Crystalline forms of a compound, polymorph of form II, pharmaceutical composition, dosage form and use.

Description

1 / 35 “Crystalline Forms of a Compound, Polymorph of Form II, Pharmaceutical Composition, Dosage Form and Use” Related Applications

[001] This application claims the benefit of U.S. Provisional Application No. 63 / 493,500, filed March 31, 2023, the full contents of which are incorporated herein by reference. Background of the Invention

[002] Polymorphism is an important consideration in the pharmaceutical industry. Different crystalline forms (polymorphs) of a drug molecule may exhibit non-equivalent physicochemical and mechanical properties due to various factors such as crystal packing and molecular orientation, which can impact several physicochemical properties of the drug material, such as hardness, hygroscopicity, solubility, stability, and pharmacokinetics. This aspect of polymorphism can have significant implications for pharmaceutical products, affecting, for example, the choice of excipients in a formulation, appropriate routes of administration, dosage, shelf life, and also appropriate methods for production and packaging.In cases where a drug molecule has more than one crystalline form (i.e., different polymorphs), one polymorph may be more suitable for a specific application, route of administration, or use than another polymorph of the same drug molecule.

[003] Pitolisant hydrochloride is a medicinal molecule that is useful for treating various diseases and disorders, particularly sleep disorders such as excessive daytime sleepiness (EDS) and cataplexy, marketed as WAKIX®. WAKIX® contains a specific crystalline form of pitolisant hydrochloride, herein referred to as Form I, which was disclosed in U.S. Patent No. 8,207,197, which is incorporated herein by reference in its entirety. Petition 870250088085, dated 09 / 29 / 2025, pp. 98 / 137 2 / 35 Brief Description of the Invention

[004] The present invention relates generally to a new crystalline form of pitolisant hydrochloride, hereinafter referred to as “Form II”, and pharmaceutical compositions and dosage forms comprising Form II, as well as methods of treating a disease or disorder with Form II or a pharmaceutical composition or dosage form comprising Form II.

[005] In some respects, the present invention relates to a crystalline form of a compound represented by Formula (I): •HCl (I), characterized by having an X-ray diffraction pattern comprising at least one of the following peaks, in terms of 2-theta (2θ), at 16.8°, 18.2°, 18.5°, 21.0° and 25.1° (± 0.2°). For example, the crystalline form can be characterized by having an X-ray diffraction pattern comprising at least one of the 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°). Alternatively, the crystalline form can be characterized by having an X-ray diffraction pattern substantially as shown in pattern A of Figure 1.

[006] In one embodiment, the present invention relates to a crystalline form of a compound represented by Formula (I): LH i I *hciCl(I), characterized by having an X-ray diffraction pattern comprising the following peaks, in terms of 2-theta (2θ), at 16.8°, 18.2°, 18.5°, 21.0° and 25.1° (± 0.2°). For example, the crystalline form may be characterized by having an X-ray diffraction pattern comprising the 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°).

[007] The XRPD standard can be obtained using any protocol Petition 870250088085, dated 09 / 29 / 2025, page 99 / 137 3 / 35 suitable and with any suitable apparatus, such as a protocol or apparatus disclosed here. The XRPD standard can be obtained using a sample between about 1 mg and about 10 mg (e.g., between about 1 and about 5 mg, e.g., about 2 mg, about 3 mg, about 4 mg, or about 5 mg). The XRPD standard can be obtained using Cu Ka radiation.

[008] A crystalline form of the present invention can also be characterized by exhibiting an endothermic peak with onset between about 90 °C and about 97 °C, as obtained by Differential Scanning Calorimetry (DSC). For example, the onset can occur between about 91 °C and about 96 °C, for example, between about 92 °C and about 95 °C, or between about 93 °C and about 94 °C. The endothermic peak can occur between about 92 °C and about 94 °C (for example, about 92 °C, about 93 °C or about 94 °C), or between about 95 °C and about 98 °C (for example, about 95 °C, about 96 °C or about 97 °C), as determined by DSC.

[009] A crystalline form of the present invention can be characterized by DSC using a sample between about 1 mg and about 10 mg (for example, between about 1 and about 5 mg, for example, about 2 mg, about 3 mg, about 4 mg or about 5 mg). DSC can be performed under nitrogen. DSC can be performed using a heating rate of 10 °C / min. DSC can be performed at a temperature between 0 °C and 150 °C, for example, between 73 °C and 150 °C.

[0010] In some respects, a crystalline form of the present invention is characterized and / or formed using the following protocol: (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 Petition 870250088085, dated 09 / 29 / 2025, pp. 100 / 137 4 / 35 °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.

[0011] In some respects, a crystalline form of the present invention is characterized and / or formed using the following protocol: (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.

[0012] In some embodiments, the present invention relates to a crystalline form of a compound represented by Formula (I): (I), characterized by having a melting point between about 90 °C and about 95 °C. For example, the crystalline form may have a melting point between about 91 °C and about 94 °C, for example, between about 92 °C and about 94 °C. In some respects, the crystalline form has a melting point of about 93 °C.

[0013] In some embodiments, the present invention relates to a crystalline form of a compound represented by Formula (I): •HCl (I), characterized by having an endothermic peak with an onset between about 90 °C and about 97 °C, as obtained by Differential Scanning Calorimetry (DSC), for example, an onset between about 91 °C and about 96 °C, for example, an onset between about 92 °C and about 95 °C, or between about 93 °C and about 94 °C. For example, the crystalline form can be characterized by having a DSC thermogram substantially as shown in Figure 2, for example, as shown in trace (7) of Figure 2, for example, as shown by peak (II) of Figure 2. Alternatively, the crystalline form can be characterized by having a Petition 870250088085, dated 09 / 29 / 2025, pp. 101 / 137 5 / 35 DSC thermogram substantially as shown in Figure 3, for example, as shown in trace (5) of Figure 3, for example, as shown by peak (II) of Figure 3.

[0014] In some embodiments, the present invention relates to a crystalline form of a compound represented by Formula (I): JT H i I -Hei Cl (I), characterized by having an X-ray diffraction pattern that does not comprise the combination of (2θ) peaks at 11.2°, 19.9°, 20.7° and 34.1° (± 0.2°). For example, a crystalline form of the present invention may be characterized by having an X-ray diffraction pattern that does not comprise the 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°).

[0015] In some respects, the present invention relates to a Form II polymorph of pitolisant hydrochloride.

[0016] In some respects, the present invention 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 a pharmaceutically acceptable excipient 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 a Form II polymorph of pitolisant hydrochloride.

[0017] In some respects, the present invention relates to a dosage form comprising a crystalline, polymorphic or Petition 870250088085, dated 09 / 29 / 2025, pp. 102 / 137 6 / 35 pharmaceutical composition disclosed herein. The dosage form may be any suitable dosage form, such as a tablet, caplet or capsule. For example, the dosage form may comprise a polymorph of Form II pitolisant hydrochloride.

[0018] In some embodiments, the present invention relates to a method for treating a disease or disorder, comprising administering to an individual 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 sleepiness. In some embodiments, the disease or disorder is excessive daytime sleepiness (EDS). In some embodiments, the disease or disorder is cataplexy. In a method disclosed herein, the individual to be treated may have narcolepsy and / or may be an adult with narcolepsy.For example, the method for treating a disease or disorder may involve administering to an individual in need thereof a polymorph of Form II pitolisant hydrochloride.

[0019] In some respects, the present invention 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 sleepiness. The disease or disorder may be in an individual with narcolepsy (e.g., an adult individual with narcolepsy). In some respects, the present invention relates to a polymorph of Form II pitolisant hydrochloride in the treatment of a disease or disorder. Petition 870250088085, dated 09 / 29 / 2025, pp. 103 / 137 7 / 35 (for example, a disease or disorder disclosed here), 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 sleepiness. The disease or disorder may occur in a subject with narcolepsy (e.g., an adult subject with narcolepsy).

[0020] In some respects, the present invention relates to the use of a crystalline form, polymorph, pharmaceutical composition or dosage form disclosed herein, for the manufacture of a medicament for the treatment of a disease or disorder (for example, a disease or disorder disclosed herein), optionally, wherein the disease or disorder is excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (for example, obstructive sleep apnea), sleep-induced apnea or daytime sleepiness. The disease or disorder may occur in an individual with narcolepsy (for example, an adult individual with narcolepsy).In some respects, the present invention relates to the use of a Form II polymorph of pitolisant hydrochloride for the manufacture of a medicament for the treatment of a disease or disorder (for example, a disease or disorder disclosed herein), optionally, wherein the disease or disorder is excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (for example, obstructive sleep apnea), sleep-induced apnea, or daytime sleepiness. The disease or disorder may occur in an individual with narcolepsy (for example, an adult individual with narcolepsy).

[0021] In some respects, the present invention relates to a crystalline form, polymorph, pharmaceutical composition or dosage form of any of the claims for use in the treatment of a disease or disorder in an individual in need thereof, such as a disease or disorder disclosed herein, for example, a sleep disorder, excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., apnea Petition 870250088085, dated 09 / 29 / 2025, pp. 104 / 137 8 / 35 obstructive sleep apnea), sleep-induced apnea, or daytime sleepiness. For example, a Form II polymorph of pitolisant hydrochloride for use in the treatment of a disease or disorder in an individual in need thereof, such as a disease or disorder disclosed herein, for example, a sleep disorder, excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, or daytime sleepiness. In some respects, the disease or disorder is excessive daytime sleepiness (EDS). In some respects, the disease or disorder is cataplexy. In some respects, the subject has narcolepsy (e.g., the subject is an adult with narcolepsy). Brief Description of the Drawings

[0022] Figure 1 is a graphical representation and overlay of powder X-ray diffraction (XRPD) patterns. The pattern in the middle of the overlay, labeled “A”, is the XRPD pattern obtained from a sample containing Form II crystals. The lower pattern in the overlay, labeled “B”, shows the XRPD pattern obtained from the same sample after 10 months of storage. The pattern labeled “C” at the top of the overlay was obtained from pure Form I crystals. The vertical dashed lines highlight the characteristic peaks of Form II.

[0023] Figure 2 shows a Differential Scanning Calorimetry (DSC) thermogram following an exemplary protocol for obtaining Form II of pitolisant hydrochloride. The endothermic peak assigned to Form II is peak (II) at trace (7).

[0024] Figure 3 shows another DSC thermogram following an exemplary protocol for obtaining Form II. The endothermic peak assigned to Form II is peak (II) in trace (5). Detailed Description of the Invention

[0025] The present invention generally relates to a novel crystalline form (polymorph) of pitolisant hydrochloride, herein referred to as “Form Petition 870250088085, dated 09 / 29 / 2025, pp. 105 / 137 9 / 35 Pharmaceutical compositions and dosage forms comprising Form II and, optionally, a pharmaceutically acceptable excipient are also disclosed. Furthermore, the present invention relates to methods of treating a disease or disorder using Form II, or a pharmaceutical composition or dosage form comprising Form II.

[0026] The structure of pitolisante hydrochloride (which may also be referred to here as pitolisante monohydrochloride) is given below as Formula (I): (I).

[0027] A crystalline form of pitolisant hydrochloride (Form I) was disclosed in U.S. Patent No. 8,207,197, which is incorporated herein by reference in its entirety. The polymorph of Form I is present in the FDA-approved pharmaceutical product WAKIX®. The crystalline form of the present invention (i.e., Form II) is different from Form I. It is believed that Form II may have certain properties different from Form I, for example, different degrees of hygroscopicity, solubility and / or pharmacokinetics, which may be advantageous for certain uses, for example, in the treatment of a disease or disorder such as EDS or cataplexy. Definitions

[0028] The articles “a” and “an” are used here to refer to one or more of an (i.e., at least one) grammatical object of the article. As an example, “an element” means one or more elements.

[0029] The term “approximately”, when referring to a measurable value, such as a quantity, a time duration and the like, is intended to encompass variations of ± 20% or less, or in some cases ± 15% or less, or in some cases ± 10% or less, or in some cases ± 5% or less, or in some cases ± 1% or less, or in some cases ± 0.1% or less, of the value Petition 870250088085, dated 09 / 29 / 2025, pp. 106 / 137 10 / 35 specified, as such variations may be appropriate.

[0030] The expression “and / or”, as used here, should be understood as “one or both” of the elements thus combined, that is, elements that are conjuncturally present in some cases and disjuncturally present in others. Multiple elements listed with “and / or” should be interpreted in the same way, that is, “one or more” of the elements thus combined. Other elements may optionally be present, in addition to the elements specifically identified by the “and / or” clause, whether or not they are related to these specifically identified elements.Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open language such as “including”, may refer, in one embodiment, only to A (optionally including elements other than B); in another embodiment, only to B (optionally including elements other than A); in yet another embodiment, to A and B (optionally including other elements); etc.

[0031] The terms “administer”, “administering” or “administration”, as used herein, refer to the implantation, absorption, ingestion, injection, inhalation or introduction of a compound (e.g., Form II), dosage form or pharmaceutical composition.

[0032] The terms “understand”, “understands” and “understanding” are used here in a non-exclusive sense, except where the context requires otherwise. Similarly, the term “include” and its grammatical variants are intended to be non-limiting, so that the recitation of items in a list does not exclude other similar items that may be substituted for or added to the listed items.

[0033] The term “effective amount” or “therapeutically effective amount,” as used in this document, refers to a quantity of a compound, dosage form, or pharmaceutical composition. Petition 870250088085, dated 09 / 29 / 2025, pp. 107 / 137 11 / 35 described herein, which is sufficient to achieve a desired result under the conditions of administration. For example, an effective amount of a compound, dosage form, or pharmaceutical composition disclosed herein for the treatment of excessive sleep disorder (EDD), for example, in an individual with narcolepsy, is an amount that can reduce the effects of ESD and / or reduce or eliminate the severity of a symptom associated with ESD. A qualified clinician can determine the appropriate dosage based on a variety of considerations, including disease severity, age, weight, the individual's general health status, and other considerations.A compound (e.g., a crystalline form, e.g., Form II), dosage form, or pharmaceutical composition disclosed herein may be administered to provide an amount of about 0.01 mg to about 250 mg (e.g., about 0.1 mg to about 100 mg) of a pharmaceutically active agent, 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] The term “pharmaceutically acceptable excipient,” as used herein, refers to a non-toxic material that can be formulated with a compound disclosed herein (e.g., a 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 with which it is formulated. Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions disclosed herein are any of those well known in the art and include, without limitation, diluents, dispersing agents, granulating agents, surfactants, emulsifiers, disintegrating agents (sometimes referred to herein as disintegrants), binding agents (sometimes referred to herein as binders), preservatives, buffering agents (at Petition 870250088085, dated 09 / 29 / 2025, pp. 108 / 137 12 / 35 times referred to here as buffers), lubricating agents (sometimes referred to here as lubricants), slip agents, adjuvants, fillers, wetting agents, suspending agents, solvents, dispersing media, ion exchangers, salts, electrolytes, waxes and / or oils and the like.

[0035] For example, a pharmaceutically acceptable excipient may be alumina, a phosphate (e.g., calcium phosphate, dicalcium phosphate, tricalcium phosphate, disodium hydrogen phosphate, potassium hydrogen phosphate), a sulfate (e.g., calcium sulfate), cellulose, kaolin, bentonite, lactose, mannitol, sorbitol, sucrose, inositol, compressible sugar, trehalose, xylitol, acacia, gelatin, glucose, maltodextrin, starch (e.g., corn starch, potato starch), sodium starch glycolate, starch derivatives, an amino acid, magnesium carbonate, polyvinylpyrrolidone (PVP, povidone) (e.g., cross-linked PVP, crospovidone), polyvinyl alcohol, tragacanth, polyethylene glycol, mineral clay powders, croscarmellose, poloxamer, fatty acids or salts thereof (e.g., lauric acid, sodium lauryl sulfate, stearic acid, calcium stearate, magnesium stearate, aluminum stearate, oleic acid), hydrogenated vegetable oils, talc,Titanium dioxide, glyceryl behenate, silicon dioxide (e.g., colloidal silicon dioxide), a silicate salt (e.g., magnesium trisilicate), lecithin, serum protein (e.g., human serum albumin), sorbic acid, potassium sorbate, a metal cation salt (e.g., a sodium salt, such as sodium chloride, a potassium salt, such as potassium chloride, a magnesium salt, such as magnesium chloride, a zinc salt, such as zinc chloride), water, dimethylacetamide, protamine sulfate, wool fat, ethylenediaminetetraacetic acid (EDTA), a cyclodextrin (e.g., CAPTISOL®), a polysorbate (e.g., TWEEN®, e.g., TWEEN® 20 or TWEEN® 80) and combinations thereof.

[0036] The term “pharmaceutically acceptable salt”, according Petition 870250088085, dated 09 / 29 / 2025, pp. 109 / 137 13 / 35 used here refers to salts of a compound prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the respective compound. When the compounds contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient quantity of the desired acid, pure or in a suitable solvent (e.g., an inert solvent).Examples of pharmaceutically acceptable acid addition salts include those 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 acids and the like, as well as 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, ptoluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, oxalic acid and the like. Also included are amino acid salts, such as arginate and similar compounds, and salts of organic acids, such as glucuronic or galacturonic acids and similar compounds.Other pharmaceutically acceptable salts known to those skilled in the art are suitable for pharmaceutical compositions related to the present invention.

[0037] The term “solvate,” as used herein, refers to forms of a compound that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), diethyl ether, and the like. The compounds of the present invention can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include solvates Petition 870250088085, dated 09 / 29 / 2025, pp. 110 / 137 14 / 35 pharmaceutically acceptable and also include stoichiometric and non-stoichiometric solvates. In certain cases, the solvate will be able to be isolated, for example, when one or more solvent molecules are incorporated into the crystalline structure of a crystalline solid. “Solvate” encompasses both solution-phase solvates and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0038] The term “hydrate”, as used herein, refers to a compound that is associated with water. Typically, the number of water molecules contained in a hydrate of a compound is in a definite ratio to the number of molecules of the compound in the hydrate. Therefore, a hydrate of a compound 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 can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrates (R*0.5H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R*2H2O) and hexahydrates (R*6H2O)).

[0039] The term “subject,” as used herein, refers to any animal, such as any mammal, including, but not limited to, humans, non-human primates, rodents, dogs, and the like. Non-human primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques (e.g., Rhesus). Rodents include mice, rats, marmots, ferrets, rabbits, and hamsters. Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species (e.g., domestic cat), canine species (e.g., dog, fox, wolf), avian species, and fish. In some embodiments, the subject is a mammal (e.g., a human, a rat, or a mouse). The subject may be male or female. The subject may be of any age, including an elderly human (e.g., 65 years or older), a human who is not elderly (e.g., under 65). Petition 870250088085, dated 09 / 29 / 2025, pp. 111 / 137 15-35 years old) or a pediatric human being (e.g., under 18 years old). In preferential aspects, the subject is a human being.

[0040] As used herein, the terms “treat,” “treatment,” “treating,” or grammatically related terms refer to a method for reducing the effects of a disease or disorder. As is readily recognized in the art, complete eradication of the disease, disorder, or its symptoms is preferable, but not a requirement for treatment. Desirable effects of treatment include, but are not limited to, preventing the occurrence or recurrence of the disease or disorder, relieving symptoms, diminishing any direct or indirect pathological consequences of the disease or disorder, or otherwise improving any sign, symptom, or consequence of the disease or disorder, such as prolonged survival, reduced morbidity, and / or reduced side effects.

[0041] Throughout this invention, various embodiments may be presented in an interval format (e.g., from X to Y). It should be understood that the interval description is merely for convenience and brevity and should not be interpreted as an inflexible limitation to the scope of the present invention. Consequently, the description of an interval should be considered as having specifically disclosed all possible subintervals as well as individual numerical values ​​within that interval. For example, the description of a range, such as 1 to 6, should be considered as having specifically disclosed sub-ranges, such as 1 to 5, 1 to 4, 1 to 3, 2 to 6, 2 to 4, 3 to 6, etc., as well as individual numbers within that range, for example, 1, 2, 2.8, 3, 3.6, 4, 5, 5.4, and 6. As another example, a range such as 95-99% includes 95%, 96%, 97%, 98%, or 99% and all sub-ranges, such as 96-99%, 96-98%, 96-97%, 97-99%, 97-98%, etc.This applies regardless of the range width.

[0042] All publications (e.g., journal articles) Petition 870250088085, dated 09 / 29 / 2025, pp. 112 / 137 16 / 35 scientific publications, patent publications and the like) cited in this invention are incorporated by reference in their entirety. To the extent that material incorporated by reference contradicts or is inconsistent with this descriptive report, it shall supersede any such material. Citation of any references contained herein does not constitute an admission that such references are prior to the present invention. Several terms relating to aspects of the description are used throughout the descriptive report and the claims. Such terms shall be given their common meaning in the art unless otherwise indicated. Other specifically defined terms shall be interpreted in a manner consistent with the definitions provided herein.

[0043] The compounds (e.g., pharmaceutically active agents) disclosed herein may also comprise one or more isotopic substitutions. For example, hydrogen (H) may be in any isotopic form, including 1H, 2H (D or deuterium), 3H (T or tritium); carbon (C) may be in any isotopic form, including 12C, 13C and 14C; oxygen (O) may be in any isotopic form, including 16O and 18O; nitrogen (N) may be in any isotopic form, including 14N and 15N; and chlorine (Cl) may be in any isotopic form, including 35Cl and 37Cl.

[0044] Various embodiments of the compounds, dosage forms, pharmaceutical compositions and methods described herein are described in more detail below, and additional definitions may be provided throughout the descriptive report. Crystalline Form of Pitolisant Hydrochloride

[0045] A crystalline form of pitolisant hydrochloride (Form II) (a polymorph of Form II pitolisant hydrochloride) is disclosed here. Pitolisant hydrochloride is also known as 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine monohydrochloride. Pitolisant hydrochloride is represented by Formula (I): Petition 870250088085, dated 09 / 29 / 2025, pp. 113 / 137 17 / 35 •HCI (I).

[0046] A crystalline form of pitolisant hydrochloride (Form I) was previously disclosed in U.S. Patent No. 8,207,197, which is incorporated herein by reference in its entirety. This invention relates to another crystalline form, Form II, the preparation or characterization of which has not been previously disclosed. It should be understood that the polymorphs disclosed herein are crystalline, i.e., not amorphous.

[0047] Form II can be characterized and / or distinguished from Form I using an appropriate analytical technique, such as X-ray powder diffraction (XRPD) or Differential Scanning Calorimetry (DSC).

[0048] For example, Form II can be characterized using XRPD, as illustrated in Example 3 and Figure 1. Similarly, XRPD can be used to distinguish Form I and Form II, which is also illustrated in Figure 1 (for example, by comparing pattern A in the middle of the overlay, corresponding to the sample containing Form II, to reference pattern C at the top of the overlay, which is the XRPD pattern of pure Form I crystals).

[0049] Form II can be characterized based on a pattern XRPD comprising one or more, or all, of the following peaks, in terms of 2-theta (2θ): 16.8°, 18.2°, 18.5°, 21.0° and 25.1° ± 0.2°. For example, Form II can be characterized based on an XRPD pattern comprising one or more, or all, of the following peaks (2θ) at 15.8°, 16.8°, 18.2°, 18.5°, 18.8°, 19.3°, 20.1°, 21.1° and 25.1° ± 0.2°. Form II can be characterized based on an XRPD pattern comprising one or more, or all, of the following peaks, in terms of 2-theta (2θ): 16.8°, 18.2°, 18.5°, 21.0°, and 25.1° ± 0.1°. For example, Form II can be characterized based on an XRPD pattern comprising one or more, or all, of the following peaks (2θ) at 15.8°, 16.8°, Petition 870250088085, dated 09 / 29 / 2025, pp. 114 / 137 18 / 35 18.2°, 18.5°, 18.8°, 19.3°, 20.1°, 21.1° and 25.1° ± 0.1°. Form II can be characterized based on an XRPD pattern comprising one or more, or all, of the following peaks, in terms of 2-theta (2θ): 16.8°, 18.2°, 18.5°, 21.0° and 25.1° ± 0.05°. For example, Form II can be characterized based on an XRPD pattern comprising one or more, or all, of the following peaks (2θ) at 15.8°, 16.8°, 18.2°, 18.5°, 18.8°, 19.3°, 20.1°, 21.1°, and 25.1° ± 0.05°. Form II can be characterized based on an XRPD pattern comprising one or more, or all, of the following peaks, in terms of 2-theta (2θ): 16.8°, 18.2°, 18.5°, 21.0°, and 25.1° ± 0.02°. For example, Form II can be characterized based on an XRPD pattern comprising one or more, or all, of the following peaks (2θ) at 15.8°, 16.8°, 18.2°, 18.5°, 18.8°, 19.3°, 20.1°, 21.1°, and 25.1° ± 0.02°.Form II can be characterized based on an XRPD pattern comprising one or more, or all, of the following peaks in terms of 2-theta (2θ): 16.8°, 18.2°, 18.5°, 21.0°, and 25.1°. For example, Form II can be characterized based on an XRPD pattern comprising one or more, or all, of the following peaks (2θ) at 15.8°, 16.8°, 18.2°, 18.5°, 18.8°, 19.3°, 20.1°, 21.1°, and 25.1°. Form II can be characterized by having an XRPD pattern substantially as shown in pattern A of Figure 1.

[0050] Form II can also be characterized, or differentiated from Form I, by the absence of peaks (2θ) in an XRPD pattern at one, more, or all of the 11.2°, 19.9°, 20.7° and 34.1° (± 0.2°). For example, Form II can be characterized, or differentiated from Form I, by the absence of peaks (2θ) in an XRPD pattern at one, or more, or all of the 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°).

[0051] The XRPD used to characterize Form II and / or differentiate Form I from Form II may be any suitable XRPD technique. For example, an XRPD pattern or peak disclosed here may be obtained using Petition 870250088085, dated 09 / 29 / 2025, pp. 115 / 137 19 / 35 Cu Kα radiation. For example, an XPRD technique disclosed here can be used (see, for example, Materials and Methods).

[0052] Form II can also be characterized using DSC and / or distinguished from Form I using DSC, as illustrated in Example 2 and Figures 2 and 3.

[0053] For example, Form II can be characterized by having an endothermic peak with an onset between about 90 °C and about 97 °C, as obtained by DSC. The endothermic peak of Form II can have an onset between about 91 °C and about 96 °C, for example, between about 92 °C and about 95 °C, or between about 93 °C and about 94 °C. For example, Form II can be characterized by having an endothermic peak with an onset between 90 °C and 97 °C, as obtained by DSC. The endothermic peak of Form II can have an onset between 91 °C and 96 °C, for example, between 92 °C and 95 °C, or between 93 °C and 94 °C.

[0054] In contrast, Form I can be characterized by having an endothermic peak with onset between about 115 °C and about 119 °C, as obtained by DSC, for example, between about 116 °C and about 118 °C, for example, about 117 °C. Form I can be characterized by having an endothermic peak with onset between 115 °C and 119 °C, as obtained by DSC, for example, between 116 °C and 118 °C, for example, 117 °C.

[0055] Thus, Form II can be characterized by having an endothermic peak with an onset lower than the onset of an endothermic peak attributed to Form I, as obtained by DSC. For example, Form II may have an endothermic peak with an onset between about 20 °C and about 30 °C lower than the onset of an endothermic peak associated with Form I, for example, between about 22 °C and about 18 °C lower, for example, about 23 °C lower, about 24 °C lower or about 25 °C lower.

[0056] Alternatively, Form II can be characterized by having an endothermic peak at a temperature between about 92 °C and about 94 °C, Petition 870250088085, dated 09 / 29 / 2025, pp. 116 / 137 20 / 35 as determined by DSC, for example, about 92 °C, about 93 °C, or about 94 °C. Alternatively, Form II can be characterized by having an endothermic peak at a temperature between about 95 °C and about 98 °C, as determined by DSC, for example, about 95 °C, about 96 °C, or about 97 °C. For example, Form II can be characterized by having an endothermic peak at a temperature between 92 °C and 94 °C, as determined by DSC, for example, 92 °C, 93 °C, or 94 °C. Alternatively, Form II can be characterized by having an endothermic peak at a temperature between 95 °C and 98 °C, as determined by DSC, for example, 95 °C, 96 °C, or 97 °C.

[0057] In contrast, Form I can be characterized by having an endothermic peak at a temperature between about 116 °C and about 120 °C, as determined by DSC, for example, about 117 °C, about 118 °C or about 119 °C. For example, Form I can be characterized by having an endothermic peak at a temperature between 116 °C and 120 °C, as determined by DSC, for example, 117 °C, 118 °C or 119 °C.

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

[0059] In contrast, Form I can 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 higher melting point. Petition 870250088085, dated 09 / 29 / 2025, pp. 117 / 137 21 / 35 approximately 20 °C to approximately 30 °C lower than the melting point of Form I, for example, between approximately 22 °C and approximately 18 °C lower, for example, approximately 23 °C lower, approximately 24 °C lower or approximately 25 °C lower.

[0060] In addition to being used to identify an endothermic peak and / or melting point of a polymorph, DSC can also be used to obtain Form II (e.g., from a sample of pitolisant hydrochloride, for example, of Form I). For example, DSC can be used to convert pitolisant hydrochloride, which is substantially Form I, into pitolisant hydrochloride, which is substantially Form II.

[0061] The DSC protocol used to determine an endothermic peak, a melting point, or to obtain Form II, as disclosed herein, may be any suitable DSC protocol, such as a DSC protocol disclosed herein, for example, Protocol 1 or Protocol 2 described in Example 2. For example, the DSC may be performed using a sample of a few milligrams of pitolisant hydrochloride, for example, between about 1 mg and about 10 mg, for example, between about 1 and about 5 mg, for example, about 2 mg, about 3 mg, about 4 mg, or about 5 mg. For example, the DSC may be performed using between 1 mg and 10 mg of pitolisant hydrochloride, for example, between 1 and 5 mg, for example, 2 mg, 3 mg, 4 mg, or 5 mg. The DSC may be performed under nitrogen. DSC can be performed at a heating rate of about 10 °C / min. DSC can be performed within a temperature range between about 0 °C and about 150 °C, for example, between about 73 °C and about 150 °C.

[0062] For example, the DSC used to determine an endothermic peak or melting point disclosed herein, or to obtain Form II, may be performed with one or more, or all, 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) Petition 870250088085, dated 09 / 29 / 2025, pp. 118 / 137 22 / 35 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, the DSC used to determine an endothermic peak or melting point disclosed herein, or to obtain Form II, may be performed with 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) maintain at 73 °C for 4 minutes; and (ix) heat from 73 °C to 150 °C at a rate of 10 °C / min.

[0064] Alternatively, the DSC used to determine an endothermic peak or melting point disclosed herein, or to obtain Form II, may be performed with one or more, or all, 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 approx. 10°C / min.

[0065] For example, the DSC used to determine a peak Petition 870250088085, dated 09 / 29 / 2025, pp. 119 / 137 23 / 35 endothermic or melting point disclosed herein, or to obtain Form II, can be carried out with 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] Form II can be characterized by having a thermogram (DSC) substantially as shown in Figure 2. For example, Form II can be characterized by having a DSC thermogram substantially as shown in trace (7) of Figure 2, and / or by having an endothermic peak substantially as shown by peak (II) in Figure 2.

[0067] Alternatively, Form II can be characterized by having a (DSC) thermogram substantially as shown in Figure 3. For example, Form II can be characterized by having a DSC thermogram substantially as shown in trace (5) of Figure 3, and / or by having a substantially endothermic peak as shown by peak (II) of Figure 3. Dosage Forms and Pharmaceutical Compositions

[0068] Dosage forms and pharmaceutical compositions comprising Form II and, optionally, one or more pharmaceutically acceptable excipients are disclosed here.

[0069] The dosage form or pharmaceutical composition may comprise a therapeutically effective amount of Form II. For example, the dosage form or pharmaceutical composition may comprise between about 1 mg and about 200 mg of Form II, for example, between about 1 mg and about 100 mg, between about 1 mg and about 50 mg, between about 10 mg and about 25 mg, or between about 1 mg and about 10 mg of Form II, 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, Petition 870250088085, dated 09 / 29 / 2025, pp. 120 / 137 24 / 35 approximately 25 mg, approximately 30 mg, approximately 40 mg, or approximately 50 mg of Form II.

[0070] It is understood that, as Form II comprises a pharmaceutically acceptable salt of pitolisant, 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 comprising 5 mg of pitolisant hydrochloride (as Form II) will comprise about 4.45 mg of pitolisant (free base). In another example, a dosage form or pharmaceutical composition disclosed herein comprising 20 mg of pitolisant hydrochloride comprises about 17.8 mg of pitolisant (free base). In some embodiments, a dosage form or pharmaceutical composition disclosed herein comprises about 5 mg of pitolisant monohydrochloride, or about 4.45 mg of pitolisant (free base).In some embodiments, a dosage form or pharmaceutical composition disclosed herein comprises approximately 20 mg of pitolisant monohydrochloride, or approximately 17.8 mg of pitolisant (free base).

[0071] The dosage forms of the present invention may be tablets, caplets, capsules, suspensions, granules, powders or the like.

[0072] The dosage forms or pharmaceutical compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients, such as diluents, dispersing agents, granulating agents, surfactants, emulsifiers, disintegrating agents (sometimes referred to herein as disintegrants), binding agents (sometimes referred to herein as binders), preservatives, buffering agents, lubricating agents (sometimes referred to herein as lubricants), glidants, adjuvants, fillers, wetting agents, suspending agents, solvents, dispersing media, ion exchangers, salts, Petition 870250088085, dated 09 / 29 / 2025, pp. 121 / 137 25 / 35 electrolytes, waxes and / or oils, and the like. The pharmaceutical composition or dosage form may comprise a pharmaceutically acceptable excipient disclosed herein or a combination of pharmaceutically acceptable excipients disclosed herein. For example, a dosage form or pharmaceutical composition of the present invention may comprise 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 the dosage form or pharmaceutical composition in any suitable amount. For example, a pharmaceutically acceptable excipient may be present in the dosage form or pharmaceutical composition in an amount between about 0.01% and about 95% by weight of the dosage form or pharmaceutical composition, for example, between about 0.1% and about 25%, between about 1% and about 10%, between about 15% and about 95%, between about 0.01% and about 2% by weight of the dosage form or pharmaceutical composition.

[0074] The dosage forms and pharmaceutical compositions of the present invention can be administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, vaginally, or by implantation.

[0075] The preparation of the dosage forms or pharmaceutical composition of the present invention may include conventional methods such as mixing, loading, compression (e.g., direct compression, compression of dry, wet or sintered granules), coating (e.g., coating in a spraying process), extrusion, granulation (e.g., wet or dry granulation), pelleting (e.g., direct pelleting), bonding, application of powder layers (e.g., in active ingredient-free spheres or neutral cores or particles of pharmaceutically active agent) and rounding. Petition 870250088085, dated 09 / 29 / 2025, pp. 122 / 137 26 / 35 Treatment Methods

[0076] The present invention further relates to a method for treating a disease or disorder, comprising administering Form II, or a dosage form or pharmaceutical composition disclosed herein, to a subject in need thereof. The disease or disorder may be a sleep disorder (e.g., excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, daytime sleepiness), central nervous system disorder (e.g., epilepsy, Alzheimer's disease, Parkinson's disease, dementia (e.g., dementia with Lewy bodies and / or vascular dementia), attention disorders, wakefulness disorders, memory disorders, cognitive deficits (e.g., in the elderly), psychiatric pathologies, depressive and asthenic states, vertigo and motion sickness), obesity, psychosomatic disorders, respiratory disorders, allergic conditions, inflammatory conditions,Cardiac conditions, gastrointestinal conditions, urogenital system conditions, skin system conditions, stress, migraine, headache, pain, psychotropic disorders, asthma, bronchitis, rhinitis, tracheitis, gastric ulcers, duodenal ulcers, ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), cystitis, metritis, urinary incontinence, fecal incontinence, urticaria, itching, arthritis, conjunctivitis, premenstrual syndrome, prostatic inflammation, genital disorders, rheumatic conditions, eye conditions, sialorrhea, seizures, depression, hypothalamic-pituitary system disorders, cerebral circulation disorders, and immune system disorders.

[0077] In preferred aspects, the disease or disorder is a sleep disorder. For example, the disease or disorder may be excessive daytime sleepiness (EDS). EDS can occur in individuals (e.g., adults) with narcolepsy. Petition 870250088085, dated 09 / 29 / 2025, pp. 123 / 137 27 / 35

[0078] The present invention further relates to a method for preventing undesirable side effects associated with the use of antipsychotic or antidepressant agents (for example, aripiprazole, clozapine, olanzapine, risperidone, quetiapine, sertindole, mirtazapine, amitriptyline and paroxetine), comprising administering Form II, or a dosage form or pharmaceutical composition of the present invention, to an individual in need thereof. Non-limiting examples of undesirable side effects associated with the use of antipsychotic or antidepressant agents include weight gain, drowsiness 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 Form II, or a dosage form or pharmaceutical composition disclosed herein, to a subject in need thereof.

[0080] Form II, or a dosage form or pharmaceutical composition disclosed herein, may be administered once daily, twice daily, or more frequently. More than one dosage form may be administered simultaneously to achieve the desired dose. Form II, or a dosage form or pharmaceutical composition disclosed herein, may be taken frequently and in such quantity that the total amount of pitolisant (in terms of free base) administered is within the range of about 10 mg to about 50 mg per day, for example, about 15 mg to about 40 mg per day. Form II, or a dosage form or pharmaceutical composition disclosed herein, may be taken frequently and in such quantity that the total amount of pitolisant (in terms of free base) administered is within the range of about 17.8 mg to about 35.6 mg per day.For example, a subject may orally receive two dosage forms once daily, where each dosage form comprises 4.45 mg of pitolisant (in terms of...). Petition 870250088085, dated 09 / 29 / 2025, pp. 124 / 137 A subject may receive one dosage form orally once daily, where the dosage form comprises 17.8 mg of pitolisant (in terms of free base), to achieve a daily dose of 8.9 mg of pitolisant (in terms of free base). A subject may receive orally one dosage form once daily, where the dosage form comprises 17.8 mg of pitolisant (in terms of free base), to achieve a daily dose of 17.8 mg of pitolisant (in terms of free base). A subject may receive orally two dosage forms once daily, where each dosage form comprises 17.8 mg of pitolisant (in terms of free base), to achieve a daily dose of 35.6 mg of pitolisant (free base). Examples Materials and methods

[0081] General Method for Differential Scanning Calorimetry (DSC): A few milligrams of sample were introduced into a 25 μL aluminum crucible, covered with a perforated lid. DSC analyses were performed under a nitrogen flow (20 mL / min), with temperature scans of 10 °C / min, adjusted according to experimental needs.

[0082] General Method for X-ray Powder Diffraction (XRPD): XRPD analyses were performed in transmission mode unless otherwise indicated. A few milligrams of the sample were wrapped in Kapton® foil (which exhibits a peak at (2θ) 5.5°). Analyses were performed from (2θ) 2° to 50°. Table 1. Characteristics of XRPD analysis. Sampling mode: Transmission Measurement Scan axis: Gonio Scan range (°): 3.0040 - 29.999 or 1.9960 - 50.0003 Step size (°): 0.0263 Measurement type: Repeated scan (20 times) Sample offsets: Omega (°): 0.000 Example of movement: Movement type: Rotating Rotation time(s): 2.0 Wavelength used Intended wavelength type: Καi Κα1 (A): 1.540598 Κα2 (A): 1.544426 Intensity ratio Κα2 / Κα1: 0.50 Κα (A): 1.541874 Κβ (A): 1.392250 Petition 870250088085, dated 09 / 29 / 2025, pp. 125 / 137 29 / 35 Incident beam path: Radius (mm): 240.0 X-ray tube Name: PW3373 / 10 Cu LFF DK174558 Anode material: Cu Voltage (kV): 40 Current (mA): 40 Focus type: Line (length (mm): 12.0 width (mm): 0.4 Takeoff angle (°): 4.4) X-ray mirror Name: Inc. Beam Cu W / Si (MPD parabolic) Crystal (W / Si Graded Parabolic) Acceptance angle (°): 0.8 Length (mm): 55.3 Slits Soller slit: Soller 0.04 rad. Aperture (rad.): 0.04 Anti-scatter slit: AS 1.4 mm slit (mirror) Type: Fixed Height (mm): 1.40 Divergence slit: 1 / 8° fixed slit Distance to sample (mm): 140 Type: Fixed Height (mm): 0.19 Angle (°): 0.1089 Diffraction beam path: Radius (mm): 240.0 Soller slit Large Soller 0.04 rad. Aperture (rad.): 0.04 Detector Name: PIXcel Type: RTMS detector PHD - Lower level (%): 25.5 PHD - Upper level (%): 70.0 Mode: Scanning Active length (°): 3.347 Instrument / Software Instrument ID: 0000000011026833 Application Software: X'Pert Data Collector vs. 2.2j Instrument Control SW: XPERT-PRO vs. 2.1D. Example 1. Synthesis of Pitolisant Monohydrochloride Crystals

[0083] Pitolisant monohydrochloride can be prepared according to methods described in U.S. Patent No. 8,207,197, for example, following the protocol provided below.

[0084] 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 in dry toluene (4.5 kg) were refluxed for 4 hours. The solvent was evaporated and the residue purified by silica gel column chromatography (eluent: methylene chloride / methanol, 9:1). The oil obtained was distilled in a fractionating apparatus under reduced pressure (0.3-0.7 mmHg) and with a heating jacket at 207-210 °C. The head fraction and the distillate fraction were collected at 0.001-0.010 mmHg with a jacket temperature of 180-200 °C, to provide pitolisant-free base (1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine) as an oil (1.0 kg; 3.38 mol). Petition 870250088085, dated 09 / 29 / 2025, pp. 126 / 137 30 / 35

[0085] 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 vessel fitted with a cooling bath and a gas inlet. A stream of gaseous hydrogen chloride was bubbled into the reaction mixture at 20–25 °C. The pH of the solution was checked by collecting a 0.5 mL sample of the reaction mixture and diluting it with 5 mL of deionized water to obtain a pH of approximately 3–4.

[0086] The mixture was cooled to a temperature between -10 °C and -12 °C and stirred for 1 h. The precipitate was filtered through 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 period of 12 hours to provide crude pitolisant monohydrochloride (1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine monohydrochloride) (1.10 kg).

[0087] A mixture of crude pitolisant monohydrochloride, anhydrous ethyl acetate (3.98 kg) and isopropanol (0.35 kg) was slowly heated to 55-60 °C in a 10 L glass container equipped with a heating and cooling system, and the resulting solution was filtered through a sintered glass filter with thermal insulation, maintaining the temperature between 55-60 °C. The solution was transferred to a 10 L glass container and the mass was slowly cooled to 0-5 °C for about 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 period of 12 hours to provide pure pitolisant monohydrochloride (1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine monohydrochloride) (Mf 117-119 °C; yield 80%; IR spectrum (KBr): bands at 1112 and 1101 (C—O Ether / St. asymmetric), 2936 and 2868 (Alkane CH(CH2)) / St.), 1455 (Alkane CH(CH2)) / Deform.), 2647 and 2551 (Amine salt / St.), 1492 (Amine / St.), 802. Petition 870250088085, dated 09 / 29 / 2025, pp. 127 / 137 31 / 35 (Aromatic / Deformed) cm-1.

[0088] A solution of pure pitolisant monohydrochloride in acetone can be evaporated and dried at 70 °C for 17 hours to provide Form I crystals for use in DSC analyses. Example 2. Preparation and analysis of the polymorphic form II of pitolisant hydrochloride.

[0089] The Form II polymorph of pitolisant hydrochloride was provided by heating pitolisant hydrochloride samples in a Differential Scanning Calorimetry (DSC) apparatus, according to the following protocols. Protocol 1

[0090] With reference to Figure 2, a sample of Form I crystals from Example 1 was placed in a DSC apparatus, and the sample was heated from 20 °C to 150 °C at a rate of 10 °C / min, revealing an endothermic peak with an onset at 116.3 °C and a peak at 118.0 °C corresponding to the melting of the crystalline sample (trace (1), peak (a1)). The molten sample was then cooled from 150 °C to 0 °C at a rate of 10 °C / min, revealing a double exothermic phenomenon with an onset at 72.0 °C and 70.7 °C (trace (2), peaks (b) and (c)), which can be attributed to the recrystallization of Form I.

[0091] The sample was then heated from 0 °C to 140 °C at a rate of 10 °C / min, causing an endothermic peak corresponding to the melting of the known phase at 117.2 °C (trace (3), peak (a3)). A melt quench was then performed by cooling the sample from 140 °C to 0 °C at a rate of 200 °C / min, resulting in a broad exothermic signal that can be attributed to the crystallization of the initial phase (see signal (d) of trace (4) in Figure 2). The sample was held for 2 minutes at 0 °C. The sample was then heated again, from 0 °C to 140 °C at a rate of 10 °C / min (2), resulting in the expected peak at approximately 118 °C corresponding to the melting of the known crystalline phase (see trace (5) peak). Petition 870250088085, dated 09 / 29 / 2025, pp. 128 / 137 32 / 35 (a5) in Figure 2).

[0092] Next, the sample was cooled from 140 °C to 73 °C at a rate of 10 °C / min (trace (6)), which is slightly above the temperature of the previously observed double endothermic peaks (peaks (b) and (c)), and the sample was held at this temperature for 4 minutes. With reference to Figure 2 (cont.), the sample was heated from 73 °C to 150 °C at a rate of 10 °C / min, resulting in an endothermic peak with an onset of 93.1 °C and a peak of 94.4 °C (trace (7), peak (II)). This corresponds to the fusion of a distinct polymorph of Form I (e.g., compare peak (II) with peaks (a1), (a3), (a5), (a9)) and is therefore assigned to a new polymorphic form of pitolisant hydrochloride, here referred to as Form II.

[0093] The sample containing Form (II) was subsequently cooled from 150 °C to 15 °C, resulting in a double endothermic peak (trace (8), peaks (f) and (g)). These peaks can be attributed to the crystallization of Form II, immediately followed by the crystallization of Form I or by a polymorphic transformation. Finally, the last step involved heating the sample from 15 °C to 145 °C at a rate of 10 °C / min, revealing an endothermic peak caused by the melting of Form (I), as evidenced by the expected onset at approximately 117 °C (trace (9) peak (a9)). Protocol 2

[0094] With reference to Figure 3, pitolisant hydrochloride was placed in a DSC apparatus, and the sample was heated from 20 °C to 130 °C at 10 °C / min, resulting in an endothermic peak with a long shoulder at 111.9 °C, with an additional signal at 106.6 °C (trace (1), peak p(1) and p(1')). Upon cooling the sample from 130 °C back to 20 °C at a rate of 10 °C / min, an exothermic event was observed, attributed to sample crystallization (trace (2) peak (b2)). The sample was heated again, from 20 °C to 130 °C at 10 °C / min, resulting in three endothermic events: a small signal around 106 Petition 870250088085, dated 09 / 29 / 2025, pp. 129 / 137 33 / 35 °C, a large peak with a shift at 109.5 °C and a sharp peak at 117.8 °C, which corresponds to the melting of Form I (trace (3), peaks (p3'), (p3) and (a3)). The sample was then cooled from 130 °C to 72 °C at a rate of 10 °C / min and held at 72 °C for 1 hour (trace (4)). The sample was then heated from 72 °C to 130 °C at a rate of 10 °C / min, resulting in an endothermic peak at 93.7 °C, which can be attributed to the melting of Form II (trace (5) peak (II)). This melting point is consistent with the melting point observed for Form II during Protocol 1 (e.g., compare peak (II) in Figure 2 with peak (II) in Figure 3).

[0095] With reference to Figure 3 (cont.), the sample was then cooled from 130 °C to 50 °C at a rate of 10 °C / min, resulting in an exothermic event around 70 °C (trace (6) peak (b6)), and was heated from 50 °C again to 130 °C causing an endothermic peak at 117.5 °C, corresponding to the melting of Form (I) (trace (7) peak (a7)). The sample was then cooled to 72 °C and held for 1 hour (trace (8), heated again to 82 °C (trace (9)) and finally cooled to 20 °C (trace (10)). No thermal event was observed during these last steps (represented by traces (8)-(10)). The sample was immediately removed from the aluminum pan and analyzed by XRPD, described in Example 3. Summary

[0096] Protocols 1 and 2 prove that Form II was obtained as follows: - In a DSC apparatus, a molten sample of pitolisant hydrochloride was cooled from 140 °C to 73 °C at a rate of 10 °C / min (trace (6) in Figure 2), which is slightly above the temperature of the previously observed double endothermic peaks (peaks (b) and (c)), and the sample was held at this temperature for 4 minutes. With reference to Figure 2 (cont.), the sample was heated from 73 °C to 150 °C at a rate of 10 °C / min, resulting Petition 870250088085, dated 09 / 29 / 2025, pp. 130 / 137 34 / 35 in an endothermic peak with an onset of 93.1 °C and a peak of 94.4 °C (trace (7), peak (II)). This corresponds to the fusion of a distinct polymorph of Form I (e.g., compare peak (II) with peaks (a1), (a3), (a5), (a9)) and is therefore assigned to a new polymorphic form of pitolisant hydrochloride, here referred to as Form II; Or alternatively, - In a DSC apparatus, a molten sample of pitolisant hydrochloride was cooled from 130 °C to 72 °C and held for 1 hour (trace 8), reheated to 82 °C (trace (9)) and finally cooled to 20 °C (trace 10). No thermal event was observed during these last steps (represented by traces (8) to (10)). The sample was immediately removed from the aluminum pan and analyzed by XRPD, described in Example 3.

[0097] Protocols 1 and 2 resulted in the formation of a second polymorphic form of pitolisant hydrochloride (Form II), with a melting point of approximately 93 °C, as determined by DSC. The melting point of Form II is lower than the known polymorph of pitolisant hydrochloride (i.e., Form I), which has a melting point of approximately 117 °C. Example 3. X-ray Powder Diffraction Study (XRPD)

[0098] After 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 methods described above. The diffraction pattern of this sample was obtained and is shown in Figure 1 (see diffractogram A). The sample was then stored for 10 months at room temperature, wrapped in polymer sheets, and then analyzed again by XRPD, yielding diffractogram B, superimposed on Figure 1. From these studies, the characteristic peaks of the crystalline Form II were identified, indicated by dashed lines in Figure 1 and also listed below in Table 2. Petition 870250088085, dated 09 / 29 / 2025, pp. 131 / 137 35 / 35 Table 2. Positions of the diffraction signals corresponding to Form II. Position 2θ (°) Intensity (counts) Relative Intensity (%) 15.81 169 9.2 16.79 1133 61.5 18.24 1226 66.6 18.49 960 52.2 18.82 129 7.0 19.30 248 13.5 20.07 343 18.6 21.08 1841 100.0 25.11 1287 69.9 Equivalents

[0099] Those skilled in the art will recognize or be able to determine, through routine experimentation, many equivalents to the specific embodiments disclosed herein. Those skilled in the art will understand that various alterations or modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims. Petition 870250088085, dated 09 / 29 / 2025, pp. 132 / 137

Claims

1 / 4 Claims 1. CRYSTALLINE FORM OF A COMPOUND, characterized by being represented by Formula (I): wherein it has an X-ray diffraction pattern comprising at least one of the following peaks, in terms of 2-theta (2θ), at 16.8°, 18.2°, 18.5°, 21.0° and 25.1° (± 0.2°).

2. A SHAPE, according to claim 1, characterized by having an X-ray diffraction pattern comprising at least one of the 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°).

3. A SHAPE, according to any one of claims 1 to 2, characterized in having an X-ray diffraction pattern substantially as shown in pattern A of Figure 1.

4. A SHAPE, according to any one of claims 1 to 3, further characterized by having an endothermic peak beginning between about 90 °C and about 97 °C, preferably between about 91 °C and about 96 °C, for example, between about 92 °C and about 95 °C, or between about 93 °C and about 94 °C; more preferably between about 92 °C and about 94 °C (for example, about 92 °C, about 93 °C or about 94 °C), or between about 95 °C and about 98 °C (for example, about 95 °C, about 96 °C or about 97 °C) as obtained by Differential Scanning Calorimetry (DSC).

5. FORM, according to claim 4, characterized in that DSC is performed by: (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; Petition 870250088085, dated 29 / 09 / 2025, p. 133 / 137 2 / 4 (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; preferably, (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; (vi) heating from 72 °C to 130 °C at 10 °C / min.

6. CRYSTALLINE FORM OF A COMPOUND, characterized by being represented by Formula (I): •HCl (I), in which it has a melting point between about 90 °C and about 95 °C, preferably between about 91 °C and about 94 °C, for example, between about 92 °C and about 94 °C, more preferably about 93 °C.

7. CRYSTALLINE FORM OF A COMPOUND, characterized by being represented by Formula (I): •HCl (I), in which it has an endothermic peak beginning between about 90 °C and about 97 °C, as obtained by Differential Scanning Calorimetry (DSC), for example, an beginning between about 91 °C and about 96 °C, for example, an beginning between about 92 °C and about 95 °C, or between about 93 °C and about 94 °C.

8. SHAPE, according to claim 7, characterized by having a DSC thermogram substantially as shown in Figure 2, preferably substantially as shown in trace (7) of Figure 2.

9. SHAPE, according to claim 7, characterized by having a substantially endothermic peak as shown by peak (II) of Figure 2.

10. SHAPE, according to claim 7, characterized by having a DSC thermogram substantially as shown in Figure 3, preferably substantially as shown in trace (5) of Figure 3.

11. SHAPE, according to claim 10, characterized by having a substantially endothermic peak as shown by peak (II) of Figure 3.

12. A FORM, according to any one of claims 1 to 11, characterized in that it does not comprise the combination of (2θ) peaks at 11.2°, 19.9°, 20.7° and 34.1° (± 0.2°), preferably not comprising the combination of (2θ) peaks 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°).

13. POLYMORPHOUS FORM II, characterized by being pitolisant hydrochloride.

14. PHARMACEUTICAL COMPOSITION, characterized by comprising the crystalline form, as defined in any one of claims 1 to 12, or polymorph, as defined in claim 13, and optionally a pharmaceutically acceptable excipient, preferably selected from the group consisting of colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. Petition 870250088085, dated 09 / 29 / 2025, pp. 135 / 137 4 / 4 15. DOSAGE FORM, characterized by comprising a crystalline form, as defined in any one of claims 1 to 12, a polymorph, as defined in claim 13, or a pharmaceutical composition, as defined in claim 14.

16. FORM, according to claim 15, characterized in being a tablet, caplet or capsule.

17. USE of a crystalline form, as defined in any one of claims 1 to 12, polymorph, as defined in claim 13, pharmaceutical composition, as defined in claim 14, or dosage form, as defined in any one of claims 15 to 16, characterized in that it is in the manufacture of a medicament for the treatment of a sleep disease or disorder.

18. USE, according to claim 17, characterized by the disease or disorder being in a subject with narcolepsy (e.g., an adult subject with narcolepsy).

19. USE, according to any of claims 17 to 18, characterized by the disease or sleep disorder being excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, or daytime sleepiness. Petition 870250088085, dated 09 / 29 / 2025, pp. 136 / 137

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