural injection, and enema. Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.

[0087] Pulmonary administration can also be employed, e.g., by use of an inhaler of nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon oar, synthetic pulmonary surfactant. In certain embodiments, Crystalline Salts or Free Acid can be formulated as a suppository, with traditional binders and excipients such as triglycerides. In another embodiment, Crystalline Salts and Free Acid can be delivered in a vesicle, specifically a liposome (see Langer, Science 249: 1527-1533 (1990) and Liposomes in Therapy of Infectious Disease and Cancer 31 '-327 and 353-365, Lopez-Berestein and Fidler (eds.), Liss, New York (1989)).

[0088] In yet another embodiment, Crystalline Salts or Free Acid can be delivered in a controlled-release system or sustained release system (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled or sustained release systems discussed in the review by Langer, Science 249: 1527-1533 (1990) can be used. In one embodiment a pump can be used (Langer, Science 249: 1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al, Surgery 88:507 (1980); and Saudek et al., N. Engl. J Med. 321 :574 (1989)). In another embodiment polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and

Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J. Macromol. Sci. Rev.

Macromol. Chem. 2:61 (1983); Levy et al, Science 228: 190 (1935); During et al, Ann.

Neural. 25:351 (1989); and Howard et al, J. Neurosurg. 71 : 105 (1989)).

[0089] In yet another embodiment, a controlled or sustained release system can be placed in proximity of a target of a Crystalline Salt or Free Acid, e.g., the spinal column, brain, skin, lung, or gastrointestinal tract, thus requiring only a fraction of the systemic dose.

[0090] In one embodiment, Crystalline Salt or Free Acid can be administered by introduction into the central nervous system of the subject, e.g., into the cerebrospinal fluid of the subject. The formulations for administration will commonly comprise a solution of a Crystalline Salt or Free Acid dissolved in a pharmaceutically acceptable carrier. In certain aspects, a Crystalline Salt or Free Acid is introduced intrathecally, e.g., into a cerebral ventricle, the lumbar area, or the cisterna magna. In another aspect, a Crystalline Salt or Free Acid is introduced intraocularly, to thereby contact retinal ganglion cells.

[0091] In one embodiment, the pharmaceutical composition comprising a Crystalline Salt or Free Acid is administered into a subject intrathecally. As used herein, the term "intrathecal administration" is intended to include delivering a pharmaceutical composition comprising a Crystalline Salt or Free Acid directly into the cerebrospinal fluid of a subject, by techniques including lateral cerebro ventricular injection through a burrhole or cisternal or lumbar puncture or the like (described in Lazorthes et al. Advances in Drug Delivery Systems and Applications in Neurosurgery, 143-192 and Omaya et al., Cancer Drug Delivery, 1 : 169- 179). The term "lumbar region" is intended to include the area between the third and fourth lumbar (lower back) vertebrae. The term "cisterna magna" is intended to include the area where the skull ends and the spinal cord begins at the back of the head. The term "cerebral ventricle" is intended to include the cavities in the brain that are continuous with the central canal of the spinal cord. Administration of a Crystalline Salt or Free Acid to any of the above mentioned sites can be achieved by direct injection of the pharmaceutical composition comprising the Crystalline Salt or Free Acid or by the use of infusion pumps. For injection, the pharmaceutical compositions can be formulated in liquid solutions, preferably in physiologically compatible buffers such as Hank's solution or Ringer's solution. In addition, the pharmaceutical compositions may be formulated in solid form and re-dissolved or suspended immediately prior to use. Lyophilized forms are also included. The injection can be, for example, in the form of a bolus injection or continuous infusion (e.g., using infusion pumps) of pharmaceutical composition.

[0092] In one embodiment, the pharmaceutical composition comprising a Crystalline Salt or Free Acid is administered by lateral cerebro ventricular injection into the brain of a subject. The injection can be made, for example, through a burr hole made in the subject's skull. In another embodiment, the encapsulated therapeutic agent is administered through a surgically inserted shunt into the cerebral ventricle of a subject. For example, the injection can be made into the lateral ventricles, which are larger, even though injection into the third and fourth smaller ventricles can also be made.

[0093] In yet another embodiment, the pharmaceutical composition comprising a Crystalline Salt or Free Acid is administered by injection into the cisterna magna, or lumbar area of a subject.

[0094] The present compositions optionally comprise a suitable amount of one or more pharmaceutically acceptable excipients so as to provide the form for proper administration to the subject.

[0095] Such pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to a subject. Water can be a useful excipient when the Crystalline Salt or Free Acid is

administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The present

compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0096] The present compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In one embodiment, the composition is in the form of a capsule (see, e.g., U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington 's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995).

[0097] In one embodiment, a Crystalline Salt or Free Acid is formulated in accordance with routine procedures as a composition adapted for oral administration to human beings. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs for example. Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving an Crystalline Salt or Free Acid are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time delay material such as glycerol monostearate or glycerol stearate can also be useful. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade.

[0098] Pharmaceutical preparations for oral use can be obtained through combination of a Crystalline Salt or Free Acid with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores. Suitable solid excipients in addition to those previously mentioned are carbohydrate or protein fillers that include, but are not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate. [0099] Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredients is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

[0100] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0101] In another embodiment, the Crystalline Salts or Free Acid can be formulated for intravenous administration. Typically, compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. Compositions for intravenous administration can optionally include a local anesthetic such as lignocaine to lessen pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water- free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent. Where the Crystalline Salts or Free Acid are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the Crystalline Salts or Free Acid are administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0102] Crystalline Salts or Free Acid can be administered by controlled-release or sustained release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,556, each of which is incorporated herein by reference in its entirety. Such dosage forms can be useful for providing controlled or sustained release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled or sustained release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled or sustained release. In some embodiments, the tablets are coated with an enteric coating.

[0103] In one embodiment a controlled or sustained release composition comprises a minimal amount of a Crystalline Salt or Free Acid to treat or prevent the neurological disorder (e.g., Alzheimer's disease, early onset Alzheimer's Disease, schizophrenia) over a period of time. Advantages of controlled or sustained release compositions include extended activity of the drug, reduced dosage frequency, and increased subject compliance. In addition, controlled or sustained release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of a Crystalline Salt or Free Acid, and can thus reduce the occurrence of adverse side effects.

[0104] Controlled or sustained release compositions can initially release an amount of a Crystalline Salt or Free Acid that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the Crystalline Salt or Free Acid to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant level of the Crystalline Salt or Free Acid in the body, the Crystalline Salt or Free Acid can be released from the dosage form at a rate that will replace the amount of Crystalline Salt or Free Acid being metabolized and excreted from the body. Controlled or sustained release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.

[0105] Oil suspensions can be formulated by suspending a Crystalline Salt or Free Acid in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281 :93-102 (1997). The pharmaceutical formulations of Crystalline Salts and Free Acid can also be in the form of oil- in- water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxy ethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.

[0106] In addition to the formulations described previously, a Crystalline Salt or Free Acid may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or transcutaneous delivery (e.g., subcutaneously or

intramuscularly), intramuscular injection or a transdermal patch. Thus, for example, the Crystalline Salt or Free Acid may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0107] For administration by inhalation, a Crystalline Salt or Free Acid can be

conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane,

trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of the Crystalline Salt or Free Acid and a suitable powder base such as lactose or starch.

[0108] The amount of a Crystalline Salt or Free Acid that is effective in the treatment or prevention of a Alzheimer's disease can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed can also depend on the route of

administration, and the seriousness of the condition being treated and can be decided according to the judgment of the practitioner and each subject's circumstances in view of, e.g., published clinical studies. Suitable effective dosage amounts, however, range from about 10 micrograms to about 5 grams about every 4 hours, although they are typically about 500 mg or less per every 4 hours. In one embodiment, the effective dosage is about 0.01 mg, 0.5 mg, about 1 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 1.2 g, about 1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, about 3.2 g, about 3.4 g, about 3.6 g, about 3.8 g, about 4.0 g, about 4.2 g, about 4.4 g, about 4.6 g, about 4.8 g, and about 5.0 g, every 4 hours. Equivalent dosages can be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one Crystalline Salt is administered, the effective dosage amounts correspond to the total amount administered.

[0109] Compositions of Crystalline Salts or Free Acid can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1% to about 99%; and in another embodiment from about 1% to about 70% of the Crystalline Salt and Free Acid by weight or by volume.

[0110] The dosage regimen utilizing the Crystalline Salt or Free Acid can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of

administration; the renal or hepatic function of the subject; and the specific Crystalline Salt or Free Acid employed. A person skilled in the art can readily determine the effective amount of the drug useful for treating or preventing the Alzheimer's disease.

[0111] A Crystalline Salt or Free Acid can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, a Crystalline Salt or Free Acid can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration can be continuous rather than intermittent throughout the dosage regimen. Other illustrative topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of a Crystalline Salt or Free Acid ranges from about 0.1 % to about 15%, w/w or w/v.

[0112] Crystalline Salts or Free Acid can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy.

[0113] The present methods for treating or preventing neurological disease (e.g.,

Alzheimer's disease, early onset Alzheimer's disease, schizophrenia) in a subject in need thereof can further comprise administering another prophylactic or therapeutic agent to the subject being administered a Crystalline Salt or Free Acid. In one embodiment, the other prophylactic or therapeutic agent is administered in an effective amount. The other prophylactic or therapeutic agent includes, but is not limited to, an anti-inflammatory agent, an anti-renal failure agent, an anti-diabetic agent, and anti-cardiovascular disease agent, an antiemetic agent, a hematopoietic colony stimulating factor, an anxiolytic agent, and an analgesic agent.

[0114] In one embodiment, the other prophylactic or therapeutic agent is an agent useful for reducing any potential side effect of an Crystalline Salt or Free Acid. Such potential side effects include, but are not limited to, nausea, vomiting, headache, low white blood cell count, low red blood cell count, low platelet count, headache, fever, lethargy, a muscle ache, general pain, bone pain, pain at an injection site, diarrhea, neuropathy, pruritis, a mouth sore, alopecia, anxiety or depression. In one embodiment, the Crystalline Salt or Free Acid can be administered prior to, concurrently with, or after an anti-inflammatory agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.

[0115] Effective amounts of the other prophylactic or therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other prophylactic or therapeutic agent's optimal effective amount range. In one embodiment of the invention, where another prophylactic or therapeutic agent is administered to a subject, the effective amount of the Crystalline Salt or Free Acid is less than its effective amount would be where the other prophylactic or therapeutic agent is not administered. In this case, without being bound by theory, it is believed that Crystalline Salts or Free Acid and the other prophylactic or therapeutic agent act synergistically to treat or prevent a Alzheimer's disease.

5. Kits

[0116] The invention provides kits that can simplify the administration of a Crystalline Salt or Free Acid to a subject. A typical kit of the invention comprises a unit dosage form of a Crystalline Salt or Free Acid.

[0117] In one embodiment, the unit dosage form is a container, which can be sterile, containing an effective amount of a Crystalline Salt or Free Acid and a physiologically acceptable carrier or vehicle. The kit can further comprise a label or printed instructions instructing the use of the Crystalline Salt or Free Acid to treat or prevent a neurological disorder such as Alzheimer's disease, early onset Alzheimer's disease and schizophrenia. The kit can also further comprise a unit dosage form of another prophylactic or therapeutic agent, for example, a container containing an effective amount of the other prophylactic or therapeutic agent. In one embodiment, the kit comprises a container containing an effective amount of an Crystalline Salt or Free Acid and an effective amount of another prophylactic or therapeutic agent. Examples of other prophylactic or therapeutic agents include, but are not limited to, those listed above.

EXAMPLES

[0118] This invention is further illustrated by the following examples, which should not be construed as limiting. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific substances and procedures described herein. Such equivalents are intended to be encompassed in the scope of the claims that follow the examples below.

X-Ray Powder Diffraction (XRPD Methods

[0119] Some X-Ray Powder Diffraction patterns were collected on a Bruker AXS C2 GADDS diffractometer using Cu Ka radiation (40 kV, 40 rnA), automated XYZ stage, laser video microscope for auto-sample positioning and a HiStar 2-dimensional area detector. X- ray

optics consists of a single Gobel multilayer mirror coupled with a pinhole collimator of 0.3 mm.

[0120] The beam divergence, i.e., the effective size of the X-ray beam on the sample, was approximately 4 mm. A Θ-Θ continuous scan mode was employed with a sample - detector distance of 20 cm which gives an effective 2Θ range of 3.2° - 29.7°. Typically the sample would be exposed to the X-ray beam for 120 seconds. The software used for data collection was GADDS for WNT 4.1.16 and the data were analyzed and presented using Diffrac Plus EVA v 9.0.0.2 or v 13.0.0.2.

[0121] Samples run under ambient conditions were prepared as flat plate specimens using powder as received without grinding. Approximately 1-2 mg of the sample was lightly pressed on a glass slide to obtain a flat surface.

[0122] Some X-Ray Powder Diffraction patterns were collected on a Bruker D8 diffractometer using Cu Ka radiation (40kV, 40rnA), θ -2Θ goniometer, and divergence of V4 and receiving slits, a Ge monochromator and a Lynxeye detector. The software used for data collection was Diffrac Plus XRD Commander v2.5.0 and the data were analyzed and presented using Diffrac Plus EVA v 11.0.0.2 or v 13.0.0.2. Samples were run under ambient conditions as flat plate specimens using powder as received. Approximately 10 mg of the sample was gently packed into a cavity cut into polished, zero background (510) silicon wafer. The sample was rotated in its own plane during analysis. The details of the data collection are: Angular range: 2 to 42° 2Θ; Step size: 0.05° 2Θ; and Collection time: 0.5 s/step.

Differential Scanning Calorimetry (DSC) Methods

[0123] DSC data were collected on a Mettler DSC 823e equipped with a 34 position auto- sampler. The instrument was calibrated for energy and temperature using certified indium. Typically 0.5-3 mg of each sample, in a pin-holed aluminum pan, was heated at 10°C/min from 25°C to 350°C. A nitrogen purge at 50 ml/min was maintained over the sample. The instrument control and data analysis software was STARe v9.20.

Single Crystal X-Ray Diffraction (SCXRD) Methods

[0124] Single Crystal X-Ray Diffraction (SCXRD) data were collected on a Bruker AXS IK SMART CCD diffractometer equipped with an Oxford Cryosystems Cryostream cooling device. Structures were solved using either the SHELXS or SHELXD programs and refined with the SHELXL program as part of the Bruker AXS SHELXTL suite. Unless otherwise stated, hydrogen atoms attached to carbon were placed geometrically and allowed to refine with a riding isotropic displacement parameter. Hydrogen atoms attached to a heteroatom were located in a difference Fourier synthesis and were allowed to refine freely with an isotropic displacement parameter. The structure solution was obtained by direct methods, full-matrix least-squares refinement on F ² with weighting w ^"1 , anisotropic displacement parameters, and no absorption correction.

Chemical Purity Determination by High Performance Liquid Chromatography (HPLC)

[0125] Purity analysis was performed on an Agilent HP 1100 series system equipped with a diode array detector and using ChemStation software vB.02.01-SRI. Purity was determined by area of the peak.

Thermodynamic Aqueous Solubility

[0126] Aqueous solubility was determined by suspending sufficient compound in water to give a maximum final concentration of >10 mg/ml of the parent free-form of the compound. The suspension was equilibrated at 25 °C for 24 hours then the pH was measured. The suspension was then filtered through a glass fiber C filter into a 96 well plate. The filtrate was then diluted by a factor of 101. Quantitation was by HPLC with reference to a standard solution of approximately 0.1 mg/ml in DMSO. Different volumes of the standard, diluted and

undiluted sample solutions were injected. The solubility was calculated using the peak areas determined by integration of the peak found at the same retention time as the principal peak in the standard injection. Analysis was performed on an Agilent HP 1100 series system equipped with a diode array detector and using ChemStation software vB.02.01-SRl.

Chemical Purity Determinations by HPLC

[0127] Purity analysis was performed on an Agilent HP 1100 series system equipped with a diode array detector and using ChemStation software vB.02.01-SRI.

[0128] Exemplary parameters are shown below:

Sample Preparation: 0.5 mg/ml in acetonitriie : water 1 : 1 (unless otherwise stated)

Column: Supeico Ascentis Express CI 8, 100 x 4.6mm, 2.7/!m

Column Temperature (°C): 25

Injection (μΐ): 5 (unless otherwise stated)

Detection Wavelength, Bandwidth (nm): 255.90 itm

Flow Rate (ml/min): 2.0

Phase A: 0,1 % TFA in water

Phase B: 0.085% TFA in acetonitriie

Time (min) % Phase A % Phase B

0 95 5

6 5 95

6.2 95 5

8 95 5

Gravimetric Vapor Sorption (GVS)

[0129] Sorption isotherms were obtained using a Hiden IGASorp moisture sorption analyser,

controlled by CFRSorp software. The sample temperature was maintained at 25°C by a Huber re-circulating water bath. The humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 250 ml/min. The relative humidity was measured by a calibrated Vaisala RH probe (dynamic range of 0-95 % RH), located near the sample. The weight change, (mass relaxation) of the sample as a function of % RH was constantly monitored by the microbalance (accuracy ±0.001 mg).

[0130] Typically, 10-20 mg of sample was placed in a tared mesh stainless steel basket under

ambient conditions. The sample was loaded and unloaded at 40 % RH and 25°C (typical room conditions). The standard isotherm was performed at 25°C at 10% RH intervals over a 0-90 % relative humidity (RH) range.

EXAMPLE 1

Free Acid Solubility Screening and Salt Selection Screening

[0131] A solubility screen of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or tromethamine (R)-2-(5-chloro- 6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl) -3-cyclobutylpropanoate was carried out. Thirteen lots of lOmg of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic were treated with solvents and heated. The solvents and results of the solubility screen are summarized in Table 1.

TABLE 1

[0132] Even upon extended evaporation no crystals were obtained from any of the tested 12 solvents. The experiment did, however, show that there were several solvents which could be used for the salt screen with the basic salt formers. Based on the pKa of (R)-2-(5- chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)bipheny l-3-yl)-3-cyclobutylpropanoic acid, the following salt formers were chosen: KOH, NaOH, L-Arginine, D-Arginine, Ca(OH) ₂ , Choline, L-Lysine monohydrate, D-Lysine monohydrate, N-Methylglucamine, Tromethamine, 4-(2-Hydroxyethyl)-morpholine.

[0133] For the initial salt screen, isopropyl alcohol (IPA) and ethanol were chosen as the solvents since both would be miscible with the aqueous solutions of the basic salt formers listed. Thus lOmg of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethy l)biphenyl- 3-yl)-3-cyclobutylpropanoic acid was dissolved in 100 μΐ of solvent and treated with 1.1 equivalents (22 μΐ) of a 1M base stock solution prepared in water at RT. The experiments were then cooled to 4°C and then finally to -18°C. The results of the initial salt screen are shown in Table 2.

TABLE 2

[0134] None of the salt formations in the initial screen produced a solid, even after addition of 500 μΐ of hexanes to the vessels. All the reactions were cooled to -18°C, which failed to yield any solid material. As such, the vessels were allowed to evaporate to dryness. Any solids produced were analyzed by XRPD. The results from slow evaporations are summarized in Table 3.

TABLE 3

[0135] The potassium and tromethamine salts of (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclob utylpropanoic acid were found to be crystalline.

Potassium Salt

[0136] XRPD diffractograms of potassium (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate (Potassium Salt) crystallized from EtOH and isopropyl alcohol are shown in Fig. 1. The solids isolated from EtOH and isopropyl alcohol both crystallized as the same crystalline polymorph.

[0137] The crystalline Potassium Salt was analyzed by DSC. DSC thermogram of the crystalline Potassium Salt is shown in Fig. 2. The Potassium Salt exhibited a broad endotherm with an onset at 134°C and a sharper second endotherm with an onset 234°C.

[0138] Potassium Salt is soluble in FASSIF, FESSIF and pH 7.4 buffer and is more thermally stable than the Free Acid. The Potassium Salt is hygroscopic above 60% RH and becomes amorphous if kept for 1 week at 40°C and 75% RH.

Tromethamine Salt

[0139] XRPD diffractograms of tromethamine (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)- 4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate (Tromethamine Salt) crystallized from EtOH and isopropyl alcohol are shown in Fig. 3. The solids isolated from EtOH and isopropyl alcohol crystallized as the same crystalline polymorph.

EXAMPLE 2

Scaled-Up Synthesis of Potassium Salt

[0140] 200 mg of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethy l)biphenyl-

3-yl)-3-cyclobutylpropanoic acid as a free acid was dissolved in tBuOH (5ml) at 60°C and treated with 0.95 equivalents of KOH (395 μΐ, 1M in H ₂ 0). After 30 minutes at 60°C the clear solution was dried via lyophilization to yield a white solid. This material was then treated with toluene (4ml, 20 volumes) and brought to reflux and then allowed to cool to room temperature. The solid produced was filtered off and dried under vacuum overnight. The yield was 171mg (79%).

[0141] The resultant material was analyzed by XRPD and DSC. The XRPD

diffractogram is shown in Fig. 4. The product of the scaled-up synthesis had the same crystalline form as the product of the smaller scale synthesis of Example 1 (Fig. 1).

[0142] The DSC thermogram, shown in Fig. 5, showed a sharp endotherm with an onset at 243 °C, which is slightly higher than the product of the smaller scale synthesis of Example, which is believed to be due to a higher chemical purity of the material produced in this Example. [0143] The chemical purity of the resultant Potassium Salt was analyzed by HPLC and was determined to be 98.1% compared to 97.0% for the free acid. The HPLC chromatogram is shown in Fig. 6. The optical purity was assayed and found to be 99.6%> ee.

EXAMPLE 3

Solubility of Potassium Salt

[0144] The solubility of the Potassium Salt was determined in FASSIF, FESSIF and pH 7.4 buffer solutions at room temperature. The results are shown in Table 4.

TABLE 4

EXAMPLE 4

Characterization of a Single Crystal of the Free Acid

[0145] A single crystal of the (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid (Free Acid) was characterized by SCXRD diffraction studies. The structure of the single crystal of the Free Acid was characterized by the parameters provided in Table 5.

TABLE 5

[0146] Experimental and calculated XRPD diffractograms of the Free Acid crystal are shown in Fig. 7.