Solid forms of zavegepant hydrochloride and methods for preparing same

Abstract

The present disclosure encompasses solid forms of zavegepant hydrochloride, in embodiments crystalline polymorphs of zavegepant hydrochloride, methods for their preparation, and pharmaceutical compositions thereof.

Description

[Technical Field]

[0001] The present disclosure encompasses solid forms of zavegepant hydrochloride, in embodiments crystalline polymorphs of zavegepant hydrochloride, methods for their preparation, and pharmaceutical compositions thereof. [Background technology]

[0002] Zavegepant ((R)N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide) has the following chemical structure: [ka]

[0003] Zavegepant is a third-generation, high-affinity, highly selective, and structurally unique small molecule CGRP receptor antagonist being developed for the acute treatment of migraine or COVID-19 respiratory infection.

[0004] This compound is described in WO 2011 / 123232 and Org. Process Res. Dev. 2012, 16, 1953-1966.

[0005] WO 2022 / 217008 describes crystalline forms of zavegepant. IPCOM000271435D describes crystalline forms of zavegepant HCl.

[0006] Polymorphism, the existence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule can exhibit different crystalline structures and physical properties, such as melting points, thermal behavior (e.g., as measured by thermogravimetric analysis (TGA) or differential scanning calorimetry (DSC)), X-ray diffraction (XRD) patterns, infrared absorption fingerprints, and solid state ( 13C) NMR spectra). One or more of these techniques can be used to distinguish between different polymorphic forms of a compound.

[0007] Different salts and solid forms (including solvated forms) of an active pharmaceutical ingredient can have different properties. Such changes in the properties of different salts, solid forms, and solvates can provide a basis for improving formulations, for example, by improving processing and handling characteristics, favorably altering dissolution profiles, and improving stability (polymorphic and chemical stability) and shelf life. These changes in the properties of different salts and solid forms can also contribute to improving the final dosage form, for example, by helping to improve bioavailability. Different salts and solid forms and solvates of an active pharmaceutical ingredient can also give rise to various polymorphs and crystalline forms, which can provide additional opportunities for evaluating changes in the properties and characteristics of the solid active pharmaceutical ingredient.

[0008] The discovery of new salts, solid forms, and solvates of pharmaceuticals may result in materials with desirable processing properties, such as ease of handling, ease of processing, storage stability, ease of purification, or as desirable intermediate crystalline forms that facilitate conversion to other polymorphs. New solid forms of pharmaceutically useful compounds may also provide opportunities to improve the performance characteristics of pharmaceuticals. This expands the repertoire of materials available to formulation scientists for formulation optimization by providing products with different properties, such as a different crystal habit, greater crystallinity, or polymorphic stability, which may provide superior processing or handling properties, an improved dissolution profile, or improved shelf life (chemical / physical stability). For at least these reasons, additional salts and solid forms of zavegepant (including solvated forms) are needed. Summary of the Invention [Means for solving the problem]

[0009] The present disclosure provides crystalline polymorphs of zavegepant hydrochloride, methods for preparing same, and pharmaceutical compositions thereof, which can be used to prepare other solid forms of zavegepant hydrochloride, other zavegepant salts, and solid forms thereof.

[0010] The present disclosure also provides the use of said solid forms of zavegepant hydrochloride in the preparation of other solid forms of zavegepant hydrochloride or other salts and solid forms thereof.

[0011] The present disclosure provides crystalline polymorphs of zavegepant hydrochloride for use in medicines, such as for the acute treatment of migraine, for the prophylaxis of migraine, or for COVID-19 respiratory infection.

[0012] The present disclosure also encompasses the use of the crystalline polymorphs of zavegepant hydrochloride of the present disclosure for preparing pharmaceutical compositions and / or formulations, particularly pharmaceutical compositions or formulations for oral or nasal administration, particularly nasal administration. More specifically, the present disclosure encompasses the use of the crystalline polymorphs of zavegepant hydrochloride of the present disclosure for preparing pharmaceutical compositions or formulations, particularly solid zavegepant hydrochloride, particularly pharmaceutical compositions or formulations comprising solid zavegepant hydrochloride. The pharmaceutical compositions or formulations may be in solid dosage forms (particularly for oral administration), particularly tablets, powders, capsules, suppositories, sachets, troches, and lozenges, or in liquid forms (particularly for intravenous or nasal administration, more particularly nasal administration), particularly solutions, suspensions, and elixirs. Most preferably, the pharmaceutical compositions or pharmaceutical formulations are solutions or suspensions, particularly solutions or suspensions for nasal administration.

[0013] In another aspect, the present disclosure provides a pharmaceutical composition comprising a crystalline polymorph of zabegepant hydrochloride according to the present disclosure. The pharmaceutical composition may comprise, in particular, solid zabegepant hydrochloride, and may be a solid dosage form (particularly for oral administration), in particular tablets, powders, capsules, suppositories, sachets, troches, and lozenges, or may be a liquid form comprising solid zabegepant hydrochloride (particularly for intravenous or nasal administration, more particularly nasal administration), in particular solutions, suspensions, and elixirs. Most preferably, the pharmaceutical composition or pharmaceutical formulation is a suspension, in particular a suspension for nasal administration. The pharmaceutical composition according to any aspect of the present disclosure may comprise a nasal dosage form or an oral dosage form. In particular, the pharmaceutical composition may be a nasal dosage form. More particularly, the pharmaceutical composition is in the form of a solution or suspension, preferably a suspension, and is preferably for nasal administration.

[0014] The present disclosure includes methods for preparing the pharmaceutical compositions described above. These methods include combining any one or a combination of crystalline polymorphs of zavegepant hydrochloride with at least one pharmaceutically acceptable excipient. In particular, the pharmaceutical composition may include a pharmaceutically acceptable excipient suitable for preparing an oral or nasal dosage form, particularly a nasal dosage form. More specifically, the pharmaceutical composition or formulation comprises solid zavegepant hydrochloride. The pharmaceutical composition or formulation may be in a solid dosage form (particularly for oral administration), particularly tablets, powders, capsules, suppositories, sachets, troches, and lozenges, or in a liquid form (particularly for intravenous or nasal administration, more particularly nasal administration), particularly solutions, suspensions, and elixirs. Most preferably, the pharmaceutical composition or formulation is a suspension, particularly a suspension for nasal administration. More particularly, the pharmaceutical composition may comprise one or more pharmaceutically acceptable excipients suitable for preparing a solution or suspension, preferably a suspension, for nasal administration.

[0015] The crystalline polymorphs of zavegepant hydrochloride and pharmaceutical compositions or formulations of crystalline polymorphs of zavegepant hydrochloride defined herein can be used as medicines, such as for the acute treatment of migraine, for the prophylaxis of migraine, or for COVID-19 respiratory infection.

[0016] The present disclosure also provides methods for treating migraine, preventing migraine, or treating a COVID-19 respiratory infection by administering to a subject suffering from, or in need of treatment for, a therapeutically effective amount of any one or combination of crystalline polymorphs of zavegepant hydrochloride of the present disclosure, or at least one of the pharmaceutical compositions described above.

[0017] The present disclosure also provides a use of at least one of the crystalline polymorphs of zavegepant hydrochloride of the present disclosure or the pharmaceutical compositions described above for the manufacture of a medicament for treating, for example, migraine or COVID-19 respiratory infection or for preventing migraine. The medicament may be administered as a nasal or oral dosage form, but is particularly a nasal dosage form. More specifically, the medicament may be in the form of a solution or suspension, preferably a suspension, for nasal administration.

[0018] According to any aspect or embodiment of the present disclosure, a pharmaceutical composition or formulation for treating migraine or COVID-19 respiratory infection is preferably in a nasal dosage form (e.g., in the form of a liquid or suspension for nasal administration). According to any aspect or embodiment of the present disclosure, a pharmaceutical composition or formulation for preventing migraine is preferably in an oral dosage form. [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of zavegepant hydrochloride form C1. [Figure 2] FIG. 1 shows a characteristic XRPD pattern of zavegepant hydrochloride form C2. [Figure 3] 1 shows a characteristic DSC thermogram of zavegepant hydrochloride form C1. [Figure 4] 1 shows a characteristic DSC thermogram of zavegepant hydrochloride form C2. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present disclosure encompasses solid forms of zavegepant hydrochloride, including crystalline polymorphs of zavegepant hydrochloride, methods for preparing same, and pharmaceutical compositions thereof.

[0021] The solid state properties of zavegepant hydrochloride and its crystalline polymorphs can be influenced by controlling the conditions under which zavegepant and its crystalline polymorphs are obtained in solid form.

[0022] A solid form (or polymorph) may be referred to herein as being polymorphically pure or substantially free of other solid (or polymorphic) forms. In this context, the phrase "substantially free of other forms" as used herein is understood to mean that the solid form contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of other forms of the subject compound, as measured, for example, by XRPD. Thus, a crystalline polymorph of zavegepant hydrochloride described herein as being substantially free of other solid forms is understood to contain more than about 80% (w / w), more than about 90% (w / w), more than about 95% (w / w), more than about 98% (w / w), more than about 99% (w / w), or about 100% of the subject crystalline polymorph of zavegepant hydrochloride. In some embodiments of the present disclosure, the described crystalline polymorphs of zavegepant hydrochloride may contain about 1% to about 20% (w / w), about 5% to about 20% (w / w), or about 5% to about 10% (w / w) of one or more other crystalline polymorphs of the same zavegepant hydrochloride.

[0023] Depending on the other crystalline polymorphs to which it is compared, the crystalline polymorphs of zavegepant hydrochloride of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability (such as chemical stability, thermal and mechanical stability against polymorphic transformation, stability against dehydration, and / or storage stability), low content of residual solvents, low hygroscopicity, flowability, and advantageous processability and handling properties such as compressibility and bulk density.

[0024] A compound, as used herein, may refer to a chemically pure or purified compound, or a compound that is substantially free of other compounds. In this context, the phrase "substantially free of other compounds," as used herein, is understood to mean that a pure compound contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of other compounds, as measured, for example, by HPLC. Thus, pure or purified zavegepant or zavegepant hydrochloride described herein as being substantially free of any compounds is understood to contain more than about 80% (w / w), more than about 90% (w / w), more than about 95% (w / w), more than about 98% (w / w), more than about 99% (w / w), or about 100% of the subject zavegepant or zavegepant hydrochloride. In some embodiments of the present disclosure, the described pure or purified zavegepant or zavegepant hydrochloride may contain about 1% to about 20% (w / w), about 5% to about 20% (w / w), or about 5% to about 10% (w / w) of one or more other compounds.

[0025] In certain embodiments, the pure or purified zavegepant or zavegepant hydrochloride described above may refer to enantiomeric purity, i.e., pure or purified zavegepant or zavegepant hydrochloride refers to zavegepant or zavegepant hydrochloride that is substantially free of its enantiomers.

[0026] A solid form, such as a crystalline or amorphous form, may be referred to herein as being characterized by graphical data "as shown in" or "substantially as shown in" a figure. Such data include, for example, powder X-ray diffractograms and solid-state NMR spectra. As is well known in the art, graphical data potentially provides additional technical information (so-called "fingerprints") to further define each solid form, which cannot necessarily be described by reference to numerical values ​​or peak positions alone. In any event, those skilled in the art will understand that such graphical representations of data may be subject to minor variations, for example, in the relative intensities and peak positions of peaks, due to certain factors well known to those skilled in the art, such as, but not limited to, variations in instrument response and variations in sample concentration and purity. Nonetheless, those skilled in the art will be readily able to compare the graphical data in the figures herein with graphical data generated for an unknown crystalline form and determine whether the two sets of graphical data characterize the same crystalline form or two different crystalline forms. Thus, a crystalline form of zavegepant referred to herein as being characterized by graphical data "as shown" or "substantially as shown" in a drawing will be understood to include any crystalline form of zavegepant characterized by graphical data having such minor variations known to those skilled in the art compared to the drawing.

[0027] As used herein, unless otherwise specified, the term "anhydrous" with respect to a crystalline form of zavegepant hydrochloride refers to a crystalline form of zavegepant hydrochloride that does not contain a defined stoichiometric amount of water of crystallization (or other solvent) within the crystal. Furthermore, unless otherwise indicated, the "anhydrous" form typically contains no more than 1% (w / w) of either water or organic solvent, as determined, for example, by TGA.

[0028] As used herein, unless otherwise indicated, the term "solvate" refers to a crystalline form that includes a solvent in the crystalline structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in a stoichiometric or non-stoichiometric amount.

[0029] As used herein, the term "isolated" with respect to the crystalline polymorphs of zavegepant hydrochloride of the present disclosure corresponds to a crystalline polymorph of zavegepant hydrochloride that has been physically separated from the reaction mixture from which it was formed.

[0030] Unless otherwise stated herein, XRPD measurements are made using copper Kα radiation with a wavelength of 1.54187 Å. XRPD peaks reported herein are measured using Cu Kα radiation (λ=1.54187 Å) at a temperature typically of 25±3° C.

[0031] In this specification, unless otherwise specified, solid 13 C NMR data is 13 C CP / MAS NMR methods. In particular, unless otherwise stated herein, the data reported herein are 13 C CP / MAS NMR is preferably measured at 500 MHz at a temperature of 293 K±3° C. More specifically, unless otherwise stated herein, the C CP / MAS NMR spectra reported herein are 13 C CP / MAS NMR is preferably performed at a temperature of 293 K±3° C. and a magic angle spinning frequency ω r / 2π=11kHz, measured at 500MHz.

[0032] A product, e.g., a reaction mixture, may be characterized herein as being at or allowed to reach "room temperature" or "ambient temperature" (often abbreviated as "RT"). This means that the temperature of the product is close to or the same as the temperature of the space in which the product is located, e.g., a room or fume hood. Typically, room temperature is about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0033] The amount of solvent used in a chemical process, such as a reaction or crystallization, may be expressed herein as a numerical value of "volume" or "vol" or "V." For example, a substance may be referred to as being suspended in 10 volumes (or 10 vol or 10 V) of solvent. In this context, this expression is understood to mean milliliters of solvent per gram of suspended substance; thus, suspending 5 grams of substance in 10 volumes of solvent means that the solvent is used in an amount of 10 milliliters of solvent per gram of suspended substance, i.e., 50 mL of solvent in this example. In other contexts, the term "v / v" may be used to indicate the numerical value of the volume of solvent added to a liquid mixture based on the volume of the mixture. For example, adding solvent X (1.5 v / v) to 100 mL of a reaction mixture means that 150 mL of solvent X has been added.

[0034] As used herein, a process or step may be referred to as occurring "overnight." This refers to, for example, a time period during the night during which the process or step may not be actively observed. This time period may be from about 8 hours to about 20 hours, or from about 10 to 18 hours, and in some cases, about 16 hours.

[0035] As used herein, the term "reduced pressure" refers to a pressure lower than atmospheric pressure. For example, reduced pressure is from about 10 mbar to about 50 mbar.

[0036] In this specification, unless otherwise stated, the term "ambient conditions" refers to atmospheric pressure and a temperature of 22-24°C.

[0037] The present disclosure includes a crystalline polymorph of zabegepant hydrochloride designated Form C1. Crystalline Form C1 can be represented by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 7.1, 9.4, 15.6, 17.5, and 21.2 °2θ ± 0.2 °2θ, an XRPD pattern substantially as shown in Figure 1, and combinations thereof.

[0038] Crystalline form C1 can be further represented by an XRPD pattern having characteristic peaks at 7.1, 9.4, 15.6, 17.5, and 21.2 °2θ ± 0.2 °2θ, and any one, two, three, four, or five additional peaks at 10.6, 12.7, 14.7, 18.1, and 19.6 °2θ ± 0.2 °2θ.

[0039] Crystalline form C1 can be represented by an XRPD pattern having characteristic peaks at 7.1, 9.4, 10.6, 12.7, 14.7, 15.6, 17.5, 18.1, 19.6, and 21.2 degrees 2θ±0.2 degrees 2θ.

[0040] In any aspect or embodiment of the present disclosure, zavegepant hydrochloride crystalline form C1 can be characterized by an X-ray powder diffraction pattern as described in any embodiment described herein, wherein the X-ray powder diffraction pattern is absent from 3.2 to 5.0°2θ ± 0.2°2θ, or from 3.2 to 6.0°2θ ± 0.2°2θ, or from 3.2 to 6.3°2θ ± 0.2°2θ. Alternatively or additionally, according to any aspect or embodiment of the present disclosure, zavegepant hydrochloride crystalline form C1 can be characterized by an X-ray powder diffraction pattern as described in any embodiment described herein, wherein the X-ray powder diffraction pattern is absent from 7.6 to 8.2°2θ ± 0.2°2θ, or from 7.6 to 8.6°2θ ± 0.2°2θ. Alternatively or additionally, according to aspects or embodiments of the present disclosure, crystalline form C1 of zavegepant hydrochloride can be characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein, wherein the X-ray powder diffraction pattern is free of a peak between 9.9 and 10.1 degrees 2θ ± 0.2 degrees 2θ.Alternatively or additionally, according to aspects or embodiments of the present disclosure, crystalline form C1 of zavegepant hydrochloride can be characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein, wherein the X-ray powder diffraction pattern is free of a peak between 11.1 and 11.7 degrees 2θ ± 0.2 degrees 2θ.Alternatively or additionally, according to any aspect or embodiment of the present disclosure, crystalline form C1 of zabegepant hydrochloride has an X-ray powder diffraction pattern as described in any of the embodiments described herein (particularly an XRPD pattern having characteristic peaks at 7.1, 9.4, 15.6, 17.5, and 21.2 °2θ ± 0.2 °2θ, and optionally any one, two, three, four, or five additional peaks at 10.6, 12.7, 14.7, 18.1, and 19.6 °2θ ± 0.2 °2θ), or The compound can be characterized by an X-ray powder diffraction pattern (XRPD pattern having characteristic peaks at 10°2θ), and the X-ray powder diffraction pattern does not include one, two, three, or four of the following peaks (i) to (iv): (i) any of 3.2 to 5.0°2θ ± 0.2°2θ, or 3.2 to 6.0° ± 0.2°2θ, or 3.2 to 6.3°2θ ± 0.2°2θ; (ii) any of 7.6 to 8.2°2θ ± 0.2°2θ, or 7.6 to 8.6°2θ ± 0.2°2θ; (iii) 9.9 to 10.1°2θ ± 0.2°2θ; and (iv) 11.1 to 11.7°2θ ± 0.2°2θ.

[0041] Typically, the DSC melting point of crystalline form C1 is about 264°C (i.e., evaluated as the onset measured at DSC 10°C / min). In some embodiments, crystalline form C1 of zavegepant can be characterized by a DSC thermogram substantially as shown in Figure 3.

[0042] According to any aspect or embodiment of the present disclosure, crystalline form C1 of zavegepant hydrochloride is preferably isolated.

[0043] Crystalline form C1 of zavegepant hydrochloride according to any aspect or embodiment may be substantially free of any other crystalline form of zavegepant hydrochloride. In particular, crystalline form C1 of zavegepant hydrochloride may contain about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other crystalline form of zavegepant hydrochloride, as measured, for example, by XRPD. Thus, crystalline form C1 of zavegepant hydrochloride described herein as being substantially free of other crystalline forms will be understood to contain more than about 80% (w / w), more than about 90% (w / w), more than about 95% (w / w), more than about 98% (w / w), more than about 99% (w / w), or about 100% form C1 of zavegepant hydrochloride.

[0044] According to any aspect or embodiment of the present disclosure, crystalline form C1 of zavegepant hydrochloride may be substantially free of amorphous zavegepant hydrochloride. In particular, crystalline form C1 of zavegepant hydrochloride may contain about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% amorphous zavegepant hydrochloride, as measured, for example, by XRPD.

[0045] According to any aspect or embodiment of the present disclosure, zavegepant or zavegepant hydrochloride, preferably zavegepant hydrochloride Form C1, can be optically pure. Optically pure means that zavegepant or zavegepant hydrochloride (preferably zavegepant hydrochloride Form C1) is substantially free of zavegepant or zavegepant hydrochloride enantiomers. In particular, in any aspect or embodiment of the present disclosure, zavegepant or zavegepant hydrochloride (preferably zavegepant hydrochloride Form C1) can be optically pure, and in particular contains 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of the other enantiomer of zavegepant or zavegepant hydrochloride, respectively, as measured, for example, by HPLC.

[0046] Zavegepant crystalline form C1 can be characterized by each and / or all possible combinations of the above features, such as an XRPD pattern having peaks at 7.1, 9.4, 15.6, 17.5, and 21.2 °2θ±0.2 °2θ; the XRPD pattern shown in FIG. 1; and combinations thereof.

[0047] The present disclosure includes a crystalline polymorph of zabegepant hydrochloride designated Form C2. Crystalline Form C2 can be represented by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 12.6, 14.1, 14.9, 19.0, and 19.7 °2θ ± 0.2 °2θ, an XRPD pattern substantially as shown in Figure 2, and combinations thereof. Crystalline Form C2 can be further represented by an XRPD pattern having characteristic peaks at 12.6, 14.1, 14.9, 19.0, and 19.7 °2θ ± 0.2 °2θ, and any one, two, three, four, or five additional peaks at 9.8, 16.2, 17.6, 20.9, and 21.8 °2θ ± 0.2 °2θ.

[0048] Crystalline form C2 can be represented by an XRPD pattern having characteristic peaks at 9.8, 12.6, 14.1, 14.9, 16.2, 17.6, 19.0, 19.7, 20.9, and 21.8 degrees 2θ±0.2 degrees 2θ.

[0049] In any aspect or embodiment of the present disclosure, crystalline form C2 of zabegepant hydrochloride can be characterized by an X-ray powder diffraction pattern according to any embodiment described herein, wherein the X-ray powder diffraction pattern is free of peaks between 3.2 and 6.0°2θ ± 0.2°2θ, or between 3.2 and 6.5°2θ ± 0.2°2θ, or between 3.2 and 7.0°2θ ± 0.2°2θ, or between 3.2 and 7.5°2θ ± 0.2°2θ, or between 3.2 and 8.0°2θ ± 0.2°2θ, or between 3.2 and 8.5°2θ ± 0.2°2θ, or between 3.2 and 9.0°2θ ± 0.2°2θ, or between 3.2 and 9.3°2θ ± 0.2°2θ. Alternatively or additionally, according to aspects or embodiments of the present disclosure, crystalline form C2 of zavegepant hydrochloride can be characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein, wherein the X-ray powder diffraction pattern is absent from a peak between 11.5 and 12.1 degrees 2θ ± 0.2 degrees 2θ. Alternatively or additionally, according to aspects or embodiments of the present disclosure, crystalline form C2 of zavegepant hydrochloride can be characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein, wherein the X-ray powder diffraction pattern is absent from a peak between 16.7 and 16.8 degrees 2θ ± 0.2 degrees 2θ. Alternatively or additionally, according to aspects or embodiments of the present disclosure, crystalline form C2 of zavegepant hydrochloride can be characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein, wherein the X-ray powder diffraction pattern is absent from a peak between 18.1 and 18.5 degrees 2θ ± 0.2 degrees 2θ.

[0050] Alternatively or additionally, according to aspects or embodiments of the present disclosure, crystalline form C2 of zabegepant hydrochloride is characterized by an X-ray powder diffraction pattern as described in any of the embodiments described herein (particularly an XRPD pattern having characteristic peaks at 12.6, 14.1, 14.9, 19.0, and 19.7 °2θ ± 0.2 °2θ, and optionally any one, two, three, four, or five additional peaks among 9.8, 16.2, 17.6, 20.9, and 21.8 °2θ ± 0.2 °2θ, or an XRPD pattern having characteristic peaks at 9.8, 12.6, 14.1, 14.9, 16.2, 17.6, 19.0, 19.7, 20.9, and 21.8 °2θ ± 0.2 °2θ). The X-ray powder diffraction pattern may include the following (i) to (iv): (i) 3.2 to 6.0° 2θ ± 0.2° 2θ, or 3.2 to 6.5° 2θ ± 0.2° 2θ, or 3.2 to 7.0° ± 0.2° 2θ, or 3.2 to 7.5° 2θ ± 0.2° 2θ, or 3.2 to 8.0° 2θ ± 0.2° 2θ, or 3.2 to 8.5° 2θ ± 0.2° 2θ Alternatively or additionally, crystalline form C2 is a solid having peaks at 170.2, 162.7, 158.4, 142.3, and 129.9 ppm ± 0.2 ppm in the range of 200 to 100 ppm. 13 and / or a solid having absolute chemical shift differences of 46.7, 39.2, 34.9, 18.8, and 6.5 ppm ± 0.1 ppm from the reference peak of 123.5 ppm ± 1 ppm. 13 Alternatively, according to any aspect or embodiment, crystalline form C2 can be characterized by a C NMR spectrum having peaks at 170.2, 162.7, 158.4, 142.3, 139.2, 138.1, 135.1, 134.3, 131.1, and 129.9 ppm±0.2 ppm in the range of 200-100 ppm. 13It can be characterized by C NMR spectroscopy.

[0051] Alternatively, crystalline form C2 according to any aspect or embodiment of the present disclosure is a solid state solution having peaks at 170.2, 162.7, 158.4, 142.3, 139.2, 138.1, 135.1, 134.3, 131.1, 129.9, and 123.5 ppm ± 0.2 ppm in the range of 200 to 100 ppm, and additionally having any one, two, three, or four peaks at 122.1, 117.5, and 116.2 ppm ± 0.2 ppm. 13 Alternatively, crystalline form C2 can be characterized by a C NMR spectrum of a solid having peaks at 170.2, 162.7, 158.4, 142.3, 139.2, 138.1, 135.1, 134.3, 131.1, 129.9, 123.5, 122.1, 117.5, and 116.2 ppm ± 0.2 ppm in the range of 200 to 100 ppm. 13 It can be represented by a C NMR spectrum.

[0052] Typically, crystalline form C2 has a DSC melting point of about 261°C (i.e., evaluated as the onset measured at DSC 10°C / min). In some embodiments, crystalline form C2 of zavegepant can be characterized by a DSC thermogram substantially as shown in Figure 4.

[0053] According to any aspect or embodiment of the present disclosure, crystalline form C2 of zavegepant hydrochloride is preferably isolated.

[0054] The crystalline form C2 of zavegepant hydrochloride may be an anhydrous form.

[0055] Crystalline form C2 of zavegepant hydrochloride according to any aspect or embodiment may be substantially free of other crystalline forms of zavegepant hydrochloride. In particular, crystalline form C2 of zavegepant hydrochloride may contain about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other crystalline form of zavegepant hydrochloride, as measured, for example, by XRPD. Thus, crystalline form C2 of zavegepant hydrochloride described herein as being substantially free of other crystalline forms will be understood to contain more than about 80% (w / w), more than about 90% (w / w), more than about 95% (w / w), more than about 98% (w / w), more than about 99% (w / w), or about 100% form C2 of zavegepant hydrochloride.

[0056] According to any aspect or embodiment of the present disclosure, crystalline form C2 of zavegepant hydrochloride may be substantially free of amorphous zavegepant hydrochloride. In particular, crystalline form C2 of zavegepant hydrochloride may contain about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% amorphous zavegepant hydrochloride, as measured, for example, by XRPD.

[0057] According to any aspect or embodiment of the present disclosure, zavegepant hydrochloride Form C2 can be optically pure. By optically pure, it is meant that zavegepant hydrochloride Form C2 is substantially free of zavegepant hydrochloride enantiomers. In particular, in any aspect or embodiment of the present disclosure, zavegepant hydrochloride Form C2 can be optically pure, and in particular, contains less than 20% (w / w), less than about 10% (w / w), less than about 5% (w / w), less than about 2% (w / w), less than about 1% (w / w), or less than about 0%, respectively, of the other enantiomer of zavegepant hydrochloride, as measured, for example, by HPLC.

[0058] Zabegepant hydrochloride crystalline form C2 can be characterized by each and / or all possible combinations of the above features, such as an XRPD pattern having peaks at 12.6, 14.1, 14.9, 19.0, and 19.7 °2θ±0.2 °2θ; the XRPD pattern shown in FIG. 2; and combinations thereof.

[0059] Crystalline form C2 of zavegepant hydrochloride can have one or more advantageous properties as described hereinabove, for example, form C2 is stable for at least 6 months at a temperature of about 25° C. and a relative humidity ("RH") of 60% and at a temperature of about 40° C. and 75% RH.

[0060] The above-mentioned crystalline polymorphs can be used to prepare other crystalline polymorphs of zavegepant hydrochloride, other zavegepant salts, and solid forms thereof, which may be crystalline polymorphs, cocrystals, and complexes of zavegepant or zavegepant salts.

[0061] The present disclosure encompasses other solid forms of zavegepant hydrochloride and methods for preparing those solid forms, including preparing any one of the crystalline polymorphs of zavegepant hydrochloride by the method of the present invention. The method may further include converting the crystalline polymorph of zavegepant hydrochloride to another crystalline polymorph of zavegepant or another zavegepant salt.

[0062] The present disclosure provides the above crystalline polymorphs of zavegepant hydrochloride for use in preparing pharmaceutical compositions comprising zavegepant hydrochloride and / or the crystalline polymorphs thereof.

[0063] The present disclosure also encompasses the use of the crystalline polymorphs of zavegepant hydrochloride of the present disclosure for the preparation of crystalline polymorphs of zavegepant hydrochloride and / or pharmaceutical compositions of the crystalline polymorphs thereof. In particular, the pharmaceutical compositions can be used for nasal or oral administration, more particularly for nasal administration.

[0064] The present disclosure includes a method for preparing the pharmaceutical composition. The method includes combining any one or a combination of the crystalline polymorphs of zavegepant hydrochloride disclosed herein with at least one pharmaceutically acceptable excipient. In particular, the pharmaceutical composition may include a pharmaceutically acceptable excipient suitable for preparing a formulation for nasal or oral administration, particularly a formulation for nasal administration. The pharmaceutical composition or formulation of the present disclosure includes any one or a combination of the solid forms of zavegepant hydrochloride disclosed herein. In addition to the active ingredient, the pharmaceutical formulation of the present disclosure may include one or more excipients. Excipients are added to the formulation for various purposes. For example, excipients may be added to assist in forming a formulation suitable for nasal administration.

[0065] Diluents can add bulk to a solid pharmaceutical composition and make a pharmaceutical dosage form containing the composition easier for patients and caregivers to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), super powdered cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugars, dextrates, dextrin, dextrose, calcium hydrogen phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0066] Solid pharmaceutical compositions that are compressed into dosage forms such as tablets may contain excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomers (e.g., Carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oils, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), hydroxypropylmethylcellulose (e.g., Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0067] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by adding a disintegrant to the composition, including alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[0068] Glidants can be added to improve the flowability of non-compacted solid compositions and improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tricalcium phosphate.

[0069] When a dosage form such as a tablet is produced by compressing a powder composition, the composition is subjected to pressure from a punch and a die. Some excipients and active ingredients tend to adhere to the surfaces of the punch and the die, which can cause holes and other surface irregularities in the product. To reduce adhesion and make the product easier to separate from the die, a lubricant can be added to the composition. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[0070] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common pharmaceutical flavoring agents and flavor enhancers that can be included in the compositions of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0071] Solid and liquid compositions may also be colored using any pharmaceutically acceptable colorant to improve appearance and / or to facilitate identification of the product and unit dose by the patient.

[0072] In liquid pharmaceutical compositions of the present invention, zavegepant and any other solid excipients may be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0073] Liquid pharmaceutical compositions may contain emulsifying agents to uniformly disperse active ingredients or other excipients that are not soluble in the liquid carrier throughout the composition. Emulsifying agents that may be useful in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methylcellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0074] The liquid pharmaceutical compositions of the present invention may contain thickening agents to improve the mouthfeel of the product and / or to coat the mucous membranes of the gastrointestinal tract, including acacia, bentonite alginate, carbomer, calcium or sodium carboxymethylcellulose, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum, and combinations thereof.

[0075] Sweeteners such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.

[0076] To improve storage stability, preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid may be added at levels safe for consumption.

[0077] According to the present disclosure, the liquid composition may also include a buffering agent such as gluconic acid, lactic acid, citric acid, acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. The choice of excipients and the amounts to be used can be readily determined by a formulation scientist empirically and with consideration of standard procedures and references in the field.

[0078] Solid compositions of the present disclosure include powders, granules, aggregates, and compressed compositions. Dosages include those suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, nasal, and ophthalmic administration. The most appropriate administration in any given case will depend on the nature and severity of the condition being treated, but in several embodiments, the route of administration is oral. Dosages are conveniently provided in unit dosage form and can be prepared by any method well known in the pharmaceutical arts.

[0079] Dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0080] The dosage form of the present disclosure may be a capsule containing a composition, such as a powdered or granular solid composition of the present disclosure, within a hard or soft shell. The shell may be made from gelatin and may optionally contain a plasticizer, such as glycerin and / or sorbitol, an opacifying agent, and / or a colorant.

[0081] The active ingredients and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0082] Compositions for tableting or capsule filling can be prepared by wet granulation. In wet granulation, the active ingredient and some or all of the excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump together into granules. The granules are sieved and / or milled, dried, and then sieved and / or milled to the desired particle size. The granules can then be tableted, or other excipients such as glidants and / or lubricants may be added prior to tableting.

[0083] Tableting compositions can be conventionally prepared by dry blending. For example, the blended composition of the active ingredients and excipients can be compressed into a slug or sheet and then comminuted into compacted granules. The compacted granules can then be compressed into tablets.

[0084] Instead of dry granulation, the blended composition may be directly compressed into a compressed dosage form using direct compression technology. Direct compression produces a more uniform tablet without granules. Excipients particularly suitable for direct compression tableting include microcrystalline cellulose, spray-dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The appropriate use of these and other excipients in direct compression tableting is known to those skilled in the art, especially those with experience and skill in the formulation challenges of direct compression tableting.

[0085] The capsule filling of the present disclosure may include any of the above blends and granules described with respect to tableting, but which do not undergo a final tableting step.

[0086] A pharmaceutical formulation of zavegepant hydrochloride can be administered. For example, it can be administered intranasally or orally. Zavegepant hydrochloride can be formulated for administration by injection to mammals, and in some embodiments, humans. Zavegepant hydrochloride can be formulated for injection as a viscous liquid solution or suspension, e.g., a clear solution. The formulation can include one or more solvents. A suitable solvent can be selected based on the solvent's physical and chemical stability at various pH levels, viscosity (injectable viscosity), flowability, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and castor oil USP. Additional substances, such as buffers, solubilizers, and antioxidants, among others, may be added to the formulation. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[0087] In some embodiments, the crystalline polymorphs of zavegepant hydrochloride and the pharmaceutical compositions and / or formulations of zavegepant hydrochloride disclosed herein can be used as medicines in the treatment of migraine or COVID-19 respiratory infection. The medicines can be administered preferably via nasal or oral forms, more preferably via nasal forms.

[0088] The present disclosure also provides methods of treating migraine or COVID-19 respiratory infection by administering to a subject in need thereof a therapeutically effective amount of any one or combination of the crystalline polymorphs of zavegepant hydrochloride of the present disclosure, or at least one of the pharmaceutical compositions and / or formulations described above.

[0089] Thus, while the present disclosure has been described with reference to certain preferred embodiments and illustrative examples, those skilled in the art will appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure disclosed herein. The examples are presented to aid in the understanding of the disclosure and are not intended to, and should not be construed as, limiting the scope of the disclosure in any way.

[0090] X-ray Powder Diffraction ("XRPD") Method Powder X-ray diffraction was performed using a PANalytical X'Pert Pro X-ray powder diffractometer; CuKα radiation (λ = 1.54187 Å); an X'Celerator detector with an effective length of 2.122°2θ; a laboratory temperature of 25 ± 3°C; and a zero-background sample holder. Prior to analysis, the samples were gently ground using a mortar and pestle to obtain a fine powder. The ground sample was placed in the cavity of the sample holder, and a cover glass was used to smooth the sample surface.

[0091] Measurement parameters Scanning range: 3~40°2θ Scanning mode: Continuous Step size: 0.0167° (or 0.0131 for form C2) Step size: 42 seconds (or 41 seconds for configuration C2) Sample rotation: 60 rpm Sample holder: Zero background silicon plate

[0092] Differential Scanning Calorimetry ("DSC") Method Equipment: TA Discovery Method: Heating rate 10°C / min, temperature range 25°C to 300°C, nitrogen flow rate 50mL / min, Tzero aluminum pan with Tzero airtight lid, 40µL.

[0093] 13 C-CP / MAS NMR method: Spectra were measured at 11.7 T using a Bruker Avance III HD 500US / WB NMR spectrometer (Karlsruhe, Germany, 2013) equipped with a 4 mm probehead. 13 C CP / MAS NMR spectra were recorded at room temperature and corrected for frictional heating of the rotating sample. 13 C CP / MAS NMR spectra were acquired at a rotation frequency of 11 kHz using a standard cross-polarization pulse scheme. Dipolar decoupling (SPINAL64) was applied during data acquisition. 13 The C scale is based on glycine ( 13 176.03 ppm for C).

[0094] Before recording the spectra, the NMR spectrometer was calibrated and all experimental parameters were carefully optimized: the magic angle was set using KBr during standard optimization procedures, and the field homogeneity was optimized using an adamantine sample (the resulting half-width Δν was less than 3.5 Hz with an acquisition time of 250 ms). [Example]

[0095] Preparation of starting materials Zavegepant can be prepared according to methods known from the literature, for example from US Pat. No. 8,481,546 or WO 2022 / 217008.

[0096] Zavegepant hydrochloride can be prepared by converting zavegepant, prepared by general methods such as those described above, to the hydrochloride salt.

[0097] Amorphous zavegepant hydrochloride can be prepared by any method, for example, according to the examples below.

[0098] Preparation of amorphous zavegepant hydrochloride: Zabegepant hydrochloride (100 mg) was dissolved in ethanol (1 mL) at elevated temperature. The resulting clear solution was cooled to a temperature of approximately 20°C, and heptane (300 μL) was added dropwise. After stirring for several minutes, the product began to precipitate. The resulting suspension was stirred for 60 minutes. The solid was then filtered and dried under vacuum for approximately 15 minutes. The solid was analyzed by XRPD and found to be amorphous.

[0099] Example 1: Preparation of Zavegepant Hydrochloride Form C1 Zabegepant hydrochloride (amorphous, 500 mg) was slurried in methyl isobutyl ketone ("MIBK", 5 mL) at a temperature of about 75° C. for about 2 hours. The resulting suspension was allowed to cool to room temperature. The solid was then filtered and dried under vacuum for about 15 minutes. The solid was analyzed by XRPD. Form C1 was obtained. The XRPD pattern is shown in FIG. 1.

[0100] Example 2: Preparation of Zavegepant Hydrochloride Form C2 Zabegepant hydrochloride (amorphous, 5 grams) was slurried in acetonitrile (80 mL) at a temperature of about 60° C. for about 2.5 hours. The resulting suspension was allowed to cool to room temperature and maintained under stirring at room temperature for an additional about 2 hours. The solid was then filtered and dried under vacuum for about 1.5 hours. The solid was analyzed by XRPD. Form 2 was obtained. The XRPD pattern is shown in FIG. 2.

[0101] Further aspects and embodiments of the present disclosure are described in the following numbered clauses: Crystalline zabegepant hydrochloride form C2, characterized by an XRPD pattern with characteristic peaks at 1.12.6, 14.1, 14.9, 19.0, and 19.7°2θ±0.2°2θ. 2. The crystalline zabegepant hydrochloride form C2 described in clause 1, characterized by an XRPD pattern having characteristic peaks at 2.12.6, 14.1, 14.9, 19.0, and 19.7 °2θ ± 0.2 °2θ, and any one, two, three, four, or five additional peaks at 9.8, 16.2, 17.6, 20.9, and 21.8 °2θ ± 0.2 °2θ. 3. The crystalline zabegepant hydrochloride form C2 of clause 1 or 2, characterized by an XRPD pattern having characteristic peaks at 3.9.8, 12.6, 14.1, 14.9, 16.2, 17.6, 19.0, 19.7, 20.9, and 21.8 °2θ ± 0.2 °2θ, or an XRPD pattern substantially as shown in Figure 2. 4.3. Crystalline form C2 of zavegepant hydrochloride according to any one of clauses 1, 2 and 3, further characterized by an X-ray powder diffraction pattern in which no peaks are present between 2 and 6.0° 2θ ± 0.2° 2θ. Crystalline form C2 of zavegepant hydrochloride according to any one of clauses 1, 2 and 3, further characterized by an X-ray powder diffraction pattern in which no peaks are present between 5.3.2 and 6.5°2θ±0.2°2θ. Crystalline form C2 of zavegepant hydrochloride according to any one of clauses 1, 2 and 3, further characterized by an X-ray powder diffraction pattern in which no peaks are present between 6.3.2 and 7.0°2θ±0.2°2θ. Crystalline form C2 of zavegepant hydrochloride according to any one of clauses 1, 2 and 3, further characterized by an X-ray powder diffraction pattern in which no peaks are present at 7.3.2 to 7.5° 2θ ± 0.2° 2θ. Crystalline form C2 of zavegepant hydrochloride according to any one of clauses 1, 2 and 3, further characterized by an X-ray powder diffraction pattern in which there is no peak at 8.3.2 to 8.0°2θ±0.2°2θ. Crystalline form C2 of zavegepant hydrochloride according to any one of clauses 1, 2 and 3, further characterized by an X-ray powder diffraction pattern in which no peaks are present between 9.3.2 and 8.5°2θ±0.2°2θ. Crystalline form C2 of zavegepant hydrochloride according to any one of clauses 1, 2 and 3, further characterized by an X-ray powder diffraction pattern that is free of peaks between 10.3.2 and 9.0°2θ±0.2°2θ. Crystalline form C2 of zavegepant hydrochloride according to any one of clauses 1, 2 and 3, further characterized by an X-ray powder diffraction pattern in which no peaks are present between 11.3.2 and 9.3°2θ±0.2°2θ. 12. The crystalline form C2 of zabegepant hydrochloride according to any one of clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11, further characterized by an X-ray powder diffraction pattern that is free of peaks at 11.5 to 12.1 degrees 2θ ± 0.2 degrees 2θ. 13. Crystalline form C2 of zabegepant hydrochloride according to any one of clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, further characterized by an X-ray powder diffraction pattern that is free of peaks at 16.7 to 16.8°2θ±0.2°2θ. 14. Crystalline form C2 of zabegepant hydrochloride according to any one of clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13, further characterized by an X-ray powder diffraction pattern that is free of peaks between 18.1 and 18.5°2θ±0.2°2θ. 15. Solids with peaks at 170.2, 162.7, 158.4, 142.3, and 129.9 ppm ± 0.2 ppm in the range of 200 to 100 ppm 13 15. The crystalline form C2 of zavegepant hydrochloride according to any one of clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, further characterized by C NMR spectrum. 16.1 Solids with absolute chemical shift differences of 46.7, 39.2, 34.9, 18.8, and 6.5 ppm ± 0.1 ppm from the reference peak of 3.5 ppm ± 1 ppm 1316. The crystalline form C2 of zavegepant hydrochloride according to any one of clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15, further characterized by C NMR spectrum. 17. Solids with peaks at 170.2, 162.7, 158.4, 142.3, 139.2, 138.1, 135.1, 134.3, 131.1, 129.9, and 123.5 ppm ± 0.2 ppm in the range of 200 to 100 ppm 13 17. The crystalline zavegepant hydrochloride form C2 according to any one of clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16, further characterized by C NMR spectrum. 18. A solid having peaks at 170.2, 162.7, 158.4, 142.3, 139.2, 138.1, 135.1, 134.3, 131.1, 129.9, and 123.5 ppm ± 0.2 ppm in the range of 200 to 100 ppm, and additionally having any one, two, three, or four peaks at 122.1, 117.5, and 116.2 ppm ± 0.2 ppm. 13 18. The crystalline zavegepant hydrochloride form C2 according to any one of clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, and 17, further characterized by C NMR spectrum. 19. Solids with peaks at 170.2, 162.7, 158.4, 142.3, 139.2, 138.1, 135.1, 134.3, 131.1, 129.9, 123.5, 122.1, 117.5, and 116.2 ppm ± 0.2 ppm in the range of 200 to 100 ppm. 13 19. The crystalline zavegepant hydrochloride form C2 according to any one of clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18, characterized by a C NMR spectrum. 20. The crystalline zavegepant hydrochloride form C2 according to any one of clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19, further characterized by a DSC melting point of about 261°C, preferably as measured by differential scanning calorimetry, or optionally by a DSC thermogram substantially as shown in Figure 4. 21. Crystalline zavegepant hydrochloride form C2 according to any one of clauses 1 to 20, which is in anhydrous form. 22. Crystalline zavegepant hydrochloride Form C2 according to any one of clauses 1-21, comprising no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1%, or no more than about 0% of any other crystalline form of zavegepant hydrochloride. 23. The crystalline zavegepant hydrochloride Form C2 according to any one of clauses 1-22, comprising less than or equal to about 20%, less than or equal to about 10%, less than or equal to about 5%, less than or equal to about 2%, less than or equal to about 1%, or less than or equal to about 0% amorphous zavegepant hydrochloride. 24. Crystalline zavegepant hydrochloride form C2 according to any one of clauses 1 to 23, which is chemically pure. Crystalline zabegepant hydrochloride form C1, characterized by an XRPD pattern with characteristic peaks at 25.7.1, 9.4, 15.6, 17.5, and 21.2°2θ±0.2°2θ. 26. The crystalline zabegepant hydrochloride form C1 of clause 25, characterized by an XRPD pattern having characteristic peaks at 26.7.1, 9.4, 15.6, 17.5, and 21.2 °2θ ± 0.2 °2θ, and any one, two, three, four, or five additional peaks at 10.6, 12.7, 14.7, 18.1, and 19.6 °2θ ± 0.2 °2θ. 27. The crystalline zabegepant hydrochloride form C1 of clause 25 or 26, characterized by an XRPD pattern having characteristic peaks at 27.7.1, 9.4, 10.6, 12.7, 14.7, 15.6, 17.5, 18.1, 19.6, and 21.2 °2θ ± 0.2 °2θ, or an XRPD pattern substantially as shown in Figure 1. 28. Zabegepant hydrochloride crystalline form C1 according to any one of clauses 25, 26 or 27, further characterized by an X-ray powder diffraction pattern that is free of peaks between 3.2 and 5.0° 2θ ± 0.2° 2θ. 29. Zabegepant hydrochloride crystalline form C1 according to any one of clauses 25, 26, or 27, further characterized by an X-ray powder diffraction pattern that is free of peaks between 3.2 and 6.0° 2θ ± 0.2° 2θ. 30. Zabegepant hydrochloride crystalline form C1 according to any one of clauses 25, 26 or 27, further characterized by an X-ray powder diffraction pattern that is free of peaks between 3.2 and 6.3°2θ±0.2°2θ. 31. Zabegepant hydrochloride crystalline form C1 according to any one of clauses 25, 26, 27, 28, 29, or 30, further characterized by an X-ray powder diffraction pattern that is free of peaks at 7.6 to 8.2° 2θ ± 0.2° 2θ. 32. The zavegepant hydrochloride crystalline form C1 of any one of clauses 25, 26, 27, 28, 29, or 30, further characterized by an X-ray powder diffraction pattern that is free of peaks at 7.6 to 8.6 degrees 2θ ± 0.2 degrees 2θ. 33. The zavegepant hydrochloride crystalline form C1 of any one of clauses 25, 26, 27, 28, 29, 30, 31, or 32, further characterized by an X-ray powder diffraction pattern that is free of peaks at 9.9 to 10.1 degrees 2θ ± 0.2 degrees 2θ. 34. The zavegepant hydrochloride crystalline form C1 of any one of clauses 25, 26, 27, 28, 29, 30, 31, 32, or 33, further characterized by an X-ray powder diffraction pattern that is free of peaks at 11.1 to 11.7 degrees 2θ ± 0.2 degrees 2θ. 35. The zavegepant hydrochloride crystalline form C1 according to any one of clauses 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34, further characterized by a DSC melting point (onset) of about 264°C or a DSC thermogram substantially as shown in Figure 3. 36. Zabegepant hydrochloride crystalline form C1 according to any one of clauses 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35, which is isolated. 37. Zavegepant hydrochloride crystalline form C1 according to any one of clauses 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, comprising no more than about 20% (w / w), no more than about 10% (w / w), no more than about 5% (w / w), no more than about 2% (w / w), no more than about 1% (w / w), or about 0% of any other crystalline form of zavegepant hydrochloride. 38. Zavegepant hydrochloride crystalline form C1 according to any one of clauses 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 37, comprising about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% amorphous zavegepant hydrochloride. 39. Zavegepant hydrochloride crystalline form C1 according to any one of clauses 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, or 38, which is substantially free of other enantiomers of zavegepant or zavegepant hydrochloride, preferably containing no more than about 20% (w / w), no more than about 10% (w / w), no more than about 5% (w / w), no more than about 2% (w / w), no more than about 1% (w / w), or no more than about 0% of other enantiomers of zavegepant or zavegepant hydrochloride, respectively. 40. A pharmaceutical composition comprising the crystalline form of any one of clauses 1 to 39. 41. A pharmaceutical formulation comprising a crystalline form according to any one of clauses 1 to 39 or a pharmaceutical composition according to clause 40, and at least one pharmaceutically acceptable excipient. 42. A pharmaceutical formulation according to clause 41, optionally in the form of a liquid or suspension, optionally wherein said formulation is an intranasal formulation. 43. A process for preparing a pharmaceutical formulation according to clause 41 or clause 42, comprising mixing a crystalline form according to any one of clauses 1 to 39 or a pharmaceutical composition according to clause 40 with at least one pharmaceutically acceptable excipient. 44. Use of a crystalline form according to any one of clauses 1 to 39 for the preparation of a pharmaceutical composition and / or formulation, optionally wherein said pharmaceutical formulation is a liquid or a suspension. 45. The use according to clause 44, wherein the pharmaceutical composition or pharmaceutical formulation is an intranasal formulation. 46. ​​A crystalline form according to any one of clauses 1 to 39, a pharmaceutical composition according to clause 40 or a pharmaceutical formulation according to clause 41 or clause 42 for use as a medicament. 47. A crystalline form according to any one of clauses 1 to 39, a pharmaceutical composition according to clause 40 or a pharmaceutical formulation according to clause 41 or clause 42 for use in the treatment or prevention of migraine or COVID-19 respiratory infection. 48. A method for the treatment or prevention of migraine or COVID-19 respiratory infection, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form according to any one of clauses 1 to 39, a pharmaceutical composition according to clause 40, or a pharmaceutical formulation according to clause 41 or clause 42. 49. The method of clause 48, wherein the treatment is administered intranasally. 50. A crystalline form according to any one of clauses 1 to 39, a pharmaceutical composition according to clause 40 or a pharmaceutical formulation according to clause 41 or clause 42 for the manufacture of a medicament for the treatment of migraine or COVID-19 respiratory infection. 51. Use of a crystalline form according to any one of clauses 1 to 39 in the preparation of other solid forms of zavegepant, zavegepant salts, co-crystals or complexes of zavegepant or zavegepant salts. 52. A process for preparing a solid form of zavegepant, zavegepant salts, and crystalline polymorphs, co-crystals, or complexes thereof, comprising preparing a crystalline form according to any one of clauses 1 to 39 and converting it into another solid form of zavegepant, zavegepant salts, or crystalline polymorphs, co-crystals, or complexes thereof.

Claims

1. Crystalline zavegepant hydrochloride form C2, characterized by an XRPD pattern with characteristic peaks at 12.6, 14.1, 14.9, 19.0, and 19.7°2θ±0.2°2θ.

2. 2. The crystalline zavegepant hydrochloride form C2 of claim 1, characterized by an XRPD pattern having characteristic peaks at 12.6, 14.1, 14.9, 19.0, and 19.7 °2θ ± 0.2 °2θ, and any one, two, three, four, or five additional peaks at 9.8, 16.2, 17.6, 20.9, and 21.8 °2θ ± 0.2 °2θ.

3. 3. The crystalline zavegepant hydrochloride form C2 of claim 1 or 2, characterized by an XRPD pattern having characteristic peaks at 9.8, 12.6, 14.1, 14.9, 16.2, 17.6, 19.0, 19.7, 20.9, and 21.8 °2θ±0.2 °2θ, or an XRPD pattern substantially as shown in Figure 2.

4. (a) A solid having peaks at 170.2, 162.7, 158.4, 142.3, and 129.9 ppm ± 0.2 ppm in the range of 200 to 100 ppm. １３ C NMR spectrum; and / or (b) Solids with absolute chemical shift differences of 46.7, 39.2, 34.9, 18.8, and 6.5 ppm ± 0.1 ppm from a reference peak of 123.5 ppm ± 1 ppm. １３ The crystalline zavegepant hydrochloride form C2 according to any one of claims 1 to 3, further characterized by a C NMR spectrum;

5. Solids having peaks at 170.2, 162.7, 158.4, 142.3, 139.2, 138.1, 135.1, 134.3, 131.1, 129.9, and 123.5 ppm ± 0.2 ppm in the range of 200 to 100 ppm １３ 5. The crystalline zavegepant hydrochloride form C2 according to any one of claims 1 to 4, further characterized by a C NMR spectrum.

6. The crystalline zavegepant hydrochloride form C2 according to any one of claims 1 to 5, which is in anhydrous form.

7. 7. The crystalline zavegepant hydrochloride form C2 of any one of claims 1 to 6, comprising less than about 20%, less than about 10%, less than about 5%, less than about 2%, less than about 1%, or less than about 0% of any other crystalline form of zavegepant hydrochloride.

8. 8. The crystalline zavegepant hydrochloride Form C2 of any one of claims 1 to 7, comprising about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% amorphous zavegepant hydrochloride.

9. The crystalline zavegepant hydrochloride form C2 according to any one of claims 1 to 8, which is chemically pure.

10. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 9.

11. A pharmaceutical formulation comprising the crystalline form of any one of claims 1 to 9 or the pharmaceutical composition of claim 10, and at least one pharmaceutically acceptable excipient.

12. 12. A pharmaceutical formulation according to claim 11, optionally in the form of a liquid or suspension and / or in a nasal formulation.

13. 12. A process for preparing the pharmaceutical formulation of claim 11, comprising mixing the crystalline form of any one of claims 1 to 9 or the pharmaceutical composition of claim 10 with at least one pharmaceutically acceptable excipient.

14. 10. Use of the crystalline form of any one of claims 1 to 9 for the preparation of a pharmaceutical composition and / or formulation, optionally wherein said pharmaceutical formulation is an intranasal formulation.

15. A crystalline form according to any one of claims 1 to 9, a pharmaceutical composition according to claim 10, or a pharmaceutical formulation according to claim 11, for use as a medicament.

16. 12. The crystalline form of any one of claims 1 to 9, the pharmaceutical composition of claim 10, or the pharmaceutical formulation of claim 11 for use in the treatment or prevention of migraine or COVID-19 respiratory infection.

17. 12. A method for treating or preventing migraine or COVID-19 respiratory infection, comprising administering a therapeutically effective amount of the crystalline form of any one of claims 1 to 9, the pharmaceutical composition of claim 10, or the pharmaceutical formulation of claim 11 to a subject in need thereof.

18. 18. The method of claim 17, wherein the treatment is administered intranasally.

19. The crystalline form of any one of claims 1 to 9, the pharmaceutical composition of claim 10, or the pharmaceutical formulation of claim 11 for the manufacture of a medicament for the treatment of migraine or COVID-19 respiratory infection.

20. Use of the crystalline form of any one of claims 1 to 9 in the preparation of other solid forms of zavegepant, zavegepant salts, co-crystals or complexes of zavegepant or zavegepant salts.

21. A method for preparing a solid form of zavegepant, zavegepant salts, and their crystalline polymorphs, co-crystals, or complexes thereof, comprising preparing a crystalline form according to any one of claims 1 to 9 and converting it to another solid form of zavegepant, zavegepant salts, or their crystalline polymorphs, co-crystals, or complexes.

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