Solid-state crystal forms of selective potassium channel modulators

Abstract

This invention provides a solid-state form of compound A for use in therapies such as the treatment of seizure disorders, a pharmaceutical composition containing this solid-state crystalline form and pharmaceutically acceptable excipients, and a method for preparing this solid-state form and the pharmaceutical composition, as well as a method for using them. [Solution] A crystal of compound A is provided, wherein compound A is N-(4-(6-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide, and the crystal of compound A is compound A form 4 characterized in the XRPD pattern by three or more peaks selected from 13.62°, 14.16°, 14.61°, 18.44°, 19.92°, 22.97°, and 23.73°²θ±0.3°²θ, ±0.2°²θ, ±0.1°²θ or ±0.05°²θ.

Description

[Technical Field]

[0001] This disclosure is directed to solid-state crystalline forms of selective potassium channel modulators, pharmaceutical compositions comprising these solid-state forms and pharmaceutically acceptable excipients, and processes for preparing these solid-state forms and pharmaceutical compositions. These solid-state crystalline forms and their pharmaceutical compositions are useful for the treatment of paroxysmal disorders in mammals, particularly humans. [Background technology]

[0002] 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). Epilepsy is characterized by abnormal electrical activity in the brain that causes seizures. Patients with epilepsy have an increased mortality risk compared to the general population, mainly due to the etiology of the disease. However, in patients with uncontrolled epilepsy, the highest risk of seizure-related death is due to sudden unexpected death (SUDEP) in epilepsy (see Hitiris, N. et al., Epilepsy and Behavior (2007), 10:363-376). Patients participating in clinical trials of investigational antiepileptic drugs (AEDs) generally have had epilepsy for more than 10 years and have failed multiple AED therapies.

[0003] N-[4-(6-fluoro-3,4-dihydro-1H-isoquinoline-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide (hereinafter referred to as “Compound A”) is a small molecule currently under development for the treatment of paroxysmal disorders. Compound A and its use as a voltage-gated potassium channel modulator are disclosed in U.S. Patent No. 8,293,911 and U.S. Patent No. 8,993,593, which are incorporated herein by reference in their entirety.

[0004] Polymorphism of the same molecule, that is, the occurrence of different solid-state crystalline forms, is a property of several molecules and molecular complexes. A single molecule may give rise to various polymorphs having different crystal structures and physical properties such as melting point, which can be measured using various techniques such as differential scanning calorimetry (DSC) or thermogravimetric analysis (TG), X-ray diffraction (XRPD or SCRXD), infrared absorption fingerprint (FT-IR), and solid-state NMR spectroscopy (SS-NMR). One or more of these techniques may be used to distinguish different polymorphs of a molecule.

[0005] The discovery of a new solid-state crystalline form of a pharmaceutical product may provide a material having desirable processing properties such as ease of handling, ease of processing, storage stability, ease of purification, or, where appropriate, a desirable intermediate crystalline form that facilitates conversion to other polymorphic forms. New solid-state crystalline forms of pharmaceutically useful compounds can also provide an opportunity to improve the performance properties of pharmaceutical products. This expands the repertoire of materials available to formulation scientists for formulation optimization by providing products with different properties, for example, different crystal habits, higher crystallinity or polymorphic stability that may provide better processing or handling properties, an improved dissolution profile, or improved shelf life (chemical / physical stability). [Prior Art Documents] [Patent Documents]

[0006] [Patent Document 1] U.S. Patent No. 8,293,911 Specification [Patent Document 2] U.S. Patent No. 8,993,593 Specification [Non-Patent Documents]

[0007] [Non-Patent Document 1] Hirtz, D. et al., Neurology. (2007), 68: 326-337 [Non-Patent Document 2] Hitiris, N. et al., Epilepsy and Behavior (2007), 10:363-376. [Overview of the initiative] [Problems that the invention aims to solve]

[0008] Therefore, it is necessary to understand and develop the solid-state crystalline form of compound A, especially when used in therapies such as the treatment of paroxysmal disorders. [Means for solving the problem]

[0009] This disclosure, as a whole, is directed to the solid state forms of compound A, particularly the solid state crystalline forms, methods for preparing them, pharmaceutical compositions containing them, and methods for using these solid states and pharmaceutical compositions.

[0010] Therefore, in one embodiment, this disclosure is directed towards the crystalline form of compound A.

[0011] In another embodiment, this disclosure is directed to a crystalline form of compound A, referred to herein as compound A form 1.

[0012] In another embodiment, this disclosure is directed to a crystalline form of compound A, referred to herein as compound A form 2.

[0013] In another embodiment, this disclosure is directed to a crystalline form of compound A, which is referred to herein as compound A form 3.

[0014] In another embodiment, this disclosure is directed to a crystalline form of compound A, which is referred to herein as compound A form 4.

[0015] In another embodiment, this disclosure is directed to a crystalline form of compound A, referred to herein as compound A form 5.

[0016] In another embodiment, this disclosure is directed to a crystalline form of compound A, referred to herein as compound A form 6.

[0017] In another embodiment, this disclosure is directed to a crystalline form of compound A, which is referred to herein as compound A form 7.

[0018] In another embodiment, this disclosure is directed to a crystalline form of compound A, referred to herein as compound form A 8.

[0019] In another embodiment, this disclosure is directed to a crystalline form of compound A, referred to herein as compound A form 9.

[0020] In another embodiment, this disclosure is directed to a crystalline form of compound A, which is referred to herein as compound A form 10.

[0021] In another embodiment, this disclosure is directed to a crystalline form of compound A, which is referred to herein as compound form A11.

[0022] In another embodiment, the disclosure is directed to a mixture of two or more crystalline forms of compound A disclosed herein.

[0023] In another embodiment, the disclosure is directed toward 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) which substantially does not include any other solid-state form of compound A disclosed herein.

[0024] In another embodiment, the disclosure is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of compound A in crystalline form.

[0025] In another embodiment, the disclosure is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred herein as Compound A Form 1, and optionally substantially not comprising any other solid-state form of Compound A disclosed herein.

[0026] In another embodiment, the disclosure is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred herein as Compound A Form 2, and optionally substantially free from any other solid-state form of Compound A disclosed herein.

[0027] In another embodiment, the disclosure is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred herein as Compound A Form 3, and optionally substantially free from any other solid-state form of Compound A disclosed herein.

[0028] In another embodiment, the disclosure is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred herein as Compound A Form 4, and optionally substantially not comprising any other solid-state form of Compound A disclosed herein.

[0029] In another embodiment, the disclosure is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred herein as Compound A Form 5, and optionally substantially not comprising any other solid-state form of Compound A disclosed herein.

[0030] In another embodiment, the disclosure is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred herein as Compound A Form 6, and optionally substantially not comprising any other solid-state form of Compound A disclosed herein.

[0031] In another embodiment, the disclosure is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a solid form of Compound A, referred herein as Compound A Form 7, and optionally substantially free of any other solid form of Compound A disclosed herein.

[0032] In another embodiment, the disclosure is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred herein as Compound A Form 8, and optionally substantially not comprising any other solid-state form of Compound A disclosed herein.

[0033] In another embodiment, the disclosure is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred herein as Compound A Form 9, and optionally substantially free from any other solid-state form of Compound A disclosed herein.

[0034] In another embodiment, the disclosure is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred herein as Compound A Form 10, and optionally substantially not comprising any other solid-state form of Compound A disclosed herein.

[0035] In another embodiment, the disclosure is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a crystalline form of Compound A, referred herein as Compound A Form 11, and optionally substantially free from any other solid-state form of Compound A disclosed herein.

[0036] In another embodiment, the disclosure is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a mixture of two or more crystalline forms of Compound A disclosed herein in a therapeutically effective amount.

[0037] In another embodiment, the present disclosure relates to a method for treating a paroxysmal disorder in a human, the method comprising the step of administering a therapeutically effective amount of a crystalline form of compound A disclosed herein to a human being in need thereof.

[0038] In another embodiment, the present disclosure is directed to a method for treating a paroxysmal disorder in a human being, comprising the step of administering to a human being in need a therapeutically effective amount of, optionally substantially free from any other solid-state form of compound A disclosed herein, compound A Form 1.

[0039] In another embodiment, the present disclosure is directed to a method for treating a paroxysmal disorder in a human being, comprising the step of administering to a human being in need a therapeutically effective amount of, optionally substantially free from any other solid-state form of compound A disclosed herein, compound A form 2.

[0040] In another embodiment, the present disclosure is directed to a method for treating a paroxysmal disorder in a human being, comprising the step of administering to a human being in need a therapeutically effective amount of, optionally substantially free from any other solid-state form of compound A disclosed herein, compound A form 3.

[0041] In another embodiment, the present disclosure is directed toward a method for treating a paroxysmal disorder in a human being, comprising the step of administering to a human being in need a therapeutically effective amount of, optionally substantially free from any other solid-state form of compound A disclosed herein, compound A form 4.

[0042] In another embodiment, the present disclosure is directed to a method for treating a paroxysmal disorder in a human being, comprising the step of administering to a human being in need a therapeutically effective amount of, optionally substantially free from any other solid-state form of compound A disclosed herein, compound A form 5.

[0043] In another embodiment, the present disclosure is directed to a method for treating a paroxysmal disorder in a human being, comprising the step of administering to a human being in need a therapeutically effective amount of compound A form 6, optionally substantially free of any other solid-state form of compound A disclosed herein.

[0044] In another embodiment, the present disclosure is directed to a method for treating a paroxysmal disorder in a human being, comprising the step of administering to a human being in need a therapeutically effective amount of, optionally substantially free from any other solid-state form of compound A disclosed herein, compound A form 7.

[0045] In another embodiment, the present disclosure is directed to a method for treating a paroxysmal disorder in a human being, comprising the step of administering to a human being in need a therapeutically effective amount of, optionally substantially free from any other solid-state form of compound A disclosed herein, compound A form 8.

[0046] In another embodiment, the present disclosure is directed toward a method for treating a paroxysmal disorder in a human being, comprising the step of administering to a human being in need a therapeutically effective amount of, optionally substantially free from any other solid-state form of compound A disclosed herein, compound A form 9.

[0047] In another embodiment, the present disclosure is directed to a method for treating a paroxysmal disorder in a human being, comprising the step of administering to a human being in need a therapeutically effective amount of compound A form 10, 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 for treating a paroxysmal disorder in a human being, comprising the step of administering to a human being in need a therapeutically effective amount of compound A form 11, optionally substantially free of any other solid-state form of compound A disclosed herein.

[0049] In another embodiment, the present disclosure is directed toward a method for treating a paroxysmal disorder in a human, comprising the step of administering a therapeutically effective amount of a mixture of two or more crystalline forms of compound A disclosed herein to a human in need.

[0050] In another embodiment, the present disclosure is directed toward the use of any one of the crystalline forms of compound A disclosed herein for the preparation of a pharmaceutical composition comprising a crystalline form of compound A disclosed herein and a pharmaceutically acceptable excipient.

[0051] In another embodiment, this disclosure is directed to a method for preparing the crystalline form of compound A disclosed herein.

[0052] In another embodiment, this disclosure may optionally be directed to a method for preparing Compound A Form 1 as described herein, which substantially does not include any other solid-state form of Compound A disclosed herein.

[0053] In another embodiment, this disclosure may optionally be directed to a method for preparing compound A form 2 as described herein, which substantially does not include any other solid-state form of compound A disclosed herein.

[0054] In another embodiment, this disclosure may optionally be directed to a method for preparing compound A form 3 described herein, which substantially does not include any other solid-state form of compound A disclosed herein.

[0055] In another embodiment, this disclosure may optionally be directed to a method for preparing compound A form 4 described herein, which substantially does not include any other solid-state form of compound A disclosed herein.

[0056] In another embodiment, this disclosure may optionally be directed to a method for preparing compound A form 5 described herein, which substantially does not include any other solid-state form of compound A disclosed herein.

[0057] In another embodiment, this disclosure may optionally be directed to a method for preparing compound A form 6 described herein, which substantially does not include any other solid-state form of compound A disclosed herein.

[0058] In another embodiment, this disclosure may optionally be directed to a method for preparing compound A form 7 described herein, which substantially does not include any other solid-state form of compound A disclosed herein.

[0059] In another embodiment, this disclosure may optionally be directed to a method for preparing compound A form 8 described herein, which substantially does not include any other solid-state form of compound A disclosed herein.

[0060] In another embodiment, this disclosure may optionally be directed to a method for preparing compound A form 9 described herein, which substantially does not include any other solid-state form of compound A disclosed herein.

[0061] In another embodiment, the disclosure may optionally be directed to a method for preparing compound A form 10 described herein, which substantially does not include any other solid-state form of compound A disclosed herein.

[0062] In another embodiment, this disclosure may optionally be directed to a method for preparing compound A form 11 described herein, which substantially does not include any other solid-state form of compound A disclosed herein.

[0063] In another embodiment, the disclosure is directed to a method for preparing the above-described pharmaceutical composition comprising one of the crystalline forms of compound A disclosed herein and a pharmaceutically acceptable excipient. In one embodiment, the method includes the step of combining one of the crystalline forms of compound A disclosed herein with at least one pharmaceutically acceptable excipient.

[0064] In another embodiment, the disclosure is directed toward the use of any one crystalline form of compound A, or any one crystalline form of compound A and a pharmaceutically acceptable excipient, as a pharmaceutically acceptable

[0065] In some embodiments of the method and use, one or more crystalline forms of compound A are orally administered to humans between 30 minutes before a meal and 2 hours after a meal, for example, one or more crystalline forms of compound A may be orally administered to mammals during a meal or within 15 minutes after a meal.

[0066] In another embodiment, the disclosure is directed toward one or more crystalline forms of compound A disclosed herein having advantageous properties, the advantageous properties being selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, e.g., chemical stability with respect to polymorphic transformation and thermal and mechanical stability, stability against dehydration and / or storage stability, low residual solvent content, low hygroscopicity, and advantageous processing and handling properties, e.g., compressibility and bulk density.

[0067] In one embodiment, the crystalline form of compound A exhibits better fluidity (i.e., superior rheological properties) than amorphous compound A or another solid-state crystalline form of compound A.

[0068] These embodiments are described in more detail below. For this purpose, various references describing in more detail some background information, procedures, compounds and / or compositions are included herein, each incorporated herein in its entirety by reference. [Brief explanation of the drawing]

[0069] [Figure 1] Figure 1 shows the X-ray powder diffraction (XRPD) patterns of compound A-form 1, compound A-form 2, and compound A-form 3. [Figure 2] Figure 2 shows unpolarized and polarized microscopy images of compound A form 1. [Figure 3] Figure 3 shows the thermogravimetric / differential thermal analysis (TG / DTA) thermogram (differential thermal analysis curve) of compound A form 1. [Figure 4] Figure 4 shows the differential scanning calorimetry (DSC) thermogram of compound A form 1 (first heating cycle). [Figure 5] Figure 5 shows the DSC thermogram (cooling cycle) of compound A form 1. [Figure 6] Figure 6 shows the DSC thermogram of compound A form 1 (second heating cycle). [Figure 7] Figure 7 shows the 1H NMR spectrum of compound A form 1. [Figure 8] Figure 8 shows the XRPD diffractogram (diffraction diagram) of compound A form 2. [Figure 9] Figure 9 shows unpolarized and polarized microscopy images of compound A form 2. [Figure 10] Figure 10 shows the TG / DTA thermogram of compound A form 2. [Figure 11] Figure 11 shows the DSC thermogram of compound A form 2 (first heating cycle). [Figure 12] Figure 12 shows the DSC thermogram (cooling cycle) of compound A form 2. [Figure 13] Figure 13 shows the DSC thermogram of compound A form 2 (second heating cycle). [Figure 14] Figure 14 shows the 1H NMR spectrum of compound A form 2. [Figure 15] Figure 15 shows the FTIR spectrogram of compound A form 2. [Figure 16] Figure 16 shows the XRPD diffractogram of compound A form 3. [Figure 17] Figure 17 shows the XRPD diffractogram of compound A form 4. [Figure 18] Figure 18 shows unpolarized and polarized microscopy images of compound A form 4. [Figure 19] Figure 19 shows the TG / DTA thermogram of compound A form 4. [Figure 20] Figure 20 shows the DSC thermogram of compound A form 4 (first heating cycle). [Figure 21] Figure 21 shows the DSC thermogram (cooling cycle) of compound A form 4. [Figure 22] Figure 22 shows the DSC thermogram of compound A form 4 (second heating cycle). [Figure 23] Figure 23 shows the 1H NMR spectrum of compound A form 4. [Figure 24] Figure 24 shows the FTIR spectrogram of compound A form 4. [Figure 25] Figure 25 shows the XRPD diffractogram of compound A form 5. [Figure 26] Figure 26 shows the XRPD diffractogram of compound A form 6. [Figure 27] Figure 27 shows the XRPD diffractogram of compound A form 7. [Figure 28] Figure 28 shows the XRPD diffractogram of compound A form 8. [Figure 29] Figure 29 shows the XRPD diffractogram of compound A form 9. [Figure 30] Figure 30 shows unpolarized and polarized microscopy images of compound A-form 9. [Figure 31] Figure 31 shows the TG / DTA thermogram of compound A form 9. [Figure 32] Figure 32 shows the DSC thermogram of compound A form 9 (first heating cycle). [Figure 33] Figure 33 shows the DSC thermogram (cooling cycle) of compound A form 9. [Figure 34] Figure 34 shows the DSC thermogram of compound A form 9 (second heating cycle). [Figure 35] Figure 35 shows the 1H NMR spectrum of compound A-form 9. [Figure 36] Figure 36 shows the FTIR spectrogram of compound A-form 9. [Figure 37] Figure 37 shows the XRPD diffractogram of compound A form 10. [Figure 38] Figure 38 shows the TG / DTA thermogram of compound A form 10. [Figure 39] Figure 39 shows the XRPD diffractogram of compound A form 11. [Figure 40] Figure 40 shows unpolarized and polarized microscopy images of compound A form 11. [Figure 41] Figure 41 shows the TG / DTA thermogram of compound A form 11. [Figure 42]Figure 42 shows the DSC thermogram of compound A form 11 (first heating cycle). [Figure 43] Figure 43 shows the DSC thermogram (cooling cycle) of compound A form 11. [Figure 44] Figure 44 shows the DSC thermogram of compound A form 11 (second heating cycle). [Figure 45] Figure 45 shows the 1H NMR spectrum of compound A-form 11. [Figure 46] Figure 46 shows the FTIR spectrogram of compound A-form 11. [Modes for carrying out the invention]

[0070] The following description includes certain specific details to provide a complete understanding of various embodiments. However, those skilled in the art will understand that this disclosure may be practiced without these details. In other examples, well-known structures are not illustrated or described in detail to avoid unnecessarily obscuring the description of embodiments. Unless inconsistent with the context, the term “comprise” and its variations (such as “comprises” and “comprising”) should be interpreted in an open and comprehensive sense, i.e., “including, but not limited to.” Furthermore, the headings provided herein are for convenience only and do not construe as to the scope or meaning of the claimed disclosure.

[0071] Throughout this specification, any reference to “one embodiment” or “one embodiment” means that the particular features, structures, or characteristics described in relation to that embodiment are included in at least one embodiment. Therefore, occurrences of the phrase “in one embodiment” or “in one embodiment” in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any preferred manner in one or more embodiments. Also, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” refer to multiple references unless the context clearly indicates that they do not. Furthermore, the terms “or” and “or” are generally used to mean “and / or” unless the context clearly indicates that they do not mean “and / or.” Additionally, as used herein, the term “about” means ±20% of the stated value, and in more specific embodiments, ±10%, ±5%, ±2%, or ±1% of the stated value.

[0072] 1. Definition As used herein and in the appended claims, unless otherwise specified, the following terms and abbreviations have the meanings shown.

[0073] As used herein, "Compound A" refers to the following chemical structure [ka] This refers to compounds having the chemical name N-(4-(6-fluoro-3,4-dihydroisoquinoline-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide. The preparation of compound A and its use as a selective potassium channel modulator, particularly as a Kv7.2 / Kv7.3 (KCNQ2 / 3) opener, are disclosed in U.S. Patent Nos. 8,293,911 and 8,993,593. The mechanism of action of compound A differs from that of most known AEDs in that it involves enhanced or strengthened opening of voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2 / Kv7.3), which are important in the control of neuronal excitability. Compound A is used in the methods and uses described herein.

[0074] The solid state form of compound A, for example, its crystalline form, may be referred to herein as being characterized by image data “depicted” or “substantially depicted” in the figures. Such data includes, for example, X-ray powder diffractograms, DSC thermograms, or NMR spectra. As is well known in the art, such image data potentially provides additional technical information (so-called “fingerprints”) for further defining each solid state form that is not necessarily described by referring only to numerical values ​​or peak positions. In any case, those skilled in the art will understand that the graphical representation of such data may be subject to slight variations in, for example, peak relative intensity and peak position due to certain factors, such as (but not limited to) variations in instrument response and variations in sample concentration and purity, as is well known to those skilled in the art. Nevertheless, those skilled in the art will be able to easily compare the image data in the accompanying figures with image data generated for an unknown crystalline form to determine whether two sets of image data characterize the same crystalline form or two different crystalline forms. Accordingly, the solid-state forms of compound A referred herein as characterized by image data “depicted” or “substantially depicted” in the figures will be understood to include any solid-state forms of compound A characterized by image data having such small variations, as will be well known to those skilled in the art, in comparison with the figures.

[0075] As used herein, "solid state form of compound A referred to as compound A form 1," "solid state form of compound A 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 may be identified in the composition by detecting the peaks of the X-ray powder diffraction pattern depicted in Figure 1.

[0076] As used herein, "solid state form of compound A referred to as compound A form 2," "solid state form of compound A 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 may be identified in the composition by detecting the peaks of the X-ray powder diffraction pattern depicted in Figure 8.

[0077] As used herein, “the solid state form of compound A referred to as compound A form 3,” “the solid state form of compound A referred to herein as compound A form 3,” “compound A form 3,” or “form 3” refers to the solid state form of compound A that may be identified in the composition by detecting the peaks of the X-ray powder diffraction pattern depicted in Figure 16.

[0078] As used herein, "solid state form of compound A referred to herein as compound A form 4", "solid state form of compound A 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 may be identified in the composition by detecting the peaks of the X-ray powder diffraction pattern depicted in Figure 17.

[0079] As used herein, “a solid state form of compound A referred to as compound A form 5,” “a solid state form of compound A referred to as compound A form in the specification,” “compound A form 5,” or “form 5” refers to a solid state form of compound A that may be identified in the composition by detecting the peaks of the X-ray powder diffraction pattern depicted in Figure 25.

[0080] As used herein, "a solid state form of compound A referred to as compound A form 6," "a solid state form of compound A 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 may be identified in the composition by detecting the peaks of the X-ray powder diffraction pattern depicted in Figure 26.

[0081] As used herein, “the solid state form of compound A referred to as compound A form 7,” “the solid state form of compound A referred to herein as compound A form 7,” “compound A form 7,” or “form 7” refers to the solid state form of compound A that may be identified in the composition by detecting the peaks of the X-ray powder diffraction pattern depicted in Figure 27.

[0082] As used herein, “the solid state form of compound A referred to as compound A form 8,” “the solid state form of compound A referred to herein as compound A form 8,” “compound A form 8,” or “form 8” refers to the solid state form of compound A that may be identified in the composition by detecting the peaks of the X-ray powder diffraction pattern depicted in Figure 28.

[0083] As used herein, “the solid state form of compound A referred to herein as compound A form 9,” “the solid state form of compound A referred to herein as compound A form 9,” “compound A form 9,” or “form 9” refers to the solid state form of compound A that may be identified in the composition by detecting the peaks of the X-ray powder diffraction pattern depicted in Figure 29.

[0084] As used herein, “solid state form of compound A referred to as compound A form 10,” “solid state form of compound A 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 may be identified in the composition by detecting the peaks of the X-ray powder diffraction pattern depicted in Figure 37.

[0085] As used herein, “the solid state form of compound A referred to herein as compound A form 11,” “the solid state form of compound A referred to herein as compound A form 11,” “compound A form 11,” or “form 11” refers to the solid state form of compound A that may be identified in the composition by detecting the peaks of the X-ray powder diffraction pattern depicted in Figure 39.

[0086] "AUC" refers to the area under the plasma concentration-time curve. AUC reflects the actual systemic exposure to the solid form of compound A after extravascular administration of a certain dose of compound A, and is expressed as a time multiple of the concentration of the solid form of compound A in plasma. For the purposes of this disclosure, AUC is expressed as time × ng / mL.

[0087] AUC inf " refers to AUC from zero to infinity.

[0088] AUC infobs " refers to the AUC from zero to infinity during the observed time.

[0089] AUC last " refers to the AUC from time zero to the last detectable plasma concentration.

[0090] "%AUC ext This refers to the AUC extrapolated as a percentage of the total AUC from time zero to infinity.

[0091] "Bioavailability" refers to the rate and extent to which the solid form of compound A is absorbed and becomes systemically available for further distribution to the site of action.

[0092] "C max " refers to the maximum plasma concentration observed.

[0093] "h (hour)" refers to one hour or multiple hours.

[0094] A "high-fat diet" refers to any solid or liquid food in which approximately 50 percent of the total calorie content comes from fat.

[0095] A "high-calorie diet" refers to any meal containing approximately 800-1000 calories. Typical high-fat, high-calorie diets contain approximately 150 calories, 250 calories, and 500-600 calories, respectively, derived from protein, carbohydrates, and fat.

[0096] As used herein, the term "highly soluble" relating to the solid state of compound A corresponds to the solid state of compound A having a solubility greater than 100 mg / mL at room temperature. In one embodiment, the solid state of compound A is highly soluble in solvents such as 1,4-dioxane, 1-butanol, 1-propanol, acetone, anisole, chloroform, cyclohexanone, dichloromethane, dimethyl sulfoxide, ethanol, ethyl acetate, 2-propanol, methyl ethyl ketone, N-methyl 2-pyrrolidone, tetrahydrofuran, and tetrahydrofuran / water (99:1 v / v).

[0097] A process or procedure may be described herein as being performed “overnight.” This refers, for example, to a time interval for a process or procedure that extends into the night, during which the process or procedure may not be actively observed. This time interval is approximately 8 to 20 hours, or approximately 10 to 18 hours, or typically approximately 16 hours.

[0098] "Pharmacologically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are understood to be acceptable for use in humans or livestock.

[0099] When a mixture of compound A in its solid state and a solvent is characterized herein as being at or approaching “room temperature” or “ambient temperature” (often abbreviated as “RT”), it is intended that the temperature of the object or mixture is close to or equal to the temperature of the space, for example, the room or ventilation 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.

[0100] "SD" refers to the standard deviation.

[0101] "Seizure disorders" include partial-onset (focal) seizures, photosensitive seizures, self-induced syncope, refractory epilepsy, Angelman syndrome, benign Rolandic epilepsy, CDKL5 disorder, childhood absence epilepsy and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, glucose transporter 1 (Glut1) deficiency, hypothalamic hamartoma, infantile spasms / West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), and myoclonic absence epilepsy. This refers to epilepsy, Ohtahara syndrome, Panayiotopoulos syndrome, PCDH19 epilepsy, progressive myoclonic epilepsy, Rasmussen syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, Lafora progressive myoclonic epilepsy, neurocutaneous syndromes, tuberous sclerosis, early infantile epileptic encephalopathy, early-onset epileptic encephalopathy, generalized epilepsy with febrile seizures plus, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia, and seizures and seizure-related disorders such as paroxysmal dyskinesia. In certain embodiments, the term “paroxysmal disorder” refers to focal-onset epilepsy (focal epilepsy), also known as partial-onset (focal) epilepsy.

[0102] As used herein, the term “substantially not containing” when referring to a solid state of compound A is intended to mean that the solid state of the disclosed herein contains only 20% (w / w) or less of any other solid state of compound A or a specific solid state of compound A.

[0103] "t1 / 2 λz " refers to the elimination half-life of compound A in its solid state from plasma (i.e., the time required for the plasma concentration of compound A in its solid state to decrease by half during the elimination phase).

[0104] "T max " refers to the time it takes for compound A to reach its peak plasma concentration after extravascular administration in its solid form.

[0105] As used herein, “therapeutic dose” refers to an amount of compound A in solid form that is sufficient to treat the indicated disease, disorder, or condition, or to have the desired described effect, including improving or preventing one or more underlying mechanisms of action of the disease, disorder, or condition. In a particular embodiment, if compound A in solid form is administered for the treatment of a paroxysmal disorder, the therapeutic dose refers to a range of amounts of compound A in solid form that, upon administration to a human, treat, improve, or prevent the paroxysmal disorder in a human, or exhibit a detectable therapeutic or preventive effect in a human having a paroxysmal disorder. This effect is detected, for example, by a reduction (frequency) of seizures or a decrease (quality) in the severity of seizures. The exact therapeutic dose for a given human will depend on the human's size and health, the nature and severity of the paroxysmal disorder, the presence of any concomitant medications, and other variables known to those skilled in the art. The therapeutic dose for a given situation can be determined by routine experimentation and is within the scope of a clinician's expertise.

[0106] As used herein, “treatment” refers to a therapeutic application relating to the administration of the solid form of compound A that improves or prevents one or more underlying mechanisms of action of the disease, disorder, or condition described herein, for example, by delaying or halting the progression of one or more of the disease, disorder, or condition, or the underlying mechanisms of action. In certain embodiments, when the solid form of compound A is administered for the treatment of a paroxysmal disorder, treatment refers to a therapeutic application to delay or halt the progression of the paroxysmal disorder, a prophylactic application to prevent the onset of the paroxysmal disorder, and / or reversal of the paroxysmal disorder. Reversal of a paroxysmal disorder differs from a therapeutic application that delays or halts the paroxysmal disorder in that, by the manner of reversal, not only does the progression of the paroxysmal disorder completely cease, but the cellular behavior shifts to some extent toward a normal state that would be observed in the absence of the paroxysmal disorder.

[0107] "Under feeding conditions" refers to the state in which food is ingested during the period from approximately 4 hours before oral administration of an effective dose of compound A in its solid form (e.g., within the therapeutically effective dose range) to approximately 4 hours after administration of compound A in its solid form. The food may be a solid, liquid, or mixture of solid and liquid food having sufficient bulk and fat content that does not rapidly dissolve and absorb in the stomach. In some examples, the food may be a meal such as breakfast, lunch, or dinner, or baby food (e.g., formula or breast milk). The therapeutically effective dose of compound A in its solid form may be administered orally to the subject, for example, approximately 30 minutes before eating to approximately 2 hours after eating, and most advantageously, the dose unit of compound A in its solid form is administered orally during or within 15 minutes after eating. This "food effect" relating to the administration of compound A in humans under feeding conditions can be found in U.S. Patent Application Publication No. 2019-0343823, the disclosure of which is incorporated herein by reference in its entirety.

[0108] "Fasting conditions" refers to a state in which no food has been consumed from at least 4 hours before oral administration of a therapeutically effective dose of compound A in its solid form until approximately 4 hours after administration of compound A in its solid form.

[0109] As used herein, the terms "under vacuum" or "in a vacuum" refer to a pressure below atmospheric pressure.

[0110] In this specification, the amount of solvent used in a chemical process, such as a reaction or crystallization, may be referred to as a certain number of “volumes,” or “vol,” or “V.” For example, it may be stated that a material is suspended in 10 volumes (or 10 vol or 10 V) of solvent. In this context, this expression is understood to mean the number of milliliters of solvent per gram of material being suspended; therefore, suspending 5 grams of material in 10 volumes of solvent means that the solvent is used at a rate of 10 milliliters per gram of material being suspended, or in this example, 50 mL of solvent. In another context, the term “v / v” may be used to indicate the number of volumes of solvent added to a liquid mixture, based on the volume of the liquid mixture. For example, adding solvent X (1.5 v / v) to 100 mL of a reaction mixture means that 150 mL of solvent X has been added.

[0111] 2. Embodiments In some embodiments, the 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) is 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, 1 It contains any other solid-state crystalline form of compound A disclosed herein, or a specific solid-state crystalline form of compound A disclosed herein, in amounts of 0% (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.

[0112] In other embodiments, the 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) is 0.1%~20% (w / w), 0.2%~20% (w / w), 0.5%~20% (w / w), 1%~20% (w / w), 2%~20% (w / w), 3%~20% (w / w), 4%~20% (w / w), 5%~20% (w / w), 6%~20% (w / w), 7%~20% (w / w), 8%~20% (w / w) It contains any other solid-state crystalline form of compound A disclosed herein, or a specific solid-state crystalline form of compound A disclosed herein, in the following proportions: w), 9%~20% (w / w), 10%~20% (w / w), 11%~20% (w / w), 12%~20% (w / w), 13%~20% (w / w), 14%~20% (w / w), 15%~20% (w / w), 16%~20% (w / w), 17%~20% (w / w), 18%~20% (w / w), or 19%~20% (w / w).

[0113] In other embodiments, the 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) is 0.1%~15% (w / w), 0.2%~15% (w / w), 0.5%~15% (w / w), 1%~15% (w / w), 2%~15% (w / w), 3%~15% (w / w), 4%~15% (w / w), 5%~15% (w / w), It contains any other solid-state crystalline form of compound A disclosed herein, or a specific solid-state crystalline form of compound A disclosed herein, in amounts of 6%-15% (w / w), 7%-15% (w / w), 8%-15% (w / w), 9%-15% (w / w), 10%-15% (w / w), 11%-15% (w / w), 12%-15% (w / w), 13%-15% (w / w), or 14%-15% (w / w).

[0114] In other embodiments, the 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 any other solid-state crystalline form of compound A disclosed herein, or a specific solid-state crystalline form of compound A disclosed herein, in amounts of 0.1% to 10% (w / w), 0.2% to 10% (w / w), 0.5% to 10% (w / w), 1% to 10% (w / w), 2% to 10% (w / w), 3% to 10% (w / w), 4% to 10% (w / w), 5% to 10% (w / w), 6% to 10% (w / w), 7% to 10% (w / w), 8% to 10% (w / w), or 9% to 10% (w / w).

[0115] In other embodiments, the 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 any other solid-state crystalline form of compound A disclosed herein, or a specific solid-state crystalline form of compound A disclosed herein, in amounts of 0.1% to 5% (w / w), 0.2% to 5% (w / w), 0.3% to 5% (w / w), 0.4% to 5% (w / w), 0.5% to 5% (w / w), 0.7% to 5% (w / w), 0.8% to 5% (w / w), 1% to 5% (w / w), 1.5% to 5% (w / w), 2% to 5% (w / w), 2.5% to 5% (w / w), 3% to 5% (w / w), or 4% to 5% (w / w).

[0116] 2.1. Compound A Form 1 Mixture In some embodiments, the solid-state crystalline form of compound A is compound A form 1 and a total of 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% ( It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 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, or specific solid-state crystalline forms 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 combinations thereof.

[0117] In a particular embodiment, the solid-state crystalline form of compound A is compound A form 1, and a total of 0.1%~20% (w / w), 0.2%~20% (w / w), 0.5%~20% (w / w), 1%~20% (w / w), 2%~20% (w / w), 3%~20% (w / w), 4%~20% (w / w), 5%~20% (w / w), 6%~20% (w / w), 7%~20% (w / w), 8%~20% (w / w), 9%~20% (w / w), 10%~20% (w / w), 11%~20% (w / w), 12%~20% (w / w), 13%~20% (w / w), and 14%~2%. It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 0% (w / w), 15%~20% (w / w), 16%~20% (w / w), 17%~20% (w / w), 18%~20% (w / w), or 19%~20% (w / w), or specific solid-state crystalline forms 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 combinations thereof.

[0118] In some embodiments, the solid-state crystalline form of compound A is compound A form 1, and the total amounts are 0.1%~15% (w / w), 0.2%~15% (w / w), 0.5%~15% (w / w), 1%~15% (w / w), 2%~15% (w / w), 3%~15% (w / w), 4%~15% (w / w), 5%~15% (w / w), 6%~15% (w / w), 7%~15% (w / w), 8%~15% (w / w), 9%~15% (w / w), 10%~15% (w / w), and 11%~15% (w / w). It contains all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0119] In a particular embodiment, the solid-state crystalline form of compound A is compound A form 1, and in total amounts of 0.1%~10% (w / w), 0.2%~10% (w / w), 0.5%~10% (w / w), 1%~10% (w / w), 2%~10% (w / w), 3%~10% (w / w), 4%~10% (w / w), 5%~10% (w / w), 6%~10% (w / w), 7%~10% (w / w), 8%~10% (w / w), or It contains 9% to 10% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0120] In some embodiments, the solid-state crystalline form of compound A is compound A form 1, and in total 0.2%~5% (w / w), 0.3%~5% (w / w), 0.4%~5% (w / w), 0.5%~5% (w / w), 0.7%~5% (w / w), 0.8%~5% (w / w), 1%~5% (w / w), 1.5%~5% (w / w), 2%~5% (w / w), 2.5%~5% (w / w), 3%~5% (w / w), or It contains 4% to 5% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0121] In other embodiments, the solid state form of compound A comprises compound A form 1 comprising 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).

[0122] 2.2. Compound A Form 2 Mixture In some embodiments, the solid-state crystalline form of compound A is compound A form 2, and the total is 20%(w / w) or less, 19%(w / w) or less, 18%(w / w) or less, 17%(w / w) or less, 16%(w / w) or less, 15%(w / w) or less, 14%(w / w) or less, 13%(w / w) or less, 12%(w / w) or less, 11%(w / w) or less, 10%(w / w) or less, 9%(w / w) or less, 8%(w / w) or less, 7%(w / w) or less, 6%(w / w) or less, 5%(w / w) or less, 4%(w / w) or less, 3%( It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 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, or specific solid-state crystalline forms 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 combinations thereof.

[0123] In a particular embodiment, the solid-state crystalline form of compound A is compound A form 2, with a total of 0.1%~20% (w / w), 0.2%~20% (w / w), 0.5%~20% (w / w), 1%~20% (w / w), 2%~20% (w / w), 3%~20% (w / w), 4%~20% (w / w), 5%~20% (w / w), 6%~20% (w / w), 7%~20% (w / w), 8%~20% (w / w), 9%~20% (w / w), 10%~20% (w / w), 11%~20% (w / w), 12%~20% (w / w), 13%~20% (w / w), and 14%~2%. It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 0% (w / w), 15%~20% (w / w), 16%~20% (w / w), 17%~20% (w / w), 18%~20% (w / w), or 19%~20% (w / w), or specific solid-state crystalline forms 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 combinations thereof.

[0124] In some embodiments, the solid-state crystalline form of compound A is compound A form 2, with a total of 0.1%~15% (w / w), 0.2%~15% (w / w), 0.5%~15% (w / w), 1%~15% (w / w), 2%~15% (w / w), 3%~15% (w / w), 4%~15% (w / w), 5%~15% (w / w), 6%~15% (w / w), 7%~15% (w / w), 8%~15% (w / w), 9%~15% (w / w), 10%~15% (w / w), and 11%~15% (w / w). It contains all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0125] In certain embodiments, the solid-state crystalline form of compound A is compound A form 2, and in total amounts of 0.1%~10% (w / w), 0.2%~10% (w / w), 0.5%~10% (w / w), 1%~10% (w / w), 2%~10% (w / w), 3%~10% (w / w), 4%~10% (w / w), 5%~10% (w / w), 6%~10% (w / w), 7%~10% (w / w), 8%~10% (w / w), or It contains 9% to 10% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0126] In some embodiments, the solid-state crystalline form of compound A is compound A form 2, and in total amounts of 0.2%~5% (w / w), 0.3%~5% (w / w), 0.4%~5% (w / w), 0.5%~5% (w / w), 0.7%~5% (w / w), 0.8%~5% (w / w), 1%~5% (w / w), 1.5%~5% (w / w), 2%~5% (w / w), 2.5%~5% (w / w), 3%~5% (w / w), or It contains 4% to 5% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0127] In other embodiments, the solid-state crystalline form of compound A includes 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) of compound A form 2.

[0128] 2.3. Compound A Form 3 Mixture In some embodiments, the solid-state crystalline form of compound A is compound A form 3, and the total is 20%(w / w) or less, 19%(w / w) or less, 18%(w / w) or less, 17%(w / w) or less, 16%(w / w) or less, 15%(w / w) or less, 14%(w / w) or less, 13%(w / w) or less, 12%(w / w) or less, 11%(w / w) or less, 10%(w / w) or less, 9%(w / w) or less, 8%(w / w) or less, 7%(w / w) or less, 6%(w / w) or less, 5%(w / w) or less, 4%(w / w) or less, 3%( It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 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, or specific solid-state crystalline forms 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 combinations thereof.

[0129] In a particular embodiment, the solid-state crystalline form of compound A is compound A form 3, and in total 0.1%~20% (w / w), 0.2%~20% (w / w), 0.5%~20% (w / w), 1%~20% (w / w), 2%~20% (w / w), 3%~20% (w / w), 4%~20% (w / w), 5%~20% (w / w), 6%~20% (w / w), 7%~20% (w / w), 8%~20% (w / w), 9%~20% (w / w), 10%~20% (w / w), 11%~20% (w / w), 12%~20% (w / w), 13%~20% (w / w), and 14%~2%. It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 0% (w / w), 15%~20% (w / w), 16%~20% (w / w), 17%~20% (w / w), 18%~20% (w / w), or 19%~20% (w / w), or specific solid-state crystalline forms 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 combinations thereof.

[0130] In some embodiments, the solid-state crystalline form of compound A is compound A form 3, and the total amounts are 0.1%~15% (w / w), 0.2%~15% (w / w), 0.5%~15% (w / w), 1%~15% (w / w), 2%~15% (w / w), 3%~15% (w / w), 4%~15% (w / w), 5%~15% (w / w), 6%~15% (w / w), 7%~15% (w / w), 8%~15% (w / w), 9%~15% (w / w), 10%~15% (w / w), and 11%~15% (w / w). It contains all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0131] In certain embodiments, the solid-state crystalline form of compound A is compound A form 3, and in total amounts of 0.1%~10% (w / w), 0.2%~10% (w / w), 0.5%~10% (w / w), 1%~10% (w / w), 2%~10% (w / w), 3%~10% (w / w), 4%~10% (w / w), 5%~10% (w / w), 6%~10% (w / w), 7%~10% (w / w), 8%~10% (w / w), or It contains 9% to 10% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0132] In some embodiments, the solid-state crystalline form of compound A is compound A form 3, and in total amounts of 0.2%~5% (w / w), 0.3%~5% (w / w), 0.4%~5% (w / w), 0.5%~5% (w / w), 0.7%~5% (w / w), 0.8%~5% (w / w), 1%~5% (w / w), 1.5%~5% (w / w), 2%~5% (w / w), 2.5%~5% (w / w), 3%~5% (w / w), or It contains 4% to 5% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0133] In other embodiments, the solid state form of compound A includes form 3 of compound A comprising 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).

[0134] 2.4. Compound A Form 4 Mixture In some embodiments, the solid-state crystalline form of compound A is compound A form 4, and the total is 20%(w / w) or less, 19%(w / w) or less, 18%(w / w) or less, 17%(w / w) or less, 16%(w / w) or less, 15%(w / w) or less, 14%(w / w) or less, 13%(w / w) or less, 12%(w / w) or less, 11%(w / w) or less, 10%(w / w) or less, 9%(w / w) or less, 8%(w / w) or less, 7%(w / w) or less, 6%(w / w) or less, 5%(w / w) or less, 4%(w / w) or less, 3%( It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 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, or specific solid-state crystalline forms 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 combinations thereof.

[0135] In a particular embodiment, the solid-state crystalline form of compound A is compound A form 4, and in total 0.1%~20% (w / w), 0.2%~20% (w / w), 0.5%~20% (w / w), 1%~20% (w / w), 2%~20% (w / w), 3%~20% (w / w), 4%~20% (w / w), 5%~20% (w / w), 6%~20% (w / w), 7%~20% (w / w), 8%~20% (w / w), 9%~20% (w / w), 10%~20% (w / w), 11%~20% (w / w), 12%~20% (w / w), 13%~20% (w / w), and 14%~2%. It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 0% (w / w), 15%~20% (w / w), 16%~20% (w / w), 17%~20% (w / w), 18%~20% (w / w), or 19%~20% (w / w), or specific solid-state crystalline forms 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 combinations thereof.

[0136] In some embodiments, the solid-state crystalline form of compound A is compound A form 4, and in total 0.1%~15% (w / w), 0.2%~15% (w / w), 0.5%~15% (w / w), 1%~15% (w / w), 2%~15% (w / w), 3%~15% (w / w), 4%~15% (w / w), 5%~15% (w / w), 6%~15% (w / w), 7%~15% (w / w), 8%~15% (w / w), 9%~15% (w / w), 10%~15% (w / w), 11%~15% (w / w). It contains all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0137] In a particular embodiment, the solid-state crystalline form of compound A is compound A form 4, and in total amounts of 0.1%~10% (w / w), 0.2%~10% (w / w), 0.5%~10% (w / w), 1%~10% (w / w), 2%~10% (w / w), 3%~10% (w / w), 4%~10% (w / w), 5%~10% (w / w), 6%~10% (w / w), 7%~10% (w / w), 8%~10% (w / w), or It contains 9% to 10% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0138] In some embodiments, the solid-state crystalline form of compound A is compound A form 4, with a total of 0.2%~5% (w / w), 0.3%~5% (w / w), 0.4%~5% (w / w), 0.5%~5% (w / w), 0.7%~5% (w / w), 0.8%~5% (w / w), 1%~5% (w / w), 1.5%~5% (w / w), 2%~5% (w / w), 2.5%~5% (w / w), 3%~5% (w / w), or It contains 4% to 5% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0139] In other embodiments, the solid-state crystalline form of compound A includes 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) of compound A form 4.

[0140] 2.5. Compound A Form 5 Mixture In some embodiments, the solid-state crystalline form of compound A is compound A form 5, and the total is 20%(w / w) or less, 19%(w / w) or less, 18%(w / w) or less, 17%(w / w) or less, 16%(w / w) or less, 15%(w / w) or less, 14%(w / w) or less, 13%(w / w) or less, 12%(w / w) or less, 11%(w / w) or less, 10%(w / w) or less, 9%(w / w) or less, 8%(w / w) or less, 7%(w / w) or less, 6%(w / w) or less, 5%(w / w) or less, 4%(w / w) or less, 3%( It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 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, or specific solid-state crystalline forms 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 combinations thereof.

[0141] In a particular embodiment, the solid-state crystalline form of compound A is compound A form 5, and in total 0.1%~20% (w / w), 0.2%~20% (w / w), 0.5%~20% (w / w), 1%~20% (w / w), 2%~20% (w / w), 3%~20% (w / w), 4%~20% (w / w), 5%~20% (w / w), 6%~20% (w / w), 7%~20% (w / w), 8%~20% (w / w), 9%~20% (w / w), 10%~20% (w / w), 11%~20% (w / w), 12%~20% (w / w), 13%~20% (w / w), 14%~2 It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 0% (w / w), 15%~20% (w / w), 16%~20% (w / w), 17%~20% (w / w), 18%~20% (w / w), or 19%~20% (w / w), or specific solid-state crystalline forms 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 combinations thereof.

[0142] In some embodiments, the solid-state crystalline form of compound A is compound A form 5, and in total 0.1%~15% (w / w), 0.2%~15% (w / w), 0.5%~15% (w / w), 1%~15% (w / w), 2%~15% (w / w), 3%~15% (w / w), 4%~15% (w / w), 5%~15% (w / w), 6%~15% (w / w), 7%~15% (w / w), 8%~15% (w / w), 9%~15% (w / w), 10%~15% (w / w), 11%~15% (w / w). It contains all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0143] In a particular embodiment, the solid-state crystalline form of compound A is compound A form 5, and in total amounts of 0.1%~10% (w / w), 0.2%~10% (w / w), 0.5%~10% (w / w), 1%~10% (w / w), 2%~10% (w / w), 3%~10% (w / w), 4%~10% (w / w), 5%~10% (w / w), 6%~10% (w / w), 7%~10% (w / w), 8%~10% (w / w), or It contains 9% to 10% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0144] In some embodiments, the solid-state crystalline form of compound A is compound A form 5, with a total of 0.2%~5% (w / w), 0.3%~5% (w / w), 0.4%~5% (w / w), 0.5%~5% (w / w), 0.7%~5% (w / w), 0.8%~5% (w / w), 1%~5% (w / w), 1.5%~5% (w / w), 2%~5% (w / w), 2.5%~5% (w / w), 3%~5% (w / w), or It contains 4% to 5% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0145] In other embodiments, the solid-state crystalline form of compound A includes form 5 of compound A comprising 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).

[0146] 2.6. Compound A Form 6 Mixture In some embodiments, the solid-state crystalline form of compound A is compound A form 6, and the total is 20%(w / w) or less, 19%(w / w) or less, 18%(w / w) or less, 17%(w / w) or less, 16%(w / w) or less, 15%(w / w) or less, 14%(w / w) or less, 13%(w / w) or less, 12%(w / w) or less, 11%(w / w) or less, 10%(w / w) or less, 9%(w / w) or less, 8%(w / w) or less, 7%(w / w) or less, 6%(w / w) or less, 5%(w / w) or less, 4%(w / w) or less, 3%( It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 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, or specific solid-state crystalline forms 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 combinations thereof.

[0147] In a particular embodiment, the solid-state crystalline form of compound A is compound A form 6, and in total 0.1%~20% (w / w), 0.2%~20% (w / w), 0.5%~20% (w / w), 1%~20% (w / w), 2%~20% (w / w), 3%~20% (w / w), 4%~20% (w / w), 5%~20% (w / w), 6%~20% (w / w), 7%~20% (w / w), 8%~20% (w / w), 9%~20% (w / w), 10%~20% (w / w), 11%~20% (w / w), 12%~20% (w / w), 13%~20% (w / w), 14%~2 It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 0% (w / w), 15%~20% (w / w), 16%~20% (w / w), 17%~20% (w / w), 18%~20% (w / w), or 19%~20% (w / w), or specific solid-state crystalline forms 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 combinations thereof.

[0148] In some embodiments, the solid-state crystalline form of compound A is compound A form 6, and in total 0.1%~15% (w / w), 0.2%~15% (w / w), 0.5%~15% (w / w), 1%~15% (w / w), 2%~15% (w / w), 3%~15% (w / w), 4%~15% (w / w), 5%~15% (w / w), 6%~15% (w / w), 7%~15% (w / w), 8%~15% (w / w), 9%~15% (w / w), 10%~15% (w / w), 11%~15% (w / w). It contains all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0149] In certain embodiments, the solid-state crystalline form of compound A is compound A form 6, and in total amounts of 0.1%~10% (w / w), 0.2%~10% (w / w), 0.5%~10% (w / w), 1%~10% (w / w), 2%~10% (w / w), 3%~10% (w / w), 4%~10% (w / w), 5%~10% (w / w), 6%~10% (w / w), 7%~10% (w / w), 8%~10% (w / w), or It contains 9% to 10% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0150] In some embodiments, the solid-state crystalline form of compound A is compound A form 6, with a total of 0.2%~5% (w / w), 0.3%~5% (w / w), 0.4%~5% (w / w), 0.5%~5% (w / w), 0.7%~5% (w / w), 0.8%~5% (w / w), 1%~5% (w / w), 1.5%~5% (w / w), 2%~5% (w / w), 2.5%~5% (w / w), 3%~5% (w / w), or It contains 4% to 5% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0151] In other embodiments, the solid state form of compound A includes form 6 of compound A comprising 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).

[0152] 2.7. Compound A Form 7 Mixture In some embodiments, the solid-state crystalline form of compound A is compound A form 1 and a total of 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, 3% ( It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 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, or specific solid-state crystalline forms 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 combinations thereof.

[0153] In a particular embodiment, the solid-state crystalline form of compound A is compound A form 7, and in total 0.1%~20% (w / w), 0.2%~20% (w / w), 0.5%~20% (w / w), 1%~20% (w / w), 2%~20% (w / w), 3%~20% (w / w), 4%~20% (w / w), 5%~20% (w / w), 6%~20% (w / w), 7%~20% (w / w), 8%~20% (w / w), 9%~20% (w / w), 10%~20% (w / w), 11%~20% (w / w), 12%~20% (w / w), 13%~20% (w / w), 14%~2 It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 0% (w / w), 15%~20% (w / w), 16%~20% (w / w), 17%~20% (w / w), 18%~20% (w / w), or 19%~20% (w / w), or specific solid-state crystalline forms 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 combinations thereof.

[0154] In some embodiments, the solid-state crystalline form of compound A is compound A form 7, and in total 0.1%~15% (w / w), 0.2%~15% (w / w), 0.5%~15% (w / w), 1%~15% (w / w), 2%~15% (w / w), 3%~15% (w / w), 4%~15% (w / w), 5%~15% (w / w), 6%~15% (w / w), 7%~15% (w / w), 8%~15% (w / w), 9%~15% (w / w), 10%~15% (w / w), 11%~15% (w / w). It contains all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0155] In certain embodiments, the solid-state crystalline form of compound A is compound A form 7, and in total amounts of 0.1%~10% (w / w), 0.2%~10% (w / w), 0.5%~10% (w / w), 1%~10% (w / w), 2%~10% (w / w), 3%~10% (w / w), 4%~10% (w / w), 5%~10% (w / w), 6%~10% (w / w), 7%~10% (w / w), 8%~10% (w / w), or It contains 9% to 10% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0156] In some embodiments, the solid-state crystalline form of compound A is compound A form 7, with a total of 0.2%~5% (w / w), 0.3%~5% (w / w), 0.4%~5% (w / w), 0.5%~5% (w / w), 0.7%~5% (w / w), 0.8%~5% (w / w), 1%~5% (w / w), 1.5%~5% (w / w), 2%~5% (w / w), 2.5%~5% (w / w), 3%~5% (w / w), or It contains 4% to 5% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0157] In other embodiments, the solid-state crystalline form of compound A includes form 7 of compound A comprising 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).

[0158] 2.8. Compound A Form 8 Mixture In some embodiments, the solid-state crystalline form of compound A is compound A form 8, and the total is 20%(w / w) or less, 19%(w / w) or less, 18%(w / w) or less, 17%(w / w) or less, 16%(w / w) or less, 15%(w / w) or less, 14%(w / w) or less, 13%(w / w) or less, 12%(w / w) or less, 11%(w / w) or less, 10%(w / w) or less, 9%(w / w) or less, 8%(w / w) or less, 7%(w / w) or less, 6%(w / w) or less, 5%(w / w) or less, 4%(w / w) or less, 3%( It contains all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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 combinations thereof, in amounts of 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.

[0159] In a particular embodiment, the solid-state crystalline form of compound A is compound A form 8, with a total of 0.1%~20% (w / w), 0.2%~20% (w / w), 0.5%~20% (w / w), 1%~20% (w / w), 2%~20% (w / w), 3%~20% (w / w), 4%~20% (w / w), 5%~20% (w / w), 6%~20% (w / w), 7%~20% (w / w), 8%~20% (w / w), 9%~20% (w / w), 10%~20% (w / w), 11%~20% (w / w), 12%~20% (w / w), 13%~20% (w / w), and 14%~2%. It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 0% (w / w), 15%~20% (w / w), 16%~20% (w / w), 17%~20% (w / w), 18%~20% (w / w), or 19%~20% (w / w), or specific solid-state crystalline forms 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 combinations thereof.

[0160] In some embodiments, the solid-state crystalline form of compound A is compound A form 8, and in total 0.1%~15% (w / w), 0.2%~15% (w / w), 0.5%~15% (w / w), 1%~15% (w / w), 2%~15% (w / w), 3%~15% (w / w), 4%~15% (w / w), 5%~15% (w / w), 6%~15% (w / w), 7%~15% (w / w), 8%~15% (w / w), 9%~15% (w / w), 10%~15% (w / w), 11%~15% (w / w). It contains all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0161] In certain embodiments, the solid-state crystalline form of compound A is compound A form 8, and in total amounts of 0.1%~10% (w / w), 0.2%~10% (w / w), 0.5%~10% (w / w), 1%~10% (w / w), 2%~10% (w / w), 3%~10% (w / w), 4%~10% (w / w), 5%~10% (w / w), 6%~10% (w / w), 7%~10% (w / w), 8%~10% (w / w), or It contains 9% to 10% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0162] In some embodiments, the solid-state crystalline form of compound A is compound A form 8, with a total of 0.2%~5% (w / w), 0.3%~5% (w / w), 0.4%~5% (w / w), 0.5%~5% (w / w), 0.7%~5% (w / w), 0.8%~5% (w / w), 1%~5% (w / w), 1.5%~5% (w / w), 2%~5% (w / w), 2.5%~5% (w / w), 3%~5% (w / w), and so on. It contains 4% to 5% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0163] In other embodiments, the solid-state crystalline form of compound A includes form 8 of compound A comprising 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).

[0164] 2.9. Compound A Form 9 Mixture In some embodiments, the solid-state crystalline form of compound A is compound A form 9, and the total is 20%(w / w) or less, 19%(w / w) or less, 18%(w / w) or less, 17%(w / w) or less, 16%(w / w) or less, 15%(w / w) or less, 14%(w / w) or less, 13%(w / w) or less, 12%(w / w) or less, 11%(w / w) or less, 10%(w / w) or less, 9%(w / w) or less, 8%(w / w) or less, 7%(w / w) or less, 6%(w / w) or less, 5%(w / w) or less, 4%(w / w) or less, 3%( It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 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, or specific solid-state crystalline forms 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 combinations thereof.

[0165] In a particular embodiment, the solid-state crystalline form of compound A is compound A form 9, with a total of 0.1%~20% (w / w), 0.2%~20% (w / w), 0.5%~20% (w / w), 1%~20% (w / w), 2%~20% (w / w), 3%~20% (w / w), 4%~20% (w / w), 5%~20% (w / w), 6%~20% (w / w), 7%~20% (w / w), 8%~20% (w / w), 9%~20% (w / w), 10%~20% (w / w), 11%~20% (w / w), 12%~20% (w / w), 13%~20% (w / w), and 14%~2%. It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 0% (w / w), 15%~20% (w / w), 16%~20% (w / w), 17%~20% (w / w), 18%~20% (w / w), or 19%~20% (w / w), or specific solid-state crystalline forms 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 combinations thereof.

[0166] In some embodiments, the solid-state crystalline form of compound A is compound A form 9, and in total 0.1%~15% (w / w), 0.2%~15% (w / w), 0.5%~15% (w / w), 1%~15% (w / w), 2%~15% (w / w), 3%~15% (w / w), 4%~15% (w / w), 5%~15% (w / w), 6%~15% (w / w), 7%~15% (w / w), 8%~15% (w / w), 9%~15% (w / w), 10%~15% (w / w), 11%~15% (w / w). It contains all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0167] In certain embodiments, the solid-state crystalline form of compound A is compound A form 9, and in total amounts of 0.1%~10% (w / w), 0.2%~10% (w / w), 0.5%~10% (w / w), 1%~10% (w / w), 2%~10% (w / w), 3%~10% (w / w), 4%~10% (w / w), 5%~10% (w / w), 6%~10% (w / w), 7%~10% (w / w), 8%~10% (w / w), or It contains 9% to 10% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0168] In some embodiments, the solid-state crystalline form of compound A is compound A form 9, with a total of 0.2%~5% (w / w), 0.3%~5% (w / w), 0.4%~5% (w / w), 0.5%~5% (w / w), 0.7%~5% (w / w), 0.8%~5% (w / w), 1%~5% (w / w), 1.5%~5% (w / w), 2%~5% (w / w), 2.5%~5% (w / w), 3%~5% (w / w), or It contains 4% to 5% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0169] In other embodiments, the solid-state crystalline form of compound A includes form 9 of compound A comprising 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).

[0170] 2.10. Compound A Form 10 Mixture In some embodiments, the solid-state crystalline form of compound A is compound A form 10 and a total of 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, and 3% It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of (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, or specific solid-state crystalline forms 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 6, compound A form 9, or compound A form 11, or combinations thereof.

[0171] In a particular embodiment, the solid-state crystalline form of compound A is compound A form 10, and in total, 0.1%~20% (w / w), 0.2%~20% (w / w), 0.5%~20% (w / w), 1%~20% (w / w), 2%~20% (w / w), 3%~20% (w / w), 4%~20% (w / w), 5%~20% (w / w), 6%~20% (w / w), 7%~20% (w / w), 8%~20% (w / w), 9%~20% (w / w), 10%~20% (w / w), 11%~20% (w / w), 12%~20% (w / w), 13%~20% (w / w), 14%~ It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 20% (w / w), 15%~20% (w / w), 16%~20% (w / w), 17%~20% (w / w), 18%~20% (w / w), or 19%~20% (w / w), or specific solid-state crystalline forms 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 combinations thereof.

[0172] In some embodiments, the solid-state crystalline form of compound A is compound A form 10, and in total 0.1%~15% (w / w), 0.2%~15% (w / w), 0.5%~15% (w / w), 1%~15% (w / w), 2%~15% (w / w), 3%~15% (w / w), 4%~15% (w / w), 5%~15% (w / w), 6%~15% (w / w), 7%~15% (w / w), 8%~15% (w / w), 9%~15% (w / w), 10%~15% (w / w), 11%~15% (w / It contains all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0173] In a particular embodiment, the solid-state crystalline form of compound A is compound A form 10, and in total amounts of 0.1%~10% (w / w), 0.2%~10% (w / w), 0.5%~10% (w / w), 1%~10% (w / w), 2%~10% (w / w), 3%~10% (w / w), 4%~10% (w / w), 5%~10% (w / w), 6%~10% (w / w), 7%~10% (w / w), 8%~10% (w / w), or It contains 9% to 10% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0174] In some embodiments, the solid-state crystalline form of compound A is compound A form 10, and in total amounts of 0.2%~5% (w / w), 0.3%~5% (w / w), 0.4%~5% (w / w), 0.5%~5% (w / w), 0.7%~5% (w / w), 0.8%~5% (w / w), 1%~5% (w / w), 1.5%~5% (w / w), 2%~5% (w / w), 2.5%~5% (w / w), 3%~5% (w / w), and so on. It contains 4% to 5% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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.

[0175] In other embodiments, the solid-state crystalline form of compound A includes 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) of compound A form 10.

[0176] 2.11. Compound A Form 11 Mixture In some embodiments, the solid-state crystalline form of compound A is compound A form 11 and a total of 20% (w / w) or less, 19% (w / w) or less, 18% (w / w) or less, 17% (w / w) or less, 16% (w / w) or less, 15% (w / w) or less, 14% (w / w) or less, 13% (w / w) or less, 12% (w / w) or less, 11% (w / w) or less, 10% (w / w) or less, 9% (w / w) or less, 8% (w / w) or less, 7% (w / w) or less, 6% (w / w) or less, 5% (w / w) or less, 4% (w / w) or less, and 3% It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of (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, or specific solid-state crystalline forms 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 combinations thereof.

[0177] In a particular embodiment, the solid-state crystalline form of compound A is compound A form 11, and in total 0.1%~20% (w / w), 0.2%~20% (w / w), 0.5%~20% (w / w), 1%~20% (w / w), 2%~20% (w / w), 3%~20% (w / w), 4%~20% (w / w), 5%~20% (w / w), 6%~20% (w / w), 7%~20% (w / w), 8%~20% (w / w), 9%~20% (w / w), 10%~20% (w / w), 11%~20% (w / w), 12%~20% (w / w), 13%~20% (w / w), 14%~ It contains all other solid-state crystalline forms of compound A disclosed herein, in amounts of 20% (w / w), 15%~20% (w / w), 16%~20% (w / w), 17%~20% (w / w), 18%~20% (w / w), or 19%~20% (w / w), or specific solid-state crystalline forms 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 combinations thereof.

[0178] In some embodiments, the solid-state crystalline form of compound A is compound A form 11, and in total 0.1%~15% (w / w), 0.2%~15% (w / w), 0.5%~15% (w / w), 1%~15% (w / w), 2%~15% (w / w), 3%~15% (w / w), 4%~15% (w / w), 5%~15% (w / w), 6%~15% (w / w), 7%~15% (w / w), 8%~15% (w / w), 9%~15% (w / w), 10%~15% (w / w), 11%~15% ( It contains all other solid-state crystalline forms of compound A disclosed herein, in w / w, 12%~15% (w / w), 13%~15% (w / w), or 14%~15% (w / w), or specific solid-state crystalline forms 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, compound A form 10, or combinations thereof.

[0179] In certain embodiments, the solid-state crystalline form of compound A is compound A form 11, with a total of 0.1%~10% (w / w), 0.2%~10% (w / w), 0.5%~10% (w / w), 1%~10% (w / w), 2%~10% (w / w), 3%~10% (w / w), 4%~10% (w / w), 5%~10% (w / w), 6%~10% (w / w), 7%~10% (w / w), 8%~10% (w / w), and so on. Alternatively, it may contain 9% to 10% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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, compound A form 10, or a combination thereof.

[0180] In some embodiments, the solid-state crystalline form of compound A is compound A form 11, with a total of 0.2%~5% (w / w), 0.3%~5% (w / w), 0.4%~5% (w / w), 0.5%~5% (w / w), 0.7%~5% (w / w), 0.8%~5% (w / w), 1%~5% (w / w), 1.5%~5% (w / w), 2%~5% (w / w), 2.5%~5% (w / w), 3%~5% (w / w), Alternatively, it may contain 4% to 5% (w / w) of all other solid-state crystalline forms of compound A disclosed herein, or specific solid-state crystalline forms 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, compound A form 10, or a combination thereof.

[0181] In other embodiments, the solid-state crystalline form of compound A includes 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) of compound A form 11.

[0182] 2.12. Treatment method using the solid form of compound A In some embodiments, the disclosure is directed to a method for treating a disease, disorder, or condition associated with Kv7 potassium channel dysfunction in a person requiring such treatment, comprising the step of orally administering a therapeutically effective amount of compound A in a solid state, e.g., crystalline form, to that person. In certain examples, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is a paroxysmal disorder, e.g., focal-onset epilepsy. In certain embodiments, the solid state 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.

[0183] In some embodiments, the present disclosure relates to a compound for use in the treatment of a disease, disorder, or condition in a human being that requires treatment for a disease, disorder, or condition associated with Kv7 potassium channel dysfunction, the compound being a solid-state form of compound A, and a therapeutically effective amount of this compound being directed to be orally administered to a human being. In certain examples, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is a paroxysmal disorder, 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.

[0184] In embodiments directed towards diseases, disorders, or conditions associated with Kv7 potassium channel dysfunction, in some examples, the method enhances the opening of Kv7 potassium channels such as one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5. In certain examples, the method or use is selective to enhance the opening of a Kv7 potassium channel selected from one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5 rather than Kv7.1. In some embodiments, the method or use is optionally selective for Kv7.2 rather than Kv7.1. In other embodiments, the method or use is optionally selective for Kv7.3 rather than Kv7.1. In yet another embodiment, the method or use is optionally selective for Kv7.4 rather than Kv7.1. In yet another embodiment, the method or use is optionally selective for Kv7.5 rather than Kv7.1. In certain embodiments, the above method or use is optionally selective for Kv7.2 and Kv7.3 over Kv7.1.

[0185] In one embodiment, the present disclosure provides a method for treating a paroxysmal disorder in a person in need, comprising the step of orally administering a certain amount of compound A in solid form to the person, wherein the amount of compound A in solid form is sufficient to treat the paroxysmal disorder in the person. In a particular embodiment, this amount is sufficient to reduce the severity of seizures, the frequency of seizures, or both. In a particular embodiment, 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.

[0186] In one embodiment, the present disclosure provides a compound for use in the treatment of a paroxysmal disorder in a person in need, wherein the compound is a solid-state form of compound A, and the compound is administered orally to the person. In a particular embodiment, this amount is sufficient to reduce the severity of seizures, the frequency of seizures, or both. In a particular embodiment, 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.

[0187] In one embodiment, the present disclosure provides a method for treating a paroxysmal disorder in a person in need, comprising the step of orally administering a certain amount of compound A in solid form to the person, wherein the amount of compound A in solid form is 2 to 200 mg. In a particular embodiment, 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.

[0188] In some embodiments, the disclosure is directed toward a method for treating a disease, disorder, or condition in a human being as needed that is associated with Kv7 potassium channel dysfunction, comprising the step of orally administering a therapeutically effective amount of compound A in solid form to a human being under feeding conditions. In certain examples, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is a seizure disorder 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.

[0189] In certain embodiments, the disclosure is directed to a method for treating a disease, disorder, or condition in a person requiring treatment for a Kv7 potassium channel dysfunction associated with it, comprising the step of orally administering a therapeutically effective amount of compound A in solid form to a person between 30 minutes before food intake and 2 hours after food intake. In certain examples, the disease, disorder, or condition associated with Kv7 potassium channel dysfunction is a seizure disorder 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.

[0190] In some embodiments, the present disclosure relates to compounds for use in the treatment of diseases, disorders, or conditions in humans as required, wherein the compound is a solid-state form of compound A, and is directed to be orally administered to humans under feeding conditions in a therapeutically effective amount of the compound. In certain examples, the diseases, disorders, or conditions associated with Kv7 potassium channel dysfunction are seizure disorders 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.

[0191] In certain embodiments, the present disclosure relates to a compound for use in the treatment of a disease, disorder, or condition in a human being that requires treatment, wherein the compound is a solid form of compound A, and a therapeutically effective amount of the compound is directed to be orally administered to a human being between 30 minutes before food ingestion and 2 hours after food ingestion. In certain embodiments, the disease, disorder, or condition that requires treatment is a seizure disorder 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.

[0192] In one embodiment, the present disclosure provides a method for treating a paroxysmal disorder in a person as needed, comprising the step of orally administering a certain amount of compound A in a solid state to a person under feeding conditions, wherein the amount of compound A is sufficient to treat a paroxysmal disorder in a person. In a particular embodiment, this amount is sufficient to reduce the severity of seizures, the frequency of seizures, or both. In a particular embodiment, the solid state 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.

[0193] In one embodiment, the present disclosure provides a compound for use in the treatment of a paroxysmal disorder in a human being in need, wherein the compound is a solid form of compound A, and the compound is administered orally to a human being under feeding conditions. In a particular embodiment, this amount is sufficient to reduce the severity of seizures, the frequency of seizures, or both. In a particular embodiment, 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.

[0194] In one embodiment, the present disclosure provides a method for treating a paroxysmal disorder in a person in need, comprising the step of orally administering a certain amount of compound A in solid form to a person between 30 minutes before or 2 hours after food intake, wherein the amount of compound A in solid form is sufficient to treat a paroxysmal disorder in a person. In a particular embodiment, this amount is sufficient to reduce the severity of seizures, the frequency of seizures, or both. In a particular embodiment, 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.

[0195] In one embodiment, the present disclosure provides a compound for use in the treatment of a paroxysmal disorder in a human being in need, wherein the compound is a solid form of compound A, and the compound is administered orally to a human being between 30 minutes before or 2 hours after food ingestion. In a particular embodiment, this amount is sufficient to reduce the severity of seizures, the frequency of seizures, or both. In a particular embodiment, 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.

[0196] In one embodiment, the present disclosure provides a method for treating a paroxysmal disorder in a person in need, comprising the step of orally administering a certain amount of compound A in solid form to a person under feeding conditions, wherein the amount of compound A in solid form is 2 to 200 mg. In a particular embodiment, 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.

[0197] In one embodiment, the present disclosure provides a method of treating a seizure disorder in a human in need thereof, comprising orally administering an amount of a solid state form of Compound A to the human from 30 minutes before food intake to 2 hours after food intake, wherein the amount of the solid state 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.

[0198] In one embodiment, the present disclosure provides a method for increasing one or more of C max , AUC inf , T max , or t1 / 2 λz of the solid state form of Compound A in a human receiving oral administration of 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), comprising orally administering an amount of the solid state form of Compound A to the human under fed conditions. In certain embodiments, the method increases one or more of C max , AUC inf , T max , or t1 / 2 λz as compared to when the same amount of the solid state form of Compound A is orally administered to the human under fasted conditions.

[0199] In one embodiment, the present disclosure provides a method for increasing one or more of C max , AUC inf , T max , or t1 / 2 λz of the solid state form of Compound A in a human receiving oral administration of 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), comprising orally administering an amount of the solid state form of Compound A to the human from 30 minutes before food intake to 2 hours after food intake. In certain embodiments, the method increases C maxAUC inf , T max , or t1 / 2 λz Increase one or more of them.

[0200] In one embodiment, the Disclosure provides a method for 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, the method comprising the step of orally administering the solid form of compound A to a person under feeding conditions. In a particular embodiment, the method provides a C of the solid form of compound A compared to the case where the same amount of the solid form of compound A is orally administered to a person under fasting conditions. max AUC inf , T max , or t1 / 2 λz Increase one or more of them.

[0201] In one embodiment, the Disclosure provides a method for 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, the method comprising the step of orally administering the solid form of compound A to the person between 30 minutes before food intake and 2 hours after food intake. In a particular embodiment, the method provides a C of the solid form of compound A compared to the case where the same amount of the solid form of compound A is orally administered to a person under fasting conditions. max AUC inf , T max , or t1 / 2 λz Increase one or more of them.

[0202] 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 dosage unit form suitable for oral administration. Compound A is present in the dosage unit form at levels ranging from about 0.05 mg / kg to about 2.0 mg / kg. More specific representative levels include 0.05 mg / kg, 0.10 mg / kg, 0.20 mg / kg, 0.30 mg / kg, 0.40 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.80 mg / kg, 0.90 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, and 2.0 mg / kg. In some embodiments, the method includes orally administering compound A in solid form at a dose of 0.1 to 1.0 mg / kg. In some embodiments, the method includes orally administering compound A in solid form at a dose of 0.2 to 0.5 mg / kg.

[0203] In some embodiments, the methods and uses described herein, for example, the methods or uses in the treatment of a paroxysmal disorder in humans as required by the methods and uses described herein, are achieved by orally administering 2 to 200 mg of compound A in solid 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). For example, this method is used for approximately 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, and 36 mg. Approximately 37mg, approximately 38mg, approximately 39mg, approximately 40mg, approximately 41mg, approximately 42mg, approximately 43mg, approximately 44mg, approximately 45mg, approximately 46mg, approximately 47mg, approximately 48mg, approximately 49mg, approximately 50mg, approximately 51mg, approximately 52mg, approximately 53mg, approximately 54mg, approximately 55mg, approximately 56mg, approximately 57mg, approximately 58mg, approximately 59mg, approximately 60mg, approximately 61mg, approximately 62mg, approximately 63mg, approximately 64mg, approximately 65mg, approximately 66mg, approximately 67mg, approximately 68mg, approximately 69mg, approximately 70mg, approximately 71mg, approximately 72mg, approximately 73mg, approximately 74mg, approximately 75mg, approximately 76mg, approximately 77mg, approximately 78mg, approximately 79mg, approximately 80mg, approximately 81mg, approximately 82mg, approximately 83mg, approximately 84mg, approximately 85mg, approximately 86mg, approximately 87mg, approximately 88mg, approximately 89mg, approximately 90mg, approximately 91mg, approximately 92mg, approximately 93mg, approximately 94mg, approximately 95mg, approximately 96mg, approximately 97mg, approximately 98mg, approximately 99mg, approximately 100mg, approximately 101mg, approximately 102mg, approximately 103mg, approximately 104 mg, about 105mg, about 106mg, about 107mg, about 108mg, about 109mg, about 110mg, about 111mg, about 112mg, about 113mg, about 114mg, about 115mg, about 116mg, about 117mg, about 118mg, about 1 19mg, about 120mg, about 121mg, about 122mg, about 123mg, about 124mg, about 125mg, about 126mg, about 127mg, about 129mg, about 130mg, about 131mg, about 132mg, about 133mg, about 134mg,Approximately 135mg, approximately 136mg, approximately 137mg, approximately 138mg, approximately 139mg, approximately 140mg, approximately 141mg, approximately 142mg, approximately 143mg, approximately 144mg, approximately 145mg, approximately 146mg, approximately 147mg, approximately 148mg, approximately 149mg, approximately 150mg, approximately 151mg, approximately 152mg, approximately 153mg, approximately 154mg, approximately 155mg, approximately 156mg, approximately 157mg, approximately 158mg, approximately 159mg, approximately 160mg, approximately 161mg, approximately 162mg, approximately 163mg, approximately 164mg, approximately 165mg, approximately 166mg, approximately 167mg, approximately 168mg, approximately 16 Oral administration of 9 mg, approximately 170 mg, approximately 171 mg, approximately 172 mg, approximately 173 mg, approximately 174 mg, approximately 175 mg, approximately 176 mg, approximately 177 mg, approximately 178 mg, approximately 179 mg, approximately 180 mg, approximately 181 mg, approximately 182 mg, approximately 183 mg, approximately 184 mg, approximately 185 mg, approximately 186 mg, approximately 187 mg, approximately 188 mg, approximately 189 mg, approximately 190 mg, approximately 191 mg, approximately 192 mg, approximately 193 mg, approximately 194 mg, approximately 195 mg, approximately 196 mg, approximately 197 mg, approximately 198 mg, approximately 199 mg, or approximately 200 mg may be included. In some embodiments, the oral administration contains 5 to 50 mg of compound A. In some embodiments, the oral administration contains 10 mg, 20 mg, or 25 mg of compound A. In some embodiments, the oral dose contains 20 mg of compound A. In some embodiments, the oral dose contains at least 20 mg of compound A.

[0204] In some embodiments, the methods and uses described herein, for example, the methods or uses in the treatment of a paroxysmal disorder in a human being as required by the methods and uses described herein, are achieved by orally administering 5 to 1000 mg of compound A in solid form per day (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, 5 to 500 mg or 5 to 250 mg of compound A in solid form per day. For example, this method involves approximately 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, and 13 mg per day. 5mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 2 00mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 2 65mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about Oral administration of 395 mg, approximately 400 mg, approximately 405 mg, approximately 410 mg, approximately 415 mg, approximately 420 mg, approximately 425 mg, approximately 430 mg, approximately 435 mg, approximately 440 mg, approximately 445 mg, approximately 450 mg, approximately 455 mg, approximately 460 mg, approximately 465 mg, approximately 470 mg, approximately 475 mg, approximately 480 mg, approximately 485 mg, approximately 490 mg, approximately 495 mg, approximately 500 mg, or approximately 1000 mg may be included.In some embodiments, oral administration includes orally administering 10 to 200 mg of compound A in solid form per day, for example 20 to 150 mg per day, or 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg to 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg of compound A in solid form per day. In some embodiments, oral administration includes 50 mg, 75 mg, 100 mg, or 125 mg per day, for example 100 mg of compound A in solid form per day.

[0205] In certain cases, the daily dose of compound A in solid form is administered orally as multiple daily doses, for example, two, three, four, or five times per day. For example, a daily dose of 100 mg may be administered as four 25 mg doses throughout the day.

[0206] In some embodiments, the daily dose of compound A described above is administered orally as a single dose. For example, compound A can be administered orally as a single dose in amounts ranging from approximately 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg per day to approximately 50 mg, 65 mg, 75 mg, 100 mg, 125 mg, or 150 mg per day, including single doses of 10-25 mg, 10-30 mg, and 10-40 mg per day, for example, 10-25 mg per day as a single dose.

[0207] In one embodiment of the present disclosure, administration of a solid form of compound A for, for example, the treatment of a paroxysmal disorder is considered to 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 a particular embodiment, the present disclosure provides a method for opening Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channels in a person in need, comprising the step of 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 use in opening Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channels in a person in need.

[0208] In certain embodiments, the methods and uses described herein involve administering compound A in solid 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) in the form of a pharmaceutically acceptable oral composition comprising compound A in solid form and one or more pharmaceutically acceptable carriers or excipients. The amount of compound A in solid form contained in these compositions corresponds to one or more of the amounts described herein. In some embodiments, this composition is a unit dose.

[0209] Examples of pharmaceutically acceptable oral compositions containing compound A in solid form include solid formulations (tablets, capsules, lozenges, sugar-coated tablets, granules, powders, multiparticle formulations, and films, etc.) and liquid formulations (aqueous solutions, elixirs, tinctures, suspensions, and dispersants, etc.). In one embodiment, a pharmaceutically acceptable oral composition of compound A in solid form is a suspension or granule for pediatric use. All of the above amounts of compound A in solid form may be contained in such formulations, for example, capsules containing 5 mg, 10 mg, 15 mg, 10 mg, 25 mg, 30 mg, or 35 mg of compound A in solid form.

[0210] In one embodiment of this disclosure, the therapeutically effective dose of compound A in solid form is approximately 0.05 mg / kg to approximately 2.0 mg / kg.

[0211] In certain embodiments of the present disclosure in which comparisons are made involving humans administered the solid form of compound A orally under fasting conditions, similar comparisons can be made involving humans who have not consumed food during the period from about 4 hours before 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, from about 4 hours, about 3 hours, about 2 hours, about 1.5 hours, about 1 hour, or from about 0.5 hours before oral administration of the solid form of compound A to about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, or about 4 hours after oral administration of the solid form of compound A.

[0212] In certain embodiments, when a paroxysmal disorder is treated with the present invention, the paroxysmal disorder is a partial-onset (focal) seizure, a photosensitive seizure, a self-induced syncope, an intractable epilepsy, Angelman syndrome, benign Rolandic epilepsy, CDKL5 disorder, childhood absence epilepsy and juvenile absence epilepsy, Dravet syndrome, frontal lobe epilepsy, glucose transporter 1 deficiency, hypothalamic hamartoma, infantile spasms / West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome (LGS), and The following conditions are selected: oclonic absence epilepsy, Ohtahara syndrome, Panaetopoulos syndrome, PCDH19 epilepsy, progressive myoclonus epilepsy, Rasmussen syndrome, ring chromosome 20 syndrome, reflex epilepsy, temporal lobe epilepsy, Lafora progressive myoclonus epilepsy, neurocutaneous syndromes, tuberous sclerosis, early infantile epileptic encephalopathy, early-onset epileptic encephalopathy, generalized epilepsy with febrile seizures plus, Rett syndrome, multiple sclerosis, Alzheimer's disease, autism, ataxia, hypotonia, and paroxysmal dyskinesia. In some embodiments, the paroxysmal disorder is focal epilepsy, also known as partial (focal) epilepsy.

[0213] Further embodiments and examples of the present disclosure are described herein. These embodiments and examples are illustrative and should not be construed as limiting the scope of the claimed disclosure.

[0214] 3. Pharmaceutical composition and administration In some embodiments, the disclosure is directed 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 disclosure is directed to a composition comprising a solid form of compound A and a pharmaceutically acceptable excipient in an amount effective to treat a seizure disorder when administered to an animal, preferably a mammal, most preferably a human.

[0215] The administration of compound A in its pure form or as a suitable pharmaceutical composition in its solid 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) can be carried out via any acceptable mode of administration of the agent to achieve similar utility. In one embodiment, the pharmaceutical composition disclosed herein can be prepared by combining the solid form of compound A disclosed herein with a suitable pharmaceutically acceptable excipient, and may be formulated into preparations in solid, semi-solid, liquid, or gaseous forms such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes for administering such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal administration. As used herein, the term parenteral includes subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques. The pharmaceutical compositions disclosed herein are formulated such that the active ingredients contained herein are bioavailable at the time of administration of the composition to a patient. Pharmaceutical compositions administered to mammals, preferably humans, take the form of one or more dosage units; for example, tablets may be single-dose units, and containers of the compounds disclosed in aerosol form may hold multiple dosage units. Practical methods of preparing such dosage forms will be known or obvious to those skilled in the art. See, for example, The Science and Practice of Pharmacy, latest edition (Philadelphia College of Pharmacy and Science, 2000). The administered composition in any case contains a therapeutically effective amount of compound A disclosed herein in solid form (e.g., crystalline form) for the treatment of the disease or condition of interest relating to this disclosure.

[0216] In one embodiment, the pharmaceutical composition disclosed herein also contains pharmaceutically acceptable excipients, which include any pharmaceutical agent that does not induce the production of antibodies harmful to the individual to whom the composition is administered and can be administered without excessive toxicity. In one embodiment, pharmaceutically acceptable excipients include, but are not limited to, liquids such as water, saline solution, glycerol, and ethanol. A detailed discussion of pharmaceutically acceptable excipients is presented in Remington's Pharmaceutical Sciences (Mack Pub. Co., New Jersey, latest edition).

[0217] In one embodiment, the pharmaceutical composition disclosed herein may be in solid or liquid form. In one embodiment, the excipient is a fine particle, and therefore the composition is, for example, in the form of a tablet or powder. The excipient may also be a liquid, in which case the composition is, for example, an oral syrup, a liquid for injection, or an aerosol useful for, for example, inhalation administration.

[0218] In one embodiment, when intended for oral administration, the pharmaceutical compositions disclosed herein are preferably in either solid or liquid form, and semi-solid, semi-liquid, suspension, and gel forms are included within the forms considered herein as either solid or liquid.

[0219] In one embodiment, as a solid composition for oral administration, the pharmaceutical composition disclosed herein may be formulated in the form of powder, granules, compressed tablets, pills, capsules, chewing gum, wafers, etc. Such a solid composition typically contains one or more inert or edible excipients. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, gum tragacanth (tragacanth gum), or gelatin; excipients such as starch, lactose, or dextrin; disintegrants such as alginic acid, sodium alginate, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotex; flow enhancers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavoring agents such as peppermint, methyl salicylate, or orange flavoring; and colorants.

[0220] In one embodiment, if the pharmaceutical composition disclosed herein is in the form of a capsule, for example, a gelatin capsule, the pharmaceutical composition may contain, in addition to the above-mentioned types of materials, a liquid excipient such as polyethylene glycol or oil.

[0221] In one embodiment, the pharmaceutical compositions disclosed herein may be in the form of a liquid, such as an elixir, syrup, solution, emulsion, or suspension. This liquid may, as two examples, be for oral administration or for delivery by injection. When intended for oral administration, a preferred composition contains, in addition to the solid form of compound A, one or more of the following: sweeteners, preservatives, dyes / colorants, and flavor enhancers. Compositions intended for administration by injection may contain one or more of the following: surfactants, preservatives, wetting agents, dispersants, suspending agents, buffers, stabilizers, and isotonic agents.

[0222] In one embodiment, the liquid pharmaceutical composition disclosed herein, whether in solution, suspension or other similar form, may contain one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, or isotonic sodium chloride; non-volatile oils such as synthetic monoglycerides or diglycerides that may function as a solvent or suspension medium; polyethylene glycol, glycerin, propylene glycol, or other solvents; antimicrobial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers (e.g., acetates, citrates, or phosphates) and agents for adjusting tonicity (osmotic pressure) such as sodium chloride or dextrose. Parenteral preparations can be sealed in glass or plastic ampoules, disposable syringes, or multi-dose vials. Physiological saline is a preferred adjuvant. The pharmaceutical composition for injection is preferably sterile.

[0223] In one embodiment, a liquid pharmaceutical composition disclosed herein, intended for either parenteral or oral administration, must contain an amount of compound A in solid form that provides an appropriate dose. In one embodiment, this amount is at least 0.01% of the solid form of compound A in the formulation. When intended for oral administration, this amount may vary in one embodiment to 0.1% to about 70% of the weight of the composition. In one embodiment, an oral pharmaceutical composition disclosed herein contains about 4% to about 50% of the solid form of compound A. In another embodiment, a pharmaceutical composition disclosed herein is prepared such that parenteral administration units contain 0.01% to 10% by weight of the solid form of compound A before dilution.

[0224] In one embodiment, the pharmaceutical composition disclosed herein may be intended for topical administration, in which case the excipients may appropriately comprise a solution, emulsion, ointment, or gel base. This base may comprise, for example, one or more of the following: diluents such as petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, water, and alcohol, as well as emulsifiers and stabilizers. A thickener may be present in the pharmaceutical composition for topical administration. If transdermal administration is intended, the composition may comprise a transdermal patch or an iontophoresis device. The topical formulation may contain compound A in solid form at a concentration of about 0.1 to about 10% w / v (weight per unit volume).

[0225] In one embodiment, the pharmaceutical compositions disclosed herein may be intended for rectal administration, for example, in the form of suppositories, which dissolve in the rectum to release the drug. Compositions for rectal administration may contain an oily base as a suitable non-irritating excipient. Examples of such bases include, but are not limited to, lanolin, cocoa butter, and polyethylene glycol.

[0226] In one embodiment, the pharmaceutical composition disclosed herein for intramuscular or intrathecal administration comprises a suspension or solution of the active ingredient in an oil, or a solution of the active ingredient in an oil, such as peanut oil or sesame oil. In one embodiment, the pharmaceutical composition disclosed herein for intravenous or intrathecal administration comprises, for example, a sterile isotonic aqueous solution containing the active ingredient and dextrose or sodium chloride or a mixture of dextrose and sodium chloride.

[0227] In one embodiment, the pharmaceutical composition disclosed herein can be formulated to provide rapid, sustained or delayed release of the solid state form of the active ingredient, i.e., Compound A, after administration to a patient by using procedures 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 shown in U.S. Pat. No. 3,845,770 and U.S. Pat. No. 4,326,525, and P.J. Kuzma et al., Regional Anesthesia 22(6):543-551(1997), all of which are incorporated herein by reference.

[0228] In one embodiment, the pharmaceutical composition disclosed herein can also be delivered via an intranasal drug delivery system for local, systemic, and nose-to-brain medical therapy. It is known to those skilled in the art that Controlled Particle Dispersion (CPD)™ technology, traditional nasal spray bottles, inhalers or nebulizers provide effective local and systemic delivery of drugs by targeting the olfactory region and paranasal sinuses.

[0229] In one embodiment, the pharmaceutical composition disclosed herein is directed to an intravaginal shell or core drug delivery device suitable for administration to a human female or female animal. The device may be composed of the active pharmaceutical ingredient in a polymer matrix that is surrounded by a sheath and is capable of releasing the solid state form of Compound A in a substantially zero-order pattern daily.

[0230] In one embodiment, the most suitable route of administration for the solid state form of Compound A or the pharmaceutical composition disclosed herein will depend on the nature and severity of the condition to be treated. Those skilled in the art are also familiar with determining the administration method (e.g., oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage forms, suitable pharmaceutical excipients, and other matters related to the delivery of the solid state form of Compound A to a subject in need thereof.

[0231] In some embodiments, the pharmaceutical composition disclosed herein may comprise various materials that modify the physical form of solid or liquid dosage units. For example, the pharmaceutical composition may comprise a material that forms a coating shell around the active ingredient. The materials forming the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredient may be enclosed in a polymer capsule.

[0232] In one embodiment, the pharmaceutical composition disclosed herein in solid or liquid form may comprise an agent that binds to the solid state form of Compound A, thereby assisting in the delivery of the solid state form. Suitable agents that can act in this capacity include monoclonal or polyclonal antibodies, proteins, or liposomes.

[0233] In one embodiment, the pharmaceutical composition disclosed herein may consist of a dosage unit that can be administered as an aerosol. The term aerosol is used to refer to various systems ranging from colloidal systems to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas, or by a suitable pump system that dispenses the active ingredient. Aerosols of the solid state form of Compound A may be delivered in a single-phase, two-phase, or three-phase system to deliver the active ingredient(s). Aerosol delivery comprises the required container, activator, valve, secondary container, etc., which may together form a kit. Those skilled in the art will be able to determine a preferred aerosol without undue experimentation.

[0234] In one embodiment, the pharmaceutical compositions disclosed herein may be prepared by methodologies well known in the pharmaceutical field. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining the solid form of compound A with sterile distilled water to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. The surfactant is a compound that interacts non-covalently with the solid form of compound A to facilitate the dissolution or homogeneous suspension of the compound in an aqueous delivery system.

[0235] In one embodiment, a pharmaceutical composition comprising compound A in a solid state, or a solid state of compound A disclosed herein, 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 dose. Generally, the therapeutically effective daily dose of compound A in a solid state is about 0.001 mg / kg (i.e., 0.07 mg) to about 100 mg / kg (i.e., 7.0 g) (for a 70 kg mammal), preferably the therapeutically effective dose is about 0.01 mg / kg (i.e., 0.70 mg) to about 50 mg / kg (i.e., 3.5 g) (for a 70 kg mammal), and more preferably the therapeutically effective dose is about 1 mg / kg (i.e., 70 mg) to about 25 mg / kg (i.e., 1.75 g) (for a 70 kg mammal).

[0236] The range of effective doses provided herein is not intended to be limiting, but rather represents a preferred dose range. However, the effective dose can be determined by methods well known to those skilled in the art (e.g., Berkow et al., The Merck Manual, 19th edition, Merck and Co., Rahway, New Jersey, 2011; Brunton et al., Goodman and Cilman's The Pharmacological Basis of Therapeutics, 12th edition, McGraw-Hill, 2011; Avery's Drug Treatment: Principles and Practice of Clinical Pharmacology and Therapeutics, 3rd edition, ADIS Press, LTD., Williams and Wilkins, Baltimore, Maryland (1987); Ebadi, Pharmacology, Little, Brown and Co., Boston (1985); Osolci et al., Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton, Pennsylvania; Katzung, Basic and Clinical Pharmacology, Appleton and See Lange, Norwalk, Connecticut (1992).

[0237] The total dose required for each treatment may be administered in multiple doses or single doses over the course of the day, as desired. Generally, treatment is initiated with a dose less than the optimal dose of the compound. Thereafter, the dose is gradually increased until the optimal effect is achieved under the circumstances. Diagnostic pharmaceutical compounds or compositions may be administered alone or in combination with other diagnostic agents and / or pharmaceuticals directed towards a disease condition or other symptoms of that condition. The effective dose of compound A in solid form is approximately 0.1 μg to approximately 100 mg / kg body weight, administered at intervals of 4 to 72 hours, for periods of 2 hours to 1 year, and / or any range or value within these periods, for example, 0.0001 to 0.001, 0.001 to 0.01, 0.01 to 0.1, 0.1 to 1.0, 1.0 to 10, 5 to 10, 10 to 20, 20 to 50, and 50 to 100 mg / kg, at intervals of 1 to 4, 4 to 10, 10 to 16, 16 to 24, 24 to 36, 24 to 36, 36 to 48, 48 to 72 hours, for periods of 1 to 14, 14 to 28, or 30 to 44 days, or 1 to 24 weeks, or any range or value within these periods.

[0238] In one embodiment, the recipient of administration of the solid form of compound A described herein or a pharmaceutical composition containing the solid form of compound A may be any animal, such as a mammal. Among mammals, preferred recipients are mammals of the order Primates (including humans, apes, and monkeys), Artiodactyla (including horses, goats, cattle, sheep, and pigs), Rodentia (including mice, rats, and hamsters), Lagomorpha (including rabbits), and Carnivora (including cats and dogs). Among birds, preferred recipients are turkeys, chickens, and other members of the same order. The most preferred recipient is human.

[0239] 4. Method for preparing the solid-state crystalline form of compound A In certain embodiments, the Disclosure provides a method for preparing the solid-state crystalline forms 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) by, for example, recrystallizing from another form of compound A.

[0240] In one embodiment, the present disclosure 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-aqueous solution (e.g., ethanol-water), optionally shaking the slurry (e.g., at ambient temperature), cooling the slurry, and separating the slurry (e.g., by centrifugation) to prepare compound A form 2.

[0241] In one embodiment, the present disclosure provides a method for preparing compound A form 3 from compound A form 2 and compound A form 4, for example, by forming slurries 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.

[0242] In one embodiment, the present disclosure 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., ethanol at 40°C), cooling the slurry, adding a poor solvent (e.g., water), and separating the precipitate (e.g., by centrifugation) to prepare compound A form 4.

[0243] In one embodiment, the present disclosure 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 an acyclic 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., 40°C to ambient temperature), and separating the slurry (e.g., by filtration) to prepare compound A form 5.

[0244] In one embodiment, the present disclosure 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 aqueous ether 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., 40°C to ambient temperature), and separating the slurry (e.g., by filtration) to prepare compound A form 6.

[0245] In one embodiment, the present disclosure provides a method for preparing compound A form 7 from compound A form 1, comprising, for example, forming a slurry of compound A form 1 in an ether solvent (e.g., tetrahydrofuran) or a ketone aqueous 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., 40°C to ambient temperature), and separating the slurry (e.g., by filtration) to prepare compound A form 7.

[0246] In one embodiment, the present disclosure 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., 40°C to ambient temperature), separating the slurry (e.g., by filtration), and slowly evaporating the supernatant to prepare compound A form 8.

[0247] In one embodiment, the present disclosure 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 pressing compound A form 4 flat before adding it to the VT-XRPD sample holder, and processing it through one or more scanning and heating cycles (e.g., 25°C to 140°C) to prepare compound A form 9.

[0248] In one embodiment, the present disclosure provides a method for preparing Compound A Form 1 to Compound A Form 9, which comprises, for example, dissolving Compound A in an alcohol solvent (e.g., methanol), adding an aqueous acid solution (e.g., 1M sulfuric acid), adding an antisolvent (e.g., water), and separating the precipitate (e.g., by filtration) to prepare Compound A Form 9.

[0249] In one embodiment, the present disclosure provides a method for preparing Compound A Form 1 to Compound A Form 10, which comprises, for example, slurrying Compound A Form 1 in an ether solvent (e.g., tetrahydrofuran), diluting the slurry with an additional ether solvent (e.g., tetrahydrofuran), treating the slurry with one or more heating and cooling cycles (e.g., 40°C to ambient temperature), and separating the slurry (e.g., by centrifugation) to prepare Compound A Form 10.

[0250] In one embodiment, the present disclosure provides a method for preparing Compound A Form 1 to Compound A Form 11, which comprises, for example, 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 dissolution, cooling the solution (e.g., at 5°C), treating with one or more heating and cooling cycles (e.g., 40°C to ambient temperature), and separating the slurry (e.g., by centrifugation) to prepare Compound A Form 11.

[0251] In another embodiment, the present disclosure provides a method for preparing a pharmaceutical composition comprising a pharmaceutical excipient and a solid-state 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), which comprises, for example, combining the solid-state crystalline form of Compound A with the pharmaceutical excipient to form the pharmaceutical composition. Examples

[0252] 1. Analytical methods The solid-state crystalline form of compound A was characterized by one or more of the following analytical methods. It should be understood that equivalent data may be generated using similar instruments.

[0253] 1.1. A. X-ray Powder Diffraction (XRPD) XRPD analysis was performed using a PANalytical X'pert pro equipped with a PIXcel detector (128 channels), scanning the sample between 3 and 35°²θ. The material was gently ground to release aggregates and loaded into a multiwell plate with Kapton or Mylar polymer film to support the sample. This multiwell plate was then placed in a diffractometer and analyzed using the Cu K line (α1λ=1.54060Å; α2=1.54443Å; β=1.39225Å; α1:α2 ratio=0.5) running in transmission mode (step size 0.0130°²θ, step time 18.87 sec) with a 40kV / 40mA generator setting. The data was visualized, and images were generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017).

[0254] 1.2. B. Polarized Light Microscopy (PLM) The presence of crystallinity (birefringence) was determined using an Olympus BX50 microscope equipped with cross-polarizing lenses and a Motic camera. Images were captured using Motic Images Plus 2.0. Unless otherwise specified, all images were recorded using a 20x objective lens. All images were collected using cross-polarizers and non-cross-polarizers to highlight the birefringent regions.

[0255] 1.3. C. Hot-stage optical microscopy Thermal phenomena were visually monitored using a calibrated Linkam THM600 hot stage with a connected 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 the microscope coverslip and heated at a rate of 10°C / min, and images were taken at conventional intervals to record the thermal transition. All images were recorded using a 10x objective lens unless otherwise specified. The following heating programs were used for all samples. 1. Initial heating from ambient temperature to 100°C was performed at a rate of 10°C / min, and images were acquired at 10°C increments. 2. Heating was performed from 100°C to 160°C at a rate of 1°C / minute, and images were acquired at 1°C increments. 3. The final heating was performed at 10°C / min from 160°C to 200°C, and images were acquired at 10°C intervals.

[0256] 1.4. D. Thermogravimetric / Differential Thermal Analysis (TG / DTA) Approximately 5 mg of the material was weighed into an open aluminum pan and loaded into a simultaneous thermogravimetric / differential thermal analyzer (TG / DTA), where it was 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 was recorded along with arbitrary differential thermal events (DTA). Nitrogen was used as a purge gas at a rate of 300 cm³. 3 It was used at a flow rate of [number] minutes.

[0257] 1.5. E. Differential Scanning Calorimetry (DSC) Approximately 5 mg of the material was weighed into an aluminum DSC pan and sealed airtight with a perforated aluminum lid. The sample pan was then loaded into a Seiko DSC6200 (equipped with a cooling device), 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 scanning rate of 10°C / min, and the resulting heat flow response was monitored. Nitrogen was used as a purge gas at a rate of 50 cm³. 3The sample was used at a flow rate of [number] / min. Similar data was then obtained in a cooling cycle in which the sample (initially at 220°C) was cooled to a final temperature of 20°C at a scanning rate of 10°C / min. After holding the sample at 20°C for 3 minutes, a second heating cycle was performed. This second heating cycle was carried out at a scanning rate of 10°C / min to a final temperature of 220°C, and then held at 220°C for 5 minutes.

[0258] 1.6. F. Karl Fischer coulometric titration (KF) Approximately 10-15 mg of solid material was accurately weighed and placed in a vial. This solid was then manually introduced into the titration cell of a Mettler Toledo C30 Compact Titrator. After adding the solid, the vial was back-weighed, and the weight of the added solid was entered into the instrument. Titration was started when the sample was completely dissolved in the cell. The water content was automatically calculated as a percentage by the instrument, and the data was printed.

[0259] 1.7. G. Fourier Transform Infrared Spectroscopy (FTIR) Infrared spectroscopy was performed using a Bruker ALPHA P spectrometer. Sufficient material was placed in the center of the spectrometer plate, and spectra were obtained using the following parameters. Resolution: 4cm -1 Background scan time: 16 scans Sample scanning time: 16 scans Data collection: 4000~400cm -1 Resulting spectrum: Transmittance Software: OPUS version 6

[0260] 1.8. H. 1 H nuclear magnetic resonance ( 1 (H NMR) 1 ¹H NMR experiments were performed using a Bruker AVIIIHD spectrometer equipped with a DCH cryoprobe operating at 500.12 MHz for protons. The experiments were conducted in deuterated DMSO-d6, and each sample was prepared to a concentration of approximately 10 mM.

[0261] 1.9. I. Gravimetric vapor sorption (GVS) Approximately 10–20 mg of sample was placed in a mesh vapor sorbing balance dish and loaded onto a Hiden Analytical IGASorp Moisture Sorption Analyser balance. The sample was subjected to ramping profiles at 40–90% relative humidity (RH) in 10% increments, and the sample was maintained at each step until a stable weight was achieved at 25°C (98% step completion, minimum step length 30 minutes, maximum step length 60 minutes). After the sorbing cycle was complete, 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 outlined above. Two complete cycles were performed. The weight change during the sorbing / desorbing cycle was plotted, allowing for the determination of the sample's hygroscopicity.

[0262] 1.10. J. Variable Temperature X-ray Powder Diffraction (VT-XRPD) VT-XRPD analysis was performed using a Philips X'Pert Pro multi-purpose diffractometer equipped with a temperature chamber. The sample was loaded onto the VT stage and scanned between 4 and 35.99°²θ using a Cu K-line (α1λ=1.54060Å; α2=1.54443Å; β=1.39225Å; α1:α2 ratio=0.5) running in a Bragg-Brentano structure (step size 0.008°²θ) with a 40kV / 40mA generator setting. Measurements were performed at various temperature profiles. Any holding at specific temperatures is described in the temperature profile for individual samples.

[0263] 1.11. K. High-performance liquid chromatography-ultraviolet detection (HPLC-UV) HPLC-UV was performed on compound A using the following parameters. Column: LC 201 / 216 Waters Acquity C18 2.1×50mm, 1.7μm Column temperature: 50℃ Autosampler temperature: Ambient temperature UV wavelength: 265nm Injection volume: 2.00μL Flow rate: 0.75mL / min Mobile phase A: 90:10v / v% water:0.1% TFA in acetonitrile Mobile phase B: 0.1% TFA in acetonitrile Diluent: 75:25v / v% acetonitrile:water

[0264] Gradient program: [Table 1] Note: Any peaks not included in the results were not present in the blanks.

[0265] 1.12. L. Gas Chromatography (GC) GC was performed on compound A using the following parameters. Column: Agilent J&W DB-624 30m x 0.32mm 1.8μm df or equivalent. Oven temperature: 35°C (hold for 0.5 minutes) → 45°C (16.5°C / min) → 70°C (5.0°C / min) → 220°C (30.0°C / min) Flow rate: 2.2mL / min (constant flow) Carrier gas: Hydrogen Injection mode: Split Injection temperature: 225℃ Injection split ratio: 5:1 Detector temperature: 270℃ Detector hydrogen: 40.0 mL / min Detector air: 400 mL / min Makeup flow: 30.0 mL / min Makeup gas: Air

[0266] Headspace parameters: Oven temperature: 100℃ Loop temperature: 110℃ Transfer line temperature: 150℃ Vial equilibration time: 10.0 minutes Pressurization time: 0.2 minutes Loop filling time: 0.2 minutes Loop equilibrium time: 0.05 minutes Loop volume: 1 mL Injection time: 1.0 minute Vial shaking: High GC cycle time: 15 minutes

[0267] 1.13. M. Particle Size Distribution (PSD) Approximately 60 mg of the sample was weighed into a 20 mL scintillation vial. 10 mL of dispersant was added and mixed. This sample was sonicated for 30 seconds, then thoroughly mixed with a pipette and added to a dispersion unit to achieve an absorbance of 8–20%. Measurements were performed according to the following parameters. Absorption 1.0 Particle RI 1.56 Dispersant RI 1.39 Dispersant: 0.05% w / v Span-85 in heptane Stirring speed: 2000 rpm Absorbance limit: 8-20% Ultrasonic treatment time: 30 seconds Measurement 3 x 10 seconds Background 10 seconds General-purpose analysis model Sensitivity: Normal Particle shape irregularity

[0268] 2. Preparation of Compound A and the solid state of Compound A 2.1. A. Preparation of Compound A Form 1 In one embodiment, compound A form 1 was prepared as described in the following reaction scheme. In the scheme, compounds (1), (2), (3), and (4) are commercially available or can be prepared according to methods known to those skilled in the art. [ka]

[0269] Step 1: An acetonitrile solution of 4-bromo-2,6-dimethylaniline (compound 1) was treated with N,N-diisopropylethylamine (DIPEA), and the mixture was cooled to 0°C. While maintaining a temperature below 10°C, tert-butylacetyl chloride (compound 2) was added to the solution of compound 1 over 90 minutes. The mixture was then diluted with acetonitrile, and this solution was heated to 20-25°C and stirred for 2 hours. Upon completion, the mixture was diluted with process water, and the resulting slurry was stirred for 30 minutes. The solid was then recovered by vacuum filtration, washed twice with process water, and dried under nitrogen for at least 2 hours. The filtered cake was 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).

[0270] 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). Nitrogen (N2) gas was injected into this mixture for 1 hour, then bis(dibenzylideneacetone)palladium (Pd(dba)2) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)biphenyl (DavePhos) were added, and the mixture was heated to 77°C under an N2 atmosphere and stirred for 12 hours. The mixture was then cooled to 40°C and diluted with 2-MeTHF. This 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 being separated. Next, the aqueous and organic phases were removed, and the reactor was rinsed with additional 2-MeTHF.

[0271] Step 2B: The combined organic matter was added to another reactor filled with SiliaMetS-DMT® and diluted with additional 2-MeTHF. The mixture was purged with nitrogen five times and stirred at 45°C for a minimum of 4 hours. The mixture was then filtered, the solid was rinsed with 2-MeTHF at 50°C, and then cooled to approximately 20-30°C. The SiliaMetS-DMT® treatment was then repeated one more time in the same manner as described above.

[0272] Next, a 2-MeTHF solution of 10% n-heptane was added to a 2-MeTHF solution of compound A form 1 isolated after treatment with SiliaMetS-DMT(registered trademark). The mixture was heated at 50°C for 15 minutes until all solids appeared to dissolve. The solution was then cooled, further diluted with 2-MeTHF, and concentrated under vacuum. The concentrated solution was then diluted again with 2-MeTHF and heated at 50°C for 15 minutes. The solution was then cooled, further diluted with 2-MeTHF, and concentrated under vacuum until the solids were visible. The solution was then heated under reflux to dissolve all present solids, then diluted with n-heptane, cooled, and concentrated under vacuum. The concentrated solution was then diluted with n-heptane, concentrated under vacuum, the solids were filtered, rinsed with the filtrate, and rinsed twice with a 2-MeTHF solution of 10% n-heptane. The filtered solids were dried under vacuum and then transferred to a vacuum oven for further drying.

[0273] Next, the solid was recrystallized a second time in 2-methyltetrahydrofuran (2-MeTHF) that had been pre-treated with N2 for at least 15 minutes. After adding the solid, N2 was further treated in the mixture 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 maintained under a steady flow of N2. The filtered cake was rinsed with heptane, dried under an N2 blanket, and then transferred to a vacuum oven and heated to 50°C under an N2 atmosphere to obtain compound A form 1 (see Figure 1).

[0274] 2.2. B. Preparation of Compound A Form 2 In one embodiment, compound A form 2 was prepared by first slurring about 500 mg of compound A form 1 in about 3 mL of ethanol:water (10:90 v / v%) solution. This slurry was then shaken at ambient temperature for about 2 hours and stored at 5°C for about 72 hours. The slurry was then separated by centrifugation, and the wet solid was dried under vacuum at 40°C for about 24 hours. The resulting dried material was found to be compound A form 2 having the XRPD pattern shown in Figure 8.

[0275] 2.3. C. Preparation of Compound A Form 3 In one embodiment, compound A form 3 was prepared by weighing approximately 15 mg each of compound A form 2 and compound A form 4 into a 2 mL glass vial. Aliquots of dichloromethane were added to the vial at ambient temperature until a movable slurry was formed. The resulting slurry was stirred at ambient temperature for approximately 24 hours. The observed solid was isolated and characterized by XRPD, and was found to be compound A form 3 with the XRPD pattern shown in Figure 16.

[0276] 2.4. D. Preparation of Compound A Form 4 In one embodiment, compound A form 4 was prepared by dissolving approximately 250 mg of compound A form 1 in approximately 3.5 mL of ethanol at 40°C. After 1 hour at 40°C, the solution was cooled to 20°C at a rate of 0.2°C / min. The solution was held at 20°C for 1 hour, then cooled to 5°C at a rate of 0.1°C / min. After 18 hours at 5°C, 15 mL of water was added as a poor solvent, and the solution was then held at 5°C for 2 hours before being separated by centrifugation. The mother liquor was then analyzed for concentration by HPLC. The wet solid was vacuum-dried at 40°C for approximately 2 hours and then analyzed. The resulting dried material was found to be compound form 4, having the XRPD pattern shown in Figure 17.

[0277] 2.5. E. Preparation of Compound A Form 5 In one embodiment, a slurry was prepared by adding approximately 40 mg of compound A form 1 to 500 μL of methyl isobutyl ketone. If dissolution occurred during preparation, additional amounts of compound A form 1 were added. The resulting slurry was subjected to a continuous 4-hour heating and cooling cycle between 40°C and ambient temperature for 72 hours. The resulting mixture was filtered, and the isolated wet solid was analyzed by XRPD, which revealed it to be compound form 5, having the XRPD pattern shown in Figure 25.

[0278] 2.6. F. Preparation of Compound A Form 6 In one embodiment, a slurry was prepared by adding approximately 40 mg of compound A form 1 to 300 μL of tetrahydrofuran / water (99:1). If dissolution occurred during preparation, additional amounts of compound A form 1 were added. The resulting slurry was subjected to a continuous 4-hour heating and cooling cycle between 40°C and ambient temperature for 72 hours. The resulting mixture was filtered, and the isolated wet solid was analyzed by XRPD, which revealed it to be compound form 6, having the XRPD pattern shown in Figure 26.

[0279] 2.7. G. Preparation of Compound A Form 7 In one embodiment, a slurry was prepared by adding approximately 40 mg of compound A form 1 to 300 μL of tetrahydrofuran. If dissolution occurred during preparation, additional amounts of compound A form 1 were added. The resulting slurry was subjected to a continuous 4-hour heating and cooling cycle between 40°C and ambient temperature for 72 hours. The resulting mixture was filtered, and the isolated wet solid was analyzed by XRPD, which revealed it to be compound form 7, having the XRPD pattern shown in Figure 27.

[0280] In another embodiment, a slurry was prepared by adding approximately 40 mg of compound A form 1 to 1500 μL of acetone / water (75:25). If dissolution occurred during preparation, additional amounts of compound A form 1 were added. The resulting slurry was subjected to a continuous 4-hour heating and cooling cycle between 40°C and ambient temperature for 72 hours. The resulting mixture was filtered, and the isolated wet solid was analyzed by XRPD, which revealed it to be compound form 7, having the XRPD pattern shown in Figure 27.

[0281] 2.8. H. Preparation of Compound A Form 8 In one embodiment, a slurry was prepared by adding approximately 40 mg of compound A form 1 to 300 μL of cyclohexanone. If dissolution occurred during preparation, additional amounts of compound A form 1 were added. The resulting slurry was subjected to a continuous 4-hour heating and cooling cycle between 40°C and ambient temperature for 72 hours. The resulting mixture was filtered, the supernatant was transferred to a bale, and allowed to evaporate at ambient temperature without capping. Once sufficient material was obtained, it was analyzed by XRPD and found to be compound form 8, having the XRPD pattern shown in Figure 28.

[0282] 2.9. I. Preparation of Compound A Form 9 In one embodiment, a sample of compound A form 4 was placed in a VT-XRPD sample holder, pressed flat, loaded into a VT-XRPD, heated to over 140°C, and then cooled using the method shown in Table 13 below.

[0283] [Table 2]

[0284] The obtained dried material was identified as compound A form 9, which has the XRPD pattern shown in Figure 29.

[0285] In another embodiment, compound A form 9 was prepared by adding approximately 500 mg of compound A form 1 to methanol (3 mL), followed by the addition of an aqueous sulfuric acid solution (1 M, 1425 μl, 1.05 equivalents). After approximately 2 minutes, water (5 mL) was added as a poor solvent to induce precipitation and prepare a concentrated slurry. The solid was filtered and analyzed by XRPD, and was found to be compound A form 9 with the XRPD pattern shown in Figure 29.

[0286] 2.10. J. Preparation of Compound A Form 10 In one embodiment, approximately 500 mg of compound A form 1 was weighed into a 20 mL scintillation vial. 500 μL aliquots of tetrahydrofuran were added until a movable slurry was formed. 2 mL of tetrahydrofuran was added. The sample was subjected to a temperature cycle between ambient temperature and 40°C for approximately 4 hours in 1-hour cycles. The observed solid was isolated by centrifugation and characterized by XRPD, and was found to be compound A form 10 as shown in Figure 37.

[0287] 2.11. K. Preparation of Compound A Form 11 In one embodiment, compound A form 11 was prepared by dissolving approximately 500 mg of compound A form 1 in approximately 3 mL of ethanol. The resulting slurry was shaken at ambient temperature for approximately 2 hours and then stored at 5°C for approximately 90 hours. Analysis of the sample by XRPD showed that the material was compound A form 4. The slurry was then heated to 40°C for approximately 2 hours until the solid was completely dissolved. The material was then stored at 5°C for 72 hours. The slurry was then subjected to a temperature cycle between ambient temperature and 40°C for approximately 72 hours. The slurry was then separated by centrifugation, and the wet solid was dried at ambient temperature for 18 hours, followed by drying under vacuum at 40°C for approximately 6 hours. Analysis of the resulting dried material by XRPD revealed that it was compound A form 11, having the XRPD pattern shown in Figure 39.

[0288] 3. Characterization of the solid state form of compound A 3.1. A. Characterization of Compound A Form 1 In one embodiment, the Disclosure provides a solid form of Compound A, referred to herein as Compound A Form 2. In some embodiments, the Disclosure provides Compound A Form 2 having an XRPD pattern substantially similar to that shown in Figure 1. In other embodiments, the Disclosure provides a mixture of Compound A Form 2 and Compound A Form 3, wherein Compound A Form 2 is dominant. These forms can be distinguished by XRPD (see Figure 1).

[0289] In one embodiment, PGM analysis of compound A form 1 showed small particles that lacked a distinct morphology and exhibited some aggregation and birefringence (see Figure 2).

[0290] In another embodiment, TG analysis of compound A form 1 showed a 0.6% weight loss up to 200°C and subsequent decomposition. DTA revealed a complex thermal event with an onset at 184°C, an endothermic peak at 186°C, an exothermic peak at 188°C, and a larger endothermic peak at 193°C (see Figure 3).

[0291] In another embodiment, DSC analysis of compound A form 1 after initial heating showed a complex thermal event with an initiation at 184°C, 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 with an initiation at 153°C and a peak at 151°C (see Figure 5). The second heating showed two endothermic events: a small endothermic peak with an initiation at 185°C and a peak at 187°C, and a second largest peak with an initiation at 191°C and a peak at 193°C (see Figure 6).

[0292] After dissolving compound A form 1 in DMSO-d6 1 Analysis was performed by 1H NMR. In one embodiment, the obtained 1 The 1H NMR spectrograph (see Figure 7) showed consistency with the structure of compound A form 1.

[0293] 3.2. B. Characterization of Compound A Form 2 In one embodiment, this disclosure is directed to a solid-state form of compound A, which is referred to herein as compound A form 2. In some embodiments, this disclosure provides compound A form 2 having an XRPD pattern substantially similar to that shown in Figure 8.

[0294] In some embodiments, compound A form 2 is identified in the composition by detecting one or more peaks in the XRPD pattern of the composition selected from those listed in Table 1 below.

[0295] [Table 3]

[0296] In some embodiments, compound A form 2 is identified in the composition by detecting two or more peaks in the XRPD pattern of the composition selected from the peaks in Table 1. In some embodiments, compound A form 2 is identified in the composition by detecting three or more peaks in the XRPD pattern of the composition selected from the peaks in Table 1. In some embodiments, compound A form 2 is identified in the composition by detecting four or more peaks in the XRPD pattern of the composition selected from the peaks in Table 1. In some embodiments, compound A form 2 is identified in the composition by detecting five or more peaks in the XRPD pattern of the composition selected from the peaks in Table 1. In some embodiments, compound A form 2 is identified in the composition by detecting six or more peaks in the XRPD pattern of the composition selected from the peaks in Table 1. In some embodiments, compound A form 2 is identified in the composition by detecting seven or more peaks in the XRPD pattern of the composition selected from the peaks in Table 1. In some embodiments, compound A form 2 is identified in the composition by detecting eight or more peaks in the XRPD pattern of the composition selected from the peaks in Table 1. In some embodiments, compound A form 2 is identified in the composition by detecting all of the peaks in Table 1 in the XRPD pattern of the composition.

[0297] In some embodiments, compound A form 2 is identified in the composition by detecting at least eight peaks in the composition's XRPD pattern, corresponding to the eight strongest peaks (based on relative percentage intensity) in Table 1 at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0298] In some embodiments, compound A form 2 is identified in the composition by detecting at least seven peaks in the composition's XRPD pattern, corresponding to the seven strongest peaks (based on relative percentage intensity) in Table 1, at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0299] In some embodiments, compound A form 2 is identified in the composition by detecting at least six peaks in the composition's XRPD pattern that correspond to the six strongest peaks (based on relative percentage intensity) in Table 1, at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0300] In some embodiments, compound A form 2 is identified in the composition by detecting at least five peaks in the composition's XRPD pattern that correspond to the five strongest peaks (based on relative percentage intensity) in Table 1, at ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ. For example, in certain embodiments, compound A form 2 is identified in the composition by detecting at least five peaks in the composition's XRPD pattern: at approximately 5.51, approximately 11.01, approximately 19.17, approximately 20.83, and approximately 21.48°2θ ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0301] In some embodiments, compound A form 2 is identified in the composition by detecting at least four peaks in the composition's XRPD pattern that correspond to the four strongest peaks (based on relative percentage intensity) in Table 1: ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ. For example, in certain embodiments, compound A form 2 is identified in the composition by detecting at least four peaks in the composition's XRPD pattern: approximately 5.51, approximately 11.01, approximately 19.17, and approximately 20.83°2θ ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0302] In some embodiments, compound A form 2 is identified in the composition by detecting at least three peaks in the composition's XRPD pattern that correspond to the three strongest peaks (based on relative percentage intensity) in Table 1: ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ. For example, in certain embodiments, compound A form 2 is identified in the composition by detecting at least three peaks in the composition's XRPD pattern: approximately 5.51, approximately 11.01, and approximately 19.17°²θ ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0303] In some embodiments, compound A form 2 is identified in the composition by detecting at least two peaks in the composition's XRPD pattern that correspond to the two strongest peaks (based on relative percent intensity) in Table 1 at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0304] In some embodiments, compound A form 2 is identified in the composition by detecting at least one peak in the composition's XRPD pattern corresponding to the strongest peak (based on relative percentage intensity) in Table 1 at ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ. In some embodiments, compound A form 2 is identified in the composition by detecting one or more peaks in the composition's XRPD pattern selected from peaks at approximately 5.51, approximately 11.01, approximately 11.53, approximately 14.91, approximately 16.54, approximately 19.17, approximately 20.83, approximately 21.48, approximately 22.68, approximately 24.18°2θ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0305] In some embodiments, compound A form 2 is identified in the composition by detecting two or more peaks, for example, at least two of the strongest peaks, in the XRPD pattern of the composition, selected from peaks at approximately 5.51, 11.01, 11.53, 14.91, 16.54, 19.17, 20.83, 21.48, 22.68, and 24.18°²θ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0306] In some embodiments, compound A form 2 is identified in the composition by detecting three or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 5.51, 11.01, 11.53, 14.91, 16.54, 19.17, 20.83, 21.48, 22.68, and 24.18°²θ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0307] In some embodiments, compound A form 2 is identified in the composition by detecting four or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 5.51, 11.01, 11.53, 14.91, 16.54, 19.17, 20.83, 21.48, 22.68, and 24.18°²θ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0308] In some embodiments, compound A form 2 is identified in the composition by detecting five or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 5.51, 11.01, 11.53, 14.91, 16.54, 19.17, 20.83, 21.48, 22.68, and 24.18°²θ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0309] In some embodiments, compound A form 2 is identified in the composition by detecting six or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 5.51, 11.01, 11.53, 14.91, 16.54, 19.17, 20.83, 21.48, 22.68, and 24.18°²θ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0310] In some embodiments, compound A form 2 is identified in the composition by detecting seven or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 5.51, 11.01, 11.53, 14.91, 16.54, 19.17, 20.83, 21.48, 22.68, and 24.18°²θ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0311] In some embodiments, compound A form 2 is identified in the composition by detecting eight or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 5.51, 11.01, 11.53, 14.91, 16.54, 19.17, 20.83, 21.48, 22.68, and 24.18°²θ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0312] In some embodiments, compound A form 2 is identified in the composition by detecting peaks in the XRPD pattern of the composition at approximately 5.51, 11.01, 11.53, 14.91, 16.54, 19.17, 20.83, 21.48, 22.68, and 24.18°²θ ± 0.3°²θ, more preferably ± 0.2°²θ, even more preferably ± 0.1°²θ, and most preferably ± 0.05°²θ.

[0313] In another embodiment, PLM analysis of compound A form 2 showed that the solid had a needle-like morphology with aggregation and birefringence.

[0314] In another embodiment, TG analysis of compound A form 2 showed a 0.9% weight loss and decomposition up to 200°C. In yet another embodiment, DTA showed multiple thermal events with an onset at approximately 183°C, an endothermic peak at 186°C, an exothermic peak at 188°C, and a second endothermic peak at 192°C (see Figure 10).

[0315] Accordingly, in some embodiments, the present disclosure provides Compound A Form 2 having a TG / DTA thermogram substantially similar to that of Figure 10. In some embodiments, Compound A Form 2 is identified in the composition by detecting a DTA thermogram having an initiation of about 183°C, an endothermic peak at 186°C, an exothermic peak at 188°C, and a second endothermic peak at 192°C.

[0316] In another embodiment, DSC analysis of compound A form 2 showed a shallow endothermic event during initial heating, starting at 122°C and having a peak at 132°C. This was followed by 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 Figure 11). During the cooling cycle, a single exothermic event was observed, starting at 151°C and having a peak at 149°C (see Figure 12). During the second heating cycle, a small exothermic event was observed, starting at 172°C and having a peak at 180°C. This was followed by a large endothermic event starting at 191°C and having a peak at 192°C (see Figure 13).

[0317] Accordingly, in some embodiments, the present disclosure provides Compound A Form 2 having a DSC thermogram substantially similar to that of Figures 11, 12, and 13. In some embodiments, Compound A Form 2 is identified in the composition by detecting a DSC thermogram having a shallow endothermic event in the first heating cycle with a start at 122°C, a characteristic peak at 132°C, followed by a start at 183°C, a second characteristic small endothermic peak at 186°C, a third characteristic exothermic peak at 187°C, and a large characteristic endothermic peak at 192°C; a single characteristic exothermic event in the cooling cycle with a start at 151°C, a peak at 149°C; and a characteristic small exothermic event in the second heating cycle with a start at 172°C, a characteristic peak at 180°C, and a subsequent start at 191°C, a characteristic peak at 192°C.

[0318] After dissolving compound A form 2 in DMSO-d6 1 Analysis was performed by 1H NMR. In another embodiment, the obtained 1 The 1H NMR spectrograph (see Figure 14) showed consistency with the structure of compound A form 2.

[0319] In another embodiment, compound A form 2 was analyzed by FTIR for reference (see Figure 15).

[0320] In another embodiment, HPLC purity analysis of compound A form 2 showed a purity value of 99.3%.

[0321] In another embodiment, GVS analysis of compound A form 2 revealed that compound A form 2 is slightly hygroscopic and has an uptake of 0.37% at 0–90% RH. Analysis of the tested material by XRPD after GVS was found to be compound A form 2.

[0322] In another embodiment, the water solubility of compound A form 2 was less than 0.1 mg / mL, and the pH of the sample after solubility was 6.4. After analysis, the excess solid was analyzed by XRPD and identified as compound A form 2.

[0323] In another embodiment, VT-XRPD analysis of compound A form 2 was performed using the heating program shown in Table 2 below.

[0324] [Table 4]

[0325] In another embodiment, the solid state of compound A form 2 at each temperature was analyzed by XRPD, and the results are shown in Table 3 below.

[0326] [Table 5]

[0327] In another embodiment, hot-stage microscopy of compound A form 2 was performed using the method described herein. Compound A form 2 was observed to begin melting at approximately 143°C, and after heating to 148°C, the material was found to be completely melted.

[0328] 3.3. C. Characterization of Compound A Form 3 In one embodiment, this disclosure is directed to a solid-state form of compound A, referred to herein as compound A form 3. In some embodiments, this disclosure provides compound A form 3 having an XRPD pattern substantially similar to that shown in Figure 16.

[0329] 3.4. D. Characterization of Compound A Form 4 In one embodiment, this disclosure is directed to a solid-state form of compound A, which is referred to herein as compound A form 4. In some embodiments, this disclosure provides compound A form 4 having an XRPD pattern substantially similar to that shown in Figure 17.

[0330] In some embodiments, compound A form 4 is identified in the composition by detecting one or more peaks in the XRPD pattern of the composition selected from those listed in Table 4 below.

[0331] [Table 6]

[0332] In some embodiments, compound A form 4 is identified in the composition by detecting two or more peaks in the XRPD pattern of the composition selected from the peaks in Table 4. In some embodiments, compound A form 4 is identified in the composition by detecting three or more peaks in the XRPD pattern of the composition selected from the peaks in Table 4. In some embodiments, compound A form 4 is identified in the composition by detecting four or more peaks in the XRPD pattern of the composition selected from the peaks in Table 4. In some embodiments, compound A form 4 is identified in the composition by detecting five or more peaks in the XRPD pattern of the composition selected from the peaks in Table 4. In some embodiments, compound A form 4 is identified in the composition by detecting six or more peaks in the XRPD pattern of the composition selected from the peaks in Table 4. In some embodiments, compound A form 4 is identified in the composition by detecting seven or more peaks in the XRPD pattern of the composition selected from the peaks in Table 4. In some embodiments, compound A form 4 is identified in the composition by detecting all of the peaks in Table 4 in the XRPD pattern of the composition.

[0333] In some embodiments, compound A form 4 is identified in the composition by detecting at least eight peaks in the composition's XRPD pattern that correspond to the eight strongest peaks (based on relative percent intensity) in Table 4, at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0334] In some embodiments, compound A form 4 is identified in the composition by detecting at least seven peaks in the composition's XRPD pattern that correspond to the seven strongest peaks (based on relative percent intensity) in Table 4, at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0335] In some embodiments, compound A form 4 is identified in the composition by detecting at least six peaks in the composition's XRPD pattern that correspond to the six strongest peaks (based on relative percent intensity) in Table 4, at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0336] In some embodiments, compound A form 4 is identified in the composition by detecting at least five peaks in the composition's XRPD pattern that correspond to the five strongest peaks (based on relative percentage intensity) in Table 4, at ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ. For example, in certain embodiments, compound A form 4 is identified in the composition by detecting at least five peaks in the composition's XRPD pattern: about 13.62, about 14.16, about 14.61, about 18.44, and about 22.97°2θ ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0337] In some embodiments, compound A form 4 is identified in the composition by detecting at least four peaks in the composition's XRPD pattern that correspond to the four strongest peaks (based on relative percentage intensity) in Table 4, at ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ. For example, in certain embodiments, compound A form 4 is identified in the composition by detecting at least four peaks in the composition's XRPD pattern: at approximately 13.62°2θ, approximately 14.61°2θ, approximately 18.44°2θ, and approximately 22.97°2θ ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0338] In some embodiments, compound A form 4 is identified in the composition by detecting at least three peaks in the composition's XRPD pattern that correspond to the three strongest peaks (based on relative percentage intensity) in Table 4: ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ. For example, in certain embodiments, compound A form 4 is identified in the composition by detecting at least three peaks in the composition's XRPD pattern: approximately 14.61°2θ, approximately 18.44°2θ, and approximately 22.97°2θ ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0339] In some embodiments, compound A form 4 is identified in the composition by detecting at least two peaks in the composition's XRPD pattern that correspond to the two strongest peaks (based on relative percent intensity) in Table 4, at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0340] In some embodiments, compound A form 4 is identified in the composition by detecting at least one peak in the composition's XRPD pattern that corresponds to the strongest peak (based on relative percentage intensity) in Table 4 at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0341] In some embodiments, compound A form 4 is identified in the composition by detecting one or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 13.62, 14.16, 14.61, 18.44, 19.92, 22.97, and 23.73°2θ ± 0.3°2θ, more preferably ± 0.2°2θ, even more preferably ± 0.1°2θ, and most preferably ± 0.05°2θ.

[0342] In some embodiments, compound A form 4 is identified in the composition by detecting two or more peaks, for example, at least two of the strongest peaks, in the XRPD pattern of the composition, selected from peaks at approximately 13.62, 14.16, 14.61, 18.44, 19.92, 22.97, 23.73°2θ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0343] In some embodiments, compound A form 4 is identified in the composition by detecting three or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 13.62, 14.16, 14.61, 18.44, 19.92, 22.97, and 23.73°2θ ± 0.3°2θ, more preferably ± 0.2°2θ, even more preferably ± 0.1°2θ, and most preferably ± 0.05°2θ.

[0344] In some embodiments, compound A form 4 is identified in the composition by detecting four or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 13.62, 14.16, 14.61, 18.44, 19.92, 22.97, 23.73°2θ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0345] In some embodiments, compound A form 4 is identified in the composition by detecting five or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 13.62, 14.16, 14.61, 18.44, 19.92, 22.97, 23.73°2θ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0346] In some embodiments, compound A form 4 is identified in the composition by detecting six or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 13.62, 14.16, 14.61, 18.44, 19.92, 22.97, 23.73°2θ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0347] In some embodiments, compound A form 4 is identified in the composition by detecting peaks in the XRPD pattern of the composition at approximately 13.62, 14.16, 14.61, 18.44, 19.92, 22.97, and 23.73°²θ ± 0.3°²θ, more preferably ± 0.2°²θ, even more preferably ± 0.1°²θ, and most preferably ± 0.05°²θ.

[0348] In another embodiment, PLM analysis of compound A form 4 showed that the solid had a lath-like morphology with aggregation and birefringence.

[0349] In another embodiment, TG analysis of compound A form 4 showed a weight loss and decomposition of 1.0% up to 200°C. In yet another embodiment, DTA showed a shallow endothermic event starting at 127°C with a peak at 135°C, followed by a larger endothermic event starting at 191°C with a peak at 193°C (see Figure 19).

[0350] Accordingly, in some embodiments, the present disclosure provides Compound A Form 4 having a TG / DTA thermogram substantially similar to that of Figure 19. In some embodiments, Compound A Form 4 is identified in the composition by detecting a DTA thermogram having a shallow endothermic event with a start at 127°C and a peak at 135°C, and a large endothermic event with a start at 191°C and a peak at 193°C.

[0351] In another embodiment, DSC analysis of compound A form 4 showed a shallow endothermic event during initial heating, starting at 122°C and having a peak at 130°C. This was followed by a larger endothermic event starting at 190°C and having a peak at 192°C (see Figure 20). During the cooling cycle, a standalone exothermic event was observed, starting at 151°C and having a peak at 150°C (see Figure 21). During the second heating cycle, a small endothermic event was observed, starting at 183°C and having a peak at 180°C. This was coupled with a larger endothermic peak at 193°C (see Figure 22).

[0352] Accordingly, in some embodiments, the present disclosure provides Compound A Form 4 having a DSC thermogram substantially similar to that of Figures 20, 21, and 22. In some embodiments, Compound A Form 4 is identified in the composition by detecting a DSC thermogram having a shallow endothermic event in the first heating cycle, starting at 122°C with a characteristic peak at 130°C, followed by a larger endothermic event in the first heating cycle, starting at 190°C with a characteristic peak at 192°C, an exothermic event in the cooling cycle, starting at 151°C with a characteristic peak at 150°C, and a smaller exothermic event in the second heating cycle, starting at 183°C with a characteristic peak at 180°C leading to a larger characteristic endothermic peak at 193°C.

[0353] After dissolving compound A form 4 in DMSO-d6 1 Analysis was performed by 1H NMR. In another embodiment, the obtained 1 The 1H NMR spectrograph (see Figure 23) showed consistency with the structure of compound A form 4.

[0354] In another embodiment, compound A form 4 was analyzed by FTIR for reference (see Figure 24).

[0355] In another embodiment, HPLC purity analysis of compound A form 4 showed a purity value of 99.5%.

[0356] In another embodiment, GVS analysis of compound A form 4 revealed that compound A form 4 is slightly hygroscopic and has an uptake of 0.4% at 90% RH. Analysis of the tested material by XRPD after GVS was found to be compound A form 4.

[0357] In another embodiment, the water solubility of compound A form 4 returned a solubility value of less than 0.1 mg / mL, and the pH of the sample after solubility was 6.3. After analysis, the excess solid was analyzed by XRPD and identified as compound A form 4.

[0358] In another embodiment, VT-XRPD analysis of compound A form 4 was performed using the heating program shown in Table 5 below.

[0359] [Table 7]

[0360] In another embodiment, the solid state of compound A form 4 at each temperature was analyzed by XRPD, and the results are shown in Table 6 below.

[0361] [Table 8]

[0362] In another embodiment, hot-stage microscopy of compound A form 4 was performed using the method described herein. Compound A form 4 was observed to begin melting at approximately 138°C, and after heating to 160°C, the material was found to be completely melted.

[0363] 3.5. E. Characterization of Compound A Form 5 In one embodiment, this disclosure is directed to a solid-state form of compound A, referred to herein as compound A form 5. In some embodiments, this disclosure provides compound A form 5 having an XRPD pattern substantially similar to that shown in Figure 25.

[0364] 3.6. F. Characterization of Compound A Form 6 In one embodiment, this disclosure is directed to a solid-state form of compound A, referred to herein as compound A form 6. In some embodiments, this disclosure provides compound A form 6 having an XRPD pattern substantially similar to that shown in Figure 26.

[0365] 3.7. G. Characterization of Compound A-form 7 In one embodiment, this disclosure is directed to a solid-state form of compound A, referred to herein as compound A form 7. In some embodiments, this disclosure provides compound A form 7 having an XRPD pattern substantially similar to that shown in Figure 27.

[0366] 3.8. H. Characterization of Compound A, Form 8 In one embodiment, this disclosure is directed to a solid-state form of compound A, referred to herein as compound A form 8. In some embodiments, this disclosure provides compound A form 8 having an XRPD pattern substantially similar to that shown in Figure 28.

[0367] 3.9. I. Characterization of Compound A Form 9 In one embodiment, this disclosure is directed to a solid-state form of compound A, referred to herein as compound A form 9. In some embodiments, this disclosure provides compound A form 9 having an XRPD pattern substantially similar to that shown in Figure 29.

[0368] In some embodiments, compound A form 9 is identified in the composition by detecting one or more peaks in the XRPD pattern of the composition selected from those listed in Table 7 below.

[0369] [Table 9]

[0370] In some embodiments, compound A form 9 is identified in the composition by detecting two or more peaks in the XRPD pattern of the composition selected from the peaks in Table 7. In some embodiments, compound A form 9 is identified in the composition by detecting three or more peaks in the XRPD pattern of the composition selected from the peaks in Table 7. In some embodiments, compound A form 9 is identified in the composition by detecting four or more peaks in the XRPD pattern of the composition selected from the peaks in Table 7. In some embodiments, compound A form 9 is identified in the composition by detecting five or more peaks in the XRPD pattern of the composition selected from the peaks in Table 7. In some embodiments, compound A form 9 is identified in the composition by detecting six or more peaks in the XRPD pattern of the composition selected from the peaks in Table 7. In some embodiments, compound A form 9 is identified in the composition by detecting seven or more peaks in the XRPD pattern of the composition selected from the peaks in Table 7. In some embodiments, compound A form 9 is identified in the composition by detecting all of the peaks in Table 7 in the XRPD pattern of the composition.

[0371] In some embodiments, compound A form 9 is identified in the composition by detecting at least eight peaks in the composition's XRPD pattern, corresponding to the eight strongest peaks (based on relative percent intensity) in Table 7 at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0372] In some embodiments, compound A form 9 is identified in the composition by detecting at least seven peaks in the composition's XRPD pattern, corresponding to the seven strongest peaks (based on relative percent intensity) in Table 7, at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0373] In some embodiments, compound A form 9 is identified in the composition by detecting at least six peaks in the composition's XRPD pattern that correspond to the six strongest peaks (based on relative percentage intensity) in Table 7, at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0374] In some embodiments, compound A form 9 is identified in the composition by detecting at least five peaks in the composition's XRPD pattern that correspond to the five strongest peaks (based on relative percentage intensity) in Table 7, at ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ. For example, in certain embodiments, compound A form 9 is identified in the composition by detecting at least the following five peaks in the composition's XRPD pattern: about 3.05, about 15.33, about 18.08, about 20.98, and about 23.49°2θ ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0375] In some embodiments, compound A form 9 is identified in the composition by detecting at least four peaks in the composition's XRPD pattern that correspond to the four strongest peaks (based on relative percentage intensity) in Table 7, at ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ. For example, in certain embodiments, compound A form 9 is identified in the composition by detecting at least four peaks in the composition's XRPD pattern: at approximately 3.05, approximately 15.33, approximately 18.08, and approximately 23.49°2θ ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0376] In some embodiments, compound A form 9 is identified in the composition by detecting at least three peaks in the composition's XRPD pattern that correspond to the three strongest peaks (based on relative percentage intensity) in Table 7 at ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ. For example, in certain embodiments, compound A form 9 is identified in the composition by detecting at least three peaks in the composition's XRPD pattern: about 3.05, about 18.08, and about 23.49°2θ ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0377] In some embodiments, compound A form 9 is identified in the composition by detecting at least two peaks in the XRPD pattern of the composition that correspond to the two strongest peaks (based on relative percent intensity) in Table 7 at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0378] In some embodiments, compound A form 9 is identified in the composition by detecting at least one peak in the composition's XRPD pattern that corresponds to the strongest peak (based on relative percentage intensity) in Table 7 at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0379] In some embodiments, compound A form 9 is identified in the composition by detecting one or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 3.05, 6.107, 10.69, 15.33, 18.08, 20.98, 23.49, 25.25°2θ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0380] In some embodiments, compound A form 9 is identified in the composition by detecting two or more peaks, for example, at least two of the strongest peaks, in the XRPD pattern of the composition, selected from peaks at approximately 3.05, 6.107, 10.69, 15.33, 18.08, 20.98, 23.49, 25.25°2θ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0381] In some embodiments, compound A form 9 is identified in the composition by detecting three or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 3.05, 6.107, 10.69, 15.33, 18.08, 20.98, 23.49, 25.25°2θ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0382] In some embodiments, compound A form 9 is identified in the composition by detecting four or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 3.05, 6.107, 10.69, 15.33, 18.08, 20.98, 23.49, 25.25°2θ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0383] In some embodiments, compound A form 9 is identified in the composition by detecting five or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 3.05, 6.107, 10.69, 15.33, 18.08, 20.98, 23.49, 25.25°2θ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0384] In some embodiments, compound A form 9 is identified in the composition by detecting six or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 3.05, 6.107, 10.69, 15.33, 18.08, 20.98, 23.49, 25.25°2θ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0385] In some embodiments, compound A form 9 is identified in the composition by detecting peaks in the XRPD pattern of the composition at approximately 6.107, 10.69, 15.33, 18.08, 20.98, 23.49, 25.25°2θ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0386] In another embodiment, PLM analysis of compound A form 9 showed that the solid had a plate-like morphology with aggregation and birefringence.

[0387] In another embodiment, TG analysis of compound A form 9 showed a 0.4% weight loss and decomposition up to 200°C. DTA showed an endothermic event with an initiation at 191°C and a peak at 192°C (see Figure 31).

[0388] Accordingly, in some embodiments, the present disclosure provides Compound A Form 9 having a TG / DTA thermogram substantially similar to that of Figure 31. In some embodiments, Compound A Form 4 is identified in the composition by detecting a DTA thermogram having an endothermic event with a start at 191°C and a peak at 192°C.

[0389] In another embodiment, DSC analysis of compound A form 9 showed a shallow exothermic event during 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 was followed by a large endothermic event starting at 189°C with a peak at 192°C (see Figure 32). During the cooling cycle, a single exothermic event was observed, starting at 157°C with a peak at 155°C (see Figure 33). During the second heating cycle, a small exothermic event was observed, starting at 140°C with a peak at 142°C, followed by a complex endothermic event starting at 181°C with a peak at 187°C, and a second event starting at 190°C with a peak at 192°C (see Figure 34).

[0390] Accordingly, in some embodiments, the present disclosure provides Compound A Form 9 having a DSC thermogram substantially similar to that of Figures 32, 33, and 34. In some embodiments, Compound A Form 9 is identified in the composition by detecting a DSC thermogram having a large endothermic event with a start at 189°C and a characteristic peak at 192°C during the first heating cycle, a single exothermic event with a start at 157°C and a characteristic peak at 155°C during the cooling cycle, and a complex endothermic event with a start at 181°C, a characteristic peak at 187°C, a second start at 190°C, and a characteristic peak at 192°C during the second heating cycle.

[0391] After dissolving compound A form 9 in DMSO-d6 1 Analysis was performed by 1H NMR. In another embodiment, the obtained 1 The 1H NMR spectrograph (see Figure 35) showed consistency with the structure of compound A form 9.

[0392] In another embodiment, compound A form 9 was analyzed by FTIR for reference (see Figure 36).

[0393] In another embodiment, HPLC purity analysis of compound A form 9 showed a purity value of 97.6%.

[0394] In another embodiment, GVS analysis of compound A form 9 revealed that compound A form 9 is slightly hygroscopic and has an uptake of 0.8% at 90% RH. Analysis of the tested material by XRPD after GVS was found to be compound A form 9.

[0395] In another embodiment, the water solubility of compound A form 9 returned a solubility value of less than 0.1 mg / mL, and the pH of the sample after solubility was 7.3. After analysis, the excess solid was analyzed by XRPD and found to have been converted to compound A form 4.

[0396] In another embodiment, VT-XRPD analysis of compound A form 9 was performed using the heating program shown in Table 8 below.

[0397] [Table 10]

[0398] In another embodiment, the solid state of compound A form 9 at each temperature was analyzed by XRPD, and the results are shown in Table 9 below.

[0399] [Table 11]

[0400] In another embodiment, hot-stage microscopy of compound A form 9 was performed using the method described herein. Compound A form 9 was observed to begin melting at approximately 156°C, and after heating to 172°C, the material was found to be completely melted.

[0401] 3.10. J. Characterization of Compound A, Form 10 In one embodiment, this disclosure is directed to a solid-state form of compound A, which is referred to herein as compound A form 10. In some embodiments, this disclosure provides compound A form 10 having an XRPD pattern substantially similar to that shown in Figure 37.

[0402] In another embodiment, TG analysis of compound A form 10 showed a weight loss of approximately 6.3% from the start of heating (see Figure 38). The observed mass loss corresponds to 0.34 equivalents of tetrahydrofuran.

[0403] In another embodiment, DTA analysis of compound A form 10 showed a small endothermic event at approximately 186°C, followed by an exothermic event at approximately 189°C, with respect to the recrystallization observed in compound A form 1 and compound A form 2. A large melting endothermic event was observed at approximately 192°C (see Figure 38).

[0404] Thermal analysis revealed that compound A form 10 is a tetrahydrofuran solvate that desolvates upon heating and is converted to compound A form 1 and compound A form 2.

[0405] 3.11. K. Characterization of Compound A, Form 11 In one embodiment, this disclosure is directed to a solid-state form of compound A, which is referred to herein as compound A form 11. In some embodiments, this disclosure provides compound A form 11 having an XRPD pattern substantially similar to that shown in Figure 39.

[0406] In some embodiments, compound A form 11 is identified in the composition by detecting one or more peaks in the XRPD pattern of the composition selected from those listed in Table 10 below.

[0407] [Table 12(1)] [Table 12(2)]

[0408] In some embodiments, compound A form 11 is identified in the composition by detecting two or more peaks in the XRPD pattern of the composition selected from the peaks in Table 10. In some embodiments, compound A form 11 is identified in the composition by detecting three or more peaks in the XRPD pattern of the composition selected from the peaks in Table 10. In some embodiments, compound A form 11 is identified in the composition by detecting four or more peaks in the XRPD pattern of the composition selected from the peaks in Table 10. In some embodiments, compound A form 11 is identified in the composition by detecting five or more peaks in the XRPD pattern of the composition selected from the peaks in Table 10. In some embodiments, compound A form 11 is identified in the composition by detecting six or more peaks in the XRPD pattern of the composition selected from the peaks in Table 10. In some embodiments, compound A form 11 is identified in the composition by detecting seven or more peaks in the XRPD pattern of the composition selected from the peaks in Table 10. In some embodiments, compound A form 11 is identified in the composition by detecting eight or more peaks in the XRPD pattern of the composition selected from the peaks in Table 10. In some embodiments, compound A form 11 is identified in the composition by detecting nine or more peaks in the XRPD pattern of the composition selected from the peaks in Table 10. In some embodiments, compound A form 11 is identified in the composition by detecting all of the peaks in Table 10 in the XRPD pattern of the composition.

[0409] In some embodiments, compound A form 11 is identified in the composition by detecting at least eight peaks in the composition's XRPD pattern that correspond to the eight strongest peaks (based on relative percent intensity) in Table 10, at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0410] In some embodiments, compound A form 11 is identified in the composition by detecting at least seven peaks in the composition's XRPD pattern that correspond to the seven strongest peaks (based on relative percent intensity) in Table 10, at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0411] In some embodiments, compound A form 11 is identified in the composition by detecting at least six peaks in the composition's XRPD pattern that correspond to the six strongest peaks (based on relative percent intensity) in Table 10, at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0412] In some embodiments, compound A form 11 is identified in the composition by detecting at least five peaks in the composition's XRPD pattern that correspond to the five strongest peaks (based on relative percentage intensity) in Table 10, at ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ. For example, in certain embodiments, compound A form 11 is identified in the composition by detecting at least five peaks in the composition's XRPD pattern: about 3.05, about 15.33, about 18.08, about 20.98, and about 23.49°2θ ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0413] In some embodiments, compound A form 11 is identified in the composition by detecting at least four peaks in the composition's XRPD pattern that correspond to the four strongest peaks (based on relative percentage intensity) in Table 10: ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ. For example, in certain embodiments, compound A form 11 is identified in the composition by detecting at least four peaks in the composition's XRPD pattern: approximately 3.05, approximately 15.33, approximately 18.08, and approximately 23.49°2θ ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0414] In some embodiments, compound A form 11 is identified in the composition by detecting at least three peaks in the composition's XRPD pattern that correspond to the three strongest peaks (based on relative percentage intensity) in Table 10: ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ. For example, in certain embodiments, compound A form 11 is identified in the composition by detecting at least three peaks in the composition's XRPD pattern: about 3.05, about 18.08, and about 23.49°2θ ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0415] In some embodiments, compound A form 11 is identified in the composition by detecting at least two peaks in the composition's XRPD pattern that correspond to the two strongest peaks (based on relative percent intensity) in Table 10, ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0416] In some embodiments, compound A form 11 is identified in the composition by detecting at least one peak in the composition's XRPD pattern that corresponds to the strongest peak (based on relative percent intensity) in Table 10 at ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0417] In some embodiments, compound A form 11 is identified in the composition by detecting one or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44, and 23.61°2θ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0418] In some embodiments, compound A form 11 is identified in the composition by detecting two or more peaks, for example, at least two of the strongest peaks, in the XRPD pattern of the composition, selected from peaks at approximately 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44, and 23.61°²θ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0419] In some embodiments, compound A form 11 is identified in the composition by detecting three or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44, and 23.61°²θ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0420] In some embodiments, compound A form 11 is identified in the composition by detecting four or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44, and 23.61°2θ±0.3°2θ, more preferably ±0.2°2θ, even more preferably ±0.1°2θ, and most preferably ±0.05°2θ.

[0421] In some embodiments, compound A form 11 is identified in the composition by detecting five or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44, and 23.61°²θ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0422] In some embodiments, compound A form 11 is identified in the composition by detecting six or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44, and 23.61°²θ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0423] In some embodiments, compound A form 11 is identified in the composition by detecting seven or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44, and 23.61°²θ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0424] In some embodiments, compound A form 11 is identified in the composition by detecting eight or more peaks in the XRPD pattern of the composition, selected from peaks at approximately 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44, and 23.61°²θ±0.3°²θ, more preferably ±0.2°²θ, even more preferably ±0.1°²θ, and most preferably ±0.05°²θ.

[0425] In some embodiments, compound A form 11 is identified in the composition by detecting peaks in the XRPD pattern of the composition at approximately 11.40, 11.69, 15.08, 19.48, 20.52, 21.40, 22.47, 23.44, and 23.61°²θ ± 0.3°²θ, more preferably ± 0.2°²θ, even more preferably ± 0.1°²θ, and most preferably ± 0.05°²θ.

[0426] In another embodiment, PLM analysis of compound A form 11 showed that the solid consisted of small particles with a rod-like morphology, exhibiting aggregation and birefringence (see Figure 40).

[0427] In another embodiment, TG analysis of compound A form 11 showed a 1.1% weight loss and decomposition up to 200°C. DTA showed an endothermic event with an initiation at 191°C and a peak at 192°C (see Figure 41).

[0428] Accordingly, in some embodiments, the present disclosure provides compound A form 11 having a TG / DTA thermogram substantially similar to that of Figure 41. In some embodiments, compound A form 4 is identified in the composition by detecting a DTA thermogram having an endothermic event with a start at 191°C and a peak at 192°C.

[0429] In another embodiment, DSC analysis of compound A form 11 showed a shallow exothermic event during initial heating, starting at 41°C with a peak at 50°C, followed by a shallow endothermic event starting at 116°C with a peak at 122°C. This was followed by a small exothermic event that led to a larger endothermic event starting at 176°C with a peak at 180°C, and then at 188°C with a peak at 192°C (see Figure 42). During the cooling cycle, a single exothermic event was observed, starting at 148°C with a peak at 147°C (see Figure 43). During the second heating cycle, two endothermic events were observed: the first starting at 184°C with a peak at 187°C, and the second starting at 191°C with a peak at 192°C (see Figure 44).

[0430] Accordingly, in some embodiments, the present disclosure provides compound A form 11 having a DSC thermogram substantially similar to that of Figures 42, 43, and 44. In some embodiments, compound A form 11 is identified in the composition by detecting a DSC thermogram in the first heating cycle having a shallow exothermic event with a start at 41°C and a characteristic peak at 50°C, followed by a shallow endothermic event with a start at 116°C and a characteristic peak at 122°C, followed by a small exothermic event with a start at 176°C and a characteristic peak at 180°C, leading to a large endothermic event with a start at 188°C and a characteristic peak at 192°C, a single exothermic event with a start at 148°C and a peak at 147°C, and in the second heating cycle having a first endothermic event with a start at 184°C and a characteristic peak at 187°C, and a second endothermic event with a start at 191°C and a characteristic peak at 192°C.

[0431] After dissolving compound A form 11 in DMSO-d6 1 Analysis was performed by 1H NMR. In another embodiment, the obtained 1 The 1H NMR spectrograph (see Figure 45) showed consistency with the structure of compound A form 11.

[0432] In another embodiment, compound A form 11 was analyzed by FTIR for reference (see Figure 46).

[0433] In another embodiment, HPLC purity analysis of compound A form 11 showed a purity value of 99.6%.

[0434] In another embodiment, GVS analysis of compound A form 11 revealed that compound A form 11 is slightly hygroscopic and has an uptake of 0.5% at 90% RH. Analysis of the tested material by XRPD after GVS revealed that it was a mixture of compound A form 4 and compound A form 11.

[0435] In another embodiment, the water solubility of compound A form 4 returned a solubility value of less than 0.1 mg / mL, and the pH of the sample after solubility was 4.9. After analysis, the excess solid was analyzed by XRPD and found to be a mixture of compound A form 4 and compound A form 11.

[0436] In another embodiment, VT-XRPD analysis of compound A form 11 was performed using the heating program shown in Table 11 below.

[0437] [Table 13]

[0438] In another embodiment, the solid state of compound A form 11 at each temperature was analyzed by XRPD, and the results are shown in Table 12 below.

[0439] [Table 14]

[0440] In another embodiment, hot-stage microscopy of compound A form 11 was performed using the method described herein. Compound A form 11 began to melt at approximately 150°C, and after heating to 185°C, the material was observed to be completely melted.

[0441] 4. Determination of the Carr Index For therapeutic use, compound A and its solid-state crystalline form are advantageously administered in acceptable dosage forms (capsules, tablets, sterile injections, topical preparations, etc.). To successfully manufacture these dosage forms (especially on a commercial scale) while meeting all relevant quality requirements, it is generally necessary that the active pharmaceutical ingredient of interest exhibits acceptable rheological (flow) properties. Active pharmaceutical ingredients with poor rheological properties are often incompatible with manufacturing equipment such as automated high-speed capsule filling systems that rely on gravity and / or vibratory feeding hoppers. Active pharmaceutical ingredients with poor rheological properties do not flow evenly through these process trains, resulting in significant and unacceptable variability in the resulting dosage forms. Therefore, it is well recognized in the art that the rheological properties of an active pharmaceutical ingredient are an important consideration when selecting its form for development.

[0442] A widely used metric for how well a powder flows is the Carr index (see, e.g., Wang, Y.B. and Williams, RO III, "Powders," Remington: Essentials of Pharmaceutics, Felton, L. ed., London: Pharmaceutical Press, 2013, pp. 422–423). The bulk density of the powder is measured along with its corresponding tap density (after compressing the powder using a standard tap density tester, e.g., Gardco JV1000, Paul N. Gardner Company, Pompano Beach, Florida, according to a standard method, e.g., the method described in Chapter 616 of the United States Pharmacopeia). Once the bulk density and tap density of the powder are experimentally determined, the Carr index can be calculated using the following formula: Carr index = (Tap density - Bulk density) / Tap density × 100

[0443] The relationship between the Carr index and powder fluidity is summarized in the table below.

[0444] [Table 15]

[0445] Both compound A and compound A form 4 are, respectively, d 50 ≤3μm and d 90 The compounds were pulverized to a specification of ≤5 μm, and their respective Carr indices were determined. Compound A showed a Carr indices of 36 (i.e., very low fluidity), while compound A form 4 was found to have a Carr indices of 8 (i.e., excellent fluidity).

[0446] 5. Stability Test To determine the thermodynamic relationship between compound A form 4 and compound A form 11, slurry tests were performed using compound A form 4 and compound A form 11 as seeds, and ethanol and 1-propanol as solvents. Samples of compound A form slurry and compound A form 11 slurry were collected for XRPD analysis after 24 hours at 40°C, 2 hours at 5°C, and 24 hours at 5°C. The results for all four experiments are shown in Table 13 below, and the solid isolated from all four experiments after 2 hours at 5°C and 24 hours at 5°C was identified as compound A form 4.

[0447] In the ethanol experiment using compound A form 4 as the seed, all sample points tested returned the compound A form 4 material. However, in the 1-propanol experiment, after 24 hours at 40°C, it was found to be a mixture of compound A form 2 and compound A form 4. This material returned to form 4 after cooling to 5°C.

[0448] Despite using compound A form 11 as a seed in both experiments, compound A form 11 material was not detected in either of the slurry samples. A slurry containing ethanol and compound A form 11 as a seed was identified as compound A form 2 after 24 hours at 40°C, which was converted to compound A form 4 after cooling to 5°C. In the 1-propanol experiment using compound A form 11 as a seed, there was insufficient solid for XRPD analysis after 24 hours at 40°C, but after 2 hours at 5°C, the amount of solid increased and was identified as compound A form 4 by XRPD.

[0449] [Table 16]

[0450] 6. Crystallization test The following crystallization tests were performed on compound A form 4.

[0451] 6.1. A. Crystallization Test 1 In one embodiment, the crystallization test of compound A form 4 was 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 seeding was performed after a clear solution was observed. Seeding persisted for approximately 1 hour, after which a poor solvent was added at 30°C. The following results were obtained for the dried solid sample and the final product. 1. After adding a poor solvent, the sample was separated by centrifugation, and the solid was analyzed by XRPD. This material was confirmed to be morphology 4. 2. The final recovered solid was analyzed by XRPD as both a wet and a dry solid, and both samples were confirmed to be morphology 4. 3. The recovered material had an isolation yield of 90% and a solid purity of 99.6% according to HPLC. 4. The recovered mother liquor had a concentration of 0.7 mg / mL, which corresponds to a theoretical recovery yield of 98%. The purity of the mother liquor was determined to be 88%. The washing solution had a concentration of less than 0.1 mg / mL. 5. PLM analysis of the dry solid showed that the material was a plate-like crystalline structure with aggregation and birefringence. 6. TG analysis of the solid showed a 0.3% weight loss up to approximately 220°C and subsequent decomposition. An endothermic event was observed in the DTA, starting at 118°C and peaking at 127°C. This was followed by a second, larger endothermic event, starting at 191°C and peaking at 192°C, which is likely related to material melting. 7. KF analysis was performed on three solid samples using the direct addition method. The average water content of 0.53% by weight was determined. 8. GC analysis of the dried solid revealed a residual ethanol value of 188 ppm. 9. Particle size analysis of the material was performed, and the following PSD values ​​were obtained. D10 = 8.0 μm D50 = 22.1 μm D90 = 52.1 μm

[0452] 6.2. B. Crystallization Test 2 In another embodiment, the crystallization test of compound A form 4 was 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 seeding was performed after a clear solution was observed. Seeding persisted for approximately 1 hour, after which a poor solvent was added at 30°C. The following results were obtained for the dried solid sample and the final product. 1. After adding a poor solvent, the sample was separated by centrifugation, and the solid was analyzed by XRPD. This material was confirmed to be morphology 4. 2. The recovered solids were analyzed by XRPD as both wet and dry solids, and both samples were confirmed to be morphology 4. 3. The final recovered material had an isolation yield of 80% and a solid purity of 99.6% according to HPLC. The recovery yield was lower due to some handling losses. 4. The recovered mother liquor had a concentration of 2.6 mg / mL, which corresponds to a theoretical recovery yield of 93%. The purity of the mother liquor was determined to be 84%. The washing solution had a concentration of less than 0.1 mg / mL. 5. PLM analysis of the dry solid showed that the material was a plate-like crystalline structure with aggregation and birefringence. Due to the large particle size, images were acquired at both 20x and 10x magnification. 6. TG analysis of the solid showed a 0.1% weight loss up to approximately 200°C and subsequent decomposition. An endothermic event was observed in the DTA, starting at 108°C and peaking at 116°C. This was followed by a second, larger endothermic event, starting at 192°C and peaking at 193°C, which is likely related to material melting. 7. KF analysis was performed on two solid samples using the direct addition method. The average water content of 0.08 wt% was determined. 8. GC analysis of the dried solid revealed a residual 1-propanol level of 391 ppm. 9. Particle size analysis of the material was performed, and the following PSD values ​​were obtained. D 10 = 18.1 μm D 50 = 65.1 μm D 90 = 152.9 μm

[0453] 6.3. C. Crystallization Test 3 In another embodiment, the crystallization test of compound A form 4 was carried out using a 1-propanol:water system, with the addition of a poor solvent at a lower temperature. The concentration was maintained at the same value as in crystallization test 2. After complete dissolution at 45°C, the system was cooled to 30°C, and seeding was performed after a clear solution was observed. The seeding persisted for about 1 hour before the container temperature was raised to 35°C. The temperature increase to 35°C resulted in some dissolution of the seed. The system was then cooled to 30°C, held for a further 30 minutes, and then cooled to 5°C. The poor solvent was then added at 5°C. The following results were obtained for the dried solid sample and the final product. 1. After being held at 5°C, the collected sample was separated by centrifugation, and the solid was analyzed by XRPD. This material was confirmed to be morphology 4. The concentration of the sample mother liquor was determined to be 52.8 mg / mL. 2. The recovered solids were analyzed by XRPD as both wet and dry materials, and both samples were confirmed to be morphology 4. 3. The recovered material had an isolation yield of 80% and a solid purity of 99.6% according to HPLC. 4. The recovered mother liquor had a concentration of 3.7 mg / mL, which corresponds to a theoretical recovery yield of 90%. The purity of the mother liquor was determined to be 92%. The washing solution had a concentration of 0.2 mg / mL. 5. PLM analysis of the dry solid showed that the material was a plate-like crystalline structure with aggregation and birefringence. 6. TG analysis of the solid showed a 0.1% weight loss up to approximately 220°C and subsequent decomposition. An endothermic event was observed in the DTA, starting at 113°C and peaking at 119°C. This was followed by a second, larger endothermic event, starting at 191°C and peaking at 192°C, which is likely related to material melting. 7. KF analysis was performed on two solid samples using the direct addition method. The average water content of 0.08 wt% was determined. 8. GC analysis of the dried solid revealed a residual 1-propanol level of 477 ppm. 9. Particle size analysis of the material was performed, and the following PSD values ​​were obtained. D 10 = 16.4 μm D 50 = 54.4 μm D 90 = 146.7 μm

[0454] 6.4. D. Crystallization Test 4 In another embodiment, the crystallization test 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 seeding was performed after a clear solution was observed. The seeding persisted for approximately 1 hour, after which it was cooled to 5°C, and the sample was taken at 5°C. A poor solvent was then added, and the following results were obtained for the dried solid sample and the final product. 1. After being held at 5°C, the collected sample was separated by centrifugation, and the solid was analyzed by XRPD. This material was confirmed to be morphology 4. The concentration of the sample mother liquor was determined to be 37.7 mg / mL. PLM images of the slurry sample showed that the material was plate-like in morphology and exhibited aggregation and birefringence. 2. The recovered solids were analyzed by XRPD as both wet and dry solids, and both samples were confirmed to be morphology 4. 3. The recovered material had an isolation yield of 87% and a solid purity of 99.6% according to HPLC. 4. The recovered mother liquor had a concentration of 3.1 mg / mL, which corresponds to a theoretical recovery yield of 90%. The purity of the mother liquor was determined to be 93%. The washing solution had a concentration of less than 0.1 mg / mL. 5. PLM analysis of the wet solid showed that the material was plate-like in morphology, and that this solid also exhibited aggregation and birefringence. 6. PLM analysis of the dried solid revealed that the material was plate-like crystalline with the presence of several rod-shaped particles. The particle size appeared visually smaller than that of previous crystallizations. The recovered solid also showed aggregation and birefringence. 7. TG analysis of the dry solid showed a 0.1% weight loss up to approximately 200°C and subsequent decomposition. An endothermic event was observed in the DTA, starting at 120°C and peaking at 127°C. This was followed by a second, larger endothermic event, starting at 191°C and peaking at 192°C, which is likely related to material melting. 8. KF analysis was performed on two solid samples using the direct addition method. The average water content of 0.06 wt% was determined. 9. GC analysis of the dried solid revealed a residual 1-propanol level of 477 ppm. 10. Particle size analysis of the material was performed, and the following PSD values ​​were obtained. D 10 = 6.0 μm D 50 = 18.0 μm D 90 = 45.8 μm

[0455] 6.5. E. Crystallization Test 5 In another embodiment, the crystallization test of compound A form 4 was carried out at a lower concentration of 1-propanol:60 mg / mL in water. After complete dissolution at 45°C, the system was cooled to 30°C, and seeding was performed after a clear solution was observed. Seeding continued for approximately 1 hour, after which the system was cooled to 25°C, and the poor solvent was added at a slower rate at this temperature. After addition, the sample was taken at 25°C, and then the system was cooled to 5°C and separated. The following results were obtained for the dried solid sample and the final product. 1. After adding a poor solvent, the sample was separated by centrifugation, and the solid was analyzed by XRPD. This material was confirmed to be morphology 4. The concentration of the sample mother liquor was determined to be 4.2 mg / mL. 2. The recovered solids were analyzed by XRPD as both wet and dry solids, and both samples were confirmed to be Form 4. Due to the preferred orientation observed in the dry sample, the material was lightly ground and re-analyzed by XRPD, and this material was also identified as Form 4. 3. The recovered material had an isolation yield of 85% and a solid purity of 99.5% according to HPLC. 4. The recovered mother liquor had a concentration of 2.3 mg / mL, which corresponds to a theoretical recovery yield of 94%. The purity of the mother liquor was determined to be 87%. The washing solution had a concentration of 0.2 mg / mL. 5. PLM analysis of the wet solid showed that the material was plate-like in morphology, and that this solid also exhibited aggregation and birefringence. Due to particle size, images were acquired at both 20x and 10x magnification. 6. PLM analysis of the dry solid showed that the material was a plate-like crystalline structure with aggregation and birefringence. 7. TG analysis of the dry solid did not show weight loss before decomposition. An endothermic event was observed in the DTA, starting at 112°C and peaking at 117°C. This was followed by a second, larger endothermic event, starting at 191°C and peaking at 192°C, which is likely related to material melting. 8. KF analysis was performed on two solid samples using the direct addition method. The average water content of 0.09 wt% was determined. 9. GC analysis of the dried solid returned a residual 1-propanol value of 380 ppm. 10. Particle size analysis of the material was performed, and the following PSD values ​​were obtained. D 10 = 13.1 μm D 50 = 54.5 μm D 90 = 162.1 μm

[0456] 6.6. F. Crystallization Test 6 In another embodiment, the crystallization test of compound A form 4 was carried out at a higher concentration of 65 mg / mL in a 1-propanol:aqueous system. After complete dissolution at 45°C, the system was cooled to 35°C, and seeding was performed after a clear solution was observed. Seeding continued for approximately 1 hour, after which it was cooled to 5°C, and then the poor solvent was added at a slow rate. The following results were obtained for the dried solid sample and the final product. 1. The recovered solids were analyzed by XRPD as both wet and dry solids, and both samples were confirmed to be Form 4. Due to the preferred orientation observed in the dry sample, the material was lightly ground and re-analyzed by XRPD, and this material was also identified as Form 4. 2. The recovered material had an isolation yield of 88% and a solid purity of 99.5% according to HPLC. 3. The recovered mother liquor had a concentration of 1.9 mg / mL, which corresponds to a theoretical recovery yield of 96%. The purity of the mother liquor was determined to be 84%. The washing solution had a concentration of 0.1 mg / mL. 4. PLM analysis of the wet solid showed that the material was plate-like in morphology, and that this solid also exhibited aggregation and birefringence. 5. PLM analysis of the dry solid showed that the material was a plate-like crystalline structure with aggregation and birefringence. Due to particle size, images were acquired at both 20x and 10x magnification. 6. TG analysis of the dry solid showed a 0.2% weight loss up to 200°C and subsequent decomposition. An endothermic event was observed in the DTA, starting at 117°C and peaking at 123°C. This was followed by a second, larger endothermic event, starting at 191°C and peaking at 192°C, which is likely related to material melting. 7. KF analysis was performed on two solid samples using the direct addition method. The average water content of 0.03 wt% was determined. 8. GC analysis of the dried solid revealed a residual 1-propanol level of 331 ppm. 9. Particle size analysis of the material was performed, and the following PSD values ​​were obtained. D 10 = 14.6 μm D50 = 45.0 μm D 90 = 119.1 μm

[0457] 6.7. G. Crystallization Test 7 In another embodiment, the crystallization test of compound A form 4 was carried out using a degassed solvent at a higher concentration of 65 mg / ml in a 1-propanol:aqueous system. After complete dissolution at 45°C, the system was cooled to 32°C, and seeding was performed after a clear solution was observed. Seeding persisted for approximately 1 hour, after which it was cooled to 5°C, and then a poor solvent was added at this temperature. The following results were obtained for the dried solid sample and the final product. 1. The recovered solids were analyzed by XRPD as both wet and dry solids, and both samples were confirmed to be Form 4. Due to the preferred orientation observed in the dry sample, the material was lightly ground and re-analyzed by XRPD, and this material was also identified as Form 4. 2. The recovered material had an isolation yield of 84% and a solid purity of 99.5% according to HPLC. 3. The recovered mother liquor had a concentration of 4.5 mg / mL, which corresponds to a theoretical recovery yield of 89%. The purity of the mother liquor was determined to be 92%. The washing solution had a concentration of 0.2 mg / mL. 4. PLM analysis of the wet solid showed that the material was plate-like in morphology, and that this solid also exhibited aggregation and birefringence. 5. PLM analysis of the dry solid showed that the material was a plate-like crystalline structure with aggregation and birefringence. 6. TG analysis of the dry solid showed a 0.2% weight loss up to 200°C and subsequent decomposition. An endothermic event was observed in the DTA, starting at 111°C and peaking at 120°C. This was followed by a second, larger endothermic event, starting at 191°C and peaking at 192°C, which is likely related to material melting. 7. KF analysis was performed on two solid samples using the direct addition method. The average water content of 0.07 wt% was determined. 8. GC analysis of the dried solid revealed a residual 1-propanol level of 349 ppm. 9. Particle size analysis of the material was performed, and the following PSD values ​​were obtained. D 10 = 13.4 μm D 50 = 48.6 μm D 90 = 132.5 μm

[0458] 6.8. H. Crystallization Test 8 In another embodiment, the crystallization test of compound A form 4 was carried out using a degassing solvent at a higher concentration of 65 mg / mL in 1-propanol:water. After complete dissolution at 45°C, the system was cooled to 32°C, and seeding was performed after a clear solution was observed. Seeding persisted for approximately 1 hour, after which the system was cooled to 30°C, and then the poor solvent was added at this temperature. After the addition of the poor solvent, the system was cooled to 5°C. The following results were obtained for the dried solid sample and the final product. 1. The recovered solids were analyzed by XRPD as both wet and dry solids, and both samples were confirmed to be Form 4. Due to the preferred orientation observed in the dry sample, the material was lightly ground and re-analyzed by XRPD, and this material was also identified as Form 4. 2. The recovered material had an isolation yield of 88% and a solid purity of 99.6% according to HPLC. 3. The recovered mother liquor had a concentration of 1.8 mg / mL, which corresponds to a theoretical recovery yield of 96%. The purity of the mother liquor was determined to be 91%. The washing solution had a concentration of 0.6 mg / mL. 4. PLM analysis of the wet solid showed that the material was plate-like in morphology, and that this solid also exhibited aggregation and birefringence. Due to particle size, images were acquired at both 20x and 10x magnification. 5. PLM analysis of the dry solid showed that the material was a plate-like crystalline structure with aggregation and birefringence. Due to particle size, images were acquired at both 20x and 10x magnification. 6. TG analysis of the dry solid showed a 0.3% weight loss up to 200°C and subsequent decomposition. An endothermic event was observed in the DTA, starting at 113°C and peaking at 115°C. This was followed by a second, larger endothermic event, starting at 191°C and peaking at 192°C, which is likely related to material melting. 7. KF analysis was performed on two solid samples using the direct addition method. The average water content of 0.11% by weight was determined. 8. GC analysis of the dried solid revealed a residual 1-propanol level of 401 ppm. 9. Particle size analysis of the material was performed, and the following PSD values ​​were obtained. D 10 = 11.9 μm D 50 = 48.3 μm D 90 = 119.9 μm

[0459] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referenced herein, including U.S. Provisional Application No. 62 / 913,574 filed October 10, 2019, are incorporated herein by reference in their entirety.

[0460] While the above disclosure is presented in some detail for ease of understanding, it will be clear that certain changes and modifications may be made within the scope of the appended claims. Accordingly, the described embodiments should be considered illustrative rather than restrictive, and the claimed inventions are not limited to the details given herein and may be modified within the scope of the appended claims and their equivalents.

Claims

1. The crystalline form of compound A.

2. The crystal form according to claim 1, wherein the aforementioned crystal form is compound form A 2.

3. The crystal form according to claim 1, wherein the aforementioned crystal form is compound form A 4.

4. The crystal form according to claim 1, wherein the aforementioned crystal form is compound form A9.

5. The crystal form according to claim 1, wherein the crystal form is compound form A 11.

6. A solid state form of compound A comprising two or more crystalline forms described in any one of claims 2 to 5.

7. The crystal form according to any one of claims 2 to 5, wherein the crystal form substantially does not include other solid state forms.

8. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the crystalline form of compound A.

9. The pharmaceutical composition according to claim 8, wherein the crystalline form of compound A is compound A form 2.

10. The pharmaceutical composition according to claim 8, wherein the crystalline form of compound A is compound A form 4.

11. The pharmaceutical composition according to claim 8, wherein the crystalline form of compound A is compound A form 9.

12. The pharmaceutical composition according to claim 8, wherein the crystalline form of compound A is compound A form 11.

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

14. A method for treating a paroxysmal disorder in humans, comprising the step of administering a therapeutically effective amount of compound A in crystalline form to a person in need of it.

15. The method according to claim 14, wherein the crystalline form of compound A is compound A form 2.

16. The method according to claim 14, wherein the crystalline form of compound A is compound A form 4.

17. The method according to claim 14, wherein the crystalline form of compound A is compound A form 9.

18. The method according to claim 14, wherein the crystalline form of compound A is compound A form 11.

19. A method for treating a paroxysmal disorder in humans, comprising the step of administering a mixture of two or more crystalline forms of compound A in a therapeutically effective amount to a person in need.

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

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

22. The method according to any one of claims 14 to 19, wherein the crystalline form of compound A is administered to the human being between 30 minutes before eating and 2 hours after eating.

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

24. Use of the crystalline form of compound A in the manufacture of a pharmaceutical product for treating paroxysmal disorders in humans who require it.

25. The use according to claim 24, wherein the crystalline form of compound A is compound A form 2.

26. The use according to claim 24, wherein the crystalline form of compound A is compound A form 4.

27. The use according to claim 24, wherein the crystalline form of compound A is compound A form 9.

28. The use according to claim 24, wherein the crystalline form of compound A is compound A form 11.

29. Use of a mixture of two or more crystalline forms of compound A in the manufacture of a pharmaceutical product for the treatment of paroxysmal disorders in humans who require it.

30. The use according to any one of claims 24 to 29, wherein the person is treated with the crystalline form of compound A from 30 minutes before eating to 2 hours after eating.

31. The use according to claim 30, wherein the person is treated with the crystalline form of compound A during or within 15 minutes after eating.

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