WO2025235577A1

WO2025235577A1 - Forms and formulations of substituted 3-((3-amino)piperidine-2,6-dione compounds

Info

Publication number: WO2025235577A1
Application number: PCT/US2025/028096
Authority: WO
Inventors: King Yeung HONG; Jian QIAN; Ajay Saxena; Elaine PU; Zongyun HUANG; Darpandeep Aulakh; Sai Jayaraman; Victor W. Rosso; Andrew Michael WERNETH; Daozhong Zou
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 2024-05-09
Filing date: 2025-05-07
Publication date: 2025-11-13
Anticipated expiration: 2026-11-09

Abstract

The present disclosure includes various embodiments directed to forms and formulations including solubilized formulations of 2-((R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2-methylpiperazin-l-yl)-N-(3-((2,6-dioxopiperidin-3-3-yl)amino)phenyl)acetamide and to methods of using the formulations.

Description

FORMS AND FORMULATIONS OF SUBSTITUTED 3-((3-AMINO)PIPERIDINE- 2, 6-DIONE COMPOUNDS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. Provisional Application No. 63/644,719, filed May 09, 2024, and U.S. Provisional Application No. 63/716,437, filed November 05, 2024, which are each incorporated by reference herein in their entireties.

TECHNICAL FIELD

Provided herein are forms and formulations for poorly water soluble pharmaceutical compounds that have shown low oral bioavailability with significant food and/or pH effect. In particular, the disclosure relates to new solubilized formulations of 2-((R)-4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl- 4-oxo-2-thioxoimidazolidin-l-yl)-2-ethylphenoxy)ethyl)-2-methylpiperazin-l-yl)-N- (3-((2,6-dioxopiperidin-3-3-yl)amino)phenyl)acetamide and to methods of using the formulations for the treatment and/or prevention of androgen receptor (AR) mediated diseases.

BACKGROUND

Androgen receptor signaling is known to play a crucial role in the pathogenesis of prostate cancer and is involved in the development of other androgen receptor positive cancers (Chen Y et al., Lancet Oncol, 2009, 10:981-91; Mills I G, Nat Rev Cancer, 2014, 14: 187-98; Taplin M E, Nat Clin Pract Oncol, 2007, 4:236-44; Wirth M P et al., Eur Urol, 2007, 51(2):306-13). The inhibition of androgen receptor signaling with anti-androgens that antagonize the androgen receptor has been used or proposed for the treatment of prostate cancer. Exemplary compounds are disclosed in U.S. Patent No. 11,149,007, issued October 19, 2021.

The compound of formula (I), 2-((R)-4-(2-(4-(3-(4-cyano-3-(trifluorom ethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-ethylphenoxy)ethyl)-2- methylpiperazin-l-yl)-N-(3-((2,6-dioxopiperidin-3-3-yl)amino)phenyl)acetamide, is heterobifunctional androgen receptor degrader and a competitive AR inhibitor. It is useful in the treatment of androgen receptor mediated diseases, e.g., prostate cancer.

The compound of formula (I) is a small molecule having high molecule weight of 818.92 and poor aqueous solubility and permeability.

The present disclosure provides forms and formulations including solubilized formulations of the compound of formula (I).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows plasma concentration-time profiles of 50 mg Formulation Example 1 hard-gelatin capsules (HGC) in dogs.

FIG. 2 shows plasma concentration-time profiles of 50 mg Formulation Example 1 hard-gelatin capsules (HGC) in fasted, low-fat fed and high-fat fed dogs.

FIG. 3 shows plasma concentration-time profiles of 50 mg Formulation Example 1 hard-gelatin capsules (HGC) in famotidine-treated and pentagastrin-treated dogs. FIG. 4 shows plasma concentration-time profiles of 25 mg (Formulation Example

1 A), 50 mg (Formulation Example 1) and 75 mg (Formulation Example IB) doses in hard-gelatin capsules (HGC) in dogs.

FIG. 5 shows plasma concentration-time profiles of 25 mg (Formulation Example

1 A), 50 mg (Formulation Example 1) and 75 mg (Formulation Example IB) doses in hard-gelatin capsules (HGC) in dogs. Dose normalized to 25 mg.

FIG. 6 shows mean plasma concentration of the API by doses in linear scale.

FIG. 7 shows population PK model predicted steady-state exposure distribution of the API across selected capsule doses.

FIG. 8 shows an X-ray powder diffraction (XRPD) pattern of the Amorphous Form.

FIG. 9 shows a modulated differential scanning calorimetry (mDSC) thermogram of the Amorphous Form.

FIG. 10 shows a thermogravimetric analysis (TGA) thermogram of the Amorphous Form.

FIG. 11 shows Moisture sorption isotherms of the Amorphous Form.

FIG. 12 shows an X-ray powder diffraction (XRPD) pattern of Form A.

FIG. 13 shows a differential scanning calorimetry (mDSC) thermogram of Form A.

FIG. 14 shows a thermogravimetric analysis (TGA) thermogram of Form A.

FIG. 15 shows an X-ray powder diffraction (XRPD) pattern of Form B.

FIG. 16 shows an X-ray powder diffraction (XRPD) pattern of Form C.

FIG. 17 shows an X-ray powder diffraction (XRPD) pattern of Form D.

FIG. 18 shows an X-ray powder diffraction (XRPD) pattern of Form E.

FIG. 19 shows an X-ray powder diffraction (XRPD) pattern of Form F.

FIG. 20 shows an X-ray powder diffraction (XRPD) pattern of Form G.

FIG. 21 shows an X-ray powder diffraction (XRPD) pattern of Form H.

FIG. 22 shows an X-ray powder diffraction (XRPD) pattern of Form I.

FIG. 23 shows chemical stability comparison of formulations Example 2A and Example 2B.

FIG. 24 shows the total degradation of formulation Example 2B decreased with the increase of HC1 concentration.

FIG. 25 shows plasma concentration-time profiles of 300 mg Formulation Example 2 Hard-Gelatin Capsules (HGC) administered to participants Under fasting, low-fat diet, and high-fat diet conditions.

FIG. 26 shows plasma concentration-time profiles of 300 mg Formulation Example 2 Hard-Gelatin Capsules (HGC) administered to participants with and without coadministration of proton pump inhibitor (PPI).

SUMMARY

Suitably stable dosage forms of the compound of formula (I) were unexpectedly obtained by solubilizing the drug in a mixture of excipients which include lipid components and filling into capsules. These dosage forms readily provide the drug in an emulsified-state which resist drug precipitation following dilution in aqueous milieu.

In some aspects, the present disclosure provides a composition comprising

(a) at least one active pharmaceutical ingredient having the formula (I): or a pharmaceutically acceptable salt thereof;

(b) at least one solubilizer;

(c) optionally at least one surfactant; and

(d) optionally at least one stabilizer.

In some aspects, The composition comprising

(a) at least one active pharmaceutical ingredient having the formula (I), or a pharmaceutically acceptable salt thereof;

(b) at least one solubilizer, wherein the at least one solubilizer is included in the range from 60 to 98% w/w;

(c) optionally at least one surfactant, wherein the at least one surfactant is included in the range up to 40% w/w; and

(d) optionally at least one stabilizer. In some aspects, the at least one active pharmaceutical ingredient is included in the range of at least 2% w/w. In some aspects, the at least one active pharmaceutical ingredient is included in the range of up to 42% w/w. In some aspects, the at least one active pharmaceutical ingredient is included in the range of 2 to 42% w/w. In some aspects, the at least one active pharmaceutical ingredient is included in the range of 2 to 20% w/w. In some aspects, the at least one active pharmaceutical ingredient is included in the range of 2.5 to 12.5 % w/w.

In some aspects, the at least one stabilizer is included in the range from about 0.01 to about 2% w/w.

In some aspects, the least one solubilizer is selected from propylene glycol esters, medium and long chain triglycerides, medium-chain fatty acid mono- and diglycerides, and a combination thereof.

In some aspects, the at least one active pharmaceutical ingredient is included in the range of at least 2% w/w, the at least one solubilizer is included in the range from about 1 to about 98% w/w, the at least one surfactant is included in the range from about 0 to about 40% w/w; and the at least one stabilizer is included in the range from about 0.01 to about 2% w/w. In some aspects, the at least one active pharmaceutical ingredient is included in the range from about 2.5 to about 12.5% w/w, the at least one solubilizer is included in the range from about 50 to about 80% w/w, the at least one surfactant is included in the range from about 0 to about 40% w/w, and the at least one stabilizer is included in the range from about 0.01 to about 2% w/w.

In some aspects, the propylene glycol ester is propylene glycol monocaprylate, propylene glycol dicaprylate, or a combination thereof.

In some aspects, the at least one surfactant is polyoxyl 40 hydrogenated castor oil or polysorbate 20. In some aspects, the at least one surfactant is polyoxyl 40 hydrogenated castor oil.

In some aspects, the at least one stabilizer is selected from butylated hydroxytoluene, citric acid, malic acid, hydrochloric acid, sodium metabisulfite, and a combination thereof. In some aspects, the at least one stabilizer is selected from butylated hydroxytoluene, citric acid anhydrous, malic acid, hydrochloric acid, and a combination thereof. In some aspects, the at least one stabilizer is selected from butylated hydroxytoluene, citric acid, malic acid, sodium metabisulfite, and a combination thereof. In some aspects, the at least one stabilizer is selected from butylated hydroxytoluene, citric acid anhydrous, and a combination thereof.

In some aspects, the composition comprises

(a) a therapeutically effective amount of at least one active pharmaceutical ingredient having the formula (I): or a pharmaceutically acceptable salt thereof;

(b) at least one solubilizer comprised of propylene glycol esters, caprylocaproyl polyoxyl-8 glycerides, and a combination of medium-chain fatty acid mono- and diglycerides;

(c) at least one surfactant which is polyoxyl 40 hydrogenated castor oil or polysorbate 20; and

(d) at least one stabilizer selected from butylated hydroxytoluene, citric acid, malic acid, hydrochloric acid, sodium metabisulfite, and a combination thereof.

In some aspects, the composition comprises

(d) at least one stabilizer selected from butylated hydroxytoluene, citric acid anhydrous, malic acid, hydrochloric acid, and a combination thereof.

In some aspects, the composition comprises (a) a therapeutically effective amount of at least one active pharmaceutical ingredient having the formula (I): or a pharmaceutically acceptable salt thereof;

(d) at least one stabilizer selected from butylated hydroxytoluene, citric acid anhydrous, and a combination thereof.

In some aspects, the composition comprises

(a) a therapeutically effective amount of at least one active pharmaceutical ingredient having the formula (I) or a pharmaceutically acceptable salt thereof;

(b) at least one solubilizer comprised of propylene glycol esters and a combination of medium-chain fatty acid mono- and diglycerides;

(c) at least one surfactant which is polyoxyl 40 hydrogenated castor oil; and

In some aspects, the composition comprises

(c) at least one surfactant which is polyoxyl 40 hydrogenated castor oil; and

In some aspects, the composition comprises (a) a therapeutically effective amount of at least one active pharmaceutical ingredient having the formula (I) or a pharmaceutically acceptable salt thereof;

(c) at least one surfactant which is polyoxyl 40 hydrogenated castor oil; and

In some aspects, the composition is a self-emulsifying oral formulation.

In some aspects, the present disclosure provides a method of treating prostate cancer comprising the step of administering to a subject in need thereof a composition comprising at least one active pharmaceutical ingredient comprising a solubilized compound having the formula (I): or a pharmaceutically acceptable salt thereof; wherein the total dose of the compound of formula (I) administered to the subject is up to 1200 mg a day.

In some aspects, the compound of formula (I) is administered to the subject up to 900 mg a day. In some aspects, the compound of formula (I) is administered to the subject up to 800 mg a day. In some aspects, the compound of formula (I) is administered to the subject up to 600 mg a day. In some aspects, the compound of formula (I) is administered to the subject up to 400 mg a day. In some aspects, the compound of formula (I) is administered to the subject up to 300 mg a day. In some aspects, the compound of formula (I) is administered to the subject up to 200 mg a day. In some aspects, the compound of formula (I) is administered to the subject from 200 mg to 900 mg a day. In some aspects, the compound of formula (I) is administered to the subject up to 600 mg twice a day. In some aspects, the compound of formula (I) is administered to the subject up to 400 mg twice a day. In some aspects, the compound of formula (I) is administered to the subject up to 300 mg twice a day. In some aspects, the compound of formula (I) is administered to the subject up to 200 mg twice a day. In some aspects, the compound of formula (I) is administered to the subject from 100 mg to 600 mg twice a day. In some aspects, the compound of formula (I) is administered to the subject 100 mg to 400 mg twice a day.

In some aspects, the composition is in a form of a capsule.

In some aspects, the subject experiences minimum food effect and/or pH effect.

In some aspects, the present disclosure provides the composition for use in the treatment of prostate cancer.

In some aspects, the composition comprises

(a) 6.25 to 20 % w/w of at least one active pharmaceutical ingredient having the formula (I): or a pharmaceutically acceptable salt thereof;

(b) up to 60% w/w a solubilizer combination comprising propylene glycol monocaprylate, glyceryl mono and di capryl ocaprate or capryl ocaproyl Polyoxyl-8 glycerides;

(c) up to 40% w/w polyoxyl 40 hydrogenated castor oil or polysorbate 20; and

(d) up to 2% w/w at least one stabilizer selected from butylated hydroxytoluene, citric acid anhydrous, malic acid, hydrochloric acid, sodium metabisulfite and a combination thereof.

In some aspects, the composition comprises

(a) 6.25 to 20 % w/w of at least one active pharmaceutical ingredient having the formula (I) or a pharmaceutically acceptable salt thereof;

(c) up to 40% w/w polyoxyl 40 hydrogenated castor oil or polysorbate 20; and (d) up to 2% w/w at least one stabilizer selected from butylated hydroxytoluene, citric acid anhydrous, malic acid, sodium metabisulfite and a combination thereof.

In some aspects, the composition comprises

(a) 12.5 to 20 % w/w of at least one active pharmaceutical ingredient having the formula (I) or a pharmaceutically acceptable salt thereof;

(b) up to 40% w/w propylene glycol monocaprylate, and up to 20% w/w glyceryl mono and dicaprylocaprate;

(c) up to 40% w/w polyoxyl 40 hydrogenated castor oil; and

In some aspects, the composition comprises

(e) 12.5 to 20 % w/w of at least one active pharmaceutical ingredient having the formula (I) or a pharmaceutically acceptable salt thereof;

(f) up to 40% w/w propylene glycol monocaprylate, and up to 20% w/w glyceryl mono and dicaprylocaprate;

(g) up to 40% w/w polyoxyl 40 hydrogenated castor oil; and

(h) up to 2% w/w at least one stabilizer selected from butylated hydroxytoluene, citric acid anhydrous, malic acid, sodium metabisulfite and a combination thereof.

In some aspects, the composition comprises

(a) 12.5% w/w of at least one active pharmaceutical ingredient having the formula (I) or a pharmaceutically acceptable salt thereof;

(c) up to 40% w/w polyoxyl 40 hydrogenated castor oil; and

(d) up to 2% at least one stabilizer selected from butylated hydroxytoluene, citric acid anhydrous, and a combination thereof.

In some aspects, the composition comprises (a) 6.25 % w/w of at least one active pharmaceutical ingredient having the formula (I) or a pharmaceutically acceptable salt thereof;

(c) up to 40% w/w polyoxyl 40 hydrogenated castor oil or polysorbate 20; and

In some aspects, the composition comprises

(a) 6.25 % w/w of at least one active pharmaceutical ingredient having the formula (I) or a pharmaceutically acceptable salt thereof;

(c) up to 40% w/w polyoxyl 40 hydrogenated castor oil or polysorbate 20; and

(d) up to 2% w/w at least one stabilizer selected from butylated hydroxytoluene, citric acid anhydrous, malic acid, sodium metabisulfite and a combination thereof.

In some aspects, the composition comprises at least one active pharmaceutical ingredient having the formula (I) or a pharmaceutically acceptable salt thereof; propylene glycol monocaprylate, polyoxyl 40 hydrogenated castor oil, glyceryl mono and dicaprylocaprate, butylated hydroxytoluene, malic acid, sodium metabisulfite and water.

In some aspects, the present disclosure provides a composition prepared using an amorphous form of the compound of formula (I): wherein the amorphous form is characterized by at least one of the following: (a) an X-ray powder diffraction pattern having no distinct peaks, which is substantially free of other forms of the compound of formula (I);

(b) an X-ray powder diffraction pattern substantially in accordance with FIG. 8;

(c) a glass transition temperature of 102-112°C, as determined by modulated differential scanning calorimetry;

(d) a modulated differential scanning calorimetry thermogram substantially in accordance with FIG. 9;

(e) weight loss of about 1.5% up heating to around 200°C, as measured by a thermal gravimetric analysis;

(f) a thermal gravimetric analysis thermogram substantially in accordance with FIG. 10; and/or

(g) moisture sorption isotherms substantially in accordance with FIG. 11.

In some aspects, the present disclosure provides a composition prepared using an amorphous form of the compound of formula (I): wherein the amorphous form of the compound of formula (I) is prepared by a spray drying process.

In some aspects, the spray drying process comprises:

1) dissolving the compound of formula (I) in acetone at about 20°C;

2) the fully dissolved solution is passed through a polish filter and then charged into the spray dryer with outlet temperature of about 60-80°C;

3) spray drying is run at pressure of 0.20-0.3MPa; and

4) the product is collected from the cyclone separator.

In some aspects, the present disclosure provides A solid solvate of formula (I): selected from: an n-butyl acetate solvate, an ethyl acetate solvate, an isopropyl acetate solvate, a heptane solvate, a tetrahydrofuran solvate, a dioxane/toluene solvate, a dichloromethane solvate, a cyclohexane solvate, a cyclopentyl methyl ether solvate, and a acetone solvate.

In some aspects, the present disclosure provides a crystalline form of the compound of formula (I), selected an n-butyl acetate solvate, an ethyl acetate solvate, and an isopropyl acetate solvate.

In some aspects, the present disclosure provides a crystalline form of the compound of formula (I), selected from Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H and Form I.

In some aspects, the present disclosure provides a crystalline form of the compound of formula (I), selected from: Forms A, B, C, D and E.

Other aspects of the present disclosure may include suitable combinations of embodiments disclosed herein.

Yet other aspects and embodiments may be found in the description provided herein.

DETAILED DESCRIPTION

Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, pharmacology and pharmaceutical science described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In general, the technical teaching of one embodiment can be combined with that disclosed in other embodiments provided herein.

As used in the present specification, the following terms have the meanings indicated:

As used herein, the terms “comprising” and “including” can be used interchangeably. The terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of’. Consequently, the term “consisting of’ can be used in place of the terms “comprising” and “including” to provide for more specific embodiments of the invention.

The term “consisting of’ means that a subject-matter has at least 90%, 95%, 97%, 98% or 99% of the stated features or components of which it consists. In another embodiment the term "consisting of’ excludes from the scope of any succeeding recitation any other features or components, excepting those that are not essential to the technical effect to be achieved.

As used herein, the term “or” is to be interpreted as an inclusive “or” meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B and C”. An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, and/or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base addition salts of the compound of formula (I) include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N’- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific nontoxic acids include hydrochloric, hydrobromic, maleic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride formic, and mesylate salts. Others are well known in the art, see for example, Remington ’s Pharmaceutical Sciences, 18^th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19^th eds., Mack Publishing, Easton PA (1995).

The term “subject” or “patient” refers to an animal, including, but not limited to, a mammal, including a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.

The term "androgen receptor" or "AR" or "NR3C4" as used herein refers to a nuclear hormone receptor activated by binding of the androgenic hormones, including testosterone or dihydrotestosterone. The term "androgen receptor" may refer to the nucleotide sequence or protein sequence of human androgen receptor (e.g., Entrez 367, Uniprot P10275, RefSeq NM_000044, or RefSeq NP_000035).

The term “AR-full length” (AR-FL) as used herein refers to AR protein that contains all four functional domains, including the N-terminal transactivation domain (NTD, exon 1), the DNA-binding domain (DBD, exons 2-3), the hinge domain (exon 4), and the C-terminal ligand binding domain (LBD, exons 4-8).

The term "castration resistant prostate cancer" (CRPC) refers to advanced prostate cancer that is worsening or progressing while the patient remains on androgen deprivation therapy or other therapies to reduce testosterone, or prostate cancer which is considered hormone refractory, hormone naive, androgen independent or chemical or surgical castration resistant. Castration resistant prostate cancer (CRPC) is an advanced prostate cancer that developed despite ongoing ADT and/or surgical castration. Castration resistant prostate cancer is defined as prostate cancer that continues to progress or worsen or adversely affect the health of the patient despite prior surgical castration, continued treatment with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (e.g., degarelix or abarelix), antiandrogens (e.g., bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec®) or gefitinib (Iressa®), cabozantinib (Cometriq®, also known as XL184)) or other prostate cancer therapies (e.g., vaccines (sipuleucel-T (Provenge®), GV AX, etc.), herbal (PC-SPES) and lyase inhibitor (abiraterone)) as evidenced by increasing or higher serum levels of prostate specific antigen (PSA), metastasis, bone metastasis, pain, lymph node involvement, increasing size or serum markers for tumor growth, worsening diagnostic markers of prognosis, or patient condition.

As used herein, and unless otherwise specified, the expression “unit dose” refers to a physically discrete unit of a formulation appropriate for a subject to be treated (e.g., for a single dose); each unit containing a predetermined quantity of an active agent selected to produce a desired therapeutic effect (it being understood that multiple doses may be required to achieve a desired or optimum effect), optionally together with a pharmaceutically acceptable carrier, which may be provided in a predetermined amount. The unit dose may be, for example, a volume of liquid (e.g. an acceptable carrier) containing a predetermined quantity of one or more therapeutic agents, a predetermined amount of one or more therapeutic agents in solid form, a sustained release formulation or drug delivery device containing a predetermined amount of one or more therapeutic agents, etc. It will be appreciated that a unit dose may contain a variety of components in addition to the therapeutic agent(s). For example, acceptable carriers (e.g., pharmaceutically acceptable carriers), diluents, stabilizers, buffers, preservatives, etc., may be included as described infra. It will be understood, however, that the total daily usage of a formulation of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism may depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active compound employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active compound employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.

A “pharmaceutically acceptable excipient,” refers to a substance that aids the administration of an active agent to a subject by for example modifying the stability of an active agent or modifying the absorption by a subject upon administration. A pharmaceutically acceptable excipient typically has no significant adverse toxicological effect on the patient. Examples of pharmaceutically acceptable excipients include, for example, water, NaCl (including salt solutions), normal saline solutions, /i normal saline, sucrose, glucose, bulking agents, buffers, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, alcohols, oils, gelatins, carbohydrates such as amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. One of skill in the art will recognize that other pharmaceutical excipients known in the art are useful in the present invention and include those listed in for example the Handbook of Pharmaceutical Excipients, Rowe R.C., Shesky P.J., and Quinn M.E., 6^th Ed., The Pharmaceutical Press, RPS Publishing (2009). The terms “bulking agent”, and “buffer” are used in accordance with the plain and ordinary meaning within the art.

As used herein, and unless otherwise specified, the term “about,” when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, means dose, amount, or weight percent that is recognized by those of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent is encompassed. Specifically, the term “about” contemplates a dose, amount, or weight percent within 30 %, 25%, 20%, 15%, 10%, or 5% of the specified dose, amount, or weight percent is encompassed.

The term "about" as used in connection with a numerical value throughout the specification and the claims denotes an interval of accuracy, familiar and acceptable to a person skilled in the art. Such interval of accuracy is ± 10 %.

As used herein, “administer” or “administration” refers to the act of physically delivering a substance as it exists outside the body into a subject. Administration includes all forms known in the art for delivering therapeutic agents, including but not limited to topical, mucosal, injections, intradermal, intravenous, intramuscular delivery or other method of physical delivery described herein or known in the art (e.g., implantation of a slow-release device, such as a mini-osmotic pump to a subject; liposomal formulations; buccal; sublingual; palatal; gingival; nasal; vaginal; rectal; intra-arteriole; intraperitoneal; intraventricular; intracranial; or transdermal).

By “co-administer” it is meant that compounds, compositions or agents described herein are administered at the same time, just prior to, or just after the administration of one or more additional compounds, compositions or agents, including for example an anti-cancer agent. Co-administration is meant to include simultaneous or sequential administration of compounds, compositions or agents individually or in combination (more than one compound or agent). Co-administration includes administering two compounds, compositions or agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Thus, co-administration can include administering one active agent (e.g. a compound described herein) within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration can also be accomplished by co-formulation, e.g., preparing a single dosage form including both active agents. The active agents can be formulated separately. In such instances, the active agents are admixed and included together in the final form of the dosage unit. Alternatively, co-administration as described herein can include administering two separate unit dosage forms of at least two separate active agents (e.g., the compound of formula (I) and a second active agent described herein).

As used herein, the term “daily” is intended to mean that a therapeutic compound, such as the compound of formula (I), is administered once or more than once each day for a period of time. The term “continuous” is intended to mean that a therapeutic compound, such as the compound of formula (I), is administered daily for an uninterrupted period of at least 10 days to 52 weeks. The term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of the compound of formula (I) is administration for one to six days per week, administration in cycles (e.g., daily administration for one to ten consecutive days of a 28 day cycle, then a rest period with no administration for rest of the 28 day cycle or daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days. The term “cycling” as used herein is intended to mean that a therapeutic compound, such as the compound of formula (I), is administered daily or continuously but with a rest period. The term “administration period” as used herein refers to a period of time a subject is continuously or actively administered a compound or composition described herein. The term “rest period” as used herein refers to a period of time, often following an administration period, where a subject is not administered a compound or composition described herein (e.g. discontinuation of treatment). In certain embodiments, a “rest period” refers to a period of time where a single agent is not administered to a subject or treatment using a particular compound is discontinued. In such embodiments, a second therapeutic agent (e.g., a different agent than the compound or composition administered in the previous administration period) can be administered to the subject.

An “effective amount” is an amount sufficient to achieve the effect for which it is administered e.g., treat a disease or reduce one or more symptoms of a disease or condition). Thus, administration of an “amount” of a compound described herein to a subject refers to administration of “an amount effective,” to achieve the desired therapeutic result. A “therapeutically effective amount” of a compound described herein for purposes herein is thus determined by such considerations as are known in the art. The term “therapeutically effective amount” of a composition described herein refers to the amount of the composition that, when administered, is sufficient to treat one or more of the symptoms of a disease described herein. Administration of a compound described herein can be determined according to factors such as, for example, the disease state, age, sex, and weight of the individual. A therapeutically effective amount also refers to any toxic or detrimental effects of the compound of formula (I) are outweighed by the therapeutically beneficial effects. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously.

The formulations are prepared so as to contain a sufficient amount, i.e., dose of the compound of formula (I) within a dosage unit, e.g., a capsule. It is preferred that the amount of the compound of the formula (I) presents in the formulation so as to provide each dosage form with a unit dosage of from about 25 to about 200 mg, and preferably about 25 to about 100 mg of the compound of the formula (I) for oral administration. Typically the compound of the formula (I) is from about 2% to about 50% of the formulation by weight. Preferably, the compound of the formula (I) is from about 2 % to about 40%, about 2 % to about 30%, about 2% to about 20% of the formulation by weight. More preferably, the compound of the formula (I) is from about 2.5 % to about 12.5%, about 2.5 % to about 20%, about 12.5 % to about 20% of the formulation by weight.

In one embodiment, it is particularly preferred that the entire amount of the compound of the formula (I) is solubilized in the composition. Also the compound of the formula (I) present in the composition is significantly solubilized. Typically, about 100% of the compound of the formula (I) is solubilized in the composition and preferably about 100% of the compound of the formula (I) is solubilized in the composition of the dosage form.

The term "treating" refers to: (i) preventing a disease, disorder or condition from occurring in a patient that may be predisposed to the disease, disorder, and/or condition but has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder, or condition, i.e., arresting its development; and (iii) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and/or condition.

The terms “active pharmaceutical ingredient” and “API,” as used herein, refer to the compound of formula (I):

It is a mixture of the RR and RS diastereomers expressed by formula (la):

Preferably, it is a 1 : 1 mixture of the RR diastereomer and the RS diastereomer.

The present invention may also include a mixture of various ratios of the RR diastereomer and the RS diastereomer, e.g., the ratio of RR diastereomer to the RS diastereomer is from about 50:50 % to 100:0 %; preferably from about 60:40 % to 100:0 %; from about 70:30 % to 100:0 %; from about 80:20 % to 100:0 %; from about 90: 10 % to 100:0 %.

Also described herein are metabolites of the compound of formula (I) (API), e.g.,

Also described herein is the “amorphous” solid form of the compound of formula (I) (API). An amorphous solid is generally defined as a non-crystalline solid in which molecules are not organized in a definite lattice. The amorphous form of the API may be prepared by any known means, including spray-drying and precipitation from an aqueous or organic solution on addition of a non-solvent.

Solvents suitable for spray-drying can be any organic compound in which the API is soluble. In some embodiments, solvents for spray drying are acetone, ethanol, methanol, DCM, mixtures thereof, and mixture with water preferably acetone.

In some embodiments, the API is in a form which contains at least 80 wt. % of the amorphous forms of the API. In some embodiments, the API is in a form which contains at least 90 wt. % of the amorphous form of the API. In some embodiments, the API is in a form which contains at least 95 wt. % of the amorphous form of the API. In some embodiments, the API is in a form which contains at least 98 wt. % of the amorphous form of the API. In some embodiments, the API is in a form which contains at least 99 wt. % of the amorphous form of the API. In some embodiments, the amorphous form of the API has a particle size distribution of D50, less than 70 pm, preferably less than 40 pm, more preferably less than 25 pm. In some embodiments, the amorphous form of the API has a particle size distribution of D90, less than 250 pm, preferably less than 100 pm, more preferably less than 50 pm.

As used herein, the notation Dx means that X% of the volume of particles have a diameter less than a specified diameter D. The particle size may be measured using, standard laser diffraction particle sizing techniques known in the art. One example of an instrument to measure the particle size of the dry powders is the Mastersizer 3000, manufactured by Malvern Instruments Ltd.

The name used herein to characterize a specific form, e.g. “Form A”, “Form B”, etc., should not be considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that the designation is a mere identifier that should be interpreted according to the characterization information also presented herein. As used herein, “polymorphs” refer to crystalline forms having the same chemical structure but different spatial arrangements of the molecules and/or ions forming the crystals.

A crystalline form may be a single-component crystalline form or a multicomponent crystalline form. Multi-component crystalline forms comprise more than one type of molecule and include salts, solvates (such as hydrates), and cocrystals. Multi-component crystalline forms may have some variability in the exact molar ratio of their components depending on a variety of conditions. For example, a molar ratio of components within a solvate or cocrystal provides information as to the general relative quantities of each component of the solvate or cocrystal. In some cases, the molar ratio may vary by ± 0.2 from a stated value or a stated range. For example, a molar ratio of 1 :0.5 should be understood to include the ratios 1 :0.4 and 1 :0.6, as well as all of the individual ratios in between; similarly, a molar ratio of 1 : 1 should be understood to include the ratios 1 :0.8 and 1 : 1.2, as well as all of the individual ratios in between.

When dissolved, a crystalline form of the API loses its crystalline structure, and is therefore referred to as a solution of the API. The crystalline Form A is a n-butyl acetate solvate of the API. The crystalline Form B and Form C are ethyl acetate solvate of the API. Form D and Form E are isopropyl acetate solvate of the API. The crystalline Form F is a mixed dioxanetoluene solvate of the API. The crystalline Form G is a cyclohexane solvate of the API. The crystalline Form H is a cyclopentyl methyl ether solvate of the API. The crystalline Form I is an acetone solvate of the API.

Form A is characterized by at least one of the following: a) single crystal structure having unit cell parameters substantially equal to Crystal system, space group Triclinic, Pl

Unit cell dimensions a = 12.87 ± 0.10 A alpha = 105.8 ± 1.0° b = 13.20 ± 0.10 A beta = 96.8 ± 1.0° c = 16.50 ± 0.10 A gamma = 112.60 ±1.0°

Volume 2409(20) A³

Density (calculated) 1.289 g/cm³ Temperature 100 °K b) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.7 ± 0.2, 8.2 ± 0.2, 9.4 ± 0.2, 10.4 ± 0.2 and 15.6 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); c) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.7 ± 0.2, 8.2 ± 0.2, 9.4 ± 0.2, 10.4 ± 0.2, 12.1 ± 0.2, 12.7 ± 0.2, 13.5 ± 0.2, 15.6 ± 0.2, 16.7 ± 0.2, 22.2 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); d) a powder X-ray diffraction pattern substantially in accordance with FIG. 12; e) a differential scanning calorimetry thermogram substantially in accordance with FIG. 13; and/or f) a thermal gravimetric analysis thermogram substantially in accordance with

FIG. 14.

Form B is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.3 ± 0.2, 6.6 ± 0.2, 10.9 ± 0.2, 11.6 ± 0.2 and 16.6 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.3 ± 0.2, 6.6 ± 0.2, 6.9 ± 0.2, 10.9 ± 0.2, 11.6 ± 0.2, 13.2 ± 0.2, 13.7 ± 0.2, 16.6 ± 0.2, 20.0 ± 0.2 and 22.5 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 15.

Form C is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.4 ± 0.2, 5.7 ± 0.2, 9.4 ± 0.2, 10.4 ± 0.2 and 15.6 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.4 ± 0.2, 5.7 ± 0.2, 7.7 ± 0.2, 8.1 ± 0.2, 9.4 ± 0.2, 10.4 ± 0.2, 15.0 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2 and 21.4 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 16.

Form D is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.3 ± 0.2, 6.7 ± 0.2, 11.0 ± 0.2, 11.5 ± 0.2 and 16.5 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.3 ± 0.2, 6.7 ± 0.2, 11.0 ± 0.2, 11.5 ± 0.2, 16.5 ± 0.2, 18.0 ± 0.2, 20.3 ± 0.2, 21.8 ± 0.2, 22.5 ± 0.2 and 25.0 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 17.

Form E is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.4 ± 0.2, 5.8 ± 0.2, 8.1 ± 0.2, 9.5 ± 0.2 and 10.6 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.4 ± 0.2, 5.8 ± 0.2, 8.1 ± 0.2, 9.5 ± 0.2 and 10.6 ± 0.2, 15.9 ± 0.2, 16.8 ± 0.2, 17.3 ± 0.2, 18.7 ± 0.2 and 20.7 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 18. Form F is characterized by at least one of the following: a) single crystal structure having unit cell parameters substantially equal Crystal system, space group Triclinic, Pl Unit cell dimensions a = 12.58 ± 0.10 A alpha = 84.8 ± 1.0' b = 12.91 ± 0.10 A beta = 81.7 ± 1.0° c = 16.98 ± 0.10 A gamma = 86.6 ±1.0'

Volume 2780(20) A³

Density (calculated) 1.299 g/cm³

Temperature 100 °K b) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.1 ± 0.2, 6.6 ± 0.2, 10.6 ± 0.2, 11.4 ± 0.2 and 16.5 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); c) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.1 ± 0.2, 6.6 ± 0.2, 10.6 ± 0.2, 11.4 ± 0.2 and 16.5 ± 0.2, 17.8 ± 0.2, 19.8 ± 0.2, 22.5 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or d) a powder X-ray diffraction pattern substantially in accordance with FIG. 19.

Form G is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.5 ± 0.2, 7.3 ± 0.2, 11.7 ± 0.2, 13.0 ± 0.2 and 21.0 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.5 ± 0.2, 7.3 ± 0.2, 11.7 ± 0.2, 13.0 ± 0.2, 14.6 ± 0.2, 18.0 ± 0.2, 21.0 ±

0.2, 23.7 ± 0.2, 24.5 ± 0.2 and 25.5 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 20.

Form H is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.1 ± 0.2, 6.6 ± 0.2, 10.9 ± 0.2, 11.4 ± 0.2 and 16.5 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.1 ± 0.2, 6.6 ± 0.2, 10.9 ± 0.2, 11.4 ± 0.2, 12.0 ± 0.2, 16.5 ± 0.2, 18.0 ± 0.2, 20.4 ± 0.2, 22.6 ± 0.2 and 25.0 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 21.

Form I is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.2 ± 0.2, 11.0 ± 0.2, 11.8 ± 0.2, 16.5 ± 0.2 and 18.0 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.2 ± 0.2, 6.7 ± 0.2, 7.1 ± 0.2, 11.0 ± 0.2, 11.8 ± 0.2, 16.5 ± 0.2, 18.0 ± 0.2, 20.7 ± 0.2, 23.1 ± 0.2 and 23.5 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 22.

The term “room temperature” generally means approximately 22°C, but can vary up or down by up to 7°C.

As used herein, “substantially pure,” when used in reference to a crystal form, means a compound having a purity greater than 90 weight %, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99 weight %, and also including equal to about 100 weight % of the crystal form of the API, based on the weight of the compound. The remaining material comprises other form(s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation. For example, a crystal form of the API can be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight % of material comprises other form(s) of the API and/or reaction impurities and/or processing impurities.

When the term “substantially in accordance” is used in relation to XRPD or PXRD patterns, it is to be understood that measurement of the peak locations for a given crystalline form of the same compound will vary within a margin of error. It is also to be understood that the intensities of the peaks can vary between different XRPD scans of the same crystalline form of the same compound. The relative intensities of the different peaks are not meant to be limiting to a comparison of different XRPD scans.

As used herein, a XRPD (x-ray powder diffraction) or XRD (powder x-ray diffraction) pattern “comprising” or having a number of peaks selected from a specified group of peaks, is intended to include PXRD patterns having additional peaks that are not included in the specified group of peaks. For example, a PXRD pattern comprising four or more peaks, preferably five or more, at degree 29 values selected from: A, B, C, D, E, F, G, H, and I, is intended to include a PXRD pattern having: (a) four or more peaks, preferably five or more, at degree 29 values selected from: A, B, C, D, E, F, G, H, and I; and (b) zero or more peaks that are not one of peaks A, B, C, D, E, F, G, H, and I.

In preparing a pharmaceutical composition, a form of the active ingredient, including an amorphous form, is sought that has a balance of desired properties, such as, for example, dissolution rate, solubility, bioavailability, and/or storage stability. For example, a form of the active ingredient is sought having sufficient solubility, bioavailability, and storage stability to prevent the sufficiently soluble and bioavailable form from converting, during the manufacture, preparation, and/or storage of the pharmaceutical composition, to another form having an undesirable solubility and/or bioavailability profile. In addition, a form of the active ingredient may also be sought that permits the active ingredient to be isolated and/or purified during, for example, a preparative process.

It is also desirable to provide a compound in a solid form that is amenable to additional processing, for example a crystalline form that can be converted to other solid forms, such as an amorphous form or other crystalline forms.

In addition, different crystalline forms can be used to modify the physiochemical properties of a compound. In some instances, the physiochemical properties of a compound can be modified through the formation of cocrystals. Cocrystallization also can be used to isolate or purify a compound during manufacturing. As described herein, crystalline forms of the API are surprisingly amenable to additional processing and can be converted to other solid forms.

As used herein, “self-emulsifying drug delivery system” (SEDDS) refers to a solid or liquid drug-loaded formulation in lipid vehicles containing surfactants to effect spontaneous emulsification upon contact with an aqueous medium, such as gastrointestinal fluids. If micro- or nano-emulsions are formed, these are referred to as “self-microemulsifying drug delivery systems” (SMEDDS) and “self- nanoemulsifying drug delivery systems” (SNEDDS). Unless specified otherwise, the term “self-emulsifying drug delivery system”, “SEDDS”, or “self-emulsifying formulation” includes “SMEDDS” and “SNEDDS”.

As used herein, the term “solubilizer” refers to any pharmaceutically acceptable agent that can dissolve API. In the present disclosure the solubilizer dissolves the API and forms the internal phase of an oil-in-water emulsion in which the API is incorporated in the oil droplet following aqueous dilution. Examples of solubilizers include polyoxylglycerides, medium-chain monoglycerides, mediumchain diglycerides, combinations of monoglycerides and diglycerides; glycerol monocaprylocaprate, glycerol monocaprylate, glycerol mono/dicaprate, and the propylene glycol mono- and di-esters of medium-chain fatty acids such as propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol dilaurate, and combinations thereof. Preferably, examples of solubilizers include polyoxylglycerides (caprylocaproyl polyoxyl-8 glycerides, e.g., Labrasol ALF), medium-chain monoglycerides, medium-chain diglycerides, combinations of monoglycerides and diglycerides (glycerol monocaprylocaprate, glycerol monocaprylate, glycerol mono/dicaprate, e.g., LAB RAF AC MC60 and Capmul MCM) and the propylene glycol mono- and di-esters of medium-chain fatty acids (propylene glycol monocaprylate, e.g., CAPRYOL™ 90) and combinations thereof.

The amount of solubilizer that can be included in a formulation of the present invention is not particularly limited. When the formulation is administered to a subject, however, the amount of any given solubilizer is limited to a bioacceptable amount. Bio-acceptable amounts of solubilizers and other components are readily determined by one of skill in the art by using routine experimentation or searching the literature. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bio-acceptable amounts, for example, to maximize the concentration of the compound of formula (I), with excess solubilizer removed prior to providing the composition to a patient. Excess solubilizer may be removed using conventional techniques such as distillation, spray drying, lyophilization or evaporation. Generally, the total amount of solubilizer(s) in the composition will be from about 50% to about 98%, preferably between about 60% to about 98% by weight.

As used herein, the term “surfactant” refers to any pharmaceutically acceptable agent that provides a finer emulsion droplet size following aqueous dilution. Examples of surfactants include polyoxyl 40 hydrogenated castor oil (e.g., Cremophor® RH40), polyoxyl 35 castor oil (e.g., Cremophor® EL), polyoxylglycerides (caprylocaproyl polyoxyl-8 glycerides, e.g., Labrasol ALF), and Polysorbate 20 (e.g., Tween 20) and combinations thereof. Preferably, examples of surfactants include polyoxyl 40 hydrogenated castor oil (e.g., Cremophor® RH40), polyoxylglycerides (caprylocaproyl polyoxyl-8 glycerides, e.g., Labrasol ALF), and Polysorbate 20 (e.g., Tween 20) and combinations thereof.

For a surfactant, the amount of a surfactant may be determined by adding gradual amounts of the surfactant until the desired wetting effect or dispersibility of the composition is achieved. The amount of surfactant, when present, in the composition will generally be about 0 wt. % to about 40 wt. %, preferably between about 20 wt. % to about 40 wt. %, more preferably about 30 wt.% to about 40 wt. %.

As used herein, the term “stabilizer” refers to any pharmaceutically acceptable agent which minimizes degradation of API. Examples of stabilizers include free radical scavengers such as butylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA), peroxide inhibitors such as sodium metabisulfite and thiol group containing compounds that release sulfite ions, chelators such as ethylenediaminetetraacetic acid, acidic compounds such as citric acid, malic acid, hydrochloric acid, and lactic acid, or a combination thereof (alternatively, acidic compounds such as citric acid, malic acid and lactic acid, or a combination thereof). Preferably, examples of stabilizers include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), citric acid, malic acid, hydrochloric acid, sodium metabisulfite, or a combination thereof; or examples of stabilizers include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), citric acid, malic acid, sodium metabisulfite, or a combination thereof. Additional stabilizers may include ascorbic acid, lactic acid, butylated hydroxyanisole, propyl gallate, ascorbyl palmitate, and alpha-tocopherol.

The amount of additional components in a formulation of the invention can be determined by one of ordinary skill in the art, according to the desired property or properties to be imparted to the composition. For example, the amount of a suspending agent may be determined by adding gradual amounts of the agent until the desired homogeneity of undissolved drug particles in the composition is achieved. For a colorant, the amount of the colorant may be determined by adding small amounts of the colorant until the desired color of the composition is achieved.

The formulation solutions described herein may contain one or more of various flavoring agents (e.g., cherry, berry, mint, vanilla, and the like) and/or sweetening agents (e.g., sucrose, sorbitol, mannitol, fructose, dextrose, saccharin, aspartame, acesulfame potassium, and the like) to enhance palatability of the dosage form.

The formulation of the invention is provided as an oral pharmaceutical composition. As such, the formulation is provided in a dosage form, for administration to a subject in need of such formulation. Administration of a formulation of the invention may be as a single composition, or as multiple compositions. The formulations and compositions thereof maybe administered at the same time or may be administered at different times. Administration may be performed by any method which results in the desired serum concentration of therapeutic agent.

In a preferred embodiment, the pharmaceutical composition is present in a single dosage form. The dosage form(s) are not limited with respect to size, shape or general configuration, and may comprise, for example, a capsule, a tablet or a caplet, or a plurality of granules, beads, powders or pellets that may or may not be encapsulated. The capsule may be in a form of a hard or soft gel capsule.

The formulation solutions described herein may be encapsulated as a solution in soft or hard capsules manufactured from various materials including gelatin, hydroxypropyl methylcellulose (HPMC), cellulose, methylcellulose, starch, and other materials. The two-piece capsules may be banded, e.g., with a gelatin-based solution for hard gelatin capsules, or an HPMC -based solution for HPMC capsules. Soft gelatin capsule shells may contain one or more appropriate plasticizers such as glycerin, sorbitol, sorbitan, propylene glycol or others to impart suitable encapsulation, elasticity, mechanical strength, stability and dissolution properties. In addition, the hard or soft gelatin capsule shell may contain and/or be imprinted with various colorants and/or opacifiers.

In one embodiment, provided herein are methods of treating, preventing, managing, and/or ameliorating an androgen receptor mediated disease, or one or more symptoms or causes thereof, by administering a composition comprising at least the compound of the formula (I) or a pharmaceutically acceptable salt thereof, or in combination with one or more second agents selected from a PI3K inhibitor, an AKT inhibitor, a BET inhibitor, JAK inhibitor, and an EZH2 inhibitor to a patient having an androgen receptor mediated disease, or one or more symptoms or causes thereof. Examples of a second agent are selected from capivasertib, ipatasertib, AZD8186, 6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepine-6-acetic acid, tazemetostat, ruxolitinib and sorafenib to a patient having an androgen receptor mediated disease, or one or more symptoms or causes thereof.

In certain embodiments, the methods and/or combinations provided herein synergistically inhibit proliferation of prostate cancer cells.

In one aspect, provided herein are methods of treating patients who have been previously treated for an androgen receptor mediated disease but are non-responsive to therapy, as well as those who have not previously been treated. Also encompassed are methods of treating patients regardless of patient’s age, although some diseases or disorders are more common in certain age groups. Further encompassed are methods of treating patients who have undergone surgery in an attempt to treat the disease or condition at issue, as well as those who have not. Because patients with an androgen receptor mediated disease have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a patient may vary, depending on the patient’s prognosis. The skilled clinician will be able to readily determine without undue experimentation specific secondary agents, types of surgery, and types of nondrug based standard therapy that can be effectively used to treat an individual patient with an androgen receptor mediated disease.

In some embodiments, the AR mediated disease is an AR wild-type mediated disease. In other embodiments, the AR mediated disease is the result of AR amplification.

In certain embodiments, the AR mediated disease is prostate cancer. In some such embodiments, the prostate cancer is castration resistant prostate cancer (CRPC). In some such embodiments, the prostate cancer is metastatic castration resistant prostate cancer (mCRPC). In still another embodiment, the prostate cancer is non- metastatic CRPC (nmCRPC). In some embodiments, the prostate cancer is hormone refractory. In some embodiments, the prostate cancer is resistant to treatment with an AR antagonist. For example, the prostate cancer is resistant to treatment with one or more of enzalutamide, bicalutamide, abiraterone, ARN-509, ODM-201, EPI-001, EPI-506, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, or spironolactone.

Provided herein are methods of reducing AR levels relative to a baseline level, the method comprising administering to a subject administering a composition comprising at least the compound of the formula (I) or a pharmaceutically acceptable salt thereof, or in combination with one or more second agents selected from a PI3K inhibitor, an AKT inhibitor, a BET inhibitor, JAK inhibitor, and an EZH2 inhibitor. In one embodiment, provided herein are methods of reducing levels of wild-type AR within a tumor, the method comprising administering a composition comprising at least the compound of the formula (I) or a pharmaceutically acceptable salt thereof, or in combination with one or more second agents selected from a PI3K inhibitor, an AKT inhibitor, a BET inhibitor, JAK inhibitor, and an EZH2 inhibitor, to reduce the level of wild-type AR within the tumor. In one embodiment, provided herein are methods of reducing levels of AR-full length (AR-FL) within a tumor, the method comprising administering a composition comprising at least the compound of the formula (I) or a pharmaceutically acceptable salt thereof, or combination with one or more second agents selected from a PI3K inhibitor, an AKT inhibitor, a BET inhibitor, JAK inhibitor, and an EZH2 inhibitor, to reduce the level of AR-full length (AR-FL) within the tumor. In some embodiments, the AR levels are reduced compared to the AR levels prior to the administration of the composition. In some embodiments, the AR levels are reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to the AR levels prior to administration of the composition, or in combination with one or more second agents selected from a PI3K inhibitor, an AKT inhibitor, a BET inhibitor, JAK inhibitor, and an EZH2 inhibitor.

As used herein, the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). However, the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a patient with a disease or disorder. E.g., “in combination” may include administration as a mixture, simultaneous administration using separate formulations, and consecutive administration in any order. “Consecutive” means that a specific time has passed between the administration of the active agents. For example, “consecutive” may be that more than 10 minutes have passed between the administration of the separate active agents. The time period can then be more than 10 min, more than 30 minutes, more than 1 hour, more than 3 hours, more than 6 hours or more than 12 hours. E.g., a first therapy (e.g., a prophylactic or therapeutic agent such as a formulation of Compound 1 provided herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein.

In one embodiment, administration of a composition comprising at least the compound of the formula (I) or a pharmaceutically acceptable salt thereof, or in combination with one or more second active agents to a patient can occur simultaneously or sequentially by the same or different routes of administration. In one embodiment, administration of a composition comprising at least the compound of the formula (I) or a pharmaceutically acceptable salt thereof, or in combination with one or more second active agents to a patient can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the androgen receptor (AR) mediated disease being treated.

In some embodiments of the methods described herein, the methods additionally comprise administering one or more additional agents selected from an AR antagonist (such as cyproterone acetate, spironolactone, bicalutamide, and enzalutamide), a 5a-reductase inhibitor (such as finasteride and dutasteride), a CYP17A1 inhibitor (such as abiraterone acetate), a gonadotropin-releasing hormone (GnRH) analog (such as leuprorelin and cetrorelix), and an anti-gonadotropin (such as megestrol acetate and medroxyprogesterone acetate).

EXAMPLES

The present disclosure will now be described in connection with certain embodiments which are not intended to limit its scope. On the contrary, the present disclosure covers all alternatives, modifications, and equivalents as can be included within the scope of the claims. Thus, the following examples, which include specific embodiments, will illustrate one practice of the present disclosure, it being understood that the examples are for the purposes of illustration of certain embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.

The compound of formula (I) can be prepared following the procedure described in U.S. Patent No. 11,149,007, which is incorporated herein in its entirety.

The inactive ingredients of the formulations include propylene glycol monocaprylate (e.g., CAPROYL®), glyceryl mono and dicaprylocaprate (e.g., CAPMUL® MCM and Labrafac™ MC60), polyoxyl 40 hydrogenated castor oil (e.g., Cremophor RH40), butylated hydroxytoluene, citric acid anhydrous, DL malic acid, and water.

The following procedure is a typical procedure for manufacturing various aspects and embodiments of the present disclosure.

1. Mix propylene glycol monocaprylate (e.g., CAPROYL®), glyceryl mono and dicaprylocaprate (e.g., CAPMUL® MCM), polyoxyl 40 hydrogenated Castor Oil (e.g., Cremophor RH40), and butylated hydroxytoluene in a mixing vessel.

2. Add citric acid stock solution to the solution in Step 1.

3. Mix the batch from Step 2 to give a homogeneous solution.

4. Add API to the solution in Step 3 and mix to dissolve.

5. Encapsulate the solution from Step 4 into a soft or hard gelatin capsules.

6. Dry the gelatin capsules to appropriate hardness or optionally apply a band to the hard gelatin capsules. This formulation was made in various strengths, e.g., 25, 50, 75, 100 and 160 mg (as dose proportional formulations) and were also intended as immediate-release capsules. Each unit dose was filled in hard gelatin capsule shell, size 00, or softgel capsule in the following Examples 1, 1 A, IB, 2, 2A, 2B, 3, 3A, 4, and 5.

Example 1

Example 1A

Example IB Example 2

Example 2 A Example 2B Example 3

Example 4 and Example 5 were prepared in a similar procedure using the ingredients listed below.

Example 4 Example 5

Example 6 Free API Recovery Measurement

Samples were spiked into FaSSIF (pH 6.5) biorelevant media in a 1 : 100 ratio. The solutions were incubated at 37 °C for an hour. They were then centrifuged at 14,000 rpm for 10 min to separate any precipitates. Supernatants were then analyzed by liquid chromatography to assess the free API recovery.

Table 1. Measurement of free API recovery in Fasted State Simulated Intestinal Fluid (FaSSIF, pH 6.5, 37 °C)

The capsules are recommended to be supplied in tightly closed high-density polyethylene bottles with oxygen scavenger and child resistant closures; and stored between 2°C and 8°C (36°F to 46°F) in the original package.

Example 7

In Vivo studies of SEDDS capsules in dog model In Vivo studies of Formulation Example 1 in capsules were conducted in dogs to evaluate the PK performance and food/pH effects. The results are shown in FIGs 1-3 and Tables 2-4.

Table 2. Summary of the pharmacokinetic parameters of dosing Formulation Example 1 hard-gelatin capsules to dogs (n = 7)

Table 3. Summary of the pharmacokinetic parameters of dosing Formulation Example 1 hard-gelatin capsules to dogs

*RR diastereomer was used in the formulation for the fasted group.

Table 4. Summary of the pharmacokinetic parameters of dosing Formulation Example 1 hard-gelatin capsules to dogs Example 8

Dose linearity and lower variability were conducted using Formulation Example 1, Formulation Example 1 A and Formulation Example IB in dogs. The results are shown in FIGs. 4-5 and Tables 5-6.

Table 5. Summary of the pharmacokinetic parameters of dosing Formulation Example

Table 6. Summary of the pharmacokinetic parameters of dosing Formulation Example 1, 1 A and IB hard-gelatin capsules to dogs at 25 mg, 50 mg and 75 mg dose. Dose normalized to 25 mg

Example 9

Phase 1 study of the safety, tolerability, pharmacokinetics (PK), relative bioavailability of capsule formulations following administration of single ascending doses (SAD) (Study CA228-1011 Part 1) Participants were administered as a single oral dose as capsules after a low-fat meal. Preliminary PK data were assessed for 59 participants as of the PK data cutoff. The mean plasma API concentration-time profile across doses was shown in FIG. 6. In this study, 100 to 400 mg doses were supported by multiples of 100 mg strength capsules, for example: 400 mg dose was supported with 4 capsules of 100 mg strength (Example 2). 200 mg dose alternate capsule was supported by 2 capsules of 100 mg strength (Example 3 A). The key PK parameters of API and its metabolites were summarized in Table 7 and Table 8 respectively.

Table 7. Summary of Pharmacokinetic Parameters of the API, RR diastereomer, and RS diastereomer in Study CA228-1011 Part 1

Tmax is presented as Median (Min-Max) [N] ; T-HALF is presented as Mean (SD) [N] ; All other data are presented as Geometric Mean (Geometric %CV) [N]

AUC(INF), area under the concentration-time curve from time zero to infinity; Cmax, maximum observed concentration; N, number of participants; T-HALF, terminal half-life; Tmax, time to reach Cmax. Table 8. Summary of Pharmacokinetic Parameters of the Metabolites in Study

CA228-1011 Part 1

AUC(INF), area under the concentration-time curve from time zero to infinity; Cmax, maximum observed concentration; M/P, metabolite to parent ratio; N, number of participants; T-HALF, terminal half-life; Tmax, time to reach Cmax.

M/P AUC(INF) Ratio is corrected by molecular weight

*Only 6 participants in 300 mg Capsule group were available for analysis as of the PK data cutoff.

For capsules, API reached peak concentration in plasma at a median time of 3 to 5 hours across the dose range following oral administration. Plasma exposure to API (AUC(INF) and Cmax) increased with dose and appeared approximately dose- proportional (100 to 400 mg single dose). The mean terminal half-life of API, approximately ranged from 18 to 20 hours. No differences in PK exposure in terms of AUC(INF) and Cmax were observed between the capsule and the alternate capsule formulation (Example 3 A) at a 200 mg dose.

The RR diastereomer of the API accounted for the majority of the total API plasma exposure, approximately 67% to 70%. The RS diastereomer accounted for approximately 30% to 33% of the total API exposure.

PK parameters of prominent human circulating metabolites Ml 5 and Ml 6 were estimated. The metabolite-to-parent (M/P) AUC(INF) ratio for M15 and M16 in plasma were in the range of 0.85 to 2.4-fold and 7 to 12-fold respectively. Tmax was observed at around 4 hours for Ml 5 and ranged from 24 to 48 hours for Ml 6. The half-life of Ml 5 and Ml 6 were estimated to be approximately 5 to 14 days and 5 to 9 days, respectively.

Example 9 A

Phase 1 study of the food and proton pump inhibitor (PPI) effects on the capsule formulation (Study CA228-1011 Part 2)

Participants were administered a single oral dose as capsules either under fasted or high-fat meal fed conditions, with a 34-day washout period before switching conditions, to evaluate the food effect. The mean plasma API concentration-time profiles across the low-fat meal diet group from Part 1 study and the fasted or high-fat meal diet groups from Part 2 were shown in FIG. 25. In this study, 300 mg doses were supported by 3 capsules of 100 mg strength (Example 2). The key PK parameters of API, its RR diastereomer, and RS diastereomer are summarized in Table 8A; and its metabolites are summarized in Table 8B. The AUCinf ratios for the high-fat meal diet group from Part 2 of the study and the low-fat meal diet group from Part 1 of the study compared to the fasted group from Part 2 of the study were 3.05 and 2.28, respectively, indicating a food effect. Importantly, the type of diet does not significantly impact the exposure.

Table 8A. Summary of the Food Effect on the Pharmacokinetic Parameters of the API, RR diastereomer, and RS diastereomer of Dosing Capsule Formulation in Part 2

Tmax is presented as Median (Min-Max) [N] ; T-HALF is presented as Mean (SD) [N] ; All other data are presented as Geometric Mean (Geometric %CV) [N] AUC(INF), area under the concentration-time curve from time zero to infinity; Cmax, maximum observed concentration; N, number of participants; T-HALF, terminal halflife; Tmax, time to reach Cmax.

Table 8B: Summary of Pharmacokinetics Parameters of the Metabolites in Food

Effect Study in Study CA228-1011 Part 2

Tmax is presented as Median (Min-Max) [N]; T-HALF is presented as Mean (SD) [N]; All other data are presented as Geometric Mean (Geometric %CV) [N]

AUC(INF), area under the concentration-time curve from time zero to infinity; Cmax, maximum observed concentration; N, number of participants; T-HALF, terminal half-life; Tmax, time to reach Cmax. M/P AUC(INF) Ratio is corrected by molecular weight Participants were administered a single oral dose as capsules in Period 1. In Period 2, the same group of participants were first administered proton pump inhibitor (PPI) (i.e., Rabeprazole 20 mg QD) for 5 days, then co-administered with 300 mg doses of capsule formulation supported by 3 capsules of 100 mg strength (Example 2), to evaluate the PPI effect. The mean plasma API concentration-time profiles of the without vs. with co-administration of PPI were shown in FIG. 26. The key PK parameters of API, its RR diastereomer, and RS diastereomer are summarized in Table 8C; and its metabolites are summarized in Table 8D. The AUCinf ratios for the PPI-treatment group to the untreated group was 1.06, suggesting PPI does not have a significant impact on the exposure.

Table 8C. Summary of the PPI Effect on the Pharmacokinetic Parameters of the API, RR diastereomer, and RS diastereomer of Dosing Capsule Formulation in Study CA228-1011 Part 2

AUC(INF), area under the concentration-time curve from time zero to infinity; Cmax, maximum observed concentration; N, number of participants; T-HALF, terminal half-life; Tmax, time to reach Cmax. Table 8D: Summary of Pharmacokinetics Parameters of the Metabolites in Proton

Pump Inhibitor (PPI) Effect Study in Study CA228-1011 Part 2

AUC(INF), area under the concentration-time curve from time zero to infinity; Cmax, maximum observed concentration; N, number of participants; T-HALF, terminal half-life; Tmax, time to reach Cmax. M/P AUC(INF) Ratio is corrected by molecular weigh

Example 10

Dose Proportionality

Dose proportionality of the API and diastereomers was assessed for capsule formulation from 100 to 400 mg single dose. The linear relationship between natural log-transformed PK exposure (Cmax, AUC(O-t), and AUC(INF)) and natural log- transformed dose was fitted by using a regression model. As shown in Table 9, proportional relationship between dose and exposure was demonstrated by a slope of approximately 1.1, with the 90% CI of the slope contains 1. For metabolites, preliminary data indicated approximately dose proportionality for Cmax and AUC(0- t). Table 9. Dose proportionality assessment for PK parameters

AUC(O-t), area under the concentration-time curve from time zero to the last measurable time point; AUC(INF), area under the concentration-time curve from time zero to infinity; CI, confidence interval; Cmax, maximum observed concentration; N, number of participants.

Population Pharmacokinetic (PPK) modelling and simulation

The PK of the API was best described using a two-compartment model with two transit compartment first-order absorption, linear elimination, and dose-dependent relative BA only for tablets, with covariate impact of capsule formulation on mean transit time, absorption rate and relative BA. Based on PPK model, the API exposure (Cmax, Cavg, and Cmin) at steady-state was simulated for capsules (N = 1000). The simulations were summarized in Table 10, and the predicted exposure distribution of capsules was depicted in FIG.7.

Table 10. Population PK Model Predicted Cmax, Cavg, and Cmin of the API Across Selected Capsule Doses (N = 1000)

BID, twice a day; Cavg,ss, averaged concentration at steady state; Cmax,ss, maximum concentration at steady state;

Cmin,ss, trough concentration at steady state;

All concentration data presented as Geometric Mean

Example 11 Preparations of amorphous API (Freebase)

Example 11 A. Aqueous precipitation process

Form A of the API was dissolved in 6 vol (kg solvent/kg input solids) of acetone. This solution was added over minimum 1.5 hours to 24 vol of 50 mM phosphate buffer (pH 7.5) at 10°C. The resulting slurry was filtered and washed twice with 5 vol of water. The solids were dried at 40°C for 12 hours, followed by drying at 50°C. The product is an amorphous API.

Example 11B. Organic precipitation process

Form A of the API was dissolved in 3 vol (kg solvent/kg input solids) of acetone and 3 vol of MTBE at 25°C. This solution was added over 30 minutes to mixture of 15 vol of heptane and 15 vol of MTBE at -5°C under agitation. The resulting slurry was stirred for at least 1 hour. The slurry was filtered and washed with 4 vol of cold heptane. The solids were dried at 35 °C for 16 hours, followed by drying at 50°C for 3 days. The product is an amorphous API. Example 11C. Spray drying process

Form A of the API is dissolved in 10 vol (kg solvent/kg input solids) acetone at 20°C in an agitated temperature-controlled vessel. After full dissolution is achieved, the solution is passed through a polish filter and then charged into the spray dryer with outlet temperature of 60-80°C (target 70°C). Spray drying is run at pressure of 0.20-0.3MPa. The product is collected from the cyclone separator. The batch is then taken to secondary drying under vacuum at jacket temperature no more than 70°C with nitrogen sweep for no less than 15 hours. The product is an amorphous API.

It was more advantageous to prepare the amorphous API from the spray drying process as compared to the amorphous precipitation processes. The amorphous precipitation processes produced larger API particle size as compared to that from the spray drying process. The DIO, D50, D90 for the largest lab-batch from the aqueous amorphous precipitation process was 6.05, 48, and 196 pm respectively. The corresponding numbers for a typical spray dried API were 4-7, 12-16, 20-35 pm respectively. Dissolution times in the SEDDS vehicle were within 4 hours in the 1 kg- scale dissolution experiments: -2 hours for the spray dried API, and -3 hours for the amorphous precipitated API. Solvent purging was also superior for the spray dried API - BuOAc levels in the Amorphous precipitated API were typically ~ 1.5 -1.8%, while in the spray dried API, BuOAc levels were typically -0.7%.

Solubility of more than 300 mg/g was observed for the amorphous API in the SEDDS formulation vehicle, independent of the manufacturing process for the amorphous API. 125 mg/g, 200 mg/g, and 300 mg/g solids loadings were studied in the SEDDS vehicle, and in all three cases, the API was fully dissolved in the vehicle. Dissolution times observed was about 1 to 2 hours for 125 mg/g loading at the 250 g scale, and 1 to 4 hours at the 1 kg scale.

Example 12 Preparations of Form A Example 12A

To a reactor was charged acetonitrile (2.0 L/kg, 30.1 equiv.) and 2-MeTHF (1.5 L/kg, 11.8 equiv.) followed by 1 -methylmidazole (0.52kg/kg, 5.0equiv), CEL- 011053-04 (l.OOkg/kg, 1.00 equiv.) and CEL-430188-01 (0.575kg/kg, 1.16 equiv.). The solid charges were rinsed with acetonitrile (1.0 L/kg, 15.1 equiv.) and the temperature of the reaction was adjusted 15~25°C. The mixture was allowed to stir until a homogenous solution formed. Next, the batch was cooled to 0~10°C (target 5°C) at which point a 50wt% T3P in 2-MeTHF solution (2.01kg/kg, 2.50 equiv.) was added slowly, maintaining a temperature of 0~10°C. The reactor was then rinsed with 2-MeTHF (0.5 L/kg, 3.9 equiv.) and the reaction was allowed to age for at least 2h at 0~10 °C until deemed complete. Aq. Na2HPO4 (6L/kg, 2.1eq, 6.0wt%) was slowly added into the reaction mixture, followed by 2-MeTHF (2.0 L/kg) and BuOAc (2.0 L/kg). The mixture was heated to 40~50°C with vigorous mixing. The layers were settled and then split. The organic phase was washed a second time with aq. Na2HPO4 (6L/kg, 2.1 eq, 6.0wt%) followed once more with 6L/kg aq. Na2HPO4 (1.69eq, 4.8wt%) & Na2HPO4 (0.50eq, 1.2wt%). The layers were separated, and the solution was cooled to 15-25°C. The organic phase was distilled at 40°C to a final volume of 3.7-4.3 L/kg (target: 4.0L/kg). 2-MeTHF (6 L/kg) was added and the solution filtered though activated carbon filter at 15-30°C. The activated carbon was rinsed with 2 L/kg 2-MeTHF at 15~30°C. The filtrates were combined and the resulting solution was distilled at 40°C to a final volume of 3.8-4.3 L/kg (target: 4.0L/kg). The batch was cooled to 25~35°C and 0.6 L/kg BuOAc and 1.3 L/kg 2- MeTHF were added to the concentrated stream. Next, a seed solution of 1% Form A in 0.1 L/kg BuOAc was charged to form a slurry which was allowed to age for 12 h. Heptane (1 L/kg) was added slowly over to 4~6h and aged once again aged for 12 h. The mixture was then cooled to -5~5°C and aged for another 3h. The resulting slurry was filtered and the cake washed with 2 L/kg Hep: BuOAc: 2-MeTHF (1 :2:4, adjusted to -5~5°C). Next, the cake was washed with 2 L/kg BuOAc (adjusted to - 5~5°C). Finally the cake was washed twice with 3 L/kg Heptane (adjusted to 15~25°C). The resulting solids were dried under vacuum to afford Form A in 85% yield. Example 12B

82 mg of the compound of formula (I) was dissolved in 400 pL acetonitrile. Solvent was evaporated to dryness. 0.5 mL of 1,4 dioxane and 1.5 mL of toluene were added and stirred overnight to afford a crystalline slurry. In a different vial, 82 mg of the compound of formula (I) was dissolved in 400 pL acetonitrile. Solvent was evaporated to dryness. Approximately 1 mL of BuOAc was added, followed by addition of approximately 1 mL of heptane. The vial was stirred overnight. A small amount of above dioxane/toluene slurry was added as seeds. The vial was stirred overnight. The slurry was filtered, and solids were dried in vacuum oven overnight, yielding Form A.

Example 12C

In vial #1, approximately 104.6 mg of the compound of formula (I) was dissolved in 1 mL of BuOAc at room temperature. The solution was cooled to 5°C and stirred overnight, which resulted in a slurry. 4 mL of heptane was added to the slurry. After stirring overnight, the slurry was equilibrated at 20°C. In vial #2, 151.1 mg of the compound of formula (I) was dissolved in 1 mL of BuOAc at room temperature. The solution was cooled to 5°C and stirred overnight, which resulted in a slurry. 4 mL of heptane was added to the slurry. After stirring overnight, the slurry was equilibrated at 20C. In vial #3, 50 mg of the compound of formula (I) was dissolved in 1 mL of BuOAc at room temperature. The solution was cooled to 5°C and stirred overnight, which resulted in a slurry. 4 mL of heptane was added to the slurry. After stirring overnight, the slurry was equilibrated at 20°C. All 3 vials were stirred for an additional 4 days at 20°C. The slurries in all three vials were filtered, filtered solids were combined and dried in vacuum oven at 50°C overnight. The solids were Form A.

Example 13 Preparations of Form B and Form C

Example 13 A

156 mg of the amorphous API was slurried in 1.5 mL of EtOAc. 1.5 mL heptane was added drop-wise. The slurry was left to mix at room temperature for 5 days to yield Form B. The solids were dried at 50°C under vacuum for 2 days. The dry solids yielded Form C.

Example 13B

4.91 g of the compound of formula (I) was dissolved in 15 mL of 2-Methly THF at 50°C. 35 mL of ethlyl acetate was charged. The reactor was cooled to 30°C over 30 minutes. 101.7 mg of Form A seeds were added, which dissolved, followed by addition of 10 mL heptane. 99.4 mg of Form A seeds were added, which dissolved, followed by addition of 10 mL heptane. 99.4 mg Form A seeds were added, followed by 1 hour of stirring. The temperature was dropped to 20°C over 1 hour. 35 mL of heptane was added over 5 hours. The slurry was held stirring at 20°C overnight to yield Form B. The solids were filtered and dried in vacuum oven at 25 °C for 24 hours. The dried solids were Form C.

Example 14 Preparations of Form D and Form E

Example 14A

82 mg of the compound of formula (I) was dissolved in 400 pL acetonitrile. Solvent was evaporated to dryness. 0.5 mL of 1,4 dioxane and 1.5 mL of toluene were added and stirred overnight to afford a crystalline slurry. In a different vial, 82 mg of the compound of formula (I) was dissolved in 400 pL acetonitrile. Solvent was evaporated to dryness. Approximately 1 mL of isopropyl acetate was added, followed by addition of approximately 1 mL of heptane. The vial was stirred overnight. A small amount of above dioxane/toluene slurry was added as seeds. The vial was stirred overnight to afford a slurry of Form D.

Example 14B

Step 1 : In a vial, 0.4 g of the compound of formula (I) was dissolved in 0.8 mL 2-Methly THF and 0.8 mL of isopropyl acetate. The vial was cooled to 0 and seeded with a small amount of Form A. After a few hours, 0.8 mL of heptane was charged dropwise. The slurry was allowed to equilibrate to room temperature under stirring.

Step 2: In another reactor, 4.87 g of the compound of formula (I) was dissolved in 15 mL of 2-methyl THF at 50°C. 35 mL of isopropyl acetate was charged. The reactor was cooled to 30°C in approximately 30 minutes. 100 mg of Form A seeds were added, followed by 1 hour of stirring. The temperature was dropped to 20°C over 1 hour. 35 mL of heptane was added over 5 hours. The temperature was raised to 30°C and 1 mL of above slurry in Step 1 was added as seeds. The slurry was stirred for 24 hours. The slurry was cooled to 20°C over 2 hours to yield Form D. The solids were filtered and dried in vacuum oven at 25°C for 24 hours. The dried solids were Form E.

Example 14C

To 220 mg of the amorphous API in 660 pL of isopropyl acetate, 880 pL of heptane were added. The slurry was left to stir overnight at room temperature to yield Form D.

Example 15 Preparation of Form F

82 mg of the compound of formula (I) was dissolved in 400 pL acetonitrile. Solvent was evaporated to dryness. 0.5 mL of 1,4 dioxane and 1.5 mL of toluene were added and stirred overnight to afford a crystalline slurry of Form F.

Example 16 Preparation of Form G

801.9 mg of the compound of formula (I) was dissolved in 1.8 mL of acetone. 9 mL of cyclohexane was added in 1 mL increment, resulting in precipitation. The slurry was stirred at room temperature for 5 days. The slurry was filtered via 0.22 pm nylon-membraned centrifuge tube filter at 14000 rpm for 10 min. The solids after filtration were placed in vacuum oven at room temperature and dried for 2 days. The resulting solids were Form G. Example 17 Preparation of Form G

45.3 mg of the compound of formula (I) was dissolved in 1 mL of cyclopentyl methyl ether at 45°C. 1 mL of tert-butyl methyl ether was added to the vial, which was allowed to cool to room temperature and stir for 7 days. 1 mL of cyclopentyl methyl ether was added to the vial and stirred for additional 6 days. The slurry afforded Form H.

Example 18 Preparation of Form I

1.0025 g of the compound of formula (I) was dissolved in 700 pL acetone. This vial was stirred for 5 days, resulting in crystallization of Form I.

Example 19 Stability Study

The chemical stability comparison of the two formulations Example 2A and Example 2B is shown in FIG. 23. The degradation rates of the new formulation at different temperature conditions are only 20-45% of those of the current formulation as shown in Table 11.

Table 11. Degradation Rate of Current Formulation and New Formulation

The total degradation of the formulation Example 2B decreased with the increase of HC1 concentration, as shown in FIG. 24. The analytical data for the amorphous solid and crystalline solvates of the API described herein were obtained using the following procedures.

X-RAY POWDER DIFFRACTION (XRPD)

XRPD data for the amorphous solid of the API were collected using a Bruker D8 Discover DaVinci with XYZ Stage. The IpS X-ray generator was operated at 50 kV and 1 mA with a Cu target (CuKa radiation). Incident beam optics included Montel mirrors with a 0.3 mm collimator. Photons were counted using an Eiger2 R 500K Detector in 2D, 29 optimized mode. Sample-to-detector distance was set to 140 mm. The samples were run for 1000 seconds in transmission, snapshot mode with the incident beam at 0° and the detector at 17.5°.

XRPD data for Forms A, B, C, D and E of the API were collected using a Bruker D8 Discover DaVinci with XYZ Stage. The IpS X-ray generator was operated at 50 kV and 1 mA with a Cu target (CuKa radiation). Incident beam optics included Montel mirrors with a 0.3 mm collimator. Photons were counted using an Eiger2 R 500K Detector in 2D, 29 optimized mode. Sample-to-detector distance was set to 137.7 or 140 mm. Each sample was loaded into a glass capillary (1 mm diameter). Data were collected over a 29 range of approximately 3-33° with an exposure time of 1000 s and an approximate step size of 0.01°.

XRPD data for Forms F, H and I of the API were obtained using Bruker D8 Discover DaVinci. The IpS X-ray generator was operated at 50 kV and 1 mA with a Cu target (CuKa radiation). Incident beam optics included Montel mirrors with a 1.0 mm collimator. Photons were counted using an VANTEC500 Detector. The sample- to-detector distance was 197.8 mm. Each sample was loaded into a 96 or 184 wellplate. Data were collected over a 29 range of approximately 2-35° with an exposure time of 60 s and an approximate step size of 0.01°.

XRPD data for Form G of the API was collected using a Rigaku SmartLab Guidance diffractometer with CuKa radiation and a D/teX Ultra detector. The generator was operated at 40 kV and 44 mA. The sample was run at a scanning rate of 5° 29/min, a step size of 0.02° 29, and a scanning range of 3 - 40° 29. MODULATED DIFFERENTIAL SCANNING CALORIMETRY (mDSC)

Modulated differential scanning calorimetry (mDSC) experiments for the amorphous solid of the API were performed using a TA Instruments Discovery DSC model 2500. The sample (about 1-5 mg) was weighed in a pin-holed aluminum pan and the weight recorded accurately to a hundredth of a milligram before transferring the sample to the instrument. The instrument was purged with nitrogen gas at 50mL/min. The sample was heated to 150°C, at 2.0°C /min, then cooled to 20°C, at 2.0°C /min. Then a heating ramp of 2.0°C /min. was applied between room temperature and 300°C with a modulation amplitude of 0.32°C applied every 60 seconds.

DIFFERENTIAL SCANNING CALORIMETRY (DSC)

Differential scanning calorimetry (DSC) experiments for Form A of the API were performed using a TA Instruments Discovery DSC model 2500. The sample (about 1-10 mg) was weighed in an aluminum pan and the weight recorded accurately to a hundredth of a milligram before transferring the sample to the DSC. The instrument was purged with nitrogen gas at 50mL/min. Data were collected between room temperature and 400 °C at a heating rate of 10 °C/min. DSC plots were generated such that the endothermic peaks pointed down.

THERMAL GRAVIMETRIC ANALYSIS (TGA)

Thermal gravimetric analysis (TGA) experiments for the amorphous solid and Form A of the API were performed using a TA Instruments Discovery TGA model 5500. The sample (about 1-10 mg) was placed in a previously cleaned and tarred platinum pan. The weight of the sample was measured accurately and recorded to a thousandth of a milligram by the instrument. The furnace was purged with nitrogen gas at 25 mL/min. Data were collected between room temperature and 400 °C at a heating rate of 10 °C/min.

MOISTURE SORPTION ISOTHERMS

Moisture sorption isotherms for the amorphous solid of the API were collected on a VTI SGA-100 Symmetric Vapor Analyzer using approximately 10 mg of sample. The sample was tested at 25°C from 0%RH to 95%RH and then back to 0%RH at 5%RH increments and decrements, respectively. Equilibration at each RH was reached when the rate of 0.0010 wt.%/min for 60 minutes was achieved or a maximum of 120 minutes.

SINGLE CRYSTAL

Single crystal X-ray data were collected for Forms A and F using a Bruker D8 Venture diffractometer equipped with a Photon III detector and monochromatic Cu Ka radiation. The single crystals were held at 100K under a nitrogen stream during data collection.

Indexing and processing of the measured intensity data were carried out with the APEX3 program suite (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711 USA).

The final unit cell parameters were determined using the full data set. The structures were solved by direct methods and refined by full-matrix least-squares approach using the SHELXTL software package (G. M. Sheldrick, SHELXTL v6.14, Bruker AXS, Madison, WI USA.). Structure refinements involved minimization of the function defined by 2 ^W(|F_O| - |F_C|)², where w is an appropriate weighting factor based on errors in the observed intensities, F_o is the structure factor based on measured reflections, and F_c is the structure factor based on calculated reflections. Agreement between the refined crystal structure model and the experimental X-ray diffraction data is assessed by using the residual factors R = EI|Fo|-|F_c||/E|Fo| and wR = E^w(Po|-|F_c|)²/^w|F_o|] ^1/2. Difference Fourier maps were examined at all stages of refinement. All non-hydrogen atoms were refined with anisotropic thermal displacement parameters. Hydrogen atoms on carbon atoms were introduced using idealized geometry with isotropic temperature factors and included in structure factor calculations with fixed parameters. Hydrogen atoms on hereoatoms were freely refined.

All measurements are subject to experimental error and are within the spirit of the invention. It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

CLAIMS What is claimed is:

1. A composition comprising

(b) at least one solubilizer;

(c) optionally at least one surfactant; and

(d) optionally at least one stabilizer.

2. The composition of claim 1, comprising

(d) optionally at least one stabilizer.

3. The composition of claim 1 or claim 2, wherein the at least one active pharmaceutical ingredient is included in the range of at least 2% w/w.

4. The composition of claim 1 or claim 2, wherein the at least one active pharmaceutical ingredient is included in the range of 2 to 20% w/w.

5. The composition of claim 1 or claim 2, wherein the at least one active pharmaceutical ingredient is included in the range of 2.5 to 12.5 % w/w.

6. The composition of any one of claims 1 to 5, wherein the at least one stabilizer is included in the range from about 0.01 to about 2% w/w.

7. The composition of any one of claim 1 to 6, wherein the least one solubilizer is selected from propylene glycol esters, medium and long chain triglycerides, medium-chain fatty acid mono- and diglycerides, and a combination thereof.

8. The composition of any one of claims 1 to 7, wherein the at least one active pharmaceutical ingredient is included in the range of at least 2% w/w, the at least one solubilizer is included in the range from about 1 to about 98% w/w, the at least one surfactant is included in the range from about 0 to about 40% w/w; and the at least one stabilizer is included in the range from about 0.01 to about 2% w/w.

9. The composition of claim 8, wherein the at least one active pharmaceutical ingredient is included in the range from about 2.5 to about 12.5% w/w, the at least one solubilizer is included in the range from about 50 to about 80% w/w, the at least one surfactant is included in the range from about 0 to about 40% w/w, and the at least one stabilizer is included in the range from about 0.01 to about 2% w/w.

10. The composition of claim 7 wherein the propylene glycol ester is propylene glycol monocaprylate, propylene glycol dicaprylate, or a combination thereof.

11. The composition of any one of claims 1 to 9, wherein the at least one surfactant is polyoxyl 40 hydrogenated castor oil or polysorbate 20.

12. The composition of any one of claims 1 to 9, wherein the at least one surfactant is polyoxyl 40 hydrogenated castor oil.

13. The composition of any one of claims 1 to 9, wherein the at least one stabilizer is selected from butylated hydroxytoluene, citric acid, malic acid, hydrochloric acid, sodium metabisulfite, and a combination thereof.

14. The composition of any one of claims 1 to 9, wherein the at least one stabilizer is selected from butylated hydroxytoluene, citric acid anhydrous, malic acid, hydrochloric acid, and a combination thereof.

15. The composition of claim 1, comprising

(b) at least one solubilizer comprised of propylene glycol esters, caprylocaproyl polyoxyl-8 glycerides, and a combination of medium -chain fatty acid mono- and diglycerides;

16. The composition of claim 15, comprising

(c) at least one surfactant which is polyoxyl 40 hydrogenated castor oil; and

17. The composition of any one of claims 1 to 16, wherein the composition is a self-emulsifying oral formulation.

18. A method of treating prostate cancer comprising the step of administering to a subject in need thereof a therapeutically effective amount of the composition of any of claims 1 to 17.

19. A method of treating prostate cancer comprising the step of administering to a subject in need thereof a composition comprising at least one active pharmaceutical ingredient comprising a solubilized compound having the formula (I): or a pharmaceutically acceptable salt thereof; wherein the total dose of the compound of formula (I) administered to the subject is up to 1200 mg a day.

20. The method of claim 19, wherein the compound of formula (I) is administered to the subject up to 900 mg a day.

21. The method of claim 19, wherein the compound of formula (I) is administered to the subject up to 800 mg a day.

22. The method of claim 19, wherein the compound of formula (I) is administered to the subject up to 600 mg a day.

23. The method of claim 19, wherein the compound of formula (I) is administered to the subject up to 400 mg a day.

24. The method of claim 19, wherein the compound of formula (I) is administered to the subject up to 200 mg a day.

25. The method of claim 19, wherein the compound of formula (I) is administered to the subject from 200 mg to 900 mg a day.

26. The method of claim 19, wherein the compound of formula (I) is administered to the subject up to 600 mg twice a day.

27. The method of claim 19, wherein the compound of formula (I) is administered to the subject up to 400 mg twice a day.

28. The method of claim 19, wherein the compound of formula (I) is administered to the subject up to 300 mg twice a day.

29. The method of claim 19, wherein the compound of formula (I) is administered to the subject up to 200 mg twice a day.

30. The method of claim 19, wherein the compound of formula (I) is administered to the subject from 100 mg to 600 mg twice a day.

31. The method of claim 19, wherein the compound of formula (I) is administered to the subject from 100 mg to 400 mg twice a day.

32. The method of any of claims 18 to 31, wherein the composition is in a form of a capsule.

33. The method of any one of claims 18 to 32, wherein the subject experiences minimum food effect and/or pH effect.

34. The composition of any one of claims 1 to 17 for use in the treatment of prostate cancer.

35. The composition for use of claim 34 comprising the step of administering to a subject in need thereof a composition comprising at least one active pharmaceutical ingredient comprising a solubilized compound having the formula (I): or a pharmaceutically acceptable salt thereof; wherein the total dose of the compound of formula (I) administered to the subject is up to 1200 mg a day.

36. The composition for use according to claim 35, wherein the compound of formula (I) is administered to the subject up to 900 mg a day.

37. The composition for use according to claim 35, wherein the compound of formula (I) is administered to the subject up to 800 mg a day.

38. The composition for use according to claim 35, wherein the compound of formula (I) is administered to the subject up to 600 mg a day.

39. The composition for use according to claim 35, wherein the compound of formula (I) is administered to the subject up to 400 mg a day.

40. The composition for use according to claim 35, wherein the compound of formula (I) is administered to the subject up to 300 mg a day.

41. The composition for use according to claim 35, wherein the compound of formula (I) is administered to the subject up to 200 mg a day.

42. The composition for use according to claim 35, wherein the compound of formula (I) is administered to the subject from 200 mg to 900 mg a day.

43. The composition for use according to claim 35, wherein the compound of formula (I) is administered to the subject up to 600 mg twice a day.

44. The composition for use according to claim 35, wherein the compound of formula (I) is administered to the subject up to 400 mg twice a day.

45. The composition for use according to claim 35, wherein the compound of formula (I) is administered to the subject up to 300 mg twice a day.

46. The composition for use according to claim 35, wherein the compound of formula (I) is administered to the subject up to 200 mg twice a day.

47. The composition for use according to claim 35, wherein the compound of formula (I) is administered to the subject from 100 mg to 600 mg twice a day.

48. The composition for use according to claim 35, wherein the compound of formula (I) is administered to the subject from 100 mg to 400 mg twice a day.

49. The composition for use of any of claims 34 to 48, wherein the composition is in a form of a capsule.

50. The composition for use of any of claims 34 to 49, wherein food effect and/or pH effect is minimum.

51. The composition of claim 1, comprising

(c) up to 40% w/w polyoxyl 40 hydrogenated castor oil or polysorbate 20; and (d) up to 2% w/w at least one stabilizer selected from butylated hydroxytoluene, citric acid anhydrous, malic acid, hydrochloric acid, sodium metabisulfite and a combination thereof.

52. The composition of claim 51, comprising

(c) up to 40% w/w polyoxyl 40 hydrogenated castor oil; and

53. The composition of claim 52, comprising

(c) up to 40% w/w polyoxyl 40 hydrogenated castor oil; and

54. The composition of claim 53, comprising

(b) up to 60% w/w a solubilizer combination comprising propylene glycol monocaprylate, glyceryl mono and dicaprylocaprate or capryl ocaproyl Polyoxyl-8 glycerides;

55. A composition prepared using an amorphous form of the compound of formula (I): wherein the amorphous form is characterized by at least one of the following:

(a) an X-ray powder diffraction pattern having no distinct peaks, which is substantially free of other forms of the compound of formula (I);

(g) moisture sorption isotherms substantially in accordance with FIG. 11.

56. A composition prepared using an amorphous form of the compound of formula

(I): wherein the amorphous form of the compound of formula (I) is prepared by a spray drying process.

57. The composition of 56, wherein the spray drying process comprises:

1) dissolving the compound of formula (I) in acetone at about 20°C;

3) spray drying is run at pressure of 0.20-0.3MPa; and

4) the product is collected from the cyclone separator.

58. The composition of claims 1-17 and 34-55, wherein the composition is prepared using an amorphous form of the compound of formula (I); wherein the amorphous form is characterized by at least one of the following:

(e) weight loss of 1.5% up heating to around 200°C, as measured by a thermal gravimetric analysis;

(g) moisture sorption isotherms substantially in accordance with FIG. 11.

59. The composition of claims 1-17 and 34-55, wherein the composition is prepared using an amorphous form of the compound of formula (I); wherein the amorphous form of the compound of formula (I) is prepared by a spray drying process.

60. The composition of 59, wherein the spray drying process comprises:

1) dissolving the compound of formula (I) in acetone at about 20°C;

3) spray drying is run at pressure of 0.20-0.3MPa; and

4) the product is collected from the cyclone separator.

61. A solid solvate of formula (I): selected from: an n-butyl acetate solvate, an ethyl acetate solvate, an isopropyl acetate solvate, a heptane solvate, a tetrahydrofuran solvate, a dioxane/toluene solvate, a dichloromethane solvate, a cyclohexane solvate, a cyclopentyl methyl ether solvate, and a acetone solvate.

62. The solid solvate of claim 60, wherein the solid solvate is selected from: an n- butyl acetate solvate, an ethyl acetate solvate, and an isopropyl acetate solvate.

63. The solid solvate of claim 61, wherein the solid solvate is selected from: Forms A,

B, C, D, E, F, G, H, and I; wherein Form A is characterized by at least one of the following: a) single crystal structure having unit cell parameters substantially equal

Crystal system, space group Triclinic, Pl

Unit cell dimensions a = 12.87 ± 0.10 A alpha = 105.8 ± l.C b = 13.20 ± 0.10 A beta = 96.8 ± 1.0° c = 16.50 ± 0.10 A gamma = 112.60 ±1

Volume 2409(20) A³

Density (calculated) 1.289 g/cm³

Temperature 100 °K b) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.7 ± 0.2, 8.2 ± 0.2, 9.4 ± 0.2, 10.4 ± 0.2 and 15.6 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); c) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.7 ± 0.2, 8.2 ± 0.2, 9.4 ± 0.2, 10.4 ± 0.2, 12.1 ± 0.2, 12.7 ± 0.2, 13.5 ± 0.2, 15.6 ± 0.2, 16.7 ± 0.2, 22.2 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); d) a powder X-ray diffraction pattern substantially in accordance with FIG. 12; e) a differential scanning calorimetry thermogram substantially in accordance with FIG. 13; and/or f) a thermal gravimetric analysis thermogram substantially in accordance with

FIG. 14; wherein Form B is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.3 ± 0.2, 6.6 ± 0.2, 10.9 ± 0.2, 11.6 ± 0.2 and 16.6 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.3 ± 0.2, 6.6 ± 0.2, 6.9 ± 0.2, 10.9 ± 0.2, 11.6 ± 0.2, 13.2 ± 0.2, 13.7 ± 0.2, 16.6 ± 0.2, 20.0 ± 0.2 and 22.5 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 15; wherein Form C is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.4 ± 0.2, 5.7 ± 0.2, 9.4 ± 0.2, 10.4 ± 0.2 and 15.6 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.4 ± 0.2, 5.7 ± 0.2, 7.7 ± 0.2, 8.1 ± 0.2, 9.4 ± 0.2, 10.4 ± 0.2, 15.0 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2 and 21.4 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 16; wherein Form D is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.3 ± 0.2, 6.7 ± 0.2, 11.0 ± 0.2, 11.5 ± 0.2 and 16.5 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.3 ± 0.2, 6.7 ± 0.2, 11.0 ± 0.2, 11.5 ± 0.2, 16.5 ± 0.2, 18.0 ± 0.2, 20.3 ± 0.2, 21.8 ± 0.2, 22.5 ± 0.2 and 25.0 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 17; wherein Form E is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.4 ± 0.2, 5.8 ± 0.2, 8.1 ± 0.2, 9.5 ± 0.2 and 10.6 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.4 ± 0.2, 5.8 ± 0.2, 8.1 ± 0.2, 9.5 ± 0.2 and 10.6 ± 0.2, 15.9 ± 0.2, 16.8

± 0.2, 17.3 ± 0.2, 18.7 ± 0.2 and 20.7 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 18; wherein Form F is characterized by at least one of the following: a) single crystal structure having unit cell parameters substantially equal

Crystal system, space group Triclinic, Pl

Unit cell dimensions a = 12.58 ± 0.10 A alpha = 84.8 ± 1.0' b = 12.91 ± 0.10 A beta = 81.7 ± 1.0° c = 16.98 ± 0.10 A gamma = 86.6 ±1.0'

Volume 2780(20) A³

Density (calculated) 1.299 g/cm³

Temperature 100 °K b) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.1 ± 0.2, 6.6 ± 0.2, 10.6 ± 0.2, 11.4 ± 0.2 and 16.5 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); c) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.1 ± 0.2, 6.6 ± 0.2, 10.6 ± 0.2, 11.4 ± 0.2 and 16.5 ± 0.2, 17.8 ± 0.2, 19.8 ± 0.2, 22.5 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or d) a powder X-ray diffraction pattern substantially in accordance with FIG. 19; wherein Form G is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.5 ± 0.2, 7.3 ± 0.2, 11.7 ± 0.2, 13.0 ± 0.2 and 21.0 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.5 ± 0.2, 7.3 ± 0.2, 11.7 ± 0.2, 13.0 ± 0.2, 14.6 ± 0.2, 18.0 ± 0.2, 21.0 ± 0.2, 23.7 ± 0.2, 24.5 ± 0.2 and 25.5 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 20; wherein Form H is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.1 ± 0.2, 6.6 ± 0.2, 10.9 ± 0.2, 11.4 ± 0.2 and 16.5 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.1 ± 0.2, 6.6 ± 0.2, 10.9 ± 0.2, 11.4 ± 0.2, 12.0 ± 0.2, 16.5 ± 0.2, 18.0 ± 0.2, 20.4 ± 0.2, 22.6 ± 0.2 and 25.0 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 21; wherein Form I is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.2 ± 0.2, 11.0 ± 0.2, 11.8 ± 0.2, 16.5 ± 0.2 and 18.0 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.2 ± 0.2, 6.7 ± 0.2, 7.1 ± 0.2, 11.0 ± 0.2, 11.8 ± 0.2, 16.5 ± 0.2, 18.0 ± 0.2, 20.7 ± 0.2, 23.1 ± 0.2 and 23.5 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 22.

64. The solid solvate of claim 61 or claim 63, wherein the solid solvate is selected from: Forms A, B, C, D and E; wherein Form A is characterized by at least one of the following: a) single crystal structure having unit cell parameters substantially equal

Crystal system, space group Triclinic, Pl

Volume 2409(20) A³

Density (calculated) 1.289 g/cm³

Temperature 100 °K b) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.7 ± 0.2, 8.2 ± 0.2, 9.4 ± 0.2, 10.4 ± 0.2 and 15.6 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); c) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.7 ± 0.2, 8.2 ± 0.2, 9.4 ± 0.2, 10.4 ± 0.2, 12.1 ± 0.2, 12.7 ± 0.2, 13.5 ± 0.2, 15.6 ± 0.2, 16.7 ± 0.2, 22.2 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); d) a powder X-ray diffraction pattern substantially in accordance with FIG. 12; e) a differential scanning calorimetry thermogram substantially in accordance with FIG. 13; and/or f) a thermal gravimetric analysis thermogram substantially in accordance with FIG. 14; wherein Form B is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.3 ± 0.2, 6.6 ± 0.2, 10.9 ± 0.2, 11.6 ± 0.2 and 16.6 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.3 ± 0.2, 6.6 ± 0.2, 6.9 ± 0.2, 10.9 ± 0.2, 11.6 ± 0.2, 13.2 ± 0.2, 13.7 ± 0.2, 16.6 ± 0.2, 20.0 ± 0.2 and 22.5 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 15; wherein Form C is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.4 ± 0.2, 5.7 ± 0.2, 9.4 ± 0.2, 10.4 ± 0.2 and 15.6 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.4 ± 0.2, 5.7 ± 0.2, 7.7 ± 0.2, 8.1 ± 0.2, 9.4 ± 0.2, 10.4 ± 0.2, 15.0 ± 0.2, 15.6 ± 0.2, 16.6 ± 0.2 and 21.4 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 16; wherein Form D is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.3 ± 0.2, 6.7 ± 0.2, 11.0 ± 0.2, 11.5 ± 0.2 and 16.5 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.3 ± 0.2, 6.7 ± 0.2, 11.0 ± 0.2, 11.5 ± 0.2, 16.5 ± 0.2, 18.0 ± 0.2, 20.3 ± 0.2, 21.8 ± 0.2, 22.5 ± 0.2 and 25.0 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 17; wherein Form E is characterized by at least one of the following: a) a powder x-ray diffraction pattern comprising 2 or more peaks at 20 values selected from 5.4 ± 0.2, 5.8 ± 0.2, 8.1 ± 0.2, 9.5 ± 0.2 and 10.6 ± 0.2 (obtained at room temperature and CuKa X= 1.5418 A); b) a powder x-ray diffraction pattern comprising 3 or more peaks at 20 values selected from 5.4 ± 0.2, 5.8 ± 0.2, 8.1 ± 0.2, 9.5 ± 0.2 and 10.6 ± 0.2, 15.9 ± 0.2, 16.8 ± 0.2, 17.3 ± 0.2, 18.7 ± 0.2 and 20.7 ± 0.2 (obtained at room temperature and CuKa =1.5418 A); and/or c) a powder X-ray diffraction pattern substantially in accordance with FIG. 18.