Single-dose, ready-to-use injectable formulation

Abstract

Provided are single-dose, ready-to-use formulations comprising the compound of formula (I), including pharmaceutically acceptable salts and amorphous and polymorphic forms thereof, as well as methods for preparing said formulations.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 418,688, filed November 7, 2016, which is incorporated by reference in its entirety.

[0002] Technical Field Provided herein is a single-dose, ready-to-use formulation containing the compound of formula (I), including its pharma- ceutically acceptable salts, polymorphs, and amorphous forms.Further provided herein is a process for preparing the same. [Background technology]

[0003] background Formula (I) The compound of TIFF0007630905000001.tif53128, N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide, is a Wnt inhibitor. The compound of formula (I) can be prepared as disclosed in U.S. Pat. No. 8,252,812, the entirety of which is incorporated herein by reference. The compound of formula (I), including its pharmaceutically acceptable salts and polymorphic and amorphous forms, can be used in the treatment of disorders characterized by activation of Wnt pathway signaling (e.g., cancer, abnormal cell proliferation, angiogenesis, Alzheimer's disease, pulmonary disease, and osteoarthritis), as well as genetic and neurological conditions / disorders / diseases due to mutations or dysregulation of one or more of the Wnt pathway and / or Wnt signaling components, and in the regulation of cellular events mediated by Wnt pathway signaling. There is a need for formulations, such as single-dose, ready-to-use formulations, that contain the compound of formula (I), including its pharmaceutically acceptable salts and polymorphic and amorphous forms. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 8,252,812 Summary of the Invention

[0005] overview Formula (I) Provided herein is a process for preparing a single dose reconstituted formulation comprising a compound of formula (I) of TIFF0007630905000002.tif53128 or a pharma- ceutically acceptable salt or amorphous or polymorphic form thereof, the process comprising: (a) providing an aqueous solution comprising water; (b) providing a slurry comprising a compound of formula (I) or a pharma- ceutically acceptable salt or an amorphous or polymorphic form thereof; (c) mixing the aqueous solution with the slurry to form a suspension; and (d) filling the suspension into a container to prepare a single-dose reconstituted product. Includes.

[0006] The process provided herein includes providing an aqueous solution comprising water. In some embodiments of the process provided herein, the aqueous solution includes a buffer. In some embodiments, the aqueous buffer is a phosphate buffer. In some embodiments, the phosphate buffer is selected from the group consisting of dibasic sodium phosphate, monobasic sodium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, and mixtures thereof. In some embodiments, the phosphate buffer is a mixture of dibasic sodium phosphate heptahydrate and monobasic sodium phosphate monohydrate. In some embodiments, the buffer is a phosphate buffered saline solution.

[0007] In some embodiments of the processes provided herein, the aqueous solution comprises an excipient. In some embodiments, the excipient comprises a surfactant, a thickener, or a mixture thereof. In some embodiments, the thickener is a water-soluble polymer. In some embodiments, the thickener is a cellulose derivative. In some embodiments, the cellulose derivative is sodium carboxymethylcellulose. In some embodiments, the aqueous solution has a concentration of from about 0.01 g / kg to about 50 g / kg; from about 0.5 g / kg to about 50 g / kg; from about 1.0 g / kg to about 50 g / kg; from about 1 g / kg to about 25 g / kg; from about 1 g / kg to about 10 g / kg; from about 1 g / kg to about 7.5 g / kg; from about 1 g / kg to about 5.5 g / kg; from about 1 g / kg to about 2.5 g / kg; from about 2.5 g / kg to about 50 g / kg; from about 5 g / kg to about 50 g / kg; from about 10 g / kg to about 50 g / kg; from about 25 g / kg to about 50 g / kg; from about 0.1 to about 5 g / kg; from about 2.5 g / kg to about 7.5 g / kg; from about 5 g / kg to about 10 g / kg; or from about 10 g / kg to about 20 In some embodiments, the aqueous solution comprises about 5.5 g / kg of a cellulose derivative.

[0008] In some aspects of the processes provided herein, the surfactant is a polysorbate. In some embodiments, the aqueous solution has a concentration of from about 0.01 g / kg to about 5 g / kg; from about 0.01 g / kg to about 2.5 g / kg; from about 0.01 g / kg to about 1 g / kg; from about 0.01 g / kg to about 0.75 g / kg; from about 0.01 g / kg to about 0.5 g / kg; from about 0.01 g / kg to about 0.25 g / kg; from about 0.025 g / kg to about 5 g / kg; from about 0.05 g / kg to about 5 g / kg; from about 1 g / kg to about 5 g / kg; from about 0.1 g / kg to about 5 g / kg; 0.1 g / kg to about 2.5 g / kg; from about 0.1 g / kg to about 1 g / kg; from about 0.1 g / kg to about 0.75 g / kg; from about 0.1 g / kg to about 0.5 g / kg; from about 0.1 g / kg to about 0.25 g / kg; about 0.25 g / kg to about 5 g / kg; about 0.25 g / kg to about 2.5 g / kg; about 0.25 g / kg to about 0.75 g / kg; about 0.5 g / kg to about 2.5 g / kg; about 0.5 g / kg to about 1 g / kg; or about 1 g / kg to about 2 g / kg of surfactant. In some embodiments, the aqueous solution comprises about 0.5 g / kg of surfactant. In some embodiments, the aqueous solution comprises about 5.55 g / kg of sodium carboxymethylcellulose and about 0.5 g / kg of polysorbate 80.

[0009] The process provided herein includes providing a slurry comprising a compound of formula (I) or a pharma- ceutically acceptable salt or amorphous or polymorphic form thereof. In some embodiments of the processes provided herein, the slurry has a concentration of from about 0.001 g / kg to about 5 g / kg; from about 0.001 g / kg to about 2.5 g / kg; from about 0.001 g / kg to about 1 g / kg; from about 0.001 g / kg to about 0.75 g / kg; from about 0.001 g / kg to about 0.5 g / kg; from about 0.001 g / kg to about 0.25 g / kg; from about 0.001 g / kg to about 0.01 g / kg; from about 0.01 g / kg to about 5 g / kg; from about 0.01 g / kg to about 2.5 g / kg; from about 0.01 g / kg to about 1 g / kg; from about 0.01 g / kg to about 0.75 g / kg; from about 0.01 g / kg to about 0.5 g / kg; from about 0.01 g / kg to about 0.25 g / kg; about 0.1 g / kg to about 2.5 g / kg; about 0.1 g / kg to about 1 g / kg; about 0.1 g / kg to about 0.75 g / kg; about 0.1 g / kg to about 0.5 g / kg; about 0.1 g / kg to about 0.25 g / kg; about 0.25 g / kg to about 5 g / kg; about 0.5 g / kg to about 5 g / kg; about 1 g / kg to about 5 g / kg; about 2.5 g / kg to about 5 g / kg; about 0.25 g / kg to about 0.75 g / kg; about 0.5 g / kg to about 1 g / kg; or about 1 g / kg to about 2 g / kg of a compound of formula (I) or a salt or an amorphous or polymorphic form thereof. In some embodiments, the slurry comprises about 0.15 g / kg, about 0.35 g / kg, or about 1.15 g / kg of the compound of formula (I) or a salt thereof or an amorphous or polymorphic form. In some embodiments, the compound of formula (I) comprises a polymorphic form. In some embodiments, the polymorph is form 1 and has an X-ray powder diffraction pattern comprising peaks at °2θ values ​​of 6.8±0.2, 12.4±0.2, and 18.5±0.2. In some embodiments, the compound of formula (I) comprises a mixture of non-stoichiometric or stoichiometric hydrates of form 1 having 1% to about 20% water by weight.

[0010] In some embodiments of the processes provided herein, the slurry comprises an excipient. In some embodiments, the excipient comprises a surfactant. In some embodiments, the surfactant is a polysorbate. In some embodiments, the slurry has a concentration of from about 0.01 g / kg to about 5 g / kg; from 0.01 g / kg to about 2.5 g / kg; from about 0.01 g / kg to about 1 g / kg; from about 0.01 g / kg to about 0.75 g / kg; from about 0.01 g / kg to about 0.5 g / kg; from about 0.01 g / kg to about 0.25 g / kg; from about 0.025 g / kg to about 5 g / kg; from about 0.05 g / kg to about 5 g / kg; from about 1 g / kg to about 5 g / kg; from about 0.1 g / kg to about 5 g / kg; 0.1 g / kg to about 2.5 g / kg; from about 0.1 g / kg to about 1 g / kg; from about 0.1 g / kg to about 0.75 g / kg; from about 0.1 g / kg to about 0.5 g / kg; from about 0.1 g / kg to about 0.25 g / kg; about 0.25 g / kg to about 5 g / kg; about 0.25 g / kg to about 2.5 g / kg; about 0.25 g / kg to about 0.75 g / kg; about 0.5 g / kg to about 5 g / kg; about 0.5 g / kg to about 2.5 g / kg; about 0.5 g / kg to about 1 g / kg; about 1 g / kg to about 5 g / kg; about 2.5 g / kg to about 5 g / kg; or about 1 g / kg to about 2 g / kg of surfactant. In some embodiments, the slurry comprises about 0.5 g / kg of surfactant.

[0011] In some embodiments of the processes provided herein, the slurry comprises about 0.15 g / kg of polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight, and about 0.5 g / kg of polysorbate 80. In some embodiments, the slurry comprises 5% or less by weight of another form, e.g., 1% or less or less than 0.1% of another form, including amorphous form. In some embodiments, the slurry comprises about 0.35 g / kg of polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight, and about 0.5 g / kg of polysorbate 80. In some embodiments, the slurry comprises about 1.15 g / kg of polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight, and about 0.5 g / kg of polysorbate 80.

[0012] In some embodiments of the process provided herein, the aqueous solution is a filtration mixture. In some embodiments, the filtration mixture comprises water. In some embodiments, the filtration mixture comprises water and an excipient. In some embodiments, the excipient comprises a surfactant, a thickener, or a mixture thereof. In some embodiments, the aqueous solution is a sterile filtration mixture. In some embodiments, the aqueous solution is a heat sterilization mixture.

[0013] In some aspects of the processes provided herein, the aqueous solution comprises a sterile diluent.

[0014] In some embodiments of the processes provided herein, the aqueous solution is a first sterilization mixture; the slurry is a second sterilization mixture; and the process includes mixing the first sterilization mixture with the second sterilization mixture.

[0015] Provided herein is a process that includes mixing an aqueous solution with a slurry to form a suspension.In some embodiments of the process provided herein, the aqueous solution is mixed with the slurry to form a suspension that contains about 0.005 mg / mL to about 2.5 mg / mL, about 0.01 mg / mL to about 2.0 mg / mL, about 0.01 mg / mL to about 1 mg / mL, about 0.01 mg / mL to about 0.5 mg / mL, about 0.01 mg / mL to about 0.2 mg / mL, or about 0.015 mg / mL to about 0.115 mg / mL of the compound of formula (I) or its salt or amorphous or polymorphic form.

[0016] Provided herein is a process that includes filling a container with the suspension to prepare a single-dose prepared formulation.In some embodiments of the process provided herein, the container contains a suspension that includes about 0.005 mg / mL to about 2.5 mg / mL, about 0.005 mg / mL to about 2 mg / mL, about 0.001 mg / mL to about 2 mg / mL, about 0.01 mg / mL to about 1.8 mg / mL, about 0.015 mg / mL to about 0.115, about 0.025 mg / mL to about 1.6 mg / mL, about 0.05 mg / mL to about 1.5 mg / mL, about 0.075 mg / mL to about 1.25 mg / mL, about 0.1 mg / mL to about 1 mg / mL, or about 0.25 mg / mL to about 0.75 mg / mL of the compound of formula (I) or its salt or amorphous or polymorphic form. In some embodiments, the container is selected from the group consisting of a vial, a bottle, an ampoule, and a syringe. In some embodiments, the vial is a glass vial or a plastic vial made of polyethylene, polypropylene, polyolefin, polyethylene terephthalate, polyethylene terephthalate G, poly(vinyl chloride), and mixtures thereof. In some embodiments, the container has a capacity of 1 mL, 2 mL, 3 mL, 4 mL, or 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, or 10 mL. In some embodiments, the container is a 3 mL polypropylene vial.

[0017] In some aspects of the processes provided herein, the mixing step is performed aseptically.

[0018] In some aspects of the processes provided herein, in some aspects of the methods provided herein, the filling step is performed aseptically.

[0019] In some embodiments, the process further comprises terminally sterilizing the filled container containing the suspension. In some embodiments, the container is terminally sterilized when the suspension contains about 0.05 mg / mL to about 10 mg / mL of the compound of formula (I) or a salt or amorphous or polymorphic form thereof. For example, the suspension may contain from about 0.05 mg / mL to about 5 mg / mL, from about 0.05 mg / mL to about 2.5 mg / mL, from about 0.05 mg / mL to about 1 mg / mL, from about 0.05 mg / mL to about 0.5 mg / mL, from about 0.05 mg / mL to about 0.1 mg / mL, from about 0.1 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 5 mg / mL, from about 0.1 mg / mL to about 2.5 mg / mL, from about 0.1 mg / mL to about 1 mg / mL, from about 0.1 mg / mL to about 0.5 mg / mL, from about 0.1 mg / mL to about 0.25 mg / mL, from about 0.25 mg / mL to about 10 mg / mL, from about 0.25 mg / mL to about 5 mg / mL, from about 0.25 mg / mL to about 2.5 mg / mL, from about 0.25 mg / mL to about 1 mg / mL, from about 0.25 The compound of formula (I) or a salt thereof or an amorphous or polymorphic form thereof may comprise from about 0.5 mg / mL to about 0.5 mg / mL, from about 0.5 mg / mL to about 10 mg / mL, from about 0.5 mg / mL to about 5 mg / mL, from about 0.5 mg / mL to about 2 ...2.5 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 2.5 mg / mL to about 5 mg / mL, or from about 5 mg / mL to about 10 mg / mL of the compound of formula (I) or a salt thereof or an amorphous or polymorphic form thereof.

[0020] (a) providing an aqueous solution comprising water; (b) providing a slurry comprising a compound of formula (I) or a pharma- ceutically acceptable salt or an amorphous or polymorphic form thereof; (c) mixing the aqueous solution with the slurry to form a suspension; and (d) filling the suspension into a container to prepare a single-dose reconstituted product. A compound of formula (I) prepared by a process comprising: Also provided herein are single dose reconstituted formulations comprising the compound of TIFF0007630905000003.tif53128 or a pharma- ceutically acceptable salt or amorphous or polymorphic form thereof.

[0021] The single-dose ready-to-use formulation prepared by the process provided herein includes providing an aqueous solution comprising water. In some embodiments, the aqueous solution comprises a buffer. In some embodiments, the aqueous buffer is a phosphate buffer. In some embodiments, the phosphate buffer is selected from the group consisting of dibasic sodium phosphate, monobasic sodium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, and mixtures thereof. In some embodiments, the phosphate buffer is a mixture of dibasic sodium phosphate heptahydrate and monobasic sodium phosphate monohydrate. In some embodiments, the buffer is phosphate buffered saline.

[0022] In some embodiments of the single-dose ready-to-use formulation prepared by the process provided herein, the aqueous solution comprises an excipient. In some embodiments, the excipient comprises a surfactant, a thickener, or a mixture thereof. In some embodiments, the thickener is a cellulose derivative. In some embodiments, the cellulose derivative is a water-soluble cellulose derivative. In some embodiments, the cellulose derivative is sodium carboxymethylcellulose. In some embodiments, the aqueous solution has a concentration of from about 0.01 g / kg to about 50 g / kg; from about 0.5 g / kg to about 50 g / kg; from about 1.0 g / kg to about 50 g / kg; from about 1 g / kg to about 25 g / kg; from about 1 g / kg to about 10 g / kg; from about 1 g / kg to about 7.5 g / kg; from about 1 g / kg to about 5.5 g / kg; from about 1 g / kg to about 2.5 g / kg; from about 2.5 g / kg to about 50 g / kg; from about 5 g / kg to about 50 g / kg; from about 10 g / kg to about 50 g / kg; from about 25 g / kg to about 50 g / kg; from about 0.1 g / kg to about 5 g / kg; from about 2.5 g / kg to about 7.5 g / kg; from about 5 g / kg to about 10 g / kg; or from about 10 g / kg to about 20 In some embodiments, the aqueous solution comprises about 5.5 g / kg of a cellulose derivative.

[0023] In some aspects of the single-dose, ready-to-use formulations prepared by the processes provided herein, the surfactant is a polysorbate. In some embodiments, the aqueous solution comprises from about 0.1 g / kg to about 5 g / kg; 0.1 g / kg to about 2.5 g / kg; from about 0.1 g / kg to about 1 g / kg; from about 0.1 g / kg to about 0.75 g / kg; from about 0.1 g / kg to about 0.5 g / kg; from about 0.1 g / kg to about 0.25 g / kg; from about 0.25 g / kg to about 5 g / kg; from about 0.5 g / kg to about 5 g / kg; from about 1 g / kg to about 5 g / kg; from about 0.1 g / kg to about 5 g / kg; 0.1 g / kg to about 2.5 g / kg; from about 0.1 g / kg to about 1 g / kg; from about 0.1 g / kg to about 0.75 g / kg; from about 0.1 g / kg to about 0.5 g / kg; from about 0.1 g / kg to about 0.25 g / kg; about 0.25 g / kg to about 5 g / kg; about 0.25 g / kg to about 2.5 g / kg; about 0.25 g / kg to about 0.75 g / kg; about 0.5 g / kg to about 2.5 g / kg; about 0.5 g / kg to about 1 g / kg; or about 1 g / kg to about 2 g / kg of surfactant. In some embodiments, the aqueous solution comprises about 0.5 g / kg of surfactant. In some embodiments, the aqueous solution comprises about 5.55 g / kg of sodium carboxymethylcellulose and about 0.5 g / kg of polysorbate 80.

[0024] The single-dose ready-to-use formulations prepared by the processes provided herein include providing a slurry comprising the compound of formula (I) or a pharma- ceutically acceptable salt or amorphous or polymorphic form thereof. In some embodiments of the processes provided herein, the slurry has a concentration of from about 0.001 g / kg to about 5 g / kg; from about 0.001 g / kg to about 2.5 g / kg; from about 0.001 g / kg to about 1 g / kg; from about 0.001 g / kg to about 0.75 g / kg; from about 0.001 g / kg to about 0.5 g / kg; from about 0.001 g / kg to about 0.25 g / kg; from about 0.001 g / kg to about 0.01 g / kg; from about 0.01 g / kg to about 5 g / kg; from about 0.01 g / kg to about 2.5 g / kg; from about 0.01 g / kg to about 1 g / kg; from about 0.01 g / kg to about 0.75 g / kg; from about 0.01 g / kg to about 0.5 g / kg; from about 0.01 g / kg to about 0.25 g / kg; about 0.1 g / kg to about 2.5 g / kg; about 0.1 g / kg to about 1 g / kg; about 0.1 g / kg to about 0.75 g / kg; about 0.1 g / kg to about 0.5 g / kg; about 0.1 g / kg to about 0.25 g / kg; about 0.25 g / kg to about 5 g / kg; about 0.5 g / kg to about 5 g / kg; about 1 g / kg to about 5 g / kg; about 2.5 g / kg to about 5 g / kg; about 0.25 g / kg to about 0.75 g / kg; about 0.5 g / kg to about 1 g / kg; or about 1 g / kg to about 2 g / kg of a compound of formula (I) or a salt or an amorphous or polymorphic form thereof. In some embodiments, the slurry comprises about 0.15 g / kg, about 0.35 g / kg, or about 1.15 g / kg of the compound of formula (I) or a salt thereof or an amorphous or polymorphic form. In some embodiments, the compound of formula (I) comprises a polymorphic form. In some embodiments, the polymorph is form 1 and has an X-ray powder diffraction pattern comprising peaks at °2θ values ​​of 6.8±0.2, 12.4±0.2, and 18.5±0.2. In some embodiments, the compound of formula (I) comprises a mixture of non-stoichiometric or stoichiometric hydrates of form 1 having 1% to about 20% water by weight. In some embodiments, the compound comprises 5% or less by weight of other forms.For example, less than 1% or less than 0.1% of the amorphous form.

[0025] In some embodiments of the single-dose reconstituted formulations prepared by the processes provided herein, the slurry comprises an excipient. In some embodiments, the excipient comprises a surfactant. In some embodiments, the surfactant is a polysorbate. In some embodiments, the slurry has a concentration of from about 0.01 g / kg to about 5 g / kg; from 0.01 g / kg to about 2.5 g / kg; from about 0.01 g / kg to about 1 g / kg; from about 0.01 g / kg to about 0.75 g / kg; from about 0.01 g / kg to about 0.5 g / kg; from about 0.01 g / kg to about 0.25 g / kg; from about 0.025 g / kg to about 5 g / kg; from about 0.05 g / kg to about 5 g / kg; from about 1 g / kg to about 5 g / kg; from about 0.1 g / kg to about 5 g / kg; 0.1 g / kg to about 2.5 g / kg; from about 0.1 g / kg to about 1 g / kg; from about 0.1 g / kg to about 0.75 g / kg; from about 0.1 g / kg to about 0.5 g / kg; from about 0.1 g / kg to about 0.25 g / kg; about 0.25 g / kg to about 5 g / kg; about 0.25 g / kg to about 2.5 g / kg; about 0.25 g / kg to about 0.75 g / kg; about 0.5 g / kg to about 5 g / kg; about 0.5 g / kg to about 2.5 g / kg; about 0.5 g / kg to about 1 g / kg; about 1 g / kg to about 5 g / kg; about 2.5 g / kg to about 5 g / kg; or about 1 g / kg to about 2 g / kg of surfactant. In some embodiments, the slurry comprises about 0.5 g / kg of surfactant.

[0026] In some embodiments of the single dose reconstituted formulation prepared by the processes provided herein, the slurry comprises about 0.15 g / kg of polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight, and about 0.5 g / kg of polysorbate 80. In some embodiments, the slurry comprises about 0.35 g / kg of polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight, and about 0.5 g / kg of polysorbate 80. In some embodiments, the slurry comprises about 1.15 g / kg of polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight, and about 0.5 g / kg of polysorbate 80.

[0027] In some embodiments of the single-dose ready-to-use formulation prepared by the process provided herein, the aqueous solution is a filtrate mixture.In some embodiments, the filtrate mixture comprises water.In some embodiments, the filtrate mixture comprises water and an excipient.In some embodiments, the excipient comprises a surfactant, a thickener, or a mixture thereof.

[0028] In some aspects of the single-dose, ready-to-use formulations prepared by the processes provided herein, the aqueous solution comprises a sterile diluent.

[0029] In some embodiments of the single-dose ready-to-use formulations prepared by the processes provided herein, the aqueous solution is a sterile filtered mixture or a first bulk sterilization mixture or both; the slurry is a second bulk sterilization mixture; and the process includes mixing the first bulk sterilization mixture and the second bulk sterilization mixture.

[0030] Provided herein is a single-dose ready-to-use formulation prepared by a process comprising mixing an aqueous solution with a slurry to form a suspension.In some embodiments, the aqueous solution is mixed with the slurry to form a suspension comprising about 0.005 mg / mL to about 2.5 mg / mL, about 0.001 mg / mL to about 2 mg / mL, about 0.01 mg / mL to about 2.0 mg / mL, about 0.01 mg / mL to about 1 mg / mL, about 0.01 mg / mL to about 0.5 mg / mL, about 0.01 mg / mL to about 0.2 mg / mL, or about 0.015 mg / mL to about 0.115 mg / mL of the compound of formula (I) or its salt or amorphous or polymorphic form.

[0031] Provided herein is a single-dose reconstituted formulation prepared by a process comprising filling a container with the suspension to prepare a single-dose reconstituted formulation. In some embodiments, the container contains a suspension comprising about 0.005 mg / mL to about 2.5 mg / mL, about 0.005 mg / mL to about 2 mg / mL, about 0.01 mg / mL to about 1.8 mg / mL, about 0.015 mg / mL to about 0.115, about 0.025 mg / mL to about 1.6 mg / mL, about 0.05 mg / mL to about 1.5 mg / mL, about 0.075 mg / mL to about 1.25 mg / mL, about 0.1 mg / mL to about 1 mg / mL, or about 0.25 mg / mL to about 0.75 mg / mL of the compound of formula (I) or a salt thereof or an amorphous or polymorphic form. In some embodiments, the container is selected from the group consisting of a vial, a bottle, an ampoule, and a syringe. In some embodiments, the vial is a glass vial or a plastic vial made of polyethylene, polypropylene, polyolefin, polyethylene terephthalate, polyethylene terephthalate G, poly(vinyl chloride), and mixtures thereof. In some embodiments, the container has a capacity of 1 mL, 2 mL, 3 mL, 4 mL, or 5 mL. In some embodiments, the container is a 3 mL polypropylene vial.

[0032] In some embodiments of the single-dose, ready-to-use formulations prepared by the processes provided herein, the mixing step is performed aseptically.

[0033] In some embodiments of the single-dose, ready-to-use formulations prepared by the processes provided herein, the filling step is performed aseptically.

[0034] In some embodiments of the single-dose ready-to-use formulation prepared by the process provided herein, the container containing the suspension is terminally sterilized. In some embodiments, when the suspension contains about 0.05 mg / mL to about 10 mg / mL of the compound of formula (I) or its salt or amorphous or polymorphic form, the container is terminally sterilized. For example, the suspension may contain from about 0.05 mg / mL to about 5 mg / mL, from about 0.05 mg / mL to about 2.5 mg / mL, from about 0.05 mg / mL to about 1 mg / mL, from about 0.05 mg / mL to about 0.5 mg / mL, from about 0.05 mg / mL to about 0.1 mg / mL, from about 0.1 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 5 mg / mL, from about 0.1 mg / mL to about 2.5 mg / mL, from about 0.1 mg / mL to about 1 mg / mL, from about 0.1 mg / mL to about 0.5 mg / mL, from about 0.1 mg / mL to about 0.25 mg / mL, from about 0.25 mg / mL to about 10 mg / mL, from about 0.25 mg / mL to about 5 mg / mL, from about 0.25 mg / mL to about 2.5 mg / mL, from about 0.25 mg / mL to about 1 mg / mL, from about 0.25 The compound of formula (I) or a salt thereof or an amorphous or polymorphic form thereof may comprise from about 0.5 mg / mL to about 0.5 mg / mL, from about 0.5 mg / mL to about 10 mg / mL, from about 0.5 mg / mL to about 5 mg / mL, from about 0.5 mg / mL to about 2 ...2.5 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 2.5 mg / mL to about 5 mg / mL, or from about 5 mg / mL to about 10 mg / mL of the compound of formula (I) or a salt thereof or an amorphous or polymorphic form thereof.

[0035] Also provided herein is a method for treating osteoarthritis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a single dose of a prepared formulation prepared by the process provided herein, comprising a therapeutically effective amount of a compound of formula (I), including its salts and amorphous and polymorphic forms. In some embodiments, administration of the formulation is intra-articular. In some embodiments, the formulation is administered to the subject once. In some embodiments, the formulation is administered two or more times, with each injection being spaced apart by about 3 months to about 60 months. In some embodiments, the formulation is administered once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, or once every 3, 6, 9, 12, 18, 24, 30, or 60 months.

[0036] [The present invention 1001] Formula (I) TIFF0007630905000004.tif53128 or a pharma- ceutically acceptable salt or an amorphous or polymorphic form thereof, comprising the steps of: (a) providing an aqueous solution; (b) providing a slurry comprising a compound of formula (I) or a pharma- ceutically acceptable salt or an amorphous or polymorphic form thereof; (c) mixing the aqueous solution with the slurry to form a suspension; and (d) filling the suspension into a container to prepare a single dose reconstituted formulation. The method comprising: [The present invention 1002] The method of claim 10, wherein said aqueous solution is sterilized by filtration or heat, or by a combination of filtration and heat. [The present invention 1003] The method according to any one of claims 1001 to 1002, wherein the slurry is sterilized by heat. [The present invention 1004] The method according to any one of claims 1001 to 1003, wherein mixing of said aqueous solution and said slurry to form a suspension is carried out aseptically, followed by aseptic filling into said container. [The present invention 1005] The method of any one of claims 1001 to 1004, wherein the final single-dose prepared formulation is sterile. [The present invention 1006] The method according to any one of claims 1001 to 1005, wherein the aqueous solution contains a buffer solution. [The present invention 1007] The method of any one of claims 1001 to 1006, wherein the aqueous solution comprises an excipient. [The present invention 1008] The method according to any one of claims 1006 to 1007, wherein the buffer solution is a phosphate buffer solution. [The present invention 1009] The method of claim 1008, wherein the phosphate buffer is selected from the group consisting of sodium phosphate dibasic, sodium phosphate monobasic, potassium phosphate monobasic, potassium phosphate dibasic, and mixtures thereof. [The present invention 1010] The method according to any one of claims 1008 to 1009, wherein the phosphate buffer is a mixture of dibasic sodium phosphate heptahydrate and monobasic sodium phosphate monohydrate. [The present invention 1011] The method of any of claims 1007 to 1010, wherein the excipient comprises a surfactant, a thickener, or a mixture thereof. [The present invention 1012] The method of claim 1011, wherein the thickening agent is a water-soluble cellulose derivative. [The present invention 1013] The method according to any one of claims 1011 to 1012, wherein the surfactant is a polysorbate. [The present invention 1014] The method according to any one of claims 1012 to 1013, wherein the water-soluble cellulose derivative is sodium carboxymethylcellulose. [The present invention 1015] The method of any one of claims 1011 to 1014, wherein the aqueous solution contains from about 0.01 g / kg to about 50 g / kg, from about 0.1 g / kg to about 50 g / kg, from about 1 g / kg to about 25 g / kg, from about 1 g / kg to about 10 g / kg, from about 1 g / kg to about 7.5 g / kg, from about 1 g / kg to about 5.5 g / kg, from about 1 g / kg to about 2.5 g / kg, from about 2.5 g / kg to about 50 g / kg, from about 5 g / kg to about 50 g / kg, from about 10 g / kg to about 50 g / kg, from about 25 g / kg to about 50 g / kg, from about 2.5 g / kg to about 7.5 g / kg, from about 5 g / kg to about 10 g / kg, or from about 10 g / kg to about 20 g / kg of a thickener. [The present invention 1016] 1016. The method of any one of claims 1011 to 1015, wherein the aqueous solution contains about 5.5 g / kg of a thickening agent. [The present invention 1017] The aqueous solution is from about 0.01 g / kg to about 5 g / kg, from about 0.01 g / kg to about 2.5 g / kg, from about 0.01 g / kg to about 1 g / kg, from about 0.01 g / kg to about 0.75 g / kg, from about 0.01 g / kg to about 0.5 g / kg, from about 0.01 g / kg to about 0.25 g / kg, from about 0.025 g / kg to about 5 g / kg, from about 0.05 g / kg to about 5 g / kg, from about 1 g / kg to about 5 g / kg, from about 0.1 g / kg to about 5 g / kg, 0.1 g / kg to about 2.5 g / kg, from about 0.1 g / kg to about 1 g / kg, from about 0.1 g / kg to about 0.75 g / kg, from about 0.1 g / kg to about 0.5 g / kg, from about 0.1 g / kg to about 0.25 g / kg, from about 0.25 The method of any of claims 1011 to 1016, comprising about 0.5 g / kg to about 5 g / kg, about 1 g / kg to about 5 g / kg, about 2.5 g / kg to about 5 g / kg, about 0.25 g / kg to about 0.75 g / kg, about 0.5 g / kg to about 1 g / kg, or about 1 g / kg to about 2 g / kg of the surfactant. [The present invention 1018] 1017. The method of any one of claims 1011 to 1017, wherein the aqueous solution contains about 0.5 g / kg of a surfactant. [The present invention 1019] The method of any of claims 1011 to 1018, wherein the aqueous solution comprises about 5.55 g / kg of sodium carboxymethylcellulose and about 0.5 g / kg of polysorbate 80. [The present invention 1020] The method according to any one of claims 1011 to 1019, wherein the buffer solution is phosphate buffered saline. [The present invention 1021] The slurry may be from about 0.001 g / kg to about 5 g / kg, from about 0.001 g / kg to about 2.5 g / kg, from about 0.001 g / kg to about 1 g / kg, from about 0.001 g / kg to about 0.75 g / kg, from about 0.001 g / kg to about 0.5 g / kg, from about 0.001 g / kg to about 0.25 g / kg, from about 0.001 g / kg to about 0.01 g / kg, from about 0.01 g / kg to about 5 g / kg, from about 0.01 g / kg to about 2.5 g / kg, from about 0.01 g / kg to about 1 g / kg, from about 0.01 g / kg to about 0.75 g / kg, from about 0.01 g / kg to about 0.5 g / kg, from about 0.01 g / kg to about 0.25 g / kg, from about 0.1 g / kg to about 2.5 10. The method of any of claims 1001-1020, comprising administering to a subject a dose of about 0.1 g / kg to about 1 g / kg, about 0.1 g / kg to about 0.75 g / kg, about 0.1 g / kg to about 0.5 g / kg, about 0.1 g / kg to about 0.25 g / kg, about 0.25 g / kg to about 5 g / kg, about 0.5 g / kg to about 5 g / kg, about 1 g / kg to about 5 g / kg, about 2.5 g / kg to about 5 g / kg, about 0.25 g / kg to about 0.75 g / kg, about 0.5 g / kg to about 1 g / kg, or about 1 g / kg to about 2 g / kg of a compound of formula (I) or a salt or an amorphous or polymorphic form thereof. [The present invention 1022] The method of any one of claims 1001 to 1021, wherein the slurry comprises about 0.15 g / kg, about 0.35 g / kg, about 0.75 g / kg, or about 1.15 g / kg of the compound of formula (I) or a salt or an amorphous or polymorphic form thereof. [The present invention 1023] The method of any one of claims 1001 to 1022, wherein the compound of formula (I) includes polymorphic forms. [The present invention 1024] The process of any of claims 1001 to 1023, wherein the polymorph used in the preparation is Form 1 and has an X-ray powder diffraction pattern comprising peaks at °2θ values ​​of 6.8±0.2, 12.4±0.2, and 18.5±0.2. [The present invention 1025] The process of any of claims 1001 to 1024, wherein the compound used in the preparation of formula (I) comprises a mixture of Form 1 and a non-stoichiometric or stoichiometric hydrate of Form 1 having from 1% to about 20% water by weight. [The present invention 1026] The process of any one of claims 1001 to 1025, wherein the compound used in the preparation of formula (I) contains about 5% by weight or less of other forms of the compound of formula (I). [The present invention 1027] The process of any one of claims 1001 to 1026, wherein the compound used in the preparation of formula (I) contains about 1% by weight or less of other forms of the compound of formula (I). [The present invention 1028] The process of any of claims 1001 to 1027, wherein the compound used in the preparation of formula (I) contains less than about 0.1% by weight of other forms of the compound of formula (I). [The present invention 1029] The method of any one of claims 1001 to 1028, wherein the slurry comprises an excipient. [The present invention 1030] The method of claim 1029, wherein the excipient comprises a surfactant. [The present invention 1031] The method of claim 1030, wherein the surfactant is a polysorbate. [The present invention 1032] The slurry is about 0.01 g / kg to about 5 g / kg, 0.01 g / kg to about 2.5 g / kg, about 0.01 g / kg to about 1 g / kg, about 0.01 g / kg to about 0.75 g / kg, about 0.01 g / kg to about 0.5 g / kg, about 0.01 g / kg to about 0.25 g / kg, about 0.025 g / kg to about 5 g / kg, about 0.05 g / kg to about 5 g / kg, about 1 g / kg to about 5 g / kg, about 0.1 g / kg to about 5 g / kg, 0.1 g / kg to about 2.5 g / kg, about 0.1 g / kg to about 1 g / kg, about 0.1 g / kg to about 0.75 g / kg, about 0.1 g / kg to about 0.5 g / kg, about 0.1 g / kg to about 0.25 g / kg, about 0.25 2.5 g / kg to about 5 g / kg, about 0.25 g / kg to about 2.5 g / kg, about 0.25 g / kg to about 0.75 g / kg, about 0.5 g / kg to about 5 g / kg, about 0.5 g / kg to about 2.5 g / kg, about 0.5 g / kg to about 1 g / kg, about 1 g / kg to about 5 g / kg, about 2.5 g / kg to about 5 g / kg, or about 1 g / kg to about 2 g / kg of the surfactant. [The present invention 1033] The method of any one of claims 1030 to 1032, wherein the slurry comprises about 0.5 g / kg of a surfactant. [The present invention 1034] The method of any of claims 1030 to 1033, wherein the slurry comprises about 0.15 g / kg of polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight, and about 0.5 g / kg of polysorbate 80. [The present invention 1035] 15. The method of any of claims 1030 to 1034, wherein the slurry comprises about 0.35 g / kg of polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight, and about 0.5 g / kg of polysorbate 80. [The present invention 1036] 1036. The method of any of claims 1030 to 1035, wherein the slurry comprises about 0.75 g / kg of polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight, and about 0.5 g / kg of Polysorbate 80. [The present invention 1037] 1036. The method of any of claims 1030 to 1036, wherein the slurry comprises about 1.15 g / kg of polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight, and about 0.5 g / kg of polysorbate 80. [The present invention 1038] The method according to any one of claims 1001 to 1037, wherein the aqueous solution is a filtered mixture. [The present invention 1039] The method of any one of claims 1001 to 1038, wherein the aqueous solution comprises a sterile diluent. [The present invention 1040] Any of the methods of claims 1001 to 1039, comprising the steps of: said aqueous solution being a first sterilization mixture; said slurry being a second sterilization mixture; and mixing said first sterilization mixture with said second sterilization mixture. [The present invention 1041] The method of any of claims 1001 to 1040, wherein said aqueous solution and said slurry are mixed to form a suspension containing from about 0.005 mg / mL to about 2.5 mg / mL, from about 0.01 mg / mL to about 2.0 mg / mL, from about 0.01 mg / mL to about 1 mg / mL, from about 0.01 mg / mL to about 0.5 mg / mL, from about 0.01 mg / mL to about 0.2 mg / mL, or from about 0.015 mg / mL to about 0.115 mg / mL of a compound of formula (I) or a salt thereof or an amorphous or polymorphic form thereof. [The present invention 1042] The method of any one of claims 1001 to 1041, wherein the container contains a suspension comprising from about 0.005 mg / mL to about 2.5 mg / mL, from about 0.005 mg / mL to about 2 mg / mL, from about 0.001 mg / mL to about 2 mg / mL, from about 0.01 mg / mL to about 1.8 mg / mL, from about 0.015 mg / mL to about 0.115, from about 0.025 mg / mL to about 1.6 mg / mL, from about 0.05 mg / mL to about 1.5 mg / mL, from about 0.075 mg / mL to about 1.25 mg / mL, from about 0.1 mg / mL to about 1 mg / mL, or from about 0.25 mg / mL to about 0.75 mg / mL of a compound of formula (I) or a salt thereof or an amorphous or polymorphic form thereof. [The present invention 1043] The method of any one of claims 1001 to 1042, wherein the container is selected from the group consisting of a vial, a bottle, an ampoule, and a syringe. [The present invention 1044] The method of claim 1043, wherein the vial is a glass vial or a plastic vial made from polyethylene, polypropylene, polyolefin, polyethylene terephthalate, polyethylene terephthalate G, poly(vinyl chloride), and mixtures thereof. [The present invention 1045] The method of any one of claims 1001 to 1044, wherein the container has a volume of 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, or 10 mL. [The present invention 1046] The method of any one of claims 1001 to 1045, wherein the container is a 3 mL polypropylene vial. [The present invention 1047] The method of any one of claims 1001 to 1046, wherein the mixing step is carried out aseptically. [The present invention 1048] Any of the methods of claims 1001 to 1047, wherein the filling step is carried out aseptically. [The present invention 1049] The method of any one of claims 1001 to 1048, further comprising a step of terminally sterilizing the filled container. [The present invention 1050] (a) providing an aqueous solution comprising water; (b) providing a slurry comprising a compound of formula (I) or a pharma- ceutically acceptable salt or an amorphous or polymorphic form thereof; (c) mixing the aqueous solution with the slurry to form a suspension; and (d) filling the suspension into a container to prepare a single dose reconstituted formulation. A compound represented by formula (I) prepared by a process comprising: TIFF0007630905000005.tif53128 or a pharma- ceutically acceptable salt or an amorphous or polymorphic form thereof. [The present invention 1051] The formulation of claim 10, wherein the aqueous solution comprises a buffer. [The present invention 1052] The formulation of any one of claims 1050 to 1051, wherein the aqueous solution comprises an excipient. [The present invention 1053] The formulation according to any one of claims 1051 to 1052, wherein the buffer is a phosphate buffer. [The present invention 1054] The formulation of any of claims 1051 to 1053, wherein the phosphate buffer is selected from the group consisting of dibasic sodium phosphate, monobasic sodium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, and mixtures thereof. [The present invention 1055] The formulation according to any one of claims 1051 to 1054, wherein the phosphate buffer is a mixture of dibasic sodium phosphate heptahydrate and monobasic sodium phosphate monohydrate. [The present invention 1056] The formulation of any of claims 1052 to 1055, wherein the excipient comprises a surfactant, a thickener, or a mixture thereof. [The present invention 1057] 1056. The formulation of claim 10, wherein the thickening agent is a water-soluble cellulose derivative. [The present invention 1058] The formulation of any one of claims 1056 to 1057, wherein the surfactant is a polysorbate. [The present invention 1059] The formulation according to any one of claims 1057 to 1058, wherein the cellulose derivative is sodium carboxymethylcellulose. [The present invention 1060] The aqueous solution comprises about 0.0.01 g / kg to about 50 g / kg, about 1.0 g / kg to about 50 g / kg, about 1 g / kg to about 25 g / kg, about 1 g / kg to about 10 g / kg, about 1 g / kg to about 7.5 g / kg, about 1 g / kg to about 5.5 g / kg, about 1 g / kg to about 2.5 g / kg, about 2.5 g / kg to about 50 g / kg, about 5 g / kg to about 50 g / kg, about 10 g / kg to about 50 g / kg, about 25 g / kg to about 50 g / kg, about 2.5 g / kg to about 7.5 g / kg, about 5 g / kg to about 10 g / kg, or about 10 g / kg to about 20 g / kg of a thickening agent. [The present invention 1061] 1057-1060. Any of the formulations of claims 1057-1060, wherein the aqueous solution comprises about 5.5 g / kg of a thickening agent. [The present invention 1062] The aqueous solution is from about 0.01 g / kg to about 5 g / kg, from about 0.01 g / kg to about 2.5 g / kg, from about 0.01 g / kg to about 1 g / kg, from about 0.01 g / kg to about 0.75 g / kg, from about 0.01 g / kg to about 0.5 g / kg, from about 0.01 g / kg to about 0.25 g / kg, from about 0.025 g / kg to about 5 g / kg, from about 0.05 g / kg to about 5 g / kg, from about 1 g / kg to about 5 g / kg, from about 0.1 g / kg to about 5 g / kg, 0.1 g / kg to about 2.5 g / kg, from about 0.1 g / kg to about 1 g / kg, from about 0.1 g / kg to about 0.75 g / kg, from about 0.1 g / kg to about 0.5 g / kg, from about 0.1 g / kg to about 0.25 g / kg, from about 0.25 Any of the formulations of the present inventions 1057 to 1061, comprising from about 0.5 g / kg to about 5 g / kg, from about 1 g / kg to about 5 g / kg, from about 2.5 g / kg to about 5 g / kg, from about 0.25 g / kg to about 0.75 g / kg, from about 0.5 g / kg to about 1 g / kg, or from about 1 g / kg to about 2 g / kg of a surfactant. [The present invention 1063] 3. The formulation of any of claims 1057 to 1062, wherein the aqueous solution comprises about 0.5 g / kg of a surfactant. [The present invention 1064] The formulation of any of claims 1057 to 1063, wherein the aqueous solution comprises about 5.55 g / kg of sodium carboxymethylcellulose and about 0.5 g / kg of polysorbate 80. [The present invention 1065] The formulation of any of claims 1053 to 1064, wherein the buffer solution is phosphate buffered saline. [The present invention 1066] The slurry may be from about 0.001 g / kg to about 5 g / kg, from about 0.001 g / kg to about 2.5 g / kg, from about 0.001 g / kg to about 1 g / kg, from about 0.001 g / kg to about 0.75 g / kg, from about 0.001 g / kg to about 0.5 g / kg, from about 0.001 g / kg to about 0.25 g / kg, from about 0.001 g / kg to about 0.01 g / kg, from about 0.01 g / kg to about 5 g / kg, from about 0.01 g / kg to about 2.5 g / kg, from about 0.01 g / kg to about 1 g / kg, from about 0.01 g / kg to about 0.75 g / kg, from about 0.01 g / kg to about 0.5 g / kg, from about 0.01 g / kg to about 0.25 g / kg, from about 0.1 g / kg to about 2.5 g / kg, about 0.1 g / kg to about 1 g / kg, about 0.1 g / kg to about 0.75 g / kg, about 0.1 g / kg to about 0.5 g / kg, about 0.1 g / kg to about 0.25 g / kg, about 0.25 g / kg to about 5 g / kg, about 0.5 g / kg to about 5 g / kg, about 1 g / kg to about 5 g / kg, about 2.5 g / kg to about 5 g / kg, about 0.25 g / kg to about 0.75 g / kg, about 0.5 g / kg to about 1 g / kg, or about 1 g / kg to about 2 g / kg of a compound of formula (I) or a salt or an amorphous or polymorphic form thereof. [The present invention 1067] The formulation of any of claims 1050 to 1066, wherein the slurry comprises about 0.15 g / kg, about 0.35 g / kg, or about 1.15 g / kg of the compound of formula (I) or a salt or an amorphous or polymorphic form thereof. [The present invention 1068] A formulation according to any one of claims 1050 to 1067, wherein the compound of formula (I) comprises a polymorphic form. [The present invention 1069] A formulation according to any one of claims 1050 to 1068, wherein the polymorph used in the manufacture is Form 1 and has an X-ray powder diffraction pattern including peaks at °2θ values ​​of 6.8±0.2, 12.4±0.2, and 18.5±0.2. [The present invention 1070] A formulation according to any of claims 1050 to 1069, wherein the compound of formula (I) comprises a mixture of Form 1 and a non-stoichiometric or stoichiometric hydrate of Form 1 having from 1% to about 20% by weight of water. [The present invention 1071] A formulation according to any one of claims 1050 to 1070, wherein the compound of formula (I) contains no more than about 5% by weight of another form of the compound of formula (I). [The present invention 1072] A formulation according to any one of claims 1050 to 1071, wherein the compound of formula (I) contains no more than about 1% by weight of other forms of the compound of formula (I). [The present invention 1073] A formulation of any of 1050 to 1072, wherein the compound of formula (I) contains less than about 0.1% by weight of other forms of the compound of formula (I). [The present invention 1074] The formulation of any one of claims 1050 to 1073, wherein the slurry comprises an excipient. [The present invention 1075] The formulation of claim 1074, wherein the excipient comprises a surfactant. [The present invention 1076] A formulation of the present invention 1075, wherein the surfactant is a polysorbate. [The present invention 1077] The slurry is about 0.01 g / kg to about 5 g / kg, 0.01 g / kg to about 2.5 g / kg, about 0.01 g / kg to about 1 g / kg, about 0.01 g / kg to about 0.75 g / kg, about 0.01 g / kg to about 0.5 g / kg, about 0.01 g / kg to about 0.25 g / kg, about 0.025 g / kg to about 5 g / kg, about 0.05 g / kg to about 5 g / kg, about 1 g / kg to about 5 g / kg, about 0.1 g / kg to about 5 g / kg, 0.1 g / kg to about 2.5 g / kg, about 0.1 g / kg to about 1 g / kg, about 0.1 g / kg to about 0.75 g / kg, about 0.1 g / kg to about 0.5 g / kg, about 0.1 g / kg to about 0.25 g / kg, about 0.25 Any of the formulations of the present inventions 1075 to 1076, comprising from about 0.25 g / kg to about 5 g / kg, from about 0.25 g / kg to about 2.5 g / kg, from about 0.25 g / kg to about 0.75 g / kg, from about 0.5 g / kg to about 5 g / kg, from about 0.5 g / kg to about 2.5 g / kg, from about 0.5 g / kg to about 1 g / kg, from about 1 g / kg to about 5 g / kg, from about 2.5 g / kg to about 5 g / kg, or from about 1 g / kg to about 2 g / kg of the surfactant. [The present invention 1078] 1078. The formulation of any of claims 1075 to 1077, wherein the slurry comprises about 0.5 g / kg of a surfactant. [The present invention 1079] Any of the formulations of 1075-1078, wherein the slurry comprises about 0.15 g / kg of polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight, and about 0.5 g / kg of polysorbate 80. [The present invention 1080] Any of the formulations of 1075-1079, wherein the slurry comprises about 0.35 g / kg of predominantly polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight, and about 0.5 g / kg of polysorbate 80. [The present invention 1081] Any of the formulations of 1075-1080, wherein the slurry comprises about 1.15 g / kg of predominantly polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight, and about 0.5 g / kg of polysorbate 80. [The present invention 1082] The formulation of any one of claims 1050 to 1081, wherein the aqueous solution is a filtered mixture. [The present invention 1083] 3. The formulation of any one of claims 1050 to 1082, wherein the aqueous solution comprises a sterile diluent. [The present invention 1084] The formulation of any of claims 1050 to 1083, wherein the aqueous solution is a first sterilization mixture; the slurry is a second sterilization mixture; and the formulation comprises a step of mixing the first sterilization mixture with the second sterilization mixture. [The present invention 1085] Any of the formulations of claims 1050 to 1084, wherein said aqueous solution and said slurry are mixed to form a suspension containing from about 0.005 mg / mL to about 2.5 mg / mL, from about 0.01 mg / mL to about 2.0 mg / mL, from about 0.01 mg / mL to about 1 mg / mL, from about 0.01 mg / mL to about 0.5 mg / mL, from about 0.01 mg / mL to about 0.2 mg / mL, or from about 0.015 mg / mL to about 0.115 mg / mL of the compound of formula (I) or a salt thereof or an amorphous or polymorphic form thereof. [The present invention 1086] The formulation of any one of 1050 to 1085 of the present invention, wherein the container contains a suspension comprising about 0.005 mg / mL to about 2.5 mg / mL, about 0.005 mg / mL to about 2 mg / mL, about 0.001 mg / mL to about 2 mg / mL, about 0.01 mg / mL to about 1.8 mg / mL, about 0.015 mg / mL to about 0.115, about 0.025 mg / mL to about 1.6 mg / mL, about 0.05 mg / mL to about 1.5 mg / mL, about 0.075 mg / mL to about 1.25 mg / mL, about 0.1 mg / mL to about 1 mg / mL, or about 0.25 mg / mL to about 0.75 mg / mL of a compound of formula (I) or a salt thereof, or an amorphous or polymorphic form thereof. [The present invention 1087] The formulation of any one of claims 1050 to 1086, wherein the container is selected from the group consisting of a vial, a bottle, an ampoule, and a syringe. [The present invention 1088] The formulation of the present invention 1087, wherein the vial is a glass vial or a plastic vial made of polyethylene, polypropylene, polyolefin, polyethylene terephthalate, polyethylene terephthalate G, poly(vinyl chloride), and mixtures thereof. [The present invention 1089] The formulation of any one of claims 1050 to 1088, wherein the container has a volume of 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, or 10 mL. [The present invention 1090] The formulation of any one of claims 1050 to 1089, wherein the container is a 3 mL polypropylene vial. [The present invention 1091] The formulation of any one of claims 1050 to 1090, wherein the mixing step is carried out aseptically. [The present invention 1092] The formulation of any one of claims 1050 to 1091, wherein the filling step is carried out aseptically. [The present invention 1093] The formulation of any one of claims 1050 to 1092, wherein the filled container is terminally sterilized. [The present invention 1094] A method for treating osteoarthritis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a single dose of any of the prepared formulations of the present invention 1050-1094. [The present invention 1095] The method of claim 1094, wherein the administration is intra-articular. [The present invention 1096] 6. The method of any one of claims 1094 to 1095, wherein the formulation is administered once. [The present invention 1097] 6. The method of any of claims 1094 to 1095, wherein the formulation is administered two or more times, each injection being spaced from about 3 months to about 60 months apart. [The present invention 1098] 8. The method of any of claims 1094 to 1095 and 1097, wherein the formulation is administered once a month, once every three months, once every six months, or once every sixty months. Other features and advantages of the processes, formulations, and uses provided herein will become apparent from the following detailed description and drawings, and from the claims. [Brief description of the drawings]

[0037] [Figure 1A]1A-1D are scans of polymorphic Form 1 of the compound of formula (I): Figure 1A is an X-ray powder diffraction scan of completely dried Form 1. [Figure 1B] 1A-1D are scans of polymorphic Form 1 of the compound of formula (I), and FIG 1B is a differential scanning calorimetry scan of Form 1. [Figure 1C] 1A-1D are scans of polymorphic Form 1 of the compound of formula (I), and FIG 1C is a thermogravimetric analysis scan of Form 1. [Figure 1D] 1A-1D are scans of polymorphic Form 1 of the compound of formula (I), and FIG. 1D is a dynamic vapor sorption scan of Form 1. [Figure 2A] Figures 2A-2H are scans of polymorphic Forms 2, 2*, and 2** of the compound of formula (I). Figure 2A is an X-ray powder diffraction scan of completely dried Form 2. [Figure 2B] Figures 2A-2H are scans of polymorphic Forms 2, 2*, and 2** of the compound of formula (I), and Figure 2B is a differential scanning calorimetry scan of Form 2. [Figure 2C] Figures 2A-2H are scans of polymorphic Forms 2, 2*, and 2** of the compound of formula (I), and Figure 2C is a thermogravimetric scan of Form 2. [Figure 2D] Figures 2A-2H are scans of polymorphic Forms 2, 2*, and 2** of the compound of formula (I), and Figure 2D is an X-ray powder diffraction scan of the completely dried Form 2*. [Figure 2E] Figures 2A-2H are scans of polymorphic Forms 2, 2*, and 2** of the compound of formula (I), and Figure 2E is a differential scanning calorimetry scan of Form 2*. [Figure 2F] Figures 2A-2H are scans of polymorphic Forms 2, 2*, and 2** of the compound of formula (I), and Figure 2F is a thermogravimetric analysis scan of Form 2*. [Figure 2G] Figures 2A-2H are scans of polymorphic Forms 2, 2*, and 2** of the compound of formula (I), and Figure 2G is an X-ray powder diffraction scan of Form 2**. [Figure 2H]Figures 2A-2H are scans of polymorphic Forms 2, 2*, and 2** of the compound of formula (I), and Figure 2H is a differential scanning calorimetry scan of Form 2**. [Figure 3A] 3A-3C are scans of polymorphic Form 3 of the compound of formula (I): Figure 3A is an X-ray powder diffraction scan of completely dried Form 3. [Figure 3B] 3A-3C are scans of polymorphic Form 3 of the compound of formula (I), and FIG 3B is a differential scanning calorimetry scan of Form 3. [Figure 3C] 3A-3C are scans of polymorphic Form 3 of the compound of Formula (I), and FIG 3C is a thermogravimetric analysis scan of Form 3. [Figure 4A] Figures 4A-4I are scans of polymorphic Forms 4, 4*, and 4** of the compound of formula (I). Figure 4A is an X-ray powder diffraction scan of completely dried Form 4. [Figure 4B] Figures 4A-4I are scans of polymorphic Forms 4, 4*, and 4** of the compound of formula (I), and Figure 4B is a differential scanning calorimetry scan of Form 4. [Figure 4C] Figures 4A-4I are scans of polymorphic Forms 4, 4*, and 4** of the compound of formula (I), and Figure 4C is a thermogravimetric scan of Form 4. [Figure 4D] Figures 4A-4I are scans of polymorphic Forms 4, 4*, and 4** of the compound of formula (I), and Figure 4D is an X-ray powder diffraction scan of the completely dried Form 4*. [Figure 4E] Figures 4A-4I are scans of polymorphic Forms 4, 4*, and 4** of the compound of formula (I), and Figure 4E is a differential scanning calorimetry scan of Form 4*. [Figure 4F] Figures 4A-4I are scans of polymorphic Forms 4, 4*, and 4** of the compound of formula (I), and Figure 4F is a thermogravimetric scan of Form 4*. [Figure 4G] Figures 4A-4I are scans of polymorphic Forms 4, 4*, and 4** of the compound of formula (I), and Figure 4G is an X-ray powder diffraction scan of Form 4**. [Figure 4H]Figures 4A-4I are scans of polymorphic Forms 4, 4*, and 4** of the compound of formula (I), and Figure 4H is a differential scanning calorimetry scan of Form 4**. [Figure 4I] Figures 4A-4I are scans of polymorphic Forms 4, 4*, and 4** of the compound of formula (I). Figure 4I is a thermogravimetric scan of Form 4**. [Figure 5A] Figures 5A-5D are scans of polymorphic Forms 5 and 5* of the compound of formula (I). Figure 5A is an X-ray powder diffraction scan of completely dried Form 5. [Figure 5B] Figures 5A-5D are scans of polymorphic Forms 5 and 5* of the compound of formula (I), and Figure 5B is a differential scanning calorimetry scan of Form 5. [Figure 5C] Figures 5A-5D are scans of polymorphic Forms 5 and 5* of the compound of formula (I), and Figure 5C is a thermogravimetric scan of Form 5. [Figure 5D] Figures 5A-5D are scans of polymorphic Forms 5 and 5* of the compound of formula (I), and Figure 5D is an X-ray powder diffraction scan of Form 5*. [Figure 6A] Figures 6A and 6B are scans of polymorphic Form 6 of the compound of formula (I). Figure 6A is an X-ray powder diffraction scan of Form 6. [Figure 6B] Figures 6A and 6B are scans of polymorphic Form 6 of the compound of formula (I). Figure 6B is a differential scanning calorimetry scan of Form 6. [Figure 7A] Figures 7A-7C are scans of polymorphic Form 7 of the compound of formula (I): Figure 7A is an X-ray powder diffraction scan of completely dried Form 7. [Figure 7B] Figures 7A-7C are scans of polymorphic Form 7 of the compound of formula (I), and Figure 7B is a differential scanning calorimetry scan of Form 7. [Figure 7C] Figures 7A-7C are scans of polymorphic Form 7 of the compound of Formula (I), and Figure 7C is a thermogravimetric analysis scan of Form 7. [Figure 8A] Figures 8A-8C are scans of polymorphic Form 8 of the compound of formula (I): Figure 8A is an X-ray powder diffraction scan of completely dried Form 8. [Figure 8B] Figures 8A-8C are scans of polymorphic Form 8 of the compound of formula (I), and Figure 8B is a differential scanning calorimetry scan of Form 8. [Figure 8C] Figures 8A-8C are scans of polymorphic Form 8 of the compound of Formula (I), and Figure 8C is a thermogravimetric analysis scan of Form 8. [Figure 9A] Figures 9A-9D are scans of polymorphic Form 9 of the compound of formula (I): Figure 9A is an X-ray powder diffraction scan of completely dried Form 9. [Figure 9B] Figures 9A-9D are scans of polymorphic Form 9 of the compound of formula (I), and Figure 9B is a differential scanning calorimetry scan of Form 9. [Figure 9C] 9A-9D are scans of polymorphic Form 9 of the compound of Formula (I), and FIG 9C is a thermogravimetric analysis scan of Form 9. [Figure 9D] 9A-9D are scans of polymorphic Form 9 of the compound of Formula (I). FIG. 9D is a dynamic vapor sorption scan of Form 9. [Figure 10A] 10A-10E are scans of polymorphic Forms 10 and 10* of the compound of formula (I). FIG 10A is an X-ray powder diffraction scan of completely dried Form 10. [Figure 10B] Figures 10A-10E are scans of polymorphic Forms 10 and 10* of the compound of formula (I), and Figure 10B is a differential scanning calorimetry scan of Form 10. [Figure 10C] Figures 10A-10E are scans of polymorphic Forms 10 and 10* of the compound of formula (I), and Figure 10C is a thermogravimetric scan of Form 10. [Figure 10D] Figures 10A-10E are scans of polymorphic Forms 10 and 10* of the compound of formula (I), and Figure 10D is an X-ray powder diffraction scan of Form 10*. [Figure 10E] Figures 10A-10E are scans of polymorphic Forms 10 and 10* of the compound of formula (I), and Figure 10E is a differential scanning calorimetry scan of Form 10*. [Figure 11A]Figures 11A-11F are scans of polymorphic forms 11 and 11* of the compound of formula (I). Figure 11A is an X-ray powder diffraction scan of completely dried form 11. [Figure 11B] Figures 11A-11F are scans of polymorphic Forms 11 and 11* of the compound of formula (I), and Figure 11B is a differential scanning calorimetry scan of Form 11. [Figure 11C] Figures 11A-11F are scans of polymorphic Forms 11 and 11* of the compound of formula (I), and Figure 11C is a thermogravimetric analysis scan of Form 11. [Figure 11D] Figures 11A-11F are scans of polymorphic forms 11 and 11* of the compound of formula (I), and Figure 11D is an X-ray powder diffraction scan of the completely dried form 11*. [Figure 11E] Figures 11A-11F are scans of polymorphic Forms 11 and 11* of the compound of formula (I), and Figure 11E is a differential scanning calorimetry scan of Form 11*. [Figure 11F] Figures 11A-11F are scans of polymorphic Forms 11 and 11* of the compound of formula (I), and Figure 11F is a thermogravimetric analysis scan of Form 11*. [Figure 12A] 12A-12C are scans of Form 12, an example of a non-stoichiometric hydrate of polymorphic Form 1 of the compound of formula (I). [Figure 12B] 12A-12C are scans of Form 12, an example of a non-stoichiometric hydrate of polymorphic Form 1 of the compound of formula (I), and FIG. 12B is a differential scanning calorimetry scan of Form 12. [Figure 12C] 12A-12C are scans of Form 12, an example of a non-stoichiometric hydrate of polymorphic Form 1 of the compound of formula (I), and FIG 12C is a thermogravimetric analysis scan of Form 12. [Figure 13A] 13A-13D are scans of Form 13, an example of a non-stoichiometric hydrate of polymorphic Form 1 of the compound of formula (I). [Figure 13B]13A-13D are scans of Form 13, an example of a non-stoichiometric hydrate of polymorphic Form 1 of the compound of formula (I). [Figure 13C] 13A-13D are scans of Form 13, an example of a non-stoichiometric hydrate of polymorphic Form 1 of the compound of formula (I). FIG. 13C is a thermogravimetric analysis scan of Form 13. [Figure 13D] 13A-13D are scans of Form 13, an example of a non-stoichiometric hydrate of polymorphic Form 1 of the compound of Formula (I). [Figure 14] FIG. 14 is a flow chart illustrating an exemplary process described herein. [Figure 15] 15A-15D are scans of polymorphic Form 1 of the compound of formula (I) in the presence of increasing relative humidity (RH), an example of a non-stoichiometric or stoichiometric hydrate of Form 1. FIG. 15A is an X-ray powder diffraction scan of Form 1 exposed to RH 10% as anhydrous Form 1. FIG. 15B is an X-ray powder diffraction scan of Form 1 exposed to RH 20% as a partial hydrate of Form 1. FIG. 15C is an X-ray powder diffraction scan of Form 1 exposed to RH 30% as a hydrate of Form 1 (about 10-12% water uptake). FIG. 15D is an X-ray powder diffraction scan of Form 1 exposed to RH 90% as a fully hydrated form of Form 1 (about 17-20% water uptake). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] Detailed Description 1. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.Methods and materials are described herein for use in this disclosure; other suitable methods and materials known in the art can also be used.Materials, methods, and examples are illustrative only and are not intended to be limiting.All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety.In case of discrepancy, the present specification, including definitions, shall prevail.

[0039] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, cosolvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic formulations is contemplated. Supplementary active ingredients can also be incorporated into the formulation. In addition, various excipients as are commonly used in the art can be included. These and other such compounds are described in the literature, for example, in Merck Index, Merck & Company, Rahway, NJ. Discussions of the inclusion of various ingredients in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.

[0040] As used herein, "single dose" refers to a sterile formulation packaged in a container for parenteral administration (injection or infusion). A single dose formulation is designed for use with one patient as a single injection / infusion. Examples of containers for use with single dose formulations include vials, ampoules, bottles, and syringes.

[0041] As used herein, "prepared" refers to a formulation that does not require constitution or dilution with a specified amount of diluent, such as water for injection or other suitable diluent, prior to use by a specified route, e.g., a formulation in a vial at a desired concentration that requires only drawing up into a syringe.

[0042] The term "polymorphs" as used herein refers to crystals of the same molecule that have different physical properties as a result of molecular order in the crystal lattice. Polymorphs of a single compound have one or more chemical, physical, mechanical, electrical, thermodynamic, and / or biological properties that differ from each other. The differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in the manufacture of compositions and formulations), dissolution rate (a key factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, moisture sorption, compactibility, and particle morphology. Differences in stability can result from changes in chemical reactivity (e.g., differences in oxidation, which cause a dosage form composed of one polymorph to discolor more quickly than one composed of another polymorph), or mechanical changes (e.g., crystal changes upon storage, in which a kinetically favored polymorph is converted to a thermodynamically more stable polymorph), or both (e.g., one polymorph is more hygroscopic than another polymorph). As a result of differences in solubility / dissolution, some transitions affect efficacy and / or toxicity. Furthermore, the physical properties of crystals may be important in processing. For example, one polymorph may be more prone to forming solvates or may be difficult to filter and wash to remove impurities (i.e., particle shape and particle size distribution may differ from one polymorph to another). "Polymorph" does not include amorphous forms of a compound. As used herein, "amorphous" refers to a non-crystalline form of a compound, which may be a solid form of a compound or a solubilized form of a compound. For example, "amorphous" refers to a compound that does not have a regularly repeating arrangement of molecules or external surfaces.

[0043] As used herein, the term "anhydrous" refers to a crystalline form of the compound of formula (I) having 1% or less water by weight, for example, 0.5% or less, 0.25% or less, or 0.1% or less water by weight.

[0044] The term "solvate" as used herein means a crystalline form of a compound of formula (I) in which the crystal lattice contains one or more solvents of crystallization, for example a polymorphic form of the compound.

[0045] The term "non-stoichiometric hydrate" refers to a crystalline form of the compound of formula I that contains water, but the variation in water content does not cause a significant change in the crystal structure. In some embodiments, non-stoichiometric hydrate can refer to a crystalline form of the compound of formula I that has a pathway or network through which water molecules can diffuse throughout the crystal structure. During drying of non-stoichiometric hydrate, a significant proportion of water can be removed without significantly disturbing the crystal network, and the crystal can then be rehydrated to obtain the original non-stoichiometric hydrate crystal form. Unlike stoichiometric hydrate, the dehydration and rehydration of non-stoichiometric hydrate does not involve a phase transition, and therefore all hydration states of non-stoichiometric hydrate represent the same crystal form. In some embodiments, non-stoichiometric hydrates can have up to about 20% water by weight, e.g., about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or more than 1% water by weight. In some embodiments, the non-stoichiometric hydrate can have from 1 wt% to about 20 wt% water, e.g., from 1 wt% to about 5 wt%, from 1 wt% to about 10 wt%, from 1 wt% to about 15 wt%, from about 2 wt% to about 5 wt%, from about 2 wt% to about 10 wt%, from about 2 wt% to about 15 wt%, from about 2 wt% to about 20 wt%, from about 5 wt% to about 10 wt%, from about 5 wt% to about 15 wt%, from about 5 wt% to about 20 wt%, from about 10 wt% to about 15 wt%, from about 10 wt% to about 20 wt%, or from about 15 wt% to about 20 wt% water.

[0046] In some embodiments, the weight percent water in a crystalline form, such as a non-stoichiometric or stoichiometric hydrate, is determined by Karl Fischer titration. In some embodiments, the crystalline form is dried prior to Karl Fischer titration.

[0047] "Purity" when used in reference to a composition comprising a polymorph of the compound of formula (I) means the proportion of one particular polymorphic form to another polymorphic form or amorphous form of the compound of formula (I) in the referenced composition. For example, a composition comprising polymorphic form 1 having a purity of 90% contains 90 parts by weight of form 1 and 10 parts by weight of other polymorphic forms and / or amorphous forms of the compound of formula (I).

[0048] As used herein, a compound or composition is "substantially free" of one or more other components when the compound or composition does not contain a significant amount of such other components. Such components may include starting materials, residual solvents, or any other impurities that may result from the preparation and / or isolation of the compounds and compositions provided herein. In some embodiments, the polymorphic forms provided herein are substantially free of other polymorphic forms. In some embodiments, a particular polymorph of a compound of formula (I) is "substantially free" of other forms when the particular polymorph of the compound of formula (I) constitutes at least about 95% by weight of the compound of formula (I) that exists. In some embodiments, a particular polymorph of a compound of formula (I) is "substantially free" of other forms when the particular polymorph of the compound of formula (I) constitutes at least about 97%, about 98%, about 99%, or about 99.5% by weight of the compound of formula (I) that exists. In certain embodiments, a polymorph is "substantially free" of water when the amount of water constitutes about 2% or less by weight, about 1% or less by weight, or about 0.5% or less by weight of the particular polymorph of the compound of formula (I).

[0049] As used herein, a compound is "substantially present" as a given polymorph when at least about 50% by weight of the compound is in the form of that polymorph. In some embodiments, at least about 60% by weight of the compound is in the form of that polymorph. In some embodiments, at least about 70% by weight of the compound is in the form of that polymorph. In some embodiments, at least about 80% by weight of the compound is in the form of that polymorph. In some embodiments, at least about 90% by weight of the compound is in the form of that polymorph. In some embodiments, at least about 95% by weight of the compound is in the form of that polymorph. In some embodiments, at least about 96% by weight of the compound is in the form of that polymorph. In some embodiments, at least about 97% by weight of the compound is in the form of that polymorph. In some embodiments, at least about 98% by weight of the compound is in the form of that polymorph. In some embodiments, at least about 99% by weight of the compound is in the form of that polymorph. In some embodiments, at least about 99.5% by weight of the compound is in the form of that polymorph.

[0050] "Room temperature" or "RT" refers to a typical laboratory ambient temperature, which is typically around 25°C.

[0051] The term "administration" or "administering" refers to a method of providing a dosage of a compound or pharmaceutical formulation to a vertebrate or invertebrate, including a mammal, bird, fish, or amphibian. The preferred method of administration can vary depending on various factors, such as the components of the pharmaceutical formulation, the site of the disease, and the severity of the disease.

[0052] As used herein, "subject" refers to a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate or bird, such as a chicken, and any other vertebrate or invertebrate. In some embodiments, the subject is a human.

[0053] As used herein, "therapeutically effective amount" is the amount of the compound of formula (I) or its salt or formulations provided herein that contain amorphous or polymorphic form, sufficient to achieve the desired effect, and may vary depending on the nature and severity of the disease state and the potency of the compound. The therapeutic effect is, to some extent, the alleviation of one or more symptoms of the disease, and may include curing the disease. "Cure" means that the symptoms of active disease are eliminated. However, even after a cure is obtained, certain long-term or permanent effects of the disease may exist (such as, for example, extensive tissue damage, etc.).

[0054] As used herein, "treat", "treatment" or "treating" refers to administering a compound or pharmaceutical formulation provided herein for therapeutic purposes. The term "therapeutic treatment" refers to administering treatment to a patient already suffering from a disease, thus causing a therapeutically beneficial effect, such as improving existing symptoms, preventing further symptoms, improving the metabolic causes of symptoms, delaying or preventing further progression of the disorder, and / or reducing the severity of symptoms that would or are expected to develop.

[0055] 2. Process for preparing single dose reconstituted formulations Formula (I), including its salts and amorphous and polymorphic forms Provided herein is a process for preparing a single dose reconstituted formulation comprising a compound of TIFF0007630905000006.tif53128, the process comprising: (a) providing an aqueous solution comprising water; (b) providing a slurry comprising a compound of formula (I), including salts thereof, and amorphous and polymorphic forms; (c) mixing the aqueous solution with the slurry to form a suspension; and (d) aseptically filling the suspension into containers to prepare unit dose formulations. Includes.

[0056] In the process provided herein, the process includes providing an aqueous solution comprising water. Suitable types of water include, but are not limited to, deionized water, distilled water, reverse osmosis filtered water, reagent grade water, water for injection (WFI), USP / EP grade water suitable for use in pharmaceuticals, and aqueous buffer solutions. The water is substantially free of contaminants, such as parasites, pathogens, chemical contaminants, and particulate contamination. In some embodiments, the aqueous solution comprises a buffer. In some embodiments, the aqueous solution comprises an excipient. In some embodiments, the aqueous solution comprises a buffer and an excipient. In some embodiments, the excipient comprises a surfactant. In some embodiments, the excipient comprises a thickener. In some embodiments, the excipient comprises a surfactant, a thickener, or a mixture thereof. For example, the aqueous solution can include a surfactant and a thickener in an aqueous buffer. In some embodiments, the thickener is a cellulose derivative. In some embodiments, the aqueous solution comprises about 5.55 g / kg sodium carboxymethylcellulose and about 0.5 g / kg polysorbate 80 in phosphate buffered saline.

[0057] In some aspects of the processes provided herein, the aqueous solution includes a thickening agent, which can be, for example, a cellulose or cellulose derivative or a synthetic polymer. Examples of thickeners include microcrystalline cellulose (Avicel: Asahi Kasei Corp., etc.), microcrystalline cellulose carmellose sodium (Avicel RC: Asahi Kasei Corp., etc.), methylcellulose (Metolose SM: Shin-Etsu Chemical Co., Ltd., etc.), ethylcellulose (Ethocel: Dow Chemical Co., etc.), hydroxypropylcellulose (Nisso HPC: Nippon Soda Co., Ltd., etc.), low-substituted hydroxypropylcellulose (L-HPC: Shin-Etsu Chemical Co., Ltd., etc.), hydroxypropyl methylcellulose 2208 (Metolose 90SH: Shin-Etsu Chemical Co., Ltd., etc.), hydroxypropyl methylcellulose 2906 (Metolose 65SH: Shin-Etsu Chemical Co., Ltd., etc.), hydroxypropyl methylcellulose 2910 (Metolose 60SH: Shin-Etsu Chemical Co., Ltd., etc.), and hydroxypropyl cellulose phthalate 200731 (HPMCP: Shin-Etsu Chemical Co., Ltd., etc.), hydroxypropyl cellulose phthalate 220824 (HPMCP: Shin-Etsu Chemical Co., Ltd., etc.), hydroxypropyl methylcellulose acetate succinate (Shin-Etsu AQOAT: Shin-Etsu Chemical Co., Ltd., etc.), carmellose (NS-300: Gotoku Chemical Co., Ltd., etc.), carmellose calcium (ECG-505: Gotoku Chemical Co., Ltd., etc.), carmellose sodium (Cellogen: Daiichi Kogyo Seiyaku Co., Ltd.Examples of the thickening agent include, but are not limited to, croscarmellose sodium (Ac-Di-Sol: Asahi Kasei Corp., etc.), carboxymethylethylcellulose (CMEC: Freund Corp., etc.), cellulose acetate phthalate (CAP: Wako Pure Chemical Industries, Ltd., etc.), hydroxyethylcellulose (NATROSOL: Aqualon Corp., etc.), polyvinyl alcohol, polyvinylpyrrolidone, or mixtures thereof. In some embodiments, the thickening agent is a cellulose derivative. In some embodiments, the cellulose derivative is water-soluble cellulose or a water-soluble cellulose derivative. In some embodiments, the cellulose derivative is carboxymethylcellulose, or a pharma- ceutically acceptable salt thereof. For example, the aqueous solution comprises sodium carboxymethylcellulose.

[0058] The thickening agent may be present in the aqueous solution in an amount of from about 0.01 g / kg to about 50 g / kg of aqueous solution. For example, about 0.01 g / kg to about 25 g / kg; about 0.01 g / kg to about 5 g / kg; about 0.1 g / kg to about 50 g / kg; about 0.1 g / kg to about 25 g / kg; about 0.1 g / kg to about 5 g / kg; about 0.5 g / kg to about 50 g / kg; about 0.5 g / kg to about 0.25 g / kg; about 0.5 g / kg to about 10 g / kg; about 0.5 g / kg to about 7.5 g / kg; about 0.5 g / kg to about 5.5 g / kg; about 0.5 g / kg to about 2.5 g / kg; about 1 g / kg to about 50 g / kg; about 1 g / kg to about 25 g / kg; about 1 g / kg to about 10 g / kg; about 1 g / kg to about 7.5 g / kg; about 1 g / kg to about 5.5 g / kg; about 1 g / kg to about 2.5 g / kg; about 2.5 g / kg to about 50 g / kg; about 5 g / kg to about 50 g / kg; about 10 g / kg to about 50 g / kg; about 25 g / kg to about 50 g / kg; about 0.1 g / kg to about 5 g / kg; about 2.5 g / kg to about 7.5 g / kg; about 5 g / kg to about 10 g / kg; and about 10 g / kg to about 20 g / kg aqueous solutions. In some embodiments, the thickener can be present in the aqueous solution at about 5 g / kg aqueous solution. In some embodiments, the thickener can be present in the aqueous solution at about 5.55 g / kg aqueous solution. For example, the aqueous solution contains about 5.55 g / kg sodium carboxymethylcellulose. In some embodiments, the cellulose derivative is present in the aqueous solution in an amount of about 0.05% to about 5% by weight of the aqueous solution.For example, about 0.05% by weight to about 2.5% by weight of the aqueous solution; about 0.05% by weight to about 1% by weight; about 0.05% by weight to about 0.75% by weight; about 0.05% by weight to about 0.55% by weight; about 0.05% by weight to about 0.25% by weight; about 0.1% by weight to about 5% by weight; about 0.1% by weight to about 2.5% by weight; about 0.1% by weight to about 1% by weight; about 0.1% by weight to about 0.75% by weight; about 0.1% by weight to about 0.55% by weight; about 0.1% by weight to about 0.25% by weight; about 0.25% by weight to about 5% by weight; about 0.5% by weight to about 5% by weight; about 1% by weight to about 5% by weight; about 2.5% by weight to about 5% by weight; about 0.25% by weight to about 0.75% by weight; about 0.5% to about 1% by weight; and about 1% to about 2% by weight. In some embodiments, the thickening agent can be present in the aqueous solution at about 0.55% by weight of the aqueous solution. For example, the aqueous solution contains about 0.55% by weight of sodium carboxymethylcellulose.

[0059] In some embodiments of the process provided herein, the aqueous solution comprises a surfactant.Examples of surfactants include polysorbates such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polysorbate 85; polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 60 and polyoxyl 35 castor oil; sorbitan fatty acid esters; sucrose fatty acid esters; polyoxyethylene polyoxypropylene glycol; polyoxyethylene fatty acid ethers; polyoxyl stearate; phosphatidylcholine; fatty acids, fatty alcohols, or combinations thereof, and phosphatidylglycerols, including but not limited to phosphatidylglycerols containing carbon chain lengths of 4 to 20 carbons; and 1,2-dimyristoyl-sn-glycero-3-(phospho-s-(1-glycerol)), 1,2-dioleoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-(phospho-rac-(1-glycerol)), 1,2-distearoyl-sn-glycero-3-(phospho-rac-(1-glycerol)), 1,2-distearoyl-sn-glycero-3-phosphocholine, deoxycholic acid, dipalmitoylphosphatidylglycerol (dl), distearoylphosphatidylcholine (dl), sodium docusate, egg phospholipids, glyceryl palmitostearate, glyceryl trioleate, hydrogenated soy lecithin, hydrolyzed soy protein (enzymatic);2000mw), hydroxyethylpiperazine ethanesulfonic acid, lecithin, myripyrium chloride, n-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phiv, oleic acid, palmitic acid, PEG vegetable oil, PEG-20 sorbitan stearate, PEG-40 castor oil, phospholipids, poloxamer 188, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 3350, polyethylene glycol 400, polyethylene Other surfactants include, but are not limited to, glycol 4000, polyethylene glycol 600, polyoxyethylene fatty acid esters, sodium cholesteryl sulfate, sodium deoxycholate, sodium n-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycol, sodium oleate, sorbitan monolaurate, sorbitan monopaltimate, stearic acid, tricaprylin, or mixtures thereof. In some embodiments, the surfactant is a polysorbate. For example, the aqueous solution includes polysorbate 80;

[0060] The surfactant can be present in the aqueous solution in an amount of about 0.01 g / kg to about 5 g / kg of aqueous solution. In some embodiments, the concentration of the surfactant depends on the critical micelle concentration of the individual surfactant. In some embodiments, the amount of surfactant is sufficient to exceed the critical micelle concentration of the surfactant, sufficient to cover the surface area of ​​the particles, or both. For example, the aqueous solution may have a concentration of about 0.01 g / kg to about 2.5 g / kg; about 0.01 g / kg to about 1 g / kg; about 0.01 g / kg to about 0.75 g / kg; about 0.01 g / kg to about 0.5 g / kg; about 0.01 g / kg to about 0.25 g / kg; about 0.025 g / kg to about 5 g / kg; about 0.05 g / kg to about 5 g / kg; about 1 g / kg to about 5 g / kg; about 0.1 g / kg to about 5 g / kg; about 0.1 g / kg to about 2.5 g / kg; about 0.1 g / kg to about 1 g / kg; about 0.1 g / kg to about 0.75 g / kg; about 0.1 g / kg to about 0.5 g / kg; about 0.1 g / kg to about 0.25 g / kg; about 0.25 g / kg to about 5 g / kg; about 0.5 g / kg to about 5 g / kg; about 1 g / kg to about 5 g / kg; about 0.25 g / kg to about 5 g / kg; about 0.25 g / kg to about 2.5 g / kg; about 0.25 g / kg to about 0.75 g / kg; about 0.5 g / kg to about 2.5 g / kg; about 0.5 g / kg to about 1 g / kg; and about 1 g / kg to about 2 g / kg. In some embodiments, the surfactant can be present in the aqueous solution at about 0.5 g / kg aqueous solution. For example, the aqueous solution contains about 0.5 g / kg polysorbate 80. In some embodiments, the surfactant can be present in the aqueous solution in an amount of about 0.001% to about 0.5% by weight of the aqueous solution.For example, about 0.001% by weight to about 0.25% by weight of the aqueous solution; about 0.001% by weight to about 0.1% by weight; about 0.001% by weight to about 0.075% by weight; about 0.001% by weight to about 0.05% by weight; about 0.001% by weight to about 0.025% by weight; about 0.0025% by weight to about 0.5% by weight; about 0.005% by weight to about 0.5% by weight; about 0.1% by weight to about 0.5% by weight; about 0.01% by weight to about 0.5% by weight; about 0.01% by weight to about 0.25% by weight; about 0.01% by weight to about 0.1% by weight; about 0.01% by weight to about 0.075% by weight; about 0.01% by weight to about 0.05% by weight; about 0.01% by weight to about 0.025% by weight; About 0.025% to about 0.5% by weight; about 0.05% to about 0.5% by weight; about 0.1% to about 0.5% by weight; about 0.025% to about 0.5% by weight; about 0.025% to about 2.5% by weight; about 0.025% to about 0.075% by weight; about 0.05% to about 2.5% by weight; about 0.05% to about 0.1% by weight; and about 0.1% to about 0.2% by weight. In some embodiments, the surfactant can be present in the aqueous solution at about 0.05% by weight of the aqueous solution. For example, the aqueous solution contains about 0.05% by weight of polysorbate 80.

[0061] In the process provided herein, the process includes providing a slurry comprising the compound of formula (I), including its salts and amorphous and polymorphic forms. In some embodiments, the compound of formula (I) is polymorphic form 1. In some embodiments, the compound of formula (I) is a non-stoichiometric or stoichiometric hydrate of form 1 having 1% to about 20% water by weight. In some embodiments, the slurry includes a surfactant. In some embodiments, the slurry includes water. For example, the slurry can include the compound of formula (I), including its salts and amorphous and polymorphic forms, and a surfactant in water.

[0062] The compound of formula (I), including salts and amorphous and polymorphic forms thereof, may be present in the slurry in an amount of from about 0.001 g / kg to about 5 g / kg of the slurry. For example, about 0.001 g / kg to about 5 g / kg; about 0.001 g / kg to about 2.5 g / kg; about 0.001 g / kg to about 1 g / kg; about 0.001 g / kg to about 0.75 g / kg; about 0.001 g / kg to about 0.5 g / kg; about 0.001 g / kg to about 0.25 g / kg; about 0.001 g / kg to about 0.01 g / kg; about 0.01 g / kg to about 2.5 g / kg; about 0.01 g / kg to about 1 g / kg; about 0.01 g / kg to about 0.75 g / kg; about 0.01 g / kg to about 0.5 g / kg; about 0.01 g / kg to about 0.25 g / kg; about 0.1 g / kg to about 2.5 g / kg; about 0.1 g / kg to about 1 g / kg; about 0.1 g / kg to about 0.75 g / kg; about 0.1 g / kg to about 0.5 g / kg; about 0.1 g / kg to about 0.25 g / kg; about 0.25 g / kg to about 5 g / kg; about 0.5 g / kg to about 5 g / kg; about 1 g / kg to about 5 g / kg; about 2.5 g / kg to about 5 g / kg; about 0.25 g / kg to about 0.75 g / kg; about 0.5 g / kg to about 1 g / kg; and about 1 g / kg to about 2 g / kg slurry. In some embodiments, the compound of formula (I), including salts and amorphous and polymorphic forms thereof, can be present in the slurry at about 0.15 g / kg slurry. In some embodiments, the compound of formula (I), including its salts and amorphous and polymorphic forms, can be present in the slurry at about 0.35 g / kg of slurry. In some embodiments, the compound of formula (I), including its salts and amorphous and polymorphic forms, can be present in the slurry at about 1.15 g / kg of slurry. In some embodiments, the slurry contains about 0.15 g / kg of polymorphic form 1 or a non-stoichiometric or stoichiometric hydrate of form 1 having 1% to about 20% water by weight. In some embodiments, the slurry contains about 0.35 g / kg of polymorphic form 1 or a non-stoichiometric or stoichiometric hydrate of form 1 having 1% to about 20% water by weight.In some embodiments, the slurry comprises about 1.15 g / kg of polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight.

[0063] In some embodiments, the compound of formula (I), including salts and amorphous and polymorphic forms thereof, may be present in the slurry in an amount of about 0.0001% to about 0.5% by weight of the slurry. For example, about 0.0001% by weight to about 0.5% by weight of the slurry; about 0.0001% by weight to about 0.25% by weight; about 0.0001% by weight to about 0.1% by weight; about 0.0001% by weight to about 0.075% by weight; about 0.0001% by weight to about 0.05% by weight; about 0.0001% by weight to about 0.025% by weight; about 0.0001% by weight to about 0.001% by weight; about 0.001% by weight to about 0.5% by weight; about 0.001% by weight to about 0.25% by weight; about 0.001% by weight to about 0.1% by weight; about 0.001% by weight to about 0.075% by weight; about 0.001% by weight to about 0.05% by weight; about 0.001% by weight to about 0.025% by weight; about 0.01% to about 0.25% by weight; about 0.01% to about 0.1% by weight; about 0.01% to about 0.075% by weight; about 0.01% to about 0.05% by weight; about 0.01% to about 0.025% by weight; about 0.025% to about 0.5% by weight; about 0.05% to about 0.5% by weight; about 0.1% to about 0.5% by weight; about 0.25% to about 0.5% by weight; about 0.025% to about 0.075% by weight; about 0.05% to about 0.1% by weight; and about 0.1% to about 0.2% by weight. In some embodiments, the compound of formula (I), including salts and amorphous and polymorphic forms thereof, can be present in the slurry at about 0.015% by weight of the slurry. For example, the slurry contains about 0.015% by weight of polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight of water. In some embodiments, the compound of formula (I), including its salts and amorphous and polymorphic forms, can be present in the slurry at about 0.035% by weight of the slurry. For example, the slurry contains about 0.035% by weight of polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight of water. In some embodiments, the compound of formula (I), including its salts and amorphous and polymorphic forms, can be present in the slurry at about 0.115% by weight of the slurry.For example, the slurry may contain about 0.115% by weight of polymorphic Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight.

[0064] In some embodiments, the slurry comprises about 0.15 g / kg of a compound of formula (I), e.g., Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight, in water, and about 0.5 g / kg of polysorbate 80. In some embodiments, the compound has 5% or less by weight of other forms, e.g., 1% or less or less than 0.1% of any additional forms, including amorphous forms. In some embodiments, the slurry comprises about 0.35 g / kg of a compound of formula (I), e.g., Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight, in water, and about 0.5 g / kg of polysorbate 80. In some embodiments, the slurry comprises about 1.15 g / kg of a compound of formula (I), e.g., Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight, in water, and about 0.5 g / kg of polysorbate 80.

[0065] In some embodiments, the slurry comprises water. Suitable types of water include, but are not limited to, deionized water, distilled water, reverse osmosis filtered water, reagent grade water, water for injection (WFI), USP grade water suitable for use in pharmaceuticals, and aqueous buffer solutions. The water is substantially free of contaminants, such as parasites, pathogens, chemical contaminants, and particulate contamination. In some embodiments, the slurry comprises water for injection.

[0066] In the processes provided herein, the process includes mixing an aqueous solution and a slurry to form a suspension. In some embodiments, the aqueous solution is added to the slurry. In some embodiments, the slurry is added to the aqueous solution. In some embodiments, the aqueous solution and the slurry are added to the vessel substantially simultaneously.

[0067] In some embodiments, the aqueous solution is a filtration mixture. In some embodiments, the filtration mixture comprises water. In some embodiments, the filtration mixture comprises water and an excipient. In some embodiments, the excipient comprises a surfactant, a thickener, or a mixture thereof. In some embodiments, the filtration mixture is prepared by filtering the aqueous solution through a 0.2 μm filter. In some embodiments, the filter comprises a membrane comprising a polymer such as cellulose acetate, cellulose nitrate, nylon, polyethersulfone or polytetrafluoroethylene, regenerated cellulose, or glass. In some embodiments, the filter membrane is a polymer membrane. In some embodiments, the filter membrane is a polyethersulfone (PES) membrane. In some embodiments, a sterile diluent is mixed with the filtration mixture.

[0068] In some embodiments, the aqueous solution, the slurry, or both are sterilized. In some embodiments, the sterilization is by heat. In some embodiments, the sterilization is by bulk steam sterilization. In some embodiments, the sterilization is by dry heat sterilization. In some embodiments, the sterilization is by irradiation. In some embodiments, the sterilization is by filtration. In some embodiments, the sterilization is by bulk steam sterilization, dry heat sterilization, irradiation, or a combination thereof. In some embodiments, the aqueous solution is sterilized by filtration or heat, or by a combination of filtration and heat. In some embodiments, the aqueous solution is sterilized before mixing with the slurry to form a first sterile mixture. In some embodiments, the filtered mixture is sterilized before mixing with the slurry. In some embodiments, the filtered mixture is aseptically mixed with a sterile diluent and sterilized before mixing with the slurry. In some embodiments, the slurry is sterilized before mixing with the aqueous solution to form a second sterile mixture. In some embodiments, the slurry is sterilized by heat. In some embodiments, the aqueous solution is sterilized to form a first sterile mixture and the slurry is sterilized to form a second sterile mixture before mixing.

[0069] In some embodiments, the aqueous solution and the slurry are mixed aseptically to form a suspension. The mixing can be performed using any sterile diluent or injectable solution. For example, any commercially available sterile diluent or injectable solution can be used. In some embodiments, the injectable sterile solution includes, but is not limited to, saline with or without potassium chloride, such as 0.9% saline solution, dextrose, such as 5% dextrose solution, phosphate buffer, lactated Ringer's solution, and combinations thereof. In some embodiments, the injectable sterile solution is a commercially available solution containing hyaluronic acid or a hyaluronic acid derivative. In some embodiments, the sterile diluent is added aseptically in an amount sufficient to provide a suspension containing 0.015 mg / mL of the compound of formula (I), including its salts and amorphous and polymorphic forms. In some embodiments, the sterile diluent is added aseptically in an amount sufficient to provide a suspension containing 0.035 mg / mL of the compound of formula (I), including its salts and amorphous and polymorphic forms. In some embodiments, a sterile diluent is aseptically added in an amount sufficient to result in a suspension containing 0.115 mg / mL of a compound of formula (I), including salts and amorphous and polymorphic forms thereof.

[0070] In the process provided herein, the aqueous solution and the slurry are mixed to form a suspension. For example, in some embodiments, the compound of formula (I), including its salts and amorphous and polymorphic forms, is not completely dissolved in the aqueous phase of the suspension. In the process provided herein, the suspension comprises about 0.005 mg / mL to about 2.5 mg / mL, about 0.01 mg / mL to about 2.0 mg / mL, about 0.01 mg / mL to about 1 mg / mL, about 0.01 mg / mL to about 0.5 mg / mL, about 0.01 mg / mL to about 0.2 mg / mL, or about 0.015 mg / mL to about 0.115 mg / mL of the compound of formula (I) or its salts or amorphous or polymorphic forms. In some embodiments, the suspension comprises 0.015 mg / mL of the compound of formula (I), including its salts and amorphous and polymorphic forms. In some embodiments, the suspension comprises 0.035 mg / mL of the compound of formula (I), including its salts and amorphous and polymorphic forms. In some embodiments, the suspension comprises 0.115 mg / mL of the compound of formula (I), including its salts and amorphous and polymorphic forms.

[0071] In some embodiments of the process provided herein, the aqueous solution, slurry, suspension, or combination thereof is prepared in a tank. For example, the tank can be a tank used for manufacturing. In some embodiments, the tank is a stainless steel tank. In some embodiments, the tank is equipped with a steam jacket. In some embodiments, the tank is equipped with one or more mixers, such as standard mixers and / or homogenizers, used to mix the ingredients added to the tank. In some embodiments, the tank is equipped with a heating device and / or a cooling device. In some embodiments, the tank includes an addition port, a recirculation device, a transfer device, a mixer, a heating device and / or a cooling device, and combinations thereof. In some embodiments, the tank has a capacity of about 5 L to about 5000 L.In some embodiments, the tank is from about 5 L to about 3000 L; from about 5 L to about 2000 L; from about 5 L to about 1000 L; from about 5 L to about 500 L; from about 5 L to about 300 L; from about 5 L to about 150 L; from about 5 L to about 100 L; from about 5 L to about 50 L; from about 5 L to about 30 L; from about 5 L to about 20 L; from about 20 L to about 5000 L; from about 20 L to about 3000 L; from about 20 L to about 2000 L; from about 20 L to about 1000 L; from about 20 L to about 500 L; from about 20 L to about 300 L; from about 20 L to about 150 L; from about 20 L to about 100 L; from about 20 L to about 50 L; from about 20 L to about 30 L; from about 30 L~5000 L; 30 L~3000 L; 30 L~2000 L; 30 L~1000 L; 30 L~500 L; 30 L~300 L; 30 L~150 L; 30 L~100 L; 30 L~50 L; L~5000 L; 50 L~3000 L; 50 L~2000 L; 50 L~1000 L; 50 L~500 L; 50 L~300 L; 50 L~150 L; 50 L~100 L; 100 L~5000 L; L~approx. 3000 L; approx. 100 L~2000 L; 100 L~1000 L; 100 L~500 L; 100 L~300 L; 100 L~150 L; 150 L~5000 L; 150 L~3000 L; 150 L~2000 L; 150 L~1000 Approx. 150 L~Approx. 500 L; Approx. 150 L~Approx. 300 L; Approx. 300 L~Approx. 5000 L; Approx. 300 L~Approx. 3000 L; Approx. L~approx. 3000 L; approx. 500 L to about 2000 L; about 500 L to about 1000 L; about 1000 L to about 5000 L; about 1000 L to about 3000 L; about 1000 L to about 2000 L; about 2000 L to about 5000 L; about 2000 L to about 3000 L; or about 3000 L to about 5000 L.In some embodiments, the tank has a capacity of about 5000 L, about 3000 L, about 2000 L, about 1000 L, about 500 L, about 300 L, about 150 L, about 100 L, about 50 L, about 30 L, about 20 L, or about 5 L. Tanks of other sizes are known and can be used with the provided processes.

[0072] In some embodiments, the process is carried out using a scaled-up manufacturing process, which can be used for volumes greater than or equal to about 1 L or greater than or equal to about 1 gallon, e.g., greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 800, 900, 1000, 1500, 2000, 2500, 3000 or more liters.

[0073] In the process provided herein, the process includes aseptically filling the suspension into a container to prepare a single-dose reconstituted formulation. Examples of containers include, but are not limited to, vials, bottles, ampoules, and syringes. In some embodiments, the suspension is aseptically filled into a single-use vial (i.e., the unused portion of each vial is discarded and not stored for later administration). In some embodiments, the vial is a plastic vial. For example, the vial can be made of polyethylene, polypropylene, polyolefin, polyethylene terephthalate, polyethylene terephthalate G, poly(vinyl chloride), and mixtures thereof. In some embodiments, the vial is a polypropylene vial. In some embodiments, the vial is a glass vial. The container can be any size that can accommodate the desired amount of the formulation. For example, the container can be a 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, or 10 mL container. In some embodiments, the container is a 3 mL vial. In some embodiments, the container is a 5 mL vial. In some embodiments, the container is a 3 mL polypropylene vial. For example, a polypropylene vial made using blow-fill-seal technology. In some embodiments, the vial is designed to easily withdraw the formulation with a syringe. In some embodiments, the vial has a Luer slip design. In some embodiments, the vial has a Luer lock design.

[0074] The resulting single-dose prepared formulation produced by the processes provided herein is filled into a container and contains about 0.005 mg / mL to about 2.5 mg / mL, e.g., about 0.005 mg / mL to about 2 mg / mL, about 0.01 mg / mL to about 1.8 mg / mL, about 0.015 mg / mL to about 0.115, about 0.025 mg / mL to about 1.6 mg / mL, about 0.05 mg / mL to about 1.5 mg / mL, about 0.075 mg / mL to about 1.25 mg / mL, about 0.1 mg / mL to about 1 mg / mL, or about 0.25 mg / mL to about 0.75 mg / mL of the compound of formula (I), including its amorphous and polymorphic forms. In some embodiments, the container contains a formulation comprising about 0.015 mg / mL of the compound of formula (I), including its amorphous and polymorphic forms. In some embodiments, the container contains a formulation comprising about 0.035 mg / mL of the compound of formula (I), including its amorphous and polymorphic forms. In some embodiments, the container contains a formulation comprising about 0.115 mg / mL of the compound of formula (I), including its amorphous and polymorphic forms. In some embodiments, the container contains a concentration of about 0.1 mg / mL to 4 mg / mL. In some embodiments, the concentration is 2 mg / mL.

[0075] In some embodiments, the process further comprises terminally sterilizing the container containing the suspension. For example, sterilization can be carried out at 121.1° C. (250° F.) or lower, e.g., about 70-100° C., to achieve a Fo of NLT 2. In some embodiments, the NLT is greater than 10 or greater than 30. In some embodiments, the container is terminally sterilized when the suspension contains about 0.05 mg / mL to about 10 mg / mL of the compound of formula (I) or a salt or amorphous or polymorphic form thereof. For example, the suspension may be from about 0.05 mg / mL to about 5 mg / mL, from about 0.05 mg / mL to about 2.5 mg / mL, from about 0.05 mg / mL to about 1 mg / mL, from about 0.05 mg / mL to about 0.5 mg / mL, from about 0.05 mg / mL to about 0.1 mg / mL, from about 0.1 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 5 mg / mL, from about 0.1 mg / mL to about 2.5 mg / mL, from about 0.1 mg / mL to about 1 mg / mL, from about 0.1 mg / mL to about 0.5 mg / mL, from about 0.1 mg / mL to about 0.25 mg / mL, from about 0.25 mg / mL to about 10 mg / mL, from about 0.25 mg / mL to about 5 mg / mL, from about 0.25 mg / mL to about 2.5 mg / mL, from about 0.25 mg / mL to about 1 mg / mL, from about 0.25 The compound of formula (I) or a salt thereof or an amorphous or polymorphic form thereof may comprise from about 0.5 mg / mL to about 0.5 mg / mL, from about 0.5 mg / mL to about 10 mg / mL, from about 0.5 mg / mL to about 5 mg / mL, from about 0.5 mg / mL to about 2 ...2.5 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 2.5 mg / mL to about 5 mg / mL, or from about 5 mg / mL to about 10 mg / mL of the compound of formula (I) or a salt thereof or an amorphous or polymorphic form thereof.

[0076] In some embodiments, the process further comprises labeling the container. In some embodiments, the process further comprises packaging the container, for example, in a box, carton, or preformed blister. In some embodiments, the process further comprises labeling the box, carton, or preformed blister.

[0077] 3. Single-dose reconstituted formulations Provided herein are single-dose, ready-to-use pharmaceutical formulations comprising the compound of formula (I), including its pharma- ceutically acceptable salts and amorphous and polymorphic forms, prepared by the processes described herein. In some embodiments, the formulations are prepared as single-dose formulations. Provided herein are pharmaceutical formulations prepared from polymorphic forms of the compound of formula (I). In some embodiments, the polymorphic form is form 1. In some embodiments, the polymorphic form is a mixture of form 1 and form 9. In some embodiments, the polymorph is a non-stoichiometric or stoichiometric hydrate of form 1 having 1% to about 20% water by weight.

[0078] In some embodiments, the single dose reconstituted pharmaceutical formulation comprises a polymorphic form of the compound of formula (I). In some embodiments, the polymorphic form is Form 1. In some embodiments, the pharmaceutical formulation comprises a polymorphic form of the compound of formula (I) that is a mixture of forms. In some embodiments, the mixture of forms is a mixture of Forms 1 and 9. In some embodiments, the pharmaceutical formulation comprises a polymorphic form of the compound of formula (I) that is a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight.

[0079] In some embodiments, the single-dose prepared pharmaceutical formulation prepared by the process provided herein contains polymorphic Form 1 with a purity of at least about 90% (excluding water or solvent). In some embodiments, the purity is at least about 95%. In some embodiments, the purity is at least about 98%. For example, the purity is at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the formulation containing Form 1 is substantially free of other forms of the compound of Formula (I), such as Form 9. In some embodiments, the formulation contains less than 15% by weight of other forms of the compound of formula (I), such as less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, 0.01%, or 0.001% by weight of other forms of the compound of formula (I). In some embodiments, the other forms of the compound of formula (I) are other anhydrous forms of the compound of formula (I). In some embodiments, the formulation contains less than about 15% by weight of one or more other compounds of formula (I). For example, the formulation contains less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, 0.01%, or 0.001% by weight of one or more other forms of the compound of formula (I). For example, the formulation can contain less than about 15% by weight of Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, non-stoichiometric or stoichiometric Form 1 hydrate, or a combination of two or more thereof.

[0080] In some embodiments, the single-dose prepared pharmaceutical formulations prepared by the processes provided herein contain a non-stoichiometric or stoichiometric hydrate of polymorphic Form 1 having 1% to about 20% water by weight with a purity of at least about 90%. In some embodiments, the purity is at least about 95%. In some embodiments, the purity is at least about 98%. For example, the purity is at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the formulations containing a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight are substantially free of other forms of the compound of Formula (I), such as Form 9. In some embodiments, the formulation contains less than 15% by weight of other forms of the compound of formula (I), such as less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, 0.01%, or 0.001% by weight of other forms of the compound of formula (I). In some embodiments, the other forms of the compound of formula (I) are other anhydrous forms of the compound of formula (I). In some embodiments, the formulation contains less than about 15% by weight of one or more other compounds of formula (I). For example, the formulation contains less than 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, 0.01%, or 0.001% by weight of one or more other forms of the compound of formula (I). For example, the formulation can contain less than about 15% by weight of Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, or a combination of two or more thereof.

[0081] In some embodiments, a single dose of the reconstituted formulation prepared by the processes provided herein contains from about 0.001 mg to about 5.0 mg of the compound of formula (I), including its amorphous and polymorphic forms, per injection. For example, the formulation in some embodiments may have a concentration of from about 0.001 mg to about 4 mg, from about 0.001 mg to about 3 mg, from about 0.001 mg to about 2 mg, from about 0.001 mg to about 1 mg, from about 0.001 mg to about 0.5 mg, 0.001 mg to about 0.4 mg, from about 0.001 mg to about 0.3 mg, from about 0.001 mg to about 0.25 mg, from about 0.001 mg to about 0.2 mg, from about 0.001 mg to about 0.15 mg, from about 0.001 mg to about 0.1 mg, from about 0.001 mg to about 0.075 mg, from about 0.001 mg to about 0.055 mg, from about 0.001 mg to about 0.05 mg, from about 0.001 mg to about 0.035 mg, from about 0.001 mg to about 0.025 mg, from about 0.001 mg ~ 0.01 mg, 0.001 mg ~ 0.005 mg, 0.005 mg ~ 5.0 mg, 0.0075 mg ~ 5.0 mg, 0.01 mg ~ 5.0 mg, 0.01 mg ~ 4.0 mg, 0.01 mg ~ 3.0 mg, 0.01 mg ~ 2.0 mg, 0.01 mg ~ 1.0 mg, about 0.01 mg to about 0.7 mg, about 0.01 mg to about 0.5 mg, about 0.01 mg to about 0.3 mg, about 0.01 mg to about 0.23 mg, about 0.01 mg to about 0.1 mg, about 0.01 mg to about 0.07 mg, about 0.01 mg to about 0.05 mg, about 0.01 mg to about 0.03 mg, about 0.03 mg ~ approx. 4.0 mg, approx. 0.03 mg ~ 3.0 mg, 0.03 mg ~ 2.0 mg, 0.03 mg ~ 1.0 mg, 0.03 mg ~ 0.7 mg, 0.03 mg ~ 0.5 mg, 0.03 mg ~ 0.3 mg, 0.03 mg ~ 0.23 mg, 0.03 mg ~ 0.1 mg, 0.03 mg ~ 0.07 mg, about 0.03 mg to about 0.05 mg, about 0.07 mg to about 4.0 mg, about 0.07 mg to about 3.0 mg, about 0.07 mg to about 2.0 mg, about 0.07 mg to about 1.0 mg, about 0.07 mg to about 0.7 mg, about 0.07 mg to about 0.5 mg, about 0.07 mg to about 0.3 mg, about 0.07 mg to about 0.23 mg, about 0.07 mg to about 0.1 mg, about 0.025 mg to about 5.0 mg, about 0.045 mg to about 5.0 mg, about 0.05 mg to about 5.0 mg, about 0.075 mg to about 5.0 mg, about 0.1 mg to about 5.0 mg, about 0.25 mg to about 5.0 mg, about 0.01 mg to about 3.0 mg, about 0.025 mg to about 2.0 mg, about 0.01 mg to about 0.1 mg, and about 0.15 mg to about 0.25 mg of the compound of formula (I), including amorphous and polymorphic forms thereof. In some embodiments, the formulation comprises about 0.001 mg, 0.005 mg, 0.01 mg, 0.03 mg, 0.05 mg, 0.07 mg, 0.1 mg, 0.23 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.2 mg, 1.5 mg, 1.7 mg, 2.0 mg, 2.2 mg, 2.5 mg, 2.7 mg, 3.0 mg, 3.2 mg, 3.5 mg, 3.7 mg, 4.0 mg, 4.2 mg, 4.5 mg, 4.7 mg, or 5.0 mg of the compound of formula (I), including its amorphous and polymorphic forms. In some embodiments, a single dose of the reconstituted formulation comprises 0.03 mg of the compound of formula (I), including its amorphous and polymorphic forms. In some embodiments, a single dose of the reconstituted formulation contains 0.07 mg of the compound of formula (I), including its amorphous and polymorphic forms. In some embodiments, a single dose of the reconstituted formulation contains 0.115 mg of the compound of formula (I), including its amorphous and polymorphic forms.

[0082] The single-dose reconstituted formulations prepared by the processes provided herein, including the compound of formula (I), including its salts and amorphous and polymorphic forms, can include conventional pharmaceutical carriers, excipients, and the like. In some embodiments, the compound of formula (I), including its salts and amorphous and polymorphic forms, is formulated as a suspension. For example, the compound of formula (I) is not completely dissolved in the pharma- ceutically acceptable carrier, i.e., the compound of formula (I) is suspended in the pharma- ceutically acceptable carrier. In some embodiments, the formulation includes the compound of formula (I) suspended in the pharma- ceutically acceptable carrier. In some embodiments, the formulation includes the polymorphic form of formula (I) suspended in the pharma- ceutically acceptable carrier. In some embodiments, the formulation includes Form 1 suspended in the pharma- ceutically acceptable carrier. In some embodiments, the formulation includes a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight suspended in the pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical formulation is a solution, ie, the compound of formula (I) is completely dissolved in the pharma- ceutically acceptable carrier.

[0083] In some embodiments, the polymorphic form is dried prior to mixing with a pharma- ceutically acceptable carrier.

[0084] In some embodiments, single-dose, ready-to-use, pharma- ceutically administrable formulations comprising a compound of formula (I), including its amorphous and polymorphic forms, may optionally contain pharmaceutical excipients in a carrier, such as water, saline, buffer, aqueous dextrose, mannitol, glycerol, glycols, ethanol, etc., to form a suspension. If desired, the pharmaceutical formulations may also contain minor amounts of non-toxic auxiliary substances, such as wetting agents, emulsifying agents, cosolvents, solubilizing agents, pH buffering agents, and the like.

[0085] In some embodiments, the single-dose prepared pharmaceutical formulation prepared by the process provided herein comprises water. Suitable types of water include, but are not limited to, deionized water, distilled water, reverse osmosis filtered water, reagent grade water, water for injection (WFI), USP / EP grade water suitable for use in pharmaceuticals, and aqueous buffer solutions. The water is substantially free of contaminants, such as parasites, pathogens, chemical contaminants, and particulate contaminants. For example, the pharmaceutical formulation can comprise an aqueous buffer solution.Examples of buffering agents include acetic acid, acetic anhydride, adipic acid, alanine, albumin, alcohol, alphadex, ammonia, ammonium acetate, ammonium sulfate, anhydrous citric acid, anhydrous dextrose, anhydrous lactose, anhydrous sodium citrate, arginine, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, calcium chloride, calcium gluceptate, calcium hydroxide, calcium, caprylic acid, carbon dioxide, citric acid monohydrate, dibasic potassium phosphate, diethyl acetate, ethyl ... Ethanolamine, disodium citrate sesquihydrate, disodium hydrogen citrate, calcium disodium edetate, disodium edetate, sodium edetate, edetic acid, ethanolamine hydrochloride, ferric chloride, sodium gluceptate, glycine hydrochloride, glycine, guanidine hydrochloride, histidine hydrochloride, isoleucine, lactic acid, lactobionic acid, leucine, lysine acetate, lysine, lysine monohydrate, magnesium chloride, magnesium stearate, maleic acid, metaphosphoric acid, methanesulfonate Examples of the phosphate buffered saline include, but are not limited to, phosphate, nitric acid, phosphate ion, phosphoric acid, potassium chloride, potassium hydroxide, potassium phosphate (monobasic), sodium acetate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium bisulfate, sodium carbonate, sodium citrate, sodium hydroxide, sodium hypochlorite, sodium phosphate dihydrate, sodium phosphate, sodium phosphate p-32, dibasic sodium phosphate dihydrate, dibasic sodium phosphate dodecahydrate, dibasic sodium phosphate, dibasic sodium phosphate (anhydrous), dibasic sodium phosphate heptahydrate, monobasic sodium phosphate (anhydrous), monobasic sodium phosphate dihydrate, monobasic sodium phosphate monohydrate, monobasic sodium phosphate, sodium sulfate (anhydrous), sodium sulfate, sodium glycolate, sodium thiomalate, sodium thiosulfate, succinic acid, sulfuric acid, tartaric acid, tartaric acid (dl) trifluoroacetic acid, tromantadine, and tromethamine. In some embodiments, the pharmaceutical formulation comprises phosphate buffered saline.

[0086] In some embodiments, the single-dose prepared pharmaceutical formulations prepared by the processes provided herein include a thickening agent. The thickening agent can be, for example, a cellulose or cellulose derivative or a synthetic polymer. Examples of thickeners include microcrystalline cellulose (Avicel: Asahi Kasei Corp., etc.), microcrystalline cellulose carmellose sodium (Avicel RC: Asahi Kasei Corp., etc.), methylcellulose (Metolose SM: Shin-Etsu Chemical Co., Ltd., etc.), ethylcellulose (Ethocel: Dow Chemical Co., etc.), hydroxypropylcellulose (Nisso HPC: Nippon Soda Co., Ltd., etc.), low-substituted hydroxypropylcellulose (L-HPC: Shin-Etsu Chemical Co., Ltd., etc.), hydroxypropyl methylcellulose 2208 (Metolose 90SH: Shin-Etsu Chemical Co., Ltd., etc.), hydroxypropyl methylcellulose 2906 (Metolose 65SH: Shin-Etsu Chemical Co., Ltd., etc.), hydroxypropyl methylcellulose 2910 (Metolose 60SH: Shin-Etsu Chemical Co., Ltd., etc.), and hydroxypropyl cellulose phthalate 200731 (HPMCP: Shin-Etsu Chemical Co., Ltd., etc.), hydroxypropyl cellulose phthalate 220824 (HPMCP: Shin-Etsu Chemical Co., Ltd., etc.), hydroxypropyl methylcellulose acetate succinate (Shin-Etsu AQOAT: Shin-Etsu Chemical Co., Ltd., etc.), carmellose (NS-300: Gotoku Chemical Co., Ltd., etc.), carmellose calcium (ECG-505: Gotoku Chemical Co., Ltd., etc.), carmellose sodium (Cellogen: Daiichi Kogyo Seiyaku Co., Ltd.Examples of thickeners include, but are not limited to, croscarmellose sodium (Ac-Di-Sol: Asahi Kasei Corp., etc.), carboxymethylethylcellulose (CMEC: Freund Corp., etc.), cellulose acetate phthalate (CAP: Wako Pure Chemical Industries, Ltd., etc.), hydroxyethylcellulose (NATROSOL: Aqualon Corp., etc.), polyvinyl alcohol, polyvinylpyrrolidone, or mixtures thereof. In some embodiments, the thickener is a cellulose derivative. In some embodiments, the cellulose derivative is water-soluble cellulose or a water-soluble cellulose derivative. In some embodiments, the cellulose derivative is carboxymethylcellulose, or a pharma- ceutically acceptable salt thereof. For example, the cellulose derivative is sodium carboxymethylcellulose. The thickener can be present in the formulation in an amount of about 0.1% to about 5% by weight of the formulation. For example, about 0.1% to about 2.5% by weight of the formulation; about 0.1% to about 1% by weight; about 0.1% to about 0.75% by weight; about 0.1% to about 0.5% by weight; about 0.1% to about 0.25% by weight; about 0.25% to about 5% by weight; about 0.5% to about 5% by weight; about 1% to about 5% by weight; about 2.5% to about 5% by weight; about 0.25% to about 0.75% by weight; about 0.5% to about 1% by weight; and about 1% to about 2% by weight. In some embodiments, the thickening agent can be present in the formulation at about 0.5% by weight of the formulation. In some embodiments, the thickening agent is a cellulose derivative and is present in the formulation at about 0.5% by weight of the formulation.

[0087] In some embodiments, the single-dose prepared pharmaceutical formulation prepared by the process provided herein comprises a surfactant.Non-limiting examples of surfactants include polysorbates such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polysorbate 85; polyoxyethylene hydrogenated castor oil such as polyoxyethylene hydrogenated castor oil 60 and polyoxyl 35 castor oil; sorbitan fatty acid esters; sucrose fatty acid esters; polyoxyethylene polyoxypropylene glycol; polyoxyethylene fatty acid ethers; polyoxyl stearate; phosphatidylcholine; fatty acids, fatty alcohols, or combinations thereof, and phosphatidylglycerols, including but not limited to phosphatidylglycerols containing carbon chain lengths of 4 to 20 carbons; and 1,2-dimyristoyl-sn-glycero-3-(phospho-s-(1-glycerol)), 1,2-dioleoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-(phospho-rac-(1-glycerol)), 1,2-distearoyl-sn-glycero-3-(phospho-rac-(1-glycerol)), 1,2-distearoyl-sn-glycero-3-phosphocholine, deoxycholic acid, dipalmitoylphosphatidylglycerol (dl), distearoylphosphatidylcholine (dl), sodium docusate, egg phospholipids, glyceryl palmitostearate, glyceryl trioleate, hydrogenated soy lecithin, hydrolyzed soy protein (enzymatic);2000mw), hydroxyethylpiperazine ethanesulfonic acid, lecithin, myripyrium chloride, n-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phiv, oleic acid, palmitic acid, PEG vegetable oil, PEG-20 sorbitan stearate, PEG-40 castor oil, phospholipids, poloxamer 188, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 3350, polyethylene glycol 40 Other surfactants include, but are not limited to, polysorbate 80, polyethylene glycol 4000, polyethylene glycol 600, polyoxyethylene fatty acid esters, sodium cholesteryl sulfate, sodium deoxycholate, sodium n-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycol, sodium oleate, sorbitan monolaurate, sorbitan monopaltimate, stearic acid, tricaprylin, or mixtures thereof. In some embodiments, the surfactant is a polysorbate. For example, the pharmaceutical formulation includes polysorbate 80. The surfactant can be present in the formulation in an amount of about 0.001% to about 0.5% by weight of the formulation. In some embodiments, the concentration of the surfactant depends on the critical micelle concentration of the individual surfactant. In some embodiments, the amount of surfactant is sufficient to exceed the critical micelle concentration of the surfactant, sufficient to cover the surface area of ​​the particle, or both. For example, about 0.001% by weight to about 0.25% by weight; about 0.001% by weight to about 0.1% by weight; about 0.001% by weight to about 0.075% by weight; about 0.001% by weight to about 0.05% by weight; about 0.001% by weight to about 0.025% by weight; about 0.0025% by weight to about 0.5% by weight; about 0.005% by weight to about 0.5% by weight; about 0.1% by weight to about 0.5% by weight; about 0.01% by weight to about 0.5% by weight; about 0.01% by weight to about 0.25% by weight; about 0.01% by weight to about 0.1% by weight; about 0.01% by weight to about 0.075% by weight; about 0.01% by weight to about 0.05% by weight; about 0.01% by weight to about 0.025% by weight; Approximately 0.025% to approximately 0.5% by weight; Approximately 0.05% to approximately 0.5% by weight; Approximately 0.1% to approximately 0.5% by weight;about 0.025% to about 0.5% by weight; about 0.025% to about 2.5% by weight; about 0.025% to about 0.075% by weight; about 0.05% to about 2.5% by weight; about 0.05% to about 0.1% by weight; and about 0.1% to about 0.2% by weight. In some embodiments, the surfactant may be present in the formulation at about 0.05% by weight of the formulation.

[0088] In some embodiments, the single-dose prepared pharmaceutical formulation prepared by the process provided herein comprises a compound of formula (I), including its amorphous and polymorphic forms, and a pharma- ceutically acceptable carrier. For example, the formulation comprises a compound of formula (I) and saline, e.g., phosphate buffered saline. In some embodiments, the pharmaceutical formulation comprises a compound of formula (I), a pharma- ceutically acceptable carrier, and one or more excipients. For example, the formulation comprises a compound of formula (I), a pharma- ceutically acceptable carrier, e.g., phosphate buffered saline, and one or more excipients, e.g., a surfactant and a cellulose derivative. In some embodiments, the surfactant is a polysorbate, e.g., polysorbate 80. In some embodiments, the cellulose derivative is sodium carboxymethylcellulose. In some embodiments, the pharmaceutical formulation comprises a compound of formula (I), e.g., a polymorphic form of formula (I), e.g., Form 1, a pharma- ceutically acceptable carrier, e.g., phosphate buffered saline, and one or more excipients, e.g., sodium carboxymethylcellulose and a polysorbate, e.g., polysorbate 80.

[0089] In some embodiments, the single-dose, ready-to-use pharmaceutical formulations prepared by the processes provided herein comprise a compound of formula (I), such as a polymorphic form of formula (I), about 0.01% to about 5% by weight of a cellulose derivative, and about and 0.01% to about 0.5% by weight of a surfactant. For example, the pharmaceutical formulations provided herein can include a compound of formula (I), such as Form 1 or a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight of water, about 0.5% by weight of sodium carboxymethylcellulose, and about 0.05% by weight of polysorbate 80 in phosphate buffered saline.

[0090] In some embodiments, the single-dose prepared pharmaceutical formulations prepared by the processes provided herein have a pH of about 6.0 to about 8.0. For example, the pharmaceutical formulations can have a pH of about 7.3 or 7.4. In some embodiments, the pharmaceutical formulations provided herein have a pH of about 3.0 to about 5.0. For example, the pharmaceutical formulations can have a pH of about 3.8.

[0091] The single-dose prepared pharmaceutical formulation prepared by the process provided herein may contain an excipient. The term "excipient" is used herein to describe any component other than the compounds provided herein, such as the compound of formula (I), including its polymorphs and amorphous forms. Pharmaceutically acceptable excipients include ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate. These include, but are not limited to, sodium, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, and wool fat, solubilizers, isotonicity agents, stabilizers, preservatives, salt formers, chelating agents / chelating agents, thickening agents, contrast agents, antifoaming agents, controlled release agents, lubricants, adhesives, analgesics, antiheparin agents, antiviral agents, colorants, emollients, propellants, and other excipients including, but not limited to, activated charcoal, barium sulfate, bivapcitide, broclinate, calcobutrol, glutathione, zinc, zinc acetate, zinc carbonate, zinc chloride, and zinc oxide. Cyclodextrins, such as alpha-cyclodextrin, beta-cyclodextrin, and gamma-cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins, including 2-hydroxypropyl-b-cyclodextrin and 3-hydroxypropyl-b-cyclodextrin, or other solubilized derivatives, can also be advantageously used to enhance delivery of the compounds described herein.Dosage forms or formulations containing the compounds described herein in the range of 0.005%-100% may be prepared, with the balance being made up of non-toxic carriers. Contemplated formulations may contain 0.001%-100%, in one embodiment 0.1-95%, in another embodiment 75-85%, and in a further embodiment 20-80% active ingredient. Actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art: see, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK. 2012).

[0092] In some embodiments, the single dose prepared pharmaceutical formulations prepared by the processes provided herein contain a solubilizing agent. Examples of solubilizing agents include acetyltryptophan (dl), alanine, albumin (aggregation), alcohol, alfadex intracavitary powder, ammonia, anhydrous dextrose, anhydrous lactose, anhydrous sodium citrate, arginine, ascorbic acid, aspartic acid, benzenesulfonic acid, benzyl alcohol, benzyl benzoate, benzyl chloride, betadex sulfobutylether sodium, butanol (mixed isomers), caprylic acid, carboxymethylcellulose, sodium carboxymethylcellulose, castor oil, cholesterol, corn oil, cottonseed oil, creatine, creatinine, croscarmellose sodium, crospovidone, cysteine ​​hydrochloride ... in, cysteine, cysteine ​​(dl), dextran 40, dextran, diacetylated monoglyceride, diethanolamine, dimethyl sulfoxide, ethanolamine hydrochloride, ethyl acetate, ethylene vinyl acetate copolymer (15% vinyl acetate), gamma cyclodextrin, gelatin, gentisic acid ethanolamide, gentisic acid, gluconolactone, glucuronic acid, glycerin, hetastarch, human albumin microspheres, sodium hyaluronate, hydroxypropyl betadex intramuscular injection, hypromellose, isopropyl alcohol, methylcellulose, methylpyrrolidone, microcrystalline cellulose, N,Non-limiting examples of suitable oleic acid extracts include N-dimethylacetamide, niacinamide, oleic acid, palmitic acid, peanut oil, PEG vegetable oil, PEG-20 sorbitan stearate, PEG-40 castor oil, phenylethyl alcohol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 3350, polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 600, polypropylene glycol, polyvinyl alcohol, poppy seed oil, povidone k12, povidone k17, povidone, proline, propyl gallate, propylene glycol, sesame oil, soybean oil, starch, stearic acid, trimethylsilyl treated dimethiconol / trimethylsiloxysilicate crosspolymer, and yellow wax, and combinations thereof.

[0093] In some aspects, the single-dose reconstituted pharmaceutical formulations prepared by the processes provided herein contain an isotonicity agent. Examples of isotonicity agents include dextrose monohydrate, dextrose solution, dextrose, dimethyl sulfoxide, fructose, gluconolactone, glucuronic acid, glycerin, glycine hydrochloride, glycine, guanidine hydrochloride, histidine, hydrochloric acid, hypertonic sodium chloride solution, isoleucine, isopropyl alcohol, isotonic sodium chloride solution, lactic acid (dl), lactobionic acid, lactose monohydrate, lactose, leucine, lysine acetate, lysine, lysine monohydrate, magnesium chloride, magnesium stearate, maleic acid, mannitol, meglumine, methionine, methylboronic acid, polypropylene glycol, potassium chloride, potassium hydroxide, potassium phosphate (monobasic), proline, propyl gallate, propylene glycol, sodium saccharin, serine, sodium acetate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium bisulfate, sodium carbonate, sodium chloride, sodium citrate. The preferred stimulants include, but are not limited to, sodium gluconate, sodium hydroxide, sodium hypochlorite, sodium lactate, sodium phosphate dihydrate, sodium phosphate, sodium phosphate p-32, dibasic sodium phosphate dihydrate, dibasic sodium phosphate dodecahydrate, dibasic sodium phosphate, dibasic sodium phosphate (anhydrous), dibasic sodium phosphate heptahydrate, monobasic sodium phosphate (anhydrous), monobasic sodium phosphate dihydrate, monobasic sodium phosphate monohydrate, monobasic sodium phosphate, sodium sulfate (anhydrous), sodium sulfate, sodium glycolate, sodium thiomalate, sodium thiosulfate, sorbitol, succinic acid, sucrose, sulfuric acid, tartaric acid, tartrate (dl), threonine, trehalose, trifluoroacetic acid, trisodium citrate dihydrate, tromethamine, tryptophan, tyrosine, urea, urethane, and valine, and combinations thereof.

[0094] In some embodiments, the single-dose prepared pharmaceutical formulations prepared by the processes provided herein contain a stabilizer. Examples of stabilizers include acetyltryptophan (dl), alanine, albumin (aggregation), alcohol, alphadex intraluminal powder, ammonia, anhydrous dextrose, anhydrous lactose, anhydrous sodium citrate, arginine, ascorbic acid, aspartic acid, benzenesulfonic acid, benzyl alcohol, benzyl benzoate, benzyl chloride, betadex sulfobutyl ether sodium, boric acid, butanol (mixed isomers), caprylic acid, carboxymethylcellulose, sodium carboxymethylcellulose, castor oil, cholesterol, creatine, creatinine, croscarmellose sodium, crospovidone, cysteine ​​hydrochloride, cysteine, cysteine ​​(dl), dextran 40, dextran, ethylene vinyl acetate copolymer (15% vinyl acetate), gelatin, gentisic acid ethanolamide, gentisic acid, hetastarch, human alginate, glyceryl stearate ... Examples of suitable glyceryl stearate inhibitors include, but are not limited to, albumin microspheres, sodium hyaluronate, hypromellose, meglumine, methionine, methylboronic acid, methylcellulose, methylpyrrolidone, microcrystalline cellulose, myripyrium chloride, n-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phiv, N,N-dimethylacetamide, niacinamide, phenylalanine, polyvinyl alcohol, povidone K12, povidone K17, povidone, serine, sodium citrate, sodium gluconate, sodium lactate, starch, threonine, trehalose, tricaprylin, trimethylsilyl-treated dimethiconol / trimethylsiloxysilicate crosspolymer, trisodium citrate dihydrate, tryptophan, tyrosine, urea, and valine, and combinations thereof.

[0095] In some embodiments, the single dose reconstituted pharmaceutical formulations prepared by the processes provided herein contain a preservative. Examples of preservatives include sodium acetone bisulfite, alpha-tocopherol, benzalkonium chloride, benzyl alcohol, benzyl benzoate, benzyl chloride, boric acid, butylated hydroxyanisole, butylated hydroxytoluene, butylparaben, chlorobutanol, chlorobutanol hemihydrate, cresol, diethyl pyrocarbonate, calcium disodium edetate, disodium edetate, sodium edetate, edetic acid, hexylresorcinol, metacresol, methylparaben, miripyrium chloride, monothiophene, ethylparaben ... These include, but are not limited to, glycerol, nitrogen, phenol, phenylethyl alcohol, phenylmercuric nitrate, potassium bisulfite, potassium metabisulfite, propylparaben, sodium ascorbate, sodium benzoate, sodium bisulfate, sodium chlorate, sodium dithionite, sodium formaldehyde sulfoxylate, sodium iodide, sodium metabisulfite, sodium sulfite, sodium tartrate, sulfur dioxide, sulfurous acid, and thimerosal and combinations thereof.

[0096] In some embodiments, the single-dose prepared pharmaceutical formulations prepared by the processes provided herein contain a salt-forming agent. Examples of salt-forming agents include acetic acid, acetic anhydride, adipic acid, ammonium acetate, ammonium sulfate, anhydrous citric acid, benzoic acid, calcium chloride, calcium gluceptate, calcium hydroxide, calcium, carbon dioxide, citric acid monohydrate, dipotassium hydrogen phosphate, diethanolamine, disodium citrate sesquihydrate, disodium hydrogen citrate, hydrochloric acid, isoleucine, lactic acid (dl), lactobionic acid, magnesium chloride, magnesium stearate, maleic acid, metaphosphoric acid, methanesulfonic acid, nitric acid, phosphate ion, phosphoric acid, sodium hydroxide, and the like. Examples of suitable salts include, but are not limited to, sodium, sodium hypochlorite, sodium phosphate dihydrate, sodium phosphate, sodium phosphate p-32, dibasic sodium phosphate dihydrate, dibasic sodium phosphate dodecahydrate, dibasic sodium phosphate, dibasic sodium phosphate anhydrous, dibasic sodium phosphate heptahydrate, monobasic sodium phosphate anhydrous, monobasic sodium phosphate dihydrate, monobasic sodium phosphate monohydrate, monobasic sodium phosphate, and trifluoroacetic acid and combinations thereof.

[0097] In some embodiments, the single-dose prepared pharmaceutical formulation prepared by the process provided herein contains a chelating agent or chelating agent. Examples of chelating agents or chelating agents include, but are not limited to, sodium cardiamide, trisodium caroxetate, cartelidol calcium, disodium edetate calcium, disodium edetate, sodium edetate, edetic acid, ferric chloride, sodium gluceptate, methylboronic acid, nioxime, disodium oxidronate, peg-60 hydrogenated castor oil, pentasodium pentetate, trisodium pentetate calcium, pentetic acid, sodium phosphite, sodium pyrophosphate, sodium succinate hexahydrate, sodium trimetaphosphate, succimer, and versetamide, and combinations thereof.

[0098] In some embodiments, the single-dose prepared pharmaceutical formulation prepared by the process provided herein contains a thickening agent.Examples of thickening agents include, but are not limited to, carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium, crospovidone, ethylene vinyl acetate copolymer (15% vinyl acetate), gelatin, hetastarch, human albumin microspheres, sodium hyaluronate, hypromellose, methylcellulose, methylpyrrolidone, microcrystalline cellulose, polyvinyl alcohol, povidone K12, povidone K17, povidone, starch, and trimethylsilyl-treated dimethiconol / trimethylsiloxysilicate crosspolymer and combinations thereof.

[0099] In some embodiments, the single-dose prepared pharmaceutical formulation prepared by the process provided herein contains a contrast agent. Examples of contrast agents include, but are not limited to, diatrizoic acid, perflutren, stannous chloride, stannous fluoride, stannous tartrate, tetrakis(2-methoxyisobutylisocyanide) copper(I) tetrafluoroborate, and tetrofosmin, and combinations thereof.

[0100] In some embodiments, the single-dose prepared pharmaceutical formulations prepared by the processes provided herein contain an anti-foaming agent. Examples of anti-foaming agents include, but are not limited to, dimethicone, polysiloxane, silicone, and simethicone, and combinations thereof.

[0101] In some embodiments, the single-dose prepared pharmaceutical formulation prepared by the process provided herein contains a controlled release agent. Examples of controlled release agents include, but are not limited to, poly(dl-lactic-co-glycolic acid), (50:50; 12000 mw), polyglactin, and polylactide, and combinations thereof.

[0102] In some embodiments, the single dose prepared pharmaceutical formulations prepared by the processes provided herein contain a lubricant. Examples of lubricants include, but are not limited to, silicone and simethicone, and combinations thereof.

[0103] In some embodiments, the single-dose prepared pharmaceutical formulations prepared by the processes provided herein contain an adhesive. Examples of adhesives include, but are not limited to, Duro-Tak 87-2287.

[0104] In some embodiments, the single-dose prepared pharmaceutical formulations prepared by the processes provided herein contain an analgesic agent, such as, but not limited to, disodium sulfosalicylate.

[0105] In some embodiments, the single-dose, ready-to-use pharmaceutical formulations prepared by the processes provided herein contain an antiheparin agent, such as, but not limited to, protamine sulfate.

[0106] In some embodiments, the single-dose, ready-to-use pharmaceutical formulations prepared by the processes provided herein contain an antiviral agent. Examples of antiviral agents include, but are not limited to, tromantadine.

[0107] In some embodiments, the single-dose prepared pharmaceutical formulations prepared by the processes provided herein contain a coloring agent, such as, but not limited to, methylene blue.

[0108] In some embodiments, the single-dose, ready-to-use pharmaceutical formulations prepared by the processes provided herein contain an emollient. Examples of emollients include, but are not limited to, urethanes.

[0109] In some embodiments, the single-dose prepared pharmaceutical formulations prepared by the processes provided herein contain a propellant. Examples of propellants include, but are not limited to, dichlorodifluoromethane.

[0110] The formulations prepared by the process provided herein are single-dose, ready-to-use pharmaceutical formulations packaged in a container for parenteral administration (injection or infusion).For example, pharmaceutical formulations are prepared to contain a therapeutically effective amount of the compound of formula (I), including its amorphous and polymorphic forms, and are intended to be used in a single subject for a single fusion or injection.The formulations provided herein are not designed for multi-dose administration or for multiple uses.The formulations provided herein are "ready-to-use", i.e., formulations that do not require constitution or dilution with a specified amount of diluent, such as water for injection or other suitable diluent, before use by a specified route.For example, a formulation in a vial at a desired concentration that only requires drawing up into a syringe.

[0111] In some embodiments, the single-dose prepared pharmaceutical formulations prepared by the processes provided herein comprise a volume of about 0.1 mL to about 10 mL per container (i.e., per injection), e.g., about 0.1 mL to about 10 mL, about 0.1 mL to about 5 mL, about 0.1 mL to about 4 mL, about 0.1 mL to about 3 mL, about 0.1 mL to about 2 mL, about 0.1 mL to about 1 mL, about 0.1 mL to about 0.5 mL, about 0.1 mL to about 0.25 mL, about 2 mL to about 10 mL, about 2 mL to about 5 mL, about 2 mL to about 4 mL, about 2 mL to about 3 mL, about 3 mL to about 5 mL, about 3 mL to about 10 mL, about 0.5 mL to about 1 mL, about 0.25 mL to about 2 mL. In some embodiments, the single-dose prepared pharmaceutical formulation prepared by the process provided herein comprises a volume of about 1 mL to about 10 mL per container (i.e., per injection). For example, about 1 mL to about 10 mL, about 1 mL to about 5 mL, about 1 mL to about 4 mL, about 1 mL to about 3 mL, about 1 mL to about 2 mL, about 2 mL to about 10 mL, about 2 mL to about 5 mL, about 2 mL to about 4 mL, about 2 mL to about 3 mL, about 3 mL to about 5 mL, about 3 mL to about 10 mL. In some embodiments, the formulation comprises a volume of about 2 mL per container (i.e., per injection).

[0112] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is from about 0.1 μg / kg body weight to about 10 μg / kg body weight in humans.

[0113] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is from about 0.1 μg / kg body weight to about 5 μg / kg body weight in humans.

[0114] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is from about 0.2 μg / kg body weight to about 9 μg / kg body weight in humans.

[0115] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is from about 0.25 μg / kg body weight to about 8 μg / kg body weight in humans.

[0116] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is from about 0.3 μg / kg body weight to about 7 μg / kg body weight in humans.

[0117] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is from about 0.4 μg / kg body weight to about 6 μg / kg body weight in humans.

[0118] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is from about 0.5 μg / kg body weight to about 5 μg / kg body weight in humans.

[0119] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is from about 0.6 μg / kg body weight to about 5 μg / kg body weight in humans.

[0120] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is from about 1.0 μg / kg body weight to about 4 μg / kg body weight in humans.

[0121] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is from about 2.0 μg / kg body weight to about 4 μg / kg body weight in humans.

[0122] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is from about 3.0 μg / kg body weight to about 5 μg / kg body weight in humans.

[0123] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is from about 4.0 μg / kg body weight to about 6 μg / kg body weight in humans.

[0124] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is from about 5.0 μg / kg body weight to about 10 μg / kg body weight in humans.

[0125] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.001 mg and 1 mg of body weight in humans.

[0126] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.001 mg and 0.5 mg of body weight in humans.

[0127] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.001 mg and 0.3 mg in humans.

[0128] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.01 mg and 1 mg of body weight in humans.

[0129] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.01 mg and 0.5 mg of body weight in humans.

[0130] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.01 mg and 0.3 mg in humans.

[0131] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.03 mg and 0.9 mg of body weight in humans.

[0132] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.03 mg and 0.23 mg of body weight in humans.

[0133] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.05 mg and 0.8 mg of body weight in humans.

[0134] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.07 mg and 0.7 mg of body weight in humans.

[0135] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.08 mg and 0.7 mg of body weight in humans.

[0136] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.1 mg and 0.6 mg of body weight in humans.

[0137] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.12 mg and 0.6 mg of body weight in humans.

[0138] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.14 mg and 0.5 mg of body weight in humans.

[0139] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.16 mg and 0.5 mg of body weight in humans.

[0140] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.18 mg and 0.4 mg of body weight in humans.

[0141] In some embodiments, the unit dosage of the compound of formula (I), including its amorphous and polymorphic forms, is between 0.2 mg and 0.4 mg of body weight in humans.

[0142] In some embodiments, the single-dose adjusted pharmaceutical formulation prepared by the process provided herein is stable for at least 3 months. For example, the formulation does not show one or more changes (e.g., more than 5%) in polymorphic form (e.g., increase or decrease of certain forms), appearance, pH, impurity percentage, activity (as measured by in vitro assay), or osmolality over time, e.g., at least 3 months, compared to the original formulation after manufacture. In some embodiments, the single-dose adjusted pharmaceutical formulation prepared by the process provided herein is stable for at least 6 months. For example, the formulation does not show one or more significant changes (e.g., more than 5%) in polymorphic form (e.g., increase or decrease of certain forms), appearance, pH, impurity percentage, activity (as measured by in vitro assay), or osmolality over time, e.g., at least 6 months, compared to the original formulation after manufacture. In some embodiments, the single-dose adjusted pharmaceutical formulation prepared by the process provided herein is stable for at least 9 months. For example, the formulation does not show a significant change (e.g., more than 5%) in one or more of polymorphic form (e.g., increase or decrease in certain forms), appearance, pH, percent impurities, activity (as measured by in vitro assays), or osmolality over time, e.g., at least 9 months, compared to the original formulation after manufacture. In some embodiments, the single-dose reconstituted pharmaceutical formulation prepared by the process provided herein is stable for at least 12 months. For example, the formulation does not show a significant change, as defined by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), in one or more of polymorphic form (e.g., increase or decrease in certain forms), appearance, pH, percent impurities, activity (as measured by in vitro assays), or osmolality over time, e.g., at least 12 months, compared to the original formulation after manufacture.

[0143] In some such embodiments, the single-dose prepared pharmaceutical formulation prepared by the processes provided herein comprises from about 0.005 mg / mL to about 2.5 mg / mL, e.g., from about 0.005 mg / mL to about 2 mg / mL, from about 0.01 mg / mL to about 1.8 mg / mL, from about 0.025 mg / mL to about 1.6 mg / mL, from about 0.05 mg / mL to about 1.5 mg / mL, from about 0.075 mg / mL to about 1.25 mg / mL, from about 0.1 mg / mL to about 1 mg / mL, or from about 0.25 mg / mL to about 0.75 mg / mL of the compound of formula (I), including its amorphous and polymorphic forms. In some such embodiments, the pharmaceutical formulation comprises from about 0.015 mg / mL to about 0.115 mg / mL of the compound of formula (I), including its amorphous and polymorphic forms. In some such embodiments, the pharmaceutical formulation comprises about 0.015 mg / mL of the compound of formula (I), including its amorphous and polymorphic forms. In some such embodiments, the pharmaceutical formulation comprises about 0.035 mg / mL of the compound of formula (I), including its amorphous and polymorphic forms. In some such embodiments, the pharmaceutical formulation comprises about 0.115 mg / mL of the compound of formula (I), including its amorphous and polymorphic forms. In some embodiments, the injection volume comprises about 0.1 mg / mL to 4 mg / mL. In some embodiments, the injection volume is 2 mg / mL.

[0144] The single dose prepared preparation prepared by the process provided herein, which includes the compound of formula (I), including its amorphous and polymorphic forms, can be formulated as a plurality of particles.For example, the particles of the compound of formula (I), including its amorphous and polymorphic forms, can have a median particle size of less than 20 μm (e.g., less than about 15 μm; less than about 10 μm; less than about 7.5 μm; less than about 5 μm; less than about 2.5 μm; less than about 1 μm; and less than about 0.5 μm).For example, the median particle size can be about 0.1 μm to 20 μm, such as about 0.5 to 20, 0.5 to 15, 0.5 to 10, 0.5 to 7.5, 0.5 to 5, 0.5 to 2.5, 0.5 to 1, 2.5 to 15, 5 to 10, 7.5 to 20, or 1 to 5 μm.In some embodiments, the particles also include a polymer. Examples of suitable polymers include biocompatible and biodegradable polymers such as poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), poly(lactide-co-glycolide), and mixtures thereof. In some embodiments, the particles comprise poly(lactic-co-glycolic acid) (PLGA).

[0145] In some embodiments, the compound of formula (I), including its amorphous and polymorphic forms, e.g., polymorphic forms of formula (I), e.g., Form 1, has a particle size distribution (D value), e.g., D50, of about 1 to about 6 μm, e.g., about 1.5 to about 5 μm, or about 2.4 to about 2.55 μm. For example, the D50 can be about 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 4, 4.5, or 5 μm. In some embodiments, the D50 value is about 2.55 μm. In some embodiments, the D50 value is about 2.45 μm. In some embodiments, the D50 value is about 2.1 μm. In some embodiments, the D50 value is about 2 μm. In some embodiments, the D50 value is about 1.6 μm. D50 can be measured by conventional particle size measurement techniques well known to those skilled in the art. Such techniques include, for example, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering, laser diffraction and disk centrifugation.

[0146] In some embodiments, the single dose prepared formulation prepared by the process provided herein, which comprises the compound of formula (I), including its amorphous and polymorphic forms, is administered parenterally, including intramuscularly, intraarticularly, periarticularly, intraspinally, intradiscally, intrasynovially, and epidurally. In some embodiments, the formulation is administered to a patient with disc degeneration. In some embodiments, the formulation is administered to a patient with osteoarthritis. In some embodiments, the formulation can be a bursal injection, a sacral injection (e.g., sacral epidural steroid injection (ESI)), a facet joint injection, a facet joint synovial injection, a hip joint injection, an intradiscal injection, an occipital nerve injection, a sciatic nerve / piriformis injection, a sacroiliac (SI) joint injection, or a combination thereof. In some embodiments, the formulation can be injected locally, for example, in a patient with osteoarthritis, at the site of osteoarthritis (e.g., knee, hip, shoulder, etc.). Injection can be performed at one or more locations surrounding the joint. In some embodiments, the injection is guided using an imaging method such as ultrasound. In some embodiments, administration (e.g., injection) of the formulation precedes or is combined with a local anesthetic.

[0147] The single-dose prepared formulations prepared by the processes provided herein containing the compound of formula (I), including its amorphous and polymorphic forms, can also be administered in combination (administered together or sequentially) with other known agents.

[0148] In some embodiments, a single dose reconstituted formulation prepared by the processes provided herein comprising a compound of formula (I), including its amorphous and polymorphic forms, can be administered in combination with one or more of the following: (a) ibuprofen, naproxen, aspirin, acetaminophen, indomethacin (e.g., INDOCIN® and TIVORBEX®), diclofenac by mouth or into the affected area (e.g., VOLTAREN®, ZIPSOR®, PENNSAID®, FLECTOR®, and CATAFLAM®), meloxicam (e.g., MOBIC®), celecoxib (e.g., CELEBREX®), piroxicam (e.g., FELDENE®), etodolac (e.g., LODINE®), nabumetone (e.g., RELAFEN®), lumiracoxib, valdecoxib (e.g., BEXTRA®), etoricoxib, parecoxib, fenoprofen (b) physical therapy; (c) injections of corticosteroid drugs such as, for example, prednisone, dexamethasone, hydrocortisone, and methylprenisolone;(d) injections of hyaluronic acid derivatives (e.g., HYALGAN®, SYNVISC®, EUFLEXXA®, GEL-ONE®, MONOVISC®, ORTHOVISC®, and SUPARTZ®); (e) injections or topical application of capsaicin (e.g., CAPSAGEL®); (f) narcotics such as codeine, fentanyl, hydrocodone, hydromorphone, morphine, meperidine, oxycodone, and tramadol (e.g., ULTRAM®, CONZIP®, and RYZOLT®); (g) antidepressants such as dulozetine (e.g., CYMBALTA®); (h) braces and / or insoles or any device that can immobilize or support a joint to help keep pressure off the joint (e.g., splints, braces, insoles, or other medical devices); (i) (j) joint replacement (arthroplasty); and (k) chronic pain class.

[0149] In some embodiments, single-dose ready-to-use formulations prepared by the processes provided herein containing the compound of formula (I), including its amorphous and polymorphic forms, can be used to treat osteoarthritis. In some embodiments, the formulations can be used to treat osteoarthritis in combination with one or more of the following drugs or methods: prednisone, methylprednisolone, SYNVISC® (hylan GF 20), ABT-981 [MAbs (2015) 7(3):605-619], stem cell injections, JNJ-42160443 (fullanumab), platelet rich plasma (PRGF) injections, tanezumab, venlafaxine, PH-797804, PG-530742 (dihydrate sodium salt PG-116800), sprifermin (AS902330, rhFGF-18), transdermal ketoprofen in transfersomes (IDEA-033) [Annals of the Rheumatic Diseases (2007) 66(9):1178-1183], FX005, and FX006. (both from Flexion Therapeutics, Inc.), JNJ-39439335 (Mavatrep) [J. Med. Chem. (2015) 58(9):3859-3874], polmacoxib (Acelex, CG100649), balicatib (AAE581), GSK3196165, cebranopadol (GRT6005), fasinumab (REGN475), TPX-100 (from OrthoTrophix), PRX167700 (from Proximagen), EP 104IAR (extended-release fluticasone propionate composition), LY2951742 and LY545694 (both from Eli Lilly & Co), adalimumab (Humira®), GW842166 (by GSK), YY1201 (Yooyoung Pharmaceutical Co., Ltd.(by Can-Fite BioPharma), CF101 (IB-MECA) and CF602 (both by Can-Fite BioPharma), PLA-695 (by Pfizer), VX-150 (by Vertex), ADL5859 and ADL5747 (both by Adolor Corporation now Cubist Pharmaceuticals), Funapide (INN) (TV-45070, XEN402), AGG-523 (by Pfizer) [Osteoarthritis Cartilage (2011) 19(3):315-323], CNTX-4975 (injectable capsaicin by Centrexion Corporation), CR845 (by Cara Therapeutics), ASP7962 (by Astellas Pharma), DA-5202 (by Dong-A ST Co., Ltd.), GZ389988 (by Sanofi-Genzyme), and MEDI 7352 (by AstraZeneca), LNA043 (by Novartis).

[0150] 4. Kit Kits are also provided herein. Typically, the kits include one or more formulations described herein, for example, a single-dose prepared formulation prepared by the process provided herein, which includes the compound of formula (I), including its amorphous and polymorphic forms. In certain embodiments, the kits can include one or more delivery systems, for example, for delivering or administering the formulations provided herein, and instructions for using the kit (e.g., instructions for treating a patient). In some embodiments, the kits can include the formulations described herein, and a label indicating that the contents should be administered to a patient with bone or cartilage disease or osteoarthritis. The actual dose of the compound of formula (I) provided herein depends on the specific compound and the condition to be treated; the selection of the appropriate dose is well within the knowledge of one of ordinary skill in the art.

[0151] 5. Methods for Treating Osteoarthritis Methods are provided for the treatment of osteoarthritis in a subject. The methods include administering to the subject a therapeutically effective amount of a single-dose prepared formulation provided herein comprising a compound of formula (I), including its salts and amorphous or polymorphic forms. In some embodiments, the formulation is prepared by a process provided herein. In some embodiments, the methods provided herein include intra-articular administration of a single-dose prepared pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I), including its salts and amorphous and polymorphic forms. In some embodiments, the methods provided herein include intra-articular administration of a single-dose prepared pharmaceutical formulation prepared by a process provided herein. In some embodiments, the polymorphic form is Form 1. In some embodiments, the polymorphic form is a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight.

[0152] In some embodiments, provided herein is a method for treating osteoarthritis in a subject, comprising intra-articular administration to the subject of a single dose of a prepared pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I). In some embodiments, the compound of formula (I) in the formulation comprises Form 1. In some embodiments, the compound of formula (I) in the formulation comprises a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight. In some embodiments, the compound of formula (I) in the formulation is substantially present as a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight.

[0153] In some embodiments of the methods provided herein, the single dose prepared formulation prepared by the process provided herein, which comprises the compound of formula (I), including its amorphous and polymorphic forms, is administered parenterally, including intramuscularly, intraarticularly, periarticularly, intradiscally, intraspinally, intrasynovially, and epidurally. In some embodiments, the formulation is administered to a patient with disc degeneration. In some embodiments, the formulation is administered to a patient with osteoarthritis. In some embodiments, the formulation can be a bursal injection, a sacral injection (e.g., sacral epidural steroid injection (ESI)), a facet joint injection, a facet joint synovial injection, a hip joint injection, an intradiscal injection, an occipital nerve injection, a sciatic nerve / piriformis injection, a sacroiliac (SI) joint injection, or a combination thereof. In some embodiments, the formulation can be injected locally, for example, in a patient with osteoarthritis, at the site of osteoarthritis (e.g., knee, hip, shoulder, etc.). The injection can be at one or more locations surrounding the joint. In some embodiments, the formulation is administered intra-articularly. In some embodiments, the injection is guided using an imaging method such as ultrasound. In some embodiments, administration (e.g., injection) of the formulation precedes or is combined with a local anesthetic.

[0154] In some embodiments of the methods provided herein, the formulation comprising the compound of formula (I), including its salts and amorphous and polymorphic forms, is administered once. In some embodiments, the formulation comprising the compound of formula (I), including its salts and amorphous and polymorphic forms, is administered two or more times. For example, the formulation is administered by injection at least 7 days apart. In some embodiments, the formulation is administered once every 2 weeks. In some embodiments, the formulation is administered once every 3 weeks. In some embodiments, the formulation is administered once every 4 weeks. In some embodiments, the formulation is administered once every 6 weeks. In some embodiments, the formulation is administered once every 8 weeks. In some embodiments, the formulation is administered once every 12 weeks (3 months).

[0155] 6. Polymorphism Formula (I), including pharma- ceutically acceptable salts thereof, and amorphous and polymorphic forms thereof Formulations comprising the compound of TIFF0007630905000007.tif46128 are provided herein.

[0156] The compounds of formula (I) provided herein can be prepared using methods known and understood by those skilled in the art. For example, synthetic methods such as those described in PCT / US2013 / 031055, which is incorporated herein by reference in its entirety, can be used.

[0157] The formulations provided herein may contain polymorphic forms of the compound of formula (I). For example, these forms include solvates, hydrates, non-stoichiometric or stoichiometric hydrates, and non-solvated forms of the compound of formula (I), including, for example, polymorphic forms 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13.

[0158] One such polymorph is the polymorph known as Form 1. Form 1 is an anhydrous polymorph of the compound of formula (I). In one embodiment, Form 1 has an X-ray powder diffraction (XRPD or XRD) pattern obtained with CuKα1 radiation with peaks at least at °2θ values ​​of 6.8±0.2, 12.4±0.2, and 18.5±0.2. In some embodiments, Form 1 has an XRPD pattern with peaks at least at °2θ values ​​of 6.8±0.2, 12.4±0.2, 16.5±0.2, 18.5±0.2, and 19.2±0.2. In some embodiments, Form 1 has an XRPD pattern with peaks at at least the following °2θ values: 6.8±0.2, 9.3±0.2, 12.4±0.2, 13.9±0.2, 16.5±0.2, 18.5±0.2, 19.2±0.2, and 24.6±0.2. For example, in some embodiments, Form 1 has an XRPD pattern with peaks at at least the following °2θ values: 6.8±0.2, 9.3±0.2, 12.4±0.2, 13.9±0.2, 14.5±0.2, 16.5±0.2, 18.5±0.2, 19.2±0.2, 20.3±0.2, and 24.6±0.2.

[0159] In some embodiments, the formulations provided herein include compositions comprising polymorphic Form 1. In some embodiments, the compositions can be substantially pure. For example, the compositions have a purity of at least about 90%. In some embodiments, the compositions have a purity of at least about 95%. In some embodiments, the compositions have a purity of at least about 98%. For example, the compositions can have a purity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the compositions are substantially free of other forms of the compound of formula (I). For example, in some embodiments, the compositions are substantially free of other anhydrous forms of the compound of formula (I). In some embodiments, the compositions include less than about 15% by weight of other forms of the compound of formula (I). For example, the compositions may contain less than 14% by weight, less than 13% by weight, less than 12% by weight, less than 11% by weight, less than 10% by weight, less than 9% by weight, less than 8% by weight, less than 7% by weight, less than 6% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, or less than or equal to ... In some embodiments, the compositions contain less than about 15% by weight of one or more other forms of the compound of formula (I), e.g., less than 14% by weight, less than 13% by weight, less than 12% by weight, less than 11% by weight, less than 10% by weight, less than 9% by weight, less than 8% by weight, less than 7% by weight, less than 6% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, or less than or equal to.For example, the composition may contain less than about 15% by weight of Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, and Form 11, non-stoichiometric or stoichiometric hydrates of Form 1 having 1% to about 20% by weight water, or a combination of two or more thereof.

[0160] In some embodiments, provided herein are formulations comprising polymorphic Form 1 that exhibit an endotherm at about 50-100° C. as measured by differential scanning calorimetry (DSC) for adsorbed water. In some embodiments, polymorphic Form 1 exhibits a crystallization phenomenon observed at about 270-290° C., e.g., about 280° C. In some embodiments, endotherms and exotherms are observed when using a scan rate of 10° C. per minute.

[0161] In some embodiments, provided herein are formulations comprising polymorphic Form 1 that recrystallizes to Form 9, which has a melting point of about 363° C. In some embodiments, polymorphic Form 1 undergoes a total mass loss of about 0.33% as measured by thermogravimetric analysis (TGA) prior to about 100° C., e.g., at about 39° C. to about 100° C.

[0162] In some embodiments, polymorphic form 1 is prepared by a method comprising drying a composition comprising the compound of formula (I), including its amorphous and polymorphic forms, to produce polymorphic form 1. In some embodiments, the composition comprises a non-stoichiometric or stoichiometric hydrate of form 1 having 1% to about 20% by weight of water. In some embodiments, polymorphic form 1 is prepared by a method comprising reslurrying a composition comprising the compound of formula (I), including its amorphous and polymorphic forms, in a solvent or solvent mixture to produce polymorphic form 1 as a residual solid. In some embodiments, the reslurrying step is performed at room temperature (RT). In some embodiments, the reslurrying step is performed at about 50° C. In some embodiments, the method further comprises drying the residual solid, for example under reduced pressure. In some embodiments, the drying step is performed at a temperature of about 60° C. to 90° C., for example about 75° C.

[0163] In some embodiments, polymorph Form 1 is prepared by a method comprising reslurrying a composition comprising the compound of formula (I), including its amorphous and polymorphic forms, in a solvent or solvent mixture to produce polymorph Form 1 as a residual solid. In some embodiments, the compound of formula (I) is a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight. In some embodiments, the solvent is methanol. In some embodiments, the solvent is toluene. In some embodiments, the solvent is heptane. In some embodiments, the solvent is dichloromethane (DCM). In some embodiments, the solvent is water. In some embodiments, the solvent is a mixture with water, for example, the solvent can be a mixture of water with acetonitrile, methanol, ethyl acetate (EA), methyl tert-butyl ether (MtBE), isopropyl alcohol (IPAc), methyl acetate (MA), methyl isobutyl ketone (MIBK), DCM, n-butyl acetate, heptane, toluene, or n-butanol. In some embodiments, water is present in an amount of about 5% by weight. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the reslurrying step is performed at about 50° C. In some embodiments, polymorphic Form 1 is prepared by a process further comprising drying the residual solid, e.g., under reduced pressure. In some embodiments, the drying step is performed at a temperature of about 60° C. to 90° C., e.g., about 75° C.

[0164] Provided herein are formulations comprising non-stoichiometric or stoichiometric hydrates of Form 1 having 1% to about 20% water by weight. In some embodiments, for example, at greater than 30% relative humidity (RH), Form 1 readily adsorbs water, exhibiting characteristic shifts of the Form 1 peak from 6.8±0.2 to 6.2±0.2 and from 12.6±0.2 to 11±0.2. In some embodiments, the non-stoichiometric or stoichiometric hydrates of Form 1 contain up to about 20% water by weight. For example, up to about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or greater than 1% water by weight. In some embodiments, the non-stoichiometric or stoichiometric hydrate of Form 1 has 1 to about 20% water by weight, e.g., 1% to about 10%, about 5% to about 15%, about 10% to about 20%, 1% to about 5%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, or about 17% to about 20% water by weight.

[0165] In some embodiments, a formulation is provided herein that includes a composition comprising a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight water. In some embodiments, the composition is substantially pure. For example, the composition can have a purity of at least about 90%. In some embodiments, the composition has a purity of at least about 95%. In some embodiments, the composition has a purity of at least about 98%. For example, the composition can have a purity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition is substantially free of other forms of the compound of Formula (I). For example, in some embodiments, the composition is substantially free of anhydrous forms of the compound of Formula (I). In some embodiments, the composition comprises less than 15% by weight of other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than or equal to other forms of the compound of formula (I) (e.g., anhydrous forms of the compound of formula (I)). In some embodiments, the composition comprises less than 20% by weight of polymorphic form 9 having an X-ray powder diffraction pattern comprising peaks at °2θ values ​​of 4.9±0.2, 18.6±0.2, and 21.1±0.2. For example, the compositions contain less than 15% by weight of other forms of the compound of Form 9, e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight. In some embodiments, the compositions contain less than 15% of one or more other forms of the compound of Formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1%.For example, the composition may contain less than about 15% of Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, or a combination of two or more thereof.

[0166] Another example of a non-stoichiometric hydrate of polymorphic Form 1 is designated Form 12.

[0167] In one embodiment, a formulation comprising polymorphic Form 12 is provided herein. In some embodiments, Form 12 has an XRPD pattern obtained with CuKα1 radiation with peaks at least at °2θ positions 6.4±0.2, 11.0±0.2, and 18.4±0.2. In some embodiments, Form 12 has an XRPD pattern with peaks at least at °2θ positions 6.4±0.2, 9.2±0.2, 11.0±0.2, 18.4±0.2, and 19.7±0.2. In some embodiments, Form 12 has an XRPD pattern with peaks at least at °2θ positions 6.4±0.2, 9.2±0.2, 11.0±0.2, 15.6±0.2, 18.4±0.2, 19.7±0.2, 24.4±0.2, and 25.2±0.2. For example, in some embodiments, Form 12 has an XRPD pattern with peaks at at least the following °2θ positions: 6.4±0.2, 9.2±0.2, 11.0±0.2, 15.6±0.2, 16.1±0.2, 18.4±0.2, 19.7±0.2, 20.8±0.2, 24.4±0.2, and 25.2±0.2.

[0168] In some embodiments, provided herein is polymorphic Form 12 that exhibits an endotherm at about 50-100° C. as measured by DSC. In some embodiments, polymorphic Form 12 exhibits an exotherm at about 283° C. In some embodiments, the endotherm and exotherm are observed when using a scan rate of 10° C. per minute.

[0169] In some embodiments, provided herein is polymorphic Form 12 having a melting point of about 364° C. In some embodiments, polymorphic Form 12 undergoes a weight loss of about 1.4% as measured by TGA before about 100° C., e.g., between about 30° C. and about 100° C.

[0170] An example of a non-stoichiometric hydrate of polymorphic Form 1 is designated Form 13.

[0171] In one embodiment, provided herein is a formulation comprising polymorphic Form 13. In some embodiments, Form 13 has an XRPD pattern obtained with CuKα1 radiation with peaks at least at °2θ values ​​of 6.8±0.2, 12.4±0.2, and 18.5±0.2. In some embodiments, Form 13 has an XRPD pattern with peaks at least at °2θ values ​​of 6.8±0.2, 12.4±0.2, 16.5±0.2, 18.5±0.2, and 19.2±0.2. In some embodiments, Form 13 has an XRPD pattern with peaks at least at °2θ values ​​of 6.8±0.2, 9.3±0.2, 12.4±0.2, 13.9±0.2, 16.5±0.2, 18.5±0.2, 19.2±0.2, and 24.6±0.2. For example, in some embodiments, Form 13 has an XRPD pattern with peaks at at least the following °2θ values: 6.8±0.2, 9.3±0.2, 12.4±0.2, 13.9±0.2, 14.5±0.2, 16.5±0.2, 18.5±0.2, 19.2±0.2, 20.3±0.2, and 24.6±0.2.

[0172] In some embodiments, polymorphic Form 13 exhibits an endotherm at about 50-100° C. as measured by DSC. In some embodiments, polymorphic Form 13 exhibits an exotherm at about 265-285° C., e.g., about 278° C. For example, in some embodiments, the endotherm and exotherm are observed when using a scan rate of 10° C. per minute.

[0173] In some embodiments, polymorphic form 13 has a melting point of about 363° C. In some embodiments, polymorphic form 13 undergoes a weight loss of about 1.9% before about 100° C. as measured by TGA.

[0174] Provided herein is a method for preparing a non-stoichiometric or stoichiometric hydrate of polymorphic Form 1. In some embodiments, the method comprises reslurrying a composition comprising a compound of formula (I) including its amorphous and polymorphic forms in a solvent or solvent mixture to produce a non-stoichiometric or stoichiometric hydrate of polymorphic Form 1 as a residual solid. In some embodiments, the composition comprising a compound of formula (I) is a mixture of a non-stoichiometric or stoichiometric hydrate of polymorphic Form 1 and Form 1. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the reslurrying step is performed at about 50° C. In some embodiments, the method further comprises drying the residual solid, for example under reduced pressure. In some embodiments, the drying step is performed at a temperature of about 60° C. to 90° C., for example about 75° C.

[0175] In some embodiments, the method includes reslurrying a composition comprising a mixture of non-stoichiometric or stoichiometric hydrate of polymorphic Form 1 and Form 1 in a solvent or solvent mixture to produce a non-stoichiometric or stoichiometric hydrate of polymorphic Form 1 as a residual solid. In some embodiments, the solvent is a mixture with water, for example, the solvent can be a mixture of water with acetonitrile, methanol, MtBE, MA, MIBK, DCM, IPAc, n-butyl acetate, heptane, toluene, or n-butanol. In some embodiments, water is present in an amount of about 5% by weight. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the reslurrying step is performed at about 50° C.

[0176] Formulations are provided herein that include a polymorph known as Form 2. Form 2 is an anhydrous polymorph of the compound of formula (I). In one embodiment, polymorph Form 2 has an XRPD pattern obtained with CuKα1 radiation with peaks at least at °2θ values ​​of 7.0±0.2, 21.5±0.2, and 22.0±0.2. In some embodiments, Form 2 has an XRPD pattern with peaks at least at °2θ values ​​of 7.0±0.2, 18.9±0.2, 21.5±0.2, 22.0±0.2, and 24.2±0.2. In some embodiments, Form 2 has an XRPD pattern with peaks at at least the following °2θ values: 7.0±0.2, 14.1±0.2, 18.9±0.2, 19.2±0.2, 21.5±0.2, 22.0±0.2, 24.2±0.2, and 26.4±0.2. For example, in some embodiments, Form 2 has an XRPD pattern with peaks at at least the following °2θ values: 7.0±0.2, 10.4±0.2, 14.1±0.2, 17.6±0.2, 18.9±0.2, 19.2±0.2, 21.5±0.2, 22.0±0.2, 24.2±0.2, and 26.4±0.2.

[0177] In some embodiments, a formulation is provided herein that includes a composition comprising polymorphic Form 2. In some embodiments, the composition is substantially pure. For example, the composition may have a purity of at least about 90%. In some embodiments, the composition may have a purity of at least about 95%. In some embodiments, the composition may have a purity of at least about 98%. For example, the composition may have a purity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition is substantially free of other forms of the compound of formula (I). For example, in some embodiments, the composition is substantially free of other anhydrous forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of other forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of one or more other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of one or more other forms of the compound of formula (I). For example, the composition may contain less than about 15% of Form 1, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, non-stoichiometric or stoichiometric hydrates of Form 1, or a combination of two or more thereof.

[0178] In some embodiments, polymorphic Form 2 exhibits an endotherm at about 50-100° C. as measured by DSC. In some embodiments, polymorphic Form 2 exhibits an endotherm at about 220-230° C. In some embodiments, polymorphic Form 2 exhibits an exotherm at about 233-238° C. In some embodiments, polymorphic Form 2 exhibits an exotherm at about 290-295° C. In some embodiments, the endotherm and exotherm are observed when using a scan rate of 10° C. per minute.

[0179] In some embodiments, polymorphic Form 2 has a melting point of about 363° C. In some embodiments, polymorphic Form 2 undergoes a weight loss of about 2.7% as measured by TGA prior to about 116° C., e.g., between about 36° C. and about 116° C.

[0180] In some embodiments, polymorph Form 2 is prepared by a method comprising reslurrying a composition comprising the compound of Formula (I), including its amorphous and polymorphic forms, in a solvent or solvent mixture to produce Form 2 as a residual solid. In some embodiments, the composition comprising the compound of Formula (I) comprises a nonstoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight water. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the slurrying step is performed at about 50° C. In some embodiments, the method further comprises drying the residual solid, e.g., under reduced pressure. In some embodiments, the drying step is performed at a temperature of about 60° C. to 90° C., e.g., about 75° C.

[0181] In some embodiments, polymorph Form 2 is prepared by a method comprising reslurrying a composition comprising a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight of water in a solvent or solvent mixture to produce polymorph Form 2 as a residual solid. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is a mixture with water, e.g., the solvent can be a mixture of water and ethanol, or a mixture of water and n-propanol. In some embodiments, water is present in an amount of about 5% by weight. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the reslurrying step is performed at about 50°C.

[0182] Formulations are provided herein that include a polymorph known as Form 3. Form 3 is an anhydrous polymorph of the compound of formula (I). In one embodiment, polymorph Form 3 has an XRPD pattern obtained with CuKα1 radiation with peaks at least at °2θ values ​​of 7.2±0.2, 22.2±0.2, and 24.4±0.2. In some embodiments, Form 3 has an XRPD pattern with peaks at least at °2θ values ​​of 6.3±0.2, 7.2±0.2, 21.6±0.2, 22.2±0.2, and 24.4±0.2. In some embodiments, Form 3 has an XRPD pattern with peaks at least at °2θ values ​​of 6.3±0.2, 7.2±0.2, 11.0±0.2, 18.4±0.2, 19.0±0.2, 21.6±0.2, 22.2±0.2, and 24.4±0.2. For example, in some embodiments, Form 3 has an XRPD pattern with peaks at at least the following °2θ values: 6.3±0.2, 7.2±0.2, 11.0±0.2, 14.2±0.2, 17.8±0.2, 18.4±0.2, 19.0±0.2, 21.6±0.2, 22.2±0.2, and 24.4±0.2.

[0183] In some embodiments, a formulation is provided herein that includes a composition comprising polymorphic Form 3. In some embodiments, the composition is substantially pure. For example, the composition may have a purity of at least about 90%. In some embodiments, the composition may have a purity of at least about 95%. In some embodiments, the composition may have a purity of at least about 98%. For example, the composition may have a purity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition is substantially free of other forms of the compound of formula (I). For example, in some embodiments, the composition is substantially free of other anhydrous forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of other forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of one or more other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of one or more other forms of the compound of formula (I). For example, the composition may contain less than about 15% of Form 1, Form 2, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, non-stoichiometric or stoichiometric hydrates of Form 1, or a combination of two or more thereof.

[0184] In some embodiments, polymorphic Form 3 exhibits an exotherm as measured by DSC at about 190-220° C. In some embodiments, polymorphic Form 3 exhibits an exotherm as measured by DSC at about 225-235° C., e.g., about 230° C. In some embodiments, polymorphic Form 3 exhibits an exotherm as measured by DSC at about 292-300° C., e.g., about 297° C. For example, in some embodiments, endotherms and exotherms are observed when using a scan rate of 10° C. per minute.

[0185] In some embodiments, polymorphic Form 3 has a melting point of about 365° C. In some embodiments, polymorphic Form 3 undergoes a weight loss of about 1.6% as measured by TGA before about 81° C. and a weight loss of about 1.7% between about 81 and 169° C.

[0186] In some embodiments, polymorph Form 3 is prepared by a method comprising reslurrying a composition comprising the compound of Formula (I), including its amorphous and polymorphic forms, in a solvent or solvent mixture to produce Form 3 as a residual solid. In some embodiments, the composition comprising the compound of Formula (I) comprises a nonstoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight water. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the slurrying step is performed at about 50° C. In some embodiments, the method further comprises drying the residual solid, e.g., under reduced pressure. In some embodiments, the drying step is performed at a temperature of about 60° C. to 90° C., e.g., about 75° C.

[0187] In some embodiments, polymorph Form 3 is prepared by a process comprising reslurrying a composition comprising a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight water in a solvent or solvent mixture to produce polymorph Form 3 as a residual solid. In some embodiments, the solvent is IPAc. In some embodiments, the solvent is n-butyl acetate. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the reslurrying step is performed at about 50° C.

[0188] Formulations are provided herein that include a polymorph known as Form 4. Form 4 is an anhydrous polymorph of the compound of formula (I). In one embodiment, polymorph Form 4 has an XRPD pattern obtained with CuKα1 radiation with peaks at least at °2θ values ​​of 7.0±0.2, 21.8±0.2, and 25.1±0.2. In some embodiments, Form 4 has an XRPD pattern with peaks at least at °2θ values ​​of 7.0±0.2, 19.5±0.2, 21.8±0.2, 23.2±0.2, and 25.1±0.2. In some embodiments, Form 4 has an XRPD pattern with peaks at at least the following °2θ values: 7.0±0.2, 17.6±0.2, 18.3±0.2, 19.5±0.2, 21.8±0.2, 23.2±0.2, 25.1±0.2, and 25.8±0.2. For example, in some embodiments, Form 4 has an XRPD pattern with peaks at at least the following °2θ values: 7.0±0.2, 9.6±0.2, 17.6±0.2, 18.3±0.2, 19.5±0.2, 21.8±0.2, 23.2±0.2, 25.1±0.2, 25.8±0.2, and 29.3±0.2.

[0189] In some embodiments, a formulation is provided herein that includes a composition comprising polymorphic Form 4. In some embodiments, the composition is substantially pure. For example, the composition may have a purity of at least about 90%. In some embodiments, the composition may have a purity of at least about 95%. In some embodiments, the composition may have a purity of at least about 98%. For example, the composition may have a purity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition is substantially free of other forms of the compound of formula (I). For example, in some embodiments, the composition is substantially free of other anhydrous forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of other forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of one or more other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of one or more other forms of the compound of formula (I). For example, the composition may contain less than about 15% of Form 1, Form 2, Form 3, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, non-stoichiometric or stoichiometric hydrates of Form 1, or a combination of two or more thereof.

[0190] In some embodiments, polymorphic form 4 exhibits an endotherm at about 50-100° C. as measured by DSC. In some embodiments, polymorphic form 4 exhibits an endotherm at about 180-215° C. In some embodiments, polymorphic form 4 exhibits an endotherm at about 220-230° C. In some embodiments, polymorphic form 4 exhibits an exotherm at about 230-240° C., e.g., about 235° C. In some embodiments, polymorphic form 4 exhibits an exotherm at about 300-310° C. For example, in some embodiments, endotherms and exotherms are observed when using a scan rate of 10° C. per minute.

[0191] In some embodiments, polymorphic Form 4 has a melting point of about 366-369° C., e.g., about 367° C. In some embodiments, polymorphic Form 4 undergoes a weight loss of about 8.3% as measured by TGA before about 200° C., e.g., at about 42° C. to about 200° C.

[0192] In some embodiments, polymorph Form 4 is prepared by a method comprising reslurrying a composition comprising the compound of formula (I), including its amorphous and polymorphic forms, in a solvent or solvent mixture to produce Form 4 as a residual solid. In some embodiments, the composition comprising the compound of formula (I) comprises a nonstoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight water. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the slurrying step is performed at about 50° C. In some embodiments, the method further comprises drying the residual solid, e.g., under reduced pressure. In some embodiments, the drying step is performed at a temperature of about 60° C. to 90° C., e.g., about 75° C.

[0193] In some embodiments, polymorph Form 4 is prepared by a method comprising reslurrying a composition comprising a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight of water in a solvent or solvent mixture to produce polymorph Form 4 as a residual solid. In some embodiments, the solvent is EA. In some embodiments, the solvent is MA. In some embodiments, the solvent is MtBE. In some embodiments, the solvent is n-propanol. In some embodiments, the solvent is acetone. In some embodiments, the solvent is a mixture with water, e.g., the solvent can be a mixture of water and MA, EA, or acetone. In some embodiments, water is present in an amount of about 5% by weight. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the reslurrying step is performed at about 50°C.

[0194] Formulations are provided herein that include a polymorph known as Form 5. Form 5 is an anhydrous polymorph of the compound of formula (I). In one embodiment, polymorph Form 5 has an XRPD pattern obtained with CuKα1 radiation with peaks at least at °2θ values ​​of 7.3±0.2, 22.3±0.2, and 24.5±0.2. In some embodiments, Form 5 has an XRPD pattern with peaks at least at °2θ values ​​of 6.3±0.2, 7.3±0.2, 21.7±0.2, 22.3±0.2, and 24.5±0.2. In some embodiments, Form 5 has an XRPD pattern with peaks at least at °2θ values ​​of 6.3±0.2, 7.3±0.2, 11.0±0.2, 19.1±0.2, 19.5±0.2, 21.7±0.2, 22.3±0.2, and 24.5±0.2. For example, in some embodiments, Form 5 has an XRPD pattern with peaks at at least the following °2θ values: 6.3±0.2, 7.3±0.2, 11.0±0.2, 14.3±0.2, 19.1±0.2, 19.5±0.2, 21.7±0.2, 22.3±0.2, 24.5±0.2, and 26.5±0.2.

[0195] In some embodiments, a formulation is provided herein that includes a composition comprising polymorphic Form 5. In some embodiments, the composition is substantially pure. For example, the composition may have a purity of at least about 90%. In some embodiments, the composition may have a purity of at least about 95%. In some embodiments, the composition may have a purity of at least about 98%. For example, the composition may have a purity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition is substantially free of other forms of the compound of formula (I). For example, in some embodiments, the composition is substantially free of other anhydrous forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of other forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of one or more other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of one or more other forms of the compound of formula (I). For example, the composition may contain less than about 15% of Form 1, Form 2, Form 3, Form 4, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, non-stoichiometric or stoichiometric hydrates of Form 1, or a combination of two or more thereof.

[0196] In some embodiments, polymorphic Form 5 exhibits an endotherm at about 50-100° C. as measured by DSC. In some embodiments, polymorphic Form 5 exhibits an endotherm at about 210-235° C., e.g., about 222° C. In some embodiments, polymorphic Form 5 exhibits an exotherm at about 227-240° C., e.g., about 235° C. In some embodiments, polymorphic Form 5 exhibits an exotherm at about 280-300° C., e.g., about 293° C. For example, in some embodiments, endotherms and exotherms are observed when using a scan rate of 10° C. per minute.

[0197] In some embodiments, polymorphic Form 5 has a melting point of about 363° C. In some embodiments, polymorphic Form 5 undergoes a weight loss of about 3.1% as measured by TGA before about 100° C. and a weight loss of about 1.7% between about 100 and 250° C.

[0198] In some embodiments, polymorph Form 5 is prepared by a method comprising reslurrying a composition comprising the compound of Formula (I), including its amorphous and polymorphic forms, in a solvent or solvent mixture to produce Form 5 as a residual solid. In some embodiments, the composition comprising the compound of Formula (I) comprises a nonstoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight water. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the slurrying step is performed at about 50° C. In some embodiments, the method further comprises drying the residual solid, e.g., under reduced pressure. In some embodiments, the drying step is performed at a temperature of about 60° C. to 90° C., e.g., about 75° C.

[0199] In some embodiments, polymorph Form 5 is prepared by a process comprising reslurrying a composition comprising a nonstoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight water in a solvent or solvent mixture to produce polymorph Form 5 as a residual solid. In some embodiments, the solvent is MtBE. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the reslurrying step is performed at about 50° C.

[0200] Provided herein are formulations containing the polymorph known as Form 6. Form 6 is an anhydrous polymorph of the compound of formula (I).

[0201] In some embodiments, a formulation is provided herein that includes a composition comprising polymorphic form 6. In some embodiments, the composition is substantially pure. For example, the composition may have a purity of at least about 90%. In some embodiments, the composition may have a purity of at least about 95%. In some embodiments, the composition may have a purity of at least about 98%. For example, the composition may have a purity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition is substantially free of other forms of the compound of formula (I). For example, in some embodiments, the composition is substantially free of other anhydrous forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of other forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of one or more other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of one or more other forms of the compound of formula (I). For example, the composition may contain less than about 15% of Form 1, Form 2, Form 3, Form 4, Form 5, Form 7, Form 8, Form 9, Form 10, Form 11, non-stoichiometric or stoichiometric hydrates of Form 1, or a combination of two or more thereof.

[0202] In some embodiments, polymorphic Form 6 exhibits an exotherm at about 245-260° C. as measured by DSC. For example, in some embodiments, an endotherm and an exotherm are observed when using a scan rate of 10° C. per minute. In some embodiments, polymorphic Form 6 has a melting point of about 364° C.

[0203] In some embodiments, polymorphic Form 6 is prepared by a method comprising reslurrying a composition comprising the compound of Formula (I), including its amorphous and polymorphic forms, in a solvent or solvent mixture to produce Form 6 as a residual solid. In some embodiments, the composition comprising the compound of Formula (I) is a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the slurrying step is performed at about 50° C. In some embodiments, the method further comprises drying the residual solid, e.g., under reduced pressure. In some embodiments, the drying step is performed at a temperature of about 60° C. to 90° C., e.g., about 75° C.

[0204] In some embodiments, polymorph Form 6 is prepared by a process comprising reslurrying a composition comprising a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight of water in a solvent or solvent mixture to produce polymorph Form 6 as a residual solid. In some embodiments, the solvent is IPAc. In some embodiments, the solvent is a mixture with water, e.g., the solvent can be a mixture of water and IPAc. In some embodiments, water is present in an amount of about 5% by weight. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the reslurrying step is performed at about 50°C.

[0205] Formulations are provided herein that include a polymorph known as Form 7. Form 7 is an anhydrous polymorph of the compound of formula (I). In one embodiment, polymorph Form 7 has an XRPD pattern obtained with CuKα1 radiation with peaks at least at °2θ values ​​of 7.1±0.2, 21.6±0.2, and 23.2±0.2. In some embodiments, Form 7 has an XRPD pattern with peaks at least at °2θ values ​​of 4.9±0.2, 7.1±0.2, 18.5±0.2, 21.6±0.2, and 23.2±0.2. In some embodiments, Form 7 has an XRPD pattern with peaks at least at °2θ values ​​of 4.9±0.2, 7.1±0.2, 10.9±0.2, 18.5±0.2, 19.4±0.2, 21.6±0.2, 23.2±0.2, and 30.3±0.2. For example, in some embodiments, Form 7 has an XRPD pattern with peaks at at least the following °2θ values: 4.9±0.2, 7.1±0.2, 8.8±0.2, 10.9±0.2, 18.5±0.2, 19.4±0.2, 21.6±0.2, 22.1±0.2, 23.2±0.2, and 30.3±0.2.

[0206] In some embodiments, a formulation is provided herein that includes a composition comprising polymorphic Form 7. In some embodiments, the composition is substantially pure. For example, the composition may have a purity of at least about 90%. In some embodiments, the composition may have a purity of at least about 95%. In some embodiments, the composition may have a purity of at least about 98%. For example, the composition may have a purity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition is substantially free of other forms of the compound of formula (I). For example, in some embodiments, the composition is substantially free of other anhydrous forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of other forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of one or more other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of one or more other forms of the compound of formula (I). For example, the composition may contain less than about 15% of Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 8, Form 9, Form 10, Form 11, non-stoichiometric or stoichiometric hydrates of Form 1, or a combination of two or more thereof.

[0207] In some embodiments, polymorphic Form 7 exhibits an exotherm as measured by DSC at about 227-235° C., e.g., about 232° C. In some embodiments, polymorphic Form 7 exhibits an exotherm at about 299-305° C., e.g., about 303° C. For example, in some embodiments, an endotherm and an exotherm are observed when using a scan rate of 10° C. per minute.

[0208] In some embodiments, polymorphic Form 7 has a melting point of about 365° C. In some embodiments, polymorphic Form 7 undergoes a weight loss of about 12% as measured by TGA before about 200° C., e.g., between about 36° C. and about 200° C.

[0209] In some embodiments, polymorph Form 7 is prepared by a method comprising reslurrying a composition comprising the compound of formula (I), including its amorphous and polymorphic forms, in a solvent or solvent mixture to produce Form 7 as a residual solid. In some embodiments, the composition comprising the compound of formula (I) is a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the slurrying step is performed at about 50° C. In some embodiments, the method further comprises drying the residual solid, e.g., under reduced pressure. In some embodiments, the drying step is performed at a temperature of about 60° C. to 90° C., e.g., about 75° C.

[0210] In some embodiments, polymorph Form 7 is prepared by a process comprising reslurrying a composition comprising a nonstoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight water in a solvent or solvent mixture to produce polymorph Form 7 as a residual solid. In some embodiments, the solvent is methyl ethyl ketone (MEK). In some embodiments, the solvent is a mixture with water, e.g., the solvent can be a mixture of water and MEK. In some embodiments, water is present in an amount of about 5% by weight. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the reslurrying step is performed at about 50° C.

[0211] Formulations are provided herein that include a polymorph known as Form 8. Form 8 is an anhydrous polymorph of the compound of formula (I). In one embodiment, polymorph Form 8 has an XRPD pattern obtained with CuKα1 radiation with peaks at least at °2θ values ​​of 6.9±0.2, 17.7±0.2, and 21.5±0.2. In some embodiments, Form 8 has an XRPD pattern with peaks at least at °2θ values ​​of 6.9±0.2, 11.5±0.2, 17.7±0.2, 21.5±0.2, and 27.6±0.2. In some embodiments, Form 8 has an XRPD pattern with peaks at at least the following °2θ values: 6.9±0.2, 11.5±0.2, 15.3±0.2, 16.9±0.2, 17.7±0.2, 21.5±0.2, 27.6±0.2, and 28.9±0.2. For example, in some embodiments, Form 8 has an XRPD pattern with peaks at at least the following °2θ values: 6.9±0.2, 11.5±0.2, 12.7±0.2, 14.2±0.2, 15.3±0.2, 16.9±0.2, 17.7±0.2, 21.5±0.2, 27.6±0.2, and 28.9±0.2.

[0212] In some embodiments, a formulation is provided herein that includes a composition comprising polymorphic Form 8. In some embodiments, the composition is substantially pure. For example, the composition may have a purity of at least about 90%. In some embodiments, the composition may have a purity of at least about 95%. In some embodiments, the composition may have a purity of at least about 98%. For example, the composition may have a purity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition is substantially free of other forms of the compound of formula (I). For example, in some embodiments, the composition is substantially free of other anhydrous forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of other forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of one or more other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of one or more other forms of the compound of formula (I). For example, the composition may contain less than about 15% of Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 9, Form 10, Form 11, non-stoichiometric or stoichiometric hydrates of Form 1, or a combination of two or more thereof.

[0213] In some embodiments, polymorphic Form 8 exhibits an endotherm at about 41-60° C. as measured by DSC. In some embodiments, polymorphic Form 8 exhibits an exotherm at about 221-235° C., e.g., about 231° C. In some embodiments, polymorphic Form 8 exhibits an endotherm at about 279-290° C., e.g., about 285° C. For example, in some embodiments, endotherms and exotherms are observed when using a scan rate of 10° C. per minute.

[0214] In some embodiments, polymorphic Form 8 has a melting point of about 364° C. In some embodiments, polymorphic Form 8 undergoes a weight loss of about 4.2% as measured by TGA before about 190° C. and a weight loss of about 3.9% between about 190 and 261° C.

[0215] In some embodiments, polymorphic Form 8 is prepared by a method comprising reslurrying a composition comprising the compound of Formula (I), including its amorphous and polymorphic forms, in a solvent or solvent mixture to produce Form 8 as a residual solid. In some embodiments, the composition comprising the compound of Formula (I) comprises a nonstoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight water. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the slurrying step is performed at about 50° C. In some embodiments, the method further comprises drying the residual solid, e.g., under reduced pressure. In some embodiments, the drying step is performed at a temperature of about 60° C. to 90° C., e.g., about 75° C.

[0216] In some embodiments, polymorph Form 8 is prepared by a process comprising reslurrying a composition comprising a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight water in a solvent or solvent mixture to produce polymorph Form 8 as a residual solid. In some embodiments, the solvent is MIBK. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the reslurrying step is performed at about 50° C.

[0217] Formulations are provided herein that include a polymorph known as Form 9. Form 9 is an anhydrous polymorph of the compound of formula (I). In one embodiment, polymorph Form 9 has an XRPD pattern obtained with CuKα1 radiation with peaks at least at °2θ values ​​of 4.9±0.2, 18.6±0.2, and 21.1±0.2. In some embodiments, Form 9 has an XRPD pattern with peaks at least at °2θ values ​​of 4.9±0.2, 18.6±0.2, 21.1±0.2, 24.1±0.2, and 25.2±0.2. In some embodiments, Form 9 has an XRPD pattern with peaks at at least the following °2θ values: 4.9±0.2, 15.3±0.2, 16.5±0.2, 18.6±0.2, 21.1±0.2, 22.4±0.2, 24.1±0.2, and 25.2±0.2. For example, in some embodiments, Form 9 has an XRPD pattern with peaks at at least the following °2θ values: 4.9±0.2, 10.1±0.2, 15.3±0.2, 16.5±0.2, 18.6±0.2, 21.1±0.2, 22.4±0.2, 24.1±0.2, 25.2±0.2, and 28.6±0.2.

[0218] In some embodiments, a formulation is provided herein that includes a composition comprising polymorphic Form 9. In some embodiments, the composition is substantially pure. For example, the composition may have a purity of at least about 90%. In some embodiments, the composition may have a purity of at least about 95%. In some embodiments, the composition may have a purity of at least about 98%. For example, the composition may have a purity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition is substantially free of other forms of the compound of formula (I). For example, in some embodiments, the composition is substantially free of other anhydrous forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of other forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of one or more other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of one or more other forms of the compound of formula (I). For example, the composition may contain less than about 15% of Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 10, Form 11, non-stoichiometric or stoichiometric hydrates of Form 1, or a combination of two or more thereof.

[0219] In some embodiments, polymorphic Form 9 exhibits a single melting endotherm at about 364° C. as measured by DSC. For example, in some embodiments, the endotherm is observed when using a scan rate of 10° C. per minute. In some embodiments, other polymorphic forms provided herein, such as Form 1 and Form 2, may be converted to Form 9 when heated to just below melting (i.e., about 364° C.).

[0220] In some embodiments, polymorphic form 9 has a melting point of about 364° C. In some embodiments, polymorphic form 9 undergoes a weight loss of about 0.28% as measured by TGA before about 100° C., e.g., between about 30.5° C. and about 100° C.

[0221] In some embodiments, polymorphic Form 9 is prepared by a method comprising reslurrying a composition comprising the compound of Formula (I), including its amorphous and polymorphic forms, in a solvent or solvent mixture to produce Form 9 as a residual solid. In some embodiments, the composition comprising the compound of Formula (I) is a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the slurrying step is performed at about 50° C. In some embodiments, the method further comprises drying the residual solid, e.g., under reduced pressure. In some embodiments, the drying step is performed at a temperature of about 60° C. to 90° C., e.g., about 75° C.

[0222] In some embodiments, polymorph Form 9 is prepared by a method comprising reslurrying a composition comprising a non-stoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight of water in a solvent or solvent mixture to produce polymorph Form 9 as a residual solid. In some embodiments, the solvent is n-butanol. In some embodiments, the solvent is IPAc. In some embodiments, the solvent is n-butyl acetate. In some embodiments, the solvent is a mixture with water, e.g., the solvent can be a mixture of water and ethanol, or a mixture of water and n-propanol. In some embodiments, water is present in an amount of about 5% by weight. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the reslurrying step is performed at about 50° C.

[0223] Formulations containing the polymorph known as Form 10 are provided herein. Polymorph Form 10 is a polymorph of the compound of formula (I) that contains DMSO. For example, DMSO is present on the surface of the polymorph. In one embodiment, polymorph Form 10 has an XRPD pattern obtained with CuKα1 radiation with peaks at least at °2θ values ​​of 20.7±0.2, 21.7±0.2, and 24.2±0.2. In some embodiments, Form 10 has an XRPD pattern with peaks at least at °2θ values ​​of 18.2±0.2, 19.0±0.2, 20.7±0.2, 21.7±0.2, and 24.2±0.2. In some embodiments, Form 10 has an XRPD pattern with peaks at at least the following °2θ values: 17.8±0.2, 18.2±0.2, 19.0±0.2, 20.7±0.2, 21.7±0.2, 23.4±0.2, 24.2±0.2, and 27.9±0.2. For example, in some embodiments, Form 10 has an XRPD pattern with peaks at at least the following °2θ values: 6.7±0.2, 17.8±0.2, 18.2±0.2, 19.0±0.2, 19.9±0.2, 20.7±0.2, 21.7±0.2, 23.4±0.2, 24.2±0.2, and 27.9±0.2.

[0224] In some embodiments, a formulation is provided herein that includes a composition comprising polymorphic form 10. In some embodiments, the composition is substantially pure. For example, the composition may have a purity of at least about 90%. In some embodiments, the composition may have a purity of at least about 95%. In some embodiments, the composition may have a purity of at least about 98%. For example, the composition may have a purity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition is substantially free of other forms of the compound of formula (I). For example, in some embodiments, the composition is substantially free of other anhydrous forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of other forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of one or more other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of one or more other forms of the compound of formula (I). For example, the composition may contain less than about 15% of Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 11, non-stoichiometric or stoichiometric hydrates of Form 1, or a combination of two or more thereof.

[0225] In some embodiments, polymorphic Form 10 exhibits an endotherm at about 212-237° C. as measured by DSC. In some embodiments, polymorphic Form 10 exhibits an endotherm at about 234-245° C., e.g., about 237° C. In some embodiments, polymorphic Form 10 exhibits an exotherm at about 300-325° C., e.g., about 308° C. For example, in some embodiments, an endotherm and an exotherm are observed when using a scan rate of 10° C. per minute.

[0226] In some embodiments, polymorphic Form 10 has a melting point of about 364-372° C., e.g., about 369° C. In some embodiments, polymorphic Form 10 undergoes about a 0.6% weight loss as measured by TGA before about 100° C., about a 3.8% weight loss between about 100-170° C., and about a 7.1% weight loss between about 170-260° C.

[0227] In some embodiments, polymorphic Form 10 is prepared by a method comprising reslurrying a composition comprising the compound of Formula (I), including its amorphous and polymorphic forms, in a solvent or solvent mixture to produce Form 10 as a residual solid. In some embodiments, the composition comprising the compound of Formula (I) is a nonstoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the slurrying step is performed at about 50° C. In some embodiments, the method further comprises drying the residual solid, e.g., under reduced pressure. In some embodiments, the drying step is performed at a temperature of about 60° C. to 90° C., e.g., about 75° C.

[0228] In some embodiments, polymorph Form 10 is prepared by a method comprising reslurrying a composition comprising a nonstoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight of water in a solvent or solvent mixture to produce polymorph Form 10 as a residual solid. In some embodiments, the solvent is DMSO. In some embodiments, the solvent is a mixture with water, e.g., the solvent can be a mixture of water and DMSO. In some embodiments, water is present in an amount of about 5% by weight. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the reslurrying step is performed at about 50° C.

[0229] Formulations are provided herein that include a polymorph known as Form 11. Form 11 is an anhydrous polymorph of the compound of formula (I). In one embodiment, polymorph Form 11 has an XRPD pattern obtained with CuKα1 radiation with peaks at least at °2θ values ​​of 6.4±0.2, 18.5±0.2, and 22.4±0.2. In some embodiments, Form 11 has an XRPD pattern with peaks at least at °2θ values ​​of 6.4±0.2, 17.8±0.2, 18.5±0.2, 19.9±0.2, and 22.4±0.2. In some embodiments, Form 11 has an XRPD pattern with peaks at at least the following °2θ values: 6.4±0.2, 8.4±0.2, 17.8±0.2, 18.5±0.2, 19.9±0.2, 22.4±0.2, 24.5±0.2, and 26.8±0.2. For example, in some embodiments, Form 11 has an XRPD pattern with peaks at at least the following °2θ values: 6.4±0.2, 8.4±0.2, 17.8±0.2, 18.5±0.2, 19.9±0.2, 20.3±0.2, 22.4±0.2, 22.9±0.2, 24.5±0.2, and 26.8±0.2.

[0230] In some embodiments, a formulation is provided herein that includes a composition comprising polymorphic form 11. In some embodiments, the composition is substantially pure. For example, the composition may have a purity of at least about 90%. In some embodiments, the composition may have a purity of at least about 95%. In some embodiments, the composition may have a purity of at least about 98%. For example, the composition may have a purity of at least 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, the composition is substantially free of other forms of the compound of formula (I). For example, in some embodiments, the composition is substantially free of other anhydrous forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of other forms of the compound of formula (I). In some embodiments, the compositions contain less than 15% by weight of one or more other forms of the compound of formula (I), e.g., less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 1% by weight of one or more other forms of the compound of formula (I). For example, the composition may contain less than about 15% of Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, non-stoichiometric or stoichiometric hydrates of Form 1, or a combination of two or more thereof.

[0231] In some embodiments, polymorphic Form 11 exhibits an endotherm at about 215-230° C. as measured by DSC. In some embodiments, polymorphic Form 11 exhibits an exotherm at about 230-240° C., e.g., about 235° C. In some embodiments, polymorphic Form 11 exhibits an exotherm at about 300-315° C., e.g., about 310° C. For example, in some embodiments, an endotherm and an exotherm are observed when using a scan rate of 10° C. per minute.

[0232] In some embodiments, polymorphic form 11 has a melting point of about 368° C. In some embodiments, polymorphic form 11 undergoes a weight loss of about 0.8% as measured by TGA before about 100° C. and a weight loss of about 7.0% between about 100 and 249° C.

[0233] In some embodiments, polymorphic Form 11 is prepared by a method comprising reslurrying a composition comprising the compound of Formula (I), including its amorphous and polymorphic forms, in a solvent or solvent mixture to produce Form 11 as a residual solid. In some embodiments, the composition comprising the compound of Formula (I) is a nonstoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% water by weight. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the slurrying step is performed at about 50° C. In some embodiments, the method further comprises drying the residual solid, e.g., under reduced pressure. In some embodiments, the drying step is performed at a temperature of about 60° C. to 90° C., e.g., about 75° C.

[0234] In some embodiments, polymorphic Form 11 is prepared by a method comprising reslurrying a composition comprising a nonstoichiometric or stoichiometric hydrate of Form 1 having 1% to about 20% by weight water in a solvent or solvent mixture to produce polymorphic Form 11 as a residual solid. In some embodiments, the solvent is dimethylformamide (DMF). In some embodiments, the solvent is a mixture with water, e.g., the solvent can be a mixture of water and DMF. In some embodiments, water is present in an amount of about 5% by weight. In some embodiments, the reslurrying step is performed at room temperature. In some embodiments, the reslurrying step is performed at about 50° C. EXAMPLES

[0235] Example 1: Preparation of a single dose ready-to-use formulation Single dose reconstituted formulations were prepared containing either 0.015 mg / mL, 0.025 mg / mL or 0.115 mg / mL of polymorphic Form 1 of the compound of formula (I). The compound of formula (I) was prepared according to the process provided in US 2013 / 0267495, which is incorporated herein by reference in its entirety. The polymorphic Form 1 was prepared as described herein.

[0236] For a 0.015 mg / mL formulation: Water, sodium carboxymethylcellulose (CMC) (5.55 g / kg), polysorbate 80 (0.50 g / kg), sodium phosphate monobasic monohydrate (0.268 g / kg), sodium phosphate dibasic heptahydrate (2.44 g / kg), and sodium chloride (9.11 g / kg) were added to a 300 L first tank. The aqueous solution in the first tank was then filtered through a 0.2 μm polyethersulfone (PES) filter into a second tank where it was bulk sterilized. 0.15 g / kg of polymorphic Form 1 of the compound of formula (I), water for injection, and 0.5 g / kg of polysorbate 80 were added to a 30 L third tank to form a slurry containing 15 μg / mL of the compound of formula (I). The slurry was sterilized by overhead steam pressure and then added to the second tank containing the aqueous solution. The slurry was homogenized at 30 Hz and produced using the principle of overkill cycle (F0≧30). The mixture was aseptically mixed with sterile diluent to form a suspension with a concentration of 0.015 mg / mL of the compound of formula (I). The bulk solution temperature, monitored by the bottom TC, was maintained at 250° F., and the overhead pressure was maintained above the steam pressure introduced into the tank jacket (approximately 5 psi above). Steam was introduced into the tank through an air filter to maintain pressure and high temperature in order to maintain overhead pressure during venting of the top valve next to the mixer monitoring the TC above the tank. The steam pressure was monitored and bulk sterilization was performed. The suspension was then aseptically filled into 3 mL polypropylene vials using a Weiler 624 BFS machine with a target volume of 2.5 mL and a final concentration of 0.015 mg / mL of the compound of formula (I). Each vial contained 0.03 mg of Form 1 of the compound of formula (I) in 2 mL of phosphate buffered saline. The vials were labeled and packaged.

[0237] For a 0.035 mg / mL formulation: Water, sodium carboxymethylcellulose (CMC) (5.55 g / kg), polysorbate 80 (0.50 g / kg), sodium phosphate monobasic monohydrate (0.268 g / kg), sodium phosphate dibasic heptahydrate (2.44 g / kg), and sodium chloride (9.11 g / kg) were added to a 300 L first tank. The aqueous solution in the first tank was then filtered through a 0.2 μm polyethersulfone (PES) filter into a second tank where it was bulk sterilized. 0.35 g / kg of polymorphic Form 1 of the compound of formula (I), water for injection, and 0.5 g / kg of polysorbate 80 were added to a 30 L third tank to form a slurry containing 35 μg / mL of the compound of formula (I). The slurry was sterilized by overhead steam pressure and then added to the second tank containing the aqueous solution. The slurry was homogenized at 30 Hz and produced using the principle of overkill cycle (F0≧30). The mixture was aseptically mixed with sterile diluent to form a suspension with a concentration of 0.035 mg / mL of the compound of formula (I). The bulk solution temperature, monitored by the bottom TC, was maintained at 250° F., and the overhead pressure was maintained above the steam pressure introduced into the tank jacket (approximately 5 psi above). Steam was introduced into the tank through an air filter to maintain pressure and high temperature in order to maintain overhead pressure during venting of the top valve next to the mixer monitoring the TC above the tank. The steam pressure was monitored and bulk sterilization was performed. The suspension was then aseptically filled into 3 mL polypropylene vials using a Weiler 624 BFS machine with a target volume of 2.5 mL and a final concentration of 0.035 mg / mL of the compound of formula (I). Each vial contained 0.07 mg of Form 1 of the compound of formula (I) in 2 mL of phosphate buffered saline. The vials were labeled and packaged.

[0238] For the 0.075 mg / mL formulation: Water, sodium carboxymethylcellulose (CMC) (5.55 g / kg), polysorbate 80 (0.50 g / kg), sodium phosphate monobasic monohydrate (0.268 g / kg), sodium phosphate dibasic heptahydrate (2.44 g / kg), and sodium chloride (9.11 g / kg) were added to a 300 L first tank. The aqueous solution in the first tank was then filtered through a 0.2 μm polyethersulfone (PES) filter into a second tank where it was bulk sterilized. 0.75 g / kg of polymorphic Form 1 of the compound of formula (I), water for injection, and 0.5 g / kg of polysorbate 80 were added to a 30 L third tank to form a slurry containing 75 μg / mL of the compound of formula (I). The slurry was sterilized by overhead steam pressure and then added to the second tank containing the aqueous solution. The slurry was homogenized at 30 Hz and produced using the principle of overkill cycle (F0≧30). The mixture was aseptically mixed with sterile diluent to form a suspension with a concentration of 0.075 mg / mL of the compound of formula (I). The bulk solution temperature, monitored by the bottom TC, was maintained at 250° F., and the overhead pressure was maintained above the steam pressure introduced into the tank jacket (approximately 5 psi above). Steam was introduced into the tank through an air filter to maintain pressure and high temperature in order to maintain overhead pressure during venting of the top valve next to the mixer monitoring the TC above the tank. The steam pressure was monitored and bulk sterilization was performed. The suspension was then aseptically filled into 3 mL polypropylene vials using a Weiler 624 BFS machine with a target volume of 2.5 mL and a final concentration of 0.075 mg / mL of the compound of formula (I). Each vial contained 0.15 mg of Form 1 of the compound of formula (I) in 2 mL of phosphate buffered saline. The vials were labeled and packaged.

[0239] For the 0.115 mg / mL formulation: Water, sodium carboxymethylcellulose (CMC) (5.55 g / kg), polysorbate 80 (0.50 g / kg), sodium phosphate monobasic monohydrate (0.268 g / kg), sodium phosphate dibasic heptahydrate (2.44 g / kg), and sodium chloride (9.11 g / kg) were added to a 300 L first tank. The aqueous solution in the first tank was then filtered through a 0.2 μm polyethersulfone (PES) filter into a second tank where it was bulk sterilized. 0.15 g / kg of polymorphic Form 1 of the compound of formula (I), water for injection, and 0.5 g / kg of polysorbate 80 were added to a 30 L third tank to form a slurry containing 115 μg / mL of the compound of formula (I). The slurry was sterilized by overhead steam pressure and then added to the second tank containing the aqueous solution. The slurry was homogenized at 30 Hz and produced using the principle of overkill cycle (F0≧30). The mixture was aseptically mixed with sterile diluent to form a suspension with a concentration of 0.115 mg / mL of the compound of formula (I). The bulk solution temperature, monitored by the bottom TC, was maintained at 250° F., and the overhead pressure was maintained above the steam pressure introduced into the tank jacket (approximately 5 psi above). Steam was introduced into the tank through an air filter to maintain pressure and high temperature in order to maintain overhead pressure during venting of the top valve next to the mixer monitoring the TC above the tank. The steam pressure was monitored and bulk sterilization was performed. The suspension was then aseptically filled into 3 mL polypropylene vials using a Weiler 624 BFS machine with a target volume of 2.5 mL and a final concentration of 0.035 mg / mL of the compound of formula (I). Each vial contained 0.23 mg of Form 1 of the compound of formula (I) in 2 mL of phosphate buffered saline. The vials were labeled and packaged.

[0240] Example 2: Polymorphism Screening Polymorphic forms of the compound of formula (I) were used in the prepared formulation described above in Example 1. Polymorph screening was performed on the compound of formula (I) to determine solubility, polymorphism, and thermodynamic stability.

[0241] A. Analysis of the starting solids X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) scans of the starting solid compound of formula (I) showed that the starting solid was a crystalline material, a mixture of Form 1 and non-stoichiometric or stoichiometric hydrates of Form 1 having 1% to about 20% water by weight. According to the DSC scan (Figure 12B), the solid exhibited a broad endotherm between 50°C and 100°C, as well as a sharp exotherm at 284°C, with the solid finally melting at 364°C. According to the TGA scan (Figure 12C), a weight loss of 1.4% was observed before 100°C.

[0242] The solubility of the starting solid was determined gravimetrically and showed that the compound exhibited low solubility in all tested solvents except DMF and DMSO at room temperature and 50° C. The results of the solubility data test at room temperature and 50° C. are shown in Table 3.

[0243] Table 3. Solubility data for starting solids (non-stoichiometric or stoichiometric hydrates of Form 1) TIFF0007630905000008.tif173128

[0244] Reslurry experiments in various solvents were performed. Approximately 30-80 mg of the starting solid (non-stoichiometric or stoichiometric hydrate of Form 1 with 1% to approximately 20% water by weight) was slurried in 39 different solvents (pure and binary; organic solvent / water ratio (V / V) 95% / 5%) at room temperature and 50°C for 5 days. Three solvates, one hydrate, and 11 nonsolvated forms were identified. The " after a particular form * ", for example, Form 2 * indicates that the forms exhibited similar XRD scans with minor differences and were considered to belong to the same class. In general, the identified forms exhibited multiple endotherms / exotherms on the Differential Scanning Calorimetry (DSC) scans, with Form 9 exhibiting a single endotherm. XRD scans of both wet and dry samples were performed (Figure 12A (Dry sample)). The data are shown in Tables 4 and 5 below.

[0245] Table 4: Results of slurry experiments at room temperature TIFF0007630905000009.tif172153

[0246] Table 5: Results of slurry experiment at 50°C TIFF0007630905000010.tif172153

[0247] Slurry experiments identified three solvated forms from wet samples (solvates 1, 2, and 3); two non-stoichiometric hydrates of Form 1 (forms 12 and 13); and eleven unsolvated forms (forms 1-11). In some cases, similar XRD scans with minor differences were obtained. These were considered to be part of the same class (i.e., the same form). For example, Form 2 and Form 2 * The XRD scans of were similar and were considered to belong to the same class. The solvated forms were obtained from wet sample analysis and after drying the samples showed different XRD.

[0248] Solvate 1 was obtained from acetone at room temperature, which after drying gave a solid with low crystallinity. Solvate 2 was obtained from acetone (at room temperature) and from acetone / water (at room temperature), which after drying gave form 4. ** The solvate 3 was obtained from EtOH / water at room temperature to give Form 2 after drying.

[0249] B. Form 1 The experiments that produced Form 1 are shown in Table 6 below. Generally, Form 1 was obtained by drying Form 13 or Form 12. Form 1 can be considered a dehydrated hydrate. Reslurrying in a number of binary solvents (with 5% water) produced Form 1. The purity of the residual solid was 98.9%. The KF of the Form 1 (one sample) solid was 5.8%, and the residual MeOH of the Form 1 solid was 0.01%. A TGA scan of the completely dried Form 1 solid was performed (Figure 1C). A weight loss of 0.33% was observed prior to 100°C.

[0250] Form 1 exhibited sharp crystalline peaks on the XRD scan (Figure 1A). The XRD peaks of Form 1 are shown in Table 7 below. According to the DSC scan (Figure 1B), the solid exhibited a broad endotherm between 50 and 100°C, a sharp exotherm at 281°C, and a melting point of 363°C. Form 1 has approximate dimensions a [Å] = 29.062, b [Å] = 23.945, c [Å] = 7.245, and approximate volume cell [Å]. 3 It has a primitive orthorhombic crystal structure with an average molecular mass (Mm / cell) = 5,041.7, and the space group defined as Pbca(61).

[0251] Form 1 solid was dried overnight under vacuum at 75° C. and XRD, DSC, and TGA scans were performed. Comparison of the first and second (after drying overnight under vacuum at 75° C.) XRD scans showed no change. However, the DSC scan showed that the endotherm was not present. The loss of the initial peak on the DSC scan showed no effect on the XRD trace. This indicates that the broad endotherm between 50-100° C. on the DSC scan was due to free solvent.

[0252] Form 1 solid was heated to 305° C. in a DSC chamber (beyond the endotherm / exotherm at about 280° C.) and then scanned by XRD. Comparison of the first and third XRD and DSC scans indicates that Form 1 was transformed to Form 9 after heating to 305° C. It can be concluded that the endotherm / exotherm at about 280° C. may be due to a melting / crystallization phenomenon.

[0253] Form 1 tended to convert to a non-stoichiometric or stoichiometric hydrate of Form 1 (Form 13) with 1% to about 20% water by weight above 40-50% relative humidity. The hydrate lost water below 30% relative humidity. Form 1 converts to Form 13 when exposed to air.

[0254] The dynamic vapor sorption (DVS) scan of the Form 1 solid showed a water absorption of 17% at 90% relative humidity (Figure 1D). The XRD data indicated that the solid used in the DVS study was converted to a hydrated form before the start of the DVS study. However, there was a loss of water at 0% relative humidity, likely indicating that the solid was Form 1.

[0255] Table 6. Summary of the experiments that produced Form 1 TIFF0007630905000011.tif165153 * The amount of water in the binary solvent is 5%

[0256] Table 7. XRD peaks of Form 1 TIFF0007630905000012.tif158139

[0257] C. Form 2, 2 * , and 2 *** Form 2, 2 * , and 2 ** The experiments that produced the above are shown in Table 8 below. * , and 2 ** XRD scans of the compounds were performed (Figures 2A, 2D, and 2G are Forms 2 and 2, respectively). * , and 2 ** The XRD scans of Forms 2 and 2 are shown. * The XRD peaks of Forms 2 and 2 are shown below in Tables 9 and 10, respectively. DSC scans were also performed (Figures 2B, 2E, and 2H are Forms 2 and 2, respectively). * , and 2 ** The DSC scans of Forms 2 and 2 are shown. * , and 2 ** Each of them showed a broad endotherm between 50°C and 100°C, as well as multiple endotherms and exotherms before melting at 363°C. The broad endotherm before 100°C may be due to the presence of water / solvent in the solid. Form 2 was obtained from acetonitrile, and Form 2 * is obtained from ethanol and in the form 2 ** was obtained from n-propanol / 5% water.

[0258] The TGA scan of Form 2 (FIG. 2C) showed a weight loss of 2.7% before 116° C. FIG. 2F shows Form 2 * 4 shows a TGA scan of

[0259] A PLM photograph was taken of Form 2, which shows that the particle size of this solid was approximately 50um.

[0260] The Form 2 solid was heated in a DSC instrument to 90°C (over a broad endotherm between 50-100°C); to 270°C (over an endotherm / exotherm at about 240°C); and finally to 330°C (over an exotherm at about 330°C). The residual solid was analyzed by XRD. According to the first and second XRD and DSC scans, the morphology did not change before and after heating to 90°C. The broad endotherm between 50-100°C could be free solvent or hydrate. According to the first and third XRD and DSC scans, after heating the Form 2 sample to 270°C, the solid was converted to a low crystallinity solid. According to the first and fourth XRD and DSC scans, after heating the sample to 330°C, the solid was converted to Form 9. Thus, the exotherm at about 290°C was a recrystallization phenomenon. According to the XRD and DSC overlay, Form 2 * The behavior was similar to that of Form 2.

[0261] Forms 2 and 2 * No residual acetonitrile or EtOH was detected in the solution.

[0262] (Table 8) Form 2, 2 * , and 2 ** Overview of the experiment that generated TIFF0007630905000013.tif68153 * The amount of water in the binary solvent is 5%

[0263] Table 9. XRD peaks of Form 2 TIFF0007630905000014.tif225140

[0264] (Table 10) Form 2 * XRD peaks TIFF0007630905000015.tif180140TIFF0007630905000016.tif98140

[0265] D. Form 3 The experiments that produced Form 3 are shown below in Table 11. XRD and DSC scans were obtained for Form 3 (Figures 3A and 3B, respectively). Table 12 below shows the XRD peaks for Form 3. Multiple exotherms and endotherms were observed from the DSC scan of Form 3.

[0266] A TGA scan of Form 3 was obtained (FIG. 3C) and the scan showed a 1.6% weight loss of the solid before 81° C., followed by a 1.7% weight loss from 81° C. to 169° C.

[0267] Form 3 was obtained from IPAc at room temperature, whereas Form 3 * was obtained by reslurrying in n-butyl acetate.

[0268] Table 11 Form 3 and Form 3 * Overview of the experiment that generated TIFF0007630905000017.tif31153

[0269] Table 12. XRD peaks of Form 3 TIFF0007630905000018.tif203140TIFF0007630905000019.tif91140

[0270] E. Form 4 Form 4, 4 * , and 4 ** The experiments that produced the above are shown in Table 13 below. Forms 4, 4 * , and 4 ** XRD was obtained for Form 4 (FIGS. 4A, 4D, and 4G, respectively). Tables 14 and 15 below show Form 4 and Form 4, respectively. * The XRD peaks of Form 4, 4 * , and 4 **DSC scans were also performed on Form 4 (Figures 4B, 4E, and 4H, respectively). The DSC scans showed that Form 4 exhibited a broad endotherm between 50°C and 100°C, followed by multiple endotherms / exotherms, and then a melt at approximately 367°C. * and 4 ** showed a similar DSC pattern to Form 4.

[0271] form 4, form 4 * , and Form 4 ** TGA scans of Form 4 were obtained (FIGS. 4C, 4F, and 4I, respectively). Form 4 exhibited a weight loss of 8.3% prior to 200° C., and Form 4 * In the case of Form 4, the weight loss was 4.4% before 102°C, followed by a weight loss of 0.5% between 102°C and 250°C. ** showed three stages of weight loss, 2.8%, 1.9%, and 1.3%, respectively.

[0272] These solid forms were obtained from methyl acetate, n-propanol, MIBK, MtBE, ethyl acetate, acetone / water, and ethyl acetate / water.

[0273] (Table 13) Form 4, 4 * , and 4 ** Overview of the experiment that generated TIFF0007630905000020.tif121153 * The amount of water in the binary solvent is 5%

[0274] Table 14. XRD peaks of Form 4 TIFF0007630905000021.tif195140

[0275] (Table 15) Form 4 * XRD peaks TIFF0007630905000022.tif210139

[0276] F. Forms 5 and 5 * Forms 5 and 5 * The experiments that produced Forms 5 and 5 are shown in Table 16 below. *XRD scans were obtained for Form 5 (Figures 5A and 5D, respectively). The XRD peaks for Form 5 are shown below in Table 17. A DSC scan of Form 5 was also performed, and the scan showed a broad endotherm between 50°C and 100°C, as well as multiple endotherms and exotherms before melting at 363°C (Figure 5B).

[0277] The TGA scan of Form 5 solid showed a 3.1% weight loss before 100 °C, followed by a 1.7% weight loss from 100 °C to 250 °C (Figure 5C).

[0278] Forms 5 and 5 * Form 12 was obtained by slurrying in MtBE at room temperature and 50° C. The wet solid was Form 5 * whereas the dried solid exhibited Form 5.

[0279] Table 16 Forms 5 and 5 * Overview of the experiment that generated TIFF0007630905000023.tif31153

[0280] Table 17. XRD peaks of Form 5 TIFF0007630905000024.tif158139TIFF0007630905000025.tif120139

[0281] G. Form 6 The experiments that produced Form 6 are shown below in Table 18. XRD and DSC scans were obtained for Form 6 (Figures 6A and 6B, respectively). The DSC scan showed that the solid exhibited a small exotherm at 250°C and a sharp melting endotherm at 358°C.

[0282] Form 6 was obtained by slurrying the starting material in IPA and IPA / 5% water at room temperature and 50°C.

[0283] Table 18. Summary of experiments that produced Form 6 TIFF0007630905000026.tif38153 * The amount of water in the binary solvent is 5%

[0284] H. Form 7 The experiments that produced Form 7 are shown in Table 19 below. XRD and DSC scans of Form 7 were obtained (Figures 7A and 7B, respectively). The XRD peaks for Form 7 are shown in Table 20 below. The DSC scan showed that the solid exhibited two exotherms at 227°C and 299°C, followed by a melting endotherm at 365°C. Form 7 showed low crystallinity on XRD. The double exotherms on the DSC scan may be related to the low crystallinity observed on the XRD scan.

[0285] The TGA scan of Form 7 solid showed a 12% weight loss prior to 200° C. (FIG. 7C).

[0286] Form 7 was obtained from MEK and MEK / 5% water at room temperature and 50°C.

[0287] Table 19. Summary of experiments that produced Form 7 TIFF0007630905000027.tif38153 * The amount of water in the binary solvent is 5%

[0288] Table 20. XRD peaks of Form 7 TIFF0007630905000028.tif218140

[0289] I. Form 8 The experiments that produced Form 8 are shown in Table 21 below. XRD and DSC scans of Form 8 were obtained (Figures 8A and 8B, respectively). The XRD peaks for Form 8 are shown in Table 22 below. The DSC scan showed that the solid exhibited two endotherms at 205°C and 231°C, followed by an exotherm at 279°C, followed by a melting endotherm at 362°C. Form 8 exhibited low crystallinity on the XRD scan. The double exotherm on the DSC scan may confirm the low crystallinity seen on the XRD (low crystallinity material is converted to a higher crystallinity solid).

[0290] The TGA scan of Form 8 showed a 4.2% weight loss before 190° C., followed by a 3.9% weight loss from 190° C. to 261° C. (FIG. 8C).

[0291] Form 8 was obtained from MIBK at room temperature and at 50° C. Reslurrying with MIBK / 5% water does not yield the same morphology.

[0292] Table 21. Summary of experiments that produced Form 8 TIFF0007630905000029.tif23153

[0293] Table 22. XRD peaks of Form 8 TIFF0007630905000030.tif120142

[0294] J. Form 9 The experiments that produced Form 9 are shown in Table 23 below. XRD and DSC scans of Form 9 were obtained (Figures 9A and 9B, respectively). The XRD peaks for Form 9 are shown in Table 24 below. The DSC scan showed that the solid exhibited a single melting endotherm at 364°C. Form 9 has approximate dimensions a [Å] = 17.135, b [Å] = 14.342, c [Å] = 10.186; α(deg) = 90, β(deg) = 95.99, γ(deg) = 90, and approximate volume cell [Å]. 3 / cell] = 2,489.5, and has a simple monoclinic crystal structure with the space group defined as P21 / c (14).

[0295] The TGA scan of Form 9 showed a weight loss of 0.28% before 100° C. (FIG. 9C).

[0296] The other form appeared to convert to Form 9 when heated just below melting at 364° C. This was confirmed for Forms 1 and 2.

[0297] The DVS scan of Morphology 9 showed a water absorption rate of 0.8% at 90% relative humidity. Morphology 9 did not change morphology before and after DVS scanning (FIG. 9D).

[0298] Table 23. Summary of the experiments that produced Form 9 TIFF0007630905000031.tif61153 * The amount of water in the binary solvent is 5%

[0299] Table 24. XRD peaks of Form 9 TIFF0007630905000032.tif135140

[0300] K. Forms 10 and 10 * Forms 10 and 10 * The experiments that produced Forms 10 and 10 are shown in Table 25 below. * XRD scans were obtained for Form 10 (Figures 10A and 10D, respectively). The XRD peaks for Form 10 are shown in Table 26 below. Forms 10 and 10 * A DSC scan was also obtained of the compound, which showed multiple endotherms / exotherms followed by a melt at 367° C. (FIGS. 10B and 10E, respectively).

[0301] Forms 10 and 10 * Forms 10 and 10 were obtained by drying of the amorphous solids (obtained by reslurrying in DMSO and DMSO / water at room temperature and 50° C.). * Both are related to DMSO.

[0302] The TGA scan of Form 10 solid showed a 0.6% weight loss before 100 °C, followed by a 3.8% weight loss from 100 °C to 170 °C, followed by a 7.1% weight loss from 170 °C to 260 °C (Figure 10C).

[0303] Table 25 Forms 10 and 10 * Overview of the experiment that generated TIFF0007630905000033.tif38153 * The amount of water in the binary solvent is 5%

[0304] Table 26. XRD peaks of Form 10 TIFF0007630905000034.tif233140

[0305] L. Forms 11 and 11 * Forms 11 and 11 * The experiments that produced Forms 11 and 11 are shown in Table 27 below. * XRD scans were obtained for Form 11 and Form 11 (FIGS. 11A and 11D, respectively). * The XRD peaks of Forms 11 and 11 are shown in Tables 28 and 29 below, respectively. * DSC scans were also obtained for (FIGS. 11B and 11E, respectively). According to the DSC scans, the solid exhibited multiple endotherms / exotherms, eventually melting at 368° C. An amorphous halo was observed in the XRD of both forms. Also, the double exotherm on DSC for both forms may be related to the amorphous halo observed on the XRD scans.

[0306] Forms 11 and 11 * TGA scans were obtained for Form 11 (FIGS. 11C and 11F, respectively). Form 11 solid showed a 0.8% weight loss before 100° C., followed by a 7.0% weight loss from 100° C. to 249° C. Form 11 * The solid exhibited a 1.0% weight loss prior to 100°C, followed by a 7.0% weight loss prior to 250°C.

[0307] Forms 11 and 11 * was obtained from DMF and DMF / 5% water at room temperature and 50°C.

[0308] Table 27 Forms 11 and 11 * Overview of the experiment that generated TIFF0007630905000035.tif46153 * The amount of water in the binary solvent is 5%

[0309] Table 28. XRD peaks of Form 11 TIFF0007630905000036.tif188139

[0310] (Table 29) Form 11 * XRD peaks TIFF0007630905000037.tif195139

[0311] Further experiments with Form 1 of compound of formula (I) showed that when Form 1 was exposed to moisture (Figures 15A-15D), Form 1 formed non-stoichiometric or stoichiometric hydrates. The crystal lattice of Form 1 expanded when water was absorbed, producing XRD peaks at about 5 degrees, about 7 degrees, and about 11 degrees while maintaining the main XRD pattern. The hydrate of Form 1 of compound of formula (I) (Form 11) was fully reversible, losing water and converting Form 11 to the hydrated form of Form 1 and to anhydrous Form 1 when exposed to RH% less than 20%.

[0312] M. Form 13 and Form 12 The experiments that produced Forms 13 and 12 are shown below in Tables 30 and 32, respectively. Forms 12 and 13 are examples of non-stoichiometric hydrates of Form 1 having between 1% and about 20% water by weight. XRD scans were obtained for Forms 13 and 12 (Figures 13A and 12A, respectively). The XRD peaks for Form 13 are shown below in Table 31. DSC scans were also obtained for Forms 13 and 12 (Figures 13B and 12B, respectively). The DSC scan showed that Form 13 solids exhibited a broad endotherm between 50°C and 100°C, followed by a small exotherm at 278°C, and a melting endotherm at 363°C. The DSC scan showed that Form 12 solids exhibited a broad endotherm between 50°C and 100°C, followed by a sharp exotherm at 283°C, and a melting endotherm at 364°C.

[0313] The purity of the Form 13 sample was 98.8%, and the KF of the undried Form 13 sample was 35.7%. The DVS scan of the Form 13 solid showed a water adsorption rate of 17% at 90% relative humidity (Figure 13D). Upon drying, Form 13 was converted to Form 1.

[0314] The TGA scan of Form 13 solid showed a weight loss of 1.9% prior to 100° C. (FIG. 13C).

[0315] Form 13 solid was heated to 170°C in a DSC chamber (over the endotherm between 50-100°C) and then scanned by XRD. Comparison of the first and second XRD and DSC scans showed that Form 13 was converted to Form 1 after heating to 170°C. It can be concluded that the endotherm between 50-100°C is due to bound water.

[0316] Form 13 has approximate dimensions a [Å] = 33.759, b [Å] = 22.590, c [Å] = 7.386, and approximate volume cell [Å 3 / cell] = 5,632.5, and has a simple orthorhombic crystal structure with the space group defined as Pbca(61).

[0317] Form 13 solid was heated to 330° C. in a DSC chamber (over an endotherm / exotherm at about 300° C.) and then scanned by XRD. Comparison of the first and third XRD and DSC scans showed that Form 13 was converted to Form 9 after heating to 170° C. It can be concluded that the endotherm / exotherm is due to a melting / crystallization phenomenon.

[0318] Table 30. Summary of experiments that produced Form 13 TIFF0007630905000038.tif180153 * The amount of water in the binary solvent is 5%

[0319] Table 31 XRD peaks of Form 13 TIFF0007630905000039.tif202137TIFF0007630905000040.tif61137

[0320] Table 32. Summary of experiments that produced Form 12 TIFF0007630905000041.tif83153 * The amount of water in the binary solvent is 5%

[0321] N. Solvates 1-3 The experiments that produced solvates 1, 2, and 3 are shown below in Table 33. The solids of solvates 1 and 2 were exposed to air overnight and then analyzed by XRD. After analysis, the solids were dried under vacuum at 50° C. and then analyzed again by XRD.

[0322] After exposure to air overnight, solvate 1 was converted to a less crystalline form, and the sample was still a less crystalline solid after drying at 50° C. After exposure to air overnight, the XRD pattern of solvate 2 changed slightly, and after drying at 50° C., the morphology remained the same as when the solid was exposed to air overnight.

[0323] Table 33. Summary of experiments to generate solvates 1-3 TIFF0007630905000042.tif45153 * The amount of water in the binary solvent is 5%

[0324] Example 2: Competitive Slurry Experiments Between Polymorphic Forms To elucidate the thermodynamic stability between the different forms, several competitive slurry experiments were performed: Form 1, Form 2, Form 2 * , form 3, form 4, form 4 * , form 4 ** , form 5, form 7, form 8, form 9, form 10, form 11, form 11 * Form 13 (10 mg each) were mixed and slurried in 2 mL of solvent at both room temperature and 50° C. The solids were slurried for 3-5 days and then analyzed by XRD. Analytical data showed that Form 2 * was the most stable form in MeOH, EtOH, and acetone systems at both room temperature and 50 °C. Form 4 or 4 * Form 13 was the most stable in water at room temperature and 50° C. Table 34 shows the XRD scan results from the competitive slurry experiments.

[0325] Table 34. XRD scan results of competitive slurry experiments TIFF0007630905000043.tif90153

[0326] Several competitive slurry experiments were performed to elucidate the thermodynamic stability between Form 13 and Form 9. 15 mg of solids of Form 1, Form 9, and Form 13 were mixed in 1 mL of toluene, IPAc, and n-butyl acetate and slurried at room temperature and 50 °C for 3 days.

[0327] The remaining solids were analyzed by XRD. After 3 days of slurrying, it was difficult to say whether Form 13 or Form 9 was more stable. The XRD scan results of this experiment are shown below in Table 35.

[0328] Table 35. XRD scan results of competitive slurry experiments TIFF0007630905000044.tif53153

[0329] Other Aspects It should be understood that the foregoing description is intended to be illustrative, but not limiting, of the scope of the present disclosure, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the appended claims.

Claims

1. Formula (I) 1. A method for preparing a single dose, ready-to-use formulation comprising the compound of (a) providing an aqueous solution; (b) providing a slurry comprising a compound of formula (I), the compound being at least 50% by weight polymorphic Form 1, and the compound being free of or containing about 5% or less by weight polymorphic Form 9, wherein polymorphic Form 1 has an X-ray powder diffraction pattern comprising peaks at °2θ values ​​of 6.8±0.2, 9.3±0.2, 12.4±0.2, 13.9±0.2, 16.5±0.2, 18.5±0.2, 19.2±0.2, and 24.6±0.2, and polymorphic Form 9 has an X-ray powder diffraction pattern comprising peaks at °2θ values ​​of 4.9±0.2, 15.3±0.2, 16.5±0.2, 18.6±0.2, 21.1±0.2, 22.4±0.2, 24.1±0.2, and 25.2±0.2; (c) mixing the aqueous solution with the slurry to form a suspension; and (d) filling the suspension into a container to prepare a single dose reconstituted formulation. The method comprising:

2. 10. The method of claim 1, wherein the aqueous solution is sterilized by filtration or heat, or by a combination of filtration and heat.

3. The method of any one of claims 1 to 2, wherein the slurry is sterilized by heat.

4. 4. The method of any one of claims 1 to 3, wherein mixing of the aqueous solution and the slurry to form a suspension is performed aseptically and is subsequently filled into the container aseptically.

5. 5. The method of any one of claims 1 to 4, wherein the final single-dose ready-to-use formulation is sterile.

6. The method of any one of claims 1 to 5, wherein the aqueous solution comprises a buffer.

7. The method of any one of claims 1 to 6, wherein the aqueous solution comprises an excipient.

8. The method of any one of claims 6 to 7, wherein the buffer is a phosphate buffer.

9. 9. The method of claim 8, wherein the phosphate buffer is selected from the group consisting of sodium phosphate dibasic, sodium phosphate monobasic, potassium phosphate monobasic, potassium phosphate dibasic, and mixtures thereof.

10. 10. The method of any one of claims 8 to 9, wherein the phosphate buffer is a mixture of sodium phosphate dibasic heptahydrate and sodium phosphate monobasic monohydrate.

11. 11. The method of any one of claims 7 to 10, wherein the excipient comprises a surfactant, a viscosity enhancing agent, or a mixture thereof.

12. 12. The method of claim 11, wherein the thickening agent is a water-soluble cellulose derivative.

13. 13. The method of any one of claims 11 to 12, wherein the surfactant is a polysorbate.

14. 14. The method according to any one of claims 12 to 13, wherein the water-soluble cellulose derivative is sodium carboxymethylcellulose.

15. 15. The method of any one of claims 11-14, wherein the aqueous solution comprises from about 0.01 g / kg to about 50 g / kg, from about 0.1 g / kg to about 50 g / kg, from about 1 g / kg to about 25 g / kg, from about 1 g / kg to about 10 g / kg, from about 1 g / kg to about 7.5 g / kg, from about 1 g / kg to about 5.5 g / kg, from about 1 g / kg to about 2.5 g / kg, from about 2.5 g / kg to about 50 g / kg, from about 5 g / kg to about 50 g / kg, from about 10 g / kg to about 50 g / kg, from about 25 g / kg to about 50 g / kg, from about 2.5 g / kg to about 7.5 g / kg, from about 5 g / kg to about 10 g / kg, or from about 10 g / kg to about 20 g / kg of thickening agent.

16. The method of any one of claims 11 to 15, wherein the aqueous solution comprises about 5.5 g / kg of a thickening agent.

17. The aqueous solution may be from about 0.01 g / kg to about 5 g / kg, from about 0.01 g / kg to about 2.5 g / kg, from about 0.01 g / kg to about 1 g / kg, from about 0.01 g / kg to about 0.75 g / kg, from about 0.01 g / kg to about 0.5 g / kg, from about 0.01 g / kg to about 0.25 g / kg, from about 0.025 g / kg to about 5 g / kg, from about 0.05 g / kg to about 5 g / kg, from about 1 g / kg to about 5 g / kg, from about 0.1 g / kg to about 5 g / kg, 0.1 g / kg to about 2.5 g / kg, from about 0.1 g / kg to about 1 g / kg, from about 0.1 g / kg to about 0.75 g / kg, from about 0.1 g / kg to about 0.5 g / kg, from about 0.1 g / kg to about 0.25 g / kg, from about 0.25 17. The method of any one of claims 11-16, comprising about 0.5 g / kg to about 5 g / kg, about 1 g / kg to about 5 g / kg, about 2.5 g / kg to about 5 g / kg, about 0.25 g / kg to about 0.75 g / kg, about 0.5 g / kg to about 1 g / kg, or about 1 g / kg to about 2 g / kg of the surfactant.

18. The method of any one of claims 11 to 17, wherein the aqueous solution comprises about 0.5 g / kg of a surfactant.

19. 19. The method of any one of claims 11 to 18, wherein the aqueous solution comprises about 5.55 g / kg sodium carboxymethylcellulose and about 0.5 g / kg polysorbate 80.

20. 20. The method of any one of claims 11 to 19, wherein the buffer is phosphate buffered saline.

21. The slurry is from about 0.001 g / kg to about 5 g / kg, from about 0.001 g / kg to about 2.5 g / kg, from about 0.001 g / kg to about 1 g / kg, from about 0.001 g / kg to about 0.75 g / kg, from about 0.001 g / kg to about 0.5 g / kg, from about 0.001 g / kg to about 0.25 g / kg, from about 0.001 g / kg to about 0.01 g / kg, from about 0.01 g / kg to about 5 g / kg, from about 0.01 g / kg to about 2.5 g / kg, from about 0.01 g / kg to about 1 g / kg, from about 0.01 g / kg to about 0.75 g / kg, from about 0.01 g / kg to about 0.5 g / kg, from about 0.01 g / kg to about 0.25 g / kg, from about 0.1 g / kg to about 2.5 21. The method of any one of claims 1-20, comprising administering to a patient a dose of about 0.1 g / kg to about 1 g / kg, about 0.1 g / kg to about 0.75 g / kg, about 0.1 g / kg to about 0.5 g / kg, about 0.1 g / kg to about 0.25 g / kg, about 0.25 g / kg to about 5 g / kg, about 0.5 g / kg to about 5 g / kg, about 1 g / kg to about 5 g / kg, about 2.5 g / kg to about 5 g / kg, about 0.25 g / kg to about 0.75 g / kg, about 0.5 g / kg to about 1 g / kg, or about 1 g / kg to about 2 g / kg of the compound of formula (I).

22. 22. The method of any one of claims 1-21, wherein the slurry comprises about 0.15 g / kg, about 0.35 g / kg, about 0.75 g / kg or about 1.15 g / kg of the compound of formula (I).

23. 23. The method of any one of claims 1 to 22, wherein the compound of formula (I) contains no more than about 1% by weight of Form 9.

24. 24. The method of any one of claims 1 to 23, wherein the compound of formula (I) contains less than about 0.1% by weight of Form 9.

25. 25. The method of any one of claims 1 to 24, wherein the slurry comprises an excipient.

26. 26. The method of claim 25, wherein the excipient comprises a surfactant.

27. 27. The method of claim 26, wherein the surfactant is a polysorbate.

28. The slurry is from about 0.01 g / kg to about 5 g / kg, 0.01 g / kg to about 2.5 g / kg, from about 0.01 g / kg to about 1 g / kg, from about 0.01 g / kg to about 0.75 g / kg, from about 0.01 g / kg to about 0.5 g / kg, from about 0.01 g / kg to about 0.25 g / kg, from about 0.025 g / kg to about 5 g / kg, from about 0.05 g / kg to about 5 g / kg, from about 1 g / kg to about 5 g / kg, from about 0.1 g / kg to about 5 g / kg, 0.1 g / kg to about 2.5 g / kg, from about 0.1 g / kg to about 1 g / kg, from about 0.1 g / kg to about 0.75 g / kg, from about 0.1 g / kg to about 0.5 g / kg, from about 0.1 g / kg to about 0.25 g / kg, from about 0.25 28. The method of any one of claims 26-27, comprising about 0.25 g / kg to about 5 g / kg, about 0.25 g / kg to about 2.5 g / kg, about 0.25 g / kg to about 0.75 g / kg, about 0.5 g / kg to about 5 g / kg, about 0.5 g / kg to about 2.5 g / kg, about 0.5 g / kg to about 1 g / kg, about 1 g / kg to about 5 g / kg, about 2.5 g / kg to about 5 g / kg, or about 1 g / kg to about 2 g / kg of the surfactant.

29. 29. The method of any one of claims 26 to 28, wherein the slurry comprises about 0.5 g / kg of surfactant.

30. 30. The method of any one of claims 26 to 29, wherein the slurry comprises about 0.15 g / kg of the compound of formula (I) and about 0.5 g / kg of polysorbate 80.

31. 30. The method of any one of claims 26 to 29, wherein the slurry comprises about 0.35 g / kg of the compound of formula (I) and about 0.5 g / kg of polysorbate 80.

32. 30. The method of any one of claims 26 to 29, wherein the slurry comprises about 0.75 g / kg of the compound of formula (I) and about 0.5 g / kg of polysorbate 80.

33. 30. The method of any one of claims 26 to 29, wherein the slurry comprises about 1.15 g / kg of the compound of formula (I) and about 0.5 g / kg of polysorbate 80.

34. The method of any one of claims 1 to 33, wherein the aqueous solution is a filtered mixture.

35. The method of any one of claims 1 to 34, wherein the aqueous solution comprises a sterile diluent.

36. 36. The method of any one of claims 1 to 35, comprising: said aqueous solution being a first sterilization mixture; said slurry being a second sterilization mixture; and mixing said first sterilization mixture and said second sterilization mixture.

37. 37. The method of any one of claims 1-36, wherein the aqueous solution and the slurry are mixed to form a suspension comprising about 0.005 mg / mL to about 2.5 mg / mL, about 0.01 mg / mL to about 2.0 mg / mL, about 0.01 mg / mL to about 1 mg / mL, about 0.01 mg / mL to about 0.5 mg / mL, about 0.01 mg / mL to about 0.2 mg / mL, or about 0.015 mg / mL to about 0.115 mg / mL of the compound of formula (I).

38. 38. The method of any one of claims 1-37, wherein the container comprises a suspension comprising from about 0.005 mg / mL to about 2.5 mg / mL, from about 0.01 mg / mL to about 2.0 mg / mL, from about 0.01 mg / mL to about 1 mg / mL, from about 0.01 mg / mL to about 0.5 mg / mL, from about 0.01 mg / mL to about 0.2 mg / mL, or from about 0.015 mg / mL to about 0.115 mg / mL of the compound of formula (I).

39. The method of any one of claims 1 to 38, wherein the container is selected from the group consisting of a vial, a bottle, an ampoule, and a syringe.

40. 40. The method of claim 39, wherein the vial is a glass vial or a plastic vial made of polyethylene, polypropylene, polyolefin, polyethylene terephthalate, polyethylene terephthalate G, poly(vinyl chloride), and mixtures thereof.

41. 41. The method of any one of claims 1 to 40, wherein the container has a volume of 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, or 10 mL.

42. The method of any one of claims 1 to 41, wherein the container is a 3 mL polypropylene vial.

43. The method of any one of claims 1 to 41, wherein the container is a 2 mL glass vial.

44. 44. The method of any one of claims 1 to 43, wherein the mixing step is performed aseptically.

45. 45. The method of any one of claims 1 to 44, wherein the filling step is performed aseptically.

46. 46. ​​The method of any one of claims 1 to 45, further comprising terminally sterilizing the filled containers.

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