Solid crystal form of selective potassium channel regulator

Abstract

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

Description

[0001] This application is a divisional application of an invention patent application with an application date of October 9, 2020, application number 202080085704.7, and invention name “A solid crystalline form of a selective potassium channel modulator”. 1. Technical Field

[0002] The present invention relates to a solid crystalline form of a selective potassium channel modulator and a pharmaceutical composition comprising the solid form and a pharmaceutically acceptable excipient, as well as a method for preparing the solid form and the pharmaceutical composition. These solid crystalline forms and the pharmaceutical composition can be used to treat epilepsy in mammals, especially humans. 2. Background technology

[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 with the general population, patients with epilepsy have an increased risk of death, primarily due to the etiology of the disease. However, in patients with uncontrolled epilepsy, the greatest risk of death associated with seizures is due to sudden unexpected death in epilepsy (SUDEP) (see, Hitiris, N. et al., Epilepsy and Behavior (2007), 10:363-376. Patients participating in investigational antiepileptic drug (AED) clinical trials typically have epilepsy for more than 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-dimethylbutanamide (referred to herein as "Compound A") is a small molecule currently under development for the treatment of epilepsy. Compound A and its use as a voltage-gated potassium channel modulator are disclosed in U.S. Pat. No. 8,293,911 and U.S. Pat. No. 8,993,593, the disclosures of which are incorporated herein by reference in their entirety.

[0005] Polymorphism, the occurrence of different solid-state crystalline forms of the same molecule, is a property of certain molecules and molecular complexes. A single molecule may give rise to multiple polymorphs with different crystal structures and physical properties (such as melting points) that 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] Discovery of new solid-state crystalline forms of drug products can result in materials with desirable processing properties, such as ease of handling, ease of processing, storage stability, ease of purification, or as desirable intermediate crystalline forms that 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 drug products. It expands the pool of materials available to formulation scientists for formulation optimization, for example by providing products with different properties, e.g., different crystallization habits, higher crystallinity or polymorphic stability, that can provide better processing or handling characteristics, improved dissolution profiles, or extended shelf life (chemical / physical stability).

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

[0008] The present disclosure relates generally to solid-state forms of Compound A, particularly solid-state crystalline forms, methods of preparing the same, pharmaceutical compositions containing the same, and methods of using the same.

[0009] Thus, 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 Compound A Form 1.

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

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

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

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

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

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

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

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

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

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

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

[0022] In another embodiment, the present disclosure relates to a crystalline form of Compound A disclosed herein (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10 or Form 11) that is substantially free of any other solid state 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 Compound A Form 1, optionally substantially free of any other solid state 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 Compound A Form 2, optionally substantially free of any other solid state 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 Compound A Form 3, optionally substantially free of any other solid state 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 Compound A Form 4, optionally substantially free of any other solid state 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 Compound A Form 5, optionally substantially free of any other solid state form 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 Compound A Form 6, optionally substantially free of any other solid state form 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 Compound A Form 7, optionally substantially free of any other solid state form 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 Compound A Form 8, optionally substantially free of any other solid state form 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 Compound A Form 9, optionally substantially free of any other solid state form 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 Compound A Form 10, optionally substantially free of any other solid state form 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 Compound A Form 11, optionally substantially free of any other solid state form 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 is directed to a method of treating epileptic seizures in a human, wherein the method comprises administering to a human 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 epileptic seizures in humans, wherein the method comprises administering to a human in need thereof a therapeutically effective amount of Compound A Form 1, wherein the Compound A Form 1 is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0038] In another embodiment, the present disclosure relates to a method of treating epileptic seizures in humans, wherein the method comprises administering to a human in need thereof a therapeutically effective amount of Compound A Form 2, wherein the Compound A Form 2 is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0039] In another embodiment, the present disclosure relates to a method of treating epileptic seizures in humans, wherein the method comprises administering to a human in need thereof a therapeutically effective amount of Compound A Form 3, wherein the Compound A Form 3 is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0040] In another embodiment, the present disclosure is directed to a method of treating epileptic seizures in humans, wherein the method comprises administering to a human in need thereof a therapeutically effective amount of Compound A Form 4, wherein the Compound A Form 4 is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0041] In another embodiment, the present disclosure relates to a method of treating epileptic seizures in humans, wherein the method comprises administering to a human in need thereof a therapeutically effective amount of Compound A Form 5, wherein the Compound A Form 5 is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0042] In another embodiment, the present disclosure relates to a method of treating epileptic seizures in humans, wherein the method comprises administering to a human in need thereof a therapeutically effective amount of Compound A Form 6, wherein the Compound A Form 6 is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0043] In another embodiment, the present disclosure relates to a method of treating epileptic seizures in humans, wherein the method comprises administering to a human in need thereof a therapeutically effective amount of Compound A Form 7, wherein the Compound A Form 7 is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0044] In another embodiment, the present disclosure relates to a method of treating epileptic seizures in humans, wherein the method comprises administering to a human in need thereof a therapeutically effective amount of Compound A Form 8, wherein the Compound A Form 8 is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0045] In another embodiment, the present disclosure relates to a method of treating epileptic seizures in humans, wherein the method comprises administering to a human in need thereof a therapeutically effective amount of Compound A Form 9, wherein the Compound A Form 9 is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0046] In another embodiment, the present disclosure is directed to a method of treating epileptic seizures in a human, wherein the method comprises administering to a human in need thereof a therapeutically effective amount of Compound A Form 10, wherein the Compound A Form 10 is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0047] In another embodiment, the present disclosure relates to a method for treating epileptic seizures in humans, wherein the method comprises administering to a human in need thereof a therapeutically effective amount of Compound A Form 11, wherein the Compound A Form 11 is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0048] In another embodiment, the present disclosure is directed to a method of treating epileptic seizures in a human, wherein the method comprises administering to a human in need thereof 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 one of the crystalline forms of Compound A for the preparation of a pharmaceutical composition comprising the 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 the crystalline form of Compound A.

[0051] In another embodiment, the present disclosure relates to a method for preparing the Compound A Form 1, which is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0052] In another embodiment, the present disclosure relates to a method for preparing the Compound A Form 2, which is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0053] In another embodiment, the present disclosure relates to a method for preparing the Compound A Form 3, which is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0054] In another embodiment, the present disclosure relates to a method for preparing the Compound A Form 4, which is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0055] In another embodiment, the present disclosure relates to a method for preparing the Compound A Form 5, which is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0056] In another embodiment, the present disclosure relates to a method for preparing the Compound A Form 6, which is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0057] In another embodiment, the present disclosure relates to a method for preparing the Compound A Form 7, which is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0058] In another embodiment, the present disclosure relates to a method for preparing the Compound A Form 8, which is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0059] In another embodiment, the present disclosure relates to a method for preparing the Compound A Form 9, which is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0060] In another embodiment, the present disclosure relates to a method of preparing the Compound A crystalline Form 10, which is optionally substantially free of any other solid-state form of Compound A disclosed herein.

[0061] In another embodiment, the present disclosure relates to a method for preparing the Compound A Form 11, which is optionally substantially free of any other solid-state form 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 one of the crystalline forms of Compound A and a pharmaceutically acceptable excipient. In one embodiment, the method comprises combining any one of the crystalline forms 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 as a medicament for treating epileptic seizures in humans, the pharmaceutical composition comprising any crystalline form of Compound A and a pharmaceutically acceptable excipient.

[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 a human being between 30 minutes before and 2 hours after a meal, 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 a meal.

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

[0066] In one embodiment, a crystalline form of Compound A exhibits better flow properties (ie, superior rheological properties) than amorphous Compound A or another solid crystalline form of Compound A.

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

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

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

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

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

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

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

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

[0075] Figure 8 It is the XRPD diffraction pattern of Compound A Form 2.

[0076] Fig. 9 These are non-polarized and polarized light microscope images of Compound A Form 2.

[0077] Fig.10 It is the TG / DTA thermogram of Compound A Form 2.

[0078] Fig.11 is the DSC thermogram of Compound A Form 2 (initial heating cycle).

[0079] Fig.12 is the DSC thermogram of Compound A Form 2 (cooling cycle).

[0080] Fig.13 is the DSC thermogram of Compound A Form 2 (second heating cycle).

[0081] Fig.14 Compound A Form 2 1 H NMR spectrum.

[0082] Fig.15 This is the FTIR spectrum of Compound A Form 2.

[0083] Fig.16 It is the XRPD diffraction pattern of Compound A Form 3.

[0084] Fig.17 It is the XRPD diffraction pattern of Compound A Form 4.

[0085] Fig.18 These are non-polarized and polarized light microscope images of Compound A Form 4.

[0086] Fig.19 It is the TG / DTA thermogram of Compound A Form 4.

[0087] Fig. 20 is the DSC thermogram of Compound A Form 4 (initial heating cycle).

[0088] Fig.21 is the DSC thermogram of Compound A Form 4 (cooling cycle).

[0089] Fig. 22 is the DSC thermogram of Compound A Form 4 (second heating cycle).

[0090] Fig.23 Compound A crystalline form 4 1 H NMR spectrum.

[0091] Fig.24 This is the FTIR spectrum of Compound A Form 4.

[0092] Fig.25 It is the XRPD diffraction pattern of Compound A Form 5.

[0093] Fig.26 It is the XRPD diffraction pattern of Compound A Form 6.

[0094] Fig. 27 It is the XRPD diffraction pattern of Compound A Form 7.

[0095] Fig.28 It is the XRPD diffraction pattern of Compound A Form 8.

[0096] Fig.29 It is the XRPD diffraction pattern of Compound A Form 9.

[0097] Fig.30 These are non-polarized and polarized light microscope images of Compound A Form 9.

[0098] Fig.31 It is the TG / DTA thermogram of Compound A Form 9.

[0099] Fig.32 is the DSC thermogram of Compound A Form 9 (initial heating cycle).

[0100] Fig.33 is the DSC thermogram of Compound A Form 9 (cooling cycle).

[0101] Fig.34 is the DSC thermogram of Compound A Form 9 (second heating cycle).

[0102] Fig.35 Compound A crystalline form 9 1 H NMR spectrum.

[0103] Fig.36 This is the FTIR spectrum of Compound A Form 9.

[0104] Fig.37 is the XRPD diffraction pattern of Compound A Form 10.

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

[0106] Fig.39 It is the XRPD diffraction pattern of Compound A Form 11.

[0107] Fig.40 These are non-polarized and polarized light microscope images of Compound A Form 11.

[0108] Fig.41It is the TG / DTA thermogram of Compound A crystalline form 11.

[0109] Fig.42 is the DSC thermogram of Compound A Form 11 (initial heating cycle).

[0110] Fig.43 is the DSC thermogram of Compound A Form 11 (cooling cycle).

[0111] Fig.44 It is the DSC thermogram of Compound A Form 11 (second heating cycle).

[0112] Fig.45 It is compound A crystalline form 11 1 H NMR spectrum.

[0113] Fig.46 This is the FTIR spectrum of Compound A Form 11. 5. Specific implementation methods

[0114] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, it will be understood by those skilled in the art that the present disclosure may be implemented without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, throughout the specification and claims, the word "include" and its variants, such as "include" and "including" are interpreted in an open, inclusive sense, i.e., "including, but not limited to." In addition, the headings provided herein are used only for convenience and do not interpret the scope or meaning of the disclosure claimed.

[0115] References in this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure or characteristic described in conjunction with the embodiment is included in at least one embodiment. Therefore, the appearance of the phrases "in one embodiment" and "in an embodiment" in different places throughout the specification does not necessarily all refer to the same embodiment. In addition, in one or more embodiments, the particular features, structures or characteristics may be combined in any suitable manner. Moreover, as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense, including "and / or", unless the content clearly dictates otherwise. In addition, the term "about" as used herein refers to ±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 appended claims, unless specified to the contrary, the following terms and abbreviations have the indicated meanings:

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

[0119]

[0120] and N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide. 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 best-known AEDs because it involves the enhancement or increased opening of voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2 / Kv7.3), which are very important in controlling neuronal excitability. Compound A is used in the methods and uses described herein.

[0121] A solid state form of Compound A, such as a crystalline form, may be referred to herein as being characterized by graphical data "as shown" or "substantially as shown". Such data include, for example, an X-ray powder diffraction pattern, a DSC thermogram, or an NMR spectrum. As is well known in the art, such graphical data may provide additional technical information to further define the corresponding solid state form (a so-called "fingerprint"), which is not necessarily described by citing only numerical values ​​or peak positions. In any case, it will be understood by those skilled in the art that such graphical representations of data may have small 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 will be able to easily compare the graphical data in the figures herein with graphical data generated for an unknown crystalline form and confirm whether the two sets of graphical data characterize the same crystalline form or two different crystalline forms. The solid state form of Compound A referred to herein as being characterized by graphical data "as depicted" or "substantially as depicted" will therefore be understood to include any solid state form of Compound A characterized by graphical data with the described small variations compared to the schematic diagram herein, as is well known to those skilled in the art.

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

[0123] As used herein, "a solid state form of Compound A referred to as Compound A Form 2", "a solid state form of Compound A as referred to herein as Compound A Form 2", "Compound A Form 2" or "Form 2" refers to a solid state form of Compound A that can be detected by, for example, Figure 8 The solid state form of component Compound A is identified by the peaks of the X-ray powder diffraction pattern shown.

[0124] As used herein, "a solid state form of Compound A referred to as Compound A Form 3", "a solid state form of Compound A as referred to herein as Compound A Form 3", "Compound A Form 3" or "Form 3" refers to a solid state form of Compound A that can be detected by, for example, Fig.16 The solid state form of component Compound A is identified by the peaks of the X-ray powder diffraction pattern shown.

[0125] As used herein, "a solid state form of Compound A referred to as Compound A Form 4", "a solid state form of Compound A as referred to herein as Compound A Form 4", "Compound A Form 4" or "Form 4" refers to a solid state form of Compound A that can be detected by, for example, Fig.17 The solid state form of component Compound A is identified by the peaks of the X-ray powder diffraction pattern shown.

[0126] As used herein, "a solid state form of Compound A referred to as Compound A Form 5", "a solid state form of Compound A as referred to herein as Compound A Form 5", "Compound A Form 5" or "Form 5" refers to a solid state form of Compound A that can be detected by, for example, Fig.25 The solid state form of component Compound A is identified by the peaks of the X-ray powder diffraction pattern shown.

[0127] As used herein, "a solid state form of Compound A referred to as Compound A Form 6", "a solid state form of Compound A as referred to herein as Compound A Form 6", "Compound A Form 6" or "Form 6" refers to a solid state form of Compound A that can be detected by, for example, Fig.26 The solid state form of component Compound A is identified by the peaks of the X-ray powder diffraction pattern shown.

[0128] As used herein, "a solid state form of Compound A referred to as Compound A Form 7", "a solid state form of Compound A as referred to herein as Compound A Form 7", "Compound A Form 7" or "Form 7" refers to a solid state form of Compound A that can be detected by, for example, Fig. 27 The solid state form of component Compound A is identified by the peaks of the X-ray powder diffraction pattern shown.

[0129] As used herein, "a solid state form of Compound A referred to as Compound A Form 8", "a solid state form of Compound A as referred to herein as Compound A Form 8", "Compound A Form 8" or "Form 8" refers to a solid state form of Compound A that can be detected by, for example, Fig.28 The solid state form of component Compound A is identified by the peaks of the X-ray powder diffraction pattern shown.

[0130] As used herein, "a solid state form of Compound A referred to as Compound A Form 9", "a solid state form of Compound A such as referred to herein as Compound A Form 9", "Compound A Form 9" or "Form 9" refers to a solid state form of Compound A that can be detected by, for example, Fig.29 The solid state form of component Compound A is identified by the peaks of the X-ray powder diffraction pattern shown.

[0131] As used herein, "a solid state form of Compound A referred to as Compound A Form 10", "a solid state form of Compound A as referred to herein as Compound A Form 10", "Compound A Form 10" or "Form 10" refers to a solid state form of Compound A that can be detected by, for example, Fig.37 The solid state form of component Compound A is identified by the peaks of the X-ray powder diffraction pattern shown.

[0132] As used herein, "a solid state form of Compound A referred to as Compound A Form 11", "a solid state form of Compound A as referred to herein as Compound A Form 11", "Compound A Form 11" or "Form 11" refers to a solid state form of Compound A that can be detected by, for example, Fig.39 The solid state form of component Compound A is identified by the peaks of the X-ray powder diffraction pattern shown.

[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 dose of the solid form of Compound A, and is expressed in hours multiplied by the concentration of the solid form of Compound A in plasma. For the purposes of this disclosure, AUC is expressed in hours multiplied by ng / ml.

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

[0135] “AUC inf "obs" 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 to the total AUC.

[0138] "Bioavailability" refers to the rate and extent to which the solid state 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 observed plasma concentration.

[0140] "h" means hour.

[0141] A "high-fat meal" is any food, solid or liquid, in which approximately 50% of the food's calories come from fat.

[0142] A "high-calorie meal" is any meal of about 800 to 1000 calories. A typical high-fat, high-calorie meal should have approximately 150, 250, and 500-600 calories from protein, carbohydrates, and fat, respectively.

[0143] Herein, the term "highly soluble" with respect to the solid state form of Compound A corresponds to a solid state form of Compound A having a solubility of greater than 100 mg / ml at room temperature. In one embodiment, the solid state form of Compound A is highly soluble in solvents such as, for example, 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 performed "overnight". This refers to a time interval, e.g., for the process or step, that spans the nighttime period 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 excipients" are understood to be those that can be applied to humans or livestock, including but not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.

[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., a room or fume hood) in which the object or mixture is located. Typically, room temperature is about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0147] "SD" means standard deviation.

[0148] “Seizure Disorders” means epileptic seizures and seizure-related disorders such as partial-onset (focal) epilepsy, photosensitive epilepsy, self-induced syncope, intractable epilepsy, Angelman syndrome, benign lateral diastolic epilepsy, CDKL5 disorder, childhood and adolescent absence epilepsy, severe myoclonic epilepsy of infancy (Dravet syndrome), frontal lobe epilepsy, GLUT1 deficiency syndrome, hypothalamic hamartoma, infantile spasms / West's syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, In some embodiments, the term "seizure disorder" refers to focal onset epilepsy, also known as partial onset (focal) epilepsy.

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

[0150] "T1 / 2 λz ” 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 maximum (peak) plasma concentration following extravascular administration of a solid state form of Compound A.

[0152] "Therapeutically effective amount" herein means that the amount of the solid form of Compound A is sufficient to treat the disease, disorder or condition or have the desired effect, including improving or preventing the disease, disorder or condition or one or more potential mechanisms of the disease, disorder or condition. In certain embodiments, when the solid form of Compound A is administered to treat epileptic seizures, the therapeutically effective amount refers to the range of the amount of the solid form of Compound A that, when applied to a human, treats, improves or prevents human epileptic seizures, or exhibits a detectable therapeutic or preventive effect in a human suffering from epilepsy. For example, the effect is detected by a reduction in epileptic seizures (frequency) or the severity (quality) of epileptic 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 epileptic seizures, the presence of any concomitant medications, and other variables known to those skilled in the art. The therapeutically effective amount for a given situation can be determined by routine experimentation and is within the capabilities of the clinician.

[0153] "Treatment" herein refers to therapeutic applications associated with the administration of a solid form of Compound A that 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 a solid form of Compound A is administered to treat epileptic seizures, treatment refers to therapeutic applications that slow or stop the progression of epileptic seizure conditions, preventive applications that prevent the development of epileptic seizure conditions, and / or reversal of epileptic seizure conditions. Reversal of epileptic seizures differs from therapeutic applications that slow or stop epileptic seizures in that the reversal method not only completely stops the progression of epileptic seizures, but also moves cellular behavior to a normal state to some extent, which can be observed in the absence of epileptic seizures.

[0154] "Under fed conditions" refers to the situation where food is consumed during this period of time. 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. Food can be a mixture of solid, liquid, or solid and liquid food, which has sufficient volume and fat content so that it cannot be quickly dissolved and absorbed in the stomach. In some cases, food is a meal, such as breakfast, lunch, dinner or other, baby food (e.g., formula or breast milk). The therapeutically effective amount of the solid form of Compound A can be orally administered to the subject, for example, between about 30 minutes before 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. Patent Application No. 2019-0343823, the disclosure of which is incorporated herein by reference in its entirety.

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

[0156] As used herein, the terms under vacuum or vacuum refer to pressures less than atmospheric pressure.

[0157] The amount of solvent used in a chemical process (e.g., a reaction or crystallization) may be referred to herein as the number of "volumes" or "vol" or "V". For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10 V) of solvent. In this case, the expression will be understood to refer to the number of milliliters of solvent per gram of material 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 material suspended, which in this example is 50 milliliters of solvent. In another case, the term "V / V" may be used to refer to 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 Implementation Method

[0159] In some embodiments, a solid crystalline form of Compound A (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or 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. 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 state crystalline form of Compound A disclosed herein or a specific solid state crystalline form of Compound A disclosed herein.

[0160] In other embodiments, a solid crystalline form of Compound A (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10 or Form 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). 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 state crystalline form of Compound A disclosed herein or a specific solid state crystalline form of Compound A disclosed herein.

[0161] In other embodiments, a solid crystalline form of Compound A (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10 or Form 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 state crystalline form of Compound A disclosed herein, or a specific solid state crystalline form of Compound A disclosed herein.

[0162] In other embodiments, a solid state crystalline form of Compound A (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 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 state crystalline form of Compound A disclosed herein, or a specific solid state crystalline form of Compound A disclosed herein.

[0163] In other embodiments, a solid crystalline form of Compound A (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 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 0.6% to 0.8% (w / w), from 0.7% to 0.9% (w / w), from 0.9% to 0.10% (w / w), from 0.1% to 5% (w / w), 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 0.6% to 0.8% (w / w), from 0.7% to 0.9% (w / w), from 0.8% to 0.9% (w / w), from 0.9% to 0.8% (w / w), from 0. 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 state crystalline form of Compound A disclosed herein, or a specific solid state crystalline form of Compound A disclosed herein.

[0164] 5.2.1 Compound A Crystalline Form 1 Mixture

[0165] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 1 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. 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0166] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 1 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0167] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 1 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0168] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 1 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). / 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 Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0169] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 1 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). 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 Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0170] In other embodiments, a solid state 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 Form 1.

[0171] 5.2.2 Compound A Crystalline Form 2 Mixture

[0172] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 2 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. 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0173] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0174] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

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

[0176] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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). 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 Form 1, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0177] In other embodiments, a solid state 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 Form 2.

[0178] 5.2.3 Compound A Form 3 Mixture

[0179] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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. 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0180] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0181] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

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

[0183] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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). 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 Form 1, Compound A Form 2, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0184] In other embodiments, a solid state 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 Form 3.

[0185] 5.2.4 Compound A Crystalline Form 4 Mixture

[0186] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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. 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0187] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0188] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0189] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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). / 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 Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0190] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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). 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 Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0191] In other embodiments, a solid state 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 Form 4.

[0192] 5.2.5 Compound A Crystalline Form 5 Mixture

[0193] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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. 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0194] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0195] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0196] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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). / 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 Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0197] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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). 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 Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0198] In other embodiments, a solid state 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 Form 5.

[0199] 5.2.6 Compound A Crystalline Form 6 Mixture

[0200] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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. 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0201] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0202] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0203] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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). / w), from 8% to 10% (w / w), or from 9% to 10% (w / w) of all other solid-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0204] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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). 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 Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 7, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0205] In other embodiments, a solid state 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 Form 6.

[0206] 5.2.7 Compound A Crystalline Form 7 Mixture

[0207] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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. 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0208] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0209] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0210] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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). / 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 Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof

[0211] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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). 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 Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 8, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0212] In other embodiments, a solid state 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 Form 7.

[0213] 5.2.8 Compound A Crystalline Form 8 Mixture

[0214] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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. 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0215] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0216] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0217] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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). / 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 Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0218] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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). 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 Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 9, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0219] In other embodiments, a solid state 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 Form 8.

[0220] 5.2.9 Compound A Crystalline Form 9 Mixture

[0221] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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. 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0222] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0223] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0224] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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). / 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 Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0225] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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). 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 Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 10, or Compound A Form 11, or a combination thereof.

[0226] In other embodiments, a solid state 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 Form 9.

[0227] 5.2.10 Compound A Crystalline Form 10 Mixture

[0228] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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. (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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, or Compound A Form 11, or a combination thereof.

[0229] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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). 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, or Compound A Form 11, or a combination thereof.

[0230] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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% 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, or Compound A Form 11, or a combination thereof.

[0231] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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). 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 Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, or Compound A Form 11, or a combination thereof.

[0232] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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 Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, or Compound A Form 11, or a combination thereof.

[0233] In other embodiments, a solid state 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 Form 10.

[0234] 5.2.11 Compound A Crystalline Form 11 Mixture

[0235] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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. (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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, or Compound A Form 10, or a combination thereof.

[0236] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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). 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, or Compound A Form 10, or a combination thereof.

[0237] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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% 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-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, or Compound A Form 10, or a combination thereof.

[0238] In certain embodiments, a solid crystalline form of Compound A contains Compound A Form 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). w / w), from 8% to 10% (w / w), or from 9% to 10% (w / w) of all other solid-state crystalline forms of Compound A disclosed herein, or a specific solid-state crystalline form of Compound A disclosed herein, such as Compound A Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, or Compound A Form 10, or a combination thereof.

[0239] In some embodiments, a solid crystalline form of Compound A contains Compound A Form 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 Form 1, Compound A Form 2, Compound A Form 3, Compound A Form 4, Compound A Form 5, Compound A Form 6, Compound A Form 7, Compound A Form 8, Compound A Form 9, or Compound A Form 10, or a combination thereof.

[0240] In other embodiments, a solid crystalline form of Compound A contains 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 Form 11.

[0241] 5.2.12 Methods of treatment using solid form of Compound A

[0242] In some embodiments, the present disclosure relates to a method for treating a disease, disorder or condition associated with Kv7 potassium channel dysfunction in a person in need thereof, comprising orally administering a therapeutically effective amount of a solid form, e.g., a crystalline form of Compound A to a person. In some cases, the disease, disorder or condition associated with Kv7 potassium channel dysfunction is epilepsy, e.g., focal onset epilepsy. In certain embodiments, the solid state 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.

[0243] 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 a person. In some cases, the disease, disorder or condition associated with Kv7 potassium channel dysfunction is epilepsy, such as focal onset epilepsy. In certain embodiments, the solid state 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.

[0244] In embodiments involving 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 some cases, the method or use can be used to selectively enhance the opening of one or more Kv7 potassium channels selected from 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 for treating epilepsy in a person in need thereof, comprising orally administering to a person a solid form of a certain amount of Compound A, wherein the amount of the solid form of Compound A is sufficient to treat epilepsy in a human. 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.

[0246] In one embodiment, the invention provides a compound for treating epilepsy 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 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.

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

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

[0249] In some embodiments, the present disclosure relates to a method for treating a disease, disorder or condition associated with Kv7 potassium channel dysfunction in a person in need thereof, comprising orally administering to a person a therapeutically effective amount of a solid form of Compound A between 30 minutes before and 2 hours after a meal. In some 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 Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10 or Form 11.

[0250] In some embodiments, the present disclosure relates to compounds for treating diseases, disorders or conditions 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 a person under fed conditions. In some 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 Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10 or Form 11.

[0251] In certain embodiments, the present disclosure relates to compounds for treating diseases, disorders or conditions associated with Kv7 potassium channel dysfunction in people 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 a person between 30 minutes before and 2 hours after a meal. In some cases, the disease, disorder or condition associated with Kv7 potassium channel dysfunction is an epileptic seizure, such as focal onset epilepsy. 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.

[0252] In one embodiment, the present invention provides a method for treating an epileptic seizure disorder in a person in need thereof, comprising orally administering to a person a solid form of a certain amount of Compound A under fed 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 epileptic seizures, the frequency of epileptic 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 a solid form of Compound A, and the compound is orally administered to a person under fed 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, comprising orally administering a solid form of a certain amount of Compound A to a person between 30 minutes before and 2 hours after eating, 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 a solid form of Compound A, and the compound is orally administered to a person between 30 minutes before and 2 hours after a meal. 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, comprising orally administering to a person an amount of a solid form of Compound A under fed conditions, wherein the solid form of Compound A is 2 to 200 mg. In certain embodiments, 2 to 200 mg of Compound A Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10 or Form 11 is orally administered.

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

[0258] In one embodiment, the present disclosure provides a method for increasing Cmax, AUCinf, Tmax, or t1 / 2λz of a solid form of Compound A (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 11) in a human receiving oral administration of a solid form of Compound A, comprising orally administering to a human an amount of a solid form of Compound A under fed conditions. In certain embodiments, the method increases Cmax, AUCinf, Tmax, or t1 / 2λz compared to orally administering the same amount of a solid form of Compound A to a human under fasting conditions.

[0259] In one embodiment, the present disclosure provides a method for increasing Cmax, AUCinf, Tmax, or t1 / 2λz of a solid form of Compound A (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 11) in a human receiving oral administration of a solid form of Compound A, comprising orally administering to a human an amount of a solid form of Compound A between 30 minutes before and 2 hours after a meal. In certain embodiments, the method increases Cmax, AUCinf, Tmax, or t1 / 2λz compared to orally administering the same amount of a solid form of Compound A to a human under fasting conditions.

[0260] In one embodiment, the present invention provides a method of orally administering a solid form of Compound A (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 11) to a person in need thereof, comprising orally administering the solid form of Compound A to a person under fed conditions. In certain embodiments, the method increases one or more of Cmax, AUCinf, Tmax, or t1 / 2λz of the solid form of Compound A compared to oral administration of the same amount of the solid form of Compound A to a person under fasting conditions.

[0261] In one embodiment, the present invention provides a method of orally administering a solid form of Compound A (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 11) to a person in need thereof, comprising orally administering the solid form of Compound A to a person between 30 minutes before and 2 hours after a meal. In certain embodiments, the method increases one or more of Cmax, AUCinf, Tmax, or t1 / 2λz of the solid form of Compound A compared to oral administration of the same amount of the solid form of Compound A to a person under fasting conditions.

[0262] In one embodiment, the solid state form of Compound A (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 11) is provided in a dosage unit suitable for oral administration. Compound A is present in a dosage unit form of 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 includes oral administration of 0.1-1.0 mg / kg of a solid form of compound A. In some aspects, the method includes oral administration of 0.2-0.5 mg / kg of a solid form of compound A.

[0263] In some embodiments, the methods and uses described herein, such as methods and uses for treating a seizure disorder in a human in need thereof according to the methods and uses described herein, are achieved by orally administering 2 to 200 mg of a solid state form of Compound A (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 11). For example, the method may include orally administering 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 4 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 includes 5 to 50 mg of Compound A. In some aspects, oral administration includes 10, 20 or 25 mg of Compound A. In some aspects, oral administration includes 20 mg of Compound A. In some aspects, the 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 a seizure disorder in a human in need thereof according to the methods and uses described herein, are achieved by orally administering 5 to 1000 mg per day of a solid state form of Compound A (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 11), such as 5 to 500 mg or 5 to 250 mg per day of a solid state form of Compound A. For example, the method may include orally administering about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg per day. , about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, or about 1000 mg. In some aspects, oral administration includes oral administration of 10-200 mg of compound A in solid form per day, for example, 10, 15, 20, 25, 30, 35, or 40 mg to 75, 100, 125, 150, 175, or 200 mg of compound A in solid form per day, including 20 to 150 mg per day.In some aspects, oral administration comprises 50, 75, 100 or 125 mg per day of a solid form of Compound A, such as 100 mg per day.

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

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

[0267] In one embodiment of the present disclosure, the solid form of Compound A is administered, for example, for the treatment of epileptic seizure disorders, which will benefit from the opening of Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channels. Compound A is a Kv7.2 / Kv7.3 (KCNQ2 / 3) opener. In certain embodiments, the present disclosure provides a method for opening a kV7.2 / Kv7.3 (KCNQ2 / 3) potassium channel in a person in need thereof, comprising administering a certain amount of a solid form of Compound A (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 11). In a similar embodiment, the present disclosure provides a solid form of Compound A for opening a 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 a solid form of Compound A in the form of a pharmaceutically acceptable oral composition comprising a solid form of Compound A (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 11) and one or more pharmaceutically acceptable carriers or excipients. The amount of the solid form of Compound A contained in these compositions corresponds to the amount of one or more 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 preparations (e.g., tablets, capsules, lozenges, dragees, granules, powders, multi-granules, and films) and liquid preparations (e.g., aqueous solutions, elixirs, tinctures, suspensions, and dispersions). In one embodiment, the pharmaceutically acceptable oral compositions of the solid form of Compound A include pediatric suspensions or granules. The amounts of all of the above-mentioned solid forms of Compound A can be included in such preparations, 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, the therapeutically effective amount of the solid state form of Compound A is from about 0.05 mg / kg to about 2.0 mg / kg.

[0271] In certain embodiments herein, comparisons relate to humans orally administered a solid form of Compound A under fasting conditions, and similar comparisons can be made involving humans who have not eaten within a time period between about 4 hours prior to oral administration of the solid form of Compound A to about 4 hours after oral administration of the solid form of Compound A, for example, between about 4, 3, 2, 1.5, 1, or 0.5 hours prior to oral administration of the solid form of Compound A 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 onset (focal) epilepsy, photosensitive epilepsy, self-induced syncope, intractable epilepsy, Angelman syndrome, benign lateral fissure epilepsy, CDKL5 disorder, childhood and adolescent absence epilepsy, severe myoclonic epilepsy of infancy (Dravet syndrome), frontal lobe epilepsy, GLUT1 deficiency syndrome, hypothalamic hamartoma, infantile spasms / West syndrome, juvenile myoclonic epilepsy, pediatric seizure-induced aphasia syndrome (Landau-Kleffner syndrome), epilepsy ... In some embodiments, the epileptic seizure disorder is a focal onset epilepsy, also known as partial onset (focal) epilepsy.

[0273] Additional embodiments of the present 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 Composition and Administration

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

[0276] Administration of a solid form of Compound A (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 11) in pure form or in an appropriate pharmaceutical composition can be performed by any acceptable mode of administration of agents for similar purposes. In one embodiment, the pharmaceutical composition disclosed herein can be prepared by combining the solid form of Compound A disclosed herein with an appropriate pharmaceutically acceptable excipient, and can be formulated into a solid, semi-solid, liquid, or gaseous form of preparation, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administration of 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, intrasternal injection, or infusion techniques. Formulate the pharmaceutical composition disclosed herein to allow the active ingredients contained therein to be bioavailable when the composition is administered to the patient. The pharmaceutical composition will be administered to a mammal, preferably a human, in the form of one or more dosage units, wherein, for example, a tablet can be a single dosage unit, and a container of the disclosed compound in aerosol form can accommodate multiple dosage units. For those skilled in the art, the actual method of preparing this dosage form is known, or it is obvious. For example, see Pharmaceutical Science and Practice, the latest version (Philadelphia School of Pharmacy and Science, 2000). In any case, the composition to be administered contains a solid form of Compound A disclosed herein in a therapeutically effective amount, such as a crystalline form, for treating a disease or condition of interest according to the present disclosure.

[0277] In one embodiment, the pharmaceutical compositions disclosed herein further contain a pharmaceutically acceptable excipient, which includes any agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which can be administered without excessive 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 Pharmaceutical Science (Mack Pub. Co., NJ, current edition).

[0278] In one embodiment, the pharmaceutical compositions disclosed herein can be in the form of solid or liquid. In one aspect, the excipient is granular, so 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 administration by inhalation.

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

[0280] In one embodiment, as a solid composition for oral administration, the pharmaceutical composition disclosed herein can be formulated into the form of powder, granules, compressed tablets, pills, capsules, chewing gum, wafers, etc. 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, etc.; lubricants such as magnesium stearate or hydrogenated vegetable oils; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavoring agents such as mint, methyl salicylate or orange flavoring; and coloring agents.

[0281] In one embodiment, when the pharmaceutical composition disclosed herein is in the form of a capsule, for example, it may contain a liquid excipient such as polyethylene glycol or oil in addition to materials of the above type.

[0282] In one embodiment, the pharmaceutical compositions disclosed herein can be in the form of a liquid, such as an elixir, syrup, solution, emulsion or suspension. The liquid can be used for oral administration or delivered by injection, as two examples. When used for oral administration, the preferred composition contains one or more sweeteners, preservatives, dyes / colorants and flavor enhancers in addition to the solid form of Compound A. In the composition intended to be administered by injection, one or more of a surfactant, a preservative, a wetting agent, a dispersant, a suspending agent, a buffer, a stabilizer and an isotonic agent can be included.

[0283] In one embodiment, the liquid pharmaceutical composition disclosed herein, whether in solution, suspension or other form, may include one or more of the following adjuvants: sterile diluents, such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils that can be used as solvents or suspension media, such as synthetic monoglycerides or diglycerides, polyethylene glycol, glycerol, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for adjusting tonicity such as sodium chloride or glucose. Parenteral preparations can be packaged in ampoules, disposable syringes or multidose vials made of glass or plastic. Physiological saline is a preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

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

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

[0286] In one embodiment, the pharmaceutical compositions disclosed herein can be used for rectal administration in the form of, for example, suppositories that will melt and release the drug in the rectum. The rectal administration composition can contain an oleaginous base as a suitable non-irritating excipient. Such bases 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 active solution in oil or a solution of the active ingredient in oil (e.g., 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, an 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 so as to provide rapid, sustained or delayed release of the active ingredient, i.e., a solid form of Compound A, after being administered to a patient using 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. Pat. Nos. 3,845,770 and 4,326,525 and PJ 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 via intranasal drug delivery systems for local, systemic, and nose-to-brain treatments. Controlled Particle Dispersion (CPD) TM Technology, conventional nasal spray bottles, inhalers or nebulizers are known to those skilled in the art to provide effective local and systemic delivery of medications by targeting the olfactory area and paranasal sinuses.

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

[0291] In one embodiment, the most suitable route of administration of the solid form or pharmaceutical composition of Compound A 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, inhaled, subcutaneous, rectal, etc.), dosage form, suitable pharmaceutical excipients, and other materials related to delivering the solid form of Compound A to a subject in need thereof.

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

[0293] In one embodiment, the solid or liquid form pharmaceutical compositions disclosed herein may include an agent that binds to the solid form of Compound A to facilitate delivery of the solid form. Suitable agents capable of this capability include monoclonal or polyclonal antibodies, proteins or liposomes.

[0294] In one embodiment, the pharmaceutical composition disclosed herein can be composed of dosage units that can be used as an aerosol. The term aerosol is used to represent a variety of systems from systems of colloidal properties to systems including pressurized packaging. Delivery can be carried out by liquefied or compressed gas or by a suitable pump system for distributing active ingredients. Aerosols in the solid form of compound A can be delivered in a single-phase, two-phase or three-phase system to deliver the active ingredient. The delivery of an aerosol includes necessary containers, activators, valves, sub-containers, etc., which can form a kit together. Those skilled in the art can determine a preferred aerosol without excessive experiments.

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

[0296] In one embodiment, a solid form of Compound A or a pharmaceutical composition containing the solid form of Compound A, such as a crystalline form (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, Form 9, Form 10, or Form 11) is administered in a therapeutically effective amount. Typically, the daily therapeutically effective dose of the solid form of Compound A (for a 70 kg mammal) is 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), 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 about 1 mg / kg (i.e., 70 mg) to about 25 mg / kg (i.e., 1.75 g).

[0297] The range of effective doses provided herein is not intended to limit and represents a preferred dosage range. However, by well-known methods, effective doses can be determined by a person skilled in the art. (See, for example, Berkow et al., ed., The Merck Manual, 19th edition, Merck & Co., Rahway, New Jersey, 2011; Brunton et al., ed., The Pharmacological Basis of Therapeutics of Goodman and Cilman, 12th edition, McGraw-Hill Group 2011; Avery's Pharmacotherapy: Principles and Practice of Clinical Pharmacology and Therapeutics, 3rd edition, ADIS Press, LTD., Williams and Wilkins, Baltimore, Maryland (1987), Ebadi, Pharmacology, Little Brown Book Co., Ltd., Boston, (1985); Osolci et al., ed., Remington Pharmaceutical Sciences, Current Edition, Mack Publishing Co., Easton, Pennsylvania; Katzung, Basic and Clinical Pharmacology, Appleton and Lange, Norwalk, Connecticut (1992)).

[0298] If desired, the total dose required for each treatment can be administered in multiple doses or a single dose in one day. Generally, treatment is started with a smaller 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 under the circumstances. The diagnostic drug compound or composition can be administered alone or in combination with other diagnostics and / or drugs for the pathology or for other symptoms of the pathology. An 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 described herein or a pharmaceutical composition comprising the solid form of Compound A can be any animal, such as a mammal. Among mammals, preferred recipients are mammals of the order Primates (including humans, apes and monkeys), Arteriodactyls (including horses, goats, cows, sheep, pigs), Rodents (including mice, rats and hamsters), Rock-dwelling animals (including rabbits) and Carnivores (including cats and dogs). Among birds, preferred recipients are turkeys, chickens and other members of the same order. The most preferred recipient is human.

[0300] 5.4 Preparation of Solid Crystalline Form of Compound A

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

[0302] In one embodiment, the present invention provides a method for preparing Compound A Form 2 from Compound A Form 1, for example, by forming a slurry of Compound A Form 1 in an alcohol-water 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 Compound A Form 2.

[0303] In one embodiment, the present invention provides a method for preparing Compound A Form 3 from Compound A Form 2 and Compound A Form 4, for example, by forming a slurry of Compound A Form 2 and Compound A Form 4 in a halocarbon 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 Compound A Form 3.

[0304] In one embodiment, the present invention provides a method for preparing Compound A Form 4 from Compound A Form 1, for example, by dissolving Compound A Form 1 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 Compound A Form 4.

[0305] In one embodiment, the present invention provides a method for preparing Compound A Form 5 from Compound A Form 1, for example, by forming a slurry of Compound A Form 1 in a non-cyclic ketone solvent (e.g., methyl isobutyl ketone), optionally adding additional Compound A Form 1, 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., filtering) to prepare Compound A Form 5.

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

[0307] In one embodiment, the present invention provides a method for preparing Compound A Form 7 from Compound A Form 1, for example, by forming a slurry of Compound A Form 1 in an ether solvent (e.g., tetrahydrofuran) or a ketone-water solution (e.g., acetone-water), optionally adding additional Compound A Form 1, 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., filtering) to prepare Compound A Form 7.

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

[0309] In one embodiment, the present invention provides a method for preparing Compound A Form 9 from Compound A Form 4, for example, by placing Compound A Form 4 in a VT-XRPD sample holder, optionally flattening Compound A Form 4 before adding it to the VT-XRPD sample holder, and treating it with one or more scanning and heating cycles (for example, between 250C and 1400C) to prepare Compound A Form 9.

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

[0311] In one embodiment, the present invention provides a method for preparing Compound A Form 10 from Compound A Form 1, for example, by slurrying Compound A Form 1 in an ether solvent (e.g., tetrahydrofuran), diluting the slurry with more ether solvent (e.g., 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 Compound A Form 10.

[0312] In one embodiment, the present invention provides a method for preparing Compound A Form 11 from Compound A Form 1, for example, by forming a slurry of Compound A Form 1 in an alcohol solvent (e.g., ethanol), shaking and cooling the slurry (e.g., at 5°C), heating the slurry until dissolved 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 Compound A Form 11.

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

[0314] 6. Embodiment

[0315] 6.1 Analytical methods

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

[0317] 6.1.1A. X-ray powder diffraction (XRPD)

[0318] XRPD analysis was performed on a PANalytical X'pert pro using a PIXcel detector (128 channels) scanning the samples between 3 and 35° 2θ. The material was lightly 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 a diffractometer and analyzed using Cu K radiation (α1 α1:α2 ratio = 0.5), operated in transmission mode (step size 0.0130° 2θ, step time 18.87 s), using 40 kV / 40 mA generator settings. Data were visualized and images were generated using HighScore Plus 4.7 desktop application (pAnalytical, 2017).

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

[0320] The presence of crystallinity (birefringence) was determined using an Olympus BX50 microscope equipped with crossed polarized 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. All images were collected with crossed and uncrossed polarizers to highlight birefringent regions.

[0321] 6.1.3C. Hot Stage Optical Microscope

[0322] Thermal events were visually monitored using a calibrated Linkam THM600 heat stage with an attached controller unit 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 material was placed on a microscope coverslip and heated at a rate of 10°C / min, with images 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 every 10°C increment.

[0325] 2. Heat at 1°C / min between 100°C and 160°C, taking an image at every 1°C increment.

[0326] 3. Final heating was performed between 160°C and 200°C at 10°C / min, with images taken every 10°C.

[0327] 6.1.4D. Thermogravimetric / differential thermal analysis (TG / DTA)

[0328] About 5 mg of material was weighed into an open aluminum pan and loaded into a simultaneous thermogravimetric / differential thermal analyzer (TG / DTA) and kept at room temperature. The sample was then 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 at a flow rate of 300 cm3 / min.

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

[0330] About 5 mg of material was weighed into an aluminum DSC pan and sealed non-hermetic with a perforated aluminum lid. The sample pan was then placed in a Seiko DSC6200 (equipped with a cooler) and cooled and maintained 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 a purge gas with a flow rate of 50cm3 / min. Similar data were then obtained in a cooling cycle, in which 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 the sample was kept at 20°C for 3 minutes, a second heating cycle was performed. The second heating cycle was performed at a scan rate of 10°C / min until a final temperature of 220°C was reached, and then kept at 220°C for 5 minutes.

[0331] 6.1.6F. Karl Fischer coulometric titration (KF)

[0332] About 10-15 mg of solid material is accurately weighed into a vial. The solid is then manually added to the titration cell of the Mettler Toledo C30 Compact Titrator titrator. The vial is weighed again after the solid is added, and the weight of the added solid is entered into the instrument. Once the sample is completely dissolved in the cell, the titration begins. The water content is automatically calculated by the instrument as a percentage, and the data is printed.

[0333] 6.1.7G. Fourier transform infrared spectroscopy (FTIR)

[0334] Infrared spectroscopy was performed on a Bruker ALPHA P spectrometer. Sufficient material was placed in the center of the spectrometer sample holder and the spectra were acquired using the following parameters:

[0335] Resolution: 4cm-1

[0336] Background scan times: 16 times

[0337] Sample scanning times: 16 times

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

[0339] Result spectrum: Transmittance

[0340] Software: OPUS Version 6

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

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

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

[0344] Approximately 10-20 mg of sample was placed in a mesh vapor sorption balance pan and loaded into an Igasorp moisture sorption instrument from Hiden Analytical. The sample was subjected to a gradual change from 40-90% relative humidity (RH) in 10% increments, holding the sample at each step until a stable weight was obtained (98% of the steps were completed, minimum step length 30 minutes, maximum step length 60 minutes) at 25°C. After the sorption cycle was completed, the sample was dried to 0% RH using the same procedure and finally returned to the starting point of 40% RH using the same parameters described above. Two complete cycles were performed. The weight change during the sorption / desorption cycle was plotted 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 multifunctional diffractometer equipped with a temperature chamber. The samples were loaded onto the VT stage and operated in Bragg-Brentano geometry (step size 0.008° 2θ) using a 40 kV / 40 mA generator setting, using Cu K radiation (α1 The α1:α2 ratio = 0.5 was scanned between 4 and 35.99° 2θ. The measurements were performed at different temperature profiles. Any hold at a specific temperature is described in the temperature profile of a single sample.

[0347] 6.1.11K. High performance liquid chromatography-ultraviolet detection (HPLC-UV)

[0348] Compound A was subjected to HPLC-UV detection using the following parameters:

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

[0350] Column temperature: 50°C

[0351] Autosampler temperature: Ambient temperature

[0352] UV wavelength: 265nm.

[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 using the following parameters:

[0364] Chromatographic column: Agilent J&W DB-624 30m x 0.32mm1.8μm df or equivalent Oven temperature: 35℃ (hold 0.5min) to 45℃@16.5℃ / min to 70℃@5.0℃ / min to 220℃@30.0℃ / min

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

[0366] Carrier gas: Hydrogen

[0367] Injection method: Split

[0368] Injection temperature: 225℃

[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] Tail blowing flow rate: 30.0 ml / min

[0374] Makeup gas: Air

[0375] Headspace parameters:

[0376] Oven temperature: 100℃.

[0377] Quantitative loop temperature: 110℃.

[0378] Transfer line temperature: 150°C.

[0379] Vial heating equilibrium time: 10.0 minutes

[0380] Pressurization time: 0.2 minutes

[0381] Quantitative loop quantification time: 0.2 minutes

[0382] Quantitative loop equilibration time: 0.05 minutes

[0383] Loop volume: 1 ml

[0384] Injection time: 1.0 min

[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 sample into a 20 ml scintillation vial. Add 10 ml of dispersant and mix. Sonicate the sample for 30 seconds, then stir well with a pipette and add to the dispersant to achieve an obscuration of 8-20%. Measure according to the following parameters:

[0389]

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

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

[0392] In one embodiment, Compound A Form 1 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 the acetonitrile solution of 4-bromo-2,6-dimethylaniline (Compound 1) 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 keeping the temperature below 10°C. The mixture is then diluted with acetonitrile, and the solution is heated to 20-25°C and stirred for 2 hours. Once completed, the mixture is diluted with process water and the resulting slurry is stirred for 30 minutes. The solid is then collected by vacuum filtration, washed twice with process water and dried under nitrogen for at least 2 hours. The filter cake is then further dried 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-dimethylbutanamide (Compound 3) was reacted with 6-fluoro-1,2,3,4-tetrahydroisoquinoline (Compound 4) and potassium tert-butoxide in 2-methyltetrahydrofuran (2-MeTHF). The mixture was sparged with nitrogen (N2) for 1 hour, then bis(dibenzylideneacetone)palladium (Pd(dba)2) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (DavePhos) were added, and the mixture was heated to 77°C under N2 atmosphere and stirred for 12 hours. The mixture was then cooled to 40°C and diluted with 2-MeTHF. The solution was further diluted with water for injection (WFI), and the mixture was cooled to 25°C and stirred for 30 minutes. The resulting two-phase mixture was allowed to settle for at least 1 hour before separation. The aqueous and organic phases were then removed and the reactor was rinsed with additional 2-MeTHF.

[0396] Step 2B: Add the combined organics to a separate reactor and add The mixture was then filtered and the solids were rinsed with 2-MeTHF at 50°C and then cooled to about 20-30°C. The same procedure was then repeated once more. deal with.

[0397] Then a solution of 10% n-heptane in 2-MeTHF was added to the The 2-MeTHF solution of the isolated compound A crystalline form 1 was treated. The mixture was heated to 50 ° C and kept for 15 minutes until all solids were dissolved. The solution was then cooled, further diluted with 2-MeTHF and concentrated in vacuo. The concentrated solution was then diluted once more with 2-MeTHF and heated to 50 ° C for 15 minutes. The solution was then cooled, diluted with additional 2-MeTHF and concentrated in vacuo until the solid was obvious. The solution was then heated to reflux to dissolve all solids present, then diluted with n-heptane, cooled and concentrated in vacuo. The concentrated solution was then diluted with n-heptane, concentrated in vacuo, the solids were filtered, rinsed with the filtrate, and rinsed twice with a 2-MeTHF solution of 10% n-heptane. The filtered solid was dried under vacuum, then transferred to a vacuum oven and further dried.

[0398] The solid was then recrystallized a second time in 2-methyltetrahydrofuran (2-MeTHF) which had been sparged with N2 for a minimum of 15 minutes. After the addition of the solid, the mixture was sparged with N2 for another 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 stream of N2. The filter cake was rinsed with heptane and then dried under a blanket of N2 before being transferred to a vacuum oven and heated to 50°C under an atmosphere of N2 to give Compound A Form 1 (see Figure 1 ).

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

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

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

[0402] In one embodiment, Compound A Form 3 is prepared by weighing about 15 mg of Compound A Form 2 and Compound A Form 4 into a 2 ml glass vial. An aliquot of dichloromethane is added to the vial at ambient temperature until a mobile slurry is formed. The resulting slurry is stirred at ambient temperature for about 24 hours. The observed solid is isolated and characterized by XRPD and found to be Compound A Form 3, whose XRPD pattern is as shown below: Fig.16 shown.

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

[0404] In one embodiment, Compound A Form 4 is prepared by dissolving about 250 mg of Compound A Form 1 in about 3.5 ml of ethanol at 40°C. After 1 hour at 40°C, the solution is cooled to 20°C at a rate of 0.2°C / min. The solution is maintained 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 is added as an anti-solvent and then maintained at 5°C for 2 hours before centrifugation. The mother liquor is then analyzed for concentration by HPLC. The wet solid is dried under vacuum at 40°C for about 2 hours and then analyzed. The resulting dried material is found to have Fig.17 The XRPD pattern of Compound A Form 4 is shown in FIG.

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

[0406] In one embodiment, approximately 40 mg of Compound A Form 1 was added to 500 μl of methyl isobutyl ketone to prepare a slurry. If dissolution occurred during the preparation, an additional amount of Compound A Form 1 was added. The resulting slurry was subjected to a continuous 4-hour heat-cool cycle between 40° C. and ambient temperature for 72 hours. The resulting mixture was filtered and the isolated wet solid was analyzed by XRPD and found to be Fig.25 The XRPD pattern of Compound A Form 5 is shown in FIG.

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

[0408] In one embodiment, approximately 40 mg of Compound A Form 1 was added to 300 μl of tetrahydrofuran / water (99:1) to prepare a slurry. If dissolution occurred during the preparation, an additional amount of Compound A Form 1 was added. The resulting slurry was subjected to a continuous 4-hour heat-cool cycle between 40° C. and ambient temperature for 72 hours. The resulting mixture was filtered and the isolated wet solid was analyzed by XRPD and found to be Fig.26 The XRPD pattern of Compound A Form 6 is shown in FIG.

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

[0410] In one embodiment, about 40 mg of Compound A Form 1 was added to 300 μl of tetrahydrofuran to prepare a slurry. If dissolution occurred during the preparation, an additional amount of Compound A Form 1 was added. The resulting slurry was subjected to a continuous 4-hour heat-cool cycle between 40° C. and ambient temperature for 72 hours. The resulting mixture was filtered and the isolated wet solid was analyzed by XRPD and found to be Fig. 27 The XRPD pattern of Compound A Form 7 is shown in FIG.

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

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

[0413] In one embodiment, approximately 40 mg of Compound A Form 1 was added to 300 μl of cyclohexanone to prepare a slurry. If dissolution occurred during the preparation, an additional amount of Compound A Form 1 was added. The resulting slurry was subjected to a continuous 4-hour heat-cool cycle between 40°C and ambient temperature for 72 hours. The resulting mixture was filtered and the supernatant was transferred to a container, uncovered, and evaporated at ambient temperature. When sufficient material was obtained, the material was analyzed by XRPD and found to be Fig.28 The XRPD pattern of Compound A Form 8 is shown in FIG.

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

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

[0416] Table 13 VT-XRPD procedure for preparing Form 9

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

[0418] The obtained dried material was found to have Fig.29 The XRPD pattern of Compound A Form 9 is shown in FIG.

[0419] In another embodiment, the compound was prepared by adding methanol (3 ml) to about 500 mg of Compound A Form 1, followed by addition of aqueous sulfuric acid (1 M, 1425 μL, 1.05 equiv). After about 2 minutes, water (5 ml) was added as an anti-solvent to cause precipitation to prepare a thick slurry. The solid was filtered and analyzed by XRPD and found to be Fig.29 The XRPD pattern of Compound A Form 9 is shown in FIG.

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

[0421] In one embodiment, about 500 mg of Compound A Form 1 was weighed into a 20 mL scintillation vial. A 500 μL aliquot of tetrahydrofuran was added until a mobile slurry was formed. 2 mL of tetrahydrofuran was added. The sample was temperature cycled between ambient temperature and 40°C for about 4 hours in 1 hour cycles. The observed solid was isolated by centrifugation and characterized by XRPD and found to be Fig.37 Compound A crystalline form 10 is shown in FIG.

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

[0423] In one embodiment, Compound A Form 11 is prepared by dissolving about 500 mg of Compound A Form 1 in about 3 ml of ethanol. The resulting slurry is shaken at ambient temperature for about 2 hours and then stored at 5°C for about 90 hours. A sample analyzed by XRPD indicated that the material was Compound A Form 4. The slurry was then heated to 40°C for about 2 hours until the solids were 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 about 72 hours. The slurry was then separated by centrifugation and the wet solids were dried at ambient temperature for 18 hours and then vacuum dried at 40°C for about 6 hours. The resulting dried material was analyzed by XRPD and was Fig.39 The XRPD pattern of Compound A Form 11 is shown in FIG.

[0424] 6.3 Characterization of the Solid State Form of Compound A

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

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

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

[0428] In another embodiment, TG analysis of Compound A Form 1 shows that Compound A Form 1 has a 0.6% weight loss up to 200°C and then decomposes. A complex thermal event is noted in the DTA starting at 184°C, with 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 the initially hot Compound A Form 1 shows a complex thermal event starting at 184°C, with 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 5The second heating showed two endothermic events; a smaller peak starting at 185°C and peaking at 187°C, and a second larger peak starting at 191°C and peaking at 193°C (see Figure 6 ).

[0430] After dissolving in DMSO-d6, 1 H NMR analysis of Compound A Form 1. In one embodiment, 1 H NMR spectrum (see Figure 7 ) shows that the structure is consistent with Compound A Form 1.

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

[0432] In one embodiment, the present invention is directed to a solid state form of Compound A, referred to herein as Compound A Form 2. In some embodiments, the present disclosure provides a solid state form of Compound A having a substantially similar Figure 8 The XRPD pattern of Compound A Form 2 is shown in FIG.

[0433] In some embodiments, Compound A Form 2 is identified by detecting one or more peaks selected from the XRPD patterns of the compositions listed in Table 1.

[0434] Table 1 XRPD peaks of Compound A Form 2

[0435]

[0436]

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

[0438] In some embodiments, Compound A Form 2 in the 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 most intense peaks in Table 1 (based on relative percentage 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, Compound A Form 2 in the 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 most intense peaks in Table 1 (based on relative percentage 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, Compound A Form 2 in the 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 most intense peaks in Table 1 (based on relative percentage 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, Compound A Form 2 in the composition is identified by detecting at least five peaks in the XRPD pattern of the composition, the at least five peaks corresponding to the five strongest peaks in Table 1 (based on relative percentage 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, Compound A Form 2 in the 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, Compound A Form 2 in the composition is identified by detecting at least four peaks in the XRPD pattern of the composition, the at least four peaks corresponding to the four strongest peaks in Table 1 (based on relative percentage 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, Compound A Form 2 in the 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, Compound A Form 2 in the composition is identified by detecting at least three peaks in the XRPD pattern of the composition, the at least three peaks corresponding to the three strongest peaks in Table 1 (based on relative percentage 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, Compound A Form 2 in the 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, Compound A Form 2 in the 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 most intense peaks in Table 1 (based on relative percentage 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, the Compound A Form 2 in the composition is identified by detecting at least one peak in the XRPD pattern of the composition, the at least one peak corresponding to the strongest peak in Table 1 (based on relative percentage 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, the Compound A Form 2 in the 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.

[0446] In some embodiments, Compound A Form 2 in the composition is identified by detecting two or more peaks, e.g., at least the two strongest peaks, in the XRPD pattern of the composition 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.

[0447] In some embodiments, the Compound A Form 2 in the composition is identified by detecting three or more peaks in the XRPD pattern of the composition 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.

[0448] In some embodiments, Compound A Form 2 in the composition is identified by detecting four or more peaks in the XRPD pattern of the composition 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.

[0449] In some embodiments, the Compound A Crystalline Form 2 in the composition is identified by detecting five or more peaks in the XRPD pattern of the composition 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.

[0450] In some embodiments, Compound A Form 2 in the composition is identified by detecting six or more peaks in the XRPD pattern of the composition 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.

[0451] In some embodiments, Compound A Form 2 in the composition is identified by detecting seven or more peaks in the XRPD pattern of the composition 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.

[0452] In some embodiments, Compound A Form 2 in the composition is identified by detecting eight or more peaks in the XRPD pattern of the composition 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.

[0453] In some embodiments, the Compound A Form 2 in the composition is identified by detecting a peak in the XRPD pattern of the composition 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.

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

[0455] In another embodiment, TG analysis of Compound A Form 2 shows that when the temperature reaches 200°, the weight loss is 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 Fig.10 ).

[0456] Thus, in some embodiments, the present disclosure provides a method having a substantially similar Fig.10 In some embodiments, the compound A crystal form 2 in the composition is identified by detecting a DTA thermogram with an onset temperature of about 183°C, an endothermic peak of 186°C, an exothermic peak of 188°C, and a second endothermic peak of 192°C.

[0457] In another embodiment, DSC analysis of Compound A Form 2 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, a small endothermic peak at 186°C, an exothermic peak at 187°C, and a large endothermic peak at 192°C (see Fig.11 During the cooling cycle, a single exothermic event was noted starting at 151°C and peaking at 149°C (see Fig.12 During the second heating cycle, a small exothermic event starting at 172°C and peaking at 180°C was noted. This was followed by a large endothermic event starting at 191°C and peaking at 192°C (see Fig.13 ).

[0458] Therefore, in some embodiments, the present invention provides Fig.11 , Fig.12 , Fig.13 Compound A Crystalline Form 2 with substantially similar DSC thermograms. In some embodiments, Compound A Crystalline Form 2 in the composition is identified by detecting a DSC thermogram having a shallow endothermic event starting at 122°C, a characteristic peak at 132°C, then starting at 183°C, 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 first heating cycle; in the cooling cycle, a single characteristic exothermic event starting at 151°C, peaking at 149°C; and, in the second heating cycle, a characteristic small exothermic event starting at 172°C with a characteristic peak at 180°C, then a characteristic peak of 192°C starting at 191°C.

[0459] After dissolution in DMSO-d6, 1 H NMR analysis of Compound A Form 2. In another embodiment, the obtained 1 HNMR spectrum (see Fig.14 ) shows consistency with the structure of Compound A Form 2.

[0460] In another embodiment, Compound A Form 2 was analyzed by FTIR as a reference (see Fig.15 ).

[0461] In another embodiment, HPLC purity analysis of Compound A Form 2 shows a purity value of 99.3%.

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

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

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

[0465] Table 2 VT-XRPD heating program for Compound A Form 2

[0466]

[0467]

[0468] In another embodiment, the solid state form of Compound A Form 2 at each temperature was analyzed by XRPD, and the results are shown in Table 3 below.

[0469] Table 3 VT-XRPD results of Compound A Form 2

[0470] temperature Polymorph 25℃ Crystal form 2 50℃ Crystal form 2 100℃ Crystal form 2 150℃ Similar to Form 2 160℃ Partial crystallization 165℃ Partial crystallization 170℃ Amorphous 180℃ Amorphous 180℃(hold for 10 minutes) Amorphous 25℃ Amorphous

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

[0472] 6.3.3C. Characterization of Compound A Form 3

[0473] In one embodiment, the present invention relates to a solid state form of Compound A, referred to herein as Compound A Form 3. In some embodiments, the present disclosure provides a solid state form having a substantially similar Fig.16 The XRPD pattern of Compound A Form 3 is shown in FIG.

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

[0475] In one embodiment, the present invention relates to a solid state form of Compound A, referred to herein as Compound A Form 4. In some embodiments, the present disclosure provides a solid state form having a substantially similar Fig.17 The XRPD pattern of Compound A Form 4 is shown in FIG.

[0476] In some embodiments, Compound A Form 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 peaks of Compound A Form 4

[0478]

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

[0480] In some embodiments, Compound A Form 4 in the 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 most intense peaks in Table 4 (based on relative percentage 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.

[0481] In some embodiments, Compound A Form 4 in the 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 most intense peaks in Table 4 (based on relative percentage 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, Compound A Form 4 in the 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 most intense peaks in Table 4 (based on relative percentage 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, the Compound A Form 4 in the composition is identified by detecting at least five peaks in the XRPD pattern of the composition, the at least five peaks corresponding to the five strongest peaks in Table 4 (based on relative percentage 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, the Compound A Form 4 in the composition is detected by at least the following five peaks in the XRPD pattern of the composition: about 13.62, about 14.16, about 14.61, about 18.44, about 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, Compound A Form 4 in the composition is identified by detecting at least four peaks in the XRPD pattern of the composition, the at least four peaks corresponding to the four strongest peaks in Table 4 (based on relative percentage 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, Compound A Form 4 in the composition is detected by at least the following four peaks in the XRPD pattern of the composition: about 13.62, about 14.61, about 18.44, about 19.92, about 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, Compound A Form 4 in the composition is identified by detecting at least three peaks in the XRPD pattern of the composition, the at least three peaks corresponding to the three most intense peaks in Table 4 (based on relative percentage 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, Compound A Form 4 in the composition is detected by at least the following three peaks in the XRPD pattern of the composition: about 14.61, about 18.44, about 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, Compound A Form 4 in the 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 most intense peaks in Table 4 (based on relative percentage 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, Compound A Form 4 in the 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 percentage 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, the Compound A Form 4 in the composition is identified by detecting one or more peaks in the XRPD pattern of the composition 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.

[0489] In some embodiments, Compound A Form 4 in the composition is identified by detecting two or more peaks, e.g., at least the two strongest peaks, in the XRPD pattern of the composition 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.

[0490] In some embodiments, Compound A Form 4 in the composition is identified by detecting three or more peaks in the XRPD pattern of the composition 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.

[0491] In some embodiments, Compound A Form 4 in the composition is identified by detecting four or more peaks in the XRPD pattern of the composition 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.

[0492] In some embodiments, Compound A Form 4 in the composition is identified by detecting five or more peaks in the XRPD pattern of the composition 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.

[0493] In some embodiments, Compound A Form 4 in the composition is identified by detecting six or more peaks in the XRPD pattern of the composition 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.

[0494] In some embodiments, Compound A Form 4 in the composition is identified by detecting a peak in the XRPD pattern of the composition 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.

[0495] In another embodiment, PLM analysis of Compound A Form 4 shows that the solid is a lath-like morphology with agglomeration and birefringence.

[0496] In another embodiment, TG analysis of Compound A Form 4 shows that when it reaches 200°C, it loses 1.0% of its weight and decomposes. In another embodiment, in DTA, a shallow endothermic event is observed at the beginning of 127°C, with a peak at 135°C, followed by a large endothermic event at the beginning of 191°C, with a peak at 193°C (see Fig.19 ).

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

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

[0499] Thus, in some embodiments, the present disclosure provides a method having a substantially similar Fig. 20 , Fig.21 and Fig. 22 Compound A Form 4 of the DSC thermogram. In some embodiments, Compound A Form 4 is identified in the composition by detecting a DSC thermogram having a shallow endothermic event starting at 122°C in the first heating cycle, a characteristic peak at 130°C, followed by a large endothermic event starting at 190°C with a characteristic peak 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 associated with a larger characteristic endothermic peak at 193°C.

[0500] After dissolution in DMSO-d6, 1 H NMR analysis of Compound A Form 4. In another embodiment, the obtained 1 HNMR spectrum (see Fig.23) shows consistency with the structure of Compound A Form 4.

[0501] In another embodiment, Compound A Form 4 was analyzed by FTIR as a reference (see Fig.24 ).

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

[0503] In another embodiment, GVS analysis of Compound A Form 4 found it to be slightly hygroscopic, with an absorption of 0.4% at 90% RH. The material tested was analyzed by XRPD after GVS and found to be Compound A Form 4.

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

[0505] In another embodiment, VT-XRPD analysis of Compound A Form 4 was performed using the heating program in Table 5 below.

[0506] Table 5 VT-XRPD heating program for Compound A Form 4

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

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

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

[0510] temperature Polymorph 25℃ Crystal form 4 50℃ Crystal form 4 60℃ Crystal form 4 70℃ Crystal form 4 80℃ Crystal form 4 95℃ Crystal form 4 100℃ Crystal form 4 110℃(hold for 5 minutes) Form 4 + additional peaks 120℃(keep for 5 minutes) Form 4 + additional peaks 130℃(keep for 5 minutes) Crystal form 4 + crystal form 9 140℃(hold for 5 minutes) Crystal form 9 25℃ Crystal form 9

[0511] In another embodiment, hot stage microscopy of Compound A Form 4 was performed using the methods described herein. It was noted that Compound A Form 4 began to melt at about 138°C, and the material was completely melted after heating to 160°C.

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

[0513] In one embodiment, the present invention is directed to a solid state form of Compound A, referred to herein as Compound A Form 5. In some embodiments, the present disclosure provides a solid state form of Compound A having a substantially similar Fig.25 The XRPD pattern of Compound A Form 5 is shown in FIG.

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

[0515] In one embodiment, the present invention relates to a solid state form of Compound A, referred to herein as Compound A Form 6. In some embodiments, the present disclosure provides a Fig.26 The XRPD pattern of Compound A Form 6 is shown in FIG.

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

[0517] In one embodiment, the present invention is directed to a solid state form of Compound A, referred to herein as Compound A Form 7. In some embodiments, the present disclosure provides a solid state form of Compound A having a substantially similar Fig. 27 The XRPD pattern of Compound A Form 7 is shown in FIG.

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

[0519] In one embodiment, the present invention relates to a solid state form of Compound A, referred to herein as Compound A Form 8. In some embodiments, the present disclosure provides a Fig.28 The XRPD pattern of Compound A Form 8 is shown in FIG.

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

[0521] In one embodiment, the present invention relates to a solid state form of Compound A, referred to herein as Compound A Form 9. In some embodiments, the present disclosure provides a solid state form having a substantially similar Fig.29 The XRPD pattern of Compound A Form 9 is shown in FIG.

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

[0523] Table 7 XRPD peaks of Compound A Form 9

[0524]

[0525]

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

[0527] In some embodiments, Compound A Form 9 in the 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 most intense peaks in Table 7 (based on relative percentage 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, Compound A Form 9 in the 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 most intense peaks in Table 7 (based on relative percentage 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, Compound A Form 9 in the 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 most intense peaks in Table 7 (based on relative percentage 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, the Compound A Form 9 in the composition is identified by detecting at least five peaks in the XRPD pattern of the composition, the at least five peaks corresponding to the five strongest peaks in Table 7 (based on relative percentage 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, the Compound A Form 9 in the composition is identified by detecting at least the following five peaks in the XRPD pattern of the composition: about 3.05, about 15.33, about 18.08, about 20.98, about 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, the Compound A crystalline Form 9 in the composition is identified by detecting at least four peaks in the XRPD pattern of the composition, the at least four peaks corresponding to the four strongest peaks in Table 7 (based on relative percentage 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, the Compound A crystalline Form 9 in the composition is identified by detecting at least the following four peaks in the XRPD pattern of the composition: about 3.05, about 15.33, about 18.08, about 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, the Compound A Form 9 in the composition is identified by detecting at least three peaks in the XRPD pattern of the composition, the at least three peaks corresponding to the three most intense peaks in Table 7 (based on relative percentage 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, the Compound A Form 9 in the composition is identified by detecting at least the following three peaks in the XRPD pattern of the composition: about 3.05, about 18.08, about 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, Compound A Form 9 in the 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 most intense peaks in Table 7 (based on relative percentage 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, Compound A Form 9 in the 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 percentage 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, the Compound A crystalline Form 9 in the composition is identified by detecting one or more peaks in the XRPD pattern of the composition 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.

[0536] In some embodiments, Compound A Form 9 in the composition is identified by detecting two or more peaks, e.g., at least the two strongest peaks, in the XRPD pattern of the composition 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.

[0537] In some embodiments, the Compound A crystalline Form 9 in the composition is identified by detecting three or more peaks in the XRPD pattern of the composition 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.

[0538] In some embodiments, the Compound A crystalline Form 9 in the composition is identified by detecting four or more peaks in the XRPD pattern of the composition 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.

[0539] In some embodiments, the Compound A crystalline Form 9 in the composition is identified by detecting five or more peaks in the XRPD pattern of the composition 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.

[0540] In some embodiments, the Compound A crystalline Form 9 in the composition is identified by detecting six or more peaks in the XRPD pattern of the composition 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.

[0541] In some embodiments, the Compound A crystalline Form 9 in the composition is identified by detecting a peak in the XRPD pattern of the composition 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.

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

[0543] In another embodiment, TG analysis of Compound A Form 9 showed that when it reached 200°C, it lost 0.4% of its weight and decomposed. In DTA, an endothermic event starting at 191°C was noted, reaching a peak at 192°C (see Fig.31 ).

[0544] Thus, in some embodiments, the present disclosure provides a method having a substantially similar Fig.31 In some embodiments, the crystalline Compound A Form 4 in the composition is identified by detecting a DTA thermogram having an endothermic event starting at 191° C. and a peak at 192° C.

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

[0546] Thus, in some embodiments, the present disclosure provides a method having a substantially similar Fig.32 , Fig.33 and Fig.34 DSC thermogram of Compound A Form 9. In some embodiments, Compound A Form 9 is identified in the composition by detecting a 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 has a characteristic peak at 155°C; and, in the second heating cycle, a complex endothermic event starts at 181°C, a characteristic peak appears at 187°C, a second starting temperature is 190°C, and a characteristic peak appears at 192°C.

[0547] After dissolution in DMSO-d6, 1 H NMR analysis of Compound A Form 9. In another embodiment, the obtained 1 HNMR spectrum (see Fig.35 ) shows consistency with the structure of Compound A Form 9.

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

[0549] In another embodiment, HPLC purity analysis of Compound A Form 9 shows a purity value of 97.6%.

[0550] In another embodiment, GVS analysis of Compound A Form 9 found it to be slightly hygroscopic, with an absorption of 0.8% at 90% RH. The material tested was analyzed by XRPD after GVS and found to be Compound A Form 9.

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

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

[0553] Table 8 VT-XRPD heating program for Compound A Form 9

[0554] temperature program 25℃ Scan and heat to the next temperature at 5°C / min 50℃ Scan and 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 heat to the next temperature at 1°C / min 180℃ Scan, then cool to 25°C 25℃ Scan at this temperature

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

[0556] Table 9 VT-XRPD results of Compound A Form 9

[0557] temperature Polymorph 25℃ Crystal form 9 50℃ Crystal form 9 100℃ Crystal form 9 150℃ Crystal form 9 155℃ Note the form conversion - similar to Form 9 160℃ Similar to Form 9 165℃ Partial crystallization 170℃ Partial crystallization 180℃ Amorphous 25℃ Amorphous

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

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

[0560] In one embodiment, the present invention relates to a solid state form of Compound A, referred to herein as Compound A Form 10. In some embodiments, the present disclosure provides a Fig.37 The XRPD pattern of Compound A Form 10 is shown.

[0561] In another embodiment, TG analysis of Compound A Form 10 showed a weight loss of about 6.3% from the start of heating (see Fig.38 ). The observed mass loss was equivalent to 0.34 equivalents of tetrahydrofuran.

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

[0563] Thermal analysis showed that Compound A Form 10 was a tetrahydrofuran solvate, which desolvated and converted into Compound A Form 1 and Compound A Form 2 upon heating.

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

[0565] In one embodiment, the present invention relates to a solid state form of Compound A, referred to herein as Compound A Form 11. In some embodiments, the present disclosure provides a Fig.39 The XRPD pattern of Compound A Form 11 is shown.

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

[0567] Table 10 XRPD peaks of Compound A Form 11

[0568]

[0569]

[0570]

[0571] In some embodiments, Compound A Crystalline Form 11 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, Compound A Crystalline Form 11 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, Compound A Crystalline Form 11 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, Compound A Crystalline Form 11 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, Compound A Crystalline Form 11 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, Compound A Crystalline Form 11 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, Compound A Crystalline Form 11 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, Compound A Form 11 in the composition is identified by detecting nine or more peaks selected from the composition XRPD pattern in Table 10. In some embodiments, Compound A Form 11 is identified by detecting all of the peaks in Table 10 in the composition XRPD pattern.

[0572] In some embodiments, Compound A Form 11 in the 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 most intense peaks in Table 10 (based on relative percentage 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.

[0573] In some embodiments, Compound A Form 11 in the 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 most intense peaks in Table 10 (based on relative percentage 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.

[0574] In some embodiments, Compound A Form 11 in the 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 most intense peaks in Table 10 (based on relative percentage 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.

[0575] In some embodiments, the Compound A Form 11 in the composition is identified by detecting at least five peaks in the XRPD pattern of the composition, the at least five peaks corresponding to the five strongest peaks in Table 10 (based on relative percentage 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, the Compound A Form 11 in the composition is identified by detecting at least the following five peaks in the XRPD pattern of the composition: about 3.05, about 15.33, about 18.08, about 20.98, about 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, the Compound A crystalline Form 11 in the composition is identified by detecting at least four peaks in the XRPD pattern of the composition, the at least four peaks corresponding to the four strongest peaks in Table 10 (based on relative percentage 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, the Compound A crystalline Form 11 in the composition is identified by detecting at least the following four peaks in the XRPD pattern of the composition: about 3.05, about 15.33, about 18.08, about 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, the Compound A crystalline Form 11 in the composition is identified by detecting at least three peaks in the XRPD pattern of the composition, the at least three peaks corresponding to the three strongest peaks in Table 10 (based on relative percentage 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, the Compound A crystalline Form 11 in the composition is identified by detecting at least the following three peaks in the XRPD pattern of the composition: about 3.05, about 18.08, about 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, Compound A Form 11 in the 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 most intense peaks in Table 10 (based on relative percentage 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, the Compound A crystalline Form 11 in the 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 10 (based on relative percentage 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, the Compound A crystalline Form 11 in the composition is identified by detecting one or more peaks in the XRPD pattern of the composition 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.

[0581] In some embodiments, Compound A Form 11 in the composition is identified by detecting two or more peaks, e.g., at least the two strongest 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.

[0582] In some embodiments, the Compound A crystalline Form 11 in the composition is identified by detecting three or more peaks in the XRPD pattern of the composition 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.

[0583] In some embodiments, the Compound A crystalline Form 11 in the composition is identified by detecting four or more peaks in the XRPD pattern of the composition 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.

[0584] In some embodiments, Compound A Form 11 in the composition is identified by detecting five or more peaks in the XRPD pattern of the composition 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.

[0585] In some embodiments, the Compound A crystalline Form 11 in the composition is identified by detecting six or more peaks in the XRPD pattern of the composition 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.

[0586] In some embodiments, the Compound A crystalline Form 11 in the composition is identified by detecting seven or more peaks in the XRPD pattern of the composition 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.

[0587] In some embodiments, Compound A Form 11 in the composition is identified by detecting eight or more peaks in the XRPD pattern of the composition 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.

[0588] In some embodiments, the Compound A Form 11 in the 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 Compound A Form 11 showed that the solid was small particles with agglomerated and birefringent rod-like morphology (see Fig.40 ).

[0590] In another embodiment, TG analysis of Compound A Form 11 shows that when it reaches 200°C, it loses 1.1% of its weight and decomposes. In DTA, an endothermic event starts at 191°C and peaks at 192°C (see Fig.41 ).

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

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

[0593] Thus, in some embodiments, the present disclosure provides a method having a substantially similar Fig.42 , Fig.43 and Fig.44 The DSC thermogram of Compound A Form 11. In some embodiments, Compound A Form 11 is identified in the composition by detecting a DSC thermogram having a shallow exothermic event starting at 41°C and a characteristic peak at 50°C in the first heating cycle, followed by a shallow endothermic event starting at 116°C and 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, and 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 with a characteristic peak at 187°C, and a second endothermic event starting at 191°C with a characteristic peak at 192°C.

[0594] After dissolution in DMSO-d6, Compound A Form 11 was analyzed by 1H NMR. In another embodiment, the 1H NMR spectrum obtained (see Fig.45 ) shows consistency with the structure of Compound A Form 11.

[0595] In another embodiment, Compound A Form 11 was analyzed by FTIR as a reference (see Fig.46 ).

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

[0597] In another embodiment, GVS analysis of Compound A Form 11 found it to be slightly hygroscopic, with an absorption of 0.5% at 90% RH. The material tested was analyzed by XRPD after GVS and found to be a mixture of Compound A Form 4 and Compound A Form 11.

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

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

[0600] Table 11 VT-XRPD heating program for Compound A Form 11

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

[0602] In another embodiment, the solid state form of Compound A Form 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 Form 11

[0604] temperature Polymorph 25℃ Crystal form 11 50℃ Crystal form 11 100℃ Crystal form 11 150℃ Form changes 155℃ Partial crystallization 160℃ Partial crystallization 165℃ Partial crystallization 170℃ Partial crystallization 180℃ Partial crystallization 190℃ Amorphous 25℃ Amorphous

[0605] In another embodiment, hot stage microscopy of Compound A Form 11 was performed using the methods described herein. It was noted that Compound A Form 11 began to melt at about 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 solid crystalline forms of Compound A are advantageously administered in acceptable dosage forms (e.g., capsules, tablets, sterile injections, topical preparations, etc.). In order to successfully manufacture these dosage forms (particularly on a commercial scale), while meeting all relevant quality requirements, it is generally required that the active pharmaceutical ingredient in question exhibits acceptable rheological (flow) properties. Active pharmaceutical ingredients with poor rheological properties are generally incompatible with manufacturing equipment such as automatic high-speed capsule fillers, which rely on gravity and / or vibration-fed hoppers, and active pharmaceutical ingredients with poor rheological properties cannot flow evenly through these process lines, resulting in significant and unacceptable variability in the resulting dosage form. Therefore, it is recognized in the art that when the form of an active pharmaceutical ingredient is selected for development, the rheological properties of the form are important considerations.

[0608] The Carr Index is a widely used measure of the flowability of a powder (see, e.g., Wang, YB and Williams, RO III, "Powders" in Remington's Essentials of Pharmaceutical Sciences, Felton, L., ed., London: Pharmaceutical Publishing House, 2013 at pp. 422-423). The bulk density of the powder is measured, as well as the corresponding tap density (after compressing the powder in a standard tap density tester, such as Gardco JV1000, Paul N. Gardner Company, Pompano Beach, FL, according to the standard method as described in Chapter 616 of the United States Pharmacopeia). Once the bulk density and tap density of the powder are determined experimentally, the Carr Index can be calculated according to the following formula:

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

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

[0611] Carr Index Liquidity >38 Very bad 35-38 Very bad 23-35 Difference 18-23 appropriate 12-18 good 5-12 Excellent

[0612] Compound A and Compound A Form 4 were each micronized to a specification of d50≤3 μm and d90≤5 μm, and their respective Carr indexes were measured. The Carr index of Compound A was 36 (i.e., poor fluidity), while the Carr index of Compound A Form 4 was 8 (i.e., excellent fluidity).

[0613] 6.5 Stability study

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

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

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

[0617] Table 13 XRPD results of slurry samples

[0618]

[0619] 6.6 Crystallization studies

[0620] The following crystallization studies were performed on Compound A Form 4:

[0621] 6.6.1A. Crystallization studies 1

[0622] In one embodiment, crystallization studies of Compound A Form 4 were completed at a concentration of 60 mg / ml using degassed ethanol and water. After complete dissolution at 45°C, the system was cooled to 30°C and a clear solution was observed before seeding. Seeding lasted for about 1 hour before adding the anti-solvent at 30°C. For samples of dried solids and the final product, the following results were obtained:

[0623] 1. The sample was obtained by centrifugation after adding the anti-solvent and the solid was analyzed by XRPD. The material was confirmed to be Form 4.

[0624] 2. The final recovered solid, wet and dry solid, was analyzed by XRPD and both samples were confirmed to be Form 4.

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

[0626] 4. The recovered mother liquor had a concentration of 0.7 mg / ml, which corresponds to a theoretical recovery of 98%. The purity of the mother liquor 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 about 220°C followed by decomposition. In the DTA, an endothermic event was noted starting at 118°C with a peak at 127°C, followed by a second larger endothermic event starting at 191°C with a peak at 192°C, possibly associated with melting of the material.

[0629] 7. Three solid samples were subjected to KF analysis using the direct addition method. The average moisture content was found to be 0.53 wt%.

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

[0631] 9. Perform particle size analysis on the material and obtain the following PSD values:

[0632] D10=8.0μm

[0633] D50=22.1μm

[0634] D90=52.1μm

[0635] 6.6.2B. Crystallization studies 2

[0636] In another embodiment, crystallization studies of Compound A Form 4 were completed at a concentration of 60 mg / ml using degassed 1-propanol and water. After complete dissolution at 45°C, the system was cooled to 30°C and a clear solution was observed before seeding. Seeding lasted for about 1 hour before adding the anti-solvent at 30°C. For samples of dried solids and the final product, the following results were obtained:

[0637] 1. The sample was obtained by centrifugation after adding the anti-solvent and the solid was analyzed by XRPD. The material was confirmed to be Form 4.

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

[0639] 3. The final recovered material had an isolated yield of 80% and a solid purity of 99.6% 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 theoretical recovery of 93%. The purity of the mother liquor 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. Due to the large particle size, images were taken at 20x and 10x magnification.

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

[0643] 7. Two solid samples were subjected to KF analysis using the direct addition method. The average moisture content was found to be 0.08 wt%.

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

[0645] 9. Perform particle size analysis on the material and obtain the following PSD values:

[0646] D10=18.1μm

[0647] D50=65.1μm

[0648] D90=152.9μm

[0649] 6.6.3C. Crystallization studies 3

[0650] In another embodiment, crystallization studies of Compound A Form 4 were performed using a 1-propanol: water system with the addition of an antisolvent at a lower temperature. 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. Seeding continued for about 1 hour before the container temperature was increased to 35°C, which resulted in some dissolution of the seed crystals. The system was then cooled to 30°C, held for an additional 30 minutes, and then cooled to 5°C. The antisolvent was then added at 5°C. For samples of dried solids and the final product, the following results were obtained:

[0651] 1. A sample was taken after holding at 5°C 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 an isolated yield of 80% and a solid purity of 99.6% by HPLC.

[0654] 4. The concentration of the recovered mother liquor was 3.7 mg / ml, corresponding to a theoretical recovery of 90%. The purity of the mother liquor was determined to be 92%. The concentration of the washing liquid 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 followed by decomposition. In the DTA, an endothermic event was noted starting at 113°C with a peak at 119°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.

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

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

[0659] 9. Perform particle size analysis on the material and obtain the following PSD values:

[0660] D10=16.4μm

[0661] D50=54.4μm

[0662] D90=146.7μm

[0663] 6.6.4D. Crystallization studies 4

[0664] In another embodiment, the crystallization study of Compound A Form 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 lasted for about 1 hour, then cooled to 5°C and sampled at 5°C. The anti-solvent was then added, and the following results for the final product of the sample and the dried solid were obtained:

[0665] 1. The sample was taken after holding at 5°C 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 37.7 mg / mL. The PLM image of the slurry sample showed that the material was flaky in morphology with obvious agglomeration and birefringence.

[0666] 2. The recovered solid, both wet and dry solids were analyzed by XRPD and both samples were confirmed to be Form 4.

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

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

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

[0670] 6. PLM analysis of the dried solids showed the material to be plate-like crystals with some rod-like particles present. The particle size visually appeared smaller than the previous crystallization and the recovered solids also showed agglomeration and birefringence.

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

[0672] In the DTA, an endothermic event was noted starting at 120 °C with a peak at 127 °C, followed by a second larger endothermic event starting at 191 °C with a peak at 192 °C, which may be related to the melting of the material.

[0673] 8. Two solid samples were subjected to KF analysis using the direct addition method. The average moisture content was determined to be 0.06 wt%.

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

[0675] 10. Perform particle size analysis on the material and obtain the following PSD values:

[0676] D10=6.0μm

[0677] D50=18.0μm

[0678] D90=45.8μm

[0679] 6.6.5E. Crystallization studies 5

[0680] In another embodiment, crystallization studies of Compound A Form 4 were conducted 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. Seeding lasted for about 1 hour and then cooled to 25°C, at which time 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 samples of dried solids and the final product:

[0681] 1. The sample obtained after adding the anti-solvent was centrifuged 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 4.2 mg / mL.

[0682] 2. The recovered wet solid and the dried solid were analyzed by XRPD and both samples were confirmed to be Form 4. Due to the apparent preferred orientation of the dried sample, the material was lightly ground and reanalyzed by XRPD and this material was also identified as Form 4.

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

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

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

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

[0687] 7. TG analysis of the dried solid showed no weight loss prior to decomposition. In the DTA, an endothermic event was noted starting at 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, likely associated with the melting of the material.

[0688] 8. Two solid samples were subjected to KF analysis 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. Perform particle size analysis on the material and obtain the following PSD values:

[0691] D10=13.1μm

[0692] D50=54.5μm

[0693] D90=162.1μm

[0694] 6.6.6F. Crystallization studies

[0695] In another embodiment, crystallization studies of Compound A Form 4 were conducted 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. Seeding lasted for about 1 hour, then cooled to 5°C, and then the antisolvent was added at a slower rate. The following results were obtained for samples of dried solids and the final product:

[0696] 1. The recovered solids, both wet and dried, were analyzed by XRPD and both samples were confirmed to be Form 4. Due to the apparent preferred orientation of the dried sample, the material was lightly ground and reanalyzed by XRPD and this material was also identified as Form 4.

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

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

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

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

[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 the DTA, an endothermic event was noted starting at 117°C with a peak at 123°C, followed by a second larger endothermic event starting at 191°C with a peak at 192°C, which may be associated with the melting of the material.

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

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

[0704] 9. Perform particle size analysis on the material and obtain the following PSD values:

[0705] D10=14.6μm

[0706] D50=45.0μm

[0707] D90=119.1μm

[0708] 6.6.7G. Crystallization studies 7

[0709] In another embodiment, a higher concentration of 65 mg / ml of degassed solvent was used in a 1-propanol: water system for crystallization studies of Compound A Form 4. After complete dissolution at 45°C, the system was cooled to 32°C and a clear solution was observed before seeding. The seed was kept for about 1 hour, then cooled to 5°C, and then the anti-solvent was added. The following results were obtained for samples of dried solids and the final product:

[0710] 1. The recovered solids, both wet and dried, were analyzed by XRPD and both samples were confirmed to be Form 4. Due to the apparent preferred orientation of the dried sample, the material was lightly ground and reanalyzed by XRPD and this material was also identified as Form 4.

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

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

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

[0714] 5. PLM analysis of the dried solid showed that the material was plate-like 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 the DTA, an endothermic event was noted starting at 111°C with a peak at 120°C, followed by a second larger endothermic event starting at 191°C with a peak at 192°C, which may be associated with the melting of the material.

[0716] 7. Two solid samples were subjected to KF analysis 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. Perform particle size analysis on the material and obtain the following PSD values:

[0719] D10=13.4μm

[0720] D50=48.6μm

[0721] D90=132.5μm

[0722] 6.6.8H. Crystallization studies 8

[0723] In another embodiment, a higher concentration of 65 mg / ml of degassed solvent was used in 1-propanol: water for crystallization studies of Compound A Form 4. After complete dissolution at 45°C, the system was cooled to 32°C and a clear solution was observed before seeding. Seeding continued for about 1 hour, then cooled to 30°C, and then the anti-solvent was added.

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

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

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

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

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

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

[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 the DTA, an endothermic event was noted starting at 113°C with a peak at 115°C, followed by a second larger endothermic event starting at 191°C with a peak at 192°C, which may be associated with the melting of the material.

[0731] 7. Two solid samples were subjected to KF analysis 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. Perform particle size analysis on the material and obtain the following PSD values:

[0734] D10=11.9μm

[0735] D50=48.3μm

[0736] D90=119.9μm

[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 on October 10, 2019.

[0739] Although the above disclosure has been described in detail for ease of understanding, it is apparent that certain changes and modifications may be made within the scope of the appended claims. Therefore, the described embodiments are considered to be 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 claims.

Claims

1. A solid state form of Compound A, wherein Compound A is N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide, and wherein the solid state form is selected from: (i) Compound A Form 1, wherein the solid state form is characterized by an XRPD pattern substantially similar to that of Figure 1; (ii) Compound A Form 2, wherein the solid state form is characterized by one or more peaks in the XRPD pattern selected from the group consisting of: 5.51, 11.01, 11.53, 14.91, 16.54, 19.17, 20.83, 21.48, 22.68, and 24.18 degrees 2θ ±0.3 degrees 2θ, ±0.2 degrees 2θ, ±0.1 degrees 2θ, or ±0.05 degrees 2θ; (iii) Compound A Form 3, wherein the solid state form is characterized by an XRPD pattern substantially similar to that of Figure 16; or (iv) Compound A Form 4, wherein the solid state form is characterized by one or more peaks in the XRPD pattern selected from the group consisting of: 13.62, 14.16, 14.61, 18.44, 19.92, 22.97, and 23.73 degrees 2θ ±0.3 degrees 2θ, ±0.2 degrees 2θ, ±0.1 degrees 2θ, or ±0.05 degrees 2θ; (v) Compound A Form 5, wherein the solid state form is characterized by an XRPD pattern substantially similar to that of Figure 25; (vi) Compound A Form 6, wherein the solid state form is characterized by an XRPD pattern substantially similar to that of Figure 26; (vii) Compound A Form 7, wherein the solid state form is characterized by an XRPD pattern substantially similar to Figure 27; (viii) Compound A Form 8, wherein the solid state form is characterized by an XRPD pattern substantially similar to Figure 28; (ix) Compound A Form 9, wherein the solid state form is characterized by one or more peaks in the XRPD pattern selected from the group consisting of: 3.05, 6.107, 10.69, 15.33, 18.08, 20.98, 23.49, and 25.25 degrees 2θ ±0.3 degrees 2θ, ±0.2 degrees 2θ, ±0.1 degrees 2θ, or ±0.05 degrees 2θ; (x) Compound A Form 10, wherein the solid state form is characterized by an XRPD pattern substantially similar to that of Figure 37; (xi) Compound A Form 11, wherein the solid state form is characterized by one or more peaks in the XRPD pattern selected from the group consisting of: 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44, and 23.61 degrees 2θ ±0.3 degrees 2θ, ±0.2 degrees 2θ, ±0.1 degrees 2θ, or ±0.05 degrees 2θ; and (xiii) Amorphous Compound A.

2. The solid form of claim 1, wherein The solid state form is Compound A Form 1, characterized by an XRPD pattern substantially similar to that of FIG. 1 .

3. The solid form of claim 1 or 2, wherein The solid state form is Compound A Form 1, further characterized by: A TG / DTA thermogram substantially similar to that of Figure 3; and / or A DSC thermogram substantially similar to Figure 4, Figure 5 or Figure 6.

4. The solid form of claim 1, wherein The solid state form is Compound A Form 2, characterized by an XRPD pattern having three or more peaks selected from the group consisting of 5.51, 11.01, 11.53, 14.91, 16.54, 19.17, 20.83, 21.48, 22.68 and 24.18 degrees 2θ ±0.3 degrees 2θ, ±0.2 degrees 2θ, ±0.1 degrees 2θ, or ±0.05 degrees 2θ.

5. The solid form of claim 1, wherein The solid state form is Compound A Form 2, characterized by an XRPD pattern having four or more peaks selected from the group consisting of 5.51, 11.01, 11.53, 14.91, 16.54, 19.17, 20.83, 21.48, 22.68 and 24.18 degrees 2θ ±0.3 degrees 2θ, ±0.2 degrees 2θ, ±0.1 degrees 2θ, or ±0.05 degrees 2θ.

6. The solid form of claim 1, wherein: The solid state form is Compound A Form 2, characterized by an XRPD pattern having five or more peaks selected from the group consisting of 5.51, 11.01, 11.53, 14.91, 16.54, 19.17, 20.83, 21.48, 22.68 and 24.18 degrees 2θ ±0.3 degrees 2θ, ±0.2 degrees 2θ, ±0.1 degrees 2θ, or ±0.05 degrees 2θ.

7. The solid form of claim 1, wherein: The solid state form is Compound A Form 2, characterized by an XRPD pattern having six or more peaks selected from the group consisting of 5.51, 11.01, 11.53, 14.91, 16.54, 19.17, 20.83, 21.48, 22.68 and 24.18 degrees 2θ ±0.3 degrees 2θ, ±0.2 degrees 2θ, ±0.1 degrees 2θ, or ±0.05 degrees 2θ.

8. The solid form of claim 1, wherein The solid state form is Compound A Form 2, characterized by an XRPD pattern having seven or more peaks selected from the group consisting of 5.51, 11.01, 11.53, 14.91, 16.54, 19.17, 20.83, 21.48, 22.68 and 24.18 degrees 2θ ±0.3 degrees 2θ, ±0.2 degrees 2θ, ±0.1 degrees 2θ, or ±0.05 degrees 2θ.

9. The solid state form of claim 1, wherein the solid state form is Compound A Form 2, characterized by an XRPD pattern having eight or more peaks selected from the group consisting of 5.51, 11.01, 11.53, 14.91, 16.54, 19.17, 20.83, 21.48, 22.68, and 24.18 degrees 2θ ±0.3 degrees 2θ, ±0.2 degrees 2θ, ±0.1 degrees 2θ, or ±0.05 degrees 2θ.

10. The solid state form of claim 1, wherein the solid state form is Compound A Form 2, characterized by the following peaks in the XRPD pattern: 5.51, 11.01, 11.53, 14.91, 16.54, 19.17, 20.83, 21.48, 22.68 and 24.18 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

11. The solid form of claim 1, wherein: The solid state form is Compound A Form 2, which is characterized by an XRPD pattern having three or more peaks selected from the group consisting of 5.51, 11.01, 16.54, 19.17, 22.68, and 24.18 degrees 2θ ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

12. The solid form of claim 1, wherein: The solid state form is Compound A Form 2, characterized by an XRPD pattern having four or more peaks selected from the group consisting of 5.51, 11.01, 16.54, 19.17, 22.68, and 24.18 degrees 2θ ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

13. The solid state form of claim 1, wherein: The solid state form is Compound A Form 2, characterized by an XRPD pattern having five or more peaks selected from the group consisting of 5.51, 11.01, 16.54, 19.17, 22.68, and 24.18 degrees 2θ ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

14. The solid form of claim 1, wherein: The solid state form is Compound A Form 2, characterized by an XRPD pattern having six or more peaks selected from the group consisting of 5.51, 11.01, 16.54, 19.17, 22.68, and 24.18 degrees 2θ ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

15. The solid state form of claim 1, wherein: The solid state form is Compound A2, which is characterized by the following peaks in an XRPD pattern: 5.51, 16.54, and 24.18 degrees 2θ ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

16. The solid state form of claim 1, wherein: The solid state form is Compound A Form 2, characterized by an XRPD pattern substantially similar to that of FIG. 8 .

17. The solid state form of any one of claims 4 to 16, wherein The solid state form is Compound A Form 2, further characterized by: A TG / DTA thermogram substantially similar to that of Figure 10; and / or A DSC thermogram substantially similar to Figure 11, Figure 12 or Figure 13.

18. The solid state form of claim 1, wherein: The solid state form is Compound A Form 3, characterized by an XRPD pattern substantially similar to that of FIG. 16 .

19. The solid form of claim 1, wherein: The solid state form is Compound A Form 4, characterized by an XRPD pattern having three or more peaks selected from the group consisting of 13.62, 14.16, 14.61, 18.44, 19.92, 22.97 and 23.73 degrees 2θ ±0.3 degrees 2θ, ±0.2 degrees 2θ, ±0.1 degrees 2θ, or ±0.05 degrees 2θ.

20. The solid state form of claim 1, wherein: The solid state form is Compound A Form 4, which is characterized by at least three peaks in the XRPD pattern: 14.61, 18.44, and 22.97 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

21. The solid form of claim 1, wherein: The solid state form is Compound A Form 4, characterized by an XRPD pattern having four or more peaks selected from the group consisting of 13.62, 14.16, 14.61, 18.44, 19.92, 22.97 and 23.73 degrees 2θ ±0.3 degrees 2θ, ±0.2 degrees 2θ, ±0.1 degrees 2θ, or ±0.05 degrees 2θ.

22. The solid state form of claim 1, wherein: The solid state form is Compound A Form 4, characterized by an XRPD pattern having five or more peaks selected from the group consisting of 13.62, 14.16, 14.61, 18.44, 19.92, 22.97 and 23.73 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

23. The solid state form of claim 1, wherein: The solid state form is Compound A Form 4, characterized by an XRPD pattern having six or more peaks selected from the group consisting of 13.62, 14.16, 14.61, 18.44, 19.92, 22.97 and 23.73 degrees 2θ ±0.3 degrees 2θ, ±0.2 degrees 2θ, ±0.1 degrees 2θ, or ±0.05 degrees 2θ.

24. The solid state form of claim 1, wherein: The solid state form is Compound A Form 4, which is characterized by the following peaks in an XRPD pattern: 13.62, 14.16, 14.61, 18.44, 19.92, 22.97 and 23.73 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

25. The solid state form of claim 1, wherein: The solid state form is Compound A Form 4, which is characterized by the following peaks in an XRPD pattern: 13.62, 14.61, and 22.97 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

26. The solid state form of claim 1, wherein: The solid state form is Compound A Form 4, which is characterized by the following peaks in an XRPD pattern: 13.62, 14.61, and 22.97 degrees 2Θ ± 0.1 degrees 2Θ, or ± 0.05 degrees 2Θ.

27. The solid state form of claim 1, wherein: The solid state form is Compound A Form 4, which is characterized by the following peaks in an XRPD pattern: 13.62, 14.16, and 19.92 degrees 2θ ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

28. The solid state form of claim 1, wherein: The solid state form is Compound A Form 4, characterized by an XRPD pattern substantially similar to that of FIG. 17 .

29. The solid state form of any one of claims 1 or 19-28, wherein The solid state form is Compound A Form 4, further characterized by: A TG / DTA thermogram substantially similar to that of Figure 19; and / or A DSC thermogram substantially similar to Figure 20, Figure 21 or Figure 22.

30. The solid state form of claim 1, wherein: The solid state form is Compound A Form 5, characterized by an XRPD pattern substantially similar to that of FIG. 25 .

31. The solid state form of claim 1, wherein: The solid state form is Compound A Form 6, characterized by an XRPD pattern substantially similar to that of FIG. 26 .

32. The solid state form of claim 1, wherein: The solid state form is Compound A Form 7, characterized by an XRPD pattern substantially similar to that of FIG. 27 .

33. The solid state form of claim 1, wherein: The solid state form is Compound A Form 8, characterized by an XRPD pattern substantially similar to that of FIG. 28 .

34. The solid state form of claim 1, wherein: The solid state form is Compound A Form 9, characterized by an XRPD pattern having three or more peaks selected from the group consisting of: 3.05, 6.107, 10.69, 15.33, 18.08, 20.98, 23.49 and 25.25 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

35. The solid state form of claim 1, wherein: The solid state form is Compound A Form 9, characterized by an XRPD pattern having four or more peaks selected from the group consisting of 3.05, 6.107, 10.69, 15.33, 18.08, 20.98, 23.49 and 25.25 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

36. The solid state form of claim 1, wherein: The solid state form is Compound A Form 9, characterized by an XRPD pattern having five or more peaks selected from the group consisting of: 3.05, 6.107, 10.69, 15.33, 18.08, 20.98, 23.49 and 25.25 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

37. The solid state form of claim 1, wherein: The solid state form is Compound A9, characterized by an XRPD pattern having six or more peaks selected from the group consisting of 3.05, 6.107, 10.69, 15.33, 18.08, 20.98, 23.49 and 25.25 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

38. The solid state form of claim 1, wherein: The solid state form is Compound A Form 9, which is characterized by the following peaks in the XRPD pattern: 3.05, 6.107, 10.69, 15.33, 18.08, 20.98, 23.49 and 25.25 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

39. The solid state form of claim 1, wherein: The solid state form is Compound A Form 9, which is characterized by the following peaks in an XRPD pattern: 3.05, 6.107, and 25.25 degrees 2θ ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

40. The solid state form of claim 1, wherein: The solid state form is Compound A Form 9, which is characterized by an XRPD pattern having three or more peaks selected from the group consisting of: 3.05, 6.107, 10.69, 15.33, 18.08, and 25.25 degrees 2θ ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

41. The solid state form of claim 1, wherein: The solid state form is Compound A Form 9, which is characterized by an XRPD pattern having four or more peaks selected from the group consisting of: 3.05, 6.107, 10.69, 15.33, 18.08, and 25.25 degrees 2θ ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

42. The solid state form of claim 1, wherein: The solid state form is Compound A Form 9, which is characterized by an XRPD pattern having five or more peaks selected from the group consisting of: 3.05, 6.107, 10.69, 15.33, 18.08, and 25.25 degrees 2θ ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

43. The solid state form of claim 1, wherein: The solid state form is Compound A Form 9, which is characterized by the following peaks in an XRPD pattern: 3.05, 6.107, 10.69, 15.33, 18.08, and 25.25 degrees 2θ ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

44. The solid state form of claim 1, wherein: The solid state form is Compound A Form 9, characterized by an XRPD pattern substantially similar to that of FIG. 29 .

45. The solid state form of any one of claims 1 or 34-44, wherein The solid state form is Compound A Form 9, further characterized by: A TG / DTA thermogram substantially similar to Figure 31; and / or A DSC thermogram substantially similar to Figure 32, Figure 33 or Figure 34.

46. ​​The solid state form of claim 1, wherein: The solid state form is Compound A Form 10, characterized by an XRPD pattern substantially similar to that of FIG. 37 .

47. The solid state form of claim 1 or 46, wherein: The solid state form is Compound A Form 10, which is also characterized by a TG / DTA thermogram substantially similar to that of Figure 381.

48. The solid state form of claim 1, wherein: The solid state form is Compound A Form 11, characterized by having three or more peaks in the XRPD pattern selected from the group consisting of: 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44 and 23.61 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

49. The solid state form of claim 1, wherein: The solid state form is Compound A Form 11, characterized by having four or more peaks in the XRPD pattern selected from the group consisting of: 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44 and 23.61 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

50. The solid state form of claim 1, wherein: The solid state form is Compound A Form 11, characterized by having five or more peaks in the XRPD pattern selected from the group consisting of: 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44 and 23.61 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

51. The solid state form of claim 1, wherein: The solid state form is Compound A Form 11, characterized by having six or more peaks in the XRPD pattern selected from the group consisting of: 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44 and 23.61 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

52. The solid state form of claim 1, wherein: The solid state form is Compound A Form 11, characterized by having seven or more peaks in the XRPD pattern selected from the group consisting of: 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44 and 23.61 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

53. The solid state form of claim 1, wherein: The solid state form is Compound A Form 11, characterized by eight or more peaks in the XRPD pattern selected from the group consisting of 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44 and 23.61 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

54. The solid state form of claim 1, wherein: The solid state form is Compound A Form 11, which is characterized by the following peaks in the XRPD pattern: 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44 and 23.61 degrees 2θ ± 0.3 degrees 2θ, ± 0.2 degrees 2θ, ± 0.1 degrees 2θ, or ± 0.05 degrees 2θ.

55. The solid state form of claim 1, wherein: The solid state form is Compound A Form 11, which is characterized by the following peaks in the XRPD pattern: 19.48, 20.52, and 22.47 degrees 2Θ ± 0.1 degrees 2Θ, or ± 0.05 degrees 2Θ.

56. The solid state form of claim 1, wherein: The solid state form is Compound A Form 11, which is characterized by the following peaks in the XRPD pattern: 11.40, 11.69, 15.08, 19.48, 20.52, 22.47 and 23.61 degrees 2Θ ± 0.05 degrees 2Θ.

57. The solid state form of claim 1, wherein: The solid state form is Compound A Form 11, characterized by an XRPD pattern substantially similar to that of FIG. 39 .

58. The solid state form of any one of claims 1 or 48-57, wherein The solid state form is Compound A Form 11, further characterized by: a TG / DTA thermogram substantially similar to Figure 41; and / or A DSC thermogram substantially similar to Figure 42, Figure 43, or Figure 44.

59. A solid form as claimed in any one of the preceding claims, wherein Each peak is ±0.2 degrees 2Θ.

60. A solid state form as claimed in any one of the preceding claims, wherein Each peak is ±0.1 degrees 2Θ.

61. A solid form as claimed in any one of the preceding claims, wherein Each peak is ±0.05 degrees 2Θ.

62. A solid state form as claimed in any one of the preceding claims, wherein The solid state form is crystalline.

63. The solid state form of claim 1, wherein: The solid state form is amorphous.

64. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a solid form of Compound A according to any one of the preceding claims.

65. The pharmaceutical composition of claim 64, wherein The solid state form is Compound A Form 1, wherein the composition is substantially free of any other solid state form of Compound A.

66. The pharmaceutical composition of claim 64, wherein The solid state form is Compound A Form 2, wherein the composition is substantially free of any other solid state form of Compound A.

67. The pharmaceutical composition of claim 64, wherein The solid state form is Compound A Form 3, wherein the composition is substantially free of any other solid state form of Compound A.

68. The pharmaceutical composition of claim 64, wherein The solid state form is Compound A Form 4, wherein the composition is substantially free of any other solid state form of Compound A.

69. The pharmaceutical composition of claim 64, wherein The solid state form is Compound A Form 5, wherein the composition is substantially free of any other solid state form of Compound A.

70. The pharmaceutical composition of claim 64, wherein The solid state form is Compound A Form 6, wherein the composition is substantially free of any other solid state form of Compound A.

71. The pharmaceutical composition of claim 64, wherein The solid state form is Compound A Form 7, wherein the composition is substantially free of any other solid state form of Compound A.

72. The pharmaceutical composition of claim 64, wherein The solid state form is Compound A Form 8, wherein the composition is substantially free of any other solid state form of Compound A.

73. The pharmaceutical composition of claim 64, wherein The solid state form is Compound A Form 9, wherein the composition is substantially free of any other solid state form of Compound A.

74. The pharmaceutical composition of claim 64, wherein The solid state form is Compound A Form 10, wherein the composition is substantially free of any other solid state form of Compound A.

75. The pharmaceutical composition of claim 64, wherein The solid state form is Compound A Form 11, wherein the composition is substantially free of any other solid state form of Compound A.

76. The pharmaceutical composition of claim 64, wherein The solid state form is amorphous Compound A, wherein the composition is substantially free of any other solid state form of Compound A.

77. A method for treating epilepsy in humans, wherein: The method comprises administering to a person in need thereof a therapeutically effective amount of a solid form of Compound A according to any one of claims 1-63, or a pharmaceutical composition according to any one of claims 64-76.

78. The method of claim 77, wherein: The solid form of Compound A is administered to humans between 30 minutes before and 2 hours after a meal.

79. The method of claim 77, wherein: The solid form of Compound A was administered during a meal or within 15 minutes after a meal.

80. Use of a solid state form of Compound A as described in any one of claims 1-63, or a pharmaceutical composition as described in any one of claims 64-76, in the preparation of a medicament for treating epilepsy in a human in need thereof.

81. The use of claim 80, wherein The drug is administered to humans between 30 minutes before and 2 hours after a meal.

82. The use of claim 80, wherein The drug is administered during meals or within 15 minutes after meals.

83. The solid form of Compound A according to any one of claims 1 to 63, or the pharmaceutical composition according to any one of claims 64 to 76, for use in a method for treating epilepsy in a human, wherein: The method comprises administering a therapeutically effective amount of the solid form of Compound A, or the pharmaceutical composition, to a person in need thereof.

84. A solid form for use as claimed in claim 83, wherein: The solid form of Compound A is administered to humans between 30 minutes before and 2 hours after a meal.

85. A solid form for use as claimed in claim 83, wherein: The solid form of Compound A was administered during a meal or within 15 minutes after a meal.

86. A method of preparing the solid state form of Compound A of any one of claims 1-63 from another solid state form of Compound A.

87. The method of claim 86, wherein: The solid state form of Compound A prepared is Compound A Form 2 or Compound A Form 4.

88. The method of claim 87, wherein: Compound A Form 4 or Compound A Form 4 is prepared from Compound A Form 1.

89. A method for preparing a pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a solid form of Compound A described in any one of claims 1-63, the method comprising combining the solid form of Compound A with a pharmaceutically acceptable excipient to form the pharmaceutical composition.

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