Solid forms of briraloxazine and briraloxazine salts

Abstract

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

Description

[Technical Field]

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

[0002] Briraloxazine, 6-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2H-benzo(b)(1,4)oxazin-3(4H)-one, is the compound shown below:

[0003] [ka]

[0004] It has the chemical structure:

[0005] Briraloxazine is an orally bioavailable small molecule that has been developed for the treatment of schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension.

[0006] The compound is described in US Pat. No. 8,188,076.

[0007] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. Single molecules can exhibit different crystalline structures and physical properties, such as melting points, thermal behavior (measured, for example, by thermogravimetric analysis ("TGA") or differential scanning calorimetry ("DSC")), X-ray diffraction (XRD) patterns, infrared absorption fingerprints, and solid state ( 13 C) Various polymorphs may occur that have NMR spectra. One or more of these techniques can be used to distinguish between different polymorphic forms of a compound.

[0008] Various salts and solid forms (including solvated forms) of an active pharmaceutical ingredient may have different properties. Such variations in the properties of various salts and solid forms and solvates may provide the basis for improving formulations, for example, by improving processability or handling, shifting the dissolution profile in a favorable direction, or improving stability (polymorphism, as well as chemical stability) and shelf life. These variations in the properties of various salts and solid forms may also result in improvements to the final dosage form, for example, if they serve to improve bioavailability. Various salts and solid forms and solvates of an active pharmaceutical ingredient may also give rise to various polymorphs or crystalline forms, which may further provide additional opportunities for evaluating variations in the properties and characteristics of the solid active pharmaceutical ingredient. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] U.S. Patent No. 8,188,076 [Non-patent literature]

[0010] [Non-Patent Document 1] Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. Summary of the Invention [Problem to be solved by the invention]

[0011] The discovery of novel solid forms and solvates of pharmaceutical products can provide materials with desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification, or desirable intermediate crystalline forms that facilitate conversion to other polymorphic forms. Novel solid forms of pharmaceutically useful compounds can also provide opportunities to improve the performance characteristics of pharmaceutical products. For example, providing products with different properties, including different crystal habits, higher crystallinity, or polymorphic stability, expands the repertoire of materials available to formulation scientists for formulation optimization, which may result in better processability or handling, improved dissolution profiles, or improved shelf life (chemical / physical stability). For at least these reasons, there is a need for additional solid forms of briraloxazine (including solvated forms), or salts of briraloxazine, particularly briraloxazine hydrochloride. [Means for solving the problem]

[0012] The present disclosure provides crystalline polymorphs or salts of briraloxazine, particularly briraloxazine hydrochloride, methods for their preparation, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other solid forms of briraloxazine, briraloxazine salts, and solid forms thereof.

[0013] The present disclosure also provides other solid forms of briraloxazine and / or briraloxazine co-crystals and / or salts thereof, particularly briraloxazine hydrochloride, and uses of said solid forms of briraloxazine and salts thereof, particularly briraloxazine hydrochloride, in the preparation of these solid forms.

[0014] The present disclosure provides crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, for use in medicine, including for the treatment of schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension.

[0015] The present disclosure also encompasses the use of the disclosed crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, for the preparation of pharmaceutical compositions and / or formulations.

[0016] In another aspect, the present disclosure provides pharmaceutical compositions comprising a crystalline polymorph of briraloxazine according to the present disclosure and a salt of briraloxazine, particularly briraloxazine hydrochloride.

[0017] The present disclosure includes a method for preparing the above-mentioned pharmaceutical composition, comprising combining any one or a combination of crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, with at least one pharmaceutically acceptable excipient.

[0018] The crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, as defined herein, and pharmaceutical compositions or formulations of the crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, can be used as medicines, such as for the treatment of schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension.

[0019] The present disclosure also provides methods for treating schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension by administering a therapeutically effective amount of at least one of the crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, of the present disclosure, or a combination thereof, or a pharmaceutical composition thereof, to a subject suffering from, or otherwise in need of treatment for, schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension.

[0020] The present disclosure also provides use of at least one of the crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, of the present disclosure, or the pharmaceutical compositions described above, for the manufacture of a medicament for treating, for example, schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension. [Brief explanation of the drawings]

[0021] [Figure 1] FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Briraloxazine form B1. [Figure 2] FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Briraloxazine form B2. [Figure 3] FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Briraloxazine form B3. [Figure 4] FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Briraloxazine form B4. [Figure 5] FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Briraloxazine form B5. [Figure 6] FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Briraloxazine form B6. [Figure 7] FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of briraloxazine hydrochloride form BR1. [Figure 8] FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of briraloxazine hydrochloride form BR2. [Figure 9] FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of briraloxazine hydrochloride form BR3. [Figure 10] FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of briraloxazine hydrochloride form BR4. [Figure 11] FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of briraloxazine hydrochloride form BR5. [Figure 12] FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of briraloxazine hydrochloride form BR6. [Figure 13] FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of briraloxazine hydrochloride form BR7. [Figure 14]FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of briraloxazine hydrobromide form BHBr1. [Figure 15] FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of amorphous briraloxazine hydrochloride. [Figure 16a] FIG. 1 shows the solid-state 13C NMR spectrum (full scan) of briraloxazine hydrochloride form BR1. [Figure 16b] FIG. 1 shows the solid-state 13C NMR spectrum (0-100 ppm) of briraloxazine hydrochloride form BR1. [Figure 16c] FIG. 1 shows the solid-state 13C NMR spectrum (100-200 ppm) of briraloxazine hydrochloride form BR1. [Figure 17a] FIG. 1 shows the solid-state C NMR spectrum (full scan) of briraloxazine hydrochloride form BR3. [Figure 17b] FIG. 1 shows the solid-state 13C NMR spectrum (0-100 ppm) of briraloxazine hydrochloride form BR3. [Figure 17c] FIG. 1 shows the solid-state C NMR spectrum (100-200 ppm) of briraloxazine hydrochloride form BR3. DETAILED DESCRIPTION OF THE INVENTION

[0022] The present disclosure encompasses crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly solid forms of briraloxazine, including briraloxazine hydrochloride, methods for their preparation, and pharmaceutical compositions thereof. In embodiments, the present disclosure provides crystalline forms of briraloxazine designated Form B1, Form B2, Form B3, Form B4, Form B5, and Form B6; briraloxazine hydrochloride designated Form BR1, Form BR2, Form BR3, Form BR4, Form BR5, Form BR6, and Form BR7; and briraloxazine hydrobromide designated Form BHBr1 (as defined herein).

[0023] The solid state properties of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride and their crystalline polymorphs, can be influenced by controlling the conditions under which briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride and their crystalline polymorphs, are obtained in solid form.

[0024] A solid form (or polymorph) may be referred to herein as being polymorphically pure or substantially free of any other solid (or polymorphic) form. As used herein, in this context, the phrase "substantially free of any other form" is understood to mean that the solid form contains 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 any other form of the subject compound, as measured, for example, by XRPD. Thus, the crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, described herein are understood to be substantially free of any other solid forms and therefore 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 polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride. In some embodiments of the present disclosure, the crystalline polymorphs of briraloxazine described herein, and salts of briraloxazine, including briraloxazine hydrobromide and briraloxazine hydrochloride, particularly briraloxazine hydrochloride, may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more other crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride. Thus, for example, the crystalline polymorphs of briraloxazine and salts of briraloxazine, including briraloxazine hydrobromide and briraloxazine hydrochloride, particularly briraloxazine hydrochloride, described in any aspect or embodiment herein may be polymorphically pure: contain 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 any other form of briraloxazine and salts of briraloxazine, including briraloxazine hydrobromide and briraloxazine hydrochloride, particularly briraloxazine hydrochloride.As another example, the crystalline polymorphs of briraloxazine and salts of briraloxazine, including briraloxazine hydrobromide and briraloxazine hydrochloride, particularly briraloxazine hydrochloride, described in any aspect or embodiment herein may be polymorphically pure: may contain 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 any other forms of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride. Thus, the crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, described in any aspect or embodiment herein may be polymorphically pure: contain 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 any other form of briraloxazine and salts of briraloxazine, including briraloxazine hydrobromide and briraloxazine hydrochloride, particularly briraloxazine hydrochloride. Alternatively, the crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, according to any aspect or embodiment of the present invention may be polymorphically pure and 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% crystalline polymorphs of briraloxazine and salts of briraloxazine, including briraloxazine hydrobromide and briraloxazine hydrochloride, particularly briraloxazine hydrochloride.

[0025] Depending on the other crystalline polymorphs to which it is compared, the crystalline polymorphs of Brillaloxazine of the present disclosure, and salts of Brillaloxazine, including Brillaloxazine hydrobromide and Brillaloxazine hydrochloride, particularly Brillaloxazine hydrochloride, 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 thermal and mechanical stability as well as chemical stability with respect to polymorphic transformation, stability against dehydration and / or storage stability, low content of residual solvents, lower hygroscopicity, flowability, and advantageous processability and handling properties, such as compressibility and bulk density.

[0026] Solid forms, such as crystalline or amorphous forms, may be referred to herein as being characterized by graphical data "as shown in the figures" or "substantially as shown in the figures." Such data include, for example, powder X-ray diffractograms and solid-state NMR spectra. As is well known in the art, graphical data may provide additional technical information (a so-called "fingerprint") to further define each solid form that cannot necessarily be explained solely by reference to numerical values ​​or peak positions. In any event, those skilled in the art will understand that such graphical representations of data may be subject to slight variations 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. Nevertheless, those skilled in the art can easily compare the graphical data in the figures herein with graphical data generated from an unknown crystalline form and determine whether the two sets of graphical data characterize the same crystalline form or two different crystalline forms. Crystalline forms of briraloxazine and salts of briraloxazine, including briraloxazine hydrobromide and briraloxazine hydrochloride, particularly briraloxazine hydrochloride, represented herein as characterized by graphical data "as shown in the Figures" or "substantially as shown in the Figures," are therefore understood to include any crystalline forms of briraloxazine and salts of briraloxazine, including briraloxazine hydrobromide and briraloxazine hydrochloride, particularly briraloxazine hydrochloride, characterized by graphical data with such slight variations as compared to the Figures, as known to those skilled in the art.

[0027] As used herein, unless otherwise specified, the term "anhydrous" in connection with crystalline forms of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, refers to crystalline forms of briraloxazine and salts of briraloxazine, including briraloxazine hydrobromide and briraloxazine hydrochloride, particularly briraloxazine hydrochloride, that do not contain a defined stoichiometric amount of water of crystallization (or other solvent) within the crystal. Moreover, the "anhydrous" forms generally do not contain more than 1% (w / w) of either water or organic solvent, as measured, for example, by TGA.

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

[0029] As used herein, in relation to the crystalline polymorphs of briraloxazine of the present disclosure, and salts of briraloxazine, including briraloxazine hydrobromide and briraloxazine hydrochloride, particularly briraloxazine hydrochloride, the term "isolated" refers to a crystalline polymorph of briraloxazine, and salts of briraloxazine, particularly briraloxazine hydrochloride, that has been physically separated from the reaction mixture in which it was formed.

[0030] As used herein, unless otherwise specified, XRPD measurements are made using copper Kα radiation at a wavelength of 1.5418 Å. XRPD peaks reported herein are measured using Cu Kα radiation, λ=1.5418 Å, typically at a temperature of 25±3° C.

[0031] As used herein, unless otherwise specified, the 13 C NMR was performed at 125 MHz with a magic angle spinning frequency of ω r / 2π=11 kHz, preferably at a temperature of 293 K±3°C.

[0032] A body, such as a reaction mixture, may be characterized herein as being at or at "room temperature" or "ambient temperature," often abbreviated as "RT." This means that the body's temperature is close to or the same as the temperature of the space in which the body 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] For example, the amount of solvent utilized in a chemical process such as a reaction or crystallization may be expressed herein as a number, such as "volume," or "vol," or "V." For example, a material may be expressed 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 material; for example, 5 grams of material suspended in 10 volumes of solvent means that the solvent is used in an amount of 10 milliliters per gram of suspended material, or, in this example, 50 mL of solvent. In other contexts, the term "v / v" may be used to indicate the number of volumes of solvent added to a liquid mixture, based on the volume of the mixture. For example, adding solvent X (1.5 v / v) to 100 ml of reaction mixture indicates that 150 ml of solvent X is added.

[0034] A process or step may be referred to herein as being carried out "overnight." This refers to the length of time for the process or step, e.g., overnight, during which the process or step cannot be observed in progress. This length of time may be from about 8 to about 20 hours, or from about 10 to 18 hours, or 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] As used herein, unless otherwise indicated, the term "ambient conditions" refers to atmospheric pressure and a temperature of 22-24°C.

[0037] The present disclosure includes a crystalline polymorph of Briraloxazine designated B1. Crystalline form B1 of Briraloxazine may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 1; an X-ray powder diffraction pattern having peaks at 15.8, 22.0, and 24.3 degrees two-theta ± 0.2 degrees two-theta; and combinations of these data.

[0038] Crystalline form B1 of Briraloxazine may be further characterized by an X-ray powder diffraction pattern having peaks at 15.8, 22.0, and 24.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 5.0, 7.5, 10.1, 18.2, and 26.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0039] Alternatively, crystalline form B1 of Briraloxazine may be characterized by an X-ray powder diffraction pattern having peaks at 5.0, 7.5, 10.1, 18.2, and 26.9 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline form B1 of Briraloxazine may be further characterized by an X-ray powder diffraction pattern having peaks at 5.0, 7.5, 10.1, 18.2, and 26.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, or four additional peaks selected from 14.9, 20.9, 21.4, and 28.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0040] Briraloxazine crystalline form B1 can be characterized by an X-ray powder diffraction pattern having peaks at 5.0, 7.5, 10.1, 14.9, 18.2, 20.9, 21.4, 26.9, and 28.0 degrees two-theta ± 0.2 degrees two-theta.

[0041] Crystalline Form B1 of Briraloxazine according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and may be further characterized by an XRPD pattern that is absent from 3.2 to 4.4 degrees 2-theta ± 0.2 degrees 2-theta, and / or an XRPD pattern that is absent from 5.6 to 6.8 degrees 2-theta ± 0.2 degrees 2-theta, and / or an XRPD pattern that is absent from 8.2 to 9.7 degrees 2-theta ± 0.2 degrees 2-theta, and / or an XRPD pattern that is absent from 10.6 to 12.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form B1 of Briraloxazine according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and may be further characterized by an XRPD pattern that is absent from one, two, three, or four peaks in the aforementioned regions.

[0042] In one embodiment of the present disclosure, crystalline form B1 of Briraloxazine is isolated.

[0043] Briraloxazine crystalline form B1 can be an anhydrous form.

[0044] Crystalline Form B1 of Briraloxazine may be characterized by each of the above characteristics alone and / or by all possible combinations, for example, an XRPD pattern having peaks at 15.8, 22.0, and 24.3 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 5.0, 7.5, 10.1, 18.2, and 26.9 degrees 2-theta ± 0.2 degrees 2-theta; the XRPD pattern shown in FIG. 1, and combinations thereof.

[0045] Crystalline Form B1 of Briraloxazine described in any aspect or embodiment of the present disclosure can be polymorphically pure and preferably contains: 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 any other form of Briraloxazine.

[0046] The present disclosure includes a crystalline polymorph of Briraloxazine designated B2. Crystalline form B2 of Briraloxazine may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 2; an X-ray powder diffraction pattern having peaks at 12.8, 15.8, and 20.8 degrees two-theta ± 0.2 degrees two-theta; and combinations of these data.

[0047] Briraloxazine crystalline form B2 may be further characterized by an X-ray powder diffraction pattern having peaks at 12.8, 15.8, and 20.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 8.5, 14.0, 17.2, 19.0, and 26.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0048] Alternatively, crystalline form B2 of Briraloxazine may be characterized by an X-ray powder diffraction pattern having peaks at 8.5, 14.0, 17.2, 19.0, and 26.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline form B2 of Briraloxazine may be further characterized by an X-ray powder diffraction pattern having peaks at 8.5, 14.0, 17.2, 19.0, and 26.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, or four additional peaks selected from 10.1, 19.6, 24.3, and 26.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0049] Briraloxazine crystalline form B2 may be characterized by an X-ray powder diffraction pattern having peaks at 8.5, 10.1, 14.0, 17.2, 19.0, 19.6, 24.3, 26.0, and 26.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0050] Crystalline Form B2 of Briraloxazine according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and may be further characterized by an XRPD pattern that is absent from 3.2 to 4.4 degrees 2-theta ± 0.2 degrees 2-theta, and / or is absent from 5.6 to 6.7 degrees 2-theta ± 0.2 degrees 2-theta, and / or is absent from 9.1 to 9.7 degrees 2-theta ± 0.2 degrees 2-theta, and / or is absent from 10.6 to 11.7 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form B2 of Briraloxazine according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and may be further characterized by an XRPD pattern that is absent from one, two, three, or four peaks in the aforementioned regions.

[0051] In one embodiment of the present disclosure, crystalline form B2 of Briraloxazine is isolated.

[0052] The crystalline form B2 of Briraloxazine can be an anhydrous form.

[0053] Crystalline form B2 of Briraloxazine may be characterized by each of the above characteristics alone and / or by all possible combinations, such as an XRPD pattern having peaks at 12.8, 15.8, and 20.8 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 8.5, 14.0, 17.2, 19.0, and 26.0 degrees 2-theta ± 0.2 degrees 2-theta; the XRPD pattern shown in FIG. 2, and combinations thereof.

[0054] The crystalline form B2 of Briraloxazine described in any aspect or embodiment of the present disclosure can be polymorphically pure and preferably contains: 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 any other form of Briraloxazine.

[0055] The present disclosure includes a crystalline polymorph of Briraloxazine designated B3. Crystalline form B3 of Briraloxazine may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 3; an X-ray powder diffraction pattern having peaks at 9.7, 23.0, and 31.2 degrees two-theta ± 0.2 degrees two-theta; and combinations of these data.

[0056] Crystalline form B3 of Briraloxazine may be further characterized by an X-ray powder diffraction pattern having peaks at 9.7, 23.0, and 31.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 15.5, 23.4, 24.0, 26.3, and 31.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0057] Alternatively, crystalline form B3 of Briraloxazine may be characterized by an X-ray powder diffraction pattern having peaks at 15.5, 23.4, 24.0, 26.3, and 31.7 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline form B3 of Briraloxazine may be further characterized by an X-ray powder diffraction pattern having peaks at 15.5, 23.4, 24.0, 26.3, and 31.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 8.7, 13.9, and 31.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0058] Briraloxazine crystalline form B3 can be characterized by an X-ray powder diffraction pattern with peaks at 8.7, 13.9, 15.5, 23.4, 24.0, 26.3, 31.2, and 31.7 degrees 2-theta ±0.2 degrees 2-theta.

[0059] In one embodiment of the present disclosure, crystalline form B3 of briraloxazine is isolated.

[0060] The crystalline form B3 of Briraloxazine can be an anhydrous form.

[0061] Crystalline form B3 of Briraloxazine according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and further characterized by an XRPD pattern having no peaks between 4.0 and 7.5 degrees 2-theta ± 0.2 degrees 2-theta, and / or no peaks between 8.0 and 8.3 degrees 2-theta ± 0.2 degrees 2-theta, and / or no peaks between 9.0 and 9.4 degrees 2-theta ± 0.2 degrees 2-theta, and / or no peaks between 10.0 and 10.5 degrees 2-theta ± 0.2 degrees 2-theta, and / or no peaks between 11.4 and 11.8 degrees 2-theta ± 0.2 degrees 2-theta; and / or no peaks between 14.3 and 14.6 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline form B3 of Briraloxazine according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and further characterized by an XRPD pattern in which one, two, three, four, five, or six peaks in the aforementioned regions are absent.

[0062] Crystalline form B3 of Briraloxazine may be characterized by each of the above characteristics alone and / or by all possible combinations, such as an XRPD pattern having peaks at 9.7, 23.0, and 31.2 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 15.5, 23.4, 24.0, 26.3, and 31.7 degrees 2-theta ± 0.2 degrees 2-theta; the XRPD pattern shown in FIG. 3, and combinations thereof.

[0063] The crystalline form B3 of briraloxazine described in any aspect or embodiment of the present disclosure can be polymorphically pure and preferably contains: 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 any other form of briraloxazine.

[0064] The present disclosure includes a crystalline polymorph of Briraloxazine designated B4. Crystalline form B4 of Briraloxazine may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 4; an X-ray powder diffraction pattern having peaks at 20.1, 23.2, and 24.3 degrees two-theta ± 0.2 degrees two-theta; and combinations of these data.

[0065] Crystalline form B4 of Briraloxazine may be further characterized by an X-ray powder diffraction pattern having peaks at 20.1, 23.2, and 24.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 11.9, 14.7, 16.2, 21.9, and 25.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0066] Alternatively, crystalline form B4 of Briraloxazine may be characterized by an X-ray powder diffraction pattern having peaks at 11.9, 14.7, 16.2, 21.9, and 25.1 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline form B4 of Briraloxazine may be further characterized by an X-ray powder diffraction pattern having peaks at 11.9, 14.7, 16.2, 21.9, and 25.1 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, or four additional peaks selected from 11.2, 24.3, 26.3, and 27.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0067] Briraloxazine crystalline form B4 may be characterized by an X-ray powder diffraction pattern having peaks at 11.2, 11.9, 14.7, 16.2, 21.9, 24.3, 26.3, 25.1, and 27.4 degrees two-theta ± 0.2 degrees two-theta.

[0068] Crystalline form B4 of Briraloxazine according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and further characterized by an XRPD pattern having no peaks present between 3.0 and 8.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0069] In one embodiment of the present disclosure, crystalline form B4 of Briraloxazine is isolated.

[0070] The crystalline form B4 of Briraloxazine can be an anhydrous form.

[0071] Crystalline form B4 of Briraloxazine may be characterized by each of the above features alone and / or by all possible combinations, such as an XRPD pattern having peaks at 20.1, 23.2, and 24.3 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 11.9, 14.7, 16.2, 21.9, and 25.1 degrees 2-theta ± 0.2 degrees 2-theta; the XRPD pattern shown in Figure 4, and combinations thereof.

[0072] The crystalline form B4 of Briraloxazine described in any aspect or embodiment of the present disclosure can be polymorphically pure and preferably contains: 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 any other form of Briraloxazine.

[0073] The present disclosure includes a crystalline polymorph of Briraloxazine designated B5. Crystalline form B5 of Briraloxazine may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 5; an X-ray powder diffraction pattern having peaks at 15.5, 25.0, and 27.3 degrees two-theta ± 0.2 degrees two-theta; and combinations of these data.

[0074] Crystalline form B5 of Briraloxazine may be further characterized by an X-ray powder diffraction pattern having peaks at 15.5, 25.0, and 27.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 14.1, 16.1, 21.6, 23.4, and 26.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0075] Alternatively, crystalline form B5 of Briraloxazine may be characterized by an X-ray powder diffraction pattern having peaks at 14.1, 16.1, 21.6, 23.4, and 26.1 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline form B5 of Briraloxazine may be further characterized by an X-ray powder diffraction pattern having peaks at 14.1, 16.1, 21.6, 23.4, and 26.1 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, or four additional peaks selected from 12.3, 25.0, 27.3, and 28.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0076] Crystalline form B5 of Briraloxazine can be characterized by an X-ray powder diffraction pattern with peaks at 12.3, 14.1, 16.1, 21.6, 23.4, 25.0, 27.3, 26.1, and 28.0 degrees two-theta ± 0.2 degrees two-theta.

[0077] Crystalline Form B5 of Briraloxazine according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and may be further characterized by an XRPD pattern that is absent from 2.5 to 4.5 degrees 2-theta ± 0.2 degrees 2-theta, and / or an XRPD pattern that is absent from 5.2 to 6.0 degrees 2-theta ± 0.2 degrees 2-theta, and / or an XRPD pattern that is absent from 7.4 to 8.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form B5 of Briraloxazine according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and may be further characterized by an XRPD pattern that is absent from one, two, or three peaks in the aforementioned regions.

[0078] In one embodiment of the present disclosure, crystalline form B5 of briraloxazine is isolated.

[0079] The crystalline form B5 of Briraloxazine can be an anhydrous form.

[0080] Crystalline form B5 of Briraloxazine may be characterized by each of the above characteristics alone and / or by all possible combinations, such as an XRPD pattern having peaks at 15.5, 25.0, and 27.3 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 14.1, 16.1, 21.6, 23.4, and 26.1 degrees 2-theta ± 0.2 degrees 2-theta; the XRPD pattern shown in FIG. 5, and combinations thereof.

[0081] The crystalline form B5 of briraloxazine described in any aspect or embodiment of the present disclosure can be polymorphically pure and preferably contains: 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 any other form of briraloxazine.

[0082] The present disclosure includes a crystalline polymorph of Briraloxazine designated B6. Crystalline form B6 of Briraloxazine may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 6; an X-ray powder diffraction pattern having peaks at 8.8, 17.7, and 20.1 degrees two-theta ± 0.2 degrees two-theta; and combinations of these data.

[0083] Crystalline form B6 of Briraloxazine may be further characterized by an X-ray powder diffraction pattern having peaks at 8.8, 17.7, and 20.1 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, or four additional peaks selected from 10.8, 18.4, 27.6, and 29.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0084] Alternatively, crystalline form B6 of Briraloxazine may be characterized by an X-ray powder diffraction pattern having peaks at 10.8, 18.4, 27.6, and 29.7 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline form B6 of Briraloxazine may be further characterized by an X-ray powder diffraction pattern having peaks at 10.8, 18.4, 27.6, and 29.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 14.5, 15.7, 18.9, 24.9, and 26.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0085] Crystalline form B6 of Briraloxazine can be characterized by an X-ray powder diffraction pattern with peaks at 10.8, 14.5, 15.7, 18.4, 18.9, 24.9, 26.6, 27.6, and 29.7 degrees 2-theta ±0.2 degrees 2-theta.

[0086] Crystalline form B6 of Briraloxazine according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and may be further characterized by an XRPD pattern that is absent from 4.5 to 8.2 degrees 2-theta ± 0.2 degrees 2-theta, and / or from 9.2 to 10.2 degrees 2-theta ± 0.2 degrees 2-theta, and / or from 11.0 to 12.0 degrees 2-theta ± 0.2 degrees 2-theta, and / or from 12.6 to 13.5 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline form B6 of Briraloxazine according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and may be further characterized by an XRPD pattern that is absent from one, two, three, or four peaks in the aforementioned regions.

[0087] In one embodiment of the present disclosure, crystalline form B6 of briraloxazine is isolated.

[0088] The crystalline form B6 of Briraloxazine can be an anhydrous form.

[0089] Crystalline form B6 of Briraloxazine may be characterized by each of the above features alone and / or by all possible combinations, such as an XRPD pattern having peaks at 8.8, 17.7, and 20.1 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 10.8, 18.4, 27.6, and 29.7 degrees 2-theta ± 0.2 degrees 2-theta; the XRPD pattern shown in FIG. 6, and combinations thereof.

[0090] The crystalline form B6 of briraloxazine described in any aspect or embodiment of the present disclosure can be polymorphically pure and preferably contains: 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 any other form of briraloxazine.

[0091] The present disclosure includes a crystalline polymorph of briraloxazine hydrochloride designated BR1. Crystalline form BR1 of briraloxazine hydrochloride has the following: an X-ray powder diffraction pattern substantially as shown in Figure 7; an X-ray powder diffraction pattern having peaks at 17.3, 21.5, and 25.7 degrees 2-theta ± 0.2 degrees 2-theta; an X-ray powder diffraction pattern having peaks at 20.6, 42.4, 97.5, 122.2, 131.0, and 165.5 ppm ± 0.2 ppm; 13 C NMR spectrum; solid with the following absolute chemical shift differences from the reference peak at 116.7 ppm ± 2 ppm: 96.11, 74.31, 19.21, 5.49, 14.29, and 48.78 ppm ± 0.1 ppm 13 C NMR spectrum; solid substantially as shown in Figure 16a, Figure 16b or Figure 16c 13 C NMR spectrum; and combinations of these data.

[0092] Briraloxazine hydrochloride crystalline form BR1 may be further characterized by an X-ray powder diffraction pattern having peaks at 17.3, 21.5, and 25.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 7.2, 16.4, 19.5, 22.4, and 24.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0093] Alternatively, crystalline form BR1 of Briraloxazine hydrochloride may be characterized by an X-ray powder diffraction pattern having peaks at 7.2, 16.4, 19.5, 22.4, and 24.7 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline BR1 of Briraloxazine hydrochloride may be further characterized by an X-ray powder diffraction pattern having peaks at 7.2, 16.4, 19.5, 22.4, and 24.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, or four additional peaks selected from 14.3, 14.9, 25.7, and 27.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0094] Briraloxazine hydrochloride crystalline form BR1 may be characterized by an X-ray powder diffraction pattern having peaks at 7.2, 14.3, 14.9, 16.4, 19.5, 22.4, 24.7, 25.7, and 27.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0095] Crystalline form BR1 of briraloxazine hydrochloride according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and may be further characterized by an XRPD pattern that is absent from 2.0 to 3.0 degrees 2-theta ± 0.2 degrees 2-theta, and / or from 4.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta, and / or from 8.0 to 10.5 degrees 2-theta ± 0.2 degrees 2-theta, and / or from 11.5 to 13.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline form BR1 of briraloxazine hydrochloride according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and may be further characterized by an XRPD pattern that is absent from one, two, three, or four peaks in the aforementioned regions.

[0096] In one embodiment of the present disclosure, crystalline form BR1 of briraloxazine hydrochloride is isolated.

[0097] Briraloxazine hydrochloride crystalline form BR1 can be an anhydrous form.

[0098] Crystalline form BR1 of briraloxazine hydrochloride may be characterized by each of the above characteristics alone and / or by all possible combinations, for example, an XRPD pattern having peaks at 17.3, 21.5, and 25.7 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 7.2, 16.4, 19.5, 22.4, and 24.7 degrees 2-theta ± 0.2 degrees 2-theta; the XRPD pattern shown in Figure 7, and combinations thereof.

[0099] The crystalline form BR1 of briraloxazine hydrochloride described in any aspect or embodiment of the present disclosure can be polymorphically pure and preferably contains: 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 any other form of briraloxazine hydrochloride.

[0100] The present disclosure provides a method for preparing briraloxazine hydrochloride Form BR1, comprising crystallizing briraloxazine hydrochloride from acetone and diethyl ether. According to any aspect or embodiment, the method can include: (a) preparing a solution of briraloxazine hydrochloride in a solvent comprising acetone; (b) combining the solution with diethyl ether; and (c) optionally isolating crystalline briraloxazine hydrochloride Form BR1. The solution in step (a) can be prepared by reacting a solution of briraloxazine in acetone with hydrochloric acid. The reaction is preferably carried out at a temperature of about 18°C ​​to about 55°C, about 20°C to about 50°C, about 23°C to about 40°C, about 23°C to about 30°C, or about 25°C.

[0101] According to any aspect or embodiment of the disclosed method, a method for preparing Briraloxazine hydrochloride Form BR1 comprises: (i) dissolving briraloxazine in acetone; (ii) adding hydrochloric acid; (iii) adding diethyl ether; (iv) isolating briraloxazine hydrochloride; (v) drying; may include:

[0102] According to any aspect or embodiment of the disclosed method for preparing Briraloxazine hydrochloride Form BR1, acetone may be used in an amount of: about 30 ml to about 70 ml, about 40 ml to about 60 ml, or about 50 ml per gram of Briraloxazine. The acetone may be added at a temperature of: about 18° C. to about 55° C., about 20° C. to about 50° C., about 23° C. to about 40° C., about 23° C. to about 30° C., or about 25° C.

[0103] According to some aspects or embodiments of the present methods for making Briraloxazine hydrochloride Form BR1, hydrochloric acid is preferably used as a 2 M HCl solution. The hydrochloric acid is preferably used in an amount of about 5 ml to about 30 ml, or about 10 ml to about 25 ml, or about 20 ml per gram of Briraloxazine.

[0104] In any aspect or embodiment of the disclosed method, hydrochloric acid can be added to the solution at a temperature of: about 18°C ​​to about 70°C, about 20°C to about 55°C, about 22°C to about 40°C, about 23°C to about 30°C, or about 25°C.

[0105] According to any aspect or embodiment of the disclosed method for preparing briraloxazine hydrochloride Form BR1, diethyl ether may be used in an amount of about 50 ml to about 500 ml, about 150 ml to about 400 ml, about 200 ml to about 350 ml, or about 300 ml per gram of briraloxazine. According to any aspect or embodiment of the disclosed method for preparing briraloxazine hydrochloride Form BR1, the volume ratio of acetone to diethyl ether may be about 1:2 to about 1:20, about 1:4 to about 1:10, about 1:5 to about 1:8, or about 1:6. According to any aspect or embodiment of the disclosed method, diethyl ether may be added at a temperature of about 10°C to about 50°C, about 15°C to about 40°C, about 18°C ​​to about 30°C, about 23°C to about 28°C, or about 25°C.

[0106] In any aspect or embodiment of the disclosed method, the reaction mixture comprising briraloxazine hydrochloride, acetone, and diethyl ether may be stirred at a temperature of about 10°C to about 50°C, about 15°C to about 40°C, about 18°C ​​to about 30°C, about 23°C to about 28°C, or about 25°C for about 6 hours to about 48 hours, about 10 hours to about 24 hours, about 12 hours to about 20 hours, about 14 hours to about 18 hours, or about 16 hours.

[0107] The method may further include isolating the resulting briraloxazine hydrochloride by any suitable procedure, such as by filtration, decantation, or centrifugation. Specifically, the product may be isolated by vacuum filtration. After isolation, the briraloxazine hydrochloride may be dried. Drying may be carried out under vacuum for about 5 minutes to 1 hour, or about 10 minutes to about 25 minutes, or about 15 minutes.

[0108] According to any aspect or embodiment of the disclosed method of preparing briraloxazine hydrochloride Form BR1, the method may further comprise combining briraloxazine Form BR1 with at least one pharmaceutically acceptable excipient to prepare a pharmaceutical composition.

[0109] The present disclosure includes a crystalline polymorph of briraloxazine hydrochloride designated BR2. Crystalline form BR2 of briraloxazine hydrochloride may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 8; an X-ray powder diffraction pattern having peaks at 10.0, 19.6, and 22.9 degrees two-theta ± 0.2 degrees two-theta; and combinations of these data.

[0110] Briraloxazine hydrochloride crystalline form BR2 may be further characterized by an X-ray powder diffraction pattern having peaks at 10.0, 19.6, and 22.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 12.1, 17.7, 20.3, 25.0, and 25.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0111] Alternatively, crystalline form BR2 of briraloxazine hydrochloride may be characterized by an X-ray powder diffraction pattern having peaks at 12.1, 17.7, 20.3, 25.0, and 25.4 degrees 2-theta ± 0.2 degrees 2-theta. Briraloxazine hydrochloride crystalline BR2 may be further characterized by an X-ray powder diffraction pattern having peaks at 12.1, 17.7, 20.3, 25.0, and 25.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, or four additional peaks selected from 4.8, 14.7, 21.8, and 24.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0112] Briraloxazine hydrochloride crystalline form BR2 can be characterized by an X-ray powder diffraction pattern having peaks at 4.8, 12.1, 14.7, 17.7, 20.3, 21.8, 24.1, 25.0, and 25.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0113] Crystalline form BR2 of briraloxazine hydrochloride according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and may be further characterized by an XRPD pattern that is absent from 3.0 to 3.6 degrees 2-theta ± 0.2 degrees 2-theta, and / or an XRPD pattern that is absent from 5.4 to 7.0 degrees 2-theta ± 0.2 degrees 2-theta, and / or an XRPD pattern that is absent from 8.4 to 9.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline form BR2 of briraloxazine hydrochloride according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and may be further characterized by an XRPD pattern that is absent from one, two, or three of the peaks in the aforementioned regions.

[0114] In one embodiment of the present disclosure, crystalline form BR2 of briraloxazine hydrochloride is isolated.

[0115] Briraloxazine hydrochloride crystalline form BR2 may be in the form of a hydrate.

[0116] Crystalline form BR2 of briraloxazine hydrochloride may be characterized by each of the above characteristics alone and / or by all possible combinations, such as an XRPD pattern having peaks at 10.0, 19.6, and 22.9 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 12.1, 17.7, 20.3, 25.0, and 25.4 degrees 2-theta ± 0.2 degrees 2-theta; the XRPD pattern shown in FIG. 8, and combinations thereof.

[0117] The crystalline form BR2 of briraloxazine hydrochloride described in any aspect or embodiment of the present disclosure can be polymorphically pure and preferably contains: 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 any other form of briraloxazine hydrochloride.

[0118] The present disclosure includes a crystalline polymorph of briraloxazine hydrochloride designated BR3. Crystalline form BR3 of briraloxazine hydrochloride has the following: an X-ray powder diffraction pattern substantially as shown in Figure 9; an X-ray powder diffraction pattern with peaks at 12.8, 15.4, and 18.9 degrees 2-theta ± 0.2 degrees 2-theta; an X-ray powder diffraction pattern with peaks at 22.7, 28.4, 59.3, 66.3, 119.5, and 155.3 ppm ± 0.2 ppm; 13 C NMR spectrum; solid with the following absolute chemical shift differences from the reference peak at 116.7 ppm ± 2 ppm: 94.01, 88.31, 50.41, 48.78, 2.79, and 38.59 ppm ± 0.1 ppm 13 C NMR spectrum; solid substantially as shown in Figure 17a, Figure 17b or Figure 17c 13 C NMR spectrum; and combinations of these data.

[0119] Briraloxazine hydrochloride crystalline form BR3 may be further characterized by an X-ray powder diffraction pattern having peaks at 12.8, 15.4, and 18.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 16.1, 17.4, 22.6, 25.3, and 27.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0120] Alternatively, crystalline form BR3 of briraloxazine hydrochloride may be characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4, 22.6, 25.3, and 27.8 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline BR3 of briraloxazine hydrochloride may be further characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4, 22.6, 25.3, and 27.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 19.8, 20.7, 21.8, 23.7, and 24.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0121] Briraloxazine hydrochloride crystalline form BR3 can be characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4, 19.8, 20.7, 21.8, 22.6, 23.7, 24.0, 25.3, and 27.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0122] Crystalline form BR3 of briraloxazine hydrochloride according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and further characterized by an XRPD pattern that has no peaks between 3.5 and 9.5 degrees 2-theta ± 0.2 degrees 2-theta or between 3.5 and 10.5 degrees 2-theta ± 0.2 degrees 2-theta, and / or has no peaks between 12.0 and 12.5 degrees 2-theta ± 0.2 degrees 2-theta, and / or has no peaks between 13.2 and 13.7 degrees 2-theta ± 0.2 degrees 2-theta, and / or has no peaks between 14.3 and 14.7 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline form BR3 of Briraloxazine hydrochloride according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and further characterized by an XRPD pattern in which one, two, three, or four peaks in the aforementioned regions are absent.

[0123] In one embodiment of the present disclosure, crystalline form BR3 of briraloxazine hydrochloride is isolated.

[0124] Briraloxazine hydrochloride crystalline form BR3 can be an anhydrous form.

[0125] Crystalline form BR3 of briraloxazine hydrochloride may be characterized by each of the above characteristics alone and / or by all possible combinations, for example, an XRPD pattern having peaks at 12.8, 15.4, and 18.9 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 16.1, 17.4, 22.6, 25.3, and 27.8 degrees 2-theta ± 0.2 degrees 2-theta; the XRPD pattern shown in Figure 9, and combinations thereof.

[0126] The crystalline form BR3 of briraloxazine hydrochloride described in any aspect or embodiment of the present disclosure can be polymorphically pure and preferably contains: 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 any other form of briraloxazine hydrochloride.

[0127] According to any aspect or embodiment, briraloxazine hydrochloride Form BR3 can be prepared by crystallization of briraloxazine hydrochloride from isopropyl alcohol. The method preferably includes the step of cooling a mixture of briraloxazine hydrochloride in isopropyl alcohol. Specifically, according to any aspect or embodiment of the method, a mixture of briraloxazine hydrochloride in isopropyl alcohol is provided, which can be heated to a temperature of preferably about 60°C to about 90°C, about 65°C to about 85°C, about 70°C to about 80°C, or about 75°C to about 80°C. Heating can be carried out for a suitable period of time, preferably about 2 hours to about 24 hours, about 8 hours to about 22 hours, about 12 hours to about 20 hours, about 14 hours to about 18 hours, or about 16 hours. The mixture is cooled. Cooling is preferably to a temperature of about 10°C to about 40°C, about 15°C to about 35°C, about 20°C to about 30°C, or about 25°C. The product can be isolated from the cooled mixture by any suitable procedure, such as, preferably, by filtration, decantation, or centrifugation. Specifically, the product can be isolated by vacuum filtration. After isolation, briraloxazine hydrochloride form BR3 can be dried. Drying can be carried out under vacuum for: about 5 minutes to 1 hour, or about 10 minutes to about 25 minutes, or about 10 minutes to about 15 minutes.

[0128] According to any aspect or embodiment of the method of the present disclosure, the method for preparing briraloxazine hydrochloride form BR3 specifically comprises: (i) combining isopropyl alcohol with briraloxazine hydrochloride, preferably Form BR2; (ii) heating; (iii) cooling; (iv) optionally isolating; (v) optionally drying; may include:

[0129] According to any aspect or embodiment of the method for preparing briraloxazine hydrochloride Form BR3, the starting material is preferably briraloxazine hydrochloride Form BR2. According to any aspect or embodiment of the method of the present disclosure, isopropyl alcohol can be combined with briraloxazine hydrochloride Form BR2.

[0130] According to any aspect or embodiment of the method for preparing Briraloxazine hydrochloride Form BR3, isopropyl alcohol may be used in an amount of: about 30 ml to about 80 ml, about 40 to about 60 ml, or about 50 ml per gram of Briraloxazine hydrochloride Form BR2. According to any aspect or embodiment, isopropyl alcohol may be combined with Briraloxazine hydrochloride at a temperature of: about 10° C. to about 50° C., about 15° C. to about 40° C., about 18° C. to about 30° C., about 23° C. to about 28° C., or about 25° C.

[0131] In any aspect or embodiment of the disclosed method for preparing briraloxazine hydrochloride form BR3, the reaction mixture can be heated to a temperature of: about 60° C. to about 90° C., about 65° C. to about 85° C., about 70° C. to about 80° C., or about 75° C. to about 80° C. In any aspect or embodiment of the disclosed method, the mixture can be stirred at a heating temperature of: about 60° C. to about 90° C., about 65° C. to about 85° C., about 70° C. to about 80° C., or about 75° C. to about 80° C. The mixture can be stirred at this temperature range, preferably for: about 2 hours to about 24 hours, about 8 hours to about 22 hours, about 12 hours to about 20 hours, about 14 hours to about 18 hours, or about 16 hours.

[0132] In any aspect or embodiment of the method of the present disclosure, the mixture may be cooled. Cooling may be to a temperature of about 10°C to about 40°C, about 15°C to about 35°C, about 20°C to about 30°C, or about 25°C. The product may be isolated by any suitable procedure, preferably by filtration, decantation, or centrifugation. Specifically, the product may be isolated by vacuum filtration. After isolation, the briraloxazine hydrochloride may be dried. Drying may be carried out under vacuum for about 5 minutes to 1 hour, or about 10 minutes to about 25 minutes, or about 10 minutes to about 15 minutes.

[0133] Alternatively, briraloxazine hydrochloride Form BR3 can be prepared by a method comprising milling briraloxazine hydrochloride, preferably briraloxazine hydrochloride Form BR2, in isopropyl alcohol. According to any aspect or embodiment of the method of the present disclosure, the method for preparing briraloxazine hydrochloride Form BR3 can comprise milling a mixture comprising briraloxazine hydrochloride (preferably Form BR2) and isopropyl alcohol. Preferably, isopropyl alcohol is used in the milling step in an amount of about 190 μl to 220 μl, or about 200 μl, per gram of briraloxazine hydrochloride; for about 1 minute to about 5 minutes, or about 2 minutes to about 3 minutes.

[0134] Alternatively, the present disclosure provides a further method for preparing briraloxazine hydrochloride Form BR3, comprising crystallizing briraloxazine hydrochloride from acetone and n-heptane. According to any aspect or embodiment, the method can include: (a) preparing a mixture of briraloxazine hydrochloride in acetone; (b) combining the mixture with n-heptane; and (c) optionally isolating crystalline briraloxazine hydrochloride Form BR3. The mixture in step (a) can be prepared by reacting a solution of briraloxazine in acetone with hydrochloric acid. The reaction is preferably carried out at a temperature of about 18°C ​​to about 55°C, about 20°C to about 50°C, about 23°C to about 40°C, about 23°C to about 30°C, or about 25°C. The reaction mixture can be stirred at this temperature for: about 30 minutes to about 6 hours, about 30 minutes to about 4 hours, about 30 minutes to about 2 hours, or about 1 hour. In step (b), n-heptane can be combined with a mixture of briraloxazine hydrochloride in acetone. Optionally, n-heptane can be added at a temperature of 18°C ​​to about 22°C, or about 20°C. The mixture can be stirred for preferably: about 2 hours to about 24 hours, about 8 hours to about 22 hours, about 12 hours to about 20 hours, about 14 hours to about 18 hours, or about 16 hours. The product can be isolated by any suitable method, such as by filtration, decantation, or centrifugation, preferably by filtration. According to any aspect or embodiment of the method of the present disclosure, a method for preparing briraloxazine hydrochloride form BR3 includes: (i) dissolving briraloxazine in acetone; (ii) adding hydrochloric acid; (iii) optionally cooling; (iv) adding n-heptane; (v) optionally cooling; (vi) isolating briraloxazine hydrochloride form BR3; (vii) optionally washing; may include:

[0135] Specifically, acetone may be used in an amount of about 30 to about 80 ml, about 40 to about 70 ml, or about 60 ml per gram of briraloxazine, and may be added at a temperature of about 18°C ​​to about 55°C, about 20°C to about 50°C, about 23°C to about 40°C, about 23°C to about 30°C, or about 25°C.

[0136] Depending on the aspect or embodiment of the present method for making Briraloxazine hydrochloride Form BR3, hydrochloric acid may be used, preferably as a 2 M HCl solution, in an amount of about 5 ml to about 30 ml, or about 10 ml to about 25 ml, or about 20 ml per gram of Briraloxazine. In any aspect or embodiment of the presently disclosed method for preparing Briraloxazine Form BR3, hydrochloric acid may be added to the solution at a temperature of about 18° C. to about 55° C., about 20° C. to about 50° C., about 23° C. to about 40° C., about 23° C. to about 30° C., or about 25° C., preferably for about 0.5 hours to about 3 hours; or about 1 hour. In any aspect or embodiment of the presently disclosed method for preparing Briraloxazine Form BR3, the reaction mixture may be cooled, preferably to a temperature of about 20° C. In any aspect or embodiment of the disclosed method for preparing briraloxazine form BR3, n-heptane may be added and the mixture may be stirred for about 3 hours to 0.5 hours; or about 1 hour. According to any aspect or embodiment of the disclosed method for preparing briraloxazine hydrochloride form BR3, n-heptane may be used in an amount of about 50 ml to about 500 ml, about 100 ml to about 300 ml, about 120 ml to about 250 ml, or about 175 ml per gram of briraloxazine. According to any aspect or embodiment of the disclosed method for preparing briraloxazine hydrochloride form BR3, the volume ratio of acetone to n-heptane may be about 1:1 to about 1:10, about 1:2 to about 1:5, about 1:2 to about 1:4, or about 1:3 to about 1:2.9. In any aspect or embodiment of the disclosed method, n-heptane can be added at a temperature of: about 10°C to about 50°C, about 15°C to about 40°C, about 18°C ​​to about 30°C, or about 20°C.

[0137] In any aspect or embodiment of the disclosed method for preparing briraloxazine hydrochloride form BR3, the reaction mixture can be cooled, preferably to a temperature of about 10° C. The mixture can be maintained at this temperature for about 10 hours to about 30 hours, or about 12 hours to about 25 hours, or about 16 hours.

[0138] The method may further comprise isolating the obtained briraloxazine hydrochloride by any suitable procedure, such as by filtration, decantation, or centrifugation. In particular, the product may be isolated by filtration.

[0139] In any aspect or embodiment of the disclosed method of preparing Briraloxazine hydrochloride Form BR3, the reaction mixture can be returned to 25° C. before isolation (preferably by filtration), and Briraloxazine hydrochloride Form BR3 can be washed with n-heptane in an amount of about 5 ml to about 30 ml, or about 10 ml, per gram of Briraloxazine.

[0140] Alternatively, the present disclosure provides a further method for preparing briraloxazine hydrochloride Form BR3, comprising crystallizing briraloxazine hydrochloride from methanol and acetone. According to any aspect or embodiment, the method may comprise: (a) preparing a solution of briraloxazine hydrochloride in methanol; (b) combining the solution with acetone; and (c) optionally isolating crystalline briraloxazine hydrochloride Form BR3. The solution in step (a) may be prepared by dissolving briraloxazine hydrochloride in methanol, preferably at a temperature of about 45°C to about 75°C, about 50°C to about 70°C, about 55°C to about 65°C, or about 60°C. The mixture may optionally be filtered. The solution of briraloxazine hydrochloride may be combined with acetone. Preferably, a solution of briraloxazine hydrochloride in methanol is added to acetone. The acetone may be cooled before addition, preferably to a temperature of about -5°C to about 15°C, about -5°C to about 10°C, or about 0°C to about 5°C. The mixture may be stirred for preferably about 30 minutes to about 4 hours, about 30 minutes to about 2 hours, or about 1 hour. The product may be isolated by any suitable method, such as by filtration, decantation, or centrifugation, preferably by filtration. After isolation, briraloxazine hydrochloride Form BR3 may be dried. Drying may be carried out under vacuum for about 5 minutes to about 1 hour, or about 10 minutes to about 25 minutes, or about 10 minutes to about 15 minutes. Drying is preferably carried out at a temperature of about 18°C ​​to about 30°C, about 20°C to about 27°C, or about 25°C. According to any aspect or embodiment of the method of the present disclosure, a method for preparing briraloxazine hydrochloride Form BR3 includes: (i) dissolving briraloxazine in methanol; (ii) adding acetone; (iii) optionally isolating briraloxazine hydrochloride Form BR3; (iv) optionally drying; may include:

[0141] According to any aspect or embodiment of the disclosed method for preparing briraloxazine hydrochloride Form BR3, methanol may be used in an amount of: about 10 ml to about 50 ml, about 15 ml to about 40 ml, about 20 ml to about 30 ml, or about 25 ml per gram of briraloxazine. Acetone may be added at a temperature of: about −5° C. to about 15° C., about −5° C. to about 10° C., or about 0° C. to about 5° C. According to any aspect or embodiment of the disclosed method for preparing briraloxazine hydrochloride Form BR3, acetone may be used in an amount of: about 2 ml to about 20 ml, about 2 ml to about 10 ml, about 2 ml to about 5 ml, or about 4 ml per gram of briraloxazine. According to any aspect or embodiment of the disclosed method for preparing Briraloxazine hydrochloride Form BR3, the volume ratio of acetone to methanol can be: about 1:1 to about 1:10, about 1:2 to about 1:8, about 1:4 to about 1:7, or about 1:6. In any aspect or embodiment of the disclosed method for preparing Briraloxazine Form BR3, the reaction mixture can be cooled, preferably to a temperature of about 10° C. The mixture can be stirred, preferably, for: about 30 minutes to about 4 hours, about 30 minutes to about 2 hours, or about 1 hour.

[0142] The method may further include isolating the resulting briraloxazine hydrochloride by any suitable procedure, such as by filtration, decantation, or centrifugation. Specifically, the product may be isolated by filtration. After isolation, the briraloxazine hydrochloride may be dried. Drying may be carried out under vacuum for about 5 minutes to 1 hour, or about 10 minutes to about 25 minutes, or about 10 minutes to about 15 minutes. Drying is preferably carried out at a temperature of about 18°C ​​to about 30°C, about 20°C to about 27°C, or about 25°C.

[0143] According to any aspect or embodiment of the disclosed method of preparing briraloxazine hydrochloride Form BR3, the method may further comprise combining briraloxazine Form BR3 with at least one pharmaceutically acceptable excipient to prepare a pharmaceutical composition.

[0144] The present disclosure includes a crystalline polymorph of briraloxazine hydrochloride designated BR4. Crystalline form BR4 of briraloxazine hydrochloride can be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 10; an X-ray powder diffraction pattern having peaks at 6.0, 10.8, and 12.6 degrees two-theta ± 0.2 degrees two-theta; and combinations of these data.

[0145] Briraloxazine hydrochloride crystalline form BR4 may be further characterized by an X-ray powder diffraction pattern having peaks at 6.0, 10.8, and 12.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 8.9, 18.7, 21.2, 24.5, and 27.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0146] Alternatively, crystalline form BR4 of briraloxazine hydrochloride may be characterized by an X-ray powder diffraction pattern having peaks at 8.9, 18.7, 21.2, 24.5, and 27.1 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline BR4 of briraloxazine hydrochloride may be further characterized by an X-ray powder diffraction pattern having peaks at 8.9, 18.7, 21.2, 24.5, and 27.1 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 12.1, 21.8, and 25.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0147] Briraloxazine hydrochloride crystalline form BR4 can be characterized by an X-ray powder diffraction pattern having peaks at 8.9, 12.1, 18.7, 21.2, 21.8, 24.5, 25.6, and 27.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0148] Crystalline form BR4 of briraloxazine hydrochloride according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and further characterized by an XRPD pattern having an absence of a peak between 3.5 and 4.0 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of a peak between 4.5 and 4.9 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of a peak between 6.3 and 6.8 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of a peak between 9.3 and 10.2 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of a peak between 11.0 and 11.8 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of a peak between 13.0 and 14.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline form BR4 of Briraloxazine hydrochloride according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and further characterized by an XRPD pattern in which one, two, three, four, five, or six peaks in the aforementioned regions are absent.

[0149] In one embodiment of the present disclosure, crystalline form BR4 of briraloxazine hydrochloride is isolated.

[0150] Briraloxazine hydrochloride crystalline form BR4 may be in the form of a hydrate.

[0151] Crystalline form BR4 of briraloxazine hydrochloride may be characterized by each of the above features alone and / or by all possible combinations, for example, an XRPD pattern having peaks at 6.0, 10.8, and 12.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 8.9, 18.7, 21.2, 24.5, and 27.1 degrees 2-theta ± 0.2 degrees 2-theta; the XRPD pattern shown in Figure 10, and combinations thereof.

[0152] The crystalline form BR4 of briraloxazine hydrochloride described in any aspect or embodiment of the present disclosure can be polymorphically pure and preferably contains: 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 any other form of briraloxazine hydrochloride.

[0153] The present disclosure includes a crystalline polymorph of briraloxazine hydrochloride designated BR5. Crystalline form BR5 of briraloxazine hydrochloride may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 11; an X-ray powder diffraction pattern having peaks at 5.4, 17.9, and 21.9 degrees two-theta ± 0.2 degrees two-theta; and combinations of these data.

[0154] Briraloxazine hydrochloride crystalline form BR5 may be further characterized by an X-ray powder diffraction pattern having peaks at 5.4, 17.9, and 21.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 14.2, 17.4, 19.8, 23.0, and 24.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0155] Alternatively, crystalline form BR5 of briraloxazine hydrochloride may be characterized by an X-ray powder diffraction pattern having peaks at 14.2, 17.4, 19.8, 23.0, and 24.6 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline BR5 of briraloxazine hydrochloride may be further characterized by an X-ray powder diffraction pattern having peaks at 14.2, 17.4, 19.8, 23.0, and 24.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 7.0, 21.9, and 26.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0156] Briraloxazine hydrochloride crystalline form BR5 can be characterized by an X-ray powder diffraction pattern having peaks at 7.0, 14.2, 17.4, 19.8, 21.9, 23.0, 24.6, and 26.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0157] Crystalline form BR5 of briraloxazine hydrochloride according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and further characterized by an XRPD pattern having no peaks present at 4.0-5.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0158] In one embodiment of the present disclosure, crystalline form BR5 of briraloxazine hydrochloride is isolated.

[0159] Briraloxazine hydrochloride crystalline form BR5 can be an anhydrous form.

[0160] Crystalline form BR5 of briraloxazine hydrochloride may be characterized by each of the above features alone and / or by all possible combinations, for example, an XRPD pattern having peaks at 5.4, 17.9, and 21.9 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 14.2, 17.4, 19.8, 23.0, and 24.6 degrees 2-theta ± 0.2 degrees 2-theta; the XRPD pattern shown in FIG. 11, and combinations thereof.

[0161] The crystalline form BR5 of briraloxazine hydrochloride described in any aspect or embodiment of the present disclosure can be polymorphically pure and preferably contains: 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 any other form of briraloxazine hydrochloride.

[0162] The present disclosure includes a crystalline polymorph of briraloxazine hydrochloride designated BR6. Crystalline form BR6 of briraloxazine hydrochloride may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 12; an X-ray powder diffraction pattern having peaks at 12.0, 18.2, and 20.4 degrees two-theta ± 0.2 degrees two-theta; and combinations of these data.

[0163] Briraloxazine hydrochloride crystalline form BR6 may be further characterized by an X-ray powder diffraction pattern having peaks at 12.0, 18.2, and 20.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 7.7, 13.2, 17.0, 18.9, and 23.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0164] Alternatively, crystalline form BR6 of briraloxazine hydrochloride may be characterized by an X-ray powder diffraction pattern having peaks at 7.7, 13.2, 17.0, 18.9, and 23.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline BR6 of briraloxazine hydrochloride may be further characterized by an X-ray powder diffraction pattern having peaks at 7.7, 13.2, 17.0, 18.9, and 23.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 14.8, 19.7, and 24.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0165] Briraloxazine hydrochloride crystalline form BR6 can be characterized by an X-ray powder diffraction pattern with peaks at 7.7, 13.2, 14.8, 17.0, 18.9, 19.7, 23.0, and 24.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0166] Crystalline form BR6 of briraloxazine hydrochloride according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and further characterized by an XRPD pattern having no peaks present between 4.0 and 6.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0167] In one embodiment of the present disclosure, crystalline form BR6 of briraloxazine hydrochloride is isolated.

[0168] Briraloxazine hydrochloride crystalline form BR6 can be an anhydrous form.

[0169] Crystalline form BR6 of Briraloxazine hydrochloride may be characterized by each of the above features alone and / or by all possible combinations, such as an XRPD pattern having peaks at 12.0, 18.2, and 20.4 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 7.7, 13.2, 17.0, 18.9, and 23.0 degrees 2-theta ± 0.2 degrees 2-theta; the XRPD pattern shown in FIG. 12, and combinations thereof.

[0170] The crystalline form BR6 of briraloxazine hydrochloride described in any aspect or embodiment of the present disclosure can be polymorphically pure and preferably contains: 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 any other form of briraloxazine hydrochloride.

[0171] The present disclosure includes a crystalline polymorph of briraloxazine hydrochloride designated BR7. Crystalline form BR7 of briraloxazine hydrochloride may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 13; an X-ray powder diffraction pattern having peaks at 9.3, 14.4, and 23.6 degrees two-theta ± 0.2 degrees two-theta; and combinations of these data.

[0172] Briraloxazine hydrochloride crystalline form BR7 may be further characterized by an X-ray powder diffraction pattern having peaks at 9.3, 14.4, and 23.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 9.9, 16.7, 18.9, 22.5, and 33.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0173] Alternatively, crystalline form BR7 of briraloxazine hydrochloride may be characterized by an X-ray powder diffraction pattern having peaks at 9.9, 16.7, 18.9, 22.5, and 33.6 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline BR7 of briraloxazine hydrochloride may be further characterized by an X-ray powder diffraction pattern having peaks at 9.9, 16.7, 18.9, 22.5, and 33.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 7.3, 18.1, and 20.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0174] Briraloxazine hydrochloride crystalline form BR7 can be characterized by an X-ray powder diffraction pattern having peaks at 7.3, 9.9, 16.7, 18.1, 18.9, 20.8, 22.5, and 33.6 degrees two-theta ± 0.2 degrees two-theta.

[0175] In one embodiment of the present disclosure, crystalline form BR7 of briraloxazine hydrochloride is isolated.

[0176] Briraloxazine hydrochloride crystalline form BR7 may be in the form of a hydrate, more preferably in the form of a dihydrate.

[0177] Crystalline form BR7 of briraloxazine hydrochloride may be characterized by each of the above features alone and / or by all possible combinations, for example, an XRPD pattern having peaks at 9.3, 14.4, and 23.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 9.9, 16.7, 18.9, 22.5, and 33.6 degrees 2-theta ± 0.2 degrees 2-theta; the XRPD pattern shown in Figure 13, and combinations thereof.

[0178] The crystalline form BR7 of briraloxazine hydrochloride described in any aspect or embodiment of the present disclosure can be polymorphically pure and preferably contains: 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 any other form of briraloxazine hydrochloride.

[0179] The present disclosure provides briraloxazine hydrobromide. Briraloxazine hydrobromide is preferably in solid form, and more preferably, briraloxazine hydrobromide is crystalline. The present disclosure includes a crystalline polymorph of briraloxazine hydrobromide designated BHBr1. Briraloxazine hydrobromide crystalline form BHBr1 can be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in FIG. 14; an X-ray powder diffraction pattern having peaks at 10.1, 11.9, and 16.4 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0180] Briraloxazine hydrobromide crystalline form BHBr1 may be further characterized by an X-ray powder diffraction pattern having peaks at 10.1, 11.9, 16.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 15.2, 17.0, 18.9, 21.2, and 25.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0181] Alternatively, crystalline form BHBr1 of Briraloxazine hydrobromide may be characterized by an X-ray powder diffraction pattern having peaks at 15.2, 17.0, 18.9, 21.2, and 25.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline BHBr1 of Briraloxazine hydrobromide may be further characterized by an X-ray powder diffraction pattern having peaks at 15.2, 17.0, 18.9, 21.2, and 25.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, or four additional peaks selected from 23.4, 24.2, 26.4, and 29.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0182] Briraloxazine hydrobromide crystalline form BHBr1 can be characterized by an X-ray powder diffraction pattern having peaks at 15.2, 17.0, 18.9, 21.2, 23.4, 24.2, 25.0, 26.4, and 29.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0183] Crystalline form BHBr1 of briraloxazine hydrobromide according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and may be further characterized by an XRPD pattern that is absent from 3.5 to 5.0 degrees 2-theta ± 0.2 degrees 2-theta and / or an XRPD pattern that is absent from 6.0 to 9.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline form BHBr1 of briraloxazine hydrobromide according to any aspect or embodiment of the present disclosure may be characterized by any of the data described herein and may be further characterized by an XRPD pattern that is absent from one or both of the aforementioned regions.

[0184] In one embodiment of the present disclosure, crystalline form BHBr1 of briraloxazine hydrobromide is isolated.

[0185] The crystalline form BHBr1 of briraloxazine hydrobromide can be anhydrous.

[0186] Crystalline form BHBr1 of Briraloxazine hydrobromide may be characterized by each of the above characteristics alone and / or by all possible combinations, for example, by an XRPD pattern having peaks at 10.1, 11.9, 16.4 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern having peaks at 15.2, 17.0, 18.9, 21.2, and 25.0 degrees 2-theta ± 0.2 degrees 2-theta; the XRPD pattern shown in Figure 14, and combinations thereof.

[0187] The crystalline form BHBr1 of briraloxazine hydrobromide described in any aspect or embodiment of the present disclosure can be polymorphically pure and preferably contains: less than about 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% of any other form of briraloxazine hydrobromide.

[0188] The present disclosure provides the above-mentioned crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, for use in preparing pharmaceutical compositions comprising briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, and / or crystalline polymorphs thereof.

[0189] The present disclosure also encompasses the use of the disclosed crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, for the preparation of pharmaceutical compositions of crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, and / or crystalline polymorphs thereof.

[0190] The present disclosure includes a method for preparing the above-described pharmaceutical composition, comprising combining any one or a combination of the crystalline polymorphs of briraloxazine and salts of briraloxazine disclosed herein, particularly briraloxazine hydrochloride, with at least one pharmaceutically acceptable excipient.

[0191] The pharmaceutical combinations or formulations of the present disclosure contain any one or combination of the solid forms of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure may contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[0192] Diluents can increase the bulk of a solid pharmaceutical composition, making pharmaceutical dosage forms containing the composition easier for patients and therapists to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugars, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0193] Solid pharmaceutical compositions that are compressed into dosage forms such as tablets may contain excipients whose function includes binding the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g., carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), hydroxypropylmethylcellulose (e.g., Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, povidone (e.g., Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0194] The dissolution rate of a compressed solid pharmaceutical composition in the patient's stomach can be increased by adding a disintegrant to the composition. Disintegrants include 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.

[0195] Glidants may be added to improve the flowability of non-compacted solid compositions and improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0196] 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 die, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and facilitate the release of the product from the die. 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.

[0197] Flavoring agents and flavor enhancers make the dosage more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the compositions of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0198] The solid and liquid compositions may also be colored using any pharmaceutically acceptable coloring agent to improve their appearance and / or to make it easier for the patient to identify the product and unit dosage level.

[0199] In the liquid pharmaceutical compositions of the present invention, briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, 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.

[0200] 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.

[0201] The liquid pharmaceutical compositions of the present invention may also contain viscosity enhancing agents to improve the mouthfeel of the product and / or coat the lining of the gastrointestinal tract. Such agents include 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.

[0202] Sweeteners such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve taste.

[0203] Preservatives and chelating agents, such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid, can be added at levels safe for consumption to improve storage stability.

[0204] According to the present disclosure, the liquid composition may also contain a buffering agent such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. The selection of excipients and the amounts to be used can be readily determined by a formulation scientist empirically and by reviewing standard procedures and references in the art.

[0205] Solid compositions of the present disclosure include powders, granules, aggregates, and compacted compositions. Dosages include those suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, and ophthalmic administration. While the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments, the route of administration is oral. Dosages are conveniently provided in unit dosage form and may be prepared by any method well known in the pharmaceutical arts.

[0206] Dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0207] The dosage form of the present disclosure may be a capsule containing a composition, such as a powdered or granulated solid composition of the present disclosure, within either a hard or soft shell, which may be made from gelatin and may optionally contain a plasticizer, such as glycerin and / or sorbitol, an opacifying agent, and / or a colorant.

[0208] The active ingredients and excipients may be formulated into compositions and dosage forms by methods known in the art.

[0209] Compositions for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed, typically in the presence of a liquid such as water, to compact the powder 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 can be added prior to tableting.

[0210] Tablet compositions can be conventionally prepared by dry blending. For example, the blended composition of the active agents and excipients can be compressed into a slug or a sheet and then comminuted into compacted granules. The compacted granules can then be compressed into tablets.

[0211] As an alternative to dry granulation, blended compositions can be directly compressed into compacted dosage forms using direct compression techniques. Direct compression produces more uniform tablets 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 with experience and skill in the specific formulation challenges of direct compression tableting.

[0212] The capsule filling of the present disclosure may include any of the foregoing blends and granules described in connection with tableting, but are not subjected to a final tableting step.

[0213] Pharmaceutical formulations of briraloxazine and briraloxazine salts, particularly briraloxazine hydrochloride, can be administered. Briraloxazine and briraloxazine salts, particularly briraloxazine hydrochloride, can be formulated for administration by injection to mammals, in embodiments, humans. Briraloxazine and briraloxazine salts, particularly briraloxazine hydrochloride, can be formulated as a viscous liquid solution or suspension, such as a clear solution for injection. The formulation may contain one or more solvents. A suitable solvent can be selected by considering the physical and chemical stability of the solvent at various pH levels, viscosity (easily passed through a syringe needle), 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.

[0214] The disclosed crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, and pharmaceutical compositions and / or formulations of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, may be used as medicines in embodiments in the treatment of schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension.

[0215] The present disclosure also provides methods for treating schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension by administering to a subject in need thereof a therapeutically effective amount of any one or combination of the crystalline polymorphs of briraloxazine and salts of briraloxazine, particularly briraloxazine hydrochloride, of the present disclosure, or at least one of the pharmaceutical compositions and / or formulations described above.

[0216] Thus, while the present disclosure has been described with particular reference to 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 set forth to aid in the understanding of the disclosure, but are not intended to, and should not be considered to, limit the scope of the disclosure in any way.

[0217] X-ray powder diffraction (XRPD) method X-ray diffraction was performed on an X-ray powder diffractometer: Bruker D8 Advance; Cu K radiation (λ = 1.5418 Å); Lynx Eye detector; laboratory temperature 22–25°C; PMMA specimen holder. Prior to analysis, the samples were gently ground with a mortar and pestle to obtain a fine powder. The ground sample was placed in the cavity of the specimen holder, and the surface of the sample was smoothed with a cover glass. Measurement parameters: Scan range: 2~40 degrees 2-theta; Scan mode: continuous; Step width: 0.05 degrees; Time per step: 0.5 seconds; Sample rotation: 30 rpm; Specimen holder: PMMA specimen holding ring.

[0218] All X-ray powder diffraction peak values ​​are calibrated with respect to standard silicon spiking in the sample.

[0219] 13 C CP / MAS NMR method: Solid-state NMR spectra were measured at 11.7 T using a Bruker Avance III HD 500 US / WB NMR spectrometer (Karlsruhe, Germany, 2013) equipped with a 3.2 mm probehead. 13 C CP / MAS NMR spectra were acquired at a spinning frequency of 15 kHz and room temperature (300 K) using standard pulse mode, with a repetition time of 8 seconds and a cross-polarization contact time of 2 milliseconds.13 C scale is α-glycerin ( 13 The NMR spectrometer was fully calibrated, and all experimental parameters were carefully optimized before the study. The magic angle was set using KBr during the standard optimization procedure, and the field homogeneity was optimized using an adamantane sample (the linewidth obtained at half maximum, Δυ, was less than 3.5 Hz at an acquisition time of 250 ms). [Example]

[0220] Preparation of starting materials Briraloxazine can be prepared by methods known from the literature, for example, US Pat. No. 8,188,076.

[0221] Example 1 Preparation of Briraloxazine Form B1 Briraloxazine (0.02 grams) was dissolved in dichloromethane (0.2 ml) at a temperature of about 25°C to obtain a clear solution. The clear solution was covered with parafilm with a pinhole, and the solvent was allowed to slowly evaporate at a temperature of about 22°C to about 25°C. After 1 hour, the solid was isolated and analyzed by XRPD. Crystalline Briraloxazine Form B1 was obtained. The XRPD pattern is shown in Figure 1.

[0222] Example 2 Preparation of Briraloxazine Form B2 Briraloxazine (0.02 grams) was dissolved in methanol (2.5 ml) at a temperature of about 25°C to obtain a clear solution. To this clear solution, water (3 ml) was added at a temperature of about 25°C to obtain a white precipitate. After maintaining for about 1 hour, the reaction mixture was filtered and washed with water (1 x 3 ml). The resulting solid was suction dried under vacuum at a temperature of about 22°C to about 25°C for about 10 to about 15 minutes. The resulting solid was analyzed by XRPD. Crystalline Briraloxazine Form B2 was obtained. The XRPD pattern is shown in Figure 2.

[0223] Example 3 Preparation of Briraloxazine Form B3 Briraloxazine (0.02 grams) was dissolved in methanol (2.5 ml) at a temperature of about 25°C to obtain a clear solution. The clear solution was covered with parafilm with a pinhole, and the solvent was allowed to slowly evaporate at a temperature of about 22°C to about 25°C. After 1 hour, the solid was isolated and analyzed by XRPD. Crystalline Briraloxazine Form B3 was obtained. The XRPD pattern is shown in Figure 3.

[0224] Example 4 Preparation of Briraloxazine Form B4 Briraloxazine (0.02 grams) was dissolved in tetrahydrofuran (0.1 ml) at a temperature of about 25°C to obtain a clear solution. The clear solution was covered with parafilm with a pinhole, and the solvent was allowed to evaporate slowly at a temperature of about 22°C to about 25°C. After 1 hour, the solid was isolated and analyzed by XRPD. Crystalline Briraloxazine Form B4 was obtained. The XRPD pattern is shown in Figure 4.

[0225] Example 5 Preparation of Briraloxazine Form B5 Briraloxazine (1 gram) was dissolved in dichloromethane (20 ml) at a temperature of about 25°C. The solution was filtered through a 0.45 micron filter, and heptane (10 ml) was added to the particle-free solution at a temperature of about 25°C, and the formation of a white precipitate was observed. The reaction mixture was maintained under stirring at a temperature of about 25°C for about 2 hours. The reaction mixture was filtered and washed with heptane (2 x 3 ml). The resulting solid was pulled dry under vacuum at a temperature of about 22°C to about 25°C for about 10 to about 15 minutes and further dried in a vacuum tray dryer at a temperature of about 60°C for about 24 hours. The resulting solid was analyzed by XRPD. Crystalline Briraloxazine Form B5 was obtained. The XRPD pattern is shown in Figure 5.

[0226] Example 6 Preparation of Briraloxazine Form B6 Briraloxazine (0.1 gram) (Form B5) was placed in a 10 ml vial and 5 ml of heptane (5 ml) was added at a temperature of about 60° C. The slurry mass was stirred at a temperature of about 60° C. for about 48 hours. The reaction mass was filtered and dried under vacuum at a temperature of about 25° C. to about 30° C. for about 20 minutes to about 30 minutes. After 48 hours and 1 hour, the solid was isolated and analyzed by XRPD. Crystalline Briraloxazine Form B4 was obtained. The XRPD pattern is shown in FIG. 6.

[0227] Example 7 Preparation of Briraloxazine Hydrochloride Form BR1 Briraloxazine (0.1 grams) was dissolved in acetone (5 ml) at a temperature of about 25°C. 2 ml of 2 M HCl solution was added, followed by diethyl ether (30 ml) at a temperature of about 25°C. The reaction mixture was stirred at a temperature of about 25°C for about 16 hours. The reaction mass was filtered and dried under vacuum for about 10 to about 15 minutes. The resulting solid was analyzed by XRPD. Crystalline Briraloxazine hydrochloride Form BR1 was obtained. The XRPD pattern is shown in Figure 7.

[0228] Example 8 Preparation of Briraloxazine Hydrochloride Form BR2 Briraloxazine (Form B1, 0.1 grams) was suspended in 5 ml of pH 1.2 buffer (prepared by using HCl) in a glass vial at a temperature of about 25°C. The slurry mass was maintained under stirring for about 1 hour to about 2 hours, at which point the reaction mass became very sticky. The reaction mass was maintained under stirring at a temperature of about 25°C for about 16 hours, at which point a white solid was observed. The slurry mass was filtered and dried under vacuum for about 10 to 15 minutes. The resulting solid was analyzed by XRPD. Crystalline Briraloxazine hydrochloride Form BR2 was obtained. The XRPD pattern is shown in Figure 8.

[0229] Example 9 Preparation of Briraloxazine Hydrochloride Form BR3 Briraloxazine hydrochloride (Form BR2, 0.1 grams) was placed in a glass vial at a temperature of about 25°C. Five milliliters of isopropyl alcohol was added, and the reaction mixture was heated to a temperature of about 75°C to about 80°C and maintained at a temperature of about 75°C to about 80°C under stirring for about 16 hours. The reaction mass was cooled to a temperature of about 25°C, filtered, and dried under vacuum for about 10 minutes to about 15 minutes. The resulting solid was analyzed by XRPD. Crystalline Briraloxazine hydrochloride Form BR3 was obtained. The XRPD pattern is shown in Figure 9.

[0230] Example 10 Preparation of Briraloxazine Hydrochloride Form BR3 Briraloxazine hydrochloride (Form BR2, 0.1 grams) was placed in a mortar with a pestle. A few drops (approximately 20 μl) of isopropyl alcohol were added and the mixture was ground for approximately 2 to 3 minutes. The resulting solid was analyzed by XRPD. Crystalline Briraloxazine hydrochloride Form BR3 was obtained.

[0231] Example 11 Preparation of Briraloxazine Hydrochloride Form BR4 Briraloxazine (0.3 grams) was dissolved in dichloromethane (4.5 ml) at a temperature of about 25° C. Aqueous HCl (0.12 ml) was added to the briraloxazine solution at a temperature of about 25° C. and maintained under stirring for about 1 hour. The material was filtered and suction dried for about 15 minutes. The resulting solid was analyzed by XRPD. Crystalline briraloxazine hydrochloride form BR4 was obtained. The XRPD pattern is shown in FIG. 10.

[0232] Example 12 Preparation of Briraloxazine Hydrochloride Form BR5 Briraloxazine (1.0 gram) was dissolved in dichloromethane (15 ml) at a temperature of about 25°C. 0.48 ml of aqueous HCl was added dropwise at a temperature of about 25°C. The reaction mixture was stirred for about 1 hour. It was filtered and dried under vacuum for about 15 to about 30 minutes. It was further dried in a vacuum tray dryer (VTD) oven at a temperature of about 50°C for about 10 hours. The sample was allowed to cool to room temperature of about 25°C. The resulting solid was analyzed by XRPD. Crystalline Briraloxazine hydrochloride form BR5 was obtained. The XRPD pattern is shown in Figure 11.

[0233] Example 13 Preparation of Briraloxazine Hydrochloride Form BR6 Briraloxazine hydrochloride (Form BR2, 0.03 grams) was suspended in a 9:1 mixture of methanol and water (1 ml) at a temperature of about 25°C. The reaction mass was maintained under stirring at a temperature of about 25°C for about 18 hours. The slurry was filtered and dried under vacuum for about 10 to about 15 minutes. The resulting solid was analyzed by XRPD. Crystalline Briraloxazine hydrochloride Form BR6 was obtained. The XRPD pattern is shown in Figure 12.

[0234] Example 14 Preparation of Briraloxazine Hydrochloride Form BR7 Briraloxazine (Form B1, 0.06 grams) was placed in a Teflon® flask (20 ml). Water (10 ml) and aqueous hydrochloric acid (37%, 0.048 ml) were added at 25°C. The reaction vessel was closed with a Teflon® lid, placed in a stainless steel jacketed block, properly clamped, and held in an oven. The reaction mixture was heated to 80°C for 8 hours and cooled to 25°C for 16 hours. This cycle was repeated three times in a sealed state. The reaction mixture was finally cooled to 25°C. After filtration, the resulting solid was sucked dry for approximately 15 minutes. The resulting solid was analyzed by XRPD. Crystalline Briraloxazine hydrochloride Form BR7 was obtained. The XRPD pattern is shown in Figure 13.

[0235] Example 15 Preparation of Briraloxazine Hydrobromide Form BHBr1 Briraloxazine free base (0.2 grams) was dissolved in acetone (6 ml) at a temperature of about 40° C. The IPA-HBr solution [isopropyl alcohol (0.5 ml) and aqueous HBr (0.036 g, about 48%)] was maintained for about 1 hour and then cooled to a temperature of about 10° C. at a rate of 1° C. per minute. The reaction mixture was maintained for about 2 hours. The reaction mixture was then allowed to return to room temperature and filtered. It was washed with MTBE (3×1 ml) and suction dried for about 15 minutes. The resulting solid was analyzed by XRPD. Crystalline Briraloxazine hydrobromide, Form BHBr1, was obtained. The XRPD pattern is shown in FIG.

[0236] Example 16 Preparation of amorphous briraloxazine hydrochloride Briraloxazine hydrochloride (0.1 grams) was dissolved in dichloromethane (4 ml) at a temperature of about 35° C. The clear solution was distilled under high vacuum (less than 100 mbar) on a rotary evaporator at a temperature of about 35° C. for about 30 to about 45 minutes. The solid was isolated and analyzed by XRPD. An amorphous form of Briraloxazine hydrochloride was obtained. The XRPD pattern is shown in FIG. 15.

[0237] Example 17 Preparation of Briraloxazine Hydrochloride Form BR3 Briraloxazine (1 gram) was dissolved in 60 ml of acetone at a temperature of about 25°C. 20 ml of a 2 M aqueous solution of HCl was added to the reaction mixture. The reaction mixture was stirred at a temperature of about 25°C for about 1 hour and then cooled to a temperature of about 20°C. n-Heptane (175 ml) was added and stirred for about 1 hour. The mixture was further cooled to a temperature of about 10°C and stirred for about 16 hours, then the temperature was returned to a temperature of about 25°C, filtered, and washed with n-heptane (3 x 10 ml). The resulting solid was analyzed by XRPD. Crystalline Briraloxazine hydrochloride Form BR3 was obtained.

[0238] Example 18 Preparation of Briraloxazine Hydrochloride Form BR3 Briraloxazine hydrochloride (0.96 grams) was dissolved in methanol (24 ml) at a temperature of about 60°C. After filtration, a clear solution was obtained, designated the stock solution. 0.5 ml of the stock solution was added to pre-cooled antisolvent (4 ml) acetone at a temperature of about 0°C to about 5°C, and the reaction mixture was stirred at the same temperature for about 1 hour. The mixture was filtered at a temperature of about 25°C and pulled dry under vacuum at a temperature of about 25°C for about 15 to about 20 minutes. The resulting solid was analyzed by XRPD. Crystalline Briraloxazine hydrochloride Form BR3 was obtained.

[0239] Example 19 Preparation of Briraloxazine Form B6 Briraloxazine (0.1 gram) (Form B5) was placed in a 10 ml vial and 5 ml of n-heptane (5 ml) was added at a temperature of about 60° C. The slurry mass was stirred at a temperature of about 60° C. for about 48 hours. The reaction mass was filtered and dried under vacuum at a temperature of about 25° C. to about 30° C. for about 20 minutes to about 30 minutes. The resulting solid was analyzed by XRPD. Crystalline Briraloxazine Form B6 was obtained.

[0240] Example 20 stability studies Storage stability at different relative humidities Samples of Briraloxazine hydrochloride Forms BR1 and BR3 were conditioned at ambient temperature with different relative humidities. After 7 days, XRPD analysis was performed on the samples. The results are shown in Table 1 below:

[0241] [Table 1]

[0242] These results demonstrate that Briraloxazine hydrochloride Forms BR1 and BR3 are stable after exposure to high and low relative humidity for at least 7 days.

[0243] Crushing experiment Samples of Briraloxazine hydrochloride Forms BR1 and BR3 were subjected to vigorous grinding and solvent drop grinding in water, ethanol, and isopropanol. Grinding was performed on the sample alone or in the presence of ethanol, water, or isopropanol. In these experiments, approximately 20 mg of sample was placed in a mortar and ground with a pestle for 2 minutes. When used, solvent was added to the crystalline material in a volume of 10 microliters before grinding. After the grinding experiments, XRPD analysis was performed on each sample, confirming no changes in the starting material (Table 2):

[0244] [Table 2]

[0245] The results demonstrate that briraloxazine hydrochloride forms BR1 and BR3 are resistant to polymorphic transformation and are highly suitable for the preparation of pharmaceutical formulations.

[0246] thermal stability Samples of Briraloxazine hydrochloride Forms BR1 and BR3 were subjected to heat treatment to 100° C. for 30 minutes. XRPD analysis of the samples confirmed no change in the starting material (Table 3):

[0247] [Table 3]

[0248] Compression stability Samples of Briraloxazine hydrochloride Forms BR1 and BR3 were subjected to a pressure of 2 tons for 1 minute (Atlas® Autopress hydraulic press, set at 2 tons). After 1 minute, XRPD analysis was performed on the samples. The results are shown in Table 4 below:

[0249] [Table 4]

[0250] Thus, Briraloxazine hydrochloride Forms BR1 and BR3 are stable under high pressure conditions, making these products highly stable for pharmaceutical processing.

Claims

1. Crystalline briraloxazine hydrochloride.

2. Form BR1, shown below: a) an XRPD pattern with peaks at 17.3, 21.5 and 25.7 degrees 2-theta ± 0.2 degrees 2-theta; b) an XRPD pattern with peaks at 7.2, 16.4, 19.5, 22.4, and 24.7 degrees 2-theta ± 0.2 degrees 2-theta; c) XRPD pattern shown in Figure 7; d) Solids with peaks at 20.6, 42.4, 97.5, 122.2, 131.0 and 165.5 ppm ± 0.2 ppm 13 C NMR spectrum; e) A solid having the following absolute chemical shift differences from the reference peak at 116.7 ppm ± 2 ppm: 96.11, 74.31, 19.21, 5.49, 14.29, and 48.78 ppm ± 0.1 ppm. 13 C NMR spectrum; f) A solid substantially as shown in Figure 16a, 16b or 16c 13 C NMR spectrum; and g) A combination of two or more of a, b, c, d, e, and f 2. The crystalline briraloxazine hydrochloride of claim 1, characterized by data selected from one or more of the following:

3. 3. The crystalline briraloxazine hydrochloride of claim 1, characterized by an X-ray powder diffraction pattern having peaks at 17.3, 21.5, and 25.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 7.2, 16.4, 19.5, 22.4, and 24.7 degrees 2-theta ± 0.2 degrees 2-theta.

4. 3. The crystalline briraloxazine hydrochloride of claim 1, characterized by an X-ray powder diffraction pattern having peaks at 7.2, 16.4, 19.5, 22.4, and 24.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, or four additional peaks selected from 14.3, 14.9, 25.7, and 27.2 degrees 2-theta ± 0.2 degrees 2-theta.

5. 5. The crystalline briraloxazine hydrochloride of claim 1, characterized by an X-ray powder diffraction pattern having peaks at 7.2, 14.3, 14.9, 16.4, 19.5, 22.4, 24.7, 25.7 and 27.

2.

6. 6. The crystalline briraloxazine hydrochloride of any one of claims 1 to 5, characterized by an X-ray powder diffraction pattern having peaks at 7.2, 14.3, 14.9, 16.4, 17.3, 19.5, 21.5, 22.4, 24.7, 25.7, and 27.2 degrees 2-theta ± 0.2 degrees 2-theta.

7. 7. The crystalline briraloxazine hydrochloride of any one of claims 1 to 6, further characterized by an X-ray powder diffraction pattern having no peaks at 2.0 to 3.0 degrees 2-theta ± 0.2 degrees 2-theta.

8. 8. The crystalline briraloxazine hydrochloride of any one of claims 1 to 7, further characterized by an X-ray powder diffraction pattern having no peaks present between 4.0 and 6.5 degrees 2-theta ± 0.2 degrees 2-theta.

9. 9. The crystalline briraloxazine hydrochloride of any one of claims 1 to 8, further characterized by an X-ray powder diffraction pattern having no peaks present between 8.0 and 10.5 degrees 2-theta ± 0.2 degrees 2-theta.

10. 10. The crystalline briraloxazine hydrochloride of any one of claims 1 to 9, further characterized by an X-ray powder diffraction pattern having no peaks present at 11.5 to 13.0 degrees 2-theta ± 0.2 degrees 2-theta.

11. 11. The crystalline briraloxazine hydrochloride of any one of claims 1 to 10, wherein the crystalline form is an anhydrous form.

12. Form BR3, shown below: a) an XRPD pattern with peaks at 12.8, 15.4 and 18.9 degrees 2-theta ± 0.2 degrees 2-theta; b) an XRPD pattern with peaks at 16.1, 17.4, 22.6, 25.3 and 27.8 degrees 2-theta ± 0.2 degrees 2-theta; b) XRPD pattern shown in Figure 9; c) Solids with peaks at 22.7, 28.4, 59.3, 66.3, 119.5 and 155.3 ppm ± 0.2 ppm 13 C NMR spectrum; d) A solid having the following absolute chemical shift differences from the reference peak at 116.7 ppm ± 2 ppm: 94.01, 88.31, 50.41, 48.78, 2.79, and 38.59 ppm ± 0.

1. 13 C NMR spectrum; e) A solid substantially as shown in Figure 17a, 17b or 17c 13 C NMR spectrum; and f) A combination of two or more of a, b, c, d, and e 2. The crystalline briraloxazine hydrochloride of claim 1, characterized by data selected from one or more of the following:

13. 13. The crystalline briraloxazine hydrochloride of claim 1 or 12, characterized by an X-ray powder diffraction pattern having peaks at 12.8, 15.4, and 18.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 16.1, 17.4, 22.6, 25.3, and 27.8 degrees 2-theta ± 0.2 degrees 2-theta.

14. 13. The crystalline briraloxazine hydrochloride of claim 1 or 12, characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4, 22.6, 25.3, and 27.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four, or five additional peaks selected from 19.8, 20.7, 21.8, 23.7, and 24.0 degrees 2-theta ± 0.2 degrees 2-theta.

15. 15. The crystalline briraloxazine hydrochloride of claim 1, 12 or 14, characterized by an X-ray powder diffraction pattern having peaks at 16.1, 17.4, 19.8, 20.7, 21.8, 22.6, 23.7, 24.0, 25.3 and 27.

8.

16. 14. The crystalline briraloxazine hydrochloride of claim 1, 12, or 13, characterized by an X-ray powder diffraction pattern having peaks at 12.8, 15.4, 16.1, 17.4, 18.9, 19.8, 20.7, 21.8, 22.6, 23.7, 24.0, 25.3, and 27.8 degrees 2-theta ± 0.2 degrees 2-theta.

17. 17. The crystalline briraloxazine hydrochloride of any one of claims 1 or 12 to 16, wherein the crystalline form is an anhydrous form.

18. 18. The crystalline briraloxazine hydrochloride of any one of claims 2 to 17, containing about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% of any other crystalline form of briraloxazine hydrochloride.

19. 19. The crystalline briraloxazine hydrochloride of any one of claims 1 to 18, containing about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% amorphous briraloxazine hydrochloride.

20. A pharmaceutical composition comprising the crystalline briraloxazine hydrochloride of any one of claims 1 to 19.

21. 20. Use of crystalline briraloxazine hydrochloride according to any one of claims 1 to 19 for the preparation of a pharmaceutical composition and / or a pharmaceutical formulation, preferably an oral formulation.

22. 21. A pharmaceutical formulation comprising the crystalline briraloxazine hydrochloride of any one of claims 1 to 19, or the pharmaceutical composition of claim 20, with at least one pharmaceutically acceptable excipient.

23. 23. A method for preparing the pharmaceutical formulation of claim 22, comprising combining the crystalline briraloxazine hydrochloride of any one of claims 1 to 19, or the pharmaceutical composition of claim 20, with at least one pharmaceutically acceptable excipient.

24. 23. The crystalline briraloxazine hydrochloride of any one of claims 1 to 19, the pharmaceutical composition of claim 20, or the pharmaceutical formulation of claim 22 for use as a medicament.

25. 23. The crystalline briraloxazine hydrochloride of any one of claims 1 to 19, the pharmaceutical composition of claim 20, or the pharmaceutical formulation of claim 22 for use in the treatment of schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension.

26. 23. A method of treatment, comprising administering a therapeutically effective amount of the crystalline briraloxazine hydrochloride of any one of claims 1 to 19, the pharmaceutical composition of claim 20, or the pharmaceutical formulation of claim 22 to a subject in need of treatment.

27. The crystalline briraloxazine hydrochloride of any one of claims 2 to 19, the pharmaceutical composition of claim 20, or the pharmaceutical formulation of claim 22 for the manufacture of a medicament for treating schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension.

28. 20. Use of the crystalline briraloxazine hydrochloride of any one of claims 2 to 19 in the preparation of another solid form of briraloxazine hydrochloride, or another briraloxazine salt or solid form thereof.

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