Polymorphic Forms of Substituted Quinoxaline-Type Crosslinked Piperidine Compounds

Abstract

Provided herein are novel crystalline forms of the crystalline compound of formula (I) that modulate the ORL-1 receptor. The crystalline compounds of formula (I), compositions thereof, and methods of use thereof described herein are particularly useful for the treatment, prevention, and management of several sleep disorders. TIFF2022519231000028.tif75169

Description

Background Art

[0001] The ability to modulate the ORL-1 receptor presents opportunities in new drug discovery for administering compounds of this class for the treatment, prevention, or management of certain diseases such as pain. U.S. Patent Nos. 8,476,271, 8,846,929, 9,145,408, 9,278,967, and 9,527,840, and U.S. Patent Application Publication No. 2016 / 0009717 A1 each disclose substituted quinoxaline-type bridged piperidine compounds having affinity for the ORL-1 receptor.

[0002] Solid forms such as salts, crystal forms, for example polymorphic forms of a compound, are known in the pharmaceutical art to affect the solubility, stability, flowability, fractionability, and compressibility of the compound, as well as the safety and efficacy of a drug product based on the compound. Thus, the potential effects of solid forms in a single drug product on the safety and efficacy of each drug product, where the U.S. Food and Drug Administration requires identification and control of solid forms, for example, the solids of each compound used in each drug product marketed in the United States, such as crystal forms, are very important. Accordingly, new crystalline forms of drug compounds can further facilitate the development of pharmaceutical formulations for the treatment, prevention, or management of certain diseases such as pain.

[0003] Any citation of references in the Background Art section of this application should not be construed as an admission that such references are prior art to this application.

Summary of the Invention

[0004] The present invention provides a crystalline form of a substituted quinoxaline-type bridged piperidine compound. One such compound has the following chemical structure set forth in formula (I).

Chemical Formula

[0005] In particular, the crystalline forms of the compounds of formula (I) are useful for the treatment, prevention or management of pain and sleep disorders. In addition, the present invention provides a crystalline form of a compound of formula (I) having a crystal purity of a single crystalline form of greater than about 90% relative to the total amount of all crystalline forms of the compound of formula (I) present.

[0006] In certain embodiments, the present invention provides crystalline or amorphous forms of large quantities of the compounds of formula (I). Such large quantities can include greater than about 1 kg, greater than about 10 kg, or greater than about 100 kg.

[0007] In certain embodiments, the crystalline forms of formula (I) provided herein are characterized by powder X-ray diffraction ("PXRD" or "XRPD") crystallography. In one aspect of the invention, the unsolvated crystalline form of the compound of formula (I), referred to herein as Form A, has an XRPD pattern that is substantially similar (e.g., 2Θ ± 0.2°) to that shown in Figure 3A. In another aspect of the invention, the crystalline form of the compound of formula (I), referred to herein as Form B, has an XRPD pattern that is substantially similar (e.g., 2Θ ± 0.2°) to that shown in Figure 1. In another aspect of the invention, the hydrate crystalline form of the compound of formula (I), referred to herein as Form C, has an XRPD pattern that is substantially similar (e.g., 2Θ ± 0.2°) to that shown in Figure 4A. In another aspect of the invention, the unsolvated crystalline form of the compound of formula (I), referred to herein as Form D, has an XRPD pattern that is substantially similar (e.g., 2Θ ± 0.2°) to that shown in Figure 5A. In another aspect of the invention, the hydrate crystalline form of the compound of formula (I), referred to herein as Form E, has an XRPD pattern that is substantially similar (e.g., 2Θ ± 0.2°) to that shown in Figure 7A.

[0008] Certain embodiments of the present invention provide crystalline forms of compounds of formula (I) and pharmaceutical compositions and dosage forms comprising a pharmaceutically acceptable diluent, excipient, or carrier. The present invention further provides methods of using them for the treatment, prevention, or management of sleep disorders. Such crystalline forms of the compounds of formula (I) exhibit affinity for the human ORL-1 receptor. In certain embodiments, the present invention provides methods for manufacturing, isolating, and / or characterizing a crystalline form of formula (I) or an amorphous form of formula (I). The crystalline forms of the present invention are useful as active pharmaceutical ingredients for the preparation of formulations for use in animals or humans. Accordingly, the present invention encompasses the use of these crystalline forms in pharmaceutical compositions and dosage forms. The crystalline forms of formula (I) in the pharmaceutical compositions and dosage forms of the present invention are useful, for example, for the treatment, prevention, or management of the diseases described herein. The pharmaceutical compositions and dosage forms can be formed with a crystalline form of formula (I) and one or more pharmaceutical carriers or excipients.

[0009] The compound forms and pharmaceutical compositions of the present invention are useful for treating or preventing sleep disorders in a subject, such as a human. In one embodiment, an effective amount of a crystalline form of formula (I) or a pharmaceutical composition comprising the same is used to treat or prevent insomnia (e.g., "adult" insomnia, pediatric insomnia, and middle-of-the-night insomnia), alcohol-induced sleep disorders (e.g., insomnia-type alcohol-induced sleep disorder, daytime-insomnia-type alcohol-induced sleep disorder, sleep-associated alcohol-induced sleep disorder, and mixed alcohol-induced sleep disorder), insomnia in alcohol use disorder, sleep disorders associated with alcohol withdrawal (e.g., insomnia associated with alcohol withdrawal), hypersomnia (such as sleep deprivation syndrome), circadian rhythm sleep-wake disorders (e.g., delayed sleep-wake phase, advanced sleep-wake phase, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm, shift work syndrome, and jet lag), or any combination thereof, but not limited thereto. When used to treat or prevent sleep disorders such as those included above, an effective amount of a crystalline form of formula (I) or a composition comprising the same can be administered to a patient receiving one or more concomitant therapies for treating or preventing toxic alcohol use disorder.

[0010] In another embodiment, an effective amount of the crystalline form of formula (I) or a pharmaceutical composition comprising the same can be used to treat or prevent sleep disorders including, but not limited to, insomnia disorders (e.g., "adult" insomnia, pediatric insomnia, and middle-of-the-night insomnia).

[0011] In another embodiment of the present disclosure, an effective amount of the crystalline form of formula (I) or a pharmaceutical composition comprising the same can be used to treat or prevent sleep disorders including, but not limited to, alcohol-related insomnia such as insomnia-type alcohol-induced sleep disorder and mixed alcohol-induced sleep disorder, insomnia in alcohol use disorder, insomnia related to alcohol withdrawal, or any combination thereof.

[0012] It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the scope and spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. Applicants intend the specification and examples to be considered as exemplary only, with the scope not being limited thereby. BRIEF DESCRIPTION OF THE DRAWINGS

[0013]

Figure 1

Figure 2

Figure 3A

Figure 3B

Figure 3C

Figure 4A

Figure 4B

Figure 4C

Figure 5A

Figure 5B

Figure 5C

Figure 6

Figure 7A

Figure 7B

Figure 7C

Figure 7D

Figure 8A

Figure 8B

Mode for Carrying Out the Invention

[0014] Formula (I):

Chemical formula

[0015] The compound of Formula (I) can be prepared by the methods described herein and the like. The crystalline forms of Formula (I) can include, for example, solvates, hydrates (e.g., monohydrates, dihydrates, etc.), and non-solvated or anhydrous forms of Formula (I). The crystalline forms of Formula (I) can include, for example, Crystalline Forms A, B, C, D, and E provided herein.

[0016] In one embodiment, the present invention provides Form A crystalline form of formula (I). In some embodiments, Form A can be obtained by the crystallization and recrystallization methods described hereinbelow.

[0017] A representative XRPD pattern of Form A of formula (I) is provided in FIG. 3A. In some embodiments, Form A of formula (I) has an XRPD pattern that is substantially similar to the pattern shown in FIG. 3A.

[0018] Representative thermal properties of Form A of formula (I) are shown in FIG. 3B. The representative DSC thermogram presented as A in FIG. 3B shows a composite endotherm at about 239.9 °C that occurs with decomposition. The representative TGA thermogram presented as B in FIG. 3B shows a weight loss where the mass loss at 25 - 150 °C is less than about 0.2%. These thermal data indicate that Form A of formula (I) does not contain any significant amount of water or solvent in the crystal lattice.

[0019] In an embodiment, the present invention provides a crystalline form of formula (I) that generates a powder X-ray diffraction spectrum containing peaks at diffraction angles (2Θ ± 0.2°) of 18.5 and 19.3. In another embodiment, the crystalline form of formula (I) may further contain peaks at diffraction angles (2Θ ± 0.2°) of 21.1 and 22.2. In another embodiment, the crystalline form of formula (I) may further contain peaks at diffraction angles (2Θ ± 0.2°) of 7.4, 9.6, 14.7, 16.7, and 17.1. In another embodiment, the present invention provides a crystalline form of formula (I) that generates a powder X-ray diffraction spectrum containing peaks at diffraction angles (2Θ ± 0.2°) of 7.4, 9.6, 14.7, 16.7, 17.1, 18.5, 19.3, 21.1, and 22.2.

[0020] In an embodiment, the present invention provides a crystalline form of formula (I) that produces a powder X-ray diffraction spectrum comprising peaks at diffraction angles (2Θ±0.2°) of 6.8 and 7.0. In another embodiment, the crystalline form of formula (I) may further comprise peaks at diffraction angles (2Θ±0.2°) of 20.7 and 20.9. In another embodiment, the crystalline form of formula (I) may further comprise peaks at diffraction angles (2Θ±0.2°) of 17.2, 19.6, and 27.8. In another embodiment, the present invention provides a crystalline form of formula (I) that produces a powder X-ray diffraction spectrum comprising peaks at diffraction angles (2Θ±0.2°) of 6.8, 7.0, 13.7, 15.5, 17.1, 17.2, 18.5, 18.6, 19.5, 19.6, 20.7, 20.9, 27.8, 28.0.

[0021] In an embodiment, the present invention provides a crystalline form of formula (I) that produces a powder X-ray diffraction spectrum comprising peaks at diffraction angles (2Θ±0.2°) of 16.0 and 19.2. In another embodiment, the crystalline form of formula (I) may further comprise peaks at diffraction angles (2Θ±0.2°) of 3.9 and 7.6. In another embodiment, the crystalline form of formula (I) may further comprise peaks at diffraction angles (2Θ±0.2°) of 18.0, 26.7, 27.0, and 28.4. In another embodiment, the present invention provides a crystalline form of formula (I) that produces a powder X-ray diffraction spectrum comprising peaks at diffraction angles (2Θ±0.2°) of 3.9, 7.6, 16.0, 18.0, 19.2, 26.7, 27.0, 28.4.

[0022] In an embodiment, the present invention provides a crystalline form of formula (I) that produces a powder X-ray diffraction spectrum containing peaks at diffraction angles (2Θ ± 0.2°) of 7.1 and 20.8. In another embodiment, the crystalline form of formula (I) may further contain peaks at diffraction angles (2Θ ± 0.2°) of 17.2 and 19.6. In another embodiment, the crystalline form of formula (I) may further contain peaks at diffraction angles (2Θ ± 0.2°) of 13.9, 15.5, and 27.9. In another embodiment, the present invention provides a crystalline form of formula (I) that produces a powder X-ray diffraction spectrum containing peaks at diffraction angles (2Θ ± 0.2°) of 7.1, 13.9, 15.5, 17.2, 19.6, 19.9, 20.8, 27.9.

[0023] In an embodiment, the present invention provides a crystalline form of formula (I) that produces a powder X-ray diffraction spectrum containing peaks at diffraction angles (2Θ ± 0.2°) of 10.1 and 16.3. In another embodiment, the crystalline form of formula (I) may further contain peaks at diffraction angles (2Θ ± 0.2°) of 18.7 and 22.0. In another embodiment, the crystalline form of formula (I) may further contain peaks at diffraction angles (2Θ ± 0.2°) of 12.5, 14.8, 23.4, and 26.2. In another embodiment, the present invention provides a crystalline form of formula (I) that produces a powder X-ray diffraction spectrum containing peaks at diffraction angles (2Θ ± 0.2°) of 10.1, 12.5, 14.8, 16.3, 16.6, 18.7, 22.0, 23.4, 26.2.

[0024] In an embodiment, the present invention provides a crystalline compound of formula (I) that is crystalline form A, wherein at least about 90% by weight of the crystalline compound of formula (I) produces a powder X-ray diffraction spectrum containing at least three peaks at diffraction angles (2Θ ± 0.2°) selected from 7.4, 9.6, 14.7, 16.7, 17.1, 18.5, 19.3, 21.1, and 22.2. In another embodiment, at least about 95% by weight of the crystalline formula (I) is in crystalline form A.

[0025] In an embodiment, the present invention provides a crystalline compound of formula (I) in crystalline form B, wherein at least about 90% by weight of the crystalline compound of formula (I) produces a powder X-ray diffraction spectrum comprising at least three peaks at diffraction angles (2Θ±0.2°) selected from 6.8, 7.0, 13.7, 15.5, 17.1, 17.2, 18.5, 18.6, 19.5, 19.6, 20.7, 20.9, 27.8, and 28.0. In another embodiment, at least about 95% by weight of the crystalline compound of formula (I) is in crystalline form B.

[0026] In an embodiment, the present invention provides a crystalline compound of formula (I) in crystalline form C, wherein at least about 90% by weight of the total amount of the crystalline compound of formula (I) produces a powder X-ray diffraction spectrum comprising at least three peaks at diffraction angles (2θ±0.2°) selected from 3.9, 7.6, 16.0, 18.0, 19.2, 26.7, 27.0, and 28.4. In another embodiment, at least about 95% by weight of the total amount of the crystalline form of formula (I) is present as the claimed crystalline form C.

[0027] In an embodiment, the present invention provides a crystalline compound of formula (I) in crystalline form D, wherein at least about 90% by weight of the crystalline compound of formula (I) produces a powder X-ray diffraction spectrum comprising at least three peaks at diffraction angles (2Θ±0.2°) selected from 7.1, 13.9, 15.5, 17.2, 19.6, 19.9, 20.8, and 27.9. In another embodiment, at least about 95% by weight of the total amount of the crystalline compound of formula (I) is in crystalline form D.

[0028] In an embodiment, the present invention provides a crystalline compound of formula (I) in crystalline form E, wherein at least about 90% by weight of the crystalline compound of formula (I) produces a powder X-ray diffraction spectrum comprising at least three peaks at diffraction angles (2Θ±0.2°) selected from 10.1, 12.5, 14.8, 16.3, 16.6, 18.7, 22.0, 23.4, and 26.2. In another embodiment, at least about 95% by weight of the total amount of the crystalline compound of formula (I) is in crystalline form E.

[0029] In certain embodiments, the present invention provides crystalline or amorphous forms of a large quantity of the compound of formula (I). In embodiments, a large quantity of the crystalline compound of formula (I) can comprise more than about 1 kg, more than about 10 kg, or more than about 100 kg. In another embodiment, a large quantity of the crystalline compound of formula (I) can comprise from about 1 kg to about 1000 kg, from about 10 kg to about 1000 kg, from about 100 kg to about 1000 kg, from about 1 kg to about 100 kg, from about 10 kg to about 100 kg, or from about 1 kg to about 10 kg.

[0030] Definitions "About" refers to approximate values such as values within ±0.5% of the recited value. For example, a crystalline form having a crystalline purity of about 90% by weight is from about 89.5% to 90.5% by weight.

[0031] As used in the present disclosure, "carrier" includes carriers, excipients, and diluents, and refers to materials, compositions, or vehicles such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that are involved in the transport or delivery of a drug from one organ, or part of the body, to another organ, or part of the body of a subject, e.g., a human.

[0032] "Treating" with respect to a subject, e.g., a human, refers to ameliorating at least one symptom of the disorder of the subject. Treatment includes curing, ameliorating, or at least partially ameliorating the disorder.

[0033] "Disorder" is used in the present disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0034] As used in the present disclosure, the terms "administer", "administering", or "administration" refer to either directly administering the disclosed compound or a pharmaceutical composition thereof to a subject, e.g., a human.

[0035] The term "effective amount", when used in connection with a method of treating or preventing a disorder by administering a disclosed compound, refers to the amount of the compound that provides a therapeutic effect when administered to a subject, e.g., a human.

[0036] As used herein, the term "crystalline" and related terms, when used to describe a substance, component or product, mean that the substance, component or product is substantially crystalline as determined by X-ray diffraction, microscopy, polarized microscopy, or other known analytical procedures known to those of skill in the art.

[0037] As used herein, the term "polymorph" refers to the crystalline forms of a compound having different unit cell structures in a crystal, which are derived from various molecular steric structures and molecular packings. Polymorphs of a single compound may have one or more different chemical, physical, mechanical, electrical, thermodynamic, and / or biological properties from each other. The differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in composition and product manufacturing), dissolution rate (an important factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, water absorption, caking, and particle morphology. Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation such that a dosage form discolors faster when composed of one polymorph than when composed of another), or mechanical changes (e.g., crystalline changes during storage when a kinetically favored polymorph converts to a more thermodynamically stable polymorph), or both (e.g., one polymorph is more hygroscopic than the other). As a result of differences in solubility / dissolution, some changes can affect efficacy and / or toxicity. In addition, the physical properties of crystals can be important in processing; for example, one polymorph may be more likely to form a solvate or may be difficult to filter and wash without impurities (i.e., particle shape and size distribution may differ when comparing one polymorph to another). As used herein, "amorphous" refers to the solid form of a compound or the amorphous form of a compound that can be in a soluble form. For example, "amorphous" refers to a compound that does not have a regular repeating arrangement of molecules or external faces.

[0038] As used herein, the term "anhydrous" refers to a crystalline form having 0.1, 0.3, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weight % or less water relative to the total weight of the composition. In some cases, the anhydrous crystalline form may be referred to as a non-solvate.

[0039] As used herein, the term "solvate" refers to a crystalline form of a compound of formula (I), such as a polymorphic form of the compound, in which the crystal lattice contains one or more solvents of crystallization. Examples of solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. A solvate in which the solvent molecule is water is typically referred to as a "hydrate". Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing a variable amount of water.

[0040] As used herein, the term "substantially pure crystalline form" means a crystalline form having a crystal purity such that no other crystalline forms can be detected using a PANalytical X'Pert Pro diffractometer with Ni-filtered Cu Kα (45 kV / 40 mA) radiation or an equivalent instrument known to those skilled in the art.

[0041] The crystalline forms of the present invention can be characterized using single crystal data, powder X-ray diffraction ("PXRD" or "XRPD"), differential scanning calorimetry ("DSC"), thermogravimetric analysis ("TGA"), and Raman spectroscopy. It should be understood that the numerical values described and claimed herein are approximate values. Variations within the values may be due, inter alia, to factors such as instrument calibration, instrument error, material purity, crystal size, and sample size. In addition, variations may be possible while obtaining the same results. For example, X-ray diffraction values are generally accurate within ±0.2 degrees, and the intensities (including relative intensities) in an X-ray diffraction pattern may vary depending on the measurement conditions used. Similarly, DSC results are typically accurate within about 2 °C. Accordingly, it should be understood that the crystalline forms of the present invention are not limited to those that provide a characterization pattern (i.e., one or more of PXRD, DSC, and TGA) that is exactly the same as the characterization pattern shown in the accompanying drawings disclosed herein. Any crystalline form that provides a characterization pattern that is substantially the same (e.g., 2Θ ± 0.2°) as that described in the accompanying figures is within the scope of the present invention. The ability to confirm substantially the same characterization pattern is within the scope of those skilled in the art.

[0042] Pharmaceutical compositions and single unit dosage forms containing the crystalline forms of the present invention are also encompassed by the present invention. The individual dosage forms of the present invention may be suitable for oral, mucosal (including sublingual, oral, rectal, nasal, or vaginal), parenteral (including subcutaneous, intramuscular, bolus injection, intraarterial, or intravenous), transdermal, or topical administration.

[0043] The single unit dosage forms of the present invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, oral, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration to a patient.

[0044] Typically, the composition, shape, and type of the dosage forms of the present invention will vary depending on their use. It will be readily apparent to those skilled in the art that the specific dosage form methods and other methods encompassed by the present invention are different from each other. See, for example, Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa (1995).

[0045] Typical pharmaceutical compositions and dosage forms include one or more carriers, excipients, or diluents. Suitable excipients are well known to those skilled in the pharmaceutical arts, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including but not limited to the manner in which the dosage form will be administered to a patient. For example, an oral dosage form such as a tablet may contain excipients that are not suitable for use in a parenteral dosage form. The compatibility of a particular excipient may also depend on the particular active ingredient in the dosage form.

[0046] Crystalline form Form A One such crystalline form of formula (I) is known as Form A. In some embodiments, Form A is a non-solvated crystalline form of formula (I). In some embodiments, Form A is an anhydrous crystalline form of formula (I).

[0047] In certain embodiments, Form A is characterized by an X-ray powder diffraction pattern obtained with Ni-filtered Cu Kα (45 kV / 40 mA) radiation and including at least two or three peaks at diffraction angles (2Θ ± 0.2°) selected from 7.4, 9.6, 14.7, 16.7, 17.1, 18.5, 19.3, 21.1, and 22.2. See, for example, FIG. 3A.

[0048] In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 18.5 and 19.3. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 18.5, 19.3, and 21.1. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 18.5, 19.3, and 22.2. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 17.1, 18.5 and 19.3. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 16.7, 18.5 and 19.3. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 14.7, 18.5 and 19.3. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 9.6, 18.5 and 19.3. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 18.5, 19.3, 21.1, and 22.2. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 16.7, 17.1, 18.5, 19.3, 21.1, and 22.2. For example, in some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 9.6, 14.7, 16.7, 17.1, 18.5, 19.2, 21.1, and 22.2.

[0049] In certain embodiments, Form A is characterized by an X-ray powder diffraction pattern obtained with Ni-filtered Cu Kα (45 kV / 40 mA) radiation and includes at least two or three d-spacing values (d-spacing ± 0.2 Å) selected from 12.0, 9.2, 6.0, 5.3, 5.2, 4.8, 4.6, 4.2, and 4.0.

[0050] In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) at least at 4.8 and 4.6. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) at least at 4.8, 4.6, and 4.2. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) at least at 4.8, 4.6, and 4.0. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) at least at 5.2, 4.8, and 4.6. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) at least at 5.3, 4.8, and 4.6. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) at least at 6.0, 4.8, and 4.6. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) at least at 9.6, 4.8, and 4.6. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) at least at 4.8, 4.6, 4.2, and 4.0. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) at least at 6.0, 5.3, 5.2, 4.8, and 4.6. For example, in some embodiments, Form A is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) at least at 9.2, 6.0, 5.3, 5.2, 4.8, 4.6, 4.2, and 4.0.

[0051] In some embodiments, Form A is characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic event in a temperature range of about 235° C. to about 250° C. with a peak temperature of about 241° C. In some embodiments, the endothermic event occurs with decomposition. In some embodiments, the endotherm is observed when using a scan rate of 15° C. / min.

[0052] In some embodiments, Form A is characterized by a thermogravimetric analysis (TGA-IR) thermogram having a weight loss event of about 0.2% in the temperature range of about 25° C. to about 150° C. In some embodiments, the weight loss is observed when using a scan rate of 15° C. / min.

[0053] Surprisingly, it has been found that Form A is the most stable crystalline form of the compound of formula (I). This was confirmed in aging studies. Thus, it may be preferable to use the more stable crystalline form of the compound of formula (I) in a pharmaceutical composition or dosage form. By using this form, decomposition or modification of the pharmaceutical composition or dosage form can be avoided.

[0054] Form B Another crystalline form of formula (I) is known as Form B.

[0055] In certain embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained with Cu Kα (50 kV / 300 mA) radiation comprising at least two or three peaks at diffraction angles (2Θ±0.2°) selected from 6.8, 7.0, 13.7, 15.5, 17.1, 17.2, 18.5, 18.6, 19.5, 19.6, 20.7, 20.9, 27.8, and 28.0. See, for example, FIG. 1.

[0056] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 6.8 and 7.0. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 6.8, 7.0, and 20.7. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 6.8, 7.0, and 20.9. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 6.8, 7.0, and 19.6. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 6.8, 7.0, and 17.2. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 6.8, 7.0, and 27.8. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 6.8, 7.0, 20.7, and 20.9. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 6.8, 7.0, 19.6, 20.7, and 20.9. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 6.8, 7.0, 17.2, 19.6, 20.7, and 20.9. For example, in some embodiments, Form B is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 6.8, 7.0, 13.7, 15.5, 17.1, 17.2, 18.5, 18.6, 19.5, 19.6, 20.7, 20.9, 27.8, and 28.0.

[0057] In certain embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained with Cu Kα (50 kV / 300 mA) radiation and includes at least two or three d-spacing values (d-spacing ± 0.2 Å) selected from 12.9, 12.6, 6.4, 5.7, 5.2, 5.1, 4.8, 4.7, 4.6, 4.5, 4.3, 4.2, and 3.2.

[0058] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) of at least 12.9 and 12.6. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) of at least 12.9, 12.6, and 4.3. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) of at least 12.9, 12.6, and 4.2. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) of at least 12.9, 12.6, and 5.1. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) of at least 12.9, 12.6, and 3.2. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) of at least 12.9, 12.6, 4.3, and 4.2. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) of at least 12.9, 12.6, 4.5, and 5.1. In some embodiments, Form B is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) of at least 12.9, 12.6, 4.3, 4.2, and 5.1. For example, in some embodiments, Form B is characterized by an X-ray powder diffraction pattern that includes d-spacing values (d-spacing ± 0.2 Å) of at least 12.9, 12.6, 6.4, 5.7, 5.2, 5.1, 4.8, 4.7, 4.6, 4.5, 4.3, 4.2, and 3.2.

[0059] Form C Another crystalline form of formula (I) is known as Form C. Form C is a monohydrate crystalline form of formula (I).

[0060] In certain embodiments, Form C is characterized by an X-ray powder diffraction pattern obtained with Ni-filtered Cu Kα (45 kV / 40 mA) radiation and containing at least two or three peaks at diffraction angles (2Θ ± 0.2°) selected from 3.9, 7.6, 16.0, 18.0, 19.2, 26.7, 27.0, and 28.4. See, for example, FIG. 4A.

[0061] In some embodiments, Form C is characterized by an X-ray powder diffraction pattern that includes peaks characteristic of diffraction angles (2Θ ± 0.2°) of at least 16.0 and 19.2. In some embodiments, Form C is characterized by an X-ray powder diffraction pattern that includes peaks characteristic of diffraction angles (2Θ ± 0.2°) of at least 3.9 and 19.2. In some embodiments, Form C is characterized by an X-ray powder diffraction pattern that includes peaks characteristic of diffraction angles (2Θ ± 0.2°) of at least 3.9, 16.0, and 19.2. In some embodiments, Form C is characterized by an X-ray powder diffraction pattern that includes peaks characteristic of diffraction angles (2Θ ± 0.2°) of at least 3.9, 7.6, 16.0, and 19.2. In some embodiments, Form C is characterized by an X-ray powder diffraction pattern that includes peaks characteristic of diffraction angles (2Θ ± 0.2°) of at least 3.9, 7.6, 16.0, 18.4 and 19.2. In some embodiments, Form C is characterized by an X-ray powder diffraction pattern that includes peaks characteristic of diffraction angles (2Θ ± 0.2°) of at least 7.6, 16.0, 18.0, 19.2, and 28.4. In some embodiments, Form C is characterized by an X-ray powder diffraction pattern that includes peaks characteristic of diffraction angles (2Θ ± 0.2°) of at least 7.6, 16.0, 18.0, 19.2, 26.7, and 28.4. For example, in some embodiments, Form C is characterized by an X-ray powder diffraction pattern that includes peaks characteristic of diffraction angles (2Θ ± 0.2°) of at least 3.9, 7.6, 16.0, 18.0, 19.2, 26.7, 27.0, and 28.4.

[0062] In certain embodiments, Form C is characterized by an X-ray powder diffraction pattern obtained with Ni-filtered Cu Kα (45 kV / 40 mA) radiation that includes at least two or three d-spacing values (d-spacing ± 0.2 Å) selected from 22.9, 5.6, 5.0, 4.8, 4.6, 3.3, and 3.2.

[0063] In some embodiments, Form C is characterized by an X-ray powder diffraction pattern that includes d-spacing values of at least 5.6 and 4.6 (d-spacing ± 0.2 Å). In some embodiments, Form C is characterized by an X-ray powder diffraction pattern that includes d-spacing values of at least 22.9 and 4.6 (d-spacing ± 0.2 Å). In some embodiments, Form C is characterized by an X-ray powder diffraction pattern that includes d-spacing values of at least 22.9, 5.6, and 4.6 (d-spacing ± 0.2 Å). In some embodiments, Form C is characterized by an X-ray powder diffraction pattern that includes d-spacing values of at least 22.9, 5.6, 4.6, and 3.2 (d-spacing ± 0.2 Å). In some embodiments, Form C is characterized by an X-ray powder diffraction pattern that includes d-spacing values of at least 5.3, 4.8, 4.6, and 3.2 (d-spacing ± 0.2 Å). In some embodiments, Form C is characterized by an X-ray powder diffraction pattern that includes d-spacing values of at least 22.9, 5.3, 4.8, 4.6, and 3.2 (d-spacing ± 0.2 Å). In some embodiments, Form C is characterized by an X-ray powder diffraction pattern that includes d-spacing values of at least 11.6, 5.3, 4.8, 4.6, and 3.2 (d-spacing ± 0.2 Å). For example, in some embodiments, Form C is characterized by an X-ray powder diffraction pattern that includes d-spacing values of at least 22.9, 5.6, 5.0, 4.8, 4.6, 3.3, and 3.2 (d-spacing ± 0.2 Å).

[0064] In some embodiments, Form C is characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic event with a peak temperature of about 105 °C at a temperature of about 50 °C to about 125 °C. In some embodiments, additional endothermic events in the range of about 225 to about 255 °C are observed at peak temperatures of about 242 °C and about 255 °C. In some embodiments, the endotherms are observed when using a scan rate of 15 °C / min.

[0065] In some embodiments, Form C is characterized by a thermogravimetric analysis (TGA-IR) thermogram having a stepwise weight loss event of about 3.2% of water in the temperature range of about 25 to about 175 °C. In some embodiments, the stepwise weight loss event of water corresponds to the dehydration of the monohydrate salt. In some embodiments, Form C can be heated up to 255 °C without observed decomposition as confirmed by FTIR after cooling. In some embodiments, a stepwise weight loss of water is observed when using a scanning rate of 15 °C / min.

[0066] Form D Another crystalline form of formula (I) is known as Form D. In some embodiments, Form D is an unsolvated crystalline form of formula (I). In some embodiments, Form D is an anhydrous crystalline form of formula (I).

[0067] In certain embodiments, Form D is characterized by an X-ray powder diffraction pattern obtained with Ni-filtered Cu Kα (45 kV / 40 mA) radiation and comprising at least two or three peaks at diffraction angles (2Θ ± 0.2°) selected from 7.1, 13.9, 15.5, 17.2, 19.6, 19.9, 20.8, and 27.9. See, for example, FIG. 5A.

[0068] In some embodiments, Form D is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 7.1 and 20.8. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 7.1 and 19.6. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 7.1, 19.6, and 20.8. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 7.1, 17.2, 19.6, and 20.8. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 7.1, 15.5, 17.2, 19.6, and 20.8. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 7.1, 15.5, 17.2, 19.6, 20.8, and 27.9. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 7.1, 17.2, 19.6, 20.8, and 27.9. For example, in some embodiments, Form D is characterized by an X-ray powder diffraction pattern that includes at least characteristic peaks at diffraction angles (2Θ ± 0.2°) of 7.1, 13.9, 15.5, 17.2, 19.6, 19.9, 20.8, and 27.9.

[0069] In certain embodiments, Form D is characterized by an X-ray powder diffraction pattern obtained with Ni-filtered Cu Kα (45 kV / 40 mA) radiation that includes at least two or three d-spacing values (d-spacing ± 0.2 Å) selected from 12.5, 6.4, 5.7, 5.2, 4.5, 4.4, 4.3, and 3.2.

[0070] In some embodiments, Form D is characterized by an X-ray powder diffraction pattern that includes d-spacing values of at least 12.5 and 4.3 (d-spacing ± 0.2 Å). In some embodiments, Form D is characterized by an X-ray powder diffraction pattern that includes d-spacing values of at least 12.5 and 4.5 (d-spacing ± 0.2 Å). In some embodiments, Form D is characterized by an X-ray powder diffraction pattern that includes d-spacing values of at least 12.5, 4.5, and 4.3 (d-spacing ± 0.2 Å). In some embodiments, Form D is characterized by an X-ray powder diffraction pattern that includes d-spacing values of at least 12.5, 5.2, 4.5, and 4.3 (d-spacing ± 0.2 Å). In some embodiments, Form D is characterized by an X-ray powder diffraction pattern that includes d-spacing values of at least 12.5, 6.4, 5.2, 4.5, and 4.3 (d-spacing ± 0.2 Å). In some embodiments, Form D is characterized by an X-ray powder diffraction pattern that includes d-spacing values of at least 12.5, 5.2, 4.5, 4.3, and 3.2 (d-spacing ± 0.2 Å). For example, in some embodiments, Form D is characterized by an X-ray powder diffraction pattern that includes d-spacing values of at least 12.5, 6.4, 5.7, 5.2, 4.5, 4.4, 4.3, and 3.2 (d-spacing ± 0.2 Å).

[0071] In some embodiments, Form D is characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic event in the temperature range of about 245 °C to about 280 °C, and a peak temperature of about 266 °C. In some embodiments, the endothermic event occurs with decomposition. In some embodiments, the endotherm is observed when using a scan rate of 15 °C / min.

[0072] In some embodiments, Form D is characterized by a thermogravimetric analysis (TGA-IR) thermogram having a weight loss event of about 0.6% in the temperature range of about 25 °C to about 150 °C. In some embodiments, the weight loss event is observed when using a scan rate of 15 °C / min.

[0073] Form E Another crystalline form of formula (I) is known as Form E. Form E is a monohydrate crystalline form.

[0074] In certain embodiments, Form E is characterized by an X-ray powder diffraction pattern obtained with Ni-filtered Cu Kα (45 kV / 40 mA) radiation and comprising at least two or three peaks at diffraction angles (2Θ ± 0.2°) selected from 10.1, 12.5, 14.8, 16.3, 16.6, 18.7, 22.0, 23.4, and 26.2. See, for example, FIG. 7A.

[0075] In some embodiments, Form E is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ±0.2°) of 10.1 and 16.3. In some embodiments, Form E is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ±0.2°) of 16.3 and 18.7. In some embodiments, Form E is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ±0.2°) of 16.3 and 22.0. In some embodiments, Form E is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ±0.2°) of 10.1, 16.3, and 18.7. In some embodiments, Form E is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ±0.2°) of 10.1, 16.3, and 22.0. In some embodiments, Form E is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ±0.2°) of 10.1, 16.3, 18.7, and 22.0. In some embodiments, Form E is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ±0.2°) of 10.1, 14.8, 16.3, 18.7, and 22.0. For example, in some embodiments, Form E is characterized by an X-ray powder diffraction pattern comprising at least characteristic peaks at diffraction angles (2Θ±0.2°) of 10.1, 12.5, 14.8, 16.3, 16.6, 18.7, 22.0, 23.4, and 26.2.

[0076] In certain embodiments, Form E is characterized by an X-ray powder diffraction pattern obtained with Ni-filtered Cu Kα (45 kV / 40 mA) radiation and comprising at least two or three d-spacing values (d-spacing ±0.2 Å) selected from 8.8, 7.1, 6.0, 5.5, 5.4, 4.8, 4.6, 4.1.

[0077] In some embodiments, Form E is characterized by an X-ray powder diffraction pattern comprising d-spacing values of at least 8.8 and 5.5 (d-spacing ± 0.2 Å). In some embodiments, Form E is characterized by an X-ray powder diffraction pattern comprising d-spacing values of at least 5.5 and 4.1 (d-spacing ± 0.2 Å). In some embodiments, Form E is characterized by an X-ray powder diffraction pattern comprising d-spacing values of at least 5.5 and 4.8 (d-spacing ± 0.2 Å). In some embodiments, Form E is characterized by an X-ray powder diffraction pattern comprising d-spacing values of at least 8.8, 5.5, and 4.1 (d-spacing ± 0.2 Å). In some embodiments, Form E is characterized by an X-ray powder diffraction pattern comprising d-spacing values of at least 8.8, 5.5, and 4.8 (d-spacing ± 0.2 Å). In some embodiments, Form E is characterized by an X-ray powder diffraction pattern comprising d-spacing values of at least 8.8, 5.5, 4.8, and 4.1 (d-spacing ± 0.2 Å). For example, in some embodiments, Form E is characterized by an X-ray powder diffraction pattern comprising d-spacing values of at least 8.8, 7.1, 6.0, 5.5, 5.4, 4.8, 4.6, and 4.1 (d-spacing ± 0.2 Å).

[0078] In some embodiments, Form E is characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic event in the temperature range of about 85°C to about 150°C and a peak temperature of about 136°C. In some embodiments, an additional endothermic event in the temperature range of about 200 to about 225°C is observed with a peak temperature of about 221°C. In some embodiments, the additional endothermic event occurs with decomposition. In some embodiments, an endotherm is observed when using a scan rate of 15°C / min.

[0079] In some embodiments, Form E is characterized by a thermogravimetric analysis (TGA-IR) thermogram having a stepwise weight loss event of about 3.1% of water in the temperature range of about 85°C to about 150°C. In some embodiments, the stepwise weight loss of water corresponds to dehydration of the monohydrate salt. In some embodiments, an additional stepwise weight loss event of about 7.1% of carbon dioxide is observed in the temperature range of about 175°C to about 210°C. In some embodiments, the additional weight loss of the carbon dioxide event occurs with decomposition. In some embodiments, the weight loss events are observed when using a scan rate of 15°C / min.

[0080] In some embodiments, the experimental powder diffraction pattern is obtained by diffraction of X-rays on a powder in a PANalytical X’Pert Pro diffractometer using Ni-filtered Cu Kα (45 kV / 40 mA) radiation as well as a 2Θ step size of 0.02° and an X’celerator™ RTMS (Real Time Multi Strip) detector. In some embodiments, the sample is placed on a glass plate without grinding and analyzed at ambient temperature and humidity. In some embodiments, the configuration on the incident beam side includes a fixed divergence slit (0.25°), a 0.04 rad Soller slit, an anti-scatter slit (0.25°), and a 10 mm beam mask. In some embodiments, the configuration on the diffracted beam side includes a fixed divergence slit (0.25°) and a 0.04 rad Soller slit. In some examples, peaks with relative intensity exceeding about 10% are considered characteristic peaks.

[0081] One skilled in the art will understand that the relative intensity and position of the peaks obtained by X-ray powder diffraction can vary depending on factors such as sample preparation techniques, sample mounting procedures, and the specific instrument used. For example, in additional embodiments, the X-ray powder diffraction pattern peaks of the crystalline form of formula (I) recited may be at 2Θ ± 0.2 degrees or at a d-spacing ± 0.2 Å.

[0082] It is known that an X-ray powder diffraction pattern having one or more measurement errors can be obtained according to measurement conditions (such as the equipment used). The intensity in the X-ray powder diffraction pattern can vary depending on the measurement conditions. Therefore, the crystal form of the present invention is not limited to crystals that provide an X-ray powder diffraction pattern identical to the X-ray powder diffraction pattern described in the present application, but any crystal that provides an X-ray powder diffraction pattern substantially the same as (for example, 2Θ ± 0.2°) that described in the present application falls within the scope of the present invention. For example, the relative intensity of the peaks can be affected by grains with a size exceeding 30 microns and having a non-uniform aspect ratio, which can affect the analysis of the sample. Those skilled in the art will recognize that the position of the reflection can be affected by the exact height at which the sample is placed on the diffractometer and the zero calibration of the diffractometer. The surface flatness of the sample can also have a small effect. Therefore, the diffraction pattern data described herein should not be regarded as absolute values. (See, for example, Jenkins, R & Snyder, R.L. 'Introduction to X-Ray Powder Diffractometry' John Wiley & Sons 1996, Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London, Klug, H.P. & Alexander, L.E. (1974), X-Ray Diffraction Procedures).

[0083] In some embodiments, the crystalline compound of formula (I) comprises at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, or at least about 80 wt% of Form A, based on the total amount of crystalline forms present in the crystalline compound of formula (I). In some embodiments, crystalline Form A of formula (I) is isolated in a substantially pure crystalline form (e.g., substantially free of one or more other crystalline forms of formula (I)). In some embodiments, the crystalline compound of formula (I) comprises at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of Form A, based on the total amount of crystalline forms present in the compound of formula (I). In some embodiments, the crystalline compound of formula (I) comprises from about 80%, about 85%, or about 90% of Form A to about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.9% of Form A, based on the total amount of crystalline forms present in the compound of formula (I); e.g., from about 80% of Form A to about 99.9% of Form A, from about 85% of Form A to about 99% of Form A, from about 90% of Form A to about 99% of Form A, or from about 90% of Form A to about 95% of Form A. In some embodiments, the compound of formula (I) is mostly in crystalline Form A and has about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% or less of other crystalline forms of formula (I), such as Forms B, C, D, and E. The crystalline purity of Form A of formula (I) can be determined by XRPD. In some embodiments, the crystalline purity of Form A is limited by the detection limit of the diffractometer such that the crystalline purity of Form A cannot exceed about 95%, about 96%, about 97%, about 98%, or about 99% based on the total amount of crystalline forms present in the compound of formula (I).

[0084] In some embodiments, the crystalline compound of formula (I) comprises at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, or at least about 80 wt% of Form B, based on the total amount of crystalline forms present in the compound of formula (I). In some embodiments, Form B of formula (I) is isolated in a substantially pure crystalline form (e.g., substantially free of one or more other crystalline forms of formula (I)). In some embodiments, the crystalline compound of formula (I) comprises at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of Form B, based on the total amount of crystalline forms present in the compound of formula (I). In some embodiments, the crystalline compound of formula (I) comprises from about 80%, about 85%, or about 90% of Form B to about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.9% of Form B, based on the total amount of crystalline forms present in the compound of formula (I), e.g., from about 80% of Form B to about 99.9% of Form B, from about 85% of Form B to about 99% of Form B, from about 90% of Form B to about 99% of Form B, or from about 90% of Form B to about 95% of Form B. In some embodiments, the compound of formula (I) is mostly in crystalline Form B and has about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% or less of other crystalline forms of formula (I), such as Forms A, C, D, and E. The crystal purity of Form B of formula (I) can be determined by XRPD. In some embodiments, the crystal purity of Form B is limited by the detection limit of the diffractometer such that the crystal purity of Form B cannot exceed about 95%, exceed about 96%, exceed about 97%, exceed about 98%, or exceed 99%, based on the total amount of crystalline forms present in the compound of formula (I).

[0085] In some embodiments, the crystalline compound of formula (I) comprises at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, or at least about 80 wt% of Form C, based on the total amount of crystalline forms present in the crystalline compound of formula (I). In some embodiments, Form C of formula (I) is isolated in a substantially pure crystalline form (e.g., substantially free of one or more other crystalline forms of formula (I)). In some embodiments, the crystalline compound of formula (I) comprises at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of Form C, based on the total amount of crystalline forms present in the compound of formula (I). In some embodiments, the crystalline compound of formula (I) comprises from about 80%, about 85%, or about 90% of Form C to about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.9% of Form C, e.g., from about 80% of Form C to about 99.9% of Form C, from about 85% of Form C to about 99% of Form C, from about 90% of Form C to about 99% of Form C, or from about 90% of Form C to about 95% of Form C. In some embodiments, the compound of formula (I) is mostly in crystalline Form C and has about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% or less of other crystalline forms of (I), such as Forms A, B, D, and E. The crystal purity of Form C of formula (I) can be determined by XRPD. In some embodiments, the crystal purity of Form C is limited by the detection limit of the diffractometer such that the crystal purity of Form C cannot exceed about 95%, about 96%, about 97%, about 98%, or about 99%, based on the total amount of crystalline forms present in the compound of formula (I).

[0086] In some embodiments, the crystalline compound of formula (I) comprises at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, or at least about 80 wt% of Form D, based on the total amount of crystalline forms present in the crystalline compound of formula (I). In some embodiments, Form D of formula (I) is isolated in a substantially pure crystalline form (e.g., substantially free of one or more other crystalline forms of formula (I)). In some embodiments, the crystalline compound of formula (I) comprises at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of Form D, based on the total amount of crystalline forms present in the compound of formula (I). In some embodiments, the crystalline compound of formula (I) comprises from about 80%, about 85%, or about 90% to about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.9% of Form D, e.g., from about 80% to about 99.9% of Form D, from about 85% to about 99% of Form D, from about 90% to about 99% of Form D, from about 90% to about 95% of Form D, based on the total amount of crystalline forms present in the compound of formula (I). In some embodiments, the compound of formula (I) is mostly in crystalline Form D and has about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% or less of other crystalline forms of formula (I), such as Forms A, B, C, and E. The crystal purity of Form D of formula (I) can be determined by XRPD. In some embodiments, the crystal purity of Form D is limited by the detection limit of the diffractometer such that the crystal purity of Form D cannot exceed about 95%, about 96%, about 97%, about 98%, or about 99% based on the total amount of crystalline forms present in the compound of formula (I).

[0087] In some embodiments, the crystalline compound of formula (I) comprises at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, or at least about 80 wt% of Form E, based on the total amount of crystalline forms present in the crystalline compound of formula (I). In some embodiments, Form E of formula (I) is isolated in a substantially pure crystalline form (e.g., substantially free of one or more other crystalline forms of formula (I)). In some embodiments, the crystalline compound of formula (I) comprises at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of Form E, based on the total amount of crystalline forms present in the compound of formula (I). In some embodiments, the crystalline compound of formula (I) comprises from about 80%, about 85%, or about 90% to about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.9% of Form E, based on the total amount of crystalline forms present in the compound of formula (I), e.g., from about 80% to about 99.9% of Form E, from about 85% to about 99% of Form E, from about 90% to about 99% of Form E, or from about 90% to about 95% of Form E. In some embodiments, the compound of formula (I) is mostly in crystalline Form E and has about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% or less of other crystalline forms of formula (I), such as Forms A, B, C, and D. The crystal purity of Form E of formula (I) can be determined by XRPD. In some embodiments, the crystal purity of Form E is limited by the detection limit of the diffractometer such that the crystal purity of Form E cannot exceed about 95%, exceed about 96%, exceed about 97%, exceed about 98%, or exceed about 99%, based on the total amount of crystalline forms present in the compound of formula (I).

[0088] In some embodiments, Forms A - E of formula (I) are crystalline solids. In other embodiments, Forms A - E of formula (I) are crystalline solids that substantially do not contain amorphous formula (I). In embodiments, the presence of amorphous formula (I) can be determined by XRPD.

[0089] In certain embodiments, substantially pure crystalline forms of formula (I) (e.g., Forms A - E) can be obtained by various crystallization or recrystallization methods. In some embodiments, substantially pure crystalline forms of formula (I) can be crystallized or recrystallized from solvents including, but not limited to, water, MeOH, 2 - methoxyethanol, 1 - propanol, nitromethane:DMSO (80:20), MeCN, DMSO, acetone, 2 - butanone, DCM, methyl acetate, 4 - methyl - 2 - pentanone, chloroform, EtOAc, chlorobenzene:DMSO (80:20), THF, 1,4 - dioxane, isopropyl ether, toluene:DMSO (80:20), cyclohexane, heptane, 1 - butanol, IPA, trifluoroethanol, dimethyl carbonate, MTBE, isopropyl acetate, ethanol, 1 - methoxy - 2 - propanol, cyclohexane, DMF, 2 - methoxyethyl ether, MeOH:water (95:5), MeCN:water (95:5), acetone:water (95:5), THF:water (95:5), IPA:water (95:5), MeOH:water (90:10), MeCN:water (90:10), acetone:water (90:10), 1 - 4 dioxane:water (90:10), 2 - propanol:water (90:10), acetone:water (80:80), THF:water (90:10), ethanol:water (20:80), 2 - propanol:DMSO (80:20), MeCN:DMSO (80:20). In some embodiments, the recrystallization solvent can have a water activity in the range of 0.1 - 1.

[0090] In certain embodiments, the crystalline forms provided herein are subjected to milling conditions so as to include particle size. The nomenclature for describing the particle size of formula (I) is generally referred to as "D" 90 ", and so it is herein. For example, D of 8 90(or D 90 = 8) means that at least 90% of the particles (determined with respect to the total mass, total volume, and / or total number of the particles) have a particle size of less than 8 microns. In some embodiments, the particle size distribution is determined by a laser diffraction dry particle size analyzer, resulting in the determination of the particle size distribution with respect to the total volume, i.e., the D 90 (or D 90 = 8) means that at least 90 volume % (or volume %) of the particles have a particle size of less than 8 microns. In some embodiments, the crystalline forms provided herein have a particle size (D 90 ) in the range of about 1 μm to 20 μm, e.g., about 2, 3, 4, or 5 μm to 15, 16, 17, 18, or 19 μm. In some embodiments, the crystalline forms provided herein have a particle size (D 90 ) of about 10, 11, 12, 13, 14, or 15 μm. In some embodiments, the crystalline forms provided herein have a particle size (D 90 ) of about 5, 6, 7, or 8 μm. In some embodiments, the crystalline forms provided herein have a particle size (D 90 ) of about 15 μm. In some embodiments, the crystalline forms provided herein have a particle size (D 90 ) of about 8 μm.

[0091] Therapeutic / Preventive Administration and the Compositions of the Disclosure The crystalline forms of formula (I) provided herein are advantageously useful in medicine. As described above, the crystalline forms of formula (I) are useful for treating or preventing insomnia disorders in a subject in need thereof, such as a human. In another embodiment, the crystalline form of formula (I) is useful for treating insomnia disorder in a subject in need thereof, such as human insomnia disorder. In another embodiment, the crystalline form of formula (I) is useful for preventing insomnia disorder in a subject in need thereof, such as preventing insomnia disorder in a human. In another embodiment, the crystalline form of formula (I) of the present disclosure can be administered to any animal that requires modulation of opioid and / or ORL-1 receptor. In another embodiment, the crystalline form of formula (I) is useful for treating insomnia associated with alcohol withdrawal in a subject in need thereof, such as treating insomnia associated with alcohol withdrawal in a human. In a particular embodiment, the useful crystalline form of formula (I) is Form A.

[0092] When administered to a subject, such as a human, the crystalline form of formula (I) can be administered as a component of a composition comprising a pharmaceutically acceptable carrier or excipient.

[0093] The methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, parenteral, intravenous, subcutaneous, intranasal, epidural, oral, transmucosal, buccal, gingival, sublingual, intraocular, intracerebral, intravaginal, transdermal (e.g., via a patch), rectal, inhalation or topical, particularly to the ear, nose, eye, or skin. In another embodiment, the methods of administration include, but are not limited to, intravenous, oral, or inhalation. The method of administration is left to the discretion of the treating physician. In some cases, administration results in the release of the crystalline form of formula (I) into the bloodstream. In other cases, administration results in only local release of the crystalline form of formula (I).

[0094] In yet another embodiment, the crystalline form of formula (I) can be delivered in a controlled release system or a sustained release system. Controlled release or sustained release pharmaceutical compositions can have the common goal of improving drug therapy over that achieved by their non-controlled or non-sustained release counterparts. In one embodiment, the controlled release or sustained release composition comprises a minimal amount of the crystalline form of formula (I) for treating or preventing an insomnia disorder or its symptoms over an extended period of time. Advantages of controlled release or sustained release compositions include extended drug activity, decreased dosing frequency, and increased compliance. Additionally, controlled or sustained release compositions can favorably affect other characteristics such as onset time of action or blood levels of the crystalline form of formula (I), and thus can reduce the occurrence of adverse side effects.

[0095] Using such dosage forms, for example, hydroxypropylmethylcellulose, ethylcellulose, other polymeric matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, multiparticulates, liposomes, microspheres, or combinations thereof, can provide controlled or sustained release of one or more active ingredients to provide the desired release profile at various rates. Suitable controlled or sustained release formulations known to those of skill in the art, including those described herein, can be readily selected for use with the active ingredients of the present disclosure. Accordingly, the present disclosure encompasses single unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gelcaps, and caplets, that are adapted for controlled release or sustained release.

[0096] The composition may optionally but preferably further comprise a suitable amount of a pharmaceutically acceptable excipient in order to provide a form suitable for administration to a subject, such as a human. Such pharmaceutical excipients can be diluents, suspending agents, solubilizing agents, binders, disintegrants, preservatives, coloring agents, lubricants, and the like. Pharmaceutical excipients can be liquids such as water, or oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Pharmaceutical excipients can be physiological saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, adjuvants, stabilizers, thickening agents, lubricants, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipient is sterilized when administered to a subject, such as a human. When the crystalline form of formula (I) is administered intravenously, water is a particularly useful excipient. Physiological saline as well as aqueous dextrose and glycerol solutions can also be used as liquid excipients, particularly for injectable solutions. Also, suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, kaolin, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The composition can also contain, if desired, small amounts of wetting or emulsifying agents, or pH buffering agents. Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms are described in Handbook of Pharmaceutical Excipients, (Amer. Pharmaceutical Ass’n, Washington, DC, 1986), which is incorporated herein by reference. Other examples of suitable pharmaceutical excipients are described in Radebough et al., “Preformulation” pp. 1447-1676 in Remington’s Pharmaceutical Sciences Vol. 2 (Gennaro, ed., 19 th Ed., Mack Publishing, Easton, PA, 1995), which is incorporated herein by reference.

[0097] The composition can take the form of a solution, suspension, emulsion, tablets such as orally disintegrating tablets (ODT), sublingual tablets, or tablets to be swallowed whole, pills, pellets, capsules, capsules containing a liquid, powder, sustained release formulation, suppository, emulsion, aerosol, spray, suspension, microparticles, multi-microparticles, rapidly dissolving films for oral or mucosal administration, or any other form suitable for use. In one embodiment, the composition is in the form of an ODT (see, e.g., U.S. Patent Nos. 7,749,533 and 9,241,910). In another embodiment, the composition is in the form of a sublingual tablet (see, e.g., U.S. Patent Nos. 6,572,891 and 9,308,175). In another embodiment, the composition is in the form of a capsule (see, e.g., U.S. Patent No. 5,698,155). In another embodiment, the composition is in a form suitable for oral administration as a tablet, lozenge, gel, patch, or film formulated by conventional methods (see, e.g., Pather et al., “Current status and the future of buccal drug delivery systems,” Drug Deliv. 5(5):531-542 (2008)). In another embodiment, the composition is in a form suitable for gingival administration, such as a polymeric film containing polyvinyl alcohol, chitosan, polycarbophil, hydroxypropyl cellulose, or Eudragit S-100 as disclosed in, e.g., Padula et al., “In Vitro Evaluation of Mucoadhesive Films for Gingival Administration of Lidocaine,” AAPS PharmSciTech 14(4):1279-1283 (2013). In another embodiment, the composition is in the form of an oral dosage form to be swallowed whole. In another embodiment, the composition is in a form suitable for intraocular administration.

[0098] In one embodiment, the crystalline form of formula (I) is formulated according to routine procedures as a composition suitable for oral administration to humans. The crystalline form of formula (I) for oral delivery can be, for example, in the form of tablets, capsules, gel caps, caplets, lozenges, aqueous or oily solutions, suspensions, granules, microparticles, multi-microparticles, powders, emulsions, syrups, or elixirs. The oral dosage form can be an oral dosage form to be swallowed, such as tablets, capsules, or gel caps. When the crystalline form of formula (I) is incorporated into an oral tablet, such tablets can be compressed, tableted, enteric-coated, sugar-coated, film-coated, multi-compressed, or multi-layered. Techniques and compositions for making solid oral dosage forms are described in Pharmaceutical Dosage Forms: Tablets (Lieberman et al., eds., 2 nd nd Ed., Marcel Dekker, Inc., 1989 and 1990). Techniques and compositions for making tablets (compression and molding), capsules (hard and soft gelatin), and pills are described by King et al. in Remington’s Pharmaceutical Sciences (Osol, ed., 16 th th Ed., Mack Publishing, Easton, PA, 1980) as “Tablets, Capsules, and Pills” pp. 1553-1593.

[0099] Examples of liquid oral dosage forms include aqueous and non-aqueous solutions, emulsions, suspensions, and solutions and / or suspensions reconstituted from non-foaming granules optionally containing one or more suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, colorants, flavoring agents, etc. Techniques and compositions for making liquid oral dosage forms are described in Pharmaceutical Dosage Forms: Disperse Systems (Lieberman et al., eds., 2 nd nd Ed., Marcel Dekker, Inc., 1996 and 1998).

[0100] The crystalline form of formula (I) for oral administration may contain one or more agents, such as sweeteners, such as fructose, aspartame, or saccharin, flavoring agents, such as peppermint, wintergreen oil, or cherry, coloring agents, and preservatives, in order to provide a pharmaceutically palatable preparation. Further, in tablet or pill form, the composition can be coated to provide a sustained action over a long period of time by delaying disintegration and absorption in the gastrointestinal tract. A selectively permeable membrane surrounding an osmotic active driving compound is also suitable for an orally administered composition. In these latter platforms, fluid from the environment surrounding the capsule is absorbed by the driving compound, which swells to displace the agent or pharmaceutical composition through an opening. These delivery platforms can provide an essentially zero-order delivery profile, in contrast to the spike profile of an immediate release formulation. Time delay materials such as glyceryl monostearate or glycerol stearate can also be used. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade.

[0101] When the crystalline form of formula (I) is administered parenterally by injection, it can be, for example, in the form of an isotonic sterile solution. Alternatively, when the crystalline form of formula (I) is inhaled, it can be formulated as a dry aerosol or as an aqueous solution or a partially aqueous solution.

[0102] In another embodiment, the crystalline form of formula (I) can be formulated for intravenous administration. In certain embodiments, the composition for intravenous administration comprises a sterile isotonic buffered aqueous solution. Optionally, the composition may contain a solubilizing agent. The crystalline form of formula (I) for intravenous administration may optionally contain a local anesthetic such as benzocaine or prilocaine to reduce pain at the injection site. Generally, the components are either supplied separately or mixed together in unit dosage forms, for example, as a dry lyophilized powder or a water-free concentrate in a sealed container such as an ampoule or sachet indicating the amount of the active agent. When the crystalline form of formula (I) is administered by injection, it can be dispensed, for example, in an infusion bottle containing sterile pharmaceutical grade water or physiological saline. When the crystalline form of formula (I) is administered by injection, an ampoule of sterile water for injection or physiological saline can be provided so that the components can be mixed prior to administration.

[0103] The amount of the crystalline form of formula (I) effective for the treatment or prevention of insomnia disorder can be determined by standard clinical techniques. Additionally, in vitro and / or in vivo assays can optionally be used to assist in identifying the optimal dosage range. The exact dosage used will also depend, for example, on the route of administration and the severity of the insomnia disorder and can be determined according to the judgment of the practicing physician and / or the circumstances of each animal. In other examples, inevitable variations will occur, inter alia, depending on the weight and physical condition of the animal being treated (e.g., liver and kidney function), the disorder being treated, the severity of the symptoms, the frequency of the dosing interval, the presence of any adverse side effects, and the particular compound utilized.

[0104] When used for the indicated effects, the effective dosage of the disclosed crystalline form of formula (I) ranges from about 0.1 mg to about 5000 mg of the crystalline form as disclosed, as required for the treatment, prevention or management of a particular disorder. For example, a pharmaceutical composition for use in vivo or in vitro can contain about 0.1, 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed crystalline form, or can contain in a range from one amount to another amount within the recited dosages. In one embodiment, a suitable effective dosage of the crystalline form of formula (I) administered as a daily dosage to humans is from about 0.16 mg to about 8.0 mg. In one embodiment, a suitable effective daily dosage of the crystalline form of formula (I) administered to humans is about 0.16 mg. In other embodiments, suitable effective daily dosages of the crystalline form of formula (I) administered to humans are about 0.20 mg, about 0.30 mg, about 0.33 mg, about 0.35 mg, about 0.40 mg, about 0.45 mg, about 0.46 mg, about 0.47 mg, about 0.48 mg, about 0.49 mg, about 0.50 mg, about 0.525 mg, about 0.55 mg, about 0.575 mg, about 0.60 mg, about 0.625 mg, about 0.65 mg, about 0.675 mg, about 0.70 mg, about 0.725 mg, about 0.75 mg, about 0.775 mg, about 0.80 mg, about 0.825 mg, about 0.85 mg, about 0.875 mg, about 0.90 mg, about 0.925 mg, about 0.95 mg, about 0.975 mg, about 1.00 mg, about 1.10 mg, about 1.20 mg, about 1.30 mg, about 1.40 mg, about 1.50 mg, about 1.60 mg, about 1.70 mg, about 1.80 mg, about 1.90 mg, about 2.00 mg, about 2.10 mg, about 2.20 mg, about 2.30 mg, about 2.40 mg, about 2.50 mg, about 2.60 mg, about 2.70 mg, about 2.80 mg, about 2.90 mg, about 3.00 mg, about 3.25 mg, about 3.50 mg, about 3.75 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 7.5 mg, or about 8.0 mg. In any of these embodiments, the daily dosage is optionally a single daily dosage.In any of these embodiments, the daily dose is optionally a divided daily dose, for example, any of 67%, 60%, 50%, 40%, or 33% of the above doses is administered before the intended bedtime, and the remaining 33%, 40%, 50%, 60%, or 67% respectively is administered in the second half of the daily period, for example, when waking up in the middle of the night and then unable to easily return to sleep.

[0105] It should be understood that the term "daily" means a 24-hour cycle starting at the time of administration of the crystalline form of formula (I). For example, for a normal overnight sleep cycle, if the crystalline form of formula (I) is administered at 9:30 PM, that "day" ends at 9:29 PM of the following calendar day. In another example, for the sleep cycle of a shift worker, if the crystalline form of formula (I) is administered at 8:15 AM, that "day" ends at 8:14 AM of the following calendar day.

[0106] As known to those skilled in the art, for humans, the daily dose (mg) can be converted to a dose in mg / kg / day by dividing the mg dose by the average mass of a human recognized in the art, which is 60 kg. For example, a daily human dose of 1.25 mg is converted to a dosage of approximately 0.021 mg / kg / day.

[0107] The effective dosage described herein refers to the total amount administered, that is, when two or more crystalline forms of formula (I) are administered, the effective dosage corresponds to the total amount administered.

[0108] Administration can be as a single dose or as divided doses. In one embodiment, the effective dose or dosage is administered only as needed, e.g., when sleep cannot be easily achieved or when waking up at night and then not being able to easily return to sleep. In another embodiment, the effective dose or dosage is administered, for example, every about 24 hours at the intended bedtime until the insomnia disorder is reduced. In another embodiment, the effective dose or dosage is administered before the intended bedtime to reduce the insomnia disorder. In other embodiments, the effective dose or dosage is administered before the intended bedtime for 2, 3, 4, 5, 6, 7, 8, 9, 10, up to 12, 12, at least 12, up to 14, 14, at least 14, up to 21, 21, at least 21, up to 28, 28, at least 28, up to 34, 34, at least 34, up to 40, 40, at least 40, up to 50, 50, at least 50, up to 60, 60, at least 60, up to 75, 75, at least 75, up to 90, 90, at least 90, up to 120, 120, at least 120, up to 150, 150, at least 150, up to 180, 180, at least 180, up to 270, 270, at least 270, up to 360, 360, or at least 360 consecutive days to reduce the insomnia disorder. In other embodiments, the effective dose or dosage is administered before the intended bedtime every day for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, up to 12, 12, at least 12, up to 16, 16, at least 16, up to 26, 26, at least 26, up to 52, 52, at least 52 weeks. In other embodiments, the effective dose or dosage is administered before the intended bedtime every day for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, up to 12, 12, at least 12 months. In any of these embodiments, the daily dose is optionally a single daily dose.

[0109] In one embodiment, the effective dose or dosage is administered in preparation for sleep, which can be, for example, about 90 minutes before the intended bedtime. In other embodiments, the effective dose or dosage is administered during the preparation for sleep, which can be about 75 minutes before, about 60 minutes before, about 45 minutes before, about 30 minutes before, about 20 minutes before, about 20 minutes or less before, about 15 minutes before, about 15 minutes or less before, about 10 minutes before, about 10 minutes or less before, about 5 minutes before, about 5 minutes or less before, about 2 minutes before, about 2 minutes or less before, or about 1 minute before the intended bedtime, or at the intended bedtime.

[0110] In one embodiment, an effective dose or dosage is administered daily to treat or prevent insomnia associated with alcohol withdrawal. In another embodiment, an effective dose or dosage is administered before the intended bedtime to treat or prevent insomnia associated with alcohol withdrawal. In another embodiment, an effective dose or dosage is initiated and administered after alcohol intake has been discontinued (e.g., after a subject, e.g., a human having an alcohol use disorder, has begun to discontinue alcohol intake). In another embodiment, an effective dose or dosage initiated and administered after alcohol intake has been discontinued may be continued after alcohol intake (e.g., a subject who has abstained from alcohol but consumes alcohol, e.g., a human). In another embodiment, an effective dose or dosage is administered before alcohol intake is discontinued (e.g., while a subject, e.g., a human having an alcohol use disorder, continues to consume). In other embodiments, an effective dose or dosage is initiated and administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, up to 12, 12, at least 12, up to 16, 16, at least 16, up to 26, 26, at least 26, up to 52, 52, at least 52 weeks after alcohol intake is discontinued, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, up to 12, 12, at least 12, up to 14, 14, at least 14, up to 21, 21, at least 21, up to 28, 28, at least 28, up to 34, 34, at least 34, up to 40, 40, at least 40, up to 50, 50, at least 50, up to 60, 60, at least 60, up to 75, 75, at least 75, up to 90, 90, at least 90, up to 120, 120, at least 120, up to 150, 150, at least 150, up to 180, 180, at least 180, up to 270, 270, at least 270, up to 360, 360, or at least 360 days after alcohol intake is discontinued.In other embodiments, the effective dose or dosage is administered starting at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, up to 12, 12, at least 12 months after alcohol intake has ceased. In any of these embodiments, the daily dose is optionally a single daily dose.

[0111] The crystalline form of formula (I) can be administered to a subject, such as a human, who has consumed alcohol, or the subject, such as a human, can consume alcohol after administration of the compound. In embodiments, the amount of ethanol consumed is from about 0.05 g / kg to about 5.0 g / kg, from about 0.05 g / kg to about 2.0 g / kg, from about 0.05 g / kg to about 1.0 g / kg, from about 0.05 g / kg to about 0.5 g / kg, from about 0.05 g / kg to about 0.2 g / kg, from about 0.2 g / kg to about 5.0 g / kg, from about 0.2 g / kg to about 2.0 g / kg, from about 0.2 g / kg to about 1.0 g / kg, from about 0.2 g / kg to about 0.8 g / kg, from about 0.2 g / kg to about 0.5 g / kg, from about 0.5 g / kg to about 5.0 g / kg, from about 0.5 g / kg to about 2.0 g / kg, from about 0.5 g / kg to about 1.0 g / kg, or from about 0.5 g / kg to about 0.8 g / kg.

[0112] In one embodiment, a composition comprising a crystalline form of formula (I) according to the present disclosure is used as a medicament. In another embodiment, a composition comprising a crystalline form of formula (I) that can be used to prepare a medicament containing the composition is disclosed.

[0113] In another embodiment, a composition comprising a crystalline form of formula (I) is useful as a medicament for the treatment or prevention of sleep disorders. In another embodiment, a composition comprising a crystalline form of formula (I) is useful as a medicament for the treatment or prevention of a sleep disorder wherein the sleep disorder is an insomnia disorder, a hypersomnia disorder, a circadian rhythm sleep-wake disorder, an alcohol-induced sleep disorder, or any combination thereof.

[0114] In another embodiment, a composition comprising a crystalline form of formula (I) is useful as a medicament for the treatment of sleep disorders. In another embodiment, a composition comprising a crystalline form of formula (I) is useful as a medicament for the treatment of a sleep disorder wherein the sleep disorder is an insomnia disorder, a hypersomnia disorder, a circadian rhythm sleep-wake disorder, an alcohol-induced sleep disorder, or any combination thereof.

[0115] In another embodiment, a composition comprising a crystalline form of formula (I) is useful as a medicament for the prevention of sleep disorders. In another embodiment, a composition comprising a crystalline form of formula (I) is useful as a medicament for the prevention of a sleep disorder wherein the sleep disorder is an insomnia disorder, a hypersomnia disorder, a circadian rhythm sleep-wake disorder, an alcohol-induced sleep disorder, or any combination thereof.

[0116] In another embodiment, a composition comprising a crystalline form of formula (I) is useful as a medicament for the treatment or prevention of an insomnia disorder. In another embodiment, a composition comprising a crystalline form of formula (I) is useful as a medicament for the treatment of an insomnia disorder. In another embodiment, a composition comprising a crystalline form of formula (I) is useful as a medicament for the prevention of an insomnia disorder.

[0117] In another embodiment, a composition comprising a crystalline form of formula (I) is useful as a medicament for the treatment or prevention of an alcohol-induced sleep disorder. In another embodiment, a composition comprising a crystalline form of formula (I) is useful as a medicament for the treatment of an alcohol-induced sleep disorder. In another embodiment, a composition comprising a crystalline form of formula (I) is useful as a medicament for the prevention of an alcohol-induced sleep disorder.

[0118] The compositions of the present disclosure are prepared by a method comprising mixing a crystalline form of formula (I) with a pharmaceutically acceptable carrier or excipient. The mixing can be accomplished using methods known for mixing the compound (or derivative) and the pharmaceutically acceptable carrier or excipient. In one embodiment, the crystalline form of formula (I) is present in the composition in an effective amount.

[0119] In another aspect, the present disclosure is directed to a method for treating, preventing, or managing a disorder, wherein the disorder is a sleep disorder, comprising administering to an animal in need thereof an effective amount of a crystalline compound disclosed herein.

[0120] In embodiments of this aspect, the sleep disorder is selected from the group consisting of insomnia, alcohol-induced sleep disorder, insomnia in alcohol use disorder, sleep disorder associated with alcohol withdrawal, hypersomnia, circadian rhythm sleep-wake disorder, or any combination thereof.

[0121] In another aspect, the present disclosure is directed to the use of a crystalline compound disclosed herein in the manufacture of a medicament for the treatment, prevention, or management of a sleep disorder.

[0122] In embodiments of this aspect, the sleep disorder is selected from the group consisting of insomnia, alcohol-induced sleep disorder, insomnia in alcohol use disorder, sleep disorder associated with alcohol withdrawal, hypersomnia, circadian rhythm sleep-wake disorder, or any combination thereof.

[0123] In another aspect, the present disclosure is directed to a crystalline compound disclosed herein for use in the treatment, prevention, or management of a sleep disorder.

[0124] In embodiments of this aspect, the sleep disorder is selected from the group consisting of insomnia, alcohol-induced sleep disorder, insomnia in alcohol use disorder, sleep disorder associated with alcohol withdrawal, hypersomnia, circadian rhythm sleep-wake disorder, or any combination thereof.

[0125] Method for preparing a crystalline form Methods for preparing the crystalline form of formula (I) are provided herein.

[0126] In some embodiments, the method for manufacturing the crystalline form of formula (I) comprises subjecting the crude form of formula (I) to crystallization or recrystallization conditions. In some embodiments, the crude formula (I) can first be dissolved in a suitable solution solvent (e.g., formic acid) at a certain temperature (e.g., 25 °C). Optionally, the solution of dissolved formula (I) can then be filtered to remove solid particles. In some embodiments, a suitable poor solvent (e.g., EtOAc) is added to the solution of dissolved formula (I). The poor solvent can include a solvent in which formula (I) is less soluble than in the solution solvent. The poor solvent can be added to the solution rapidly or slowly over a time period that varies depending on the scale of the reaction at a temperature of about 10 °C to about 60 °C. In some embodiments, the solution containing the poor solvent is aged by stirring at a temperature of about 10 °C to about 60 °C for a period of time (e.g., 1 to 48 hours) to form a slurry. In some embodiments, the aged solution forms a slurry. In some embodiments, the aged solution is seeded with a crystalline form of formula (I) (e.g., Form A) to form a slurry. In certain embodiments, the slurry is further treated with p-toluenesulfonic acid (p-TsOH) in a suitable solvent (e.g., ethanol). The slurry can then be optionally cooled and filtered to form a filtered cake. In some embodiments, the process can further include drying the filter cake under reduced pressure at a certain temperature (e.g., 50 °C) and for a time of about 2 hours to about 24 hours, or until a mobile solid of the crystalline form of formula (I) is achieved. In certain embodiments, the crystalline form of formula (I) is Form A as determined by powder X-ray diffraction. Optionally, Form A is obtained in a substantially pure crystalline form. In some embodiments, the recrystallization process can be repeated to obtain a substantially pure crystalline form of Form A.

Example

[0127] Apparatus and Analytical Methods FT-Raman spectroscopy (FTIR). Raman spectra were collected using a Nicolet NXR9650 or NXR960 spectrometer (Thermo Electron) equipped with a 1064 nm Nd:YVO4 excitation laser, an InGaAs and a liquid-N2 cooled Ge detector, and a MicroStage. All spectra were acquired at a resolution of 4 cm -1 −1 with 64 scans using a Happ-Genzel apodization function and two levels of zero filling through a glass cover.

[0128] Polarizing microscopy (PLM). Micrographs were collected using an Olympus BX60 polarizing microscope equipped with an Olympus DP70 camera.

[0129] Powder X-ray diffraction (PXRD). PXRD diffractograms were obtained as follows: (1) A PANalytical X’Pert Pro diffractometer using Ni-filtered Cu Kα (45 kV / 40 mA) radiation, a 2Θ step size of 0.02°, and an X’celerator™ RTMS (Real Time Multi Strip) detector, with the incident beam side configuration: a fixed divergence slit (0.25°), a 0.04 rad Soller slit, an anti-scatter slit (0.25°), and a 10 mm beam mask, and the diffracted beam side configuration: a fixed divergence slit (0.25°) and a 0.04 rad Soller slit, or (2) A Rigaku RINT TTR III diffractometer using Cu Kα (50 kV / 300 mA) radiation.

[0130] Differential scanning calorimetry (DSC). DSC was performed using a TA Instruments Q100 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system under a N2 purge of 40 mL / min. Unless otherwise specified, DSC thermograms were obtained in an Al pan crimped with an Al pan at 15 °C / min. The transition temperatures recorded by DSC analysis are reported as onset values.

[0131] Thermogravimetric analysis (TGA). Unless otherwise specified, the TGA thermograms were obtained using a TA Instruments Q500 thermogravimetric analyzer at 15 °C / min in an Al pan under a N2 purge of 40 mL / min.

[0132] Thermogravimetric analysis by IR off-gas detection (TGA-IR). TGA-IR was performed using a TA Instruments Q5000 thermogravimetric analyzer connected to a Nicolet 6700 FT-IR spectrometer (Thermo Electron) equipped with an external TGA-IR module with a gas flow cell and a DTGS detector. Unless otherwise specified, TGA was performed in a Pt or Al pan at a N2 flow rate of 60 mL / min and a heating rate of 15 °C / min. IR spectra were collected at a resolution of 4 cm -1 and 32 scans were performed at each time point.

[0133] Example 1: Synthesis of Formula (I)

Chemical formula

[0134] Step 1. A mixture of ABKE (15 kg), o-phenylenediamine, tetraethoxysilane, tetrahydrofuran, and acetic acid was stirred for a certain time and then mixed with NaBH(OAc)3 in THF. When the reaction reached an acceptable conversion, the reaction mixture was poured into an aqueous sodium hydroxide solution (NaOH). After phase separation, the organic layer was washed with an aqueous NaOH solution and then with an aqueous sodium chloride solution. Methanol and water were added to the organic layer, followed by ABDA seed crystals. After adding water dropwise, the resulting slurry was filtered and the filter cake was washed with cold methanol. The obtained cake was dried to give ABDA (15.68 kg, 77.3%) as a solid. The ABKE starting material can be prepared, for example, according to Example 1 of US Patent No. 8,476,271.

[0135] Step 2. A solution of ABDA (15.5 kg) and diethyl ketomalonate in toluene was mixed with hot acetic acid to form ABES. The reaction mixture was diluted with toluene and quenched with triethylamine. After the mixture was washed with water and phase-separated, the organic phase was concentrated under reduced pressure and filled with 2-propanol. The concentration and filling of 2-propanol were repeated for solvent exchange. The slurry was filtered and the filter cake was washed with 2-propanol. By drying, ABES (18.48 kg, 90.9%) was obtained as a solid.

[0136] Step 3. An aqueous NaOH solution was added to a slurry of ABES (18 kg) in ethanol and purified water. The mixture was stirred by heating to form the corresponding intermediate carboxylate sodium salt. A solution of p-toluenesulfonic acid (p-TsOH) in purified water was added to the reaction mixture to neutralize the intermediate carboxylate sodium salt and form formula (I). The slurry was filtered and the filter cake of formula (I) was washed with purified water. The identity of formula (I) was 1 confirmed using 1H NMR and LC / MS. The polymorphic form observed by PXRD was named Form B. Figure 1 shows the PXRD pattern of formula (I) as Form B. The peaks of the X-ray powder diffraction pattern are shown in Table 1 below. Table 1. PXRD Peaks of Form B of Formula (I) [Table 1]

[0137] The formula (I) from Step 3 was further dried and then dissolved in formic acid and purified by filtration. Ethyl acetate and seed crystals of formula (I) (Form A) were added to the solution to increase the crystallization rate, resulting in a slurry of formula (I). Form (A) would crystallize slowly without using seed crystals. After aging, additional ethyl acetate and a small amount of p-TsOH were added. The slurry was filtered and the filter cake was washed with ethyl acetate. By drying, purified formula (I) was obtained as a crystalline solid. After grinding, 21.14 kg of formula (I) (API) was obtained in an 89.6% yield from ABES. The identity of formula (I) was 1It was confirmed using \(^1H\) NMR and LC / MS. The polymorphic forms observed by PXRD were named Form A. Figure 2 shows the PXRD pattern of formula (I) as Form A. The peaks of the PXRD pattern are shown in Table 2 below. All of the remaining formula (I) as Form B can be removed by repeating recrystallization. Table 2. PXRD Peaks of Form A of Formula (I)

Table 2

[0138] The PXRD pattern obtained in Example 1 was obtained with a Rigaku RINT TTR III diffractometer using Cu Kα (50 kV / 300 mA) radiation.

[0139] Example 2: Solubility Study of Formula (I) Solubility was evaluated in an array of diverse solvents, facilitating the selection of solvent systems and corresponding dosing strategies for subsequent crystal form screening experiments. The solubility of Form A of formula (I) was visually estimated at room temperature and, where applicable, at 40 °C in 12 solvents by dosing aliquots of the solvent to a fixed amount of API (10.0 mg) until the melting point or a maximum volume of 1.8 mL was reached. As shown in Table 3, formula (I) shows moderate solubility (21 - 52 mg / mL) in DMSO and low solubility (7 mg / mL or less) in all other solvents evaluated. Table 3. Solubility Test Results

Table 3

[0140] Example 3: Polymorph Screening Study of Formula (I) Overview The polymorph screening study of formula (I) involved approximately 156 crystallization experiments, which were complemented by focused experiments aimed at the reproduction and / or characterization of novel / important crystal forms.

[0141] Solvent Selection Sixty solvent systems were utilized as neat and binary mixtures to provide a diverse set of polarities, dielectric constants, dipole moments, and hydrogen bond donor / acceptor attributes. Water-containing solvents with various water activities were also included; see, for example, G.M. Wilson, J. Am. Chem. Soc. 1964, 86(2) pp. 127-133, and Bell G. et al., Enzyme Microb. Technol., 1997, 20(6), pp. 471-477.

[0142] Crystallization Mode Polymorph screening studies were conducted using Form A of the formula (I) (API) as the starting material and the following crystallization modes. a) Thermocycling (TC): The API was added to an HPLC vial and the solvent (1 mL) was added. The sample was stirred at room temperature for 1 hour and observations regarding dissolution were made. The sample was stirred at 50 °C for 1 hour and observations regarding dissolution were made again. The sample was thermocycled from 50 to 5 °C for 96 hours. The solid was collected and air-dried on a filter plate for 4 hours. (TC, n = 48) b) Recrystallization (RC): The sample vial from TC was stirred and heated to 50 °C. Clear filtration was performed at 50 °C and the filtrate was added to a clean 2 mL vial. The vial was placed in a freezer at -20 °C for 3 - 4 days and then transferred to a refrigerator at 5 °C for 16 - 24 hours. The solid was collected as described above. (RC, n = 48) c) Evaporation (EV): The solution from the RC experiment was slowly evaporated in a draft over 10 days. The experimentals that yielded solids from RC were refiltered and the filtrate was evaporated as described above. d) Anti-solvent addition (ASA): The anti-solvent was added to a saturated and clear solution of the API at room temperature (ASA, n = 12).

[0143] Analysis of Screening Products FT-Raman spectroscopy was selected as the first method for the analysis and grouping of samples. Representative samples from the grouping were analyzed by PXRD to verify their uniqueness. Where possible / practical, representative samples of the distinct groups were further characterized by PLM, DSC, and TGA-IR.

[0144] Results As shown in Tables 4 and 5, the polymorph screening of formula (I) produced three crystal forms: · Form A - the main output of the screening · Form C - the monohydrate form · Form D - the non-solvated form observed in some EV experiments

[0145] Form B, which is the crystal formed during the initial precipitation of formula (I) in Example I, was not observed during the screening described in Example 3. Another monohydrate crystal form, Form E, was identified in batches of formula (I) that did not recrystallize but was not observed during the screening described in Example 3. As shown in Tables 4 and 5, the parent free acid form of formula (I) (the "parent") was also observed in some solution phase experiments during the screening process. Table 4. Products of slurry, cooling, evaporation crystallization

Table 4

Table 5

Table 6

[0146] Description of polymorphic forms Form A Form A is the non-solvated form that was the main output of the polymorph screening. Form A of formula (I) prepared as described above was analyzed by FTIR, TGA, DSC, PXRD, and PLM (Figures 3A - 3C). The PXRD pattern is shown in Figure 3A. The peaks of the X-ray powder diffraction pattern are shown in Table 7 below. DSC shows a complex endotherm at 239.9 °C that occurs with decomposition, and TGA-IR shows a 0.2% weight loss from 25 - 150 °C (Figure 3B). The FTIR spectrum is shown in Figure 3C. Form A is crystalline by PXRD and PLM analysis. Table 7. PXRD Peaks of Form A of Formula (I)

Table 7

[0147] Form C Form C is the monohydrate crystal form identified from the polymorph screening. Form C was observed as a mixture with Form A in two THF / water experiments in the TC mode. Phase purity was observed in two RC experiments and as a mixture in two EV experiments. Form C of formula (I) prepared as described above was analyzed by FTIR, TGA, DSC, PXRD, and PLM (Figures 4A - 4C). The PXRD pattern is shown in Figure 4A. The peaks of the X-ray powder diffraction pattern are shown in Table 8 below. DSC shows a broad endotherm from 50 - 125 °C, followed by two broad shallow endotherms from 225 - 255 °C, and TGA-IR shows a stepwise weight loss of 3.2% of water from 25 - 175 °C (Figure 4B). The FTIR spectrum is shown in Figure 4C. Form C is crystalline by PXRD and PLM analysis. Table 8. PXRD Peaks of Form C of Formula (I)

Table 8

[0148] Form D Form D is the unsolvated form observed from several EV experiments. Form D of formula (I) prepared as described above was analyzed by FTIR, TGA-IR, DSC, PXRD, and PLM (Figures 5A - 5C). The X-ray powder diffraction pattern is shown in Figure 5A. The peaks of the PXRD pattern are shown in Table 9 below. DSC shows an endotherm at 248.0 °C, and TGA-IR shows a negligible weight loss (about 0.6%) from 25 - 150 °C (Figure 5B). The FTIR spectrum is shown in Figure 5C. Form D is crystalline by PXRD and PLM analysis. Table 9. PXRD Peaks of Form D of Formula (I)

Table 9

[0149] An overlay of the PXRD patterns of polymorphic forms A, C, and D of formula (I) is shown in Figure 6.

[0150] Form E Form E is the monohydrate form identified in batches of formula (I) that do not recrystallize. Form E of formula (I) was analyzed by FTIR, TGA-IR, DSC, PXRD, and PLM (Figures 7A - 7D). The X-ray powder diffraction pattern is shown in Figure 7A. The peaks of the PXRD pattern are shown in Table 10 below. DSC shows a broad endotherm from 85 - 150 °C, followed by an endotherm at 215.4 °C, and TGA-IR analysis shows a stepwise weight loss of 3.1% water (1 equivalent) that occurs with the broad DSC endotherm (Figure 7B). A second stepwise weight loss of 7.1% carbon dioxide (decomposition) is observed at 175 - 210 °C. Both Form E and Form C are monohydrate forms, but the TGA-IR data suggest that the water in Form E is more tightly bound (higher dehydration temperature) than in Form C, as shown in Figure 7C. The FTIR spectrum is shown in Figure 7D. Form E is crystalline by PXRD and PLM analysis. Table 10. PXRD Peaks of Form E of Formula (I)

Table 10

[0151] The PXRD pattern obtained in Example 3 was obtained using a PANalytical X’Pert Pro diffractometer with Ni-filtered Cu Kα (45 kV / 40 mA) radiation.

[0152] Example 4: Grinding 21.98 kg of crystalline Form A of formula (I) was processed in a fluidized bed opposed jet mill (model number 100AFG, Hosokawa Micron) at a feed rate of 8 kg / h under nitrogen at 15,000 rpm and 0.6 MPa. After grinding, 20.9 kg (recovery rate 94.6%) was collected and analyzed by a laser diffraction dry particle size analyzer (HELOS&RODOS). The particle size distribution results are reported in Table 11. Table 11. Particle size distribution results

Table 11

[0153] Example 5: Relative stability test The relative stability test was carried out at 25 °C to determine the thermodynamic crystal stability at various water activity levels in the range of a w = 0 to a w = 0.94. Both the non-solvated forms (Forms A and D) and the hydrate forms (Forms C and E) were aged during the test.

[0154] A saturated suspension of formula (I) was prepared by stirring an excess amount of API in the specified solvent system. The suspension was stirred at 25 °C overnight. Clear filtration was carried out and the filtrate was added to 2 mL vials containing seeds or a small amount of the related form. The resulting suspension was stirred at 25 °C for 7 days. The solid was isolated, air dried for 45 minutes, and analyzed by FTIR.

[0155] The FTIR spectra are shown in Figures 8A and 8B, indicating that Form A was the only crystal form remaining after the maturation test. The results of the test are summarized in Table 12. Table 12. Maturation test results

Table 12

[0156] All publications, patents, patent applications, and other documents cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other document were individually indicated to be incorporated by reference for all purposes.

[0157] Although various specific embodiments have been illustrated and described, it will be understood that various changes can be made without departing from the spirit and scope of the invention(s).

Claims

1. A crystal of the compound of formula (I), 【Chemical 1】 wherein the powder X-ray diffraction spectrum has peaks with relative intensities exceeding 10% at diffraction angles (2Θ ± 0.2°) of 7.4, 9.6, 14.7, 16.7, 17.1, 18.5, 19.3, 21.1, and 22.

2.

2. A crystal of the compound of formula (I), [Chemical Formula 2] wherein at least 90% by weight of the total amount of the crystal of the compound of formula (I) is in crystal form A having a powder X-ray diffraction spectrum with peaks having relative intensities exceeding 10% at diffraction angles (2Θ ± 0.2°) of 7.4, 9.6, 14.7, 16.7, 17.1, 18.5, 19.3, 21.1, and 22.

2.

3. The crystal according to claim 2, wherein at least 95% by weight of the crystal of the compound of formula (I) is in crystal form A.

4. The crystal according to claim 2, wherein at least 98% by weight of the crystal of the compound of formula (I) is in crystal form A.

5. The crystal has a particle size D of 15 μm ９０ The crystal according to any one of claims 1 to 4, having the same

6. The crystal has a particle size D of 8 μm ９０ The crystal according to any one of claims 1 to 4, having the same

7. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 6 and at least one pharmaceutically acceptable excipient.

8. A composition for use as a single-dose unit, comprising 0.16 mg to 8.0 mg of the crystal according to any one of claims 1 to 6.

9. The composition according to claim 8, which is a solid oral dosage form.

10. The composition according to claim 9, wherein the solid oral dosage form is a tablet or a capsule.

11. The composition according to any one of claims 8 to 10, comprising 0.5 mg to 6.0 mg of the crystal of formula (I).

12. The composition according to any one of claims 8 to 10, comprising 0.5 mg to 3.0 mg of the crystal of formula (I).

13. A process for producing a crystal of the compound of formula (I) in crystal form A, [Chemical Formula 3] comprising the steps of dissolving the compound of formula (I) in formic acid to form a solution, diluting the solution with an ethyl acetate solvent to form a diluted solution, forming a slurry in the diluted solution, and filtering the slurry to isolate the crystal form A of the compound of formula (I), wherein the crystal form A has a powder X-ray diffraction spectrum with peaks having relative intensities exceeding 10% at diffraction angles (2Θ ± 0.2°) of 7.4, 9.6, 14.7, 16.7, 17.1, 18.5, 19.3, 21.1, and 22.

2.

14. The process according to claim 13, further comprising the step of adding p-toluenesulfonic acid to the solution.

15. Use of a crystal according to any one of claims 1 to 6 in the manufacture of a medicament for the treatment, prevention or management of sleep disorders.

16. The use according to claim 15, wherein the sleep disorder is selected from the group consisting of insomnia, alcohol-induced sleep disorder, insomnia in alcohol use disorder, sleep disorder associated with alcohol withdrawal, hypersomnia, circadian rhythm sleep-wake disorder, or any combination thereof.

17. A composition comprising a crystal according to any one of claims 1 to 6 for use in the treatment, prevention or management of sleep disorders.

18. The composition according to claim 17, wherein the sleep disorder is selected from the group consisting of insomnia, alcohol-induced sleep disorder, insomnia in alcohol use disorder, sleep disorder associated with alcohol withdrawal, hypersomnia, circadian rhythm sleep-wake disorder, or any combination thereof.

Images