Polymorphs of Pitrisanto Hydrochloride

Abstract

This disclosure generally relates to a novel crystalline form (i.e., polymorph) (Form II) of pyrisant hydrochloride, a pharmaceutical composition containing Form II, a dosage form containing Form II, and a method for treating a disease or disorder with Form II or a pharmaceutical composition or dosage form containing Form II.

Description

[Technical Field]

[0001] Related applications This application claims the benefits of U.S. Provisional Application No. 63 / 493,500, filed on 31 March 2023, all of which are incorporated herein by reference. [Background technology]

[0002] Polymorphism is a crucial consideration in the pharmaceutical industry. Different crystalline forms (polymorphs) of drug molecules can exhibit non-equivalent physicochemical and mechanical properties due to various factors such as crystal packing and molecular orientation, affecting various physicochemical properties of drug materials, including hardness, hygroscopicity, solubility, stability, and pharmacokinetics. This characteristic of polymorphism can have significant implications for pharmaceuticals, for example, influencing the selection of excipients in formulations, preferred routes of administration, dosage, shelf life, and even preferred manufacturing and packaging methods. When a drug molecule has two or more crystalline forms (i.e., different polymorphs), one polymorph may be more suitable for a particular application, route of administration, or use than another polymorph of the same drug molecule.

[0003] Pitrisant hydrochloride is a drug molecule useful for treating a variety of diseases and disorders, particularly sleep disorders such as excessive daytime sleepiness (EDS) and cataplexy, and is marketed as WAKIX®. WAKIX® includes a specific crystalline form of pitrisant hydrochloride, referred to herein as Form I, disclosed in U.S. Patent No. 8,207,197 (which is incorporated herein by reference in its entirety). [Overview of the project]

[0004] This disclosure generally relates to a novel crystalline form of pyrisant hydrochloride (hereinafter referred to as "Form II"), pharmaceutical compositions and dosage forms containing Form II, and methods for treating diseases or disorders using Form II or pharmaceutical compositions or dosage forms containing Form II.

[0005] In some embodiments, this disclosure relates to a compound represented by formula (I): [ka] The present invention relates to a crystalline morphology characterized by having an X-ray diffraction pattern with respect to two theta (2θ) theta including at least one peak at 16.8°, 18.2°, 18.5°, 21.0°, and 25.1° (±0.2°). For example, the crystalline morphology may be characterized by having an X-ray diffraction pattern including at least one characteristic peak (2θ) at 15.8°, 16.8°, 18.2°, 18.5°, 18.8°, 19.3°, 20.1°, 21.1°, and 25.1° (±0.2°). Alternatively, the crystalline morphology may be characterized by having an X-ray diffraction pattern substantially shown in pattern A of Figure 1. In one embodiment, the present disclosure relates to a compound represented by formula (I): [ka] The present invention relates to a crystalline form characterized by having an X-ray diffraction pattern with peaks at 16.8°, 18.2°, 18.5°, 21.0°, and 25.1° (±0.2°) with respect to two theta (2θ). For example, the crystalline form may be characterized by having an X-ray diffraction pattern with characteristic peaks (2θ) at 15.8°, 16.8°, 18.2°, 18.5°, 18.8°, 19.3°, 20.1°, 21.1°, and 25.1° (±0.2°).

[0006] XRPD patterns can be obtained using any suitable protocol and any suitable apparatus, such as the protocols or apparatus disclosed herein. XRPD patterns may be obtained using a sample of about 1 mg to about 10 mg (e.g., about 1 mg to about 5 mg, e.g., about 2 mg, about 3 mg, about 4 mg, or about 5 mg). XRPD patterns may also be obtained using Cu Kα radiation.

[0007] The crystalline morphology of the present disclosure may also be characterized by having an endothermic peak with an initiation point at about 90°C to about 97°C, as obtained by differential scanning calorimetry (DSC). For example, the initiation point may be about 91°C to about 96°C, e.g., about 92°C to about 95°C or about 93°C to about 94°C. The endothermic peak may be about 92°C to about 94°C (e.g., about 92°C, about 93°C, or about 94°C) or about 95°C to about 98°C (e.g., about 95°C, about 96°C, or about 97°C), as measured by DSC.

[0008] The crystalline morphology of this disclosure may be characterized by DSC using a sample of about 1 mg to about 10 mg (e.g., about 1 mg to about 5 mg, e.g., about 2 mg, about 3 mg, about 4 mg, or about 5 mg). DSC can be performed under a nitrogen atmosphere. DSC can be performed using a heating rate of 10°C / min. DSC can be performed at a temperature of 0°C to 150°C, e.g., 73°C to 150°C.

[0009] In some embodiments, the crystalline morphology of the present disclosure is characterized and / or formed using the following protocols: (i) heating from 20°C to 150°C at a rate of 10°C / min, (ii) cooling from 150°C to 0°C at a rate of 10°C / min, (iii) heating from 0°C to 140°C at a rate of 10°C / min, (iv) cooling from 140°C to 0°C at a rate of 200°C / min, (v) holding at 0°C for 2 minutes, (vi) heating from 0°C to 140°C at a rate of 10°C / min, (vii) cooling from 140°C to 73°C at a rate of 10°C / min, (viii) holding at 73°C for 4 minutes, and (ix) heating from 73°C to 150°C at a rate of 10°C / min.

[0010] In some embodiments, the crystalline morphology of the present disclosure is characterized and / or formed using the following protocols: (i) heating from 20°C to 130°C at 10°C / min, (ii) cooling from 130°C to 20°C at 10°C / min, (iii) heating from 20°C to 130°C at 10°C / min, (iv) cooling from 130°C to 72°C at 10°C / min, (v) holding at 72°C for 1 hour, and (vi) heating from 72°C to 130°C at 10°C / min.

[0011] In some embodiments, the present disclosure relates to a compound represented by formula (I): [ka] This invention relates to a crystalline form characterized by having a melting point of about 90°C to about 95°C. For example, the crystalline form has a melting point of about 91°C to about 94°C, for example, about 92°C to about 94°C. In some embodiments, the crystalline form has a melting point of about 93°C.

[0012] In some embodiments, the present disclosure relates to a compound represented by formula (I): [ka] The present invention relates to a crystalline morphology characterized by having an endothermic peak having an initiation point at approximately 90°C to approximately 97°C, for example, at approximately 91°C to approximately 96°C, for example, at approximately 92°C to approximately 95°C or at approximately 93°C to approximately 94°C, obtained by differential scanning calorimetry (DSC). For example, the crystalline morphology may be characterized by having a DSC thermogram substantially shown in Figure 2, for example, the DSC thermogram shown in trace (7) of Figure 2, for example, the DSC thermogram shown in peak (II) of Figure 2. Alternatively, the crystalline morphology may be characterized by having a DSC thermogram substantially shown in Figure 3, for example, the DSC thermogram shown in trace (5) of Figure 3, for example, the DSC thermogram shown in peak (II) of Figure 3.

[0013] In some embodiments, the present disclosure relates to a compound represented by formula (I): [ka] Regarding a crystalline form characterized by having an X-ray diffraction pattern that does not include a combination of peaks (2θ) at 11.2°, 19.9°, 20.7°, and 34.1° (±0.2°). For example, the crystalline form of the present disclosure may be characterized by having an X-ray diffraction pattern that does not include a combination of peaks (2θ) at 11.2°, 15.4°, 16.3°, 16.9°, 17.8°, 19.9°, 20.7°, 21.0°, 21.8°, 22.6°, 24.5°, 24.6°, 25.0°, 25.5°, 26.3°, 28.3°, 30.3°, 34.1°, 35.8°, 40.0°, and 46.0° (±0.2°).

[0014] In some embodiments, the present disclosure relates to Form II polymorph of pitolisant hydrochloride.

[0015] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a crystalline form or polymorph disclosed herein and optionally a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be any suitable pharmaceutically acceptable excipient such as the pharmaceutically acceptable excipients disclosed herein. In some embodiments, the pharmaceutically acceptable excipient is selected from the group consisting of colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. For example, the pharmaceutical composition may comprise Form II polymorph of pitolisant hydrochloride.

[0016] In some embodiments, the present disclosure relates to a dosage form comprising a crystalline form, polymorph, or pharmaceutical composition disclosed herein. The dosage form may be any suitable dosage form such as tablets, caplets, or capsules. For example, the dosage form may comprise Form II polymorph of pitolisant hydrochloride.

[0017] In some embodiments, the present disclosure relates to a method of treating a disease or disorder, the method comprising administering to a subject in need thereof a crystalline form, polymorph, pharmaceutical composition, or dosage form disclosed herein. The disease or disorder may be a sleep disorder. For example, the disease or disorder may be excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep induced apnea, or daytime somnolence. In some embodiments, the disease or disorder may be excessive daytime sleepiness (EDS). In some embodiments, the disease or disorder is cataplexy. In the methods disclosed herein, the subject being treated may have narcolepsy and / or may be an adult having narcolepsy. For example, the method of treating a disease or disorder may comprise administering to a subject in need thereof the Form II polymorph of pitolisant hydrochloride.

[0018] In some aspects, the present disclosure relates to a crystalline form, polymorph, pharmaceutical composition, or dosage form disclosed herein for use in the treatment of a disease or disorder (e.g., a disease or disorder disclosed herein), optionally wherein the disease or disorder is excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep induced apnea, or daytime somnolence. The disease or disorder may be in a subject having narcolepsy (e.g., an adult subject having narcolepsy). In some aspects, the present disclosure relates to the Form II polymorph of pitolisant hydrochloride in the treatment of a disease or disorder (e.g., a disease or disorder disclosed herein), optionally wherein the disease or disorder is excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep induced apnea, or daytime somnolence. The disease or disorder may be in a subject having narcolepsy (e.g., an adult subject having narcolepsy).

[0019] In some embodiments, this disclosure relates to the use of the crystalline forms, polymorphs, pharmaceutical compositions, or dosage forms disclosed herein for the manufacture of a medicament for the treatment of a disease or disorder (e.g., a disease or disorder disclosed herein), optionally, the disease or disorder being excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, or daytime somnolence. The disease or disorder may be in subjects with narcolepsy (e.g., adult subjects with narcolepsy). In some embodiments, this disclosure relates to the use of form II polymorph of pyrisant hydrochloride for the manufacture of a medicament for the treatment of a disease or disorder (e.g., a disease or disorder disclosed herein), optionally, the disease or disorder being excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, or daytime somnolence. The disease or disorder may be present in subjects with narcolepsy (for example, in adult subjects with narcolepsy). In some embodiments, this disclosure relates to a crystalline form, polymorph, pharmaceutical composition, or dosage form according to any one of the claims for use in the treatment of a disease or disorder in a subject requiring treatment, for example, a disease or disorder disclosed herein, for example, sleep disorders, excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, or daytime somnolence. For example, a form II polymorph of pitrisant hydrochloride for use in the treatment of a disease or disorder in a subject requiring treatment, for example, a disease or disorder disclosed herein, for example, sleep disorders, excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, or daytime somnolence. In some embodiments, the disease or disorder is excessive daytime sleepiness (EDS). In some embodiments, the disease or disorder is cataplexy. In some embodiments, the subjects have narcolepsy (for example, the subjects are adults with narcolepsy). [Brief explanation of the drawing]

[0020] [Figure 1] Figure 1 shows a graphical representation and superposition of X-ray powder diffraction (XRPD) patterns. The pattern in the center of the superposition labeled "A" is the XRPD pattern obtained from a sample containing morphology II crystals. The pattern at the bottom of the superposition labeled "B" shows the XRPD pattern obtained from the same sample after 10 months of storage. The pattern at the top of the superposition labeled "C" is obtained from pure morphology I crystals. The vertical dashed lines highlight the characteristic peaks of morphology II.

[0021] [Figure 2-1] Figure 2 shows a differential scanning calorimetry (DSC) thermogram obtained using an exemplary protocol for obtaining morph II of pyrisant hydrochloride. The endothermic peak attributable to morph II is peak (II) in trace (7).

[0022] [Figure 2-2] Figure 2 shows a differential scanning calorimetry (DSC) thermogram obtained using an exemplary protocol for obtaining morph II of pyrisant hydrochloride. The endothermic peak attributable to morph II is peak (II) in trace (7).

[0023] [Figure 3-1] Figure 3 shows another DSC thermogram obtained using an exemplary protocol for obtaining morphology II. The endothermic peak attributable to morphology II is peak (II) in trace (5).

[0024] [Figure 3-2] Figure 3 shows another DSC thermogram obtained using an exemplary protocol for obtaining morphology II. The endothermic peak attributable to morphology II is peak (II) in trace (5). [Modes for carrying out the invention]

[0025] This disclosure relates to a novel crystalline form (polymorph) of pyrisant hydrochloride, generally referred to herein as "Form II." Pharmaceutical compositions and dosage forms comprising Form II and optionally pharmaceutically acceptable excipients are also disclosed. Furthermore, this disclosure relates to methods for treating diseases or disorders using Form II or pharmaceutical compositions or dosage forms comprising Form II.

[0026] The structure of pyrisant hydrochloride (which may be referred to as pyrisant monohydrochloride in this specification) is given by the following formula (I): [ka] It is given by.

[0027] The crystalline form (Form I) of pitrisant hydrochloride is disclosed in U.S. Patent No. 8,207,197, which is incorporated herein by reference in its entirety. The Form I polymorph is present in the FDA-approved drug WAKIX®. The crystalline form of this disclosure (i.e., Form II) is different from Form I. Form II is thought to have certain properties different from Form I, such as different degrees of hygroscopicity, solubility, and / or pharmacokinetics, which may be advantageous for certain applications, such as the treatment of diseases or disorders such as EDS or cataplexy.

[0028] definition The articles "a" and "an" are used herein to refer to one or more (i.e., at least one) grammatical objects of the article. For example, "element" means one or more elements.

[0029] When referring to measurable values ​​such as quantity or temporal duration, the term "approximately" means that a variation of ±20%, in some cases ±15%, in some cases ±10%, in some cases ±5%, in some cases ±1%, or in some cases ±0.1% from the specified value is included, where such variation is appropriate.

[0030] As used herein, the phrase "and / or" should be understood to mean "either or both" of the elements thus connected, that is, elements that exist conjunctively in some cases and disjunctively in others. Multiple elements listed using "and / or" should be interpreted similarly, that is, "one or more" of the elements thus connected. In addition to the elements specifically identified by the phrase "and / or," other elements may exist at will, whether related to or unrelated to those specifically identified elements. Thus, as a non-restrictive example, a reference to "A and / or B," when used in combination with open-ended language such as "includes," may in one embodiment refer to A only (optionally including elements other than B), in another embodiment refer to B only (optionally including elements other than A), and in yet another embodiment refer to both A and B (optionally including other elements), and so on.

[0031] As used herein, the terms “administer,” “administering,” or “administration” refer to the act of implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound (e.g., Form II), dosage form, or pharmaceutical composition.

[0032] The terms “comprise,” “comprises,” and “comprising” are used herein in a non-exclusive sense unless otherwise required by context. Similarly, the term “comprise” and its grammatical variations are intended to be non-restrictive, and the listing of items in an enumeration does not exclude other similar items that may substitute for or add to the listed items.

[0033] As used herein, the terms “effective dose” or “therapeutic effective dose” refer to the amount of the compound, dosage form, or pharmaceutical composition disclosed herein that is sufficient to achieve the desired outcome under the conditions of administration. For example, the effective dose of the compound, dosage form, or pharmaceutical composition disclosed herein for the treatment of excessive sleep disturbance (EDS) in a patient with narcolepsy is the amount that can reduce the effects of EDS and / or reduce or eliminate the severity of symptoms associated with EDS. A skilled clinician can determine a suitable dose based on a variety of considerations, including the severity of the disease, the age, weight, overall health, and other considerations. The compounds (e.g., crystalline form, e.g., form II), dosage forms, or pharmaceutical compositions disclosed herein may be administered to provide a pharmaceutically active agent in amounts ranging from about 0.01 mg to about 250 mg (e.g., about 0.1 mg to about 100 mg), for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, or about 40 mg.

[0034] As used herein, the term “pharmaceutically acceptable excipient” refers to a non-toxic substance that can be formulated together with the compounds disclosed herein (e.g., in crystalline form, e.g., form II) to provide a pharmaceutical composition. Preferably, the pharmaceutically acceptable excipient is inert and does not interfere with the pharmacological activity of the compound formulated together with it. pharmaceutically acceptable excipients useful for the manufacture of the pharmaceutical compositions disclosed herein include, but are not limited to, any excipients well known in the art, such as diluents, dispersants, granulators, surfactants, emulsifiers, disintegrating agents (sometimes referred to herein as disintegrants), binding agents (sometimes referred to herein as binders), preservatives, buffering agents (sometimes referred to herein as buffers), lubricating agents (sometimes referred to herein as lubricants), flow promoters, auxiliaries, fillers, wetting agents, suspending agents, solvents, dispersion media, ion exchangers, salts, electrolytes, waxes, and / or oils.

[0035] For example, pharmaceutically acceptable excipients include alumina, phosphates (e.g., calcium phosphate, dicalcium phosphate, tricalcium phosphate, disodium hydrogen phosphate, potassium hydrogen phosphate), sulfates (e.g., calcium sulfate), cellulose, kaolin, bentonite, lactose, mannitol, sorbitol, sucrose, inositol, and compressible sugars. Sugar, trehalose, xylitol, acacia, gelatin, glucose, maltodextrin, starch (e.g., corn starch, potato starch), sodium starch glycolate, starch derivatives, amino acids, magnesium carbonate, polyvinylpyrrolidone (PVP, povidone) (e.g., cross-linked PVP, crospovidone), polyvinyl alcohol, tragacanth, polyethylene glycol, mineral clay powder, croscarmellose, poloxamer, fatty acids or their salts (e.g., lauric acid, sodium lauryl sulfate, stearic acid, calcium stearate, magnesium stearate, aluminum stearate, oleic acid), hydrogenated vegetable oil, talc, titanium dioxide, behenate Lyceryl, silicon dioxide (e.g., colloidal silicon dioxide), silicates (e.g., magnesium trisilicate), lecithin, serum proteins (e.g., human serum albumin), sorbic acid, potassium sorbate, metal cation salts (e.g., sodium salts such as sodium chloride, potassium salts such as potassium chloride, magnesium salts such as magnesium chloride, zinc salts such as zinc chloride), water, dimethylacetamide, protamine sulfate, lanolin, ethylenediaminetetraacetic acid (EDTA), cyclodextrin (e.g., CAPTISOL®), polysorbate (e.g., TWEEN®, TWEEN® 20, or TWEEN® 80), and combinations thereof may be used.

[0036] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a compound prepared with a relatively non-toxic acid or base, depending on the specific substituents found in each compound. If the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound in its neutral form neat or in a sufficient amount of the desired acid in a suitable solvent (e.g., an inert solvent). Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, pamoic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and oxalic acid. Salts of amino acids such as alginates and salts of organic acids such as glucuronic acid or galacturonic acid are also included. Other pharmaceutically acceptable salts known to those skilled in the art are suitable for the pharmaceutical compositions relating to this disclosure.

[0037] As used herein, the term “solvate” typically refers to a form of compound associated with a solvent by solvolysis. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), and diethyl ether. The compounds of this disclosure may be prepared, for example, in crystalline form and may be solvated. Preferred solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In certain cases, for example, if one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate is separable. “Solvates” include both solution-phase solvates and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0038] As used herein, the term “hydrate” refers to a compound associated with water. Typically, the number of water molecules in a compound hydrate is in a constant ratio to the number of compound molecules in the hydrate. Thus, a compound hydrate can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound may form two or more hydrates, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, e.g., a hemihydrate (R·0.5H₂O)), and a polyhydrate (x is a number greater than 1, e.g., a dihydrate (R·2H₂O) and a hexahydrate (R·6H₂O)).

[0039] As used herein, the term “subject” refers to any animal, including but not limited to any mammal, such as humans, non-human primates, rodents, and dogs. Non-human primates include chimpanzees, crab-eating macaques, spider monkeys, and macaques (e.g., rhesus macaques). Rodents include mice, rats, woodchucks, ferrets, rabbits, and hamsters. Domestic and game animals include cattle, horses, pigs, deer, bison, buffalo, felines (e.g., domestic cats), canids (e.g., dogs, foxes, wolves), birds, and fish. In some embodiments, the subject is a mammal (e.g., human, rat, or mouse). The subject may be male or female. The subject may be of any age, including elderly human subjects (e.g., 65 years or older), non-elderly human subjects (e.g., under 65 years), or human child subjects (e.g., under 18 years). In preferred embodiments, the subject is human.

[0040] As used herein, the terms “treat,” “treatment,” and “treating,” or grammatically related terms, refer to methods of reducing the effects of a disease or disorder. As readily understood in the art, complete disappearance of the disease, disorder, or its symptoms is preferred but not a requirement of treatment. Desired effects of treatment include, but are not limited to, prevention of the onset or recurrence of the disease or disorder, relief of symptoms, reduction of any direct or indirect pathological consequences of the disease or disorder, or other improvement of any signs, symptoms, or consequences of the disease or disorder, such as extension of survival, reduction of morbidity, and / or reduction of side effects.

[0041] Throughout this disclosure, various embodiments may be provided in range form (e.g., from X to Y). It should be understood that range form is merely for convenience and conciseness and should not be interpreted as an inflexible limitation to the scope of this disclosure. Therefore, range descriptions should be considered to specifically disclose all possible subranges and the individual numbers within those ranges. For example, a range description, e.g., 1–6, should be considered to specifically disclose subranges, e.g., 1–5, 1–4, 1–3, 2–6, 2–4, 3–6, etc., as well as the individual numbers within those ranges, e.g., 1, 2, 2.8, 3, 3.6, 4, 5, 5.4, and 6, etc. As another example, a range such as 95–99% includes all subranges such as 95%, 96%, 97%, 98%, or 99%, and 96–99%, 96–98%, 96–97%, 97–99%, 97–98%, etc. This applies regardless of the range width.

[0042] All conventional practices referenced herein (e.g., scientific journal articles, patent publications, etc.) are incorporated by reference in their entirety. In the event that any material incorporated by reference is inconsistent with or contradicts this Specification, this Specification shall prevail over any such material. Any reference to a reference herein does not constitute an endorsement that such reference is prior art to this Specification. Various terms relating to the manner of description are used throughout this Specification and the claims. Unless otherwise stated, such terms shall be given their common meaning in the art. Other specifically defined terms shall be construed to be consistent with the definitions provided herein.

[0043] Compounds disclosed herein (e.g., pharmaceutically active drugs) may also contain one or more isotopic substitutions. For example, hydrogen (H) may be: 1 H, 2 H (D or deuterium), 3 It may be any isotopic form containing H (T or tritium), and carbon (C) is 12 C, 13 C, and 14It may be in any isotopic form containing C, and oxygen (O) is 16 O and 18 It may be in any isotopic form containing O, and nitrogen (N) is 14 N and 15 It may be in any isotopic form containing N, and chlorine (Cl) is 35 CI and 37 It may be in any isotopic form containing CI.

[0044] Various embodiments of the compounds, dosage forms, pharmaceutical compositions, and methods herein are further described in detail below, and additional definitions may be provided throughout this specification.

[0045] Crystal form of pitolisant hydrochloride As used herein, the crystal form (Form II) of pitolisant hydrochloride (polymorph of Form II of pitolisant hydrochloride) is disclosed. Pitolisant hydrochloride is also known as 1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine monohydrochloride. Pitolisant hydrochloride has the formula (I):

Chemical formula

[0046] The crystal form (Form I) of pitolisant hydrochloride has been previously disclosed in U.S. Patent No. 8,207,197, which is hereby incorporated by reference in its entirety. The present disclosure relates to Form II, which is another crystal form whose preparation or characteristics have not been previously disclosed. It is understood that the polymorphs disclosed herein are crystalline, i.e., not amorphous.

[0047] Form II can be characterized using suitable analytical techniques such as X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC), and / or can be distinguished from Form I.

[0048] For example, as illustrated in Example 3 and Figure 1, morphology II can be characterized using XRPD. Similarly, morphology I and morphology II can be distinguished using XRPD, which is also shown in Figure 1 (for example, comparing the central pattern A of the superposition corresponding to a sample containing morphology II with the reference pattern C at the top of the superposition, which is the XRPD pattern of a pure morphology I crystal).

[0049] Morphology II may be characterized based on an XRPD pattern that includes one or more or all of the peaks at 16.8°, 18.2°, 18.5°, 21.0°, and 25.1°±0.2° with respect to two theta (2θ). For example, morphology II can be characterized based on an XRPD pattern that includes one or more or all of the peaks (2θ) at 15.8°, 16.8°, 18.2°, 18.5°, 18.8°, 19.3°, 20.1°, 21.1°, and 25.1°±0.2°. Morphology II may be characterized based on an XRPD pattern that includes one or more or all of the peaks at 16.8°, 18.2°, 18.5°, 21.0°, and 25.1°±0.1° with respect to two theta (2θ). For example, morphology II can be characterized based on an XRPD pattern that includes one or more of the peaks (2θ) at 15.8°, 16.8°, 18.2°, 18.5°, 18.8°, 19.3°, 20.1°, 21.1°, and 25.1°±0.1°. Morphology II may also be characterized based on an XRPD pattern that includes one or more of the peaks (2θ) at 16.8°, 18.2°, 18.5°, 21.0°, and 25.1°±0.05° with respect to 2-theta (2θ). For example, morphology II can be characterized based on an XRPD pattern that includes one or more of the peaks (2θ) at 15.8°, 16.8°, 18.2°, 18.5°, 18.8°, 19.3°, 20.1°, 21.1°, and 25.1°±0.05°. Morphology II may be characterized based on an XRPD pattern that includes one or more of the following peaks with respect to 2-theta (2θ): 16.8°, 18.2°, 18.5°, 21.0°, and 25.1°±0.02°. For example, morphology II can be characterized based on an XRPD pattern that includes one or more of the following peaks (2θ): 15.8°, 16.8°, 18.2°, 18.5°, 18.8°, 19.3°, 20.1°, 21.1°, and 25.1°±0.02°. Morphology II may be characterized based on an XRPD pattern that includes one or more of the following peaks with respect to 2-theta (2θ): 16.8°, 18.2°, 18.5°, 21.0°, and 25.1°.For example, morphology II can be characterized based on an XRPD pattern that includes one or more of the peaks (2θ) at 15.8°, 16.8°, 18.2°, 18.5°, 18.8°, 19.3°, 20.1°, 21.1°, and 25.1°. Morphology II is characterized by having an XRPD pattern substantially shown in pattern A of Figure 1.

[0050] Morphology II may also be characterized by the absence of peaks (2θ) in the XRPD pattern at one or more of 11.2°, 19.9°, 20.7°, and 34.1° (±0.2°), or may be distinguished from Morphology I. For example, Morphology II may be characterized by the absence of peaks (2θ) in the XRPD pattern at one or more of 11.2°, 15.4°, 16.3°, 16.9°, 17.8°, 19.9°, 20.7°, 21.0°, 21.8°, 22.6°, 24.5°, 24.6°, 25.0°, 25.5°, 26.3°, 28.3°, 30.3°, 34.1°, 35.8°, 40.0°, and 46.0° (±0.2°), or may be distinguished from Morphology I.

[0051] The XRPD used for characterizing morphology II and / or distinguishing morphology I from morphology II may be any suitable XRPD technique. For example, the XRPD patterns or peaks disclosed herein can be obtained using Cu Kα radiation. For example, the XPRD techniques disclosed herein can be used (see, e.g., Materials and Methods).

[0052] As illustrated in Example 2 and Figures 2 and 3, morphology II can also be characterized using DSCs and / or distinguished from morphology I using DSCs.

[0053] For example, form II may be characterized by having an endothermic peak obtained by DSC with an initiation point at approximately 90°C to approximately 97°C. The endothermic peak of form II may have an initiation point at approximately 91°C to approximately 96°C, for example, at approximately 92°C to approximately 95°C or at approximately 93°C to approximately 94°C. For example, form II may be characterized by having an endothermic peak obtained by DSC with an initiation point at 90°C to 97°C. The endothermic peak of form II may have an initiation point at 91°C to 96°C, for example, at 92°C to 95°C or at 93°C to 94°C.

[0054] In contrast, morphology I may be characterized by having an endothermic peak obtained by DSC with an initiation point at approximately 115°C to approximately 119°C, for example, approximately 116°C to approximately 118°C, for example, approximately 117°C.

[0055] Therefore, morphology II may be characterized by having an endothermic peak with a lower onset point than the onset point of the endothermic peak resulting from morphology I obtained by DSC. For example, morphology II may have an endothermic peak with an onset point about 20°C to about 30°C lower than the onset point of the endothermic peak associated with morphology I, e.g., about 22°C to about 18°C ​​lower, e.g., about 23°C, about 24°C, or about 25°C lower.

[0056] Alternatively, form II may be characterized by having an endothermic peak at a temperature of approximately 92°C to approximately 94°C, for example, approximately 92°C, approximately 93°C, or approximately 94°C, as measured by DSC. Alternatively, form II may be characterized by having an endothermic peak at a temperature of approximately 95°C to approximately 98°C, for example, approximately 95°C, approximately 96°C, or approximately 97°C, as measured by DSC. For example, form II may be characterized by having an endothermic peak at a temperature of approximately 92°C to approximately 94°C, for example, 92°C, 93°C, or 94°C, as measured by DSC. Alternatively, form II may be characterized by having an endothermic peak at a temperature of 95°C to 98°C, for example, 95°C, 96°C, or 97°C, as measured by DSC.

[0057] In contrast, morphology I may be characterized by having an endothermic peak at a temperature of approximately 116°C to approximately 120°C, for example, approximately 117°C, approximately 118°C, or approximately 119°C, as measured by DSC.

[0058] Form II may be characterized by having a melting point of about 90°C to about 95°C, as measured by any preferred technique (e.g., a closed capillary tube or DSC). For example, Form II may be characterized by having a melting point of 90°C to 95°C. For example, Form II may be characterized by having a melting point of about 91°C to about 94°C, for example, about 92°C to about 94°C. For example, Form II may be characterized by having a melting point of 91°C to 94°C, for example, 92°C to 94°C. Form II may be characterized by having a melting point of about 93°C. Form II may be characterized by having a melting point of 93°C.

[0059] In contrast, form I may be characterized by having a higher melting point than form II. The melting point of form I is approximately 117°C. Thus, form II can be identified by having a melting point about 20°C to about 30°C lower than the melting point of form I, for example, about 22°C to about 18°C ​​lower, for example, about 23°C lower, about 24°C lower, or about 25°C lower.

[0060] DSC can be used to identify the endothermic peaks and / or melting points of polymorphs, and can also be used to obtain form II (for example, from a sample of pyrisant hydrochloride (e.g., from form I)). For example, DSC can be used to convert pyrisant hydrochloride that is substantially form I to pyrisant hydrochloride that is substantially form II.

[0061] The DSC protocols disclosed herein for determining endothermic peaks, determining melting points, or obtaining Form II may be any preferred DSC protocol, such as Protocol 1 or Protocol 2 described in Example 2. For example, DSC can be performed using a sample of several milligrams of pyrisant hydrochloride, e.g., about 1 mg to about 10 mg, e.g., about 1 mg to about 5 mg, e.g., about 2 mg, about 3 mg, about 4 mg, or about 5 mg. For example, DSC can be performed using 1 mg to 10 mg, e.g., 1 to 5 mg, e.g., 2 mg, 3 mg, 4 mg, or 5 mg of pyrisant hydrochloride. DSC may be performed under a nitrogen atmosphere. DSC may be performed at a heating rate of about 10°C / min. DSC may be performed within a temperature range of about 0°C to about 150°C, e.g., about 73°C to about 150°C.

[0062] For example, a DSC used to determine the endothermic peak or melting point disclosed herein, or to obtain form II, can be performed using one or more of the following steps: (i) heating from about 20°C to about 150°C at a rate of about 10°C / min, (ii) cooling from about 150°C to about 0°C at a rate of 10°C / min, (iii) heating from about 0°C to about 140°C at a rate of about 10°C / min, (iv) cooling from about 140°C to about 0°C at a rate of about 200°C / min, (v) holding at about 0°C for about 2 minutes, (vi) heating from about 0°C to about 140°C at a rate of about 10°C / min, (vii) cooling from about 140°C to about 73°C at a rate of 10°C / min, (viii) holding at about 73°C for about 4 minutes, and (ix) heating from about 73°C to about 150°C at a rate of about 10°C / min.

[0063] For example, a DSC used to determine the endothermic peak or melting point disclosed herein, or to obtain form II, can be performed using one or more or all of the following steps: (i) heating from 20°C to 150°C at a rate of 10°C / min, (ii) cooling from 150°C to 0°C at a rate of 10°C / min, (iii) heating from 0°C to 140°C at a rate of 10°C / min, (iv) cooling from 140°C to 0°C at a rate of 200°C / min, (v) holding at 0°C for 2 minutes, (vi) heating from 0°C to 140°C at a rate of 10°C / min, (vii) cooling from 140°C to 73°C at a rate of 10°C / min, (viii) holding at 73°C for 4 minutes, and (ix) heating from 73°C to 150°C at a rate of 10°C / min.

[0064] Alternatively, a DSC used to determine the endothermic peak or melting point disclosed herein, or to obtain form II, may be performed using one or more of the following steps: (i) heating from about 20°C to about 130°C at about 10°C / min, (ii) cooling from about 130°C to about 20°C at about 10°C / min, (iii) heating from about 20°C to about 130°C at about 10°C / min, (iv) cooling from about 130°C to about 72°C at about 10°C / min, (v) holding at about 72°C for about 1 hour, and (vi) heating from about 72°C to about 130°C at about 10°C / min.

[0065] For example, a DSC used to determine the endothermic peak or melting point disclosed herein, or to obtain form II, can be performed using one or more or all of the following steps: (i) heating from 20°C to 130°C at 10°C / min, (ii) cooling from 130°C to 20°C at 10°C / min, (iii) heating from 20°C to 130°C at 10°C / min, (iv) cooling from 130°C to 72°C at 10°C / min, (v) holding at 72°C for 1 hour, and (vi) heating from 72°C to 130°C at 10°C / min.

[0066] Morphology II may be characterized by having a (DSC) thermogram substantially shown in Figure 2. For example, Morphology II may be characterized by having a DSC thermogram substantially shown in trace (7) in Figure 2, and / or by having an endothermic peak substantially shown in peak (II) in Figure 2.

[0067] Alternatively, morphology II may be characterized by having a (DSC) thermogram substantially shown in Figure 3. For example, morphology II may be characterized by having a DSC thermogram substantially shown in trace (5) of Figure 3, and / or by having an endothermic peak substantially shown in peak (II) of Figure 3.

[0068] Dosage forms and pharmaceutical compositions This specification discloses dosage forms and pharmaceutical compositions comprising Form II and, optionally, one or more pharmaceutically acceptable excipients.

[0069] The dosage form or pharmaceutical composition may contain a therapeutically effective amount of Form II. For example, the dosage form or pharmaceutical composition may contain Form II in amounts of about 1 mg to about 200 mg, for example, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 10 mg to about 25 mg, or about 1 mg to about 10 mg, for example, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, or about 50 mg of Form II.

[0070] Since Form II contains a pharmaceutically acceptable salt of pitrisant, it will be understood that the amount of pharmaceutically active agent in the dosage form or pharmaceutical composition will be slightly greater than the equivalent amount of free base. For example, a dosage form or pharmaceutical composition disclosed herein containing 5 mg of pitrisant hydrochloride (as Form II) contains about 4.45 mg of pitrisant (free base). In another example, a dosage form or pharmaceutical composition disclosed herein containing 20 mg of pitrisant hydrochloride contains about 17.8 mg of pitrisant (free base). In some embodiments, a dosage form or pharmaceutical composition disclosed herein contains about 5 mg of pitrisant monohydrochloride or about 4.45 mg of pitrisant (free base). In some embodiments, a dosage form or pharmaceutical composition disclosed herein contains about 20 mg of pitrisant monohydrochloride or about 17.8 mg of pitrisant (free base).

[0071] The dosage forms of the present disclosure may include tablets, caplets, capsules, suspensions, granules, powders, and the like.

[0072] The dosage forms or pharmaceutical compositions of this disclosure may further include one or more pharmaceutically acceptable excipients, such as diluents, dispersants, granules, surfactants, emulsifiers, disintegrating agents (sometimes referred to as disintegrants herein), binding agents (sometimes referred to as binders herein), preservatives, buffers, lubricating agents (sometimes referred to as lubricants herein), flow promoters, auxiliaries, fillers, wetting agents, suspending agents, solvents, dispersions, ion exchangers, salts, electrolytes, waxes, and / or oils. The pharmaceutical compositions or dosage forms may include the pharmaceutically acceptable excipients disclosed herein or combinations of the pharmaceutically acceptable excipients disclosed herein. For example, the dosage forms or pharmaceutical compositions of this disclosure may contain one or more or all of the following pharmaceutically acceptable excipients: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

[0073] Each pharmaceutically acceptable excipient may be present in any suitable amount in the dosage form or pharmaceutical composition. For example, a pharmaceutically acceptable excipient may be present in the dosage form or pharmaceutical composition in an amount of about 0.01% to about 95% of the weight of the dosage form or pharmaceutical composition, for example, about 0.1% to about 25%, about 1% to about 10%, about 15% to about 95%, or about 0.01% to about 2% of the weight of the dosage form or pharmaceutical composition.

[0074] The dosage forms and pharmaceutical compositions of this disclosure may be administered orally, parenterally, by inhalation, topically, rectally, nasally, orally, vaginally, or by implant.

[0075] Preparation of the dosage forms or pharmaceutical compositions of this disclosure may include conventional methods such as mixing, filling, compression (e.g., direct compression, drying, wetting, or compression of sintered granules), coating (e.g., coating in a spray process), extrusion, granulation (e.g., wet or dry granulation), pelletization (e.g., direct pelletization), binding, powder layering (e.g., onto beads or neutral cores or particles of pharmaceutically active agents that do not contain any components), and rounding off.

[0076] Treatment method The present invention further relates to a method for treating a disease or disorder, comprising administering to a subject in need thereof one of the Form II or dosage forms or pharmaceutical compositions disclosed herein. Diseases or disorders include sleep disorders (e.g., excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, daytime somnolence), central nervous system disorders (e.g., epilepsy, Alzheimer's disease, Parkinson's disease, dementia (e.g., Lewy body dementia and / or vascular dementia), attention deficit, arousal disorder, memory impairment, cognitive impairment (e.g., in the elderly), psychiatric conditions, depressive and asthenic states, dizziness, and motion sickness), obesity, psychosomatic disorders, respiratory disorders It may also include disorders, allergic conditions, inflammatory conditions, cardiac conditions, gastrointestinal conditions, genitourinary conditions, skin conditions, stress, migraines, headaches, pain, mental disorders, asthma, bronchitis, rhinitis, tracheitis, gastric ulcers, duodenal ulcers, ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), cystitis, myomitis, urinary incontinence, fecal incontinence, urticaria, itching, arthritis, conjunctivitis, premenstrual syndrome, prostatitis, genital disorders, rheumatic conditions, eye conditions, excessive salivation, convulsions, depression, hypothalamic-pituitary system disorders, cerebral circulatory disorders, and immune system disorders.

[0077] In a preferred embodiment, the disorder or condition is a sleep disorder. For example, the disorder or condition may be excessive daytime sleepiness (EDS). EDS may be present in subjects with narcolepsy (e.g., adults).

[0078] The present invention further relates to a method for preventing undesirable side effects associated with the use of antipsychotics or antidepressants (e.g., aripiprazole, clozapine, olanzapine, risperidone, quetiapine, certindol, mirtazapine, amitriptyline, and paroxetine), comprising administering Form II or dosage form or pharmaceutical composition of the present invention to a subject in need thereof. Non-limited examples of undesirable side effects associated with the use of antipsychotics or antidepressants include weight gain, somnolence, and cognitive impairment.

[0079] The present invention further relates to a method for (i) inducing a prolonged state of wakefulness, (ii) improving cognitive processes, (iii) reducing food intake, and / or (iv) normalizing vestibular reflexes, comprising administering the Form II or dosage form or pharmaceutical composition disclosed herein to a subject in need thereof.

[0080] Form II or dosage forms or pharmaceutical compositions disclosed herein may be administered once daily, twice daily, or more frequently. Two or more dosage forms may be administered at once to achieve a desired dose. Form II or dosage forms or pharmaceutical compositions disclosed herein may be ingested at a frequency and in an amount such that the total amount of pitrisant (as free base) administered is in the range of about 10 mg to about 50 mg per day, for example, in the range of about 15 mg to about 40 mg per day. Form II or dosage forms or pharmaceutical compositions disclosed herein may be ingested at a frequency and in an amount such that the total amount of pitrisant (as free base) administered is in the range of about 17.8 mg to about 35.6 mg per day. For example, a subject may be orally administered two dosage forms once daily, each containing 4.45 mg of pitrisant (as free base), to achieve a daily dose of 8.9 mg of pitrisant (as free base). The subject may be administered one dosage form orally once daily, each dosage form containing 17.8 mg of pitrisant (as free base), thereby achieving a daily dose of 17.8 mg of pitrisant (as free base). Alternatively, the subject may be administered two dosage forms orally once daily, each dosage form containing 17.8 mg of pitrisant (as free base), thereby achieving a daily dose of 35.6 mg of pitrisant (as free base). [Examples]

[0081] Materials and methods General method for differential scanning calorimetry (DSC): A few milligrams of sample were placed in a 25 μL aluminum crucible and covered with a perforated lid. DSC analysis was performed under nitrogen flash (20 mL / min) with a temperature scanning rate of 10°C / min, adjusted as needed for the experiment.

[0082] General method of X-ray powder diffraction (XRPD): Unless otherwise specified, XRPD analysis was performed in transmission mode. A few milligrams of sample were wrapped in Kapton® foil (showing a peak at (2θ)5.5°). Analysis was performed from (2θ)2° to 50°.

[0083] [Table 1]

[0084] Example 1. Synthesis of pyrisant monohydrochloride crystals Pitrisanto monohydrochloride can be prepared according to the method described in U.S. Patent No. 8,207,197, for example, according to the protocol shown below.

[0085] Sodium 3-piperidinopropanolate (2.13 kg; 12.88 mol), 3-(4-chlorophenyl)propyl mesylate (1.12 kg; 4.51 mol), and 0.322 mol of 15-crown-5 were refluxed in dry toluene (4.5 kg) for 4 hours. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (eluate: methylene chloride / methanol, 9:1). The resulting oily substance was distilled under reduced pressure (0.3-0.7 mmHg) at 207-210°C in a fractional distillation apparatus equipped with a heating jacket. The head fraction and distillation fraction were collected at a jacket temperature of 180-200°C at 0.001-0.010 mmHg to obtain the pyrisant free base (1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine) as an oily substance (1.0 kg, 3.38 mol).

[0086] Distilled 1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine (1.0 kg) and anhydrous ethyl acetate (4.5 kg) were transferred to a 10 L glass container equipped with a cooling bath and a gas inlet. A stream of hydrogen chloride gas was blown into the reaction mixture at 20-25°C. A 0.5 mL sample of the reaction mixture was taken and diluted with 5 mL of deionized water to check the pH of the solution, obtaining a pH of approximately 3-4.

[0087] The mixture was cooled to -10°C to -12°C and stirred for 1 hour. The precipitate was filtered using a sintered glass filter and washed with 0.5 L of anhydrous ethyl acetate cooled to 0-5°C. The product was dried in a vacuum oven at 50°C for a minimum of 12 hours to obtain crude pyrisant monohydrochloride (1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine monohydrochloride) (1.10 kg).

[0088] A mixture of crude pyrisant monohydrochloride, anhydrous ethyl acetate (3.98 kg), and isopropanol (0.35 kg) was slowly heated at 55-60°C in a 10 L glass container equipped with a heating and cooling system. The resulting solution was filtered through an insulated sintered glass filter while maintaining the temperature at 55-60°C. The solution was transferred to a 10 L glass container, and the mass was slowly cooled to 0-5°C over approximately 1 hour. The mixture was stirred at this temperature for 1 hour, and the precipitate was filtered through a sintered glass filter. The solid was washed with a mixture of anhydrous ethyl acetate (1.6 kg) and isopropanol (0.14 kg) cooled to 0-5°C. The solid was dried in a vacuum oven at 50°C for a minimum of 12 hours to obtain pure pyrisant monohydrochloride (1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine monohydrochloride) (melting point: 117~119°C; yield 80%; IR spectrum (KBr): 1112 and 1101 (CO ether / St. asym), 2936 and 2868 (alkane CH(CH2)) / St.), 1455 (alkane CH(CH2)) / Deform.), 2647 and 2551 (amine salt / St.), 1492 (amine / St.), 802 (aromatic / Deform.) cm -1 He got the band.

[0089] A solution of pure pyrisant monohydrochloride in acetone is evaporated and dried at 70°C for 17 hours to obtain morphological I crystals for use in DSC analysis.

[0090] Example 2. Preparation and analysis of Pitrisanto hydrochloride polymorph II Pitrisant hydrochloride polymorph II was obtained by heating a sample of pitrisant hydrochloride in a differential scanning calorimetry (DSC) system according to the following protocol.

[0091] Protocol 1 Referring to Figure 2, a sample of morphology I crystal from Example 1 was placed in a DSC apparatus and heated from 20°C to 150°C at a rate of 10°C / min. An endothermic peak was revealed with an initiation point of 116.3°C and a peak at 118.0°C corresponding to the melting of the crystalline sample (trace (1), peak (a1)). Subsequently, the molten sample was cooled from 150°C to 0°C at a rate of 10°C / min. A dual exothermic phenomenon with initiation points of 72.0°C and 70.7°C was revealed (trace (2), peaks (b) and (c)), which may be due to recrystallization of morphology I.

[0092] Next, the sample was heated from 0°C to 140°C at a rate of 10°C / min, resulting in an endothermic peak at 117.2°C corresponding to the melting of the known phase (trace (3), peak (a3)). Then, the sample was rapidly cooled from the molten state by cooling from 140°C to 0°C at a rate of 200°C / min, yielding a broad exothermic signal that may be due to the crystallization of the starting phase (see trace (4), signal (d) in Figure 2). The sample was held at 0°C for 2 minutes. Next, the sample was heated again from 0°C to 140°C at a rate of 10°C / min, resulting in a predicted peak at approximately 118°C corresponding to the melting of the known crystalline phase (see trace (5), peak (a5) in Figure 2).

[0093] Next, the sample was cooled from 140°C to 73°C at a rate of 10°C / min (trace (6)), where 73°C was slightly above the temperature of the previously observed double endothermic peaks (peaks (b) and (c)), and the sample was maintained at this temperature for 4 minutes. Referring to Figure 2 (continued), the sample was heated from 73°C to 150°C at a rate of 10°C / min, yielding an endothermic peak with an initial temperature of 93.1°C and a peak temperature of 94.4°C (trace (7), peak (II)). This corresponds to the melting of a polymorph distinct from morph I (e.g., compare peak (II) with peaks (a1), (a3), (a5), and (a9)), and is therefore attributed to a new polymorph of pyrisant hydrochloride, which is referred to herein as morph II.

[0094] Subsequently, when the sample containing morphology (II) was cooled from 150°C to 15°C, a double endothermic peak was obtained (trace (8), peaks (f) and (g)). These peaks may be due to the crystallization of morphology II, followed immediately by the crystallization or polymorphic transformation of morphology I. Finally, in the last step, when the sample was heated from 15°C to 145°C at a rate of 10°C / min, an endothermic peak resulting from the melting of morphology (I) became apparent, as is evident from the expected starting point of approximately 117°C (trace (9), peak (a9)).

[0095] Protocol 2 Referring to Figure 3, when the pyrisant hydrochloride was placed in a DSC instrument and the sample was heated from 20°C to 130°C at 10°C / min, an endothermic peak with a long shoulder shape at 111.9°C and an additional signal at 106.6°C was obtained (trace (1), peaks p(1) and p(1')). By cooling the sample from 130°C to 20°C at a rate of 10°C / min, an exothermic event due to crystallization of the sample was observed (trace (2), peak (b2)). When the sample was heated again from 20°C to 130°C at 10°C / min, three endothermic events occurred (a small signal at approximately 106°C, a large peak with an offset of 109.5°C, and a sharp peak at 117.8°C corresponding to melting in morphology I) (trace (3), peaks (p3'), (p3), and (a3)). Next, the sample was cooled from 130°C to 72°C at a rate of 10°C / min and held at 72°C for 1 hour (Trace (4)). Then, the sample was heated from 72°C to 130°C at a rate of 10°C / min, and an endothermic peak was obtained at 93.7°C, which may be due to the melting of Form II (Trace (5) Peak (II)). This melting point is consistent with the melting point observed for Form II in Protocol 1 (e.g., compare Peak (II) in Figure 2 with Peak (II) in Figure 3).

[0096] Referring to Figure 3 (continued), the sample was then cooled from 130°C to 50°C at a rate of 10°C / min, yielding an exothermic peak at approximately 70°C (trace (6), peak (b6)). When heated from 50°C to 130°C, an endothermic peak at 117.5°C, corresponding to melting in morphology (I), was obtained (trace (7), peak (a7)). The sample was then cooled to 72°C and maintained for 1 hour (trace 8), heated again to 82°C (trace (9)), and finally cooled to 20°C (trace 10). No thermal events were observed during these final steps (represented by traces (8) to (10)). The sample was immediately removed from the aluminum pan and analyzed by XRPD as described in Example 3. Summary Protocols 1 and 2 demonstrate the acquisition of morphology II as follows: In a DSC apparatus, the molten pitrisant hydrochloride sample was cooled from 140°C to 73°C at a rate of 10°C / min (Trace (6) in Figure 2), where 73°C was slightly above the temperature of the previously observed double endothermic peaks (peaks (b) and (c)). The sample was maintained at this temperature for 4 minutes. Referring to Figure 2 (continued), the sample was heated from 73°C to 150°C at a rate of 10°C / min, yielding an endothermic peak with an initial temperature of 93.1°C and a peak temperature of 94.4°C (Trace (7), Peak (II)). This corresponds to the melting of a polymorph distinct from morphology I (e.g., comparing Peak (II) with Peaks (a1), (a3), (a5), and (a9)), and is therefore attributed to a new polymorph of pitrisant hydrochloride, which is referred to herein as morphology II. or In a DSC instrument, the molten pitrisant hydrochloride sample was cooled from 130°C to 72°C and maintained for 1 hour (trace 8), then reheated to 82°C (trace 9), and finally cooled to 20°C (trace 10). No thermal events were observed in these final steps (represented by traces (8) to (10)). The sample was immediately removed from the aluminum pan and analyzed by XRPD as described in Example 3.

[0097] In protocols 1 and 2, a second polymorph (morph II) of pyrisant hydrochloride was formed, each with a melting point of approximately 93°C as measured by DSC. The melting point of morph II is lower than that of the known polymorph (morph I) of pyrisant hydrochloride, which has a melting point of approximately 117°C.

[0098] Example 3. X-ray Powder Diffraction (XRPD) Research Following the DSC study described in Protocol 2 of Example 2, the sample was removed from the aluminum pan and analyzed by XRPD according to the XPRD method described above. The diffraction pattern of this sample was obtained and is shown in Figure 1 (see diffraction pattern A). The sample was then wrapped in polymer foil and stored at room temperature for 10 months, and then analyzed again by XRPD, yielding diffraction pattern B, which is superimposed on Figure 1. From these studies, characteristic peaks of crystal morphology II, shown by dashed lines in Figure 1 and also listed in Table 2 below, were identified.

[0099] [Table 2]

[0100] Those skilled in the art will be able to identify or confirm numerous equivalents to the specific embodiments disclosed herein simply by using routine experiments. Those skilled in the art will understand that various changes or modifications can be made to this description without departing from the spirit or scope of the disclosure as set forth in the following claims.

Claims

1. Compounds represented by formula (I): 【Chemistry 1】 The crystal morphology is characterized by having an X-ray diffraction pattern that includes at least one peak at 16.8°, 18.2°, 18.5°, 21.0°, and 25.1° (±0.2°) with respect to two theta (2θ).

2. The crystal morphology according to claim 1, characterized by having an X-ray diffraction pattern that includes at least one characteristic peak (2θ) at 15.8°, 16.8°, 18.2°, 18.5°, 18.8°, 19.3°, 20.1°, 21.1°, and 25.1° (±0.2°).

3. The crystal morphology according to claim 1 or 2, characterized by having an X-ray diffraction pattern substantially shown in pattern A of Figure 1.

4. The crystalline morphology according to any one of claims 1 to 3, further characterized by having an endothermic peak having an initiation point at approximately 90°C to approximately 97°C, as obtained by differential scanning calorimetry (DSC).

5. The crystal morphology according to claim 4, wherein the starting point is approximately 91°C to approximately 96°C, for example, approximately 92°C to approximately 95°C or approximately 93°C to approximately 94°C.

6. The crystal morphology according to claim 4 or 5, wherein the endothermic peak is located at approximately 92°C to approximately 94°C (for example, approximately 92°C, approximately 93°C, or approximately 94°C), or approximately 95°C to approximately 98°C (for example, approximately 95°C, approximately 96°C, or approximately 97°C).

7. The crystalline form according to any one of claims 4 to 6, wherein the DSC is performed using a sample of about 1 mg to about 10 mg (for example, about 1 mg to about 5 mg, for example, about 2 mg, about 3 mg, about 4 mg, or about 5 mg).

8. The crystal morphology according to any one of claims 4 to 7, wherein the DSC is carried out under nitrogen.

9. The crystal morphology according to any one of claims 4 to 8, wherein the DSC is carried out at a heating rate of 10°C / min.

10. The crystal morphology according to any one of claims 4 to 9, wherein the DSC is carried out at a temperature of 0°C to 150°C, for example, 73°C to 150°C.

11. The aforementioned DSC, (i) Heat from 20°C to 150°C at a rate of 10°C / min. (ii) Cooling from 150°C to 0°C at a rate of 10°C / min. (iii) Heat from 0°C to 140°C at a rate of 10°C / min. (iv) Cooling from 140°C to 0°C at a rate of 200°C / min. (v) Hold at 0°C for 2 minutes. (vi) Heat from 0°C to 140°C at a rate of 10°C / min. (vii) Cooling from 140°C to 73°C at a rate of 10°C / min. (viiii) Hold at 73°C for 4 minutes, and (ix) Heat from 73°C to 150°C at a rate of 10°C / min. The crystal form according to any one of claims 4 to 8, as implemented by [the method described].

12. The aforementioned DSC, (i) Heat from 20°C to 130°C at a rate of 10°C / min. (ii) Cool from 130°C to 20°C at a rate of 10°C / min. (iii) Heat from 20°C to 130°C at a rate of 10°C / min. (iv) Cool from 130°C to 72°C at a rate of 10°C / min. (v) Hold at 72°C for 1 hour. (vi) Heat from 72°C to 130°C at a rate of 10°C / min. The crystal form according to any one of claims 4 to 8, as implemented by [the method described].

13. Compounds represented by formula (I): 【Chemistry 2】 A crystalline form characterized by having a melting point of approximately 90°C to approximately 95°C.

14. The crystalline form according to claim 13, wherein the melting point is approximately 91°C to approximately 94°C, for example, approximately 92°C to approximately 94°C.

15. The crystalline form according to claim 13 or 14, wherein the melting point is approximately 93°C.

16. Compounds represented by formula (I): 【Transformation 3】 A crystalline form characterized by an endothermic peak having an initiation point at approximately 90°C to approximately 97°C, for example, having an initiation point at approximately 91°C to approximately 96°C, for example, having an initiation point at approximately 92°C to approximately 95°C or approximately 93°C to approximately 94°C, obtained by differential scanning calorimetry (DSC).

17. The crystalline morphology according to claim 16, characterized by having a DSC thermogram substantially shown in Figure 2.

18. The crystalline morphology according to claim 16 or 17, characterized by having a DSC thermogram substantially shown in trace (7) of Figure 2.

19. The crystalline morphology according to any one of claims 16 to 18, characterized by having an endothermic peak substantially shown in peak (II) of Figure 2.

20. The crystalline morphology according to claim 16, characterized by having a DSC thermogram substantially shown in Figure 3.

21. The crystalline morphology according to claim 20, characterized by having a DSC thermogram substantially shown in trace (5) of Figure 3.

22. The crystalline form according to claim 20 or 21, characterized by having an endothermic peak substantially shown in peak (II) of Figure 3.

23. The crystal morphology according to any one of claims 1 to 22, characterized by having an X-ray diffraction pattern that does not include the combination of peaks (2θ) at 11.2°, 19.9°, 20.7°, and 34.1° (±0.2°).

24. A crystal morphology according to any one of claims 1 to 23, characterized by an X-ray diffraction pattern that does not include a combination of peaks (2θ) at 11.2°, 15.4°, 16.3°, 16.9°, 17.8°, 19.9°, 20.7°, 21.0°, 21.8°, 22.6°, 24.5°, 24.6°, 25.0°, 25.5°, 26.3°, 28.3°, 30.3°, 34.1°, 35.8°, 40.0°, and 46.0° (±0.2°).

25. Pitrisanto hydrochloride polymorph II.

26. A pharmaceutical composition comprising a crystalline form or polymorph according to any one of claims 1 to 25, and optionally a pharmaceutically acceptable excipient.

27. The pharmaceutical composition according to claim 26, wherein the pharmaceutically acceptable excipient is selected from the group consisting of colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

28. A dosage form comprising the crystalline form, polymorph, or pharmaceutical composition described in any one of claims 1 to 27.

29. The dosage form according to claim 28, wherein the dosage form is a tablet, a caplet, or a capsule.

30. A method for treating a disease or disorder, comprising administering to a subject in need thereof a crystalline form, polymorph, pharmaceutical composition, or dosage form described in any one of claims 1 to 29.

31. The method according to claim 30, wherein the disease or disorder is a sleep disorder.

32. The method according to claim 30 or 31, wherein the disease or disorder is excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, or daytime somnolence.

33. The method according to any one of claims 30 to 32, wherein the disease or disorder is excessive daytime sleepiness (EDS).

34. The method according to any one of claims 30 to 32, wherein the disease or disorder is cataplexy.

35. The method according to any one of claims 30 to 32, wherein the subject has narcolepsy (for example, the subject is an adult with narcolepsy).

36. A crystalline form, polymorph, pharmaceutical composition, or dosage form according to any one of claims 1 to 29 for use in the treatment of a disease or disorder (for example, a disease or disorder disclosed herein), wherein the disease or disorder is optionally excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (for example, obstructive sleep apnea), sleep-induced apnea, or daytime somnolence.

37. The crystalline form, polymorph, pharmaceutical composition, or dosage form for use according to claim 36, wherein the disease or disorder is in a subject having narcolepsy (for example, an adult subject having narcolepsy).

38. Use of a crystalline form, polymorph, pharmaceutical composition, or dosage form according to any one of claims 1 to 29 in the manufacture of a medicament for the treatment of a disease or disorder (for example, a disease or disorder disclosed herein), wherein the disease or disorder is optionally excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (for example, obstructive sleep apnea), sleep-induced apnea, or daytime somnolence.

39. The use according to claim 38, wherein the disease or disorder is in a subject having narcolepsy (for example, an adult subject having narcolepsy).

40. A crystalline form, polymorph, pharmaceutical composition, or dosage form according to any one of claims 1 to 29, for use in the treatment of a disease or disorder in a subject requiring treatment of a disease or disorder.

41. The crystalline form, polymorph, pharmaceutical composition, or dosage form for use according to claim 40, wherein the disease or disorder is a sleep disorder.

42. The crystalline form, polymorph, pharmaceutical composition, or dosage form for use according to claim 40 or 41, wherein the disease or disorder is excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, or daytime somnolence.

43. The crystalline form, polymorph, pharmaceutical composition, or dosage form for use according to any one of claims 40 to 42, wherein the disease or disorder is excessive daytime sleepiness (EDS).

44. The crystalline form, polymorph, pharmaceutical composition, or dosage form for use according to any one of claims 40 to 42, wherein the disease or disorder is cataplexy.

45. The subject having narcolepsy (for example, the subject being an adult having narcolepsy), the crystalline form, polymorph, pharmaceutical composition, or dosage form for use according to any one of claims 40 to 42.

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