Solid crystal form of selective potassium channel regulator

Abstract

The present disclosure provides solid crystalline forms of a selective potassium channel modulator and pharmaceutical compositions comprising the solid crystalline forms and pharmaceutically acceptable excipients, as well as methods of making and using the solid forms and pharmaceutical compositions thereof.

Description

[0001] This application is a divisional application of a Chinese invention patent application (filing date: October 9, 2020; application number: 202080085704.7 (international application number: PCT / US2020 / 055129); invention title: Solid crystalline forms of a selective potassium channel modulator). 1. Technical Field

[0002] The present invention relates to solid crystalline forms of a selective potassium channel modulator and pharmaceutical compositions comprising the solid forms and pharmaceutically acceptable excipients, as well as methods for preparing the solid forms and the pharmaceutical compositions. These solid crystalline forms and their pharmaceutical compositions can be used to treat epilepsy in mammals, particularly in humans. 2. Background Art

[0003] Epilepsy is a common neurological disorder with an estimated global prevalence of 0.7% of the population (50 million people) (see Hirtz, D. et al., Neurology. (2007), 68:326 - 337). It is characterized by abnormal electrical activity in the brain leading to seizures. Compared to the general population, the risk of death is increased in epilepsy patients, mainly due to the etiology of the disease. However, in patients with uncontrolled epilepsy, the greatest risk of death related to seizures is due to sudden unexpected death in epilepsy (SUDEP) (see, Hitiris, N. et al., Epilepsy & Behavior (2007), 10:363 - 376). Patients participating in clinical trials of investigational antiepileptic drugs (AEDs) typically have epilepsy for over 10 years and have failed multiple AED treatments.

[0004] N-[4-(6-Fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutyramide (referred to herein as "Compound A") is a small molecule currently being developed for the treatment of epilepsy. Compound A and its use as a voltage-gated potassium channel modulator are disclosed in U.S. Patent Nos. 8,293,911 and 8,993,593, the disclosures of which are incorporated herein by reference in their entirety.

[0005] Polymorphism, the occurrence of different solid crystalline forms of the same molecule, is a characteristic of certain molecules and molecular complexes. A single molecule can give rise to multiple polymorphs with different crystal structures and physical properties such as melting point, which can be measured using a range of techniques such as differential scanning calorimetry (DSC) or thermogravimetric analysis (TG), X-ray diffraction (XRPD or SCRXD), infrared absorption fingerprinting (FT-IR), and solid-state nuclear magnetic resonance spectroscopy (SS-NMR). One or more of these techniques can be used to distinguish between different polymorphic forms of a molecule.

[0006] Discovering new solid-state crystalline forms of pharmaceutical products can result in materials with desired processing properties, such as being easy to handle, process, store stably, purify, or serving as a desired intermediate crystalline form to facilitate conversion to other polymorphic forms. New solid-state crystalline forms of pharmaceutically acceptable compounds can also provide opportunities to improve the performance characteristics of pharmaceutical products. It expands the library of materials available to formulation scientists for formulation optimization, for example, by providing products with different properties, such as different crystallization habits, higher crystallinity, or polymorphic stability, which can offer better processing or handling characteristics, improve dissolution profiles, or extend shelf life (chemical / physical stability).

[0007] Therefore, there is a need to understand and develop solid-state crystalline forms of Compound A, especially when used for treatment, such as for treating epilepsy. 3. Summary of the Invention

[0008] The present disclosure generally relates to solid forms of Compound A, especially solid-state crystalline forms, methods for their preparation, pharmaceutical compositions containing said solid forms, and methods of using said solid forms and said pharmaceutical compositions.

[0009] Accordingly, in one embodiment, the present disclosure relates to a crystalline form of Compound A.

[0010] In another embodiment, the present disclosure relates to a crystalline form of Compound A referred to herein as Polymorph 1 of Compound A.

[0011] In another embodiment, the present disclosure relates to a crystalline form of Compound A referred to herein as Polymorph 2 of Compound A.

[0012] In another embodiment, the present disclosure relates to a crystalline form of Compound A referred to herein as Polymorph 3 of Compound A.

[0013] In another embodiment, the present disclosure relates to a crystalline form of Compound A referred to herein as Polymorph 4 of Compound A.

[0014] In another embodiment, the present disclosure relates to a crystalline form of Compound A referred to herein as Polymorph 5 of Compound A.

[0015] In another embodiment, the present disclosure relates to a crystalline form of Compound A referred to herein as Polymorph 6 of Compound A.

[0016] In another embodiment, the present disclosure relates to a crystalline form of Compound A referred to herein as Polymorph 7 of Compound A.

[0017] In another embodiment, the present disclosure relates to a crystalline form of Compound A referred to herein as Polymorph 8 of Compound A.

[0018] In another embodiment, the present disclosure relates to a crystalline form of Compound A referred to herein as Polymorph 9 of Compound A.

[0019] In another embodiment, the present disclosure relates to a crystalline form of Compound A referred to herein as Polymorph 10 of Compound A.

[0020] In another embodiment, the present disclosure relates to a crystalline form of Compound A referred to herein as Polymorph 11 of Compound A.

[0021] In another embodiment, the present disclosure relates to a mixture of two or more of the crystalline forms disclosed herein.

[0022] In another embodiment, the present disclosure relates to a crystalline form of Compound A (e.g., Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10 or Polymorph 11) disclosed herein that is substantially free of any other solid form of Compound A disclosed herein.

[0023] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A.

[0024] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A referred to herein as Polymorph 1 of Compound A, optionally substantially free of any other solid form of Compound A disclosed herein.

[0025] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A referred to herein as Polymorph 2 of Compound A, optionally substantially free of any other solid form of Compound A disclosed herein.

[0026] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A referred to herein as Polymorph 3 of Compound A, optionally substantially free of any other solid form of Compound A disclosed herein.

[0027] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A referred to herein as Polymorph 4 of Compound A, optionally substantially free of any other solid form of Compound A disclosed herein.

[0028] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred to herein as Crystal Form 5 of Compound A, optionally substantially free of any other solid forms of Compound A disclosed herein.

[0029] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred to herein as Crystal Form 6 of Compound A, optionally substantially free of any other solid forms of Compound A disclosed herein.

[0030] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred to herein as Crystal Form 7 of Compound A, optionally substantially free of any other solid forms of Compound A disclosed herein.

[0031] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred to herein as Crystal Form 8 of Compound A, optionally substantially free of any other solid forms of Compound A disclosed herein.

[0032] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred to herein as Crystal Form 9 of Compound A, optionally substantially free of any other solid forms of Compound A disclosed herein.

[0033] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred to herein as Crystal Form 10 of Compound A, optionally substantially free of any other solid forms of Compound A disclosed herein.

[0034] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred to herein as Crystal Form 11 of Compound A, optionally substantially free of any other solid forms of Compound A disclosed herein.

[0035] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a mixture of two or more crystalline forms of Compound A disclosed herein.

[0036] In another embodiment, the present disclosure relates to a method of treating human seizures, wherein the method comprises administering to a person in need thereof a therapeutically effective amount of a crystalline form of Compound A disclosed herein.

[0037] In another embodiment, the present disclosure relates to a method of treating human seizures, wherein the method comprises administering to a person in need a therapeutically effective amount of polymorph 1 of compound A, which polymorph 1 of compound A is optionally substantially free of any other solid forms of compound A disclosed herein.

[0038] In another embodiment, the present disclosure relates to a method of treating human seizures, wherein the method comprises administering to a person in need a therapeutically effective amount of polymorph 2 of compound A, which polymorph 2 of compound A is optionally substantially free of any other solid forms of compound A disclosed herein.

[0039] In another embodiment, the present disclosure relates to a method of treating human seizures, wherein the method comprises administering to a person in need a therapeutically effective amount of polymorph 3 of compound A, which polymorph 3 of compound A is optionally substantially free of any other solid forms of compound A disclosed herein.

[0040] In another embodiment, the present disclosure relates to a method of treating human seizures, wherein the method comprises administering to a person in need a therapeutically effective amount of polymorph 4 of compound A, which polymorph 4 of compound A is optionally substantially free of any other solid forms of compound A disclosed herein.

[0041] In another embodiment, the present disclosure relates to a method of treating human seizures, wherein the method comprises administering to a person in need a therapeutically effective amount of polymorph 5 of compound A, which polymorph 5 of compound A is optionally substantially free of any other solid forms of compound A disclosed herein.

[0042] In another embodiment, the present disclosure relates to a method of treating human seizures, wherein the method comprises administering to a person in need a therapeutically effective amount of polymorph 6 of compound A, which polymorph 6 of compound A is optionally substantially free of any other solid forms of compound A disclosed herein.

[0043] In another embodiment, the present disclosure relates to a method of treating human seizures, wherein the method comprises administering to a person in need a therapeutically effective amount of polymorph 7 of compound A, which polymorph 7 of compound A is optionally substantially free of any other solid forms of compound A disclosed herein.

[0044] In another embodiment, the present disclosure relates to a method of treating human seizures, wherein the method comprises administering to a person in need a therapeutically effective amount of polymorph 8 of compound A, which polymorph 8 of compound A is optionally substantially free of any other solid forms of compound A disclosed herein.

[0045] In another embodiment, the present disclosure relates to a method of treating human seizures, wherein the method comprises administering to a person in need a therapeutically effective amount of polymorph 9 of compound A, and the polymorph 9 of compound A is optionally substantially free of any other solid forms of compound A disclosed herein.

[0046] In another embodiment, the present disclosure relates to a method of treating human seizures, wherein the method comprises administering to a person in need a therapeutically effective amount of polymorph 10 of compound A, and the polymorph 10 of compound A is optionally substantially free of any other solid forms of compound A disclosed herein.

[0047] In another embodiment, the present disclosure relates to a method of treating human seizures, wherein the method comprises administering to a person in need a therapeutically effective amount of polymorph 11 of compound A, and the polymorph 11 of compound A is optionally substantially free of any other solid forms of compound A disclosed herein.

[0048] In another embodiment, the present disclosure relates to a method of treating human seizures, wherein the method comprises administering to a person in need a therapeutically effective amount of a mixture of two or more crystalline forms of compound A disclosed herein.

[0049] In another embodiment, the present disclosure relates to the use of any crystalline form of compound A for the preparation of a pharmaceutical composition, the pharmaceutical composition comprising a crystalline form of compound A disclosed herein and a pharmaceutically acceptable excipient.

[0050] In another embodiment, the present disclosure relates to a method for preparing a crystalline form of compound A.

[0051] In another embodiment, the present disclosure relates to a method for preparing polymorph 1 of compound A, and the polymorph 1 of compound A is optionally substantially free of any other solid forms of compound A disclosed herein.

[0052] In another embodiment, the present disclosure relates to a method for preparing polymorph 2 of compound A, and the polymorph 2 of compound A is optionally substantially free of any other solid forms of compound A disclosed herein.

[0053] In another embodiment, the present disclosure relates to a method for preparing polymorph 3 of compound A, and the polymorph 3 of compound A is optionally substantially free of any other solid forms of compound A disclosed herein.

[0054] In another embodiment, the present disclosure relates to a method for preparing polymorph 4 of compound A, and the polymorph 4 of compound A is optionally substantially free of any other solid forms of compound A disclosed herein.

[0055] In another embodiment, the present disclosure relates to a method for preparing polymorph 5 of Compound A, wherein polymorph 5 of Compound A is optionally substantially free of any other solid forms of Compound A disclosed herein.

[0056] In another embodiment, the present disclosure relates to a method for preparing polymorph 6 of Compound A, wherein polymorph 6 of Compound A is optionally substantially free of any other solid forms of Compound A disclosed herein.

[0057] In another embodiment, the present disclosure relates to a method for preparing polymorph 7 of Compound A, wherein polymorph 7 of Compound A is optionally substantially free of any other solid forms of Compound A disclosed herein.

[0058] In another embodiment, the present disclosure relates to a method for preparing polymorph 8 of Compound A, wherein polymorph 8 of Compound A is optionally substantially free of any other solid forms of Compound A disclosed herein.

[0059] In another embodiment, the present disclosure relates to a method for preparing polymorph 9 of Compound A, wherein polymorph 9 of Compound A is optionally substantially free of any other solid forms of Compound A disclosed herein.

[0060] In another embodiment, the present disclosure relates to a method for preparing polymorph 10 of Compound A, wherein polymorph 10 of Compound A is optionally substantially free of any other solid forms of Compound A disclosed herein.

[0061] In another embodiment, the present disclosure relates to a method for preparing polymorph 11 of Compound A, wherein polymorph 11 of Compound A is optionally substantially free of any other solid forms of Compound A disclosed herein.

[0062] In another embodiment, the present disclosure relates to a method for preparing the above-mentioned pharmaceutical composition, which comprises any crystalline form of Compound A and a pharmaceutically acceptable excipient. In one embodiment, the method comprises combining any crystalline form of Compound A with at least one pharmaceutically acceptable excipient.

[0063] In another embodiment, the present disclosure relates to the use of any crystalline form of Compound A or a pharmaceutical composition, which comprises any crystalline form of Compound A and a pharmaceutically acceptable excipient, as a medicament for treating human seizures.

[0064] In some embodiments of the methods and uses of the present invention, one or more crystalline forms of Compound A are orally administered to humans during the 30 minutes before to 2 hours after eating. For example, one or more crystalline forms of Compound A can be orally administered to a mammal during a meal or within 15 minutes after eating.

[0065] In another embodiment, the present disclosure relates to one or more crystalline forms of Compound A as described above, which have advantageous properties, where the advantageous properties are selected from at least one or more of the following group: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability and thermal and mechanical stability with respect to polymorphic transformation, dehydration stability, and / or storage stability, low residual solvent content, low hygroscopicity, and advantageous processing and handling characteristics, such as compressibility and bulk density.

[0066] In one embodiment, a crystalline form of Compound A exhibits better flowability (i.e., excellent rheological properties) than the amorphous form of Compound A or another solid crystalline form of Compound A.

[0067] These examples are described in more detail below. To this end, a number of references are set forth herein, which describe certain background information, procedures, compounds, and / or compositions in more detail, and each is incorporated herein by reference in its entirety. 4. Description of the Drawings

[0068] Figure 1 are the X-ray powder diffraction (XRPD) patterns of Form 1, Form 2, and Form 3 of Compound A.

[0069] Figure 2 are the non-polarized and polarized light microscopy images of Form 1 of Compound A.

[0070] Figure 3 is the thermogravimetric analysis / differential thermal analysis (TG / DTA) thermogram of Form 1 of Compound A.

[0071] Figure 4 is the differential scanning calorimetry (DSC) thermogram (initial heating cycle) of Form 1 of Compound A.

[0072] Figure 5 is the DSC thermogram (cooling cycle) of Form 1 of Compound A.

[0073] Figure 6 is the DSC thermogram (second heating cycle) of Form 1 of Compound A.

[0074] Figure 7 is of Form 1 of Compound A 1 1H NMR spectrum.

[0075] Figure 8 It is the XRPD diffraction pattern of polymorph 2 of compound A.

[0076] Figure 9 It is the non-polarized and polarized light microscope images of polymorph 2 of compound A.

[0077] Figure 10 It is the TG / DTA thermogram of polymorph 2 of compound A.

[0078] Figure 11 It is the DSC thermogram (initial heating cycle) of polymorph 2 of compound A.

[0079] Figure 12 It is the DSC thermogram (cooling cycle) of polymorph 2 of compound A.

[0080] Figure 13 It is the DSC thermogram (second heating cycle) of polymorph 2 of compound A.

[0081] Figure 14 It is of polymorph 2 of compound A 1 1H NMR spectrum.

[0082] Figure 15 It is the FTIR spectrum of polymorph 2 of compound A.

[0083] Figure 16 It is the XRPD diffraction pattern of polymorph 3 of compound A.

[0084] Figure 17 It is the XRPD diffraction pattern of polymorph 4 of compound A.

[0085] Figure 18 It is the non-polarized and polarized light microscope images of polymorph 4 of compound A.

[0086] Figure 19 It is the TG / DTA thermogram of polymorph 4 of compound A.

[0087] Figure 20 It is the DSC thermogram (initial heating cycle) of polymorph 4 of compound A.

[0088] Figure 21 It is the DSC thermogram (cooling cycle) of polymorph 4 of compound A.

[0089] Figure 22 It is the DSC thermogram (second heating cycle) of polymorph 4 of compound A.

[0090] Figure 23 It is of polymorph 4 of compound A 1 1H NMR spectrum.

[0091] Figure 24 It is the FTIR spectrum of polymorph 4 of compound A.

[0092] Figure 25 It is the XRPD diffraction pattern of crystalline form 5 of compound A.

[0093] Figure 26 It is the XRPD diffraction pattern of crystalline form 6 of compound A.

[0094] Figure 27 It is the XRPD diffraction pattern of crystalline form 7 of compound A.

[0095] Figure 28 It is the XRPD diffraction pattern of crystalline form 8 of compound A.

[0096] Figure 29 It is the XRPD diffraction pattern of crystalline form 9 of compound A.

[0097] Figure 30 It is the non-polarized and polarized light microscope images of crystalline form 9 of compound A.

[0098] Figure 31 It is the TG / DTA thermogram of crystalline form 9 of compound A.

[0099] Figure 32 It is the DSC thermogram (initial heating cycle) of crystalline form 9 of compound A.

[0100] Figure 33 It is the DSC thermogram (cooling cycle) of crystalline form 9 of compound A.

[0101] Figure 34 It is the DSC thermogram (second heating cycle) of crystalline form 9 of compound A.

[0102] Figure 35 It is of crystalline form 9 of compound A 1 1H NMR spectrum.

[0103] Figure 36 It is the FTIR spectrum of crystalline form 9 of compound A.

[0104] Figure 37 It is the XRPD diffraction pattern of crystalline form 10 of compound A.

[0105] Figure 38 It is the TG / DTA thermogram of crystalline form 10 of compound A.

[0106] Figure 39 It is the XRPD diffraction pattern of crystalline form 11 of compound A.

[0107] Figure 40 It is the non-polarized and polarized light microscope images of crystalline form 11 of compound A.

[0108] Figure 41It is the TG / DTA thermogram of polymorph 11 of compound A.

[0109] Figure 42 It is the DSC thermogram (initial heating cycle) of polymorph 11 of compound A.

[0110] Figure 43 It is the DSC thermogram (cooling cycle) of polymorph 11 of compound A.

[0111] Figure 44 It is the DSC thermogram (second heating cycle) of polymorph 11 of compound A.

[0112] Figure 45 It is of polymorph 11 of compound A 1 1H NMR spectrum.

[0113] Figure 46 It is the FTIR spectrum of polymorph 11 of compound A. 5. Specific embodiments

[0114] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the present disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the specification and the claims that follow, the word "comprising" and its variations, such as "comprises" and "comprising," are to be construed in an open, inclusive sense, that is, "including, but not limited to." Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed disclosure.

[0115] References to "an embodiment" or "embodiments" in this specification mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in an embodiment" and "in an embodiment" at various places throughout this specification are not necessarily all referring to the same embodiment. Moreover, in one or more embodiments, the particular features, structures, or characteristics may be combined in any suitable manner. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally used in its inclusive sense, including "and / or," unless the context clearly dictates otherwise. Additionally, the term "about" as used herein means ±20% of the stated value, and in more specific embodiments, ±10%, ±5%, ±2%, or ±1% of the stated value.

[0116] 5.1 Definitions

[0117] As used in the specification and the appended claims, unless specified to the contrary, the following terms and abbreviations have the indicated meanings:

[0118] As used herein, "Compound A" refers to a compound having the following chemical structure:

[0119]

[0120] and the chemical name of N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutyramide. The preparation of Compound A and its use as a selective potassium channel modulator, particularly a Kv7.2 / Kv7.3 (KCNQ2 / 3) opener, are disclosed in U.S. Patent No. 8,293,911 and U.S. Patent No. 8,993,593. The mechanism of action of Compound A is different from the most well-known AEDs because it involves the enhancement or potentiation of the voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2 / Kv7.3), which is important in controlling neuronal excitability. Compound A is used in the methods and uses described herein.

[0121] A solid form of Compound A, such as a crystalline form, may be referred to herein as being characterized by graphic data "as shown" or "substantially as shown". Such data includes, for example, an X-ray powder diffraction pattern, a DSC thermogram, or an NMR spectrum. As is well known in the art, such graphic data may provide additional technical information to further define the corresponding solid form (the so-called "fingerprint"), which is not necessarily described by simply referring to numerical values or peak positions. In any case, those skilled in the art will understand that such a graphic representation of the data may have minor variations, for example, due to factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to those skilled in the art. However, those skilled in the art can easily compare the graphic data in the figures herein with the graphic data generated from an unknown crystalline form and confirm whether the two sets of graphic data characterize the same crystalline form or two different crystalline forms. A solid form of Compound A characterized by graphic data "as depicted in the figure" or "substantially as depicted in the figure" as referred to herein will thus be understood to include any solid form of Compound A characterized by graphic data having the described minor variations compared to the schematic diagrams herein, as is well known to those skilled in the art.

[0122] As used herein, "the solid form of Compound A referred to as Polymorph 1 of Compound A", "the solid form of Compound A referred to herein as Polymorph 1 of Compound A", "Compound A Polymorph 1" or "Polymorph 1" refers to a form that can be detected by, for example Figure 1The peaks of the X-ray powder diffraction pattern shown are used to identify the solid forms of Compound A of the component.

[0123] As used herein, the "solid form of Compound A referred to as Polymorph 2 of Compound A", the "solid form of Compound A referred to as Polymorph 2 of Compound A herein", "Polymorph 2 of Compound A", or "Polymorph 2" refers to the solid form of Compound A of the component that can be identified by detecting the peaks of the X-ray powder diffraction pattern as Figure 8 shown.

[0124] As used herein, the "solid form of Compound A referred to as Polymorph 3 of Compound A", the "solid form of Compound A referred to as Polymorph 3 of Compound A herein", "Polymorph 3 of Compound A", or "Polymorph 3" refers to the solid form of Compound A of the component that can be identified by detecting the peaks of the X-ray powder diffraction pattern as Figure 16 shown.

[0125] As used herein, the "solid form of Compound A referred to as Polymorph 4 of Compound A", the "solid form of Compound A referred to as Polymorph 4 of Compound A herein", "Polymorph 4 of Compound A", or "Polymorph 4" refers to the solid form of Compound A of the component that can be identified by detecting the peaks of the X-ray powder diffraction pattern as Figure 17 shown.

[0126] As used herein, the "solid form of Compound A referred to as Polymorph 5 of Compound A", the "solid form of Compound A referred to as Polymorph 5 of Compound A herein", "Polymorph 5 of Compound A", or "Polymorph 5" refers to the solid form of Compound A of the component that can be identified by detecting the peaks of the X-ray powder diffraction pattern as Figure 25 shown.

[0127] As used herein, the "solid form of Compound A referred to as Polymorph 6 of Compound A", the "solid form of Compound A referred to as Polymorph 6 of Compound A herein", "Polymorph 6 of Compound A", or "Polymorph 6" refers to the solid form of Compound A of the component that can be identified by detecting the peaks of the X-ray powder diffraction pattern as Figure 26 shown.

[0128] As used herein, the "solid form of Compound A referred to as Polymorph 7 of Compound A", the "solid form of Compound A referred to as Polymorph 7 of Compound A herein", "Polymorph 7 of Compound A", or "Polymorph 7" refers to the solid form of Compound A of the component that can be identified by detecting the peaks of the X-ray powder diffraction pattern as Figure 27 shown.

[0129] As used herein, the "solid form of Compound A designated as Polymorph 8", the "solid form of Compound A referred to herein as Polymorph 8", "Compound A Polymorph 8" or "Polymorph 8" refers to the solid form of Compound A whose components can be identified by detecting the peaks of the X-ray powder diffraction pattern as shown in Figure 28 below.

[0130] As used herein, the "solid form of Compound A designated as Polymorph 9", the "solid form of Compound A referred to herein as Polymorph 9", "Compound A Polymorph 9" or "Polymorph 9" refers to the solid form of Compound A whose components can be identified by detecting the peaks of the X-ray powder diffraction pattern as shown in Figure 29 below.

[0131] As used herein, the "solid form of Compound A designated as Polymorph 10", the "solid form of Compound A referred to herein as Polymorph 10", "Compound A Polymorph 10" or "Polymorph 10" refers to the solid form of Compound A whose components can be identified by detecting the peaks of the X-ray powder diffraction pattern as shown in Figure 37 below.

[0132] As used herein, the "solid form of Compound A designated as Polymorph 11", the "solid form of Compound A referred to herein as Polymorph 11", "Compound A Polymorph 11" or "Polymorph 11" refers to the solid form of Compound A whose components can be identified by detecting the peaks of the X-ray powder diffraction pattern as shown in Figure 39 below.

[0133] "AUC" refers to the area under the plasma concentration-time curve. AUC reflects the actual systemic exposure to the solid form of Compound A after extravascular administration of a certain dose of the solid form of Compound A, and is expressed as hours multiplied by the concentration of the solid form of Compound A in plasma. For the purposes of this disclosure, AUC is expressed as hours multiplied by ng / ml.

[0134] "AUC inf " refers to the AUC from time zero to infinity.

[0135] "AUC infobs " refers to the observed AUC from time zero to infinity.

[0136] "AUC last " refers to the AUC from time zero to the last detectable plasma concentration.

[0137] "%AUC ext " refers to the percentage of the AUC extrapolated from time zero to infinity relative to the total AUC.

[0138] "Bioavailability" refers to the rate and extent to which a solid form of Compound A is absorbed and becomes systemically available for further distribution to the site of action.

[0139] "C max " refers to the maximum plasma concentration observed.

[0140] "h" refers to hour.

[0141] "High-fat meal" refers to any food, solid or liquid, in which approximately 50% of the food calories are from fat.

[0142] "High-calorie meal" refers to any meal of approximately 800 to 1000 calories. A representative high-fat, high-calorie meal should obtain approximately 150, 250, and 500 - 600 calories from protein, carbohydrates, and fat, respectively.

[0143] As used herein, the term "highly soluble" with respect to a solid form of Compound A corresponds to a solid form of Compound A having a solubility greater than 100 mg / mL at room temperature. In one embodiment, the solid form of Compound A is highly soluble in solvents such as 1,4-dioxane, 1-butanol, 1-propanol, acetone, anisole, chloroform, cyclohexanone, dichloromethane, dimethyl sulfoxide, ethanol, ethyl acetate, 2-propanol, methyl ethyl ketone, N-methyl-2-pyrrolidone, tetrahydrofuran, and tetrahydrofuran / water (99:1 v / v).

[0144] A process or step may be referred to herein as being carried out "overnight". This refers to a time interval, e.g., for the process or step, which spans the time of night when the process or step may not be actively observed. The time interval is about 8 to about 20 hours, or about 10 - 18 hours, or typically about 16 hours.

[0145] "Pharmaceutically acceptable excipient" is understood to be applicable to humans or livestock and includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifying agent.

[0146] When a mixture, such as a solid form of Compound A and a solvent, is described herein as being at or allowed to reach "room temperature" or "ambient temperature" (commonly abbreviated as "RT"), it is intended to mean that the temperature of the object or mixture is close to or equal to the temperature of the space (e.g., room or fume hood) in which the object or mixture is located. Generally, room temperature is about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0147] "SD" refers to standard deviation.

[0148] "Seizure disorders" refers to seizures and disorders associated with seizures, such as partial (focal) seizures, photosensitive epilepsy, self-induced syncope, intractable epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorder, childhood and adolescent absence epilepsy, severe myoclonic epilepsy in infancy (Dravet syndrome), frontal lobe epilepsy, GLUT1 deficiency syndrome, hypothalamic hamartoma, infantile spasms / West's syndrome, juvenile myoclonic epilepsy, pediatric epilepsy with speech arrest (Landau-Kleffner syndrome), Lennox-Gastaut syndrome (LGS), myoclonic absence epilepsy, Ohtahara syndrome, Panayiotopoulos syndrome, PCDH19 epilepsy, progressive myoclonic epilepsy, Rasmussen syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, Lafora progressive myoclonic epilepsy, neurocutaneous syndromes, tuberous sclerosis, early infantile epileptic encephalopathy, early-onset epileptic encephalopathy, generalized epilepsy with febrile seizures plus, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia, and paroxysmal dyskinesia. In certain embodiments, the term "seizure disorder" refers to focal onset epilepsy, also known as partial (focal) seizures.

[0149] As used herein, when referring to the solid form of Compound A, "substantially free of" means that the solid form of the present invention contains 20% (w / w) or less of any other solid form of Compound A or a specific solid form of Compound A.

[0150] Refers to the terminal elimination half-life of the solid form of Compound A in plasma (i.e., the time required for the plasma concentration of the solid form of Compound A to decrease by half during the terminal elimination phase).

[0151] "T max " refers to the time to reach the maximum (peak) plasma concentration after extravascular administration of the solid form of Compound A.

[0152] As used herein, "therapeutically effective amount" means an amount of the solid form of Compound A sufficient to treat the disease, disorder or condition or to have the desired effect, including improving or preventing the disease, disorder or condition or one or more underlying mechanisms of the disease, disorder or condition. In certain embodiments, when the solid form of Compound A is administered to treat seizures, a therapeutically effective amount means the range of amounts of the solid form of Compound A that, when administered to a human, treats, improves or prevents human seizure disorders or exhibits a detectable therapeutic or preventive effect in a human having a seizure disorder. For example, the effect is detected by a reduction (frequency) of seizures or the severity (quality) of seizures. The precise therapeutically effective amount for a given human depends on the size and health of the human, the nature and extent of the seizure disorder, the presence of any concomitant medications, and other variables known to those of skill in the art. The therapeutically effective amount for a given situation can be determined by routine experimentation and is within the competence of the clinician.

[0153] "Treatment" as used herein refers to the therapeutic application associated with the administration of the solid form of Compound A, which improves or prevents the disease, disorder or condition or one or more underlying mechanisms of the disease, disorder or condition, including slowing or stopping the progression of the disease, disorder or condition or one or more underlying mechanisms. In certain embodiments, when the solid form of Compound A is administered to treat seizure disorders, treatment refers to the therapeutic application of slowing or stopping the progression of seizure disorders, the preventive application of preventing the development of seizure disorders, and / or the reversal of seizure disorders. The reversal of seizures differs from the therapeutic application of slowing or stopping seizures in that the reversal method not only completely stops the progression of seizures, but the cell behavior also moves to some extent towards the normal state, which can be observed in the absence of seizures.

[0154] "Under fed conditions" means the situation where food is consumed during this period. The time period is from about 4 hours before the oral administration of an effective amount (e.g., within the therapeutically effective dose range) of the solid form of Compound A to about 4 hours after the administration of the solid form of Compound A. The food can be solid, liquid or a mixture of solid and liquid foods, which has a sufficient volume and fat content such that it cannot be rapidly dissolved and absorbed in the stomach. In certain cases, the food is a meal, such as breakfast, lunch, dinner or others, baby food (e.g., formula or breast milk). The therapeutically effective amount of the solid form of Compound A can be orally administered to a subject, for example, between about 30 minutes before a meal and 2 hours after a meal, and most advantageously, the dosage unit of the solid form of Compound A is orally administered during or within 15 minutes after a meal. Under fed conditions, this "food effect" associated with the administration of Compound A in humans can be found in U.S. Published Patent Application No. 2019-0343823, the disclosure of which is incorporated herein by reference in its entirety.

[0155] "Under fasting conditions" means a period of time during which no food is ingested. The time period extends from about 4 hours before the oral administration of a therapeutically effective amount of the solid form of Compound A to about 4 hours after the administration of the solid form of Compound A.

[0156] As used herein, the term under vacuum or in vacuo means a pressure less than atmospheric pressure.

[0157] The amount of solvent used in a chemical process (e.g., reaction or crystallization) can be referred to herein as the "volume" or the amount of "vol" or "V". For example, a material can be said to be suspended in 10 volumes (or 10 vol or 10 V) of solvent. In this case, the expression is understood to mean the number of milliliters of solvent per gram of the material being suspended, such that suspending 5 grams of material in 10 volumes of solvent means that the solvent is used in an amount of 10 milliliters of solvent per gram of the material being suspended, which is 50 milliliters of solvent in this example. In another case, the term "V / V" can be used to indicate the number of volumes of solvent added to a liquid mixture based on the volume of the mixture. For example, adding Solvent X (1.5 v / v) to 100 milliliters of a reaction mixture indicates that 150 milliliters of Solvent X are added.

[0158] 5.2 Embodiments

[0159] In some embodiments, a solid crystalline form of Compound A (e.g., Crystal Form 1, Crystal Form 2, Crystal Form 3, Crystal Form 4, Crystal Form 5, Crystal Form 6, Crystal Form 7, Crystal Form 8, Crystal Form 9, Crystal Form 10, or Crystal Form 11) contains 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% (w / w) or less, 2% (w / w) or less, 1% (w / w) or less, 0.5% (w / w) or less, or 0.2% (w / w) or less of any other solid crystalline form of Compound A disclosed herein or a specific solid crystalline form of Compound A disclosed herein.

[0160] In other embodiments, a solid crystalline form of Compound A (e.g., Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10, or Polymorph 11) contains from 0.1% to 20% (w / w), from 0.2% to 20% (w / w), from 0.5% to 20% (w / w), from 1% to 20% (w / w), from 2% to 20% (w / w), from 3% to 20% (w / w), from 4% to 20% (w / w), from 5% to 20% (w / w), from 6% to 20% (w / w), from 7% to 20% (w / w), from 8% to 20% (w / w), from 9% to 20% (w / w), from 10% to 20% (w / w), from 11% to 20% (w / w), from 12% to 20% (w / w), from 13% to 20% (w / w), from 14% to 20% (w / w), from 15% to 20% (w / w), from 16% to 20% (w / w), from 17% to 20% (w / w), from 18% to 20% (w / w), or from 19% to 20% (w / w) of any other solid crystalline form of Compound A disclosed herein or a specific solid crystalline form of Compound A disclosed herein.

[0161] In other embodiments, a solid crystalline form of Compound A (e.g., Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10, or Polymorph 11) contains from 0.1% to 15% (w / w), from 0.2% to 15% (w / w), from 0.5% to 15% (w / w), from 1% to 15% (w / w), from 2% to 15% (w / w), from 3% to 15% (w / w), from 4% to 15% (w / w), from 5% to 15% (w / w), from 6% to 15% (w / w), from 7% to 15% (w / w), from 8% to 15% (w / w), from 9% to 15% (w / w), from 10% to 15% (w / w), from 11% to 15% (w / w), from 12% to 15% (w / w), from 13% to 15% (w / w), or from 14% to 15% (w / w) of any other solid crystalline form of Compound A disclosed herein or a specific solid crystalline form of Compound A disclosed herein.

[0162] In other embodiments, a solid crystalline form of Compound A (e.g., Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10, or Polymorph 11) contains from 0.1% to 10% (w / w), from 0.2% to 10% (w / w), from 0.5% to 10% (w / w), from 1% to 10% (w / w), from 2% to 10% (w / w), from 3% to 10% (w / w), from 4% to 10% (w / w), from 5% to 10% (w / w), from 6% to 10% (w / w), 7% to 10% (w / w), from 8% to 10% (w / w), or from 9% to 10% (w / w) of any other solid crystalline form of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein.

[0163] In other embodiments, a solid crystalline form of Compound A (e.g., Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10, or Polymorph 11) contains from 0.1% to 5% (w / w), from 0.2% to 5% (w / w), 0.3% to 5% (w / w), from 0.4% to 5% (w / w), from 0.5% to 5% (w / w), from 0.7% to 5% (w / w), from 0.8% to 5% (w / w), from 1% to 5% (w / w), from 1.5% to 5% (w / w), from 2% to 5% (w / w), from 2.5% to 5% (w / w), from 3% to 5% (w / w), or from 4% to 5% (w / w) of any other solid crystalline form of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein.

[0164] 5.2.1 Compound A Polymorph 1 Mixture

[0165] In some embodiments, a solid crystalline form of Compound A contains Form 1 of Compound A and 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% (w / w) or less, 2% (w / w) or less, 1% (w / w) or less, 0.5% (w / w) or less, or 0.2% (w / w) or less of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Form 2 of Compound A, Form 3 of Compound A, Form 4 of Compound A, Form 5 of Compound A, Form 6 of Compound A, Form 7 of Compound A, Form 8 of Compound A, Form 9 of Compound A, Form 10 of Compound A, or Form 11 of Compound A, or a combination thereof.

[0166] In certain embodiments, a solid crystalline form of Compound A contains Form 1 of Compound A and from 0.1% to 20% (w / w), from 0.2% to 20% (w / w), from 0.5% to 20% (w / w), from 1% to 20% (w / w), from 2% to 20% (w / w), from 3% to 20% (w / w), from 4% to 20% (w / w), from 5% to 20% (w / w), from 6% to 20% (w / w), from 7% to 20% (w / w), from 8% to 20% (w / w), from 9% to 20% (w / w), from 10% to 20% (w / w), from 11% to 20% (w / w), from 12% to 20% (w / w), from 13% to 20% (w / w), from 14% to 20% (w / w), from 15% to 20% (w / w), from 16% to 20% (w / w), from 17% to 20% (w / w), from 18% to 20% (w / w), or from 19% to 20% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Form 2 of Compound A, Form 3 of Compound A, Form 4 of Compound A, Form 5 of Compound A, Form 6 of Compound A, Form 7 of Compound A, Form 8 of Compound A, Form 9 of Compound A, Form 10 of Compound A, or Form 11 of Compound A, or a combination thereof.

[0167] In some embodiments, a solid crystalline form of Compound A contains Form 1 of Compound A and from 0.1% to 15% (w / w), from 0.2% to 15% (w / w), from 0.5% to 15% (w / w), from 1% to 15% (w / w), from 2% to 15% (w / w), from 3% to 15% (w / w), from 4% to 15% (w / w), from 5% to 15% (w / w), from 6% to 15% (w / w), from 7% to 15% (w / w), from 8% to 15% (w / w), from 9% to 15% (w / w), from 10% to 15% (w / w), from 11% to 15% (w / w), from 12% to 15% (w / w), from 13% to 15% (w / w), or from 14% to 15% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Form 2 of Compound A, Form 3 of Compound A, Form 4 of Compound A, Form 5 of Compound A, Form 6 of Compound A, Form 7 of Compound A, Form 8 of Compound A, Form 9 of Compound A, Form 10 of Compound A, or Form 11 of Compound A, or a combination thereof.

[0168] In certain embodiments, a solid crystalline form of Compound A contains Form 1 of Compound A and from 0.1% to 10% (w / w), from 0.2% to 10% (w / w), from 0.5% to 10% (w / w), from 1% to 10% (w / w), from 2% to 10% (w / w), from 3% to 10% (w / w), from 4% to 10% (w / w), from 5% to 10% (w / w), from 6% to 10% (w / w), 7% to 10% (w / w), from 8% to 10% (w / w), or from 9% to 10% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Form 2 of Compound A, Form 3 of Compound A, Form 4 of Compound A, Form 5 of Compound A, Form 6 of Compound A, Form 7 of Compound A, Form 8 of Compound A, Form 9 of Compound A, Form 10 of Compound A, or Form 11 of Compound A, or a combination thereof.

[0169] In some embodiments, a solid crystalline form of Compound A contains Form 1 of Compound A and from 0.2% to 5% (w / w), 0.3% to 5% (w / w), from 0.4% to 5% (w / w), from 0.5% to 5% (w / w), from 0.7% to 5% (w / w), from 0.8% to 5% (w / w), from 1% to 5% (w / w), from 1.5% to 5% (w / w), from 2% to 5% (w / w), from 2.5% to 5% (w / w), from 3% to 5% (w / w), or from 4% to 5% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Form 2 of Compound A, Form 3 of Compound A, Form 4 of Compound A, Form 5 of Compound A, Form 6 of Compound A, Form 7 of Compound A, Form 8 of Compound A, Form 9 of Compound A, Form 10 of Compound A, or Form 11 of Compound A, or a combination thereof.

[0170] In other embodiments, a solid crystalline form of Compound A comprises at least 25% (w / w), at least 50% (w / w), at least 75% (w / w), at least 80% (w / w), at least 85% (w / w), at least 90% (w / w), at least 95% (w / w), at least 98% (w / w), or at least 99% (w / w) Form 1 of Compound A.

[0171] 5.2.2 Mixture of Form 2 of Compound A

[0172] In some embodiments, a solid crystalline form of Compound A contains Form 2 of Compound A and 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% (w / w) or less, 2% (w / w) or less, 1% (w / w) or less, 0.5% (w / w) or less, or 0.2% (w / w) or less of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Form 1 of Compound A, Form 3 of Compound A, Form 4 of Compound A, Form 5 of Compound A, Form 6 of Compound A, Form 7 of Compound A, Form 8 of Compound A, Form 9 of Compound A, Form 10 of Compound A, or Form 11 of Compound A, or a combination thereof.

[0173] In certain embodiments, a solid crystalline form of Compound A comprises Compound A Polymorph 2 and from 0.1% to 20% (w / w), from 0.2% to 20% (w / w), from 0.5% to 20% (w / w), from 1% to 20% (w / w), from 2% to 20% (w / w), from 3% to 20% (w / w), from 4% to 20% (w / w), from 5% to 20% (w / w), from 6% to 20% (w / w), from 7% to 20% (w / w), from 8% to 20% (w / w), from 9% to 20% (w / w), from 10% to 20% (w / w), from 11% to 20% (w / w), from 12% to 20% (w / w), from 13% to 20% (w / w), from 14% to 20% (w / w), from 15% to 20% (w / w), from 16% to 20% (w / w), from 17% to 20% (w / w), from 18% to 20% (w / w), or from 19% to 20% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or combinations thereof.

[0174] In some embodiments, a solid crystalline form of Compound A comprises Compound A Polymorph 2 and from 0.1% to 15% (w / w), from 0.2% to 15% (w / w), from 0.5% to 15% (w / w), from 1% to 15% (w / w), from 2% to 15% (w / w), from 3% to 15% (w / w), from 4% to 15% (w / w), from 5% to 15% (w / w), from 6% to 15% (w / w), from 7% to 15% (w / w), from 8% to 15% (w / w), from 9% to 15% (w / w), from 10% to 15% (w / w), from 11% to 15% (w / w), from 12% to 15% (w / w), from 13% to 15% (w / w), or from 14% to 15% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or combinations thereof.

[0175] In certain embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 2 and from 0.1% to 10% (w / w), from 0.2% to 10% (w / w), from 0.5% to 10% (w / w), from 1% to 10% (w / w), from 2% to 10% (w / w), from 3% to 10% (w / w), from 4% to 10% (w / w), from 5% to 10% (w / w), from 6% to 10% (w / w), 7% to 10% (w / w), from 8% to 10% (w / w), or from 9% to 10% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0176] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 2 and from 0.2% to 5% (w / w), from 0.3% to 5% (w / w), from 0.4% to 5% (w / w), from 0.5% to 5% (w / w), from 0.7% to 5% (w / w), from 0.8% to 5% (w / w), from 1% to 5% (w / w), from 1.5% to 5% (w / w), from 2% to 5% (w / w), from 2.5% to 5% (w / w), from 3% to 5% (w / w), or from 4% to 5% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0177] In other embodiments, a solid crystalline form of Compound A comprises at least 25% (w / w), at least 50% (w / w), at least 75% (w / w), at least 80% (w / w), at least 85% (w / w), at least 90% (w / w), at least 95% (w / w), at least 98% (w / w), or at least 99% (w / w) Compound A Polymorph 2.

[0178] 5.2.3 Compound A Polymorph 3 Mixture

[0179] In some embodiments, a solid crystalline form of Compound A comprises Compound A Polymorph 3 and 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% (w / w) or less, 2% (w / w) or less, 1% (w / w) or less, 0.5% (w / w) or less, or 0.2% (w / w) or less of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0180] In certain embodiments, a solid crystalline form of Compound A comprises Compound A Polymorph 3 and from 0.1% to 20% (w / w), from 0.2% to 20% (w / w), from 0.5% to 20% (w / w), from 1% to 20% (w / w), from 2% to 20% (w / w), from 3% to 20% (w / w), from 4% to 20% (w / w), from 5% to 20% (w / w), from 6% to 20% (w / w), from 7% to 20% (w / w), from 8% to 20% (w / w), from 9% to 20% (w / w), from 10% to 20% (w / w), from 11% to 20% (w / w), from 12% to 20% (w / w), from 13% to 20% (w / w), from 14% to 20% (w / w), from 15% to 20% (w / w), from 16% to 20% (w / w), from 17% to 20% (w / w), from 18% to 20% (w / w), or from 19% to 20% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0181] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 3 and from 0.1% to 15% (w / w), from 0.2% to 15% (w / w), from 0.5% to 15% (w / w), from 1% to 15% (w / w), from 2% to 15% (w / w), from 3% to 15% (w / w), from 4% to 15% (w / w), from 5% to 15% (w / w), from 6% to 15% (w / w), from 7% to 15% (w / w), from 8% to 15% (w / w), from 9% to 15% (w / w), from 10% to 15% (w / w), from 11% to 15% (w / w), from 12% to 15% (w / w), from 13% to 15% (w / w), or from 14% to 15% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0182] In certain embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 3 and from 0.1% to 10% (w / w), from 0.2% to 10% (w / w), from 0.5% to 10% (w / w), from 1% to 10% (w / w), from 2% to 10% (w / w), from 3% to 10% (w / w), from 4% to 10% (w / w), from 5% to 10% (w / w), from 6% to 10% (w / w), 7% to 10% (w / w), from 8% to 10% (w / w), or from 9% to 10% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0183] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 3 and from 0.2% to 5% (w / w), from 0.3% to 5% (w / w), from 0.4% to 5% (w / w), from 0.5% to 5% (w / w), from 0.7% to 5% (w / w), from 0.8% to 5% (w / w), from 1% to 5% (w / w), from 1.5% to 5% (w / w), from 2% to 5% (w / w), from 2.5% to 5% (w / w), from 3% to 5% (w / w), or from 4% to 5% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0184] In other embodiments, a solid crystalline form of Compound A comprises at least 25% (w / w), at least 50% (w / w), at least 75% (w / w), at least 80% (w / w), at least 85% (w / w), at least 90% (w / w), at least 95% (w / w), at least 98% (w / w), or at least 99% (w / w) Compound A Polymorph 3.

[0185] 5.2.4 Compound A Polymorph 4 Mixture

[0186] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 4 and 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% (w / w) or less, 2% (w / w) or less, 1% (w / w) or less, 0.5% (w / w) or less, or 0.2% (w / w) or less of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0187] In certain embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 4 and from 0.1% to 20% (w / w), from 0.2% to 20% (w / w), from 0.5% to 20% (w / w), from 1% to 20% (w / w), from 2% to 20% (w / w), from 3% to 20% (w / w), from 4% to 20% (w / w), from 5% to 20% (w / w), from 6% to 20% (w / w), from 7% to 20% (w / w), from 8% to 20% (w / w), from 9% to 20% (w / w), from 10% to 20% (w / w), from 11% to 20% (w / w), from 12% to 20% (w / w), from 13% to 20% (w / w), from 14% to 20% (w / w), from 15% to 20% (w / w), from 16% to 20% (w / w), from 17% to 20% (w / w), from 18% to 20% (w / w), or from 19% to 20% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or specific solid crystalline forms of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or combinations thereof.

[0188] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 4 and from 0.1% to 15% (w / w), from 0.2% to 15% (w / w), from 0.5% to 15% (w / w), from 1% to 15% (w / w), from 2% to 15% (w / w), from 3% to 15% (w / w), from 4% to 15% (w / w), from 5% to 15% (w / w), from 6% to 15% (w / w), from 7% to 15% (w / w), from 8% to 15% (w / w), from 9% to 15% (w / w), from 10% to 15% (w / w), from 11% to 15% (w / w), from 12% to 15% (w / w), from 13% to 15% (w / w), or from 14% to 15% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or specific solid crystalline forms of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or combinations thereof.

[0189] In certain embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 4 and from 0.1% to 10% (w / w), from 0.2% to 10% (w / w), from 0.5% to 10% (w / w), from 1% to 10% (w / w), from 2% to 10% (w / w), from 3% to 10% (w / w), from 4% to 10% (w / w), from 5% to 10% (w / w), from 6% to 10% (w / w), 7% to 10% (w / w), from 8% to 10% (w / w), or from 9% to 10% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0190] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 4 and from 0.2% to 5% (w / w), from 0.3% to 5% (w / w), from 0.4% to 5% (w / w), from 0.5% to 5% (w / w), from 0.7% to 5% (w / w), from 0.8% to 5% (w / w), from 1% to 5% (w / w), from 1.5% to 5% (w / w), from 2% to 5% (w / w), from 2.5% to 5% (w / w), from 3% to 5% (w / w), or from 4% to 5% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0191] In other embodiments, a solid crystalline form of Compound A comprises at least 25% (w / w), at least 50% (w / w), at least 75% (w / w), at least 80% (w / w), at least 85% (w / w), at least 90% (w / w), at least 95% (w / w), at least 98% (w / w), or at least 99% (w / w) Compound A Polymorph 4.

[0192] 5.2.5 Compound A Polymorph 5 Mixtures

[0193] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 5 and 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% (w / w) or less, 2% (w / w) or less, 1% (w / w) or less, 0.5% (w / w) or less, or 0.2% (w / w) or less of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0194] In certain embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 5 and from 0.1% to 20% (w / w), from 0.2% to 20% (w / w), from 0.5% to 20% (w / w), from 1% to 20% (w / w), from 2% to 20% (w / w), from 3% to 20% (w / w), from 4% to 20% (w / w), from 5% to 20% (w / w), from 6% to 20% (w / w), from 7% to 20% (w / w), from 8% to 20% (w / w), from 9% to 20% (w / w), from 10% to 20% (w / w), from 11% to 20% (w / w), from 12% to 20% (w / w), from 13% to 20% (w / w), from 14% to 20% (w / w), from 15% to 20% (w / w), from 16% to 20% (w / w), from 17% to 20% (w / w), from 18% to 20% (w / w), or from 19% to 20% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0195] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 5 and from 0.1% to 15% (w / w), from 0.2% to 15% (w / w), from 0.5% to 15% (w / w), from 1% to 15% (w / w), from 2% to 15% (w / w), from 3% to 15% (w / w), from 4% to 15% (w / w), from 5% to 15% (w / w), from 6% to 15% (w / w), from 7% to 15% (w / w), from 8% to 15% (w / w), from 9% to 15% (w / w), from 10% to 15% (w / w), from 11% to 15% (w / w), from 12% to 15% (w / w), from 13% to 15% (w / w), or from 14% to 15% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0196] In certain embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 5 and from 0.1% to 10% (w / w), from 0.2% to 10% (w / w), from 0.5% to 10% (w / w), from 1% to 10% (w / w), from 2% to 10% (w / w), from 3% to 10% (w / w), from 4% to 10% (w / w), from 5% to 10% (w / w), from 6% to 10% (w / w), 7% to 10% (w / w), from 8% to 10% (w / w), or from 9% to 10% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0197] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 5 and from 0.2% to 5% (w / w), from 0.3% to 5% (w / w), from 0.4% to 5% (w / w), from 0.5% to 5% (w / w), from 0.7% to 5% (w / w), from 0.8% to 5% (w / w), from 1% to 5% (w / w), from 1.5% to 5% (w / w), from 2% to 5% (w / w), from 2.5% to 5% (w / w), from 3% to 5% (w / w), or from 4% to 5% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0198] In other embodiments, a solid crystalline form of Compound A comprises at least 25% (w / w), at least 50% (w / w), at least 75% (w / w), at least 80% (w / w), at least 85% (w / w), at least 90% (w / w), at least 95% (w / w), at least 98% (w / w), or at least 99% (w / w) Compound A Polymorph 5.

[0199] 5.2.6 Compound A Polymorph 6 Mixture

[0200] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 6 and 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% (w / w) or less, 2% (w / w) or less, 1% (w / w) or less, 0.5% (w / w) or less, or 0.2% (w / w) or less of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0201] In certain embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 6 and from 0.1% to 20% (w / w), from 0.2% to 20% (w / w), from 0.5% to 20% (w / w), from 1% to 20% (w / w), from 2% to 20% (w / w), from 3% to 20% (w / w), from 4% to 20% (w / w), from 5% to 20% (w / w), from 6% to 20% (w / w), from 7% to 20% (w / w), from 8% to 20% (w / w), from 9% to 20% (w / w), from 10% to 20% (w / w), from 11% to 20% (w / w), from 12% to 20% (w / w), from 13% to 20% (w / w), from 14% to 20% (w / w), from 15% to 20% (w / w), from 16% to 20% (w / w), from 17% to 20% (w / w), from 18% to 20% (w / w), or from 19% to 20% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or specific solid crystalline forms of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or combinations thereof.

[0202] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 6 and from 0.1% to 15% (w / w), from 0.2% to 15% (w / w), from 0.5% to 15% (w / w), from 1% to 15% (w / w), from 2% to 15% (w / w), from 3% to 15% (w / w), from 4% to 15% (w / w), from 5% to 15% (w / w), from 6% to 15% (w / w), from 7% to 15% (w / w), from 8% to 15% (w / w), from 9% to 15% (w / w), from 10% to 15% (w / w), from 11% to 15% (w / w), from 12% to 15% (w / w), from 13% to 15% (w / w), or from 14% to 15% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or specific solid crystalline forms of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or combinations thereof.

[0203] In certain embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 6 and from 0.1% to 10% (w / w), from 0.2% to 10% (w / w), from 0.5% to 10% (w / w), from 1% to 10% (w / w), from 2% to 10% (w / w), from 3% to 10% (w / w), from 4% to 10% (w / w), from 5% to 10% (w / w), from 6% to 10% (w / w), 7% to 10% (w / w), from 8% to 10% (w / w), or from 9% to 10% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or combinations thereof.

[0204] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 6 and from 0.2% to 5% (w / w), from 0.3% to 5% (w / w), from 0.4% to 5% (w / w), from 0.5% to 5% (w / w), from 0.7% to 5% (w / w), from 0.8% to 5% (w / w), from 1% to 5% (w / w), from 1.5% to 5% (w / w), from 2% to 5% (w / w), from 2.5% to 5% (w / w), from 3% to 5% (w / w), or from 4% to 5% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or combinations thereof.

[0205] In other embodiments, a solid crystalline form of Compound A comprises at least 25% (w / w), at least 50% (w / w), at least 75% (w / w), at least 80% (w / w), at least 85% (w / w), at least 90% (w / w), at least 95% (w / w), at least 98% (w / w), or at least 99% (w / w) Compound A Polymorph 6.

[0206] 5.2.7 Compound A Polymorph 7 Mixtures

[0207] In some embodiments, a solid crystalline form of Compound A comprises Compound A Polymorph 7 and 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% (w / w) or less, 2% (w / w) or less, 1% (w / w) or less, 0.5% (w / w) or less, or 0.2% (w / w) or less of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0208] In certain embodiments, a solid crystalline form of Compound A comprises Compound A Polymorph 7 and from 0.1% to 20% (w / w), from 0.2% to 20% (w / w), from 0.5% to 20% (w / w), from 1% to 20% (w / w), from 2% to 20% (w / w), from 3% to 20% (w / w), from 4% to 20% (w / w), from 5% to 20% (w / w), from 6% to 20% (w / w), from 7% to 20% (w / w), from 8% to 20% (w / w), from 9% to 20% (w / w), from 10% to 20% (w / w), from 11% to 20% (w / w), from 12% to 20% (w / w), from 13% to 20% (w / w), from 14% to 20% (w / w), from 15% to 20% (w / w), from 16% to 20% (w / w), from 17% to 20% (w / w), from 18% to 20% (w / w), or from 19% to 20% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0209] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 7 and from 0.1% to 15% (w / w), from 0.2% to 15% (w / w), from 0.5% to 15% (w / w), from 1% to 15% (w / w), from 2% to 15% (w / w), from 3% to 15% (w / w), from 4% to 15% (w / w), from 5% to 15% (w / w), from 6% to 15% (w / w), from 7% to 15% (w / w), from 8% to 15% (w / w), from 9% to 15% (w / w), from 10% to 15% (w / w), from 11% to 15% (w / w), from 12% to 15% (w / w), from 13% to 15% (w / w), or from 14% to 15% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or combinations thereof.

[0210] In certain embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 7 and from 0.1% to 10% (w / w), from 0.2% to 10% (w / w), from 0.5% to 10% (w / w), from 1% to 10% (w / w), from 2% to 10% (w / w), from 3% to 10% (w / w), from 4% to 10% (w / w), from 5% to 10% (w / w), from 6% to 10% (w / w), 7% to 10% (w / w), from 8% to 10% (w / w), or from 9% to 10% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or combinations thereof

[0211] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 7 and from 0.2% to 5% (w / w), from 0.3% to 5% (w / w), from 0.4% to 5% (w / w), from 0.5% to 5% (w / w), from 0.7% to 5% (w / w), from 0.8% to 5% (w / w), from 1% to 5% (w / w), from 1.5% to 5% (w / w), from 2% to 5% (w / w), from 2.5% to 5% (w / w), from 3% to 5% (w / w), or from 4% to 5% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 8, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or combinations thereof.

[0212] In other embodiments, a solid crystalline form of Compound A comprises at least 25% (w / w), at least 50% (w / w), at least 75% (w / w), at least 80% (w / w), at least 85% (w / w), at least 90% (w / w), at least 95% (w / w), at least 98% (w / w), or at least 99% (w / w) Compound A Polymorph 7.

[0213] 5.2.8 Compound A Polymorph 8 Mixture

[0214] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 8 and 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% (w / w) or less, 2% (w / w) or less, 1% (w / w) or less, 0.5% (w / w) or less, or 0.2% (w / w) or less of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or combinations thereof.

[0215] In certain embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 8 and from 0.1% to 20% (w / w), from 0.2% to 20% (w / w), from 0.5% to 20% (w / w), from 1% to 20% (w / w), from 2% to 20% (w / w), from 3% to 20% (w / w), from 4% to 20% (w / w), from 5% to 20% (w / w), from 6% to 20% (w / w), from 7% to 20% (w / w), from 8% to 20% (w / w), from 9% to 20% (w / w), from 10% to 20% (w / w), from 11% to 20% (w / w), from 12% to 20% (w / w), from 13% to 20% (w / w), from 14% to 20% (w / w), from 15% to 20% (w / w), from 16% to 20% (w / w), from 17% to 20% (w / w), from 18% to 20% (w / w), or from 19% to 20% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0216] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 8 and from 0.1% to 15% (w / w), from 0.2% to 15% (w / w), from 0.5% to 15% (w / w), from 1% to 15% (w / w), from 2% to 15% (w / w), from 3% to 15% (w / w), from 4% to 15% (w / w), from 5% to 15% (w / w), from 6% to 15% (w / w), from 7% to 15% (w / w), from 8% to 15% (w / w), from 9% to 15% (w / w), from 10% to 15% (w / w), from 11% to 15% (w / w), from 12% to 15% (w / w), from 13% to 15% (w / w), or from 14% to 15% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0217] In certain embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 8 and from 0.1% to 10% (w / w), from 0.2% to 10% (w / w), from 0.5% to 10% (w / w), from 1% to 10% (w / w), from 2% to 10% (w / w), from 3% to 10% (w / w), from 4% to 10% (w / w), from 5% to 10% (w / w), from 6% to 10% (w / w), 7% to 10% (w / w), from 8% to 10% (w / w), or from 9% to 10% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or combinations thereof.

[0218] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 8 and from 0.2% to 5% (w / w), from 0.3% to 5% (w / w), from 0.4% to 5% (w / w), from 0.5% to 5% (w / w), from 0.7% to 5% (w / w), from 0.8% to 5% (w / w), from 1% to 5% (w / w), from 1.5% to 5% (w / w), from 2% to 5% (w / w), from 2.5% to 5% (w / w), from 3% to 5% (w / w), or from 4% to 5% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 9, Compound A Polymorph 10, or Compound A Polymorph 11, or combinations thereof.

[0219] In other embodiments, a solid crystalline form of Compound A comprises at least 25% (w / w), at least 50% (w / w), at least 75% (w / w), at least 80% (w / w), at least 85% (w / w), at least 90% (w / w), at least 95% (w / w), at least 98% (w / w), or at least 99% (w / w) Compound A Polymorph 8.

[0220] 5.2.9 Compound A Polymorph 9 Mixtures

[0221] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 9 and 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% (w / w) or less, 2% (w / w) or less, 1% (w / w) or less, 0.5% (w / w) or less, or 0.2% (w / w) or less of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0222] In certain embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 9 and from 0.1% to 20% (w / w), from 0.2% to 20% (w / w), from 0.5% to 20% (w / w), from 1% to 20% (w / w), from 2% to 20% (w / w), from 3% to 20% (w / w), from 4% to 20% (w / w), from 5% to 20% (w / w), from 6% to 20% (w / w), from 7% to 20% (w / w), from 8% to 20% (w / w), from 9% to 20% (w / w), from 10% to 20% (w / w), from 11% to 20% (w / w), from 12% to 20% (w / w), from 13% to 20% (w / w), from 14% to 20% (w / w), from 15% to 20% (w / w), from 16% to 20% (w / w), from 17% to 20% (w / w), from 18% to 20% (w / w), or from 19% to 20% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0223] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 9 and from 0.1% to 15% (w / w), from 0.2% to 15% (w / w), from 0.5% to 15% (w / w), from 1% to 15% (w / w), from 2% to 15% (w / w), from 3% to 15% (w / w), from 4% to 15% (w / w), from 5% to 15% (w / w), from 6% to 15% (w / w), from 7% to 15% (w / w), from 8% to 15% (w / w), from 9% to 15% (w / w), from 10% to 15% (w / w), from 11% to 15% (w / w), from 12% to 15% (w / w), from 13% to 15% (w / w), or from 14% to 15% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0224] In certain embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 9 and from 0.1% to 10% (w / w), from 0.2% to 10% (w / w), from 0.5% to 10% (w / w), from 1% to 10% (w / w), from 2% to 10% (w / w), from 3% to 10% (w / w), from 4% to 10% (w / w), from 5% to 10% (w / w), from 6% to 10% (w / w), 7% to 10% (w / w), from 8% to 10% (w / w), or from 9% to 10% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0225] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 9 and from 0.2% to 5% (w / w), from 0.3% to 5% (w / w), from 0.4% to 5% (w / w), from 0.5% to 5% (w / w), from 0.7% to 5% (w / w), from 0.8% to 5% (w / w), from 1% to 5% (w / w), from 1.5% to 5% (w / w), from 2% to 5% (w / w), from 2.5% to 5% (w / w), from 3% to 5% (w / w), or from 4% to 5% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 10, or Compound A Polymorph 11, or a combination thereof.

[0226] In other embodiments, a solid crystalline form of Compound A comprises at least 25% (w / w), at least 50% (w / w), at least 75% (w / w), at least 80% (w / w), at least 85% (w / w), at least 90% (w / w), at least 95% (w / w), at least 98% (w / w), or at least 99% (w / w) Compound A Polymorph 9.

[0227] 5.2.10 Compound A Polymorph 10 Mixture

[0228] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 10 and 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% (w / w) or less, 2% (w / w) or less, 1% (w / w) or less, 0.5% (w / w) or less, or 0.2% (w / w) or less of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, or Compound A Polymorph 11, or a combination thereof.

[0229] In certain embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 10 and from 0.1% to 20% (w / w), from 0.2% to 20% (w / w), from 0.5% to 20% (w / w), from 1% to 20% (w / w), from 2% to 20% (w / w), from 3% to 20% (w / w), from 4% to 20% (w / w), from 5% to 20% (w / w), from 6% to 20% (w / w), from 7% to 20% (w / w), from 8% to 20% (w / w), from 9% to 20% (w / w), from 10% to 20% (w / w), from 11% to 20% (w / w), from 12% to 20% (w / w), from 13% to 20% (w / w), from 14% to 20% (w / w), from 15% to 20% (w / w), from 16% to 20% (w / w), from 17% to 20% (w / w), from 18% to 20% (w / w), or from 19% to 20% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, or Compound A Polymorph 11, or combinations thereof.

[0230] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 10 and from 0.1% to 15% (w / w), from 0.2% to 15% (w / w), from 0.5% to 15% (w / w), from 1% to 15% (w / w), from 2% to 15% (w / w), from 3% to 15% (w / w), from 4% to 15% (w / w), from 5% to 15% (w / w), from 6% to 15% (w / w), from 7% to 15% (w / w), from 8% to 15% (w / w), from 9% to 15% (w / w), from 10% to 15% (w / w), from 11% to 15% (w / w), from 12% to 15% (w / w), from 13% to 15% (w / w), or from 14% to 15% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, or Compound A Polymorph 11, or combinations thereof.

[0231] In certain embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 10 and from 0.1% to 10% (w / w), from 0.2% to 10% (w / w), from 0.5% to 10% (w / w), from 1% to 10% (w / w), from 2% to 10% (w / w), from 3% to 10% (w / w), from 4% to 10% (w / w), from 5% to 10% (w / w), from 6% to 10% (w / w), 7% to 10% (w / w), from 8% to 10% (w / w), or from 9% to 10% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, or Compound A Polymorph 11, or a combination thereof.

[0232] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 10 and from 0.2% to 5% (w / w), from 0.3% to 5% (w / w), from 0.4% to 5% (w / w), from 0.5% to 5% (w / w), from 0.7% to 5% (w / w), from 0.8% to 5% (w / w), from 1% to 5% (w / w), from 1.5% to 5% (w / w), from 2% to 5% (w / w), from 2.5% to 5% (w / w), from 3% to 5% (w / w), or from 4% to 5% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, or Compound A Polymorph 11, or a combination thereof.

[0233] In other embodiments, a solid crystalline form of Compound A comprises at least 25% (w / w), at least 50% (w / w), at least 75% (w / w), at least 80% (w / w), at least 85% (w / w), at least 90% (w / w), at least 95% (w / w), at least 98% (w / w), or at least 99% (w / w) Compound A Polymorph 10.

[0234] 5.2.11 Compound A Polymorph 11 Mixture

[0235] In some embodiments, a solid crystalline form of Compound A comprises Compound A Polymorph 11 and 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% (w / w) or less, 2% (w / w) or less, 1% (w / w) or less, 0.5% (w / w) or less, or 0.2% (w / w) or less of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, or Compound A Polymorph 10, or combinations thereof.

[0236] In certain embodiments, a solid crystalline form of Compound A comprises Compound A Polymorph 11 and from 0.1% to 20% (w / w), from 0.2% to 20% (w / w), from 0.5% to 20% (w / w), from 1% to 20% (w / w), from 2% to 20% (w / w), from 3% to 20% (w / w), from 4% to 20% (w / w), from 5% to 20% (w / w), from 6% to 20% (w / w), from 7% to 20% (w / w), from 8% to 20% (w / w), from 9% to 20% (w / w), from 10% to 20% (w / w), from 11% to 20% (w / w), from 12% to 20% (w / w), from 13% to 20% (w / w), from 14% to 20% (w / w), from 15% to 20% (w / w), from 16% to 20% (w / w), from 17% to 20% (w / w), from 18% to 20% (w / w), or from 19% to 20% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, or Compound A Polymorph 10, or combinations thereof.

[0237] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 11 and from 0.1% to 15% (w / w), from 0.2% to 15% (w / w), from 0.5% to 15% (w / w), from 1% to 15% (w / w), from 2% to 15% (w / w), from 3% to 15% (w / w), from 4% to 15% (w / w), from 5% to 15% (w / w), from 6% to 15% (w / w), from 7% to 15% (w / w), from 8% to 15% (w / w), from 9% to 15% (w / w), from 10% to 15% (w / w), from 11% to 15% (w / w), from 12% to 15% (w / w), from 13% to 15% (w / w), or from 14% to 15% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, or Compound A Polymorph 10, or combinations thereof.

[0238] In certain embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 11 and from 0.1% to 10% (w / w), from 0.2% to 10% (w / w), from 0.5% to 10% (w / w), from 1% to 10% (w / w), from 2% to 10% (w / w), from 3% to 10% (w / w), from 4% to 10% (w / w), from 5% to 10% (w / w), from 6% to 10% (w / w), 7% to 10% (w / w), from 8% to 10% (w / w), or from 9% to 10% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, or Compound A Polymorph 10, or combinations thereof.

[0239] In some embodiments, a solid crystalline form of Compound A contains Compound A Polymorph 11 and from 0.2% to 5% (w / w), from 0.3% to 5% (w / w), from 0.4% to 5% (w / w), from 0.5% to 5% (w / w), from 0.7% to 5% (w / w), from 0.8% to 5% (w / w), from 1% to 5% (w / w), from 1.5% to 5% (w / w), from 2% to 5% (w / w), from 2.5% to 5% (w / w), from 3% to 5% (w / w), or from 4% to 5% (w / w) of all other solid crystalline forms of Compound A disclosed herein, or a specific solid crystalline form of Compound A disclosed herein, such as Compound A Polymorph 1, Compound A Polymorph 2, Compound A Polymorph 3, Compound A Polymorph 4, Compound A Polymorph 5, Compound A Polymorph 6, Compound A Polymorph 7, Compound A Polymorph 8, Compound A Polymorph 9, or Compound A Polymorph 10, or a combination thereof.

[0240] In other embodiments, a solid crystalline form of Compound A comprises at least 25% (w / w), at least 50% (w / w), at least 75% (w / w), at least 80% (w / w), at least 85% (w / w), at least 90% (w / w), at least 95% (w / w), at least 98% (w / w), or at least 99% (w / w) Compound A Polymorph 11.

[0241] 5.2.12 Therapeutic Methods Using Solid Forms of Compound A

[0242] In some embodiments, the present disclosure relates to methods for treating diseases, disorders, or conditions associated with Kv7 potassium channel dysfunction in a subject in need thereof, comprising orally administering a therapeutically effective amount of a solid form, e.g., a crystalline form of Compound A for human use. In certain cases, the diseases, disorders, or conditions associated with Kv7 potassium channel dysfunction are epilepsy, such as focal onset epilepsy. In certain embodiments, the solid form of Compound A is Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10, or Polymorph 11.

[0243] In some embodiments, the present disclosure relates to compounds for treating diseases, disorders, or conditions associated with Kv7 potassium channel dysfunction in a subject in need thereof, wherein the compound is a solid form of Compound A and a therapeutically effective amount of the compound is orally administered to the subject. In certain cases, the diseases, disorders, or conditions associated with Kv7 potassium channel dysfunction are epilepsy, such as focal onset epilepsy. In certain embodiments, the solid form of Compound A is Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10, or Polymorph 11.

[0244] In embodiments related to diseases, disorders or conditions associated with Kv7 potassium channel dysfunction, in some cases, the method enhances the opening of Kv7 potassium channels, such as one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5. In certain cases, the method or use can be used to selectively enhance the opening of Kv7 potassium channels selected from one or more of Kv7.2, Kv7.3, Kv7.4 and Kv7.5 relative to Kv7.1. In some embodiments, the method or use is selectively directed to Kv7.2 relative to Kv7.1. In other embodiments, the method or use is selectively directed to Kv7.3 relative to Kv7.1. In other embodiments, the method or use is selectively directed to Kv7.4 relative to Kv7.1. In other embodiments, the method or use is selectively directed to Kv7.5 relative to Kv7.1. In certain embodiments, the method or use is selectively directed to Kv7.2 and Kv7.3 relative to Kv7.1.

[0245] In one embodiment, the present disclosure provides a method of treating a seizure disorder in a human in need thereof, comprising orally administering to the human an amount of a solid form of Compound A, wherein the amount of the solid form of Compound A is sufficient to treat seizures in a human. In certain embodiments, the amount is sufficient to reduce the severity of seizures, the frequency of seizures, or both. In certain embodiments, the solid form of Compound A is Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10 or Polymorph 11.

[0246] In one embodiment, the present invention provides a compound for treating a seizure disorder in a human in need thereof, wherein the compound is a solid form of Compound A and the compound is orally administered to the human. In certain embodiments, the amount is sufficient to reduce the severity of seizures, the frequency of seizures, or both. In certain embodiments, the solid form of Compound A is Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10 or Polymorph 11.

[0247] In one embodiment, the present disclosure provides a method of treating a seizure disorder in a human in need thereof, comprising orally administering to the human an amount of a solid form of Compound A, wherein the amount of the solid form of Compound A is 2 to 200 milligrams. In certain embodiments, 2 to 200 milligrams of Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10 or Polymorph 11 of Compound A is orally administered.

[0248] In some embodiments, the present disclosure relates to methods of treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a person in need thereof, comprising orally administering to the person a therapeutically effective amount of a solid form of Compound A under fed conditions. In certain cases, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is epilepsy, such as focal onset epilepsy. In certain embodiments, the solid form of Compound A is Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10, or Polymorph 11.

[0249] In some embodiments, the present disclosure relates to methods of treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a person in need thereof, comprising orally administering to the person a therapeutically effective amount of a solid form of Compound A between 30 minutes before feeding and 2 hours after feeding. In certain cases, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is epilepsy, such as focal onset epilepsy. In certain embodiments, the solid form of Compound A is Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10, or Polymorph 11.

[0250] In some embodiments, the present disclosure relates to a compound for treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a person in need thereof, wherein the compound is a solid form of Compound A, and a therapeutically effective amount of the compound is orally administered to the person under fed conditions. In certain cases, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is epilepsy, such as focal onset epilepsy. In certain embodiments, the solid form of Compound A is Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10, or Polymorph 11.

[0251] In certain embodiments, the present disclosure relates to a compound for treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a person in need thereof, wherein the compound is a solid form of Compound A, and a therapeutically effective amount of the compound is orally administered to the person between 30 minutes before feeding and 2 hours after feeding. In certain cases, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is seizure, such as focal onset epilepsy. In certain embodiments, the solid form of Compound A is Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10, or Polymorph 11.

[0252] In one embodiment, the present invention provides a method for treating seizure disorders in a person in need thereof, comprising orally administering to the person a certain amount of the solid form of compound A under feeding conditions, wherein the amount of compound A is sufficient to treat epilepsy in the person. In certain embodiments, the amount is sufficient to reduce the severity of seizures, the frequency of seizures, or both. In certain embodiments, the solid form of compound A is Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 11.

[0253] In one embodiment, the present disclosure provides a compound for treating epilepsy in a person in need thereof, wherein the compound is the solid form of compound A, and the compound is orally administered to the person under feeding conditions. In certain embodiments, the amount is sufficient to reduce the severity of epilepsy, the frequency of epilepsy, or both. In certain embodiments, the solid form of compound A is Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 11.

[0254] In one embodiment, the present disclosure provides a method for treating epilepsy in a person in need thereof, which comprises orally administering to the person a certain amount of the solid form of compound A between 30 minutes before feeding and 2 hours after feeding, wherein the amount of the solid form of compound A is sufficient to treat epilepsy in humans. In certain embodiments, the amount is sufficient to reduce the severity of epilepsy, the frequency of epilepsy, or both. In certain embodiments, the solid form of compound A is Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 11.

[0255] In one embodiment, the present disclosure provides a compound for treating epilepsy in a person in need thereof, wherein the compound is the solid form of compound A, and the compound is orally administered to the person between 30 minutes before feeding and 2 hours after feeding. In certain embodiments, the amount is sufficient to reduce the severity of epilepsy, the frequency of epilepsy, or both. In certain embodiments, the solid form of compound A is Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 11.

[0256] In one embodiment, the present disclosure provides a method for treating epilepsy in a person in need thereof, which comprises orally administering to the person a certain amount of the solid form of compound A under feeding conditions, wherein the solid form of compound A is from 2 to 200 mg. In certain embodiments, 2 to 200 mg of Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 11 of compound A is orally administered.

[0257] In one embodiment, the present disclosure provides a method for treating epilepsy in a person in need thereof, which comprises orally administering a certain amount of the solid form of Compound A to the person between 30 minutes before eating and 2 hours after eating, wherein the solid form of Compound A is 2 to 200 mg. In certain embodiments, 2 to 200 mg of polymorph 1, polymorph 2, polymorph 3, polymorph 4, polymorph 5, polymorph 6, polymorph 7, polymorph 8, polymorph 9, polymorph 10, or polymorph 11 of Compound A is orally administered.

[0258] In one embodiment, the present disclosure provides a method for increasing one or more of Cmax, AUCinf, Tmax, or t 1 / 2λz of the solid form of Compound A (e.g., polymorph 1, polymorph 2, polymorph 3, polymorph 4, polymorph 5, polymorph 6, polymorph 7, polymorph 8, polymorph 9, polymorph 10, or polymorph 11) in a person receiving oral administration of the solid form of Compound A, which comprises orally administering a certain amount of the solid form of Compound A to the person under fed conditions. In certain embodiments, compared to orally administering the same amount of the solid form of Compound A to the person under fasted conditions, this method increases one or more of Cmax, AUCinf, Tmax, or t 1 / 2λz.

[0259] In one embodiment, the present disclosure provides a method for increasing one or more of Cmax, AUCinf, Tmax, or t 1 / 2λz of the solid form of Compound A (e.g., polymorph 1, polymorph 2, polymorph 3, polymorph 4, polymorph 5, polymorph 6, polymorph 7, polymorph 8, polymorph 9, polymorph 10, or polymorph 11) in a person receiving oral administration of the solid form of Compound A, which comprises orally administering a certain amount of the solid form of Compound A to the person between 30 minutes before eating and 2 hours after eating. In certain embodiments, compared to orally administering the same amount of the solid form of Compound A to the person under fasted conditions, this method increases one or more of Cmax, AUCinf, Tmax, or t 1 / 2λz.

[0260] In one embodiment, the present invention provides a method for orally administering the solid form of Compound A (e.g., polymorph 1, polymorph 2, polymorph 3, polymorph 4, polymorph 5, polymorph 6, polymorph 7, polymorph 8, polymorph 9, polymorph 10, or polymorph 11) to a person in need thereof, which comprises orally administering the solid form of Compound A to the person under fed conditions. In certain embodiments, compared to orally administering the same amount of the solid form of Compound A to the person under fasted conditions, this method increases Cmax, AUCinf, Tmax, or t of the solid form of Compound A 1one or more of / 2λz.

[0261] In one embodiment, the present invention provides a method of orally administering a solid form of compound A (e.g., polymorph 1, polymorph 2, polymorph 3, polymorph 4, polymorph 5, polymorph 6, polymorph 7, polymorph 8, polymorph 9, polymorph 10, or polymorph 11) to a human in need thereof, which comprises orally administering the solid form of compound A to the human between 30 minutes before eating and 2 hours after eating. In certain embodiments, compared to orally administering the same amount of the solid form of compound A to a human under fasting conditions, this method increases the Cmax, AUCinf, Tmax, or t of the solid form of compound A 1 one or more of / 2λz.

[0262] In one embodiment, the solid form of compound A (e.g., polymorph 1, polymorph 2, polymorph 3, polymorph 4, polymorph 5, polymorph 6, polymorph 7, polymorph 8, polymorph 9, polymorph 10, or polymorph 11) is provided in a dosage unit form suitable for oral administration. Compound A is present in a dosage unit form of from about 0.05 mg / kg to about 2.0 mg / kg. More specific representative levels include 0.05 mg / kg, 0.10 mg / kg, 0.20 mg / kg, 0.30 mg / kg, 0.40 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.80 mg / kg, 0.90 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, and 2.0 mg / kg. In some aspects, the method comprises orally administering 0.1 - 1.0 mg / kg of the solid form of compound A. In some aspects, the method comprises orally administering 0.2 - 0.5 mg / kg of the solid form of compound A.

[0263] In some embodiments, the methods and uses described herein, such as methods and uses for treating seizure disorders in a person in need thereof according to the methods and uses described herein, are achieved by oral administration of 2 to 200 mg of a solid form of Compound A (e.g., Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10, or Polymorph 11). For example, the method may include oral administration of about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, about 120 mg, about 121 mg, about 122 mg, about 123 mg, about 124 mg, about 125 mg, about 126 mg, about 127 mg, about 129 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 136 mg, about 137 mg, about 138 mg, about 139 mg, about 140 mg,About 141 mg, about 142 mg, about 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147 mg, about 148 mg, about 149 mg, about 150 mg, about 151 mg, about 152 mg, about 153 mg, about 154 mg, about 155 mg, about 156 mg, about 157 mg, about 158 mg, about 159 mg, about 160 mg, about 161 mg, about 162 mg, about 163 mg, about 164 mg, about 165 mg, about 166 mg, about 167 mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg, about 174 mg, about 175 mg, about 176 mg, about 177 mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182 mg, about 183 mg, about 184 mg, about 185 mg, about 186 mg, about 187 mg, about 188 mg, about 189 mg, about 190 mg, about 191 mg, about 192 mg, about 193 mg, about 194 mg, about 195 mg, about 196 mg, about 197 mg, about 198 mg, about 199 mg, or about 200 mg. In some aspects, oral administration comprises 5 to 50 mg of Compound A. In some aspects, oral administration comprises 10, 20, or 25 mg of Compound A. In some aspects, oral administration comprises 20 mg of Compound A. In some aspects, oral administration comprises at least 20 mg of Compound A.,

[0264] In some embodiments, the methods and uses described herein, such as methods and uses for treating seizure disorders in a person in need thereof according to the methods and uses described herein, are achieved by oral administration of a solid form of Compound A at 5 to 1000 milligrams per day (e.g., Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10, or Polymorph 11), such as a solid form of Compound A at 5 to 500 milligrams or 5 to 250 milligrams per day. For example, the method can include oral administration of about 5 milligrams, about 10 milligrams, about 15 milligrams, about 20 milligrams, about 25 milligrams, about 30 milligrams, about 35 milligrams, about 40 milligrams, about 45 milligrams, about 50 milligrams, about 55 milligrams, about 60 milligrams, about 65 milligrams, about 70 milligrams, about 75 milligrams, about 80 milligrams, about 85 milligrams, about 90 milligrams, about 95 milligrams, about 100 milligrams, about 105 milligrams, about 110 milligrams, about 115 milligrams, about 120 milligrams, about 125 milligrams, about 130 milligrams, about 135 milligrams, about 140 milligrams, about 145 milligrams, about 150 milligrams, about 155 milligrams, about 160 milligrams, about 165 milligrams, about 170 milligrams, about 175 milligrams, about 180 milligrams, about 185 milligrams, about 190 milligrams, about 195 milligrams, about 200 milligrams, about 205 milligrams, about 210 milligrams, about 215 milligrams, about 220 milligrams, about 225 milligrams, about 230 milligrams, about 235 milligrams, about 240 milligrams, about 245 milligrams, about 250 milligrams, about 255 milligrams, about 260 milligrams, about 265 milligrams, about 270 milligrams, about 275 milligrams, about 280 milligrams, about 285 milligrams, about 290 milligrams, about 295 milligrams, about 300 milligrams, about 305 milligrams, about 310 milligrams, about 315 milligrams, about 320 milligrams, about 325 milligrams, about 330 milligrams, about 335 milligrams, about 340 milligrams, about 345 milligrams, about 350 milligrams, about 355 milligrams, about 360 milligrams, about 365 milligrams, about 370 milligrams, about 375 milligrams, about 380 milligrams, about 385 milligrams, about 390 milligrams, about 395 milligrams, about 400 milligrams, about 405 milligrams, about 410 milligrams, about 415 milligrams, about 420 milligrams, about 425 milligrams, about 430 milligrams, about 435 milligrams, about 440 milligrams, about 445 milligrams, about 450 milligrams, about 455 milligrams, about 460 milligrams, about 465 milligrams, about 470 milligrams, about 475 milligrams, about 480 milligrams, about 485 milligrams, about 490 milligrams, about 495 milligrams, about 500 milligrams, or about 1000 milligrams per day. In some aspects, oral administration includes oral administration of 10 - 200 milligrams of a solid form of Compound A per day, such as 10, 15, 20, 25, 30, 35, or 40 milligrams to 75, 100, 125, 150, 175, or 200 milligrams of a solid form of Compound A per day, including 20 to 150 milligrams per day.In some aspects, oral administration includes a solid form of Compound A at 50, 75, 100, or 125 milligrams per day, such as 100 milligrams per day.

[0265] In certain cases, the solid form of Compound A at the above daily doses is orally administered in multiple daily doses, such as two, three, four, or five doses per day. For example, a dose of 100 milligrams per day can be administered as four doses of 25 milligrams each throughout the day.

[0266] In some embodiments, the daily dose of the solid form of Compound A is administered as a single oral dose. For example, a solid form of Compound A at about 5, 10, 15, 20, 25, or 30 milligrams to about 50, 65, 75, 100, 125, or 150 milligrams per day can be administered as a single oral dose, including single doses of 10 - 25 milligrams, 10 - 30 milligrams, 10 - 40 milligrams per day, such as a single dose of 10 - 25 milligrams per day.

[0267] In one embodiment of the present disclosure, administering a solid form of Compound A, such as for treating seizure disorders, would benefit from the opening of the Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channel. Compound A is a Kv7.2 / Kv7.3 (KCNQ2 / 3) opener. In certain embodiments, the present disclosure provides a method of opening the Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channel in a person in need thereof, which includes administering a dosage of a solid form of Compound A (e.g., polymorph 1, polymorph 2, polymorph 3, polymorph 4, polymorph 5, polymorph 6, polymorph 7, polymorph 8, polymorph 9, polymorph 10, or polymorph 11). In similar embodiments, the present disclosure provides a solid form of Compound A for opening the Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channel in a person in need thereof.

[0268] In certain embodiments, the methods and uses described herein administer the solid form of Compound A in the form of a pharmaceutically acceptable oral composition, which composition comprises a solid form of Compound A (e.g., polymorph 1, polymorph 2, polymorph 3, polymorph 4, polymorph 5, polymorph 6, polymorph 7, polymorph 8, polymorph 9, polymorph 10, or polymorph 11) and one or more pharmaceutically acceptable carriers or excipients. The amount of the solid form of Compound A included in these compositions corresponds to one or more of the amounts described herein. In some embodiments, the composition is a unit dose.

[0269] Examples of pharmaceutically acceptable oral compositions comprising a solid form of Compound A include solid formulations (e.g., tablets, capsules, lozenges, dragees, granules, powders, multiparticulates, and films) and liquid formulations (e.g., aqueous solutions, elixirs, tinctures, suspensions, and dispersions). In one embodiment, the pharmaceutically acceptable oral composition of the solid form of Compound A comprises a pediatric suspension or granules. The amounts of all of the above solid forms of Compound A can be included in such formulations, such as capsules containing 5, 10, 15, 20, 25, 30, or 35 milligrams of the solid form of Compound A.

[0270] In one embodiment of the present disclosure, a therapeutically effective amount of the solid form of Compound A is from about 0.05 mg / kg to about 2.0 mg / kg.

[0271] In certain embodiments herein, comparisons involving humans orally administered a solid form of Compound A under fasting conditions can be made, and similar comparisons can be made involving humans who have not eaten during a period of time from about 4 hours before to about 4 hours after oral administration of the solid form of Compound A, such as from about 4, 3, 2, 1.5, 1, or 0.5 hours before to about 0.5, 1, 1.5, 2, 3, or 4 hours after oral administration of the solid form of Compound A.

[0272] In certain embodiments, when treating epilepsy, the seizure disorder is selected from partial (focal) seizures, photosensitive epilepsy, self-induced syncope, intractable epilepsy, Angelman syndrome, benign rolandic epilepsy, CDKL5 disorder, childhood and adolescent absence epilepsy, severe myoclonic epilepsy in infancy (Dravet syndrome), frontal lobe epilepsy, GLUT1 deficiency syndrome, hypothalamic hamartoma, infantile spasms / West's syndrome, juvenile myoclonic epilepsy, childhood epilepsy with speech arrest (Landau-Kleffner syndrome), Lennox-Gastaut syndrome (LGS), myoclonic absence epilepsy, Ohtahara syndrome, Panayiotopoulos syndrome, PCDH19 epilepsy, progressive myoclonic epilepsy, Rasmussen syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, Lafora progressive myoclonic epilepsy, neurocutaneous syndromes, tuberous sclerosis, early infantile epileptic encephalopathy, early-onset epileptic encephalopathy, generalized epilepsy with febrile seizures plus, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia, and paroxysmal dyskinesia. In certain embodiments, the seizure disorder is focal onset epilepsy, also known as partial (focal) seizures.

[0273] Additional embodiments of the disclosure are described herein. These embodiments are illustrative and should not be construed as limiting the scope of the claimed disclosure.

[0274] 5.3 Pharmaceutical Compositions and Administration

[0275] In some embodiments, the disclosure relates to a pharmaceutical composition comprising a solid form of Compound A described herein (e.g., Crystal Form 1, Crystal Form 2, Crystal Form 3, Crystal Form 4, Crystal Form 5, Crystal Form 6, Crystal Form 7, Crystal Form 8, Crystal Form 9, Crystal Form 10, or Crystal Form 11) and a pharmaceutically acceptable excipient. In one embodiment, the invention relates to a composition comprising a solid form of Compound A and a pharmaceutically acceptable excipient, wherein the amount of the composition is effective to treat a seizure disorder when administered to an animal, preferably a mammal, and most preferably a human.

[0276] The solid forms of Compound A (e.g., Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10, or Polymorph 11), in pure form or in a suitable pharmaceutical composition, can be administered by any acceptable mode of administration of a reagent for a similar use. In one embodiment, the pharmaceutical compositions disclosed herein can be prepared by combining the solid forms of Compound A disclosed herein with suitable pharmaceutically acceptable excipients and can be formulated into preparations in solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administering such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injection, intravenous injection, intramuscular injection, intracostal injection, or infusion techniques. The pharmaceutical compositions disclosed herein are formulated to allow the active ingredient contained therein to be bioavailable when the composition is administered to a patient. The pharmaceutical composition will be administered to a mammal, preferably a human, in the form of one or more dosage units, where, for example, a tablet can be a single dosage unit, and a container of the disclosed compound in aerosol form can contain multiple dosage units. For those skilled in the art, the actual methods of preparing such dosage forms are known or will be apparent. See, for example, Pharmaceutical Sciences and Practice, latest edition (Philadelphia College of Pharmacy and Science, 2000). In any case, the composition to be administered contains a therapeutically effective amount of the solid form of Compound A disclosed herein, such as a crystalline form, for treating a disease or disorder of interest according to the present disclosure.

[0277] In one embodiment, the pharmaceutical compositions disclosed herein further contain pharmaceutically acceptable excipients, which include any agent that does not itself induce the production of antibodies harmful to the individual receiving the composition and which can be administered without undue toxicity. In one embodiment, pharmaceutically acceptable excipients include, but are not limited to, liquids such as water, saline, glycerol, and ethanol. An in-depth discussion of pharmaceutically acceptable excipients is published in Remington: The Science and Practice of Pharmacy (Mack Pub. Co., N.J., current edition).

[0278] In one embodiment, the pharmaceutical compositions disclosed herein can be in solid or liquid form. In one aspect, the excipient is particulate such that the composition is, for example, in tablet or powder form. The excipient can be liquid and the composition is, for example, an oral syrup, an injectable liquid, or an aerosol, which can be used, for example, for inhalation administration.

[0279] In one embodiment, when used for oral administration, the pharmaceutical compositions disclosed herein are preferably in solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the solid or liquid forms contemplated herein.

[0280] In one embodiment, as a solid composition for oral administration, the pharmaceutical compositions disclosed herein can be formulated in the form of powders, granules, compressed tablets, pills, capsules, chewing gums, wafers, and the like. Such solid compositions generally contain one or more inert or edible excipients. In addition, one or more of the following may be present: binders such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, chewing gum or gelatin; excipients such as starch, lactose or dextrin, disintegrants such as alginic acid, sodium alginate, sodium starch glycolate, corn starch, and the like; lubricants such as magnesium stearate or hydrogenated vegetable oil; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavoring agents such as peppermint, methyl salicylate or orange flavoring; and coloring agents.

[0281] In one embodiment, when the pharmaceutical compositions disclosed herein are in the form of capsules, for example, in addition to materials of the above types, it can contain liquid excipients such as polyethylene glycol or oil.

[0282] In one embodiment, the pharmaceutical compositions disclosed herein can be in liquid form, such as elixirs, syrups, solutions, emulsions or suspensions. The liquid can be used for oral administration or delivered by injection, as two examples. When used for oral administration, the preferred compositions contain, in addition to the solid form of Compound A, one or more sweeteners, preservatives, dyes / coloring agents, and flavor enhancers. In compositions intended to be administered by injection, one or more of surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffers, stabilizers and isotonic agents can be included.

[0283] In one embodiment, the liquid pharmaceutical compositions disclosed herein, whether in solution, suspension or other form, can include one or more of the following adjuvants: sterile diluents such as water for injection, saline solutions, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils that can be used as solvents or suspending media, such as synthetic mono- or di-glycerides of glycerol, polyethylene glycol, glycerol, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetate, citrate or phosphate, and agents for adjusting tonicity such as sodium chloride or glucose. Parenteral preparations can be enclosed in ampoules, disposable syringes or multi-dose vials made of glass or plastic. Physiological saline is the preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

[0284] In one embodiment, the liquid pharmaceutical compositions disclosed herein for parenteral or oral administration should contain a certain amount of the solid form of Compound A to obtain a suitable dose. In one embodiment, the amount of the solid form of Compound A in the formulation is at least 0.01%. When used for oral administration, in one embodiment, this amount can vary between 0.1% and about 70% by weight of the composition. In one embodiment, the oral pharmaceutical compositions disclosed herein contain from about 4% to about 50% of the solid form of Compound A. In another embodiment, the pharmaceutical compositions disclosed herein are prepared such that the parenteral dose unit contains from 0.01% to 10% by weight of the solid form of Compound A before dilution.

[0285] In one embodiment, the pharmaceutical compositions disclosed herein can be used for topical administration, in which case the excipient may suitably comprise a solution, an emulsion, an ointment or a gel matrix. For example, the matrix may include one or more of the following: petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, diluents such as water and alcohol, and emulsifying and stabilizing agents. Thickeners may be present in the pharmaceutical compositions for topical administration. If transdermal administration is intended, the composition may include a transdermal patch or an iontophoresis device. The topical preparation may contain from about 0.1% to about 10% w / v (weight / unit volume) of the solid form of Compound A.

[0286] In one embodiment, the pharmaceutical compositions disclosed herein can be used for rectal administration in the form of, for example, suppositories, which will melt in the rectum and release the drug. The compositions for rectal administration may contain an oily matrix as a suitable non-irritating excipient. Such matrices include, but are not limited to, lanolin, cocoa butter and polyethylene glycol.

[0287] The pharmaceutical compositions disclosed herein for intramuscular or intrathecal administration will consist of an active suspension or solution in oil or a solution of the active ingredient in oil (such as peanut oil or sesame oil). In one embodiment, the pharmaceutical compositions disclosed herein for intravenous or intrathecal administration will consist of a sterile isotonic aqueous solution containing, for example, the active ingredient and glucose or sodium chloride or a mixture of glucose and sodium chloride.

[0288] In one embodiment, the pharmaceutical compositions disclosed herein can be formulated to provide rapid, sustained, or delayed release of the active ingredient, i.e., the solid form of Compound A, after administration to a patient by methods known in the art. Controlled-release drug delivery systems include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770 and 4,326,525 and P.J. Kuzma et al., Regional Anesthesia 22(6):543-551 (1997), all of which are incorporated herein by reference.

[0289] In one embodiment, the pharmaceutical compositions disclosed herein can also be delivered by intranasal drug delivery systems for topical, systemic, and nose-to-brain therapies. Controlled particle dispersion (CPD) TM techniques, conventional nasal spray bottles, inhalers, or nebulizers are known to those skilled in the art to provide effective topical and systemic delivery of drugs by targeting the olfactory region and paranasal sinuses.

[0290] In one embodiment, the pharmaceutical compositions disclosed herein relate to intravaginal shell or core drug delivery devices suitable for administration to humans or female animals. The device can consist of an active pharmaceutical ingredient in a polymer matrix, surrounded by a sheath, and capable of releasing the solid form of Compound A substantially in a zero-order mode on a daily basis.

[0291] In one embodiment, the most suitable route of administration of the solid form of Compound A or the pharmaceutical composition disclosed herein will depend on the nature and severity of the condition being treated. Those skilled in the art are also familiar with determining the method of administration (e.g., oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, suitable pharmaceutical excipients, and other substances related to delivering the solid form of Compound A to a subject in need thereof.

[0292] In some embodiments, the pharmaceutical compositions disclosed herein can include a variety of materials that alter the physical form of solid or liquid dosage units. For example, the pharmaceutical composition can include materials that form a coating shell around the active ingredient. The materials forming the coating shell are generally inert and can be selected from, for example, sugars, shellac, and other enteric coating agents. Alternatively, the active ingredient can be encapsulated in a polymer capsule.

[0293] In one embodiment, the pharmaceutical compositions in solid or liquid form disclosed herein can include reagents that bind to the solid form of Compound A, thereby facilitating the delivery of the solid form. Suitable reagents having such an ability include monoclonal or polyclonal antibodies, proteins, or liposomes.

[0294] In one embodiment, the pharmaceutical compositions disclosed herein can consist of dosage units that can be administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from colloidal nature systems to systems including pressurized packages. Delivery can be effected by liquefied or compressed gases or by a suitable pump system that dispenses the active ingredient. The aerosol of the solid form of Compound A can be delivered in a single-phase, two-phase, or three-phase system to deliver the active ingredient. Delivery of the aerosol includes the necessary containers, activators, valves, sub-containers, etc., which together can form a kit. A person skilled in the art can determine the preferred aerosol without undue experimentation.

[0295] In one embodiment, the pharmaceutical compositions disclosed herein can be prepared by methods well known in pharmaceutical technology. For example, a pharmaceutical composition for administration by injection can be prepared by combining the solid form of Compound A with sterile distilled water to form a solution. A surfactant can be added to facilitate the formation of a homogeneous solution or suspension. A surfactant is a compound that non-covalently interacts with the solid form of Compound A to facilitate the dissolution or homogeneous suspension of the compound in an aqueous delivery system.

[0296] In one embodiment, the solid form of Compound A or a pharmaceutical composition containing the solid form of Compound A, such as a crystalline form (e.g., crystal form 1, crystal form 2, crystal form 3, crystal form 4, crystal form 5, crystal form 6, crystal form 7, crystal form 8, crystal form 9, crystal form 10, or crystal form 11) is administered in a therapeutically effective amount. Generally, the daily therapeutically effective dose of the solid form of Compound A (for a 70 kg mammal) is from about 0.001 mg / kg (i.e., 0.07 mg) to about 100 mg / kg (i.e., 7.0 g); preferably, the therapeutically effective dose is (for a 70 kg mammal), from about 0.01 mg / kg (i.e., 0.70 mg) to about 50 mg / kg (i.e., 3.5 g); more preferably, the therapeutically effective dose (for a 70 kg mammal) is from about 1 mg / kg (i.e., 70 mg) to about 25 mg / kg (i.e., 1.75 g).

[0297] The ranges of effective doses provided herein are not intended to be limiting and represent preferred dose ranges. However, effective doses can be determined by those skilled in the relevant art by well-known methods. (See, e.g., Berkow et al., eds., The Merck Manual, 19th ed., Merck & Co., Inc., Rahway, NJ, 2011; Brunton et al., eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th ed., McGraw-Hill Companies 2011; Avery's Drug Treatment: Principles and Practice of Clinical Pharmacology and Therapeutics, 3rd ed., ADIS Press, LTD., Williams and Wilkins, Baltimore, MD (1987), Ebadi, Pharmacology, Little, Brown Book Co., Boston, (1985); Osolci et al., eds., Remington's Pharmaceutical Sciences, current ed., Mack Publishing Co., Easton, PA; Katzung, Basic and Clinical Pharmacology, Appleton and Lange, Norwalk, CT (1992)).

[0298] If desired, the total dose required for each treatment can be administered in multiple doses or a single dose during the day. Generally, treatment is started at a lower dose that is less than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimal effect is achieved in that setting. The diagnostic pharmaceutical compound or composition can be administered alone or in combination with other diagnostic and / or pharmaceutical agents directed against the pathology or other symptoms of the pathology. The effective amount of the solid form of Compound A is from about 0.1 μg to about 100 mg / kg body weight, administered at intervals of 4 - 72 hours for a period of 2 hours to 1 year, and / or any range or value therein, such as 0.0001 - 0.001, 0.001 - 0.01, 0.01 - 0.1, 0.1 - 1.0, 1.0 - 10, 5 - 10, 10 - 20, 20 - 50, and 50 - 100 mg / kg, at intervals of 1 - 4, 4 - 10, 10 - 16, 16 - 24, 24 - 36, 24 - 36, 36 - 48, 48 - 72 hours for a period of 1 - 14, 14 - 28, or 30 - 44 days or 1 - 24 weeks, or any range or value therein.

[0299] In one embodiment, the recipient of the solid form of Compound A or a pharmaceutical composition comprising the solid form of Compound A described herein can be any animal, such as a mammal. Among mammals, preferred recipients are mammals of the order Primates (including humans, apes, and monkeys), Artiodactyla (including horses, goats, cows, sheep, pigs), Rodentia (including mice, rats, and hamsters), Lagomorpha (including rabbits), and Carnivora (including cats and dogs). Among birds, preferred recipients are turkeys, chickens, and other members of the same order. The most preferred recipient is a human.

[0300] 5.4 Preparation Method of Solid Crystalline Forms of Compound A

[0301] In certain embodiments, the present disclosure provides a method for preparing the solid crystalline forms of Compound A (e.g., Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10, or Polymorph 11), for example, by recrystallization from another form of Compound A.

[0302] In one embodiment, the present invention provides a method for preparing Polymorph 2 of Compound A from Polymorph 1 of Compound A, for example, by forming a slurry of Polymorph 1 of Compound A in an alcohol - aqueous solution (e.g., ethanol - water), optionally shaking the slurry (e.g., at ambient temperature), cooling the slurry, and separating the slurry (e.g., by centrifugation) to prepare Polymorph 2 of Compound A.

[0303] In one embodiment, the present invention provides a method for preparing Polymorph 3 of Compound A from Polymorph 2 and Polymorph 4 of Compound A, for example, by forming a slurry of Polymorph 2 and Polymorph 4 of Compound A in a halogenated carbon solvent (e.g., dichloromethane), optionally shaking the slurry (e.g., at ambient temperature), cooling the slurry, and separating the slurry (e.g., by centrifugation) to prepare Polymorph 3 of Compound A.

[0304] In one embodiment, the present invention provides a method for preparing Polymorph 4 of Compound A from Polymorph 1 of Compound A, for example, by dissolving Polymorph 1 of Compound A in a warm alcohol solvent (e.g., 40 °C alcohol), cooling the slurry, adding an anti - solvent (e.g., water), and separating the precipitate (e.g., by centrifugation) to prepare Polymorph 4 of Compound A.

[0305] In one embodiment, the present invention provides a method for preparing Polymorph 5 of Compound A from Polymorph 1 of Compound A, for example, by forming a slurry of Polymorph 1 of Compound A in an acyclic ketone solvent (e.g., methyl isobutyl ketone), optionally adding additional Polymorph 1 of Compound A, treating the slurry with one or more heating and cooling cycles (e.g., between 40 °C and ambient temperature), and separating the slurry (e.g., by filtration) to prepare Polymorph 5 of Compound A.

[0306] In one embodiment, the present invention provides a method for preparing Polymorph 6 of Compound A from Polymorph 1 of Compound A, for example, by forming a slurry of Polymorph 1 of Compound A in an ether - aqueous solution (e.g., tetrahydrofuran - water), optionally adding additional Polymorph 1 of Compound A, treating the slurry with one or more heating and cooling cycles (e.g., between 40 °C and ambient temperature), and separating the slurry (e.g., by filtration) to prepare Polymorph 6 of Compound A.

[0307] In one embodiment, the present invention provides a method for preparing Form 7 of Compound A from Form 1 of Compound A. For example, by forming a slurry of Form 1 of Compound A in an ether solvent (such as tetrahydrofuran) or a ketone-aqueous solution (such as acetone-water), optionally adding additional Form 1 of Compound A, treating the slurry with one or more heating and cooling cycles (e.g., between 40 °C and ambient temperature), and separating the slurry (e.g., by filtration) to prepare Form 7 of Compound A.

[0308] In one embodiment, the present invention provides a method for preparing Form 8 of Compound A from Form 1 of Compound A. For example, by forming a slurry of Form 1 of Compound A in a cyclic ketone solvent (such as cyclohexanone), optionally adding additional Form 1 of Compound A, treating the slurry with one or more heating and cooling cycles (e.g., between 40 °C and ambient temperature), separating the slurry (e.g., by filtration), and slowly evaporating the supernatant to prepare Form 8 of Compound A.

[0309] In one embodiment, the present invention provides a method for preparing Form 9 of Compound A from Form 4 of Compound A. For example, by placing Form 4 of Compound A in a VT-XRPD sample holder, optionally flattening Form 4 of Compound A before adding it to the VT-XRPD sample holder, and treating it with one or more scanning and heating cycles (e.g., between 25 °C and 140 °C) to prepare Form 9 of Compound A.

[0310] In one embodiment, the present invention provides a method for preparing Form 9 of Compound A from Form 1 of Compound A. For example, by dissolving in an alcohol solvent (such as methanol), adding an aqueous solution of an acid (such as 1 M sulfuric acid), adding an anti-solvent (such as water), and separating the precipitate (e.g., by filtration) to prepare Form 9 of Compound A.

[0311] In one embodiment, the present invention provides a method for preparing Form 10 of Compound A from Form 1 of Compound A. For example, by slurrying Form 1 of Compound A in an ether solvent (such as tetrahydrofuran), diluting the slurry with more ether solvent (such as tetrahydrofuran), treating the slurry with one or more heating and cooling cycles (e.g., between 40 °C and ambient temperature), and separating the slurry (e.g., by centrifugation) to prepare Form 10 of Compound A.

[0312] In one embodiment, the present invention provides a method for preparing Form 11 of Compound A from Form 1 of Compound A. For example, by forming a slurry of Form 1 of Compound A in an alcohol solvent (such as ethanol), shaking and cooling the slurry (e.g., at 5 °C), heating the slurry until it dissolves and cooling the solution (e.g., at 5 °C), treating the slurry with one or more heating and cooling cycles (e.g., between 40 °C and ambient temperature), and separating the slurry (e.g., by centrifugation) to prepare Form 11 of Compound A.

[0313] The present disclosure provides a method for preparing a pharmaceutical composition comprising a pharmaceutical excipient and a solid crystalline form of Compound A described herein (e.g., Polymorph 1, Polymorph 2, Polymorph 3, Polymorph 4, Polymorph 5, Polymorph 6, Polymorph 7, Polymorph 8, Polymorph 9, Polymorph 10, or Polymorph 11), for example, by combining the solid crystalline form of Compound A with a pharmaceutical excipient to form a pharmaceutical composition.

[0314] 6 Examples

[0315] 6.1 Analytical Methods

[0316] The solid crystalline forms of Compound A are characterized using one or more of the following analytical methods. It should be understood that equivalent data can be obtained using similar instrumentation:

[0317] 6.1.1 A. X-Ray Powder Diffraction (XRPD)

[0318] XRPD analysis was performed on a PANalytical X’pert pro using a PIXcel detector (128 channels), scanning the sample between 3 and 35° 2θ. The material was gently ground to release any agglomerates and loaded onto a porous plate with a Kapton or Mylar polymer film to support the sample. The porous plate was then placed in the diffractometer and analyzed using Cu K radiation ( α1:α2 ratio = 0.5), run in transmission mode (step size 0.0130° 2θ, step time 18.87 s), using a 40 kV / 40 mA generator setting. The data was visualized and images were generated using the HighScore Plus 4.7 desktop application (pAnalytical, 2017).

[0319] 6.1.2 B. Polarized Light Microscopy (PLM)

[0320] The presence of crystallinity (birefringence) was determined using an Olympus BX50 microscope equipped with crossed polarizing lenses and a Motic camera. Images were captured using Motic Images Plus 2.0. Unless otherwise stated, all images were recorded using a 20x objective lens. All images were collected with crossed and uncrossed polarizers to highlight birefringent regions.

[0321] 6.1.3 C. Hot Stage Optical Microscopy

[0322] Calibrated Linkam THM600 hot stage was used to visually monitor thermal events. The hot stage has a connected controller unit which is coupled to an Olympus BX50 polarizing microscope equipped with a Motic camera and image capture software (Motic Images Plus 2.0). A sufficient amount of the material was placed on a microscope coverslip and heated at a rate of 10 °C / min. Images were taken at regular intervals to record any thermal transitions.

[0323] Unless otherwise stated, all images were recorded using a 10x objective. The following heating program was used for all samples:

[0324] 1. Initial heating: Heat from ambient temperature to 100 °C at 10 °C / min and take an image at each 10 °C increment.

[0325] 2. Heating between 100 °C and 160 °C at 1 °C / min and take an image at each 1 °C increment.

[0326] 3. Final heating between 160 °C and 200 °C at 10 °C / min and take an image every 10 °C.

[0327] 6.1.4D. Thermogravimetry / Differential Thermal Analysis (TG / DTA)

[0328] Approximately 5 mg of the material was weighed into an open aluminum pan and loaded into a synchronous thermogravimetry / differential thermal analyzer (TG / DTA) and kept at room temperature. Then the sample was heated from 20 °C to 400 °C at a rate of 10 °C / min, during which the change in sample weight and any differential thermal events (DTA) were recorded. Nitrogen was used as the purge gas with a flow rate of 300 cm3 / min.

[0329] 6.1.5E. Differential Scanning Calorimetry (DSC)

[0330] Approximately 5 mg of the material was weighed into an aluminum DSC pan and non-hermetically sealed with a perforated aluminum lid. Then the sample pan was loaded into a Seiko DSC6200 (equipped with a cooler), cooled and kept at 20 °C. Once a stable heat flow response was obtained, the sample and reference were heated to 220 °C at a scan rate of 10 °C / min and the resulting heat flow response was monitored. Nitrogen was used as the purge gas with a flow rate of 50 cm3 / min. Then similar data were obtained during a cooling cycle where the sample (initially at 220 °C) was cooled at a scan rate of 10 °C / min until a final temperature of 20 °C was reached. After holding the sample at 20 °C for 3 minutes, a second heating cycle was performed. The second heating cycle was carried out at a scan rate of 10 °C / min until a final temperature of 220 °C, and then held at 220 °C for 5 minutes.

[0331] 6.1.6 F. Karl Fischer Coulometric Titration (KF)

[0332] Weigh approximately 10 - 15 mg of solid material precisely into a vial. Then manually add the solid into the titration cell of a Mettler Toledo C30 Compact Titrator. Reweigh the vial after adding the solid and input the weight of the added solid into the instrument. Once the sample is completely dissolved in the cell, start the titration. The water content is automatically calculated as a percentage by the instrument and the data is printed.

[0333] 6.1.7 G. Fourier Transform Infrared Spectroscopy (FTIR)

[0334] The infrared spectroscopy test is carried out on a Bruker ALPHA P spectrometer. Place sufficient material at the center of the spectrometer sample holder and obtain the spectrum using the following parameters:

[0335] Resolution: 4 cm-1

[0336] Number of background scans: 16 times

[0337] Number of sample scans: 16 times

[0338] Data acquisition: 4000 to 400 cm-1

[0339] Resultant spectrum: Transmittance

[0340] Software: OPUS version 6

[0341] 6.1.8 H. 1H Nuclear Magnetic Resonance (1H NMR)

[0342] The 1H NMR experiment is carried out on a Bruker AVIIIHD spectrometer equipped with a DCH cryoprobe for hydrogen atoms at 500.12 MHz. The experiment is carried out in deuterated DMSO-d6 and each sample is prepared to a concentration of approximately 10 mM.

[0343] 6.1.9 I. Gravimetric Vapor Sorption (GVS)

[0344] Place a sample of approximately 10 - 20 mg in a wire mesh vapor sorption balance pan and load it into an Igasorp moisture sorption instrument from Hiden Analytical. Subject the sample to a gradient of 40 - 90% relative humidity (RH) in 10% increments and hold the sample at each step at 25 °C until a stable weight is obtained (98% of the steps completed, minimum step time 30 minutes, maximum step time 60 minutes). After completing the sorption cycle, dry the sample to 0% RH using the same procedure and finally restore it to the starting point of 40% RH using the same parameters as above. Conduct two complete cycles. Plot the weight changes during the sorption / desorption cycle to determine the hygroscopicity of the sample.

[0345] 6.1.10J. Variable Temperature X-ray Powder Diffraction (VT-XRPD)

[0346] VT-XRPD analysis was performed on a Philips X’Pert Pro multi-functional diffractometer equipped with a temperature chamber. The sample was loaded onto the VT stage and run in Bragg-Brentano geometry (step size 0.008° 2θ) using a 40 kV / 40 mA generator setting, scanning between 4 and 35.99° 2θ using Cu K radiation ( α1:α2 ratio = 0.5). Measurements were made under different temperature profiles. Any holds at specific temperatures are described in the temperature profile for an individual sample.

[0347] 6.1.11K. High Performance Liquid Chromatography - Ultraviolet Detection (HPLC-UV)

[0348] Compound A was detected by HPLC-UV using the following parameters:

[0349] Column: LC 201 / 216 Waters Acquity C18 2.1x 50mm, 1.7μm

[0350] Column temperature: 50 °C

[0351] Autosampler temperature: Ambient temperature

[0352] Ultraviolet wavelength: 265 nm.

[0353] Injection volume: 2.00 μl

[0354] Flow rate: 0.75 ml / min

[0355] Mobile phase A: 90:10 v / v% water: acetonitrile containing 0.1% trifluoroacetic acid

[0356] Mobile phase B: Acetonitrile containing 0.1% trifluoroacetic acid

[0357] Diluent: 75:25 v / v% acetonitrile: water

[0358] Gradient program:

[0359]

[0360]

[0361] Note: Any peaks not integrated in the results are present in the blank.

[0362] 6.1.12 L Gas Chromatography (GC)

[0363] Compound A was detected by GC with the following parameters:

[0364] Column: Agilent J&W DB-624 30 m x 0.32 mm 1.8 μm d.f. or equivalent Oven temperature: 35 °C (held for 0.5 min) to 45 °C @ 16.5 °C / min to 70 °C @ 5.0 °C / min to 220 °C @ 30.0 °C / min

[0365] Flow rate: 2.2 mL / min (constant flow)

[0366] Carrier gas: Hydrogen

[0367] Injection mode: Split

[0368] Injection temperature: 225 °C

[0369] Injection split ratio: 5:1

[0370] Detector temperature: 270 °C

[0371] Hydrogen flow rate: 40.0 mL / min

[0372] Air flow rate: 400 mL / min

[0373] Make-up flow rate: 30.0 mL / min

[0374] Make-up gas: Air

[0375] Headspace parameters:

[0376] Oven temperature: 100 °C.

[0377] Quantitative loop temperature: 110 °C.

[0378] Transfer line temperature: 150 °C.

[0379] Vial heating equilibration time: 10.0 minutes

[0380] Pressurization time: 0.2 minutes

[0381] Quantitative loop quantitative time: 0.2 minutes

[0382] Quantitative loop equilibration time: 0.05 minutes

[0383] Quantitative loop volume: 1 mL

[0384] Injection time: 1.0 minute

[0385] Vial shaking: High

[0386] Gas chromatograph working time: 15 minutes

[0387] 6.1.13M. Particle Size Distribution (PSD)

[0388] Weigh approximately 60 mg of the sample into a 20 mL scintillation vial. Add 10 mL of the dispersant and mix. Sonicate the sample for 30 seconds and then stir well with a pipette and add to the disperser to achieve an obscuration of 8 - 20%. Measure according to the following parameters:

[0389]

[0390] 6.2 Preparation of Compound A and Solid Forms of Compound A

[0391] 6.2.1A. Preparation of Polymorph 1 of Compound A

[0392] In one embodiment, polymorph 1 of Compound A is prepared as described in the following reaction scheme, wherein Compounds (1), (2), (3), and (4) are commercially available or can be prepared according to methods known to those skilled in the art: Reaction Scheme

[0393]

[0394] Step 1: Treat a solution of 4 - bromo - 2,6 - dimethylaniline (Compound 1) in acetonitrile with N,N - diisopropylethylamine (DIPEA) and cool the mixture to 0 °C. Add tert - butylacetyl chloride (Compound 2) to the solution of Compound 1 over 90 minutes while maintaining the temperature below 10 °C. Then dilute the mixture with acetonitrile and heat the solution to 20 - 25 °C and stir for 2 hours. Once complete, dilute the mixture with process water, stir the resulting slurry for 30 minutes. Then collect the solid by vacuum filtration, wash twice with process water and dry under nitrogen for at least 2 hours. Then further dry the filter cake in a vacuum oven at 50 °C under N2 to obtain N - (4 - bromo - 2,6 - dimethylphenyl) - 3,3 - dimethylbutanamide (Compound 2).

[0395] Step 2A: N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutyramide (Compound 3) reacts with 6-fluoro-1,2,3,4-tetrahydroisoquinoline (Compound 4) and potassium tert-butoxide in 2-methyltetrahydrofuran (2-MeTHF). The mixture is sparged with nitrogen (N2) for 1 hour, then bis(dibenzylideneacetone)palladium (Pd(dba)2) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (DavePhos) are added, and the mixture is heated to 77 °C and stirred for 12 hours under a N2 atmosphere. Then the mixture is cooled to 40 °C and diluted with 2-MeTHF. The solution is further diluted with water for injection (WFI), the mixture is cooled to 25 °C and stirred for 30 minutes. Before separation, the resulting two-phase mixture is allowed to settle for at least 1 hour. Then the aqueous and organic phases are removed, and the reactor is rinsed with additional 2-MeTHF.

[0396] Step 2B: The combined organics are added to a separate reactor, and SiliaMetS- is added and diluted with additional 2-MeTHF. The mixture is purged with nitrogen five times and stirred at 45 °C for at least 4 hours. Then the mixture is filtered, the solid is rinsed with 2-MeTHF at 50 °C, and then cooled to about 20 - 30 °C. Then the SiliaMetS- treatment is repeated one more time in the same manner as described above.

[0397] Then a solution of 10% n-heptane in 2-MeTHF is added to the 2-MeTHF solution of crystalline form 1 of Compound A separated after treatment with SiliaMetS- The mixture is heated to 50 °C and held for 15 minutes until all solids are dissolved. Then the solution is cooled, further diluted with 2-MeTHF and concentrated in vacuo. Then the concentrated solution is diluted again with 2-MeTHF and heated to 50 °C for 15 minutes. Then the solution is cooled, diluted with additional 2-MeTHF and concentrated in vacuo until solids are apparent. Then the solution is heated to reflux to dissolve all the solids present, then diluted with n-heptane, cooled and concentrated in vacuo. Then the concentrated solution is diluted with n-heptane, concentrated in vacuo, the solid is filtered, rinsed with the filtrate, and rinsed twice with a 2-MeTHF solution of 10% n-heptane. The filtered solid is dried under vacuum, then transferred to a vacuum oven and dried further.

[0398] The solid was then recrystallized a second time in 2-methyltetrahydrofuran (2-MeTHF), which had been purged with N2 for at least 15 minutes beforehand. After addition of the solid, the mixture was purged with N2 for an additional 15 minutes and then heated to 76 °C. The solution was then cooled to 20 - 25 °C and stirred for at least 1 hour. The suspension was then filtered and the solid was kept under a steady N2 flow. The filter cake was rinsed with heptane and then dried under a layer of N2 before transfer to a vacuum oven and heated to 50 °C under an atmosphere of N2 to obtain polymorph 1 of Compound A (see Figure 1 ).

[0399] 6.2.2 B. Preparation of Polymorph 2 of Compound A

[0400] In one embodiment, polymorph 2 of Compound A was prepared by first slurrying approximately 500 mg of polymorph 1 of Compound A in approximately 3 mL of an ethanol:water (10:90 v / v%) solution. The slurry was then shaken at ambient temperature for approximately 2 hours and then stored at 5 °C for approximately 72 hours. The slurry was then centrifuged and the wet solid was dried in vacuo at 40 °C for approximately 24 hours. The resulting dried material was found to be polymorph 2 of Compound A, the XRPD pattern of which is as shown in Figure 8 .

[0401] 6.2.3 C. Preparation of Polymorph 3 of Compound A

[0402] In one embodiment, polymorph 3 of Compound A was prepared by weighing approximately 15 mg of polymorph 2 of Compound A and polymorph 4 of Compound A into a 2 mL glass vial. An aliquot of dichloromethane was added to the vial at ambient temperature until a flowing slurry was formed. The resulting slurry was stirred at ambient temperature for approximately 24 hours. The observed solid was separated and characterized by XRPD and found to be polymorph 3 of Compound A, the XRPD pattern of which is as shown in Figure 16 .

[0403] 6.2.4 D. Preparation of Polymorph 4 of Compound A

[0404] In one embodiment, polymorph 4 of Compound A was prepared by dissolving approximately 250 mg of polymorph 1 of Compound A in approximately 3.5 mL of ethanol at 40 °C. After 1 hour at 40 °C, the solution was cooled to 20 °C at a rate of 0.2 °C / min. The solution was held at 20 °C for 1 hour and then cooled to 5 °C at 0.1 °C / min. After 18 hours at 5 °C, 15 mL of water was added as an anti-solvent and the mixture was held at 5 °C for 2 hours before centrifugation. The concentration of the mother liquor was then analyzed by HPLC. The wet solid was dried in vacuo at 40 °C for approximately 2 hours and then analyzed. The resulting dried material was found to be polymorph 4 of Compound A with the XRPD pattern as shown in Figure 17 .

[0405] 6.2.5 E. Preparation of Polymorph 5 of Compound A

[0406] In one embodiment, about 40 mg of polymorph 1 of Compound A was added to 500 μl of methyl isobutyl ketone to prepare a slurry. If dissolution occurred during the preparation, an additional amount of polymorph 1 of Compound A was added. The resulting slurry was subjected to 72 hours of continuous 4-hour hot-cold cycles between 40 °C and ambient temperature. The resulting mixture was filtered, and the separated wet solid was analyzed by XRPD and found to be polymorph 5 of Compound A having the Figure 25 XRPD pattern shown in

[0407] 6.2.6 F. Preparation of Polymorph 6 of Compound A

[0408] In one embodiment, about 40 mg of polymorph 1 of Compound A was added to 300 μl of tetrahydrofuran / water (99:1) to prepare a slurry. If dissolution occurred during the preparation, an additional amount of polymorph 1 of Compound A was added. The resulting slurry was subjected to 72 hours of continuous 4-hour hot-cold cycles between 40 °C and ambient temperature. The resulting mixture was filtered, and the separated wet solid was analyzed by XRPD and found to be polymorph 6 of Compound A having the Figure 26 XRPD pattern shown in

[0409] 6.2.7 G. Preparation of Polymorph 7 of Compound A

[0410] In one embodiment, about 40 mg of polymorph 1 of Compound A was added to 300 μl of tetrahydrofuran to prepare a slurry. If dissolution occurred during the preparation, an additional amount of polymorph 1 of Compound A was added. The resulting slurry was subjected to 72 hours of continuous 4-hour hot-cold cycles between 40 °C and ambient temperature. The resulting mixture was filtered, and the separated wet solid was analyzed by XRPD and found to be polymorph 7 of Compound A having the Figure 27 XRPD pattern shown in

[0411] In another embodiment, about 40 mg of polymorph 1 of Compound A was added to 1500 μl of acetone / water (75:25) to prepare a slurry. If dissolution occurred during the preparation, an additional amount of polymorph 1 of Compound A was added. The resulting slurry was subjected to 72 hours of continuous 4-hour hot-cold cycles between 40 °C and ambient temperature. The resulting mixture was filtered, and the separated wet solid was analyzed by XRPD and found to be polymorph 7 of Compound A having the Figure 27 XRPD pattern shown in

[0412] 6.2.8 H. Preparation of Polymorph 8 of Compound A

[0413] In one embodiment, approximately 40 mg of Compound A Polymorph 1 was added to 300 μl of cyclohexanone to prepare a slurry. If dissolution occurred during preparation, an additional amount of Compound A Polymorph 1 was added. The resulting slurry was subjected to 72 hours of continuous hot-cold cycling between 40 °C and ambient temperature for 4 hours. The filtered mixture was transferred to a container without a lid and evaporated at ambient temperature. When sufficient material was obtained, the material was analyzed by XRPD and found to be Compound A Polymorph 8 with the XRPD pattern shown in Figure 28 Compound A Polymorph 8 with the XRPD pattern shown in

[0414] 6.2.9I. Preparation of Compound A Polymorph 9

[0415] In one embodiment, a sample of Compound A Polymorph 4 was placed in a VT-XRPD sample holder, flattened before loading into the VT-XRPD, heated to above approximately 140 °C, and then cooled using the method in Table 13 below.

[0416] Table 13 VT-XRPD Procedure for Making Polymorph 9

[0417] Temperature Program 25℃ Scan and then heat to the next temperature within 10 minutes 50℃ Scan and then heat to the next temperature within 10 minutes 60℃ Scan and then heat to the next temperature within 10 minutes 70℃ Scan and then heat to the next temperature within 10 minutes 80℃ Scan and then heat to the next temperature within 10 minutes 90℃ Scan and then heat to the next temperature within 10 minutes 100℃ Scan and wait for 5 minutes, then heat to the next temperature within 10 minutes 110℃ Scan and wait for 5 minutes, then heat to the next temperature within 10 minutes 120℃ Scan and wait for 5 minutes, then heat to the next temperature within 10 minutes 130℃ Scan and wait for 5 minutes, then heat to the next temperature within 10 minutes 140℃ Scan and then cool to the starting temperature 25℃ Scan at this temperature

[0418] The resulting dried material was found to be Compound A Polymorph 9 with the XRPD pattern shown in Figure 29 Compound A Polymorph 9 with the XRPD pattern shown in

[0419] In another embodiment, the compound was prepared by adding methanol (3 ml) to approximately 500 mg of Compound A Polymorph 1, followed by addition of an aqueous sulfuric acid solution (1 M, 1425 μL, 1.05 equivalents). After approximately 2 minutes, water (5 ml) was added as an antisolvent to cause precipitation to prepare a thick slurry. The solid was filtered and analyzed by XRPD and found to be Compound A Polymorph 9 with the XRPD pattern shown in Figure 29 Compound A Polymorph 9 with the XRPD pattern shown in

[0420] 6.2.10J. Preparation of Compound A Polymorph 10

[0421] In one embodiment, approximately 500 mg of Compound A Polymorph 1 was weighed into a 20 ml scintillation vial. Aliquots of 500 μL of tetrahydrofuran were added until a flowing slurry was formed. 2 ml of tetrahydrofuran was added. The sample was subjected to temperature cycling between ambient temperature and 40 °C for approximately 4 hours in 1-hour cycles. The observed solid was separated by centrifugation and characterized by XRPD and found to be Compound A Polymorph 10 with the pattern shown in Figure 37 Compound A Polymorph 10 with the pattern shown in

[0422] 6.2.11K. Preparation of Compound A Polymorph 11

[0423] In one embodiment, Form 1 of Compound A was prepared by dissolving approximately 500 mg of Form 1 of Compound A in approximately 3 mL of ethanol. The resulting slurry was shaken at ambient temperature for approximately 2 hours and then stored at 5 °C for approximately 90 hours. Samples analyzed by XRPD indicated that the material was Form 4 of Compound A. The slurry was then heated to 40 °C for approximately 2 hours until the solid was completely dissolved. The material was then stored at 5 °C for 72 hours. The slurry was then temperature cycled between ambient temperature and 40 °C for approximately 72 hours. The slurry was then centrifuged and the wet solid was dried at ambient temperature for 18 hours and then dried under vacuum at 40 °C for approximately 6 hours. The dried material obtained by XRPD analysis was Form 11 of Compound A having the Figure 39 XRPD pattern shown in

[0424] 6.3 Characterization of Solid Forms of Compound A

[0425] 6.3.1A. Characterization of Form 1 of Compound A

[0426] In one embodiment, the present invention provides a solid form of Compound A, herein referred to as Form 2 of Compound A. In some embodiments, the present disclosure provides Form 2 of Compound A having an XRPD pattern substantially similar to that shown in Figure 1 . In other embodiments, the present disclosure provides a mixture of Form 2 of Compound A and Form 3 of Compound A, with Form 2 of Compound A being predominant. These forms can be distinguished by XRPD (see Figure 1 ).

[0427] In one embodiment, PGM analysis of Form 1 of Compound A showed small particles with no distinct morphology, some agglomeration, and birefringence (see Figure 2 ).

[0428] In another embodiment, TG analysis of Form 1 of Compound A showed that Form 1 of Compound A had a weight loss of 0.6% up to 200 °C, followed by decomposition. A complex thermal event was noted in DTA starting at 184 °C, having an endothermic peak at 186 °C, an exothermic peak at 188 °C, and a larger endothermic peak at 193 °C (see Figure 3 ).

[0429] In another embodiment, DSC analysis of initially heated Form 1 of Compound A showed a complex thermal event starting at 184 °C, having an endothermic peak at 186 °C, an exothermic peak at 188 °C, and a larger endothermic peak at 193 °C (see Figure 4 ). The cooling cycle showed an exothermic peak starting at 153 °C and peaking at 151 °C (see Figure 5)。The second heating showed two endothermic events; a smaller peak starting at 185 °C with a peak at 187 °C and a second larger peak starting at 191 °C with a peak at 193 °C (see Figure 6 )。

[0430] After dissolving in DMSO-d6, compound A polymorph 1 was analyzed by 1 1H NMR. In one embodiment, 1 the 1H NMR spectrum (see Figure 7 ) was shown to be consistent with the structure of compound A polymorph 1.

[0431] 6.3.2B. Characterization of Compound A Polymorph 2

[0432] In one embodiment, the present invention relates to a solid form of compound A, herein referred to as compound A polymorph 2. In some embodiments, the present disclosure provides compound A polymorph 2 having an XRPD pattern substantially similar to that Figure 8 shown in.

[0433] In some embodiments, compound A polymorph 2 is identified by detecting one or more peaks from the XRPD pattern of the compositions listed in Table 1.

[0434] Table 1 XRPD Peaks of Compound A Polymorph 2

[0435]

[0436]

[0437] In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting two or more peaks in the XRPD pattern of the composition selected from Table 1. In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting three or more peaks in the XRPD pattern of the composition selected from Table 1. In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting four or more peaks in the XRPD pattern of the composition selected from Table 1. In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting five or more peaks in the XRPD pattern of the composition selected from Table 1. In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting six or more peaks in the XRPD pattern of the composition selected from Table 1. In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting seven or more peaks in the XRPD pattern of the composition selected from Table 1. In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting eight or more peaks in the XRPD pattern of the composition selected from Table 1. In some embodiments, polymorph 2 of Compound A is identified by detecting all of the peaks in Table 1 in the composition XRPD pattern.

[0438] In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting at least eight peaks in the XRPD pattern of the composition, said at least eight peaks corresponding to the eight strongest peaks in Table 1 (based on relative percent intensity) ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ.

[0439] In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting at least seven peaks in the XRPD pattern of the composition, said at least seven peaks corresponding to the seven strongest peaks in Table 1 (based on relative percent intensity) ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ.

[0440] In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting at least six peaks in the XRPD pattern of the composition, said at least six peaks corresponding to the six strongest peaks in Table 1 (based on relative percent intensity) ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ.

[0441] In some embodiments, polymorph 2 of compound A in a composition is identified by detecting at least five peaks in the XRPD pattern of the composition, wherein the at least five peaks correspond to the five strongest peaks in Table 1 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ. For example, in certain embodiments, polymorph 2 of compound A in a composition is detected by at least the following five peaks in the XRPD pattern of the composition: about 5.51, about 11.01, about 19.17, about 20.83, about 21.48 degrees 2θ ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0442] In some embodiments, polymorph 2 of compound A in a composition is identified by detecting at least four peaks in the XRPD pattern of the composition, wherein the at least four peaks correspond to the four strongest peaks in Table 1 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ. For example, in certain embodiments, polymorph 2 of compound A in a composition is detected by at least the following four peaks in the XRPD pattern of the composition: about 5.51, about 11.01, about 19.17, about 20.83 degrees 2θ ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0443] In some embodiments, polymorph 2 of compound A in a composition is identified by detecting at least three peaks in the XRPD pattern of the composition, wherein the at least three peaks correspond to the three strongest peaks in Table 1 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ. For example, in certain embodiments, polymorph 2 of compound A in a composition is detected by at least the following three peaks in the XRPD pattern of the composition: about 5.51, about 11.01, about 19.17 degrees 2θ ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0444] In some embodiments, polymorph 2 of compound A in a composition is identified by detecting at least two peaks in the XRPD pattern of the composition, wherein the at least two peaks correspond to the two strongest peaks in Table 1 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0445] In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting at least one peak in the XRPD pattern of the composition, wherein the at least one peak corresponds to the strongest peak in Table 1 (based on relative percent intensity) ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ. In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting one or more peaks selected from the group consisting of: about 5.51, about 11.01, about 11.53, about 14.91, about 16.54, about 19.17, about 20.83, about 21.48, about 22.68, about 24.18 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0446] In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting two or more peaks selected from the group consisting of: about 5.51, about 11.01, about 11.53, about 14.91, about 16.54, about 19.17, about 20.83, about 21.48, about 22.68, about 24.18 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition, such as at least two of the strongest peaks.

[0447] In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting three or more peaks selected from the group consisting of: about 5.51, about 11.01, about 11.53, about 14.91, about 16.54, about 19.17, about 20.83, about 21.48, about 22.68, about 24.18 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0448] In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting four or more peaks selected from the group consisting of: about 5.51, about 11.01, about 11.53, about 14.91, about 16.54, about 19.17, about 20.83, about 21.48, about 22.68, about 24.18 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0449] In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting five or more peaks selected from the group consisting of: about 5.51, about 11.01, about 11.53, about 14.91, about 16.54, about 19.17, about 20.83, about 21.48, about 22.68, about 24.18 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0450] In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting six or more peaks selected from the group consisting of: about 5.51, about 11.01, about 11.53, about 14.91, about 16.54, about 19.17, about 20.83, about 21.48, about 22.68, about 24.18 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0451] In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting seven or more peaks selected from the group consisting of: about 5.51, about 11.01, about 11.53, about 14.91, about 16.54, about 19.17, about 20.83, about 21.48, about 22.68, about 24.18 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0452] In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting eight or more peaks selected from the group consisting of: about 5.51, about 11.01, about 11.53, about 14.91, about 16.54, about 19.17, about 20.83, about 21.48, about 22.68, about 24.18 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0453] In some embodiments, polymorph 2 of Compound A in a composition is identified by detecting peaks selected from the group consisting of: about 5.51, about 11.01, about 11.53, about 14.91, about 16.54, about 19.17, about 20.83, about 21.48, about 22.68, about 24.18 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0454] In another embodiment, the PLM analysis of Form 2 of Compound A shows that the solid has an agglomerated and birefringent needle-like morphology.

[0455] In another embodiment, the TG analysis of Form 2 of Compound A shows that at 200 °C, there is a weight loss of 0.9% and decomposition occurs. In another embodiment, in DTA, multiple thermal events are observed starting at about 183 °C, an endothermic peak appears at 186 °C, an exothermic peak appears at 188 °C, and a second endothermic peak appears at 192 °C (see Figure 10 ).

[0456] Thus, in some embodiments, the present disclosure provides Form 2 of Compound A having a TG / DTA thermogram substantially similar to Figure 10 . In some embodiments, Form 2 of Compound A in a composition is identified by detecting a DTA thermogram with an onset temperature of about 183 °C, an endothermic peak at 186 °C, an exothermic peak at 188 °C, and a second endothermic peak at 192 °C.

[0457] In another embodiment, the DSC analysis of Form 2 of Compound A shows a shallow endothermic event in the initial heating starting at 122 °C, with a peak at 132 °C. Subsequently, multiple thermal events starting at 183 °C, with a small endothermic peak at 186 °C, an exothermic peak at 187 °C, and a large endothermic peak at 192 °C (see Figure 11 ). In the cooling cycle, a single exothermic event is noted starting at 151 °C, with a peak at 149 °C (see Figure 12 ). During the second heating cycle, a small exothermic event starting at 172 °C and a peak at 180 °C are noted. Subsequently, a large endothermic event occurs starting at 191 °C, reaching a peak at 192 °C (see Figure 13 ).

[0458] Thus, in some embodiments, the present invention provides Form 2 of Compound A having a DSC thermogram substantially similar to Figure 11 , Figure 12 , Figure 13 . In some embodiments, Form 2 of Compound A in a composition is identified by detecting a DSC thermogram that has a shallow endothermic event starting at 122 °C with a characteristic peak at 132 °C in the first heating cycle, followed by starting at 183 °C, having a second small endothermic characteristic peak at 186 °C, a third characteristic exothermic peak at 187 °C, and a large characteristic endothermic peak at 192 °C; in the cooling cycle, a single characteristic exothermic event starting at 151 °C, reaching a peak at 149 °C; and, in the second heating cycle, a characteristic small exothermic event starting at 172 °C having a characteristic peak at 180 °C, followed by a characteristic peak at 192 °C starting at 191 °C.

[0459] After dissolution in DMSO-d6, compound A polymorph 2 was analyzed by 1 1H NMR. In another embodiment, the resulting 1 1H NMR spectrum (see Figure 14 ) showed consistency with the structure of compound A polymorph 2.

[0460] In another embodiment, compound A polymorph 2 was analyzed by FTIR as a reference (see Figure 15 ).

[0461] In another embodiment, HPLC purity analysis of compound A polymorph 2 showed a purity value of 99.3%.

[0462] In another embodiment, GVS analysis of compound A polymorph 2 found it to be slightly hygroscopic, with a moisture absorption rate of 0.37% between 0 - 90% RH. The tested material was analyzed by XRPD after GVS and found to be compound A polymorph 2.

[0463] In another embodiment, the water solubility dissolution value of compound A polymorph 2 was <0.1 mg / mL, and the pH after sample dissolution was 6.4. After analysis, the excess solid was analyzed by XRPD and found to be compound A polymorph 2.

[0464] In another embodiment, VT-XRPD analysis of compound A polymorph 2 was performed using the heating program in Table 2 below:

[0465] Table 2 VT-XRPD heating program for compound A polymorph 2

[0466]

[0467]

[0468] In another embodiment, the solid state forms of compound A polymorph 2 at each temperature were analyzed by XRPD, and the results are shown in Table 3 below.

[0469] Table 3 VT-XRPD results for compound A polymorph 2

[0470] Temperature Polymorph 25℃ Polymorph 2 50℃ Polymorph 2 100℃ Polymorph 2 150℃ Similar to Polymorph 2 160℃ Partially crystalline 165℃ Partially crystalline 170℃ Amorphous 180℃ Amorphous 180 °C (after holding for 10 minutes) Amorphous 25℃ Amorphous

[0471] In another embodiment, hot stage microscopy of compound A polymorph 2 was performed using the method described herein. It was noted that compound A polymorph 2 began to melt at approximately 143 °C and the material was completely melted after heating to 148 °C.

[0472] 6.3.3C. Characterization of compound A polymorph 3

[0473] In one embodiment, the present invention relates to a solid form of Compound A, referred to herein as Compound A Polymorph 3. In some embodiments, the present disclosure provides a Compound A Polymorph 3 having an XRPD pattern substantially similar to that shown in Figure 16 .

[0474] 6.3.4D. Characterization of Compound A Polymorph 4

[0475] In one embodiment, the present invention relates to a solid form of Compound A, referred to herein as Compound A Polymorph 4. In some embodiments, the present disclosure provides a Compound A Polymorph 4 having an XRPD pattern substantially similar to that shown in Figure 17 .

[0476] In some embodiments, Compound A Polymorph 4 is identified by detecting one or more peaks selected from the XRPD patterns of the compositions listed in Table 4.

[0477] Table 4 XRPD Peak Positions of Compound A Polymorph 4

[0478]

[0479] In some embodiments, Compound A Polymorph 4 in a composition is identified by detecting two or more peaks selected from the XRPD pattern of the composition of Table 4. In some embodiments, Compound A Polymorph 4 in a composition is identified by detecting three or more peaks selected from the XRPD pattern of the composition of Table 4. In some embodiments, Compound A Polymorph 4 in a composition is identified by detecting four or more peaks selected from the XRPD pattern of the composition of Table 4. In some embodiments, Compound A Polymorph 4 in a composition is identified by detecting five or more peaks selected from the XRPD pattern of the composition of Table 4. In some embodiments, Compound A Polymorph 4 in a composition is identified by detecting six or more peaks selected from the XRPD pattern of the composition of Table 4. In some embodiments, Compound A Polymorph 4 in a composition is identified by detecting seven or more peaks selected from the XRPD pattern of the composition of Table 4. In some embodiments, Compound A Polymorph 4 is identified by detecting all of the peaks in Table 4 in the composition XRPD pattern.

[0480] In some embodiments, Compound A Polymorph 4 in a composition is identified by detecting at least eight peaks in the XRPD pattern of the composition, the at least eight peaks corresponding to the eight strongest peaks (based on relative percent intensity) in Table 4 ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ.

[0481] In some embodiments, polymorph 4 of Compound A in a composition is identified by detecting at least seven peaks in the XRPD pattern of the composition, wherein the at least seven peaks correspond to the seven strongest peaks in Table 4 (based on relative percent intensity) ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ.

[0482] In some embodiments, polymorph 4 of Compound A in a composition is identified by detecting at least six peaks in the XRPD pattern of the composition, wherein the at least six peaks correspond to the six strongest peaks in Table 4 (based on relative percent intensity) ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ.

[0483] In some embodiments, polymorph 4 of Compound A in a composition is identified by detecting at least five peaks in the XRPD pattern of the composition, wherein the at least five peaks correspond to the five strongest peaks in Table 4 (based on relative percent intensity) ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ. For example, in certain embodiments, polymorph 4 of Compound A in a composition is detected by at least the following five peaks in the XRPD pattern of the composition: approximately 13.62, approximately 14.16, approximately 14.61, approximately 18.44, approximately 22.97 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ.

[0484] In some embodiments, polymorph 4 of Compound A in a composition is identified by detecting at least four peaks in the XRPD pattern of the composition, wherein the at least four peaks correspond to the four strongest peaks in Table 4 (based on relative percent intensity) ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ. For example, in certain embodiments, polymorph 4 of Compound A in a composition is detected by at least the following four peaks in the XRPD pattern of the composition: approximately 13.62, approximately 14.61, approximately 18.44, approximately 19.92, approximately 22.97 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ.

[0485] In some embodiments, polymorph 4 of Compound A in a composition is identified by detecting at least three peaks in the XRPD pattern of the composition, wherein the at least three peaks correspond to the three strongest peaks in Table 4 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ. For example, in certain embodiments, polymorph 4 of Compound A in a composition is detected by at least the following three peaks in the XRPD pattern of the composition: approximately 14.61, approximately 18.44, approximately 22.97 degrees 2θ ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0486] In some embodiments, polymorph 4 of Compound A in a composition is identified by detecting at least two peaks in the XRPD pattern of the composition, wherein the at least two peaks correspond to the two strongest peaks in Table 4 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0487] In some embodiments, polymorph 4 of Compound A in a composition is identified by detecting at least one peak in the XRPD pattern of the composition, wherein the at least one peak corresponds to the strongest peak in Table 4 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0488] In some embodiments, polymorph 4 of Compound A in a composition is identified by detecting one or more peaks selected from the group consisting of: approximately 13.62, approximately 14.16, approximately 14.61, approximately 18.44, approximately 19.92, approximately 22.97, approximately 23.73 degrees 2θ ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ in the XRPD pattern of the composition.

[0489] In some embodiments, polymorph 4 of Compound A in a composition is identified by detecting two or more peaks selected from the group consisting of: approximately 13.62, approximately 14.16, approximately 14.61, approximately 18.44, approximately 19.92, approximately 22.97, approximately 23.73 degrees 2θ ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ, such as at least the two strongest peaks, in the XRPD pattern of the composition.

[0490] In some embodiments, polymorph 4 of compound A in a composition is identified by detecting three or more peaks selected from the group consisting of: about 13.62, about 14.16, about 14.61, about 18.44, about 19.92, about 22.97, about 23.73 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0491] In some embodiments, polymorph 4 of compound A in a composition is identified by detecting four or more peaks selected from the group consisting of: about 13.62, about 14.16, about 14.61, about 18.44, about 19.92, about 22.97, about 23.73 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0492] In some embodiments, polymorph 4 of compound A in a composition is identified by detecting five or more peaks selected from the group consisting of: about 13.62, about 14.16, about 14.61, about 18.44, about 19.92, about 22.97, about 23.73 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0493] In some embodiments, polymorph 4 of compound A in a composition is identified by detecting six or more peaks selected from the group consisting of: about 13.62, about 14.16, about 14.61, about 18.44, about 19.92, about 22.97, about 23.73 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0494] In some embodiments, polymorph 4 of compound A in a composition is identified by detecting peaks selected from the group consisting of: about 13.62, about 14.16, about 14.61, about 18.44, about 19.92, about 22.97, about 23.73 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0495] In another embodiment, the PLM analysis of polymorph 4 of compound A shows that the solid has a plate-like morphology with aggregation and birefringence.

[0496] In another embodiment, the TG analysis of Form 4 of Compound A shows a weight loss of 1.0% up to 200 °C and decomposition occurs. In another embodiment, in DTA, a shallow endothermic event is observed starting at 127 °C, with a peak at 135 °C, and subsequently a large endothermic event is observed starting at 191 °C, with a peak at 193 °C (see Figure 19 ).

[0497] Thus, in some embodiments, the present disclosure provides Form 4 of Compound A having a TG / DTA thermogram substantially similar to Figure 19 . In some embodiments, Form 4 of Compound A is identified in a composition by detecting a DTA thermogram that has a shallow endothermic event starting at 127 °C, with a peak at 135 °C, and a large endothermic event starting at 191 °C, with a peak at 193 °C.

[0498] In another embodiment, the DSC analysis of Form 4 of Compound A shows a shallow endothermic event in the initial heating at an onset temperature of 122 °C, with a peak at 130 °C. Subsequently, a large endothermic event at an onset temperature of 190 °C, with a peak at 192 °C (see Figure 20 ). In the cooling cycle, a single exothermic event is observed starting at 151 °C, reaching a peak at 150 °C (see Figure 21 ). During the second heating cycle, a small endothermic event is observed starting at 183 °C, with a peak at 180 °C. This is related to a larger endothermic peak at 193 °C (see Figure 22 ).

[0499] Thus, in some embodiments, the present disclosure provides Form 4 of Compound A having a DSC thermogram substantially similar to Figure 20 , Figure 21 and Figure 22 . In some embodiments, Form 4 of Compound A is identified in a composition by detecting a DSC thermogram that has a shallow endothermic event starting at 122 °C in the first heating cycle, with a characteristic peak at 130 °C, and subsequently, at an onset temperature of 190 °C, a characteristic peak of a large endothermic event at 192 °C; in the cooling cycle, an exothermic event starting at 151 °C has a characteristic peak at 150 °C; and, in the second heating cycle, a small exothermic event starting at 183 °C has a characteristic peak at 180 °C, which is related to a larger characteristic endothermic peak at 193 °C.

[0500] After dissolution in DMSO-d6, Form 4 of Compound A is analyzed by 1 1H NMR. In another embodiment, the resulting 1 1H NMR spectrum (see Figure 23) shows consistency with the structure of Compound A Polymorph 4.

[0501] In another embodiment, Compound A Polymorph 4 is analyzed by FTIR as a reference (see Figure 24 ).

[0502] In another embodiment, HPLC purity analysis of Compound A Polymorph 4 shows a purity value of 99.5%.

[0503] In another embodiment, GVS analysis of Compound A Polymorph 4 finds that it has slight hygroscopicity, with an uptake of 0.4% at 90% RH. The tested material is analyzed by XRPD after GVS and found to be Compound A Polymorph 4.

[0504] In another embodiment, the water solubility dissolution value of Compound A Polymorph 4 is < 0.1 mg / mL, and the pH after sample dissolution is 6.3. After analysis, the excess solid is analyzed by XRPD and found to be Compound A Polymorph 4.

[0505] In another embodiment, VT-XRPD analysis of Compound A Polymorph 4 is carried out using the heating program in Table 5 below.

[0506] Table 5 Heating program for VT-XRPD of Compound A Polymorph 4

[0507] Temperature Program 25℃ Scan and then heat to the next temperature within 10 minutes 50℃ Scan and then heat to the next temperature within 10 minutes 60℃ Scan and then heat to the next temperature within 10 minutes 70℃ Scan and then heat to the next temperature within 10 minutes 80℃ Scan and then heat to the next temperature within 10 minutes 90℃ Scan and then heat to the next temperature within 10 minutes 100℃ Scan and wait for 5 minutes, then heat to the next temperature within 10 minutes 110℃ Scan and wait for 5 minutes, then heat to the next temperature within 10 minutes 120℃ Scan and wait for 5 minutes, then heat to the next temperature within 10 minutes 130℃ Scan and wait for 5 minutes, then heat to the next temperature within 10 minutes 140℃ Scan and then cool to the starting temperature 25℃ Scan at this temperature

[0508] In another embodiment, the solid state form of Compound A Polymorph 4 at each temperature is analyzed by XRPD, and the results are shown in Table 6 below:

[0509] Table 6 VT-XRPD results of Compound A Polymorph 4

[0510] Temperature Polymorph 25℃ Polymorph 4 50℃ Polymorph 4 60℃ Polymorph 4 70℃ Polymorph 4 80℃ Polymorph 4 95℃ Polymorph 4 100℃ Polymorph 4 110 °C (holding for 5 minutes) Polymorph 4 + additional peak 120 °C (holding for 5 minutes) Polymorph 4 + additional peak 130 °C (holding for 5 minutes) Polymorph 4 + Polymorph 9 140 °C (holding for 5 minutes) Polymorph 9 25℃ Polymorph 9

[0511] In another embodiment, hot stage microscopy of Compound A Polymorph 4 is carried out using the method described herein. It is noted that Compound A Polymorph 4 begins to melt at approximately 138 °C and the material is completely melted after heating to 160 °C.

[0512] 6.3.5E. Characterization of Compound A Polymorph 5

[0513] In one embodiment, the present invention relates to a solid state form of Compound A, herein referred to as Compound A Polymorph 5. In some embodiments, the present disclosure provides Compound A Polymorph 5 having an XRPD pattern substantially similar to that shown in Figure 25 .

[0514] 6.3.6F. Characterization of Compound A Polymorph 6

[0515] In one embodiment, the present invention relates to a solid form of Compound A, referred to herein as Compound A Polymorph 6. In some embodiments, the present disclosure provides a Compound A Polymorph 6 having an XRPD pattern substantially similar to that shown in Figure 26 .

[0516] 6.3.7G. Characterization of Compound A Polymorph 7

[0517] In one embodiment, the present invention relates to a solid form of Compound A, referred to herein as Compound A Polymorph 7. In some embodiments, the present disclosure provides a Compound A Polymorph 7 having an XRPD pattern substantially similar to that shown in Figure 27 .

[0518] 6.3.8H. Characterization of Compound A Polymorph 8

[0519] In one embodiment, the present invention relates to a solid form of Compound A, referred to herein as Compound A Polymorph 8. In some embodiments, the present disclosure provides a Compound A Polymorph 8 having an XRPD pattern substantially similar to that shown in Figure 28 .

[0520] 6.3.9I. Characterization of Compound A Polymorph 9

[0521] In one embodiment, the present invention relates to a solid form of Compound A, referred to herein as Compound A Polymorph 9. In some embodiments, the present disclosure provides a Compound A Polymorph 9 having an XRPD pattern substantially similar to that shown in Figure 29 .

[0522] In some embodiments, Compound A Polymorph 9 is identified by detecting one or more peaks from the XRPD patterns of the compositions listed in Table 7.

[0523] Table 7 XRPD Peak Positions of Compound A Polymorph 9

[0524]

[0525]

[0526] In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting two or more peaks in the XRPD pattern of the composition selected from Table 7. In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting three or more peaks in the XRPD pattern of the composition selected from Table 7. In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting four or more peaks in the XRPD pattern of the composition selected from Table 7. In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting five or more peaks in the XRPD pattern of the composition selected from Table 7. In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting six or more peaks in the XRPD pattern of the composition selected from Table 7. In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting seven or more peaks in the XRPD pattern of the composition selected from Table 7. In some embodiments, polymorph 9 of Compound A is identified by detecting all the peaks in Table 7 in the composition XRPD pattern.

[0527] In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting at least eight peaks in the XRPD pattern of the composition, wherein the at least eight peaks correspond to the eight strongest peaks in Table 7 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0528] In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting at least seven peaks in the XRPD pattern of the composition, wherein the at least seven peaks correspond to the seven strongest peaks in Table 7 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0529] In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting at least six peaks in the XRPD pattern of the composition, wherein the at least six peaks correspond to the six strongest peaks in Table 7 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0530] In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting at least five peaks in the XRPD pattern of the composition, wherein the at least five peaks correspond to the five strongest peaks in Table 7 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ. For example, in certain embodiments, polymorph 9 of Compound A in a composition is identified by detecting at least the following five peaks in the XRPD pattern of the composition: approximately 3.05, approximately 15.33, approximately 18.08, approximately 20.98, approximately 23.49 degrees 2θ ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0531] In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting at least four peaks in the XRPD pattern of the composition, wherein the at least four peaks correspond to the four strongest peaks in Table 7 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ. For example, in certain embodiments, polymorph 9 of Compound A in a composition is identified by detecting at least the following four peaks in the XRPD pattern of the composition: approximately 3.05, approximately 15.33, approximately 18.08, approximately 23.49 degrees 2θ ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0532] In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting at least three peaks in the XRPD pattern of the composition, wherein the at least three peaks correspond to the three strongest peaks in Table 7 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ. For example, in certain embodiments, polymorph 9 of Compound A in a composition is identified by detecting at least the following three peaks in the XRPD pattern of the composition: approximately 3.05, approximately 18.08, approximately 23.49 degrees 2θ ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0533] In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting at least two peaks in the XRPD pattern of the composition, wherein the at least two peaks correspond to the two strongest peaks in Table 7 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0534] In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting at least one peak in the XRPD pattern of the composition, wherein the at least one peak corresponds to the strongest peak in Table 7 (based on relative percent intensity) ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ.

[0535] In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting one or more peaks selected from the group consisting of: about 3.05, about 6.107, about 10.69, about 15.33, about 18.08, about 20.98, about 23.49, about 25.25 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0536] In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting two or more peaks selected from the group consisting of: about 3.05, about 6.107, about 10.69, about 15.33, about 18.08, about 20.98, about 23.49, about 25.25 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition, such as at least two of the strongest peaks.

[0537] In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting three or more peaks selected from the group consisting of: about 3.05, about 6.107, about 10.69, about 15.33, about 18.08, about 20.98, about 23.49, about 25.25 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0538] In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting four or more peaks selected from the group consisting of: about 3.05, about 6.107, about 10.69, about 15.33, about 18.08, about 20.98, about 23.49, about 25.25 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0539] In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting five or more peaks selected from the group consisting of: about 3.05, about 6.107, about 10.69, about 15.33, about 18.08, about 20.98, about 23.49, about 25.25 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0540] In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting six or more peaks selected from the group consisting of: about 3.05, about 6.107, about 10.69, about 15.33, about 18.08, about 20.98, about 23.49, about 25.25 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0541] In some embodiments, polymorph 9 of Compound A in a composition is identified by detecting peaks selected from the group consisting of: about 6.107, about 10.69, about 15.33, about 18.08, about 20.98, about 23.49, about 25.25 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0542] In another embodiment, the PLM analysis of polymorph 9 of Compound A shows that the solid is flaky in morphology, with agglomeration and birefringence.

[0543] In another embodiment, the TG analysis of polymorph 9 of Compound A shows that at up to 200 °C, there is a weight loss of 0.4% and decomposition occurs. In DTA, an endothermic event starting at 191 °C and peaking at 192 °C is noted (see Figure 31 ).

[0544] Thus, in some embodiments, the present disclosure provides polymorph 9 of Compound A having a TG / DTA thermogram substantially similar to Figure 31 . In some embodiments, polymorph 4 of Compound A in a composition is identified by detecting a DTA thermogram that has an endothermic event starting at 191 °C and a peak at 192 °C.

[0545] In another embodiment, the DSC analysis of polymorph 9 of Compound A shows a shallow exothermic event starting at the initial heating at 42 °C, peaking at 55 °C, followed by a shallow endothermic event starting at 127 °C and peaking at 133 °C. Subsequently, there is a large endothermic event starting at 189 °C and peaking at 192 °C (see Figure 32)。During the cooling cycle, a single exothermic event was observed starting at 157 °C and reaching a peak at 155 °C (see Figure 33 )。During the second heating cycle, a small exothermic event was noted starting at 140 °C, with a peak at 142 °C, followed by a complex endothermic event starting at 181 °C, with a peak at 187 °C, and a second start temperature of 190 °C and a peak of 192 °C (see Figure 34 )。

[0546] Thus, in some embodiments, the present disclosure provides polymorph 9 of Compound A having a DSC thermogram substantially similar to Figure 32 , Figure 33 and Figure 34 . In some embodiments, polymorph 9 of Compound A is identified in a composition by detecting the DSC thermogram. In the first heating cycle, there is a large endothermic event starting at 189 °C and a characteristic peak at 192 °C; in the cooling cycle, a single exothermic event starting at 157 °C, with a characteristic peak at 155 °C; and, in the second heating cycle, a complex endothermic event starting at 181 °C, with a characteristic peak at 187 °C, and a second start temperature of 190 °C, with a characteristic peak at 192 °C.

[0547] After dissolution in DMSO-d6, polymorph 9 of Compound A was analyzed by 1 1H NMR. In another embodiment, the resulting 1 1H NMR spectrum (see Figure 35 ) shows consistency with the structure of polymorph 9 of Compound A.

[0548] In another embodiment, polymorph 9 of Compound A was analyzed by FTIR as a reference (see Figure 36 ).

[0549] In another embodiment, the HPLC purity analysis of polymorph 9 of Compound A showed a purity value of 97.6%.

[0550] In another embodiment, the GVS analysis of polymorph 9 of Compound A found it to have slight hygroscopicity, with an uptake of 0.8% at 90% RH. The tested material was analyzed by XRPD after GVS and found to be polymorph 9 of Compound A.

[0551] In another embodiment, the water solubility dissolution value of polymorph 9 of Compound A was <0.1 mg / mL, and the pH after dissolution of the sample was 7.3. After analysis, the excess solid was analyzed by XRPD and found to have been converted to polymorph 4 of Compound A.

[0552] In another embodiment, the VT-XRPD analysis of polymorph 9 of Compound A was performed using the heating program in Table 8 below:

[0553] Table 8 VT-XRPD Heating Program for Polymorph 9 of Compound A

[0554] Temperature Program 25℃ Scan and then heat to the next temperature at 5 °C / min 50℃ Scan and then heat to the next temperature at 5 °C / min 100℃ Scan and then heat to the next temperature at 3.3 °C / min 150℃ Scan and then heat to the next temperature at 0.5 °C / min 155℃ Scan and then heat to the next temperature at 0.5 °C / min 160℃ Scan and then heat to the next temperature at 0.5 °C / min 165℃ Scan and then heat to the next temperature at 0.5 °C / min 170℃ Scan and then heat to the next temperature at 1 °C / min 180℃ Scan, and then cool to 25 °C 25℃ Scan at this temperature

[0555] In another embodiment, the solid form of polymorph 9 of Compound A was analyzed by XRPD at each temperature, and the results are shown in Table 9 below.

[0556] Table 9 VT-XRPD Results for Polymorph 9 of Compound A

[0557] Temperature Polymorph 25℃ Crystal form 9 50℃ Crystal form 9 100℃ Crystal form 9 150℃ Crystal form 9 155℃ Note form conversion - similar to crystal form 9 160℃ Similar to crystal form 9 165℃ Partially crystalline 170℃ Partially crystalline 180℃ Amorphous 25℃ Amorphous

[0558] In another embodiment, hot stage microscopy of polymorph 9 of Compound A was performed using the method described herein. It was noted that polymorph 9 of Compound A began to melt at approximately 156 °C and the material was completely melted after heating to 172 °C.

[0559] 6.3.10 J. Characterization of Polymorph 10 of Compound A

[0560] In one embodiment, the present invention relates to a solid form of Compound A, referred to herein as polymorph 10 of Compound A. In some embodiments, the present disclosure provides polymorph 10 of Compound A having an XRPD pattern substantially similar to Figure 37 the XRPD pattern shown.

[0561] In another embodiment, TG analysis of polymorph 10 of Compound A showed a weight loss of approximately 6.3% from the start of heating (see Figure 38 ). The mass loss observed corresponded to 0.34 equivalents of tetrahydrofuran.

[0562] In another embodiment, DTA analysis of polymorph 10 of Compound A showed a small endothermic event at approximately 186 °C, followed by an exothermic event at approximately 189 °C, which is related to recrystallization observed in polymorph 1 and polymorph 2 of Compound A. A large melting endotherm was observed at approximately 192 °C (see Figure 38 ).

[0563] Thermal analysis indicated that polymorph 10 of Compound A is a tetrahydrofuran solvate that desolvates upon heating and converts to polymorph 1 and polymorph 2 of Compound A.

[0564] 6.3.11 K. Characterization of Polymorph 11 of Compound A

[0565] In one embodiment, the present invention relates to a solid form of Compound A, referred to herein as polymorph 11 of Compound A. In some embodiments, the present disclosure provides polymorph 11 of Compound A having an XRPD pattern substantially similar to Figure 39 the XRPD pattern shown.

[0566] In some embodiments, polymorph 11 of Compound A in the composition is identified by detecting one or more peaks selected from those listed in Table 10 below in the XRPD pattern of the composition.

[0567] Table 10 XRPD Peak Positions of Polymorph 11 of Compound A

[0568]

[0569]

[0570]

[0571] In some embodiments, polymorph 11 of Compound A in the composition is identified by detecting two or more peaks in the XRPD pattern of the composition selected from Table 10. In some embodiments, polymorph 11 of Compound A in the composition is identified by detecting three or more peaks in the XRPD pattern of the composition selected from Table 10. In some embodiments, polymorph 11 of Compound A in the composition is identified by detecting four or more peaks in the XRPD pattern of the composition selected from Table 10. In some embodiments, polymorph 11 of Compound A in the composition is identified by detecting five or more peaks in the XRPD pattern of the composition selected from Table 10. In some embodiments, polymorph 11 of Compound A in the composition is identified by detecting six or more peaks in the XRPD pattern of the composition selected from Table 10. In some embodiments, polymorph 11 of Compound A in the composition is identified by detecting seven or more peaks in the XRPD pattern of the composition selected from Table 10. In some embodiments, polymorph 11 of Compound A in the composition is identified by detecting eight or more peaks in the XRPD pattern of the composition selected from Table 10. In some embodiments, polymorph 11 of Compound A in the composition is identified by detecting nine or more peaks in the XRPD pattern of the composition selected from Table 10. In some embodiments, polymorph 11 of Compound A is identified by detecting all of the peaks in Table 10 in the XRPD pattern of the composition.

[0572] In some embodiments, polymorph 11 of Compound A in the composition is identified by detecting at least eight peaks in the XRPD pattern of the composition, the at least eight peaks corresponding to the eight strongest peaks (based on relative percent intensity) in Table 10 ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ.

[0573] In some embodiments, polymorph 11 of compound A in a composition is identified by detecting at least seven peaks in the XRPD pattern of the composition, wherein the at least seven peaks correspond to the seven strongest peaks (based on relative percent intensity) in Table 10 ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ.

[0574] In some embodiments, polymorph 11 of compound A in a composition is identified by detecting at least six peaks in the XRPD pattern of the composition, wherein the at least six peaks correspond to the six strongest peaks (based on relative percent intensity) in Table 10 ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ.

[0575] In some embodiments, polymorph 11 of compound A in a composition is identified by detecting at least five peaks in the XRPD pattern of the composition, wherein the at least five peaks correspond to the five strongest peaks (based on relative percent intensity) in Table 10 ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ. For example, in certain embodiments, polymorph 11 of compound A in a composition is identified by detecting at least the following five peaks in the XRPD pattern of the composition: approximately 3.05, approximately 15.33, approximately 18.08, approximately 20.98, approximately 23.49 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ.

[0576] In some embodiments, polymorph 11 of compound A in a composition is identified by detecting at least four peaks in the XRPD pattern of the composition, wherein the at least four peaks correspond to the four strongest peaks (based on relative percent intensity) in Table 10 ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ. For example, in certain embodiments, polymorph 11 of compound A in a composition is identified by detecting at least the following four peaks in the XRPD pattern of the composition: approximately 3.05, approximately 15.33, approximately 18.08, approximately 23.49 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ.

[0577] In some embodiments, polymorph 11 of Compound A in a composition is identified by detecting at least three peaks in the XRPD pattern of the composition, where the at least three peaks correspond to three of the strongest peaks in Table 10 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ. For example, in certain embodiments, polymorph 11 of Compound A in a composition is identified by detecting at least the following three peaks in the XRPD pattern of the composition: approximately 3.05, approximately 18.08, approximately 23.49 degrees 2θ ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0578] In some embodiments, polymorph 11 of Compound A in a composition is identified by detecting at least two peaks in the XRPD pattern of the composition, where the at least two peaks correspond to two of the strongest peaks in Table 10 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0579] In some embodiments, polymorph 11 of Compound A in a composition is identified by detecting at least one peak in the XRPD pattern of the composition, where the at least one peak corresponds to the strongest peak in Table 10 (based on relative percent intensity) ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0580] In some embodiments, polymorph 11 of Compound A in a composition is identified by detecting one or more peaks selected from the group consisting of: approximately 11.40, approximately 11.69, approximately 15.08, approximately 19.48, approximately 20.52, approximately 21.40, approximately 22.47, approximately 23.44, approximately 23.61 degrees 2θ ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ.

[0581] In some embodiments, polymorph 11 of Compound A in a composition is identified by detecting two or more peaks selected from the group consisting of: approximately 11.40, approximately 11.69, approximately 15.08, approximately 19.48, approximately 20.52, approximately 21.40, approximately 22.47, approximately 23.44, approximately 23.61 degrees 2θ ±0.3 degrees 2θ, more preferably ±0.2 degrees 2θ, even more preferably ±0.1 degrees 2θ, and most preferably ±0.05 degrees 2θ. For example, the at least two strongest peaks.

[0582] In some embodiments, polymorph 11 of Compound A in a composition is identified by detecting three or more peaks selected from the group consisting of: about 11.40, about 11.69, about 15.08, about 19.48, about 20.52, about 21.40, about 22.47, about 23.44, about 23.61 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0583] In some embodiments, polymorph 11 of Compound A in a composition is identified by detecting four or more peaks selected from the group consisting of: about 11.40, about 11.69, about 15.08, about 19.48, about 20.52, about 21.40, about 22.47, about 23.44, about 23.61 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0584] In some embodiments, polymorph 11 of Compound A in a composition is identified by detecting five or more peaks selected from the group consisting of: about 11.40, about 11.69, about 15.08, about 19.48, about 20.52, about 21.40, about 22.47, about 23.44, about 23.61 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0585] In some embodiments, polymorph 11 of Compound A in a composition is identified by detecting six or more peaks selected from the group consisting of: about 11.40, about 11.69, about 15.08, about 19.48, about 20.52, about 21.40, about 22.47, about 23.44, about 23.61 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0586] In some embodiments, polymorph 11 of Compound A in a composition is identified by detecting seven or more peaks selected from the group consisting of: about 11.40, about 11.69, about 15.08, about 19.48, about 20.52, about 21.40, about 22.47, about 23.44, about 23.61 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0587] In some embodiments, polymorph 11 of Compound A in a composition is identified by detecting eight or more peaks selected from the group consisting of: about 11.40, about 11.69, about 15.08, about 19.48, about 20.52, about 21.40, about 22.47, about 23.44, about 23.61 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ in the XRPD pattern of the composition.

[0588] In some embodiments, polymorph 11 of Compound A in a composition is identified by detecting peaks in the XRPD pattern of the composition: about 11.40, about 11.69, about 15.08, about 19.48, about 20.52, about 21.40, about 22.47, about 23.44, about 23.61 degrees 2θ ± 0.3 degrees 2θ, more preferably ± 0.2 degrees 2θ, even more preferably ± 0.1 degrees 2θ, and most preferably ± 0.05 degrees 2θ.

[0589] In another embodiment, PLM analysis of polymorph 11 of Compound A indicates that the solid is small particles with an aggregated and birefringent rod-like morphology (see Figure 40 ).

[0590] In another embodiment, TG analysis of polymorph 11 of Compound A shows that up to 200 °C, there is a 1.1% weight loss and decomposition occurs. In DTA, an endothermic event starts at 191 °C with a peak at 192 °C (see Figure 41 ).

[0591] Thus, in some embodiments, the present disclosure provides polymorph 11 of Compound A having a TG / DTA thermogram substantially similar to Figure 41 . In some embodiments, polymorph 4 of Compound A in a composition is identified by detecting a DTA thermogram that has an endothermic event starting at 191 °C and a peak at 192 °C.

[0592] In another embodiment, DSC analysis of polymorph 11 of Compound A indicates that in the initial heating, there is a shallow exothermic phenomenon starting at 41 °C with a peak at 50 °C, followed by a shallow endothermic phenomenon starting at 116 °C with a peak at 122 °C. Subsequently, there is a small exothermic event starting at 176 °C with a peak at 180 °C, associated with a large endothermic event starting at 188 °C with a peak at 192 °C (see Figure 42 ). In the cooling cycle, a single exothermic event is observed starting at 148 °C with a peak at 147 °C (see Figure 43 ). During the second heating cycle, two endothermic events are noted, the first starting at 184 °C with a peak at 187 °C and the second starting at 191 °C with a peak at 192 °C (seeFigure 44 )。

[0593] Thus, in some embodiments, the present disclosure provides Compound A Polymorph 11 having a DSC thermogram substantially similar to Figure 42 , Figure 43 and Figure 44 . In some embodiments, Compound A Polymorph 11 is identified in a composition by detecting a DSC thermogram that has a shallow exothermic event at the start at 41 °C, a characteristic peak at 50 °C, followed by a shallow endothermic event starting at 116 °C, a characteristic peak at 122 °C, followed by a small exothermic event starting at 176 °C, a characteristic peak at 180 °C associated with a large endothermic event starting at 188 °C, a characteristic peak at 192 °C; a single exothermic event starting at 148 °C with a peak at 147 °C; and, in the second heating cycle, a first endothermic event starting at 184 °C having a characteristic peak at 187 °C and a second endothermic event starting at 191 °C having a characteristic peak at 192 °C.

[0594] Compound A Polymorph 11 is analyzed by 1H NMR after dissolution in DMSO-d6. In another embodiment, the resulting 1H NMR spectrum (see Figure 45 ) shows consistency with the structure of Compound A Polymorph 11.

[0595] In another embodiment, Compound A Polymorph 11 is analyzed by FTIR as a reference (see Figure 46 ).

[0596] In another embodiment, the HPLC purity analysis of Compound A Polymorph 11 shows a purity value of 99.6%.

[0597] In another embodiment, the GVS analysis of Compound A Polymorph 11 finds that it has slight hygroscopicity with an uptake of 0.5% at 90% RH. The tested material is analyzed by XRPD after GVS and found to be a mixture of Compound A Polymorph 4 and Compound A Polymorph 11.

[0598] In another embodiment, the water solubility dissolution value of Compound A Polymorph 4 is <0.1 mg / mL and the pH after dissolution of the sample is 4.9. After analysis, the excess solid is analyzed by XRPD and found to be a mixture of Compound A Polymorph 4 and Compound A Polymorph 11.

[0599] In another embodiment, the VT-XRPD analysis of Compound A Polymorph 11 is performed using the heating program in Table 11 below.

[0600] Table 11 Heating Program for VT-XRPD of Compound A Polymorph 11

[0601] Temperature Procedure 25℃ Scan and then heat to the next temperature at 2 °C / min 50℃ Scan and then heat to the next temperature at 2 °C / min 100℃ Scan and then heat to the next temperature at 1 °C / min 150℃ Scan and then heat to the next temperature at 0.5 °C / min 155℃ Wait for 5 minutes, then scan and heat to the next temperature at 1 °C / min 160℃ Wait for 5 minutes, then scan and heat to the next temperature at 0.5 °C / min 165℃ Wait for 5 minutes, then scan and heat to the next temperature at 0.5 °C / min 170℃ Scan and then heat to the next temperature at 1 °C / min 180℃ Scan and then heat to the next temperature at 1 °C / min 190℃ Scan, and then cool to 25 °C 25℃ Scan at this temperature

[0602] In another embodiment, the solid form of Compound A Polymorph 11 at each temperature was analyzed by XRPD, and the results are shown in Table 12 below.

[0603] Table 12 VT-XRPD Results of Compound A Polymorph 11

[0604] Temperature Polymorph 25℃ Crystal form 11 50℃ Crystal form 11 100℃ Crystal form 11 150℃ Form change 155℃ Partially crystalline 160℃ Partially crystalline 165℃ Partially crystalline 170℃ Partially crystalline 180℃ Partially crystalline 190℃ Amorphous 25℃ Amorphous

[0605] In another embodiment, hot stage microscopy of Compound A Polymorph 11 was performed using the method described herein. It was noted that Compound A Polymorph 11 began to melt at approximately 150 °C and the material was completely melted after heating to 185 °C.

[0606] 6.4 Determination of Carr's Index

[0607] For therapeutic use, Compound A and the solid crystalline forms of Compound A are advantageously administered in an acceptable dosage form (e.g., capsules, tablets, sterile injectables, topical formulations, etc.). To successfully manufacture these dosage forms (especially on a commercial scale), while meeting all relevant quality requirements, it is generally required that the active pharmaceutical ingredient under discussion exhibits acceptable rheological (flow) properties. An active pharmaceutical ingredient with poor rheological properties is usually incompatible with manufacturing equipment such as automatic high-speed capsule fillers, which rely on gravity and / or vibration-fed hoppers, and an active pharmaceutical ingredient with poor rheological properties cannot flow uniformly through these process lines, resulting in significant and unacceptable variability in the resulting dosage forms. Thus, it is well recognized in the art that when selecting the form of an active pharmaceutical ingredient for development, the rheological properties of that form are an important consideration.

[0608] Carr's Index is a widely used measure of the flowability of powders (see, e.g., Wang, Y.B. and Williams, R.O. III, "Powders" in Remington: The Science and Practice of Pharmacy, Felton, L., ed., London: Pharmaceutical Press, 2013 at pp. 422-423). The bulk density of the powder is measured, as well as the corresponding tapped density (after compressing the powder in a standard tapped density tester, e.g., Gardco JV1000, Paul N. Gardner Company, Pompano Beach, FL, according to standard methods as described in Chapter 616 of the United States Pharmacopeia). Once the bulk density and tapped density of the powder have been experimentally determined, Carr's Index can be calculated according to the following formula:

[0609] Carr's Index = (tapped density - bulk density) / tapped density × 100.

[0610] The relationship between Carr's index and powder flowability is summarized in the following table:

[0611] Carr index Flowability >38 Very poor 35-38 Poor 23-35 Fair 18-23 Suitable 12-18 Good 5-12 Excellent

[0612] Compound A and polymorph 4 of Compound A were each micronized to specifications of d50 ≤ 3 μm and d90 ≤ 5 μm, and their respective Carr's indices were measured. The Carr's index of Compound A was 36 (i.e., very poor flowability), while the Carr's index of polymorph 4 of Compound A was 8 (i.e., excellent flowability).

[0613] 6.5 Stability studies

[0614] To determine the thermodynamic relationship between polymorph 4 of Compound A and polymorph 11 of Compound A, slurry experiments were conducted using polymorph 4 of Compound A and polymorph 11 of Compound A as seeds and ethanol and 1-propanol as solvents. Samples of the slurry of polymorph 4 of Compound A and the slurry of polymorph 11 of Compound A were taken for XRPD analysis after 24 hours at 40 °C, after 2 hours at 5 °C, and after 24 hours at 5 °C. The results of all four experiments are shown in Table 13 below, where the solids separated from all four experiments after 2 hours at 5 °C and after 24 hours at 5 °C were identified as polymorph 4 of Compound A.

[0615] The ethanol experiment seeded with polymorph 4 of Compound A yielded polymorph 4 of Compound A at all tested sample points, while the 1-propanol experiment yielded a mixture of polymorph 2 and polymorph 4 of Compound A after 24 hours at 40 °C. After cooling to 5 °C, the material reverted to polymorph 4.

[0616] Although both experiments used polymorph 11 of Compound A as the seed, no polymorph 11 material of Compound A was observed in any of the slurry samples. After 24 hours at 40 °C, the slurry containing ethanol and the seed of polymorph 11 of Compound A was observed to become polymorph 2 of Compound A, which converted to polymorph 4 of Compound A after cooling to 5 °C. After 24 hours at 40 °C, there was not enough solid for XRPD analysis in the 1-propanol experiment seeded with polymorph 11 of Compound A. However, after 2 hours at 5 °C, the amount of solid increased and was identified as polymorph 4 of Compound A by XRPD.

[0617] XRPD results of slurry samples

[0618]

[0619] 6.6 Crystallization studies

[0620] The following crystallization studies were conducted on polymorph 4 of Compound A:

[0621] 6.6.1A. Crystallization study 1

[0622] In one embodiment, crystallization studies of Compound A polymorph 4 were completed using degassed ethanol and water at a concentration of 60 mg / mL. After complete dissolution at 45 °C, the system was cooled to 30 °C and a clear solution was observed before seeding. The seeds persisted for approximately 1 hour before the addition of the antisolvent at 30 °C. For samples of the dried solid and the final product, the following results were obtained:

[0623] 1. Samples obtained after the addition of the antisolvent were separated by centrifugation and the solids were analyzed by XRPD. The material was confirmed to be polymorph 4.

[0624] 2. The final recovered solids, both the wet and the dried solids, were confirmed to be polymorph 4 by XRPD analysis.

[0625] 3. The recovered material had a separation yield of 90% and a solid purity of 99.6% as detected by HPLC.

[0626] 4. The recovered mother liquor had a concentration of 0.7 mg / mL, which corresponded to a 98% theoretical recovery. The mother liquor purity was determined to be 88%. The concentration of the wash liquor was < 0.1 mg / mL.

[0627] 5. PLM analysis of the dried solid showed that the material was plate-like crystals with agglomeration and birefringence.

[0628] 6. TG analysis of the solid showed a 0.3% weight loss up to approximately 220 °C followed by decomposition. In DTA, an endothermic event was noted starting at 118 °C with a peak at 127 °C, and then a second larger endothermic event starting at 191 °C with a peak at 192 °C, possibly related to the melting of the material.

[0629] 7. KF analysis was performed on three solid samples using the direct addition method. The average moisture content was measured to be 0.53 wt%.

[0630] 8. GC analysis of the dried solid returned a residual ethanol value of 188 ppm.

[0631] 9. Particle size analysis of the material was performed and the following PSD values were obtained:

[0632] D10 = 8.0 μm

[0633] D50 = 22.1 μm

[0634] D90 = 52.1 μm

[0635] 6.6.2B. Crystallization Study 2

[0636] In another embodiment, degassed 1-propanol and water were used to complete the crystallization study of Compound A Polymorph 4 at a concentration of 60 mg / mL. After complete dissolution at 45 °C, the system was cooled to 30 °C and a clear solution was observed before seeding. The seed crystals persisted for about 1 hour before the anti-solvent was added at 30 °C. For samples of the dried solid and the final product, the following results were obtained:

[0637] 1. Samples obtained after addition of the anti-solvent were separated by centrifugation and the solids were analyzed by XRPD. The material was confirmed to be Polymorph 4.

[0638] 2. The recovered solids, both wet and dry, were analyzed by XRPD and both samples were confirmed to be Polymorph 4.

[0639] 3. The isolated yield of the final recovered material was 80% and the solid purity was 99.6% as determined by HPLC. The recovery yield was lower due to some processing losses.

[0640] 4. The recovered mother liquor had a concentration of 2.6 mg / mL, corresponding to a 93% theoretical recovery. The mother liquor purity was determined to be 84%. The concentration of the wash liquor was < 0.1 mg / mL.

[0641] 5. PLM analysis of the dried solid showed that the material was plate-like crystals with agglomeration and birefringence. Images were taken at magnifications of 20x and 10x due to the large particle size.

[0642] 6. TG analysis of the solid showed a 0.1% weight loss up to about 220 °C followed by decomposition. In DTA, an endothermic event was noted at the start at 108 °C with a peak at 116 °C, and then a second larger endothermic event started at 192 °C with a peak at 193 °C, likely related to melting of the material.

[0643] 7. KF analysis was performed on two solid samples using the direct addition method. The average moisture content was measured to be 0.08 wt%.

[0644] 8. GC analysis of the dried solid returned a residual 1-propanol value of 391 ppm.

[0645] 9. Particle size analysis of the material was performed and the following PSD values were obtained:

[0646] D10 = 18.1 μm

[0647] D50 = 65.1 μm

[0648] D90 = 152.9 μm

[0649] 6.6.3C. Crystallization Study 3

[0650] In another embodiment, a 1-propanol∶water system was used, and the antisolvent was added at a lower temperature to conduct crystallization studies on Form 4 of Compound A. The concentration was maintained at the same value as in Crystallization Study 2. After complete dissolution at 45 °C, the system was cooled to 30 °C and a clear solution was observed before seeding. The seed crystals persisted for about 1 hour before the vessel temperature increased to 35 °C, which led to some dissolution of the seed crystals. Then the system was cooled to 30 °C and held for another 30 minutes, and then cooled to 5 °C. Then the antisolvent was added at 5 °C. For samples of the dried solid and the final product, the following results were obtained:

[0651] 1. The sample obtained after holding at 5 °C was separated by centrifugation, and the solid was analyzed by XRPD. The material was confirmed to be Form 4. The concentration of the sample mother liquor was determined to be 52.8 mg / mL.

[0652] 2. The recovered wet solid and dried solid were analyzed by XRPD, and both samples were confirmed to be Form 4.

[0653] 3. The recovered material had a separation yield of 80% and a solid purity of 99.6% as detected by HPLC.

[0654] 4. The concentration of the recovered mother liquor was 3.7 mg / mL, corresponding to a 90% theoretical recovery. The mother liquor purity was determined to be 92%. The concentration of the wash liquor was 0.2 mg / mL.

[0655] 5. PLM analysis of the dried solid showed that the material was plate-like crystals with agglomeration and birefringence.

[0656] 6. TG analysis of the solid showed a 0.1% weight loss up to about 220 °C and then decomposition. In DTA, an endothermic event was noted at the start at 113 °C, with a peak at 119 °C, and then a second larger endothermic event occurred at the start at 191 °C, with a peak at 192 °C, possibly related to the melting of the material.

[0657] 7. KF analysis was performed on two solid samples using the direct addition method. The average moisture content was determined to be 0.08 wt%.

[0658] 8. GC analysis of the dried solid gave a residual 1-propanol value of 477 ppm.

[0659] 9. Particle size analysis of the material was carried out, and the following PSD values were obtained:

[0660] D10 = 16.4 μm

[0661] D50 = 54.4 μm

[0662] D90 = 146.7 μm

[0663] 6.6.4D. Crystallization Study 4

[0664] In another embodiment, the crystallization study of Compound A polymorph 4 was carried out at a higher concentration of 65 mg / mL. The solvent system used was again 1-propanol: water, with a final solvent ratio of 65:35 v / v%. After complete dissolution at 45 °C, the system was cooled to 30 °C and a clear solution was observed before seeding. The seeding was continued for about 1 hour, then cooled to 5 °C, and samples were taken at 5 °C. Then an anti-solvent was added, and the following results for the final product of the sample and the dried solid were obtained:

[0665] 1. The samples taken after holding at 5 °C were separated by centrifugation, and the solid was analyzed by XRPD. The material was confirmed to be polymorph 4. The concentration of the sample mother liquor was determined to be 37.7 mg / mL. The PLM image of the slurry sample showed that the material was flaky in morphology and had significant agglomeration and birefringence.

[0666] 2. The recovered solid, the wet and the dried solid, were analyzed by XRPD, and both samples were confirmed to be polymorph 4.

[0667] 3. The recovered material had a separation yield of 87% and a solid purity of 99.6% as detected by HPLC.

[0668] 4. The concentration of the recovered mother liquor was 3.1 mg / mL, corresponding to a theoretical recovery of 90%. The mother liquor purity was determined to be 93%. The concentration of the wash liquor was <0.1 mg / mL.

[0669] 5. The PLM analysis of the wet solid showed that the material was flaky in morphology, and the solid also showed agglomeration and birefringence.

[0670] 6. The PLM analysis of the dried solid showed that the material was flaky crystals with some rod-shaped particles. The particle size visually appeared smaller than that of the previous crystallization, and the recovered solid also showed agglomeration and birefringence.

[0671] 7. The TG analysis of the dried solid showed a 0.1% weight loss up to about 200 °C, followed by decomposition.

[0672] In DTA, an endothermic event was noted at the start of 120 °C, with a peak at 127 °C, and then a second larger endothermic event occurred at the start of 191 °C, with a peak at 192 °C, probably related to the melting of the material.

[0673] 8. KF analysis was carried out on two solid samples using the direct addition method. The average moisture content was determined to be 0.06 wt%.

[0674] 9. The GC analysis of the dried solid gave a residual 1-propanol value of 477 ppm.

[0675] 10. Perform a particle size analysis of the material to obtain the following PSD values:

[0676] D10 = 6.0 μm

[0677] D50 = 18.0 μm

[0678] D90 = 45.8 μm

[0679] 6.6.5E. Crystallization study 5

[0680] In another embodiment, the crystallization study of Compound A polymorph 4 was carried out at a lower concentration of 60 mg / mL in 1-propanol: water. After complete dissolution at 45 °C, the system was cooled to 30 °C and a clear solution was observed before seeding. The seed crystal was maintained for about 1 hour and then cooled to 25 °C, at which point the antisolvent was added at a slower rate. Samples were taken at 25 °C after addition and the system was cooled to 5 °C before separation. The following results were obtained for the samples of the dried solid and the final product:

[0681] 1. The sample obtained after adding the antisolvent was separated by centrifugation and the solid was analyzed by XRPD. It was confirmed that the material was polymorph 4. The concentration of the sample mother liquor was determined to be 4.2 mg / mL.

[0682] 2. The recovered wet solid and dried solid were analyzed by XRPD and both samples were confirmed to be polymorph 4. Due to the obvious preferred orientation of the dried sample, the material was gently ground and re-analyzed by XRPD, and the material was also identified as polymorph 4.

[0683] 3. The recovered material had a separation yield of 85% and a solid purity of 99.5% as detected by HPLC.

[0684] 4. The concentration of the recovered mother liquor was 2.3 mg / mL, corresponding to a theoretical recovery of 94%. The mother liquor purity was determined to be 87%. The concentration of the wash liquor was 0.2 mg / mL.

[0685] 5. PLM analysis of the wet solid showed that the material was flaky in morphology and the solid also showed agglomeration and birefringence. Due to the particle size, images were taken at 20x and 10x magnifications.

[0686] 6. PLM analysis of the dried solid showed that the material was flaky crystals with agglomeration and birefringence.

[0687] 7. TG analysis of the dried solid showed no weight loss before decomposition. In DTA, an endothermic event was noted at the start of 112 °C, with a peak at 117 °C, followed by a second larger endothermic event starting at 191 °C with a peak at 192 °C, possibly related to the melting of the material.

[0688] 8. KF analysis was performed on two solid samples using the direct addition method. The average moisture content was determined to be 0.09 wt%.

[0689] 9. GC analysis of the dried solid returned a residual 1-propanol value of 380 ppm.

[0690] 10. Particle size analysis of the material was carried out, and the following PSD values were obtained:

[0691] D10 = 13.1 μm

[0692] D50 = 54.5 μm

[0693] D90 = 162.1 μm

[0694] 6.6.6F. Crystallization Study 6

[0695] In another embodiment, the crystallization study of Compound A polymorph 4 was carried out at a higher concentration of 65 mg / mL in a 1-propanol:water system. After complete dissolution at 45 °C, the system was cooled to 35 °C and a clear solution was observed before seeding. The seed crystal was maintained for about 1 hour and then cooled to 5 °C, and the anti-solvent was added at a slower rate. The following results were obtained for the dried solid sample and the final product:

[0696] 1. The recovered solid, the wet and dried solids, were confirmed to be polymorph 4 by XRPD analysis. Due to the obvious preferred orientation of the dried sample, the material was gently ground and re-analyzed by XRPD, and the material was also identified as polymorph 4.

[0697] 2. The recovered material had a separation yield of 88% and a solid purity of 99.5% as detected by HPLC.

[0698] 3. The concentration of the recovered mother liquor was 1.9 mg / mL, corresponding to a theoretical recovery of 96%. The mother liquor purity was determined to be 84%. The concentration of the wash liquor was 0.1 mg / mL.

[0699] 4. PLM analysis of the wet solid showed that the material was flaky in morphology, and the solid also showed agglomeration and birefringence.

[0700] 5. PLM analysis of the dried solid showed that the material was flaky crystals with agglomeration and birefringence. Due to the particle size, images were taken at 20x and 10x magnifications.

[0701] 6. TG analysis of the dried solid showed a weight loss of 0.2% at temperatures up to 200 °C, followed by decomposition. In DTA, an endothermic event was noted at the start at 117 °C, with a peak at 123 °C, and then a second larger endothermic event started at 191 °C, with a peak at 192 °C, which may be related to the melting of the material.

[0702] 7. KF analysis was performed on two solid samples using the direct addition method. The average moisture content was determined to be 0.03 wt%.

[0703] 8. The residual 1-propanol value returned by GC analysis of the dried solid was 331 ppm.

[0704] 9. Particle size analysis of the material was carried out and the following PSD values were obtained:

[0705] D10 = 14.6 μm

[0706] D50 = 45.0 μm

[0707] D90 = 119.1 μm

[0708] 6.6.7G. Crystallization Study 7

[0709] In another embodiment, crystallization studies of polymorph 4 of compound A were carried out using a degassed solvent at a higher concentration of 65 mg / mL in a 1-propanol:water system. After complete dissolution at 45 °C, the system was cooled to 32 °C and a clear solution was observed before seeding. The seed was held for about 1 hour and then cooled to 5 °C, followed by addition of the antisolvent. The following results were obtained for the samples of the dried solid and the final product:

[0710] 1. The solids recovered by XRPD analysis, the wet and dried solids, both samples were confirmed to be polymorph 4. Due to the significant preferred orientation of the dried sample, the material was gently ground and reanalyzed by XRPD, and the material was also identified as polymorph 4.

[0711] 2. The recovered material had a separation yield of 84% and a solid purity of 99.5% as detected by HPLC.

[0712] 3. The concentration of the recovered mother liquor was 4.5 mg / mL, corresponding to a theoretical recovery of 89%. The mother liquor purity was determined to be 92%. The concentration of the wash liquor was 0.2 mg / mL.

[0713] 4. PLM analysis of the wet solid showed that the material was flaky in morphology, and the solid also showed agglomeration and birefringence.

[0714] 5. PLM analysis of the dried solid showed that the material was flaky crystals with agglomeration and birefringence.

[0715] 6. TG analysis of the dried solid showed a weight loss of 0.2% at temperatures up to 200 °C, followed by decomposition. In DTA, an endothermic event was noted at the start at 111 °C, with a peak at 120 °C, and then a second larger endothermic event occurred at the start at 191 °C, with a peak at 192 °C, which may be related to the melting of the material.

[0716] 7. KF analysis was performed on two solid samples using the direct addition method. The average moisture content was determined to be 0.07 wt%.

[0717] 8. GC analysis of the dried solid returned a residual 1-propanol value of 349 ppm.

[0718] 9. Particle size analysis of the material was carried out, and the following PSD values were obtained:

[0719] D10 = 13.4 μm

[0720] D50 = 48.6 μm

[0721] D90 = 132.5 μm

[0722] 6.6.8H. Crystallization Study 8

[0723] In another embodiment, crystallization studies of Compound A polymorph 4 were carried out using a degassed solvent at a higher concentration of 65 mg / in 1-propanol: water. After complete dissolution at 45 °C, the system was cooled to 32 °C and a clear solution was observed before seeding. The seed crystal was maintained for about 1 hour, then cooled to 30 °C, and then the antisolvent was added.

[0724] After adding the antisolvent, the system was cooled to 5 °C. The following results were obtained for the samples of the dried solid and the final product:

[0725] 1. The recovered solid, the wet and dried solids, were analyzed by XRPD, and both samples were confirmed to be polymorph 4. Due to the obvious preferred orientation of the dried sample, the material was gently ground and reanalyzed by XRPD, and the material was also identified as polymorph 4.

[0726] 2. The recovered material had a separation yield of 88% and a solid purity of 99.6% as detected by HPLC.

[0727] 3. The concentration of the recovered mother liquor was 1.8 mg / ml, corresponding to a theoretical recovery of 96%. The mother liquor purity was determined to be 91%. The concentration of the wash liquor was 0.6 mg / ml.

[0728] 4. PLM analysis of the wet solid showed that the material was flaky in morphology, and the solid also showed agglomeration and birefringence. Due to the particle size, images were taken at 20x and 10x magnifications.

[0729] 5. PLM analysis of the dried solid showed that the material was flaky crystals with agglomeration and birefringence. Due to the particle size, images were taken at 20x and 10x magnifications.

[0730] 6. TG analysis of the dried solid showed a weight loss of 0.3% at temperatures up to 200 °C, followed by decomposition. In DTA, an endothermic event was noted at the onset of 113 °C, with a peak at 115 °C, and a second, larger endothermic event occurred at the onset of 191 °C, with a peak at 192 °C, which may be related to the melting of the material.

[0731] 7. KF analysis was performed on two solid samples using the direct addition method. The average moisture content was determined to be 0.11 wt%.

[0732] 8. GC analysis of the dried solid returned a residual 1-propanol value of 401 ppm.

[0733] 9. Particle size analysis of the material was performed, and the following PSD values were obtained:

[0734] D10 = 11.9 μm

[0735] D50 = 48.3 μm

[0736] D90 = 119.9 μm

[0737] *******

[0738] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications cited in this specification are hereby incorporated by reference in their entirety, including U.S. Provisional Application No. 62 / 913,574, filed October 10, 2019.

[0739] This application also specifically relates to the following embodiments:

[0740] 1. A crystalline form of compound A.

[0741] 2. The crystalline form according to embodiment 1, wherein the crystalline form is polymorph 2 of compound A.

[0742] 3. The crystalline form according to embodiment 1, wherein the crystalline form is polymorph 4 of compound A.

[0743] 4. The crystalline form according to embodiment 1, wherein the crystalline form is polymorph 9 of compound A.

[0744] 5. The crystalline form according to embodiment 1, wherein the crystalline form is polymorph 11 of compound A.

[0745] 6. A solid form of compound A, comprising two or more of the crystalline forms according to embodiments 2-5.

[0746] 7. The crystalline form according to any one of embodiments 2-5, wherein the crystalline form is substantially free of other solid forms.

[0747] 8. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a crystalline form of Compound A.

[0748] 9. The pharmaceutical composition according to embodiment 8, wherein the crystalline form of Compound A is Crystal Form 2 of Compound A.

[0749] 10. The pharmaceutical composition according to embodiment 8, wherein the crystalline form of Compound A is Crystal Form 4 of Compound A.

[0750] 11. The pharmaceutical composition according to embodiment 8, wherein the crystalline form of Compound A is Crystal Form 9 of Compound A.

[0751] 12. The pharmaceutical composition according to embodiment 8, wherein the crystalline form of Compound A is Crystal Form 11 of Compound A.

[0752] 13. A pharmaceutical composition comprising a pharmaceutically acceptable excipient, a carrier and / or a diluent, and a mixture of two or more crystalline forms of Compound A.

[0753] 14. A method for treating human epilepsy, wherein the method comprises administering to a person in need thereof a therapeutically effective amount of a crystalline form of Compound A.

[0754] 15. The method according to embodiment 14, wherein the crystalline form of Compound A is Crystal Form 2 of Compound A.

[0755] 16. The method according to embodiment 14, wherein the crystalline form of Compound A is Crystal Form 4 of Compound A.

[0756] 17. The method according to embodiment 14, wherein the crystalline form of Compound A is Crystal Form 9 of Compound A.

[0757] 18. The method according to embodiment 14, wherein the crystalline form of Compound A is Crystal Form 11 of Compound A.

[0758] 19. A method for treating human epilepsy, wherein the method comprises administering to a person in need thereof a therapeutically effective amount of a mixture of two or more crystalline forms of Compound A.

[0759] 20. A method for preparing a crystalline form of Compound A from another crystalline form of Compound A.

[0760] 21. A method for preparing a pharmaceutical composition comprising a pharmaceutical excipient and a crystalline form of Compound A, the method comprising combining the crystalline form of Compound A with the pharmaceutical excipient to form a pharmaceutical composition.

[0761] 22. The method according to any one of embodiments 14 - 19, wherein the crystalline form of compound A is administered to a human between 30 minutes before a meal and 2 hours after a meal.

[0762] 23. The method according to embodiment 22, wherein the crystalline form of compound A is administered during a meal or within 15 minutes after a meal.

[0763] 24. Use of a crystalline form of compound A in the preparation of a pharmaceutical composition for treating epilepsy in a human in need thereof.

[0764] 25. The use according to embodiment 24, wherein the crystalline form of compound A is polymorph 2 of compound A.

[0765] 26. The use according to embodiment 24, wherein the crystalline form of compound A is polymorph 4 of compound A.

[0766] 27. The use according to embodiment 24, wherein the crystalline form of compound A is polymorph 9 of compound A.

[0767] 28. The use according to embodiment 24, wherein the crystalline form of compound A is polymorph 11 of compound A.

[0768] 29. Use of a mixture of two or more crystalline forms of compound A in the preparation of a pharmaceutical composition for treating epilepsy in a human in need thereof.

[0769] 30. The use according to any one of embodiments 24 - 29, wherein the crystalline form of compound A is administered to a human between 30 minutes before a meal and 2 hours after a meal.

[0770] 31. The use according to embodiment 30, wherein the crystalline form of compound A is administered to a human during a meal or within 15 minutes after a meal.

[0771] Although the foregoing disclosure has been described in detail for purposes of understanding, it will be apparent that certain changes and modifications may be made within the scope of the appended embodiments. Accordingly, the described embodiments are to be considered illustrative rather than restrictive, and the claimed invention is not limited to the details given herein but may be modified within the scope and equivalents of the appended embodiments.

Claims

1. A crystalline or amorphous form of compound A.

2. A solid form of compound A, which comprises two or more crystalline forms selected from: Compound A Polymorph 2, Compound A Polymorph 4, Compound A Polymorph 9, and Compound A Polymorph 11.

3. A pharmaceutical composition, which comprises a pharmaceutically acceptable excipient and a crystalline form of compound A.

4. A pharmaceutical composition, which comprises a pharmaceutically acceptable excipient, carrier and / or diluent, and a mixture of two or more crystalline forms of compound A.

5. A method for treating epilepsy in humans, wherein the method comprises administering to a person in need thereof a therapeutically effective amount of a crystalline form of compound A.

6. A method for treating epilepsy in humans, wherein the method comprises administering to a person in need thereof a therapeutically effective amount of a mixture of two or more crystalline forms of compound A.

7. A method for preparing a crystalline form of compound A from another crystalline form of compound A.

8. A method for preparing a pharmaceutical composition comprising a pharmaceutical excipient and a crystalline form of compound A, the method comprising combining the crystalline form of compound A with the pharmaceutical excipient to form the pharmaceutical composition.

9. Use of a crystalline form of compound A in the preparation of a pharmaceutical composition for treating epilepsy in a person in need thereof.

10. Use of a mixture of two or more crystalline forms of compound A in the preparation of a pharmaceutical composition for treating epilepsy in a person in need thereof.

Images