Solid state forms of brilaroxazine and brilaroxazine salts

Abstract

The present disclosure encompasses solid state forms of Brilaroxazine, in embodiments crystalline polymorphs or salts of Brilaroxazine, particularly Brilaroxazine hydrochloride, processes for preparation thereof, and pharmaceutical compositions thereof.

Description

SOLID STATE FORMS OF BRILAROXAZINE AND BRILAROXAZINE SALTSFIELD OF THE DISCLOSURE

[0001] The present disclosure encompasses solid state forms of Brilaroxazine, in embodiments crystalline polymorphs or salts of Brilaroxazine, particularly Brilaroxazine hydrochloride, processes for preparation thereof, and pharmaceutical compositions thereof.BACKGROUND OF THE DISCLOSURE

[0002] Brilaroxazine, 6-(4-(4-(2,3-dichlorophenyl)piperazin-l-yl)butoxy)-2H- benzo(b)(l,4)oxazin-3(4H)-one, has the following chemical structure:

[0003] Brilaroxazine is an orally bioavailable small molecule and it is developed for the treatment of Schizophrenia, Schizoaffective disorder, Idiopathic pulmonary fibrosis and Pulmonary arterial hypertension.

[0004] The compound is described in U.S. Patent No. 8,188,076.

[0005] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state (13C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0006] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an activepharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

[0007] Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemi cal / phy si cal stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Brilaroxazine or salts of Brilaroxazine, particularly Brilaroxazine hydrochloride.SUMMARY OF THE DISCLOSURE

[0008] The present disclosure provides crystalline polymorphs or salts of Brilaroxazine, particularly Brilaroxazine hydrochloride, processes for preparation thereof, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other solid state forms of Brilaroxazine, Brilaroxazine salts and their solid state forms.

[0009] The present disclosure also provides uses of the said solid state forms of Brilaroxazine and salts thereof, particularly Brilaroxazine hydrochloride in the preparation of other solid state forms of Brilaroxazine and / or Brilaroxazine co-crystals and / or salts, particularly Brilaroxazine hydrochloride thereof, and their solid state forms thereof.

[0010] The present disclosure provides crystalline polymorphs of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride, for use in medicine, including for the treatment of Schizophrenia, Schizoaffective disorder, Idiopathic pulmonary fibrosis and Pulmonary arterial hypertension.

[0011] The present disclosure also encompasses the use of crystalline polymorphs of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride of the present disclosure, for the preparation of pharmaceutical compositions and / or formulations.

[0012] In another aspect, the present disclosure provides pharmaceutical compositions comprising crystalline polymorphs of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride according to the present disclosure.

[0013] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorphs of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride, with at least one pharmaceutically acceptable excipient.

[0014] The crystalline polymorph of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride as defined herein, and the pharmaceutical compositions or formulations of the crystalline polymorph of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride, may be used as medicaments, such as for the treatment of Schizophrenia, Schizoaffective disorder, Idiopathic pulmonary fibrosis and Pulmonary arterial hypertension.

[0015] The present disclosure also provides methods of treating Schizophrenia, Schizoaffective disorder, Idiopathic pulmonary fibrosis and Pulmonary arterial hypertension, by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from Schizophrenia, Schizoaffective disorder, Idiopathic pulmonary fibrosis and Pulmonary arterial hypertension, or otherwise in need of the treatment.

[0016] The present disclosure also provides uses of crystalline polymorphs of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g. Schizophrenia, Schizoaffective disorder, Idiopathic pulmonary fibrosis and Pulmonary arterial hypertension.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Brilaroxazine Form Bl;

[0018] Figure 2 shows a characteristic X-ray powder diffraction pattern (XRPD) of Brilaroxazine Form B2;

[0019] Figure 3 shows a characteristic X-ray powder diffraction pattern (XRPD) ofBrilaroxazine Form B3;

[0020] Figure 4 shows a characteristic X-ray powder diffraction pattern (XRPD) of Brilaroxazine Form B4;

[0021] Figure 5 shows a characteristic X-ray powder diffraction pattern (XRPD) of Brilaroxazine Form B5;

[0022] Figure 6 shows a characteristic X-ray powder diffraction pattern (XRPD) of Brilaroxazine Form B6;

[0023] Figure 7 shows a characteristic X-ray powder diffraction pattern (XRPD) ofBrilaroxazine hydrochloride Form BRI;

[0024] Figure 8 shows a characteristic X-ray powder diffraction pattern (XRPD) of Brilaroxazine hydrochloride Form BR2;

[0025] Figure 9 shows a characteristic X-ray powder diffraction pattern (XRPD) ofBrilaroxazine hydrochloride Form BR3;

[0026] Figure 10 shows a characteristic X-ray powder diffraction pattern (XRPD) of Brilaroxazine hydrochloride Form BR4;

[0027] Figure 11 shows a characteristic X-ray powder diffraction pattern (XRPD) of Brilaroxazine hydrochloride Form BR5;

[0028] Figure 12 shows a characteristic X-ray powder diffraction pattern (XRPD) of Brilaroxazine hydrochloride Form BR6;

[0029] Figure 13 shows a characteristic X-ray powder diffraction pattern (XRPD) of Brilaroxazine hydrochloride Form BR7;

[0030] Figure 14 shows a characteristic X-ray powder diffraction pattern (XRPD) of Brilaroxazine hydrobromide Form BHBrl;

[0031] Figure 15 shows a characteristic X-ray powder diffraction pattern (XRPD) of amorphous Brilaroxazine hydrochloride;

[0032] Figure 16a shows solid state13C NMR spectrum (full scan) of Brilaroxazine hydrochloride Form BRI;

[0033] Figure 16b shows solid state13C NMR spectrum (0-100 ppm) of Brilaroxazine hydrochloride Form BRI;

[0034] Figure 16c shows solid state13C NMR spectrum (100-200 ppm) of Brilaroxazine hydrochloride Form BRI;

[0035] Figure 17a shows solid state13C NMR spectrum (full scan) of Brilaroxazine hydrochloride Form BR3;

[0036] Figure 17b shows solid state13C NMR spectrum (0-100 ppm) of Brilaroxazine hydrochloride Form BR3; and

[0037] Figure 17c shows solid state13C NMR spectrum (100-200 ppm) of Brilaroxazine hydrochloride Form BR3.DETAILED DESCRIPTION OF THE DISCLOSURE

[0038] The present disclosure encompasses solid state forms of Brilaroxazine, including crystalline polymorphs of Brilaroxazine, and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride, processes for preparation thereof, and pharmaceutical compositions thereof. In embodiments, the present disclosure provides crystalline forms of Brilaroxazine designated as Form Bl, Form B2, Form B3, Form B4, Form B5 and Form B6; Brilaroxazine hydrochloride designated as Form BRI, Form BR2, Form BR3, Form BR4, Form BR5, Form BR6 and Form BR7; and Brilaroxazine hydrobromide designated as Form BHBrl (defined herein).

[0039] Solid state properties of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride and crystalline polymorphs thereof, can be influenced by controlling the conditions under which Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride and crystalline polymorphs thereof, are obtained in solid form.

[0040] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to mean that the solid state form contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. Thus, a crystalline polymorph of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride described herein, as substantially free of any other solid state forms would be understood to contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the subject crystalline polymorph of Brilaroxazine, and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride. In some embodiments of the disclosure, the described crystalline polymorph of Brilaroxazine, and salts of Brilaroxazine, including Brilaroxazine hydrobromide and Brilaroxazine hydrochloride, and particularly Brilaroxazine 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 polymorph of the same Brilaroxazine, and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride. Thus, for example, a crystalline polymorph of Brilaroxazine, and salts of Brilaroxazine, including Brilaroxazine hydrobromide and Brilaroxazine hydrochloride, and particularly Brilaroxazine hydrochloride, as described inany aspect or embodiment herein, which is polymorphically pure, may contain: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Brilaroxazine, and salts of Brilaroxazine, including Brilaroxazine hydrobromide and Brilaroxazine hydrochloride, and particularly Brilaroxazine hydrochloride. As another example, a crystalline polymorph of Brilaroxazine, and salts of Brilaroxazine, including Brilaroxazine hydrobromide and Brilaroxazine hydrochloride, and particularly Brilaroxazine hydrochloride, as described in any aspect or embodiment herein, which is polymorphically pure, may contain: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of the Brilaroxazine, and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride. Thus, a crystalline polymorph of Brilaroxazine, and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride as described in any aspect or embodiment herein, which is polymorphically pure, may contain: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Brilaroxazine, and salts of Brilaroxazine, including Brilaroxazine hydrobromide and Brilaroxazine hydrochloride, and particularly Brilaroxazine hydrochloride. Alternatively, a crystalline polymorph of Brilaroxazine, and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride according to any aspect or embodiment of the present invention, may be polymorphically pure and may contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the crystalline polymorph of Brilaroxazine, and salts of Brilaroxazine, including Brilaroxazine hydrobromide and Brilaroxazine hydrochloride, and particularly Brilaroxazine hydrochloride.

[0041] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Brilaroxazine, and salts of Brilaroxazine, including Brilaroxazine hydrobromide and Brilaroxazine hydrochloride, and particularly Brilaroxazine hydrochloride, of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and / or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.

[0042] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depictedin” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Brilaroxazine, and salts of Brilaroxazine, including Brilaroxazine hydrobromide and Brilaroxazine hydrochloride, and particularly Brilaroxazine hydrochloride, referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Brilaroxazine, and salts of Brilaroxazine, including Brilaroxazine hydrobromide and Brilaroxazine hydrochloride, and particularly Brilaroxazine hydrochloride, characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0043] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride, relates to a crystalline form of Brilaroxazine and salts of Brilaroxazine, including Brilaroxazine hydrobromide and Brilaroxazine hydrochloride, and particularly Brilaroxazine hydrochloride, which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w / w), of either water or organic solvents as measured for example by TGA.

[0044] The term "solvate," as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0045] As used herein, the term "isolated" in reference to crystalline polymorph of Brilaroxazine, and salts of Brilaroxazine, including Brilaroxazine hydrobromide and Brilaroxazine hydrochloride, and particularly Brilaroxazine hydrochloride, of the present disclosure corresponds to a crystalline polymorph of Brilaroxazine, and salts of Brilaroxazine,particularly Brilaroxazine hydrochloride, that is physically separated from the reaction mixture in which it is formed.

[0046] As used herein, unless stated otherwise, the XRPD measurements are taken using copper Ka radiation wavelength 1.5418 A. XRPD peaks reported herein are measured using CuK a radiation, = 1.5418 A, typically at a temperature of 25 ± 3°C.

[0047] As used herein, unless stated otherwise,13C NMR reported herein are measured at 125 MHz at a magic angle spinning frequency ®r / 27t = 11 kHz, preferably at a temperature of at 293 K ± 3°C.

[0048] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature”, often abbreviated as “RT .” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0049] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term "v / v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v / v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.

[0050] A process or step may be referred to herein as being carried out "overnight." This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.

[0051] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.

[0052] As used herein and unless indicated otherwise, the term "ambient conditions" refer to atmospheric pressure and a temperature of 22-24°C.

[0053] The present disclosure includes a crystalline polymorph of Brilaroxazine, designated B 1. The crystalline Form B 1 of Brilaroxazine may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; 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 combinations of these data.

[0054] Crystalline Form Bl of Brilaroxazine 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.

[0055] Alternatively, crystalline Form Bl of Brilaroxazine 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 Bl of Brilaroxazine 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.

[0056] Crystalline Form Bl of Brilaroxazine may 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 2-theta ± 0.2 degrees 2-theta.

[0057] Crystalline Form B 1 of Brilaroxazine according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at 3.2 to 4.4 degrees 2-theta ± 0.2 degrees 2- theta, and / or an XRPD pattern having an absence of peaks at 5.6 to 6.8 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 8.2 to 9.7 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 10.6 to 12.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form Bl of Brilaroxazine according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at any one, two, three, or four of the aforementioned regions.

[0058] In one embodiment of the present disclosure, crystalline Form Bl of Brilaroxazine is isolated.

[0059] Crystalline Form Bl of Brilaroxazine may be anhydrous form.

[0060] Crystalline Form Bl of Brilaroxazine may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., 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 at5.0, 7.5, 10.1, 18.2 and 26.9 degrees 2 -theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1, and combinations thereof.

[0061] Crystalline Form Bl of Brilaroxazine as described in any aspect or embodiment of the disclosure may be polymorphically pure, and preferably contains: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Brilaroxazine.

[0062] The present disclosure includes a crystalline polymorph of Brilaroxazine, designated B2. The crystalline Form B2 of Brilaroxazine may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2; 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 combinations of these data.

[0063] Crystalline Form B2 of Brilaroxazine 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.

[0064] Alternatively, crystalline Form B2 of Brilaroxazine 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 Brilaroxazine 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.

[0065] Crystalline Form B2 of Brilaroxazine 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.

[0066] Crystalline Form B2 of Brilaroxazine according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at 3.2 to 4.4 degrees 2-theta ± 0.2 degrees 2- theta, and / or an XRPD pattern having an absence of peaks at 5.6 to 6.7 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 9.1 to 9.7 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 10.6 to 11.7 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form B2 of Brilaroxazine according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at any one, two, three, or four of the aforementioned regions.

[0067] In one embodiment of the present disclosure, crystalline Form B2 of Brilaroxazine is isolated.

[0068] Crystalline Form B2 of Brilaroxazine may be anhydrous form.

[0069] Crystalline Form B2 of Brilaroxazine may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., 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; an XRPD pattern as depicted in Figure 2, and combinations thereof.

[0070] Crystalline Form B2 of Brilaroxazine as described in any aspect or embodiment of the disclosure may be polymorphically pure, and preferably contains: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Brilaroxazine..

[0071] The present disclosure includes a crystalline polymorph of Brilaroxazine, designated B3. The crystalline Form B3 of Brilaroxazine may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 3; 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 combinations of these data.

[0072] Crystalline Form B3 of Brilaroxazine 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.

[0073] Alternatively, crystalline Form B3 of Brilaroxazine 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 Brilaroxazine 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.

[0074] Crystalline Form B3 of Brilaroxazine may be characterized by an X-ray powder diffraction pattern having 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.

[0075] In one embodiment of the present disclosure, crystalline Form B3 of Brilaroxazine is isolated.

[0076] Crystalline Form B3 of Brilaroxazine may be anhydrous form.

[0077] Crystalline Form B3 of Brilaroxazine according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at 4.0 to 7.5 degrees 2-theta ± 0.2 degrees 2- theta, and / or an XRPD pattern having an absence of peaks at 8.0 to 8.3 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 9.0 to 9.4 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 10.0 to 10.5 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 11.4 to 11.8 degrees 2-theta ± 0.2 degrees 2-theta; and / or an absence of peaks at 14.3 to 14.6 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form B3 of Brilaroxazine according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at any one, two, three, four, five, or six of the aforementioned regions.

[0078] Crystalline Form B3 of Brilaroxazine may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at9.7, 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; an XRPD pattern as depicted in Figure 3, and combinations thereof.

[0079] Crystalline Form B3 of Brilaroxazine as described in any aspect or embodiment of the disclosure may be polymorphically pure, and preferably contains: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Brilaroxazine.

[0080] The present disclosure includes a crystalline polymorph of Brilaroxazine, designated B4. The crystalline Form B4 of Brilaroxazine may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; 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 combinations of these data.

[0081] Crystalline Form B4 of Brilaroxazine 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.

[0082] Alternatively, crystalline Form B4 of Brilaroxazine 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 Brilaroxazine 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.

[0083] Crystalline Form B4 of Brilaroxazine 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 2-theta ± 0.2 degrees 2-theta.

[0084] Crystalline Form B4 of Brilaroxazine according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at 3.0 to 8.0 degrees 2-theta ± 0.2 degrees 2- theta.

[0085] In one embodiment of the present disclosure, crystalline Form B4 of Brilaroxazine is isolated.

[0086] Crystalline Form B4 of Brilaroxazine may be anhydrous form.

[0087] Crystalline Form B4 of Brilaroxazine may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at20.1, 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; an XRPD pattern as depicted in Figure 4, and combinations thereof.

[0088] Crystalline Form B4 of Brilaroxazine as described in any aspect or embodiment of the disclosure may be polymorphically pure, and preferably contains: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Brilaroxazine.

[0089] The present disclosure includes a crystalline polymorph of Brilaroxazine, designated B5. The crystalline Form B5 of Brilaroxazine may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 5; 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 combinations of these data.

[0090] Crystalline Form B5 of Brilaroxazine 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.

[0091] Alternatively, crystalline Form B5 of Brilaroxazine 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 Brilaroxazine 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.

[0092] Crystalline Form B5 of Brilaroxazine may be characterized by an X-ray powder diffraction pattern having peaks at 12.3, 14.1, 16.1, 21.6, 23.4, 25.0, 27.3, 26.1 and 28.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0093] Crystalline Form B5 of Brilaroxazine according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at 2.5 to 4.5 degrees 2-theta ± 0.2 degrees 2- theta, and / or an XRPD pattern having an absence of peaks at 5.2 to 6.0 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 7.4 to 8.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form B5 of Brilaroxazine according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at any one, two or three of the aforementioned regions.

[0094] In one embodiment of the present disclosure, crystalline Form B5 of Brilaroxazine is isolated.

[0095] Crystalline Form B5 of Brilaroxazine may be anhydrous form.

[0096] Crystalline Form B5 of Brilaroxazine may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., 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; an XRPD pattern as depicted in Figure 5, and combinations thereof.

[0097] Crystalline Form B5 of Brilaroxazine as described in any aspect or embodiment of the disclosure may be polymorphically pure, and preferably contains: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Brilaroxazine.

[0098] The present disclosure includes a crystalline polymorph of Brilaroxazine, designated B6. The crystalline Form B6 of Brilaroxazine may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 6; 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 combinations of these data.

[0099] Crystalline Form B6 of Brilaroxazine 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, four, or five additional peaks selected from 10.8, 18.4, 27.6 and 29.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0100] Alternatively, crystalline Form B6 of Brilaroxazine 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 Brilaroxazine 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.

[0101] Crystalline Form B6 of Brilaroxazine may be characterized by an X-ray powder diffraction pattern having 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.

[0102] Crystalline Form B6 of Brilaroxazine according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at 4.5 to 8.2 degrees 2-theta ± 0.2 degrees 2- theta, and / or an XRPD pattern having an absence of peaks at 9.2 to 10.2 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 11.0 to 12.0 degrees 2-theta ± 0.2 degrees 2- theta, and / or an absence of peaks at 12.6 to 13.5 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form B6 of Brilaroxazine according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at any one, two, three, or four of the aforementioned regions.

[0103] In one embodiment of the present disclosure, crystalline Form B6 of Brilaroxazine is isolated.

[0104] Crystalline Form B6 of Brilaroxazine may be anhydrous form.

[0105] Crystalline Form B6 of Brilaroxazine may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., 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; an XRPD pattern as depicted in Figure 6, and combinations thereof.

[0106] Crystalline Form B6 of Brilaroxazine as described in any aspect or embodiment of the disclosure may be polymorphically pure, and preferably contains: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Brilaroxazine.

[0107] The present disclosure includes a crystalline polymorph of Brilaroxazine hydrochloride, designated BRI . The crystalline Form BRI of Brilaroxazine hydrochloride may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted 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; a solid state13C NMR spectrum having peaks at 20.6, 42.4, 97.5, 122.2, 131.0 and 165.5 ppm ± 0.2 ppm ± 0.2 ppm; a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 116.7 ppm ± 2 ppm of 96.11, 74.31, 19.21, 5.49, 14.29 and 48.78 ppm ± 0.1 ppm; a solid state13C NMR spectrum substantially as depicted in Figures 16a, 16b or 16c; and combinations of these data..

[0108] Crystalline Form BRI of Brilaroxazine hydrochloride 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.

[0109] Alternatively, crystalline Form BRI of Brilaroxazine 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 BRI of Brilaroxazine 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.

[0110] Crystalline Form BRI of Brilaroxazine hydrochloride 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.

[0111] Crystalline Form BRI of Brilaroxazine hydrochloride according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at 2.0 to 3.0 degrees 2- theta ± 0.2 degrees 2-theta, and / or an XRPD pattern having an absence of peaks at 4.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 8.0 to 10.5 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 11.5 to 13.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form BRI of Brilaroxazine hydrochloride according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at any one, two, three, or four of the aforementioned regions.

[0112] In one embodiment of the present disclosure, crystalline Form BRI of Brilaroxazine hydrochloride is isolated.

[0113] Crystalline Form BRI of Brilaroxazine hydrochloride may be anhydrous form.

[0114] Crystalline Form BRI of Brilaroxazine hydrochloride may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., 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; an XRPD pattern as depicted in Figure 7, and combinations thereof.

[0115] Crystalline Form BRI of Brilaroxazine hydrochloride as described in any aspect or embodiment of the disclosure may be polymorphically pure, and preferably contains: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Brilaroxazine hydrochloride.

[0116] The present disclosure provides a process for preparing Form BRI of Brilaroxazine Hydrochloride, comprising crystallising Brilaroxazine Hydrochloride from acetone and diethylether. According to any aspect or embodiment, the process may comprise: (a) preparing a solution of Brilaroxazine Hydrochloride in a solvent comprising acetone, (b) combining the solution with diethyl ether, and (c) optionally isolating the crystalline Brilaroxazine hydrochloride Form BRI. The solution in step (a) may be prepared by reacting a solution of Brilaroxazine in acetone with hydrochloric acid. Preferably, the reaction is 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.

[0117] According to any aspect or embodiment of the disclosed processes, the process for preparing Form BRI of Brilaroxazine Hydrochloride may comprise:(i) dissolving Brilaroxazine in acetone;(ii) adding hydrochloric acid;(iii) adding diethyl ether(iv) isolating Brilaroxazine Hydrochloride; and(v) drying.

[0118] According to any aspect or embodiment of the disclosed processes for preparing Form BRI of Brilaroxazine hydrochloride, the 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 Brilaroxazine. The acetone may be added at 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.

[0119] According to an aspect or embodiment of the process for making Form BRI of Brilaroxazine hydrochloride, hydrochloric acid is preferably used as a 2M HC1 solution. The hydrochloric acid is preferably be 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 Brilaroxazine.

[0120] In any aspect or embodiment of the disclosed processes, the hydrochloric acid may be added to the solution at 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.

[0121] According to any aspect or embodiment of the disclosed process for preparing Form BRI of Brilaroxazine hydrochloride, 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 Brilaroxazine. According to any aspect or embodiment of the disclosed process for preparing Form BRI of Brilaroxazine hydrochloride, 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. In any aspect or embodiment of the disclosed processes, the diethyl ether may be added at 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.

[0122] In any aspect or embodiment of the disclosed processes, the reaction mixture comprising Brilaroxazine hydrochloride, acetone and diethylether may be stirred at 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 a period of: about 6 hours to about 48 hours, about 10 hours to 24 hours; about 12 hours to about 20 hours; about 14 hours to about 18 hours, or about 16 hours.

[0123] The process may further include isolating the obtained Brilaroxazine Hydrochloride, by any suitable procedure, such as filtration, decantation, or by centrifuge. Particularly the product may be isolated by vacuum filtration. Following isolation, the Brilaroxazine Hydrochloride may be dried. The drying may be carried out under vacuum for the period of: about 5 minutes to 1 hour, or about 10 minutes to about 25 minutes, or about 15 minutes.

[0124] According to any aspect or embodiment of the disclosed processes for preparing Form BRI of Brilaroxazine hydrochloride, the process may further comprise combining the Form BRI of Brilaroxazine with at least one pharmaceutically acceptable excipient to prepare pharmaceutical composition.

[0125] The present disclosure includes a crystalline polymorph of Brilaroxazine hydrochloride, designated BR2. The crystalline Form BR2 of Brilaroxazine hydrochloride maybe characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 8; 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 combinations of these data.

[0126] Crystalline Form BR2 of Brilaroxazine hydrochloride 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.

[0127] Alternatively, crystalline Form BR2 of Brilaroxazine 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. Crystalline BR2 of Brilaroxazine hydrochloride 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.

[0128] Crystalline Form BR2 of Brilaroxazine hydrochloride may 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.

[0129] Crystalline Form BR2 of Brilaroxazine hydrochloride according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at 3.0 to 3.6 degrees 2- theta ± 0.2 degrees 2-theta, and / or an XRPD pattern having an absence of peaks at 5.4 to 7.0 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 8.4 to 9.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form BR2 of Brilaroxazine hydrochloride according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at any one, two or three of the aforementioned regions.

[0130] In one embodiment of the present disclosure, crystalline Form BR2 of Brilaroxazine hydrochloride is isolated.

[0131] Crystalline Form BR2 of Brilaroxazine hydrochloride may be hydrate form.

[0132] Crystalline Form BR2 of Brilaroxazine hydrochloride may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 10.0, 19.6 and 22.9 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern havingpeaks at 12.1, 17.7, 20.3, 25.0 and 25.4 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 8, and combinations thereof.

[0133] Crystalline Form BR2 of Brilaroxazine hydrochloride as described in any aspect or embodiment of the disclosure may be polymorphically pure, and preferably contains: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Brilaroxazine hydrochloride.

[0134] The present disclosure includes a crystalline polymorph of Brilaroxazine hydrochloride, designated BR3. The crystalline Form BR3 of Brilaroxazine hydrochloride may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 9; an X-ray powder diffraction pattern having peaks at 12.8, 15.4 and 18.9 degrees 2-theta± 0.2 degrees 2-theta; a solid state13C NMR spectrum having peaks at 22.7, 28.4, 59.3, 66.3, 119.5 and 155.3 ppm ± 0.2 ppm ± 0.2 ppm; a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 116.7 ppm ± 2 ppm of 94.01, 88.31, 50.41, 48.78, 2.79 and 38.59 ppm ± 0.1 ppm; a solid state13C NMR spectrum substantially as depicted in Figures 17a, 17b or 17c; and combinations of these data.

[0135] Crystalline Form BR3 of Brilaroxazine hydrochloride 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.

[0136] Alternatively, crystalline Form BR3 of Brilaroxazine 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 Brilaroxazine 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.

[0137] Crystalline Form BR3 of Brilaroxazine hydrochloride may 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.

[0138] Crystalline Form BR3 of Brilaroxazine hydrochloride according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at 3.5 to 9.5 degrees 2- theta± 0.2 degrees 2-theta or 3.5 to 10.5 degrees 2-theta ± 0.2 degrees 2-theta, and / or an XRPDpattern having an absence of peaks at 12.0 to 12.5 degrees 2-th eta ± 0.2 degrees 2-theta, and / or an absence of peaks at 13.2 to 13.7 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 14.3 to 14.7 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form BR3 of Brilaroxazine hydrochloride according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at any one, two, three or four of the aforementioned regions.

[0139] In one embodiment of the present disclosure, crystalline Form BR3 of Brilaroxazine hydrochloride is isolated.

[0140] Crystalline Form BR3 of Brilaroxazine hydrochloride may be anhydrous form.

[0141] Crystalline Form BR3 of Brilaroxazine hydrochloride may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., 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; an XRPD pattern as depicted in Figure 9, and combinations thereof.

[0142] Crystalline Form BR3 of Brilaroxazine hydrochloride as described in any aspect or embodiment of the disclosure may be polymorphically pure, and preferably contains: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Brilaroxazine hydrochloride.

[0143] According to any aspect or embodiment, Form BR3 of Brilaroxazine hydrochloride may be prepared by crystallization of Brilaroxazine hydrochloride from isopropyl alcohol. The process preferably comprises cooling a mixture of Brilaroxazine hydrochloride in isopropyl alcohol. In particular, according to any aspect or embodiment of this process, the mixture of Brilaroxazine hydrochloride in isopropyl alcohol may be provided, and heated, preferably 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. The heating may 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. Preferably, the cooling is 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 from the cooled mixture, preferably by any suitable procedure, such as filtration, decantation, or by centrifuge. Particularly the product may be isolated by vacuum filtration. Following isolation, the Brilaroxazine Hydrochloride Form BR3 may be dried. The drying may be carried out under vacuum for the period of: about 5 minutes to 1 hour, or about 10 minutes to about 25 minutes, or about 10 minutes to about 15 minutes.

[0144] According to any aspect or embodiment of the disclosed processes, the process for preparation of Form BR3 of Brilaroxazine hydrochloride may particularly comprise:(i) combining isopropyl alcohol and Brilaroxazine hydrochloride, preferably Form BR2;(ii) heating;(iii) cooling;(iv) optionally isolating; and(v) optionally drying.

[0145] According to any aspect or embodiment of the process for preparing Form BR3 of Brilaroxazine hydrochloride, the starting material is preferably Form BR2 of Brilaroxazine hydrochloride. According to any aspect or embodiment of the disclosed processes, the isopropyl alcohol may be combined with Form BR2 of Brilaroxazine hydrochloride.

[0146] According to any aspect or embodiment of the process for preparing Form BR3 of Brilaroxazine hydrochloride, the isopropyl alcohol may be used at an amount of: about 30 ml to about 80 ml, about 40 to about 60 ml, or about 50 ml, per gram of Form BR2 of Brilaroxazine Hydrochloride. According to any aspect or embodiment, the isopropyl alcohol may be combined with the Brilaroxazine hydrochloride at 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.

[0147] In any aspect or embodiment of the disclosed processes for preparing Form BR3 of Brilaroxazine hydrochloride, the reaction mixture may 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 processes, the mixture may be stirred at the heated 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 may be stirred at this temperature range preferably for a period of: 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.

[0148] In any aspect or embodiment of the disclosed processes, the mixture may be cooled. The 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, preferably by any suitable procedure, such as filtration, decantation, or by centrifuge. Particularly the product may be isolated by vacuum filtration. Following isolation, the Brilaroxazine Hydrochloride may be dried. The drying may be carried out under vacuum for the period of: about 5 minutes to 1 hour, or about 10 minutes to about 25 minutes, or about 10 minutes to about 15 minutes.

[0149] Alternatively, Form BR3 of Brilaroxazine hydrochloride may be prepared by a process comprising grinding Brilaroxazine hydrochloride, preferably by grinding Form BR2 of Brilaroxazine hydrochloride, in isopropyl alcohol. According to any aspect or embodiment of the disclosed processes, the process for preparation of Form BR3 of Brilaroxazine hydrochloride may comprise: grinding a mixture comprising Brilaroxazine hydrochloride (preferably Form BR2), and isopropyl alcohol. Preferably, the isopropyl alcohol is used in an amount of: about 190 pl to 220 pl, or about 200 pl, per gram of Brilaroxazine hydrochloride; and grinding for a period of about 1 minute to about 5 minutes, or about 2 minutes to about 3 minutes.

[0150] Alternatively, the present disclosure provides a further process for preparing Form BR3 of Brilaroxazine Hydrochloride, comprising crystallising Brilaroxazine Hydrochloride from acetone and n-heptane. According to any aspect or embodiment, the process may comprise: (a) preparing a mixture of Brilaroxazine Hydrochloride in acetone, (b) combining the mixture with n-heptane, and (c) optionally isolating the crystalline Brilaroxazine hydrochloride Form BR3. The mixture in step (a) may be prepared by reacting a solution of Brilaroxazine in acetone with hydrochloric acid. Preferably, the reaction is 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 may be stirred at this temperature for a period of: 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), the n-heptane may be combined with the mixture of Brilaroxazine Hydrochloride in acetone. Optionally, the n- heptane may be added at temperature of 18°C to about 22°C, or about 20°C. The mixture may be stirred, preferably for a period of: 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 may be isolated any suitable method, such as by filtration, decantation, or centrifuge, preferably by filtration. According to any aspect or embodiment of the disclosed processes, the process for preparation of Form BR3 of Brilaroxazine hydrochloride may comprise:(i) dissolving Brilaroxazine in acetone;(ii) adding hydrochloric acid;(iii) optionally cooling;(iv) adding n-heptane;(v) optionally cooling;(vi) isolating Brilaroxazine Hydrochloride form BR3; and(vii) optionally washing.

[0151] Particularly, acetone may be used at an amount of: about 30 to about 80 ml, about 40 to about 70 ml, or about 60 ml, per gram of Brilaroxazine. Acetone may be added at 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. .

[0152] According to an aspect or embodiment of the process for making Form BR3 of Brilaroxazine hydrochloride, hydrochloric acid is preferably used as a 2M HC1 solution, and may preferably be 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 Brilaroxazine. In any aspect or embodiment of the disclosed processes for preparing Form BR3 of Brilaroxazine, the hydrochloric acid may be added to the solution at 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 a period of about 0.5 hours to about 3 hours; or about 1 hour. In any aspect or embodiment of the disclosed processes for preparing Form BR3 of Brilaroxazine, the reaction mixture may be cooled, preferably to a temperature of about 20°C. In any aspect or embodiment of the disclosed processes for preparing Form BR3 of Brilaroxazine, the n-heptane may be added, and the mixture stirred for a period of about 3 hours to 0.5 hours; or about 1 hour. According to any aspect or embodiment of the disclosed process for preparing Form BR3 of Brilaroxazine hydrochloride, 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 Brilaroxazine. According to any aspect or embodiment of the disclosed process for preparing Form BR3 of Brilaroxazine hydrochloride, 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 about 1 :2.9. In any aspect or embodiment of the disclosed processes, the n-heptane may be added at 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.

[0153] In any aspect or embodiment of the disclosed processes for preparing Form BR3 of Brilaroxazine hydrochloride, the reaction mixture may be cooled, preferably to a temperature of about 10 °C. The mixture may be maintained at this temperature for a period of about 10 hours to about 30 hours, or about 12 hours to about 25 hours, or about 16 hours.

[0154] The process may further include isolating the obtained Brilaroxazine Hydrochloride by any suitable procedure, such as filtration, decantation, or by centrifuge. Particularly the product may be isolated by filtration.

[0155] In any aspect or embodiment of the disclosed processes for preparing Form BR3 of Brilaroxazine hydrochloride, the reaction mixture may be brought to 25°C prior to isolation(preferably by filtration), and the Form BR3 of Brilaroxazine hydrochloride may be washed with n-heptane at an amount of: about 5 ml to about 30 ml, or about 10 ml, per gram of Brilaroxazine.

[0156] Alternatively, the present disclosure provides a further process for preparing Form BR3 of Brilaroxazine Hydrochloride, comprising crystallising Brilaroxazine Hydrochloride from methanol and acetone. According to any aspect or embodiment, the process may comprise: (a) preparing a solution of Brilaroxazine Hydrochloride in methanol, (b) combining the solution with acetone, and (c) optionally isolating the crystalline Brilaroxazine hydrochloride Form BR3. The solution in step (a) may be prepared by dissolving Brilaroxazine 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 Brilaroxazine hydrochloride may be combined with the acetone. Preferably the solution of Brilaroxazine hydrochloride in methanol is added to acetone. The acetone may be cooled prior to the addition, preferably wherein the cooling is 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, preferably for a period of: about 30 minutes to about 4 hours, about 30 minutes to about 2 hours, or about 1 hour. The product may be isolated any suitable method, such as by filtration, decantation, or centrifuge, preferably by filtration. Following isolation, the Brilaroxazine Hydrochloride Form BR3 may be dried. The drying may be carried out under vacuum for the period of: about 5 minutes to 1 hour, or about 10 minutes to about 25 minutes, or about 10 minutes to about 15 minutes. Preferably the drying is 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 disclosed processes, the process for preparation of Form BR3 of Brilaroxazine hydrochloride may comprise:(i) dissolving Brilaroxazine in methanol;(ii) adding acetone;(iii) optionally isolating Brilaroxazine Hydrochloride form BR3; and(iv) optionally drying.

[0157] According to any aspect of the processes for preparing Form BR3 of Brilaroxazine hydrochloride, methanol may be used at 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 Brilaroxazine. Acetone may be added at 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 process for preparing Form BR3 of Brilaroxazine hydrochloride, the acetone may be used in an amountof: 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 Brilaroxazine. According to any aspect or embodiment of the disclosed process for preparing Form BR3 of Brilaroxazine hydrochloride, the volume ratio of acetone to methanol may 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 processes for preparing Form BR3 of Brilaroxazine the reaction mixture may be cooled, preferably to a temperature of about 10 °C. The mixture may be stirred, preferably for a period of: about 30 minutes to about 4 hours, about 30 minutes to about 2 hours, or about 1 hour.

[0158] The process may further include isolating the obtained Brilaroxazine Hydrochloride by any suitable procedure, such as filtration, decantation, or by centrifuge. Particularly the product may be isolated by filtration. Following isolation, the Brilaroxazine Hydrochloride may be dried. The drying may be carried out under vacuum for the period of: about 5 minutes to 1 hour, or about 10 minutes to about 25 minutes, or about 10 minutes to about 15 minutes. Preferably the drying is carried out at a temperature of: about 18°C to about 30°C, about 20°C to about 27°C, or about 25°C.

[0159] According to any aspect or embodiment of the disclosed processes for preparing Form BR3 of Brilaroxazine hydrochloride, the process may further comprise combining the Form BR3 of Brilaroxazine with at least one pharmaceutically acceptable excipient to prepare pharmaceutical composition.

[0160] The present disclosure includes a crystalline polymorph of Brilaroxazine hydrochloride, designated BR4. The crystalline Form BR4 of Brilaroxazine hydrochloride may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 10; 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 combinations of these data.

[0161] Crystalline Form BR4 of Brilaroxazine hydrochloride 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.

[0162] Alternatively, crystalline Form BR4 of Brilaroxazine 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 Brilaroxazine 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.

[0163] Crystalline Form BR4 of Brilaroxazine hydrochloride may 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.

[0164] Crystalline Form BR4 of Brilaroxazine hydrochloride according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at 3.5 to 4.0 degrees 2- theta ± 0.2 degrees 2-theta, and / or an XRPD pattern having an absence of peaks at 4.5 to 4.9 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 6.3 to 6.8 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 9.3 to 10.2 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 11.0 to 11.8 degrees 2-theta ± 0.2 degrees 2-theta, and / or an absence of peaks at 13.0 to 14.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form BR4 of Brilaroxazine hydrochloride according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at any one, two, three, four, five, or six of the aforementioned regions.

[0165] In one embodiment of the present disclosure, crystalline Form BR4 of Brilaroxazine hydrochloride is isolated.

[0166] Crystalline Form BR4 of Brilaroxazine hydrochloride may be hydrate form.

[0167] Crystalline Form BR4 of Brilaroxazine hydrochloride may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., 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; an XRPD pattern as depicted in Figure 10, and combinations thereof.

[0168] Crystalline Form BR4 of Brilaroxazine hydrochloride as described in any aspect or embodiment of the disclosure may be polymorphically pure, and preferably contains: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Brilaroxazine hydrochloride.

[0169] The present disclosure includes a crystalline polymorph of Brilaroxazine hydrochloride, designated BR5. The crystalline Form BR5 of Brilaroxazine hydrochloride may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 11; an X-ray powder diffraction patternhaving peaks at 5.4, 17.9 and 21.9 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0170] Crystalline Form BR5 of Brilaroxazine hydrochloride 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.

[0171] Alternatively, crystalline Form BR5 of Brilaroxazine 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 Brilaroxazine 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.

[0172] Crystalline Form BR5 of Brilaroxazine hydrochloride may 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.

[0173] Crystalline Form BR5 of Brilaroxazine hydrochloride according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at 4.0 to 5.0 degrees 2- theta ± 0.2 degrees 2-theta.

[0174] In one embodiment of the present disclosure, crystalline Form BR5 of Brilaroxazine hydrochloride is isolated.

[0175] Crystalline Form BR5 of Brilaroxazine hydrochloride may be anhydrous form.

[0176] Crystalline Form BR5 of Brilaroxazine hydrochloride may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., 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; an XRPD pattern as depicted in Figure 11, and combinations thereof.

[0177] Crystalline Form BR5 of Brilaroxazine hydrochloride as described in any aspect or embodiment of the disclosure may be polymorphically pure, and preferably contains: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Brilaroxazine hydrochloride.

[0178] The present disclosure includes a crystalline polymorph of Brilaroxazine hydrochloride, designated BR6. The crystalline Form BR6 of Brilaroxazine hydrochloride may be characterized by data selected from one or more of the following: an X-ray powderdiffraction pattern substantially as depicted in Figure 12; 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 combinations of these data.

[0179] Crystalline Form BR6 of Brilaroxazine hydrochloride 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.

[0180] Alternatively, crystalline Form BR6 of Brilaroxazine 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 Brilaroxazine 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.

[0181] Crystalline Form BR6 of Brilaroxazine hydrochloride may be characterized by an X-ray powder diffraction pattern having 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.

[0182] Crystalline Form BR6 of Brilaroxazine hydrochloride according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at 4.0 to 6.0 degrees 2- theta ± 0.2 degrees 2-theta.

[0183] In one embodiment of the present disclosure, crystalline Form BR6 of Brilaroxazine hydrochloride is isolated.

[0184] Crystalline Form BR6 of Brilaroxazine hydrochloride may be anhydrous form.

[0185] Crystalline Form BR6 of Brilaroxazine hydrochloride may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., 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; an XRPD pattern as depicted in Figure 12, and combinations thereof.

[0186] Crystalline Form BR6 of Brilaroxazine hydrochloride as described in any aspect or embodiment of the disclosure may be polymorphically pure, and preferably contains: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Brilaroxazine hydrochloride.

[0187] The present disclosure includes a crystalline polymorph of Brilaroxazine hydrochloride, designated BR7. The crystalline Form BR7 of Brilaroxazine hydrochloride maybe characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 13; 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 combinations of these data.

[0188] Crystalline Form BR7 of Brilaroxazine hydrochloride 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.

[0189] Alternatively, crystalline Form BR7 of Brilaroxazine 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 Brilaroxazine 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.

[0190] Crystalline Form BR7 of Brilaroxazine hydrochloride may 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 2-theta ± 0.2 degrees 2-theta.

[0191] In one embodiment of the present disclosure, crystalline Form BR7 of Brilaroxazine hydrochloride is isolated.

[0192] Crystalline Form BR7 of Brilaroxazine hydrochloride may be hydrate form, more preferably dihydrate form.

[0193] Crystalline Form BR7 of Brilaroxazine hydrochloride may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., 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; an XRPD pattern as depicted in Figure 13, and combinations thereof.

[0194] Crystalline Form BR7 of Brilaroxazine hydrochloride as described in any aspect or embodiment of the disclosure may be polymorphically pure, and preferably contains: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Brilaroxazine hydrochloride.

[0195] The present disclosure provides Brilaroxazine hydrobromide. Brilaroxazine hydrobromide is preferably in the form of solid, and more preferably Brilaroxazine hydrobromide is crystalline. The present disclosure includes a crystalline polymorph of Brilaroxazine hydrobromide, designated BHBrl . The crystalline Form BHBrl of Brilaroxazinehydrobromide may be characterized by data selected from one or more of the following: an X- ray powder diffraction pattern substantially as depicted in Figure 14; an X-ray powder diffraction pattern having peaks at 10.1, 11.9, 16.4 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0196] Crystalline Form BHBrl of Brilaroxazine hydrobromide 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.

[0197] Alternatively, crystalline Form BHBrl of Brilaroxazine 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 BHBrl of Brilaroxazine 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.

[0198] Crystalline Form BHBrl of Brilaroxazine hydrobromide may 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.

[0199] Crystalline Form BHBrl of Brilaroxazine hydrobromide according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at 3.5 to 5.0 degrees 2- theta ± 0.2 degrees 2-theta, and / or an XRPD pattern having an absence of peaks at 6.0 to 9.0 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form BHBrl of Brilaroxazine hydrobromide according to any aspect or embodiment of the disclosure may be characterized by any of the data described herein, and further characterized by an XRPD pattern having an absence of peaks at one or both of the aforementioned regions.

[0200] In one embodiment of the present disclosure, crystalline Form BHBrl of Brilaroxazine hydrobromide is isolated.

[0201] Crystalline Form BHBrl of Brilaroxazine hydrobromide may be anhydrous form.

[0202] Crystalline Form BHBrl of Brilaroxazine hydrobromide may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., 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; an XRPD pattern as depicted in Figure 14, and combinations thereof.

[0203] Crystalline Form BHBrl of Brilaroxazine hydrobromide as described in any aspect or embodiment of the disclosure may be polymorphically pure, and preferably contains: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of Brilaroxazine hydrobromide.

[0204] The present disclosure provides the above described crystalline polymorphs of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride, for use in the preparation of pharmaceutical compositions comprising Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride and / or crystalline polymorphs thereof.

[0205] The present disclosure also encompasses the use of crystalline polymorphs of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride of the present disclosure, for the preparation of pharmaceutical compositions of crystalline polymorph Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride and / or crystalline polymorphs thereof.

[0206] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes includes combining any one or a combination of the crystalline polymorphs of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride of the present disclosure, with at least one pharmaceutically acceptable excipient.

[0207] Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid state forms of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[0208] Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, 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.

[0209] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositionsinclude acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0210] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of 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, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®), and starch.

[0211] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0212] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. 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.

[0213] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0214] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and / or facilitate patient identification of the product and unit dosage level.

[0215] In liquid pharmaceutical compositions of the present invention, Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride, and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0216] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0217] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and / or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.

[0218] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0219] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[0220] According to the present disclosure, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[0221] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although 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. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

[0222] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0223] The dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and / or sorbitol, an opacifying agent and / or colorant.

[0224] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0225] A composition 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 in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and / or milled, dried, and then screened and / or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and / or a lubricant.

[0226] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.

[0227] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

[0228] A capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[0229] A pharmaceutical formulation of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride, can be administered. Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride, may be formulated for administration to a mammal, in embodiments to a human, by injection. Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride, can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection. The formulationcan contain one or more solvents. A suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[0230] The crystalline polymorphs of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride, and the pharmaceutical compositions and / or formulations of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride of the present disclosure, can be used as medicaments, in embodiments in the treatment of Schizophrenia, Schizoaffective disorder, Idiopathic pulmonary fibrosis and Pulmonary arterial hypertension.

[0231] The present disclosure also provides methods of treating Schizophrenia, Schizoaffective disorder, Idiopathic pulmonary fibrosis and Pulmonary arterial hypertension by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Brilaroxazine and salts of Brilaroxazine, particularly Brilaroxazine hydrochloride of the present disclosure, or at least one of the above pharmaceutical compositions and / or formulations, to a subject in need of the treatment.

[0232] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way.Powder X-ray Diffraction ("XRPD") method

[0233] X-ray diffraction was performed on X-Ray powder diffractometer:Bruker D8 Advance; CuK_ radiation (k = 1.5418 A); Lynx eye detector; laboratory temperature 22-25 °C; PMMA specimen holder ring. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.Measurement parameters:Scan range: 2 - 40 degrees 2-theta;Scan mode: continuous;Step size: 0.05 degrees;Time per step: 0.5 s;Sample spin: 30 rpm;Sample holder: PMMA specimen holder ring.

[0234] All X-Ray Powder Diffraction peak values are calibrated with regard to standard silicon spiking in the sample.13C CP / MAS NMR Method:

[0235] Solid-state NMR spectra were measured at 11.7 T using a Bruker Avance III HD 500 US / WB NMR spectrometer (Karlsruhe, Germany, 2013) with 3.2 mm probehead. The13C CP / MAS NMR spectra employing cross-polarization were acquired using the standard pulse scheme at spinning frequency of 15 kHz and a room temperature (300 K). The recycle delay was 8 s and the cross-polarization contact time was 2 ms. The13C scale was referenced to a- glycine (176.03 ppm for13C). Frictional heating of the spinning samples was offset by active cooling, and the temperature calibration was performed with Pb(NO3)2. The NMR spectrometer was completely calibrated and all experimental parameters were carefully optimized prior the investigation. Magic angle was set using KBr during standard optimization procedure and homogeneity of magnetic field was optimized using adamantane sample (resulting line-width at half-height Au 1 / 2 was less than 3.5 Hz at 250 ms of acquisition time).EXAMPLESPreparation of starting materials

[0236] Brilaroxazine can be prepared according to methods known from the literature, for example U.S. Patent No. 8,188,076.Example 1: Preparation of Brilaroxazine Form Bl

[0237] Brilaroxazine (0.02 grams) was dissolved in dichloromethane (0.2 ml) at temperature of about 25°C and clear solution was obtained. The clear solution was covered with a parafilm with a pin hole and kept for slow solvent evaporation at temperature of about 22°C to about 25°C. After one hour, solid was isolated and analyzed by XRPD. Crystalline Brilaroxazine Form Bl was obtained. An XRPD pattern is shown in Figure 1.Example 2: Preparation of Brilaroxazine Form B2

[0238] Brilaroxazine (0.02 grams) was dissolved in methanol (2.5 ml) at temperature of about 25°C and clear solution was obtained. Water (3 ml) was added in to the clear solution at temperature of about 25°C and white precipitate was obtained. After maintaining for about 1 hour, the reaction mixture was filtered and washed with water (3 ml x 1). The obtained solid was suck dried under vacuum for a period of about 10 minutes to about 15 minutes attemperature of about 22°C to about 25°C. The obtained solid was analyzed by XRPD. Crystalline Brilaroxazine Form B2 was obtained. An XRPD pattern is shown in Figure 2.Example 3: Preparation of Brilaroxazine Form B3

[0239] Brilaroxazine (0.02 grams) was dissolved in Methanol (2.5 ml) at temperature of about 25°C and obtained a clear solution. The clear solution was covered with a parafilm with a pin hole and kept for slow solvent evaporation at temperature of about 22°C to about 25°C. After one hour, solid was isolated and analyzed by XRPD. Crystalline Brilaroxazine Form B3 was obtained. An XRPD pattern is shown in Figure 3.Example 4: Preparation of Brilaroxazine Form B4

[0240] Brilaroxazine (0.02 grams) was dissolved in tetrahydrofuran (0.1 ml) at temperature of about 25 °C and obtained a clear solution. The clear solution was covered with a parafilm with a pin hole and kept for slow solvent evaporation at temperature of about 22°C to about 25°C. After one hour, solid was isolated and analyzed by XRPD. Crystalline Brilaroxazine Form B4 was obtained. An XRPD pattern is shown in Figure 4.Example 5: Preparation of Brilaroxazine Form B5

[0241] Brilaroxazine (1 gram) was dissolved in di chloromethane (20 ml) at temperature of about 25°C. The solution was filtered through 0.45 micron filter and in particle free solution, Heptane (10 ml) was added at temperature of about 25°C and white precipitate formation was observed. The reaction mixture was maintained under stirring for a period of about 2 hours at temperature of about 25°C. The reaction mixture was filtered and washed with heptane (3 ml x 2). The obtained solid was suck dried under vacuum for a period of about 10 minutes to about 15 minutes at temperature of about 22°C to about 25°C and further dried in the Vacuum Tray Dryer at temperature of about 60 °C for a period of about 24 hours. The obtained solid was analyzed by XRPD. Crystalline Brilaroxazine Form B5 was obtained. An XRPD pattern is shown in Figure 5.Example 6: Preparation of Brilaroxazine Form B6

[0242] Brilaroxazine (0.1 grams) (Form B5) was taken in a 10 mL vial and 5 mL of heptane (5 ml) was added at temperature of about 60°C. The slurry mass was stirred at temperature of about 60°C for a period of about 48 hours. The reaction mass was filtered and dried under vacuum at temperature of about 25°C to about 30°C for a period of about 20 minutes to about 30 minutes. After 48 hour, After one hour, solid was isolated and analyzed by XRPD. Crystalline Brilaroxazine Form B4 was obtained. An XRPD pattern is shown in Figure 6.Example 7: Preparation of Brilaroxazine hydrochloride Form BRI

[0243] Brilaroxazine (0.1 grams) was dissolved in acetone (5 ml) at temperature of about 25°C. 2 ml 2M HC1 solution was added and then diethyl ether (30 ml) was added at temperature of about 25°C. The reaction mixture was stirred at temperature of about 25°C for a period of about 16 hours. The reaction mass was filtered and dried under vacuum for a period of about 10 minutes to about 15 minutes. The obtained solid was analyzed by XRPD. Crystalline Brilaroxazine hydrochloride Form BRI was obtained. An XRPD pattern is shown in Figure 7.Example 8: Preparation of Brilaroxazine hydrochloride Form BR2

[0244] Brilaroxazine (Form Bl, 0.1 grams) was suspended in buffer pH 1.2 (prepared by using HC1) (5 ml) in a glass vial at temperature of about 25°C. The slurry mass was maintained under stirring for a period of about 1 hour to about 2 hours and reaction mass became very sticky. The reaction mass was maintained under stirring for a period of about 16 hours at temperature of about 25°C and white solid was observed. The slurry mass was filtered and dried under vacuum for a period of about 10 minutes to 15 minutes. The obtained solid was analyzed by XRPD. Crystalline Brilaroxazine hydrochloride Form BR2 was obtained. An XRPD pattern is shown in Figure 8.Example 9: Preparation of Brilaroxazine hydrochloride Form BR3

[0245] Brilaroxazine hydrochloride (Form BR2, 0.1 grams) was charged in a glass vial at temperature of about 25°C. 5 ml Isopropyl alcohol was added and reaction mixture was heated up to a temperature of about 75°C to about 80°C and was maintained under stirring for a period of about 16 hours at temperature of about 75°C to about 80°C. The reaction mass was cooled down to a temperature of about 25°C and filtered and dried under vacuum for a period of about 10 minutes to about 15 minutes. The obtained solid was analyzed by XRPD. Crystalline Brilaroxazine hydrochloride Form BR3 was obtained. An XRPD pattern is shown in Figure 9.Example 10: Preparation of Brilaroxazine hydrochloride Form BR3

[0246] Brilaroxazine hydrochloride (Form BR2, 0.1 grams) was taken in a mortar and pestle. Few drops (about 20 pl) of Isopropyl alcohol was added and grinded for a period of about 2 minutes to about 3 minutes. The obtained solid was analyzed by XRPD. Crystalline Brilaroxazine hydrochloride Form BR3 was obtained.Example 11: Preparation of Brilaroxazine hydrochloride Form BR4

[0247] Brilaroxazine (0.3 grams) was dissolved in dichloromethane (4.5 ml) at temperature of about 25°C. Aq. HC1 solution (0.12 ml) was added in to Brilaroxazine solution at temperature of about 25 °C and maintained under stirring for a period of about one hour. Filtered and suck dried the material for a period of about 15 minutes. The obtained solid wasanalyzed by XRPD. Crystalline Brilaroxazine hydrochloride Form BR4 was obtained. An XRPD pattern is shown in Figure 10.Example 12: Preparation of Brilaroxazine hydrochloride Form BR5

[0248] Brilaroxazine (1.0 gram) was dissolved in dichloromethane (15 ml) at temperature of about 25°C. 0.48 ml aqueous HC1 solution was added dropwise at temperature of about 25°C. The reaction mixture was maintained under stirring for a period of about 1 hour. Filtered and dried under vacuum for a period of about 15 minutes to about 30 minutes. Further dried in Vacuum tray dryer (VTD) oven at temperature of about 50°C for a period of about 10 hours. The sample was brought down to room temperature for a period of about 25°C. The obtained solid was analyzed by XRPD. Crystalline Brilaroxazine hydrochloride Form BR5 was obtained. An XRPD pattern is shown in Figure 11.Example 13: Preparation of Brilaroxazine hydrochloride Form BR6

[0249] Brilaroxazine hydrochloride salt (Form BR2, 0.03 grams) was suspended in methanol-water mixture 9: 1 (1 ml) at temperature of about 25°C. The reaction mass was maintained under stirring at temperature of about 25°C for a period of about 18 hours. The slurry was filtered and dried under vacuum for a period of about 10 minutes to about 15 minutes. The obtained solid was analyzed by XRPD. Crystalline Brilaroxazine hydrochloride Form BR6 was obtained. An XRPD pattern is shown in Figure 12.Example 14: Preparation of Brilaroxazine hydrochloride Form BR7

[0250] Brilaroxazine (Form Bl, 0.06 grams) was taken 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 and kept inside a stainless steel jacketed block and tightened up properly and was kept in an oven and heated the reaction mixture up to 80°C for 8 hours, and cooled down to 25°C for 16 hrs. This cycle was repeated thrice in a closed condition. The reaction mixture was finally cooled to 25°C. Filtered and obtained solid was suck dried for about 15 minutes. The obtained solid was analyzed by XRPD. Crystalline Brilaroxazine hydrochloride Form BR7 was obtained. An XRPD pattern is shown in Figure 13.Example 15: Preparation of Brilaroxazine hydrobromide Form BHBrl

[0251] Brilaroxazine Free base (0.2 grams) was dissolved was in acetone (6 ml) at temperature of about 40°C. IPA-HBr solution [(Isopropyl alcohol (0.5 ml) and aqueous HBr solution (0.036 g, about 48%)] and maintained for a period of about 1 hour then cooled down to a temperature of about 10°C at the rate of 1°C per minute. The reaction mixture was maintained for a period of about 2 hours. Then temperature of reaction mixture was brought down to room temperature and filtered. Washed with MTBE (1 ml x 3 times) and suck driedfor a period of about 15 minutes. The obtained solid was analyzed by XRPD. Crystalline Brilaroxazine hydrobromide Form BHBrl was obtained. An XRPD pattern is shown in Figure 14.Example 16: Preparation of amorphous Brilaroxazine hydrochloride

[0252] Brilaroxazine Hydrochloride (0.1 grams) was dissolved in dichloromethane (4 ml) at temperature of about 35°C. The clear solution was subjected to distillation under high vacuum (below 100 mbar) on rotary evaporator at temperature of about 35°C for a period of about 30 minutes to about 45 minutes. The solid was isolated and was analyzed by XRPD. Amorphous form of Brilaroxazine Hydrochloride was obtained. An XRPD pattern is shown in Figure 15.Example 17: Preparation of Brilaroxazine hydrochloride Form BR3

[0253] Brilaroxazine (1 gram) was dissolved in 60 ml acetone at temperature of about 25°C. 2M aqueous solution of HC1 (20 ml) was added in the reaction mixture. Reaction mixture was maintained under stirring at temperature of about 25°C for a period of about 1 hour then cooled down to a temperature of about 20°C. n-heptane (175 ml) was added and maintained under stirring for a period of about 1 hour. Further cooled down to a temperature of about 10°C and maintained under stirring for a period of about 16 hours, then the temperature was brought to a temperature of about 25°C and filtered, washed with n- heptane (10 ml x 3). The obtained solid was analyzed by XRPD. Crystalline Brilaroxazine hydrochloride Form BR3 was obtained.Example 18: Preparation of Brilaroxazine hydrochloride Form BR3

[0254] Brilaroxazine hydrochloride (0.96 grams) was dissolved in methanol (24 ml) at temperature of about 60°C. Filtered to get clear solution and clear solution was called stock solution. 0.5 ml stock solution was added into the precooled anti solvent (4 ml) acetone at temperature of about 0°C to about 5°C and stirred the reaction mixture for a period of about 1 hour at same temperature. Filtered at temperature of about 25°C and suck dried under vacuum for at temperature of about 25°C for a period of about 15 minutes to about 20 minutes. The obtained solid was analyzed by XRPD. Crystalline Brilaroxazine hydrochloride Form BR3 was obtained.Example 19: Preparation of Brilaroxazine Form B6

[0255] Brilaroxazine (0.1 grams) (Form B5) was taken in a 10 mL vial and 5 mL of n- heptane (5 ml) was added at temperature of about 60°C. The slurry mass was stirred at temperature of about 60°C for a period of about 48 hours. The reaction mass was filtered and dried under vacuum at temperature of about 25 °C to about 30°C for a period of about 20minutes to about 30 minutes. The obtained solid was analyzed by XRPD. Crystalline Brilaroxazine Form B6 was obtained.Example 20: Stability StudiesStorage stability at different relative humidities

[0256] Samples of Brilaroxazine hydrochloride Forms BRI and BR3 were subjected to conditions of different relative humidities at ambient temperature. XRPD analysis was performed on the samples after 7 days. The results are shown in Table 1 below:Table 1

[0257] These results demonstrate that Forms BRI and BR3 of Brilaroxazine hydrochloride are stable after exposure to high and low relative humidity for at least 7 days.Grinding experiments

[0258] Samples of Brilaroxazine hydrochloride Forms BRI and BR3 were subjected to strong grinding, and to solvent drop grinding in water, ethanol and isopropanol. Grinding was carried out on the samples alone, or in the presence of ethanol, water, or isopropanol. In these experiments, about 20 mg of the sample is placed in a mortar and ground with a pestle for 2 minutes. The solvent, when used, as added to the crystalline material before grinding, in a volume of 10 microlitres. XRPD analysis performed on each of the samples after the grinding experiment, confirmed no change in the starting material (Table 2):Table 2

[0259] The results demonstrate that Brilaroxazine hydrochloride Forms BRI and BR3 are resistant to polymorphic changes and are highly suitable for preparing pharmaceutical formulations.Thermal stability

[0260] Samples of Brilaroxazine hydrochloride Forms BRI and BR3 were subjected was subjected to heating up to 100°C for 30 minutes. XRPD analysis of the sample confirmed no change in the starting material (Table 3):Table 3Stability to compression

[0261] Samples of Brilaroxazine hydrochloride Forms BRI and BR3 were subjected to pressures of 2 tons over 1 minute. (Atlas® Autopress hydraulic press, set to 2 tons). XRPD analysis was performed on the samples after 1 minute. The results are shown in Table 4 below:

[0262] Accordingly Brilaroxazine hydrochloride Forms BRI and BR3 are stable under high pressure conditions, making these products highly suitable for pharmaceutical processing.

Claims

CLAIMS1. Crystalline Brilaroxazine Hydrochloride.

2. Crystalline Brilaroxazine Hydrochloride according to claim 1, designated form BRI, which is characterized by data selected from one or more of the following: a) an XRPD pattern having peaks at 17.3, 21.5 and 25.7 degrees 2-theta ± 0.2 degrees 2-theta degrees 2-theta ± 0.2 degrees 2-theta; b) 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; c) an XRPD pattern as depicted in Figure 7; d) a solid state13C NMR spectrum having peaks at 20.6, 42.4, 97.5, 122.2, 131.0 and 165.5 ppm ± 0.2 ppm; e) a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 116.7 ppm ± 2 ppm of 96.11, 74.31, 19.21, 5.49, 14.29 and 48.78 ppm ± 0.1 ppm; f) a solid-state13C NMR spectrum substantially as depicted in Figures 16a, 16b or 16c; and g) combinations of two or more of: a, b, c, d, e, and f.

3. Crystalline Brilaroxazine Hydrochloride according to any of claims 1 or 2, which is 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. Crystalline Brilaroxazine Hydrochloride according to claim 1 or 2, 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. Crystalline Brilaroxazine Hydrochloride according to claim 1, 2, 3, or 4, 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. Crystalline Brilaroxazine Hydrochloride according to any of claims 1, 2, 3, 4, or 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. Crystalline Brilaroxazine Hydrochloride according to any of claims 1, 2, 3, 4, 5, or 6, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 2.0 to 3.0 degrees 2-theta ± 0.2 degrees 2-theta.

8. Crystalline Brilaroxazine Hydrochloride according to any of claims 1, 2, 3, 4, 5, 6, and 7, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 4.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta.

9. Crystalline Brilaroxazine Hydrochloride according to any of claims 1, 2, 3, 4, 5, 6, 7, or 8, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 8.0 to 10.5 degrees 2-theta ± 0.2 degrees 2-theta10. Crystalline Brilaroxazine Hydrochloride according to any of claims 1, 2, 3, 4, 5, 6, 7, 8, or 9, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 11.5 to 13.0 degrees 2-theta ± 0.2 degrees 2-theta.

11. Crystalline Brilaroxazine Hydrochloride according to any of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein the crystalline form is an anhydrous form.

12. Crystalline Brilaroxazine Hydrochloride according to claim 1, designated form BR3, which is characterized by data selected from one or more of the following: a) an XRPD pattern having peaks at 12.8, 15.4 and 18.9 degrees 2-theta ± 0.2 degrees 2-theta degrees 2-theta ± 0.2 degrees 2-theta; b) 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 degrees 2-theta ± 0.2 degrees 2-theta; b) an XRPD pattern as depicted in Figure 9; c) a solid state13C NMR spectrum having peaks at 22.7, 28.4, 59.3, 66.3, 119.5 and 155.3 ppm ± 0.2 ppm; d) a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 116.7 ppm ± 2 ppm of 94.01, 88.31, 50.41, 48.78, 2.79 and 38.59 ppm ± 0.1; e) a solid-state13C NMR spectrum substantially as depicted in Figures 17a, 17b or 17c; and f) combinations of two or more of: a, b, c, d, and e.

13. Crystalline Brilaroxazine Hydrochloride according to any of claims 1 or 12, which is 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. Crystalline Brilaroxazine Hydrochloride according to 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. Crystalline Brilaroxazine Hydrochloride according to 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. Crystalline Brilaroxazine Hydrochloride according to any of claims 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. Crystalline Brilaroxazine Hydrochloride according to any of claims 1, 12, 13, 14, 15, or 16, wherein the crystalline form is an anhydrous form.

18. Crystalline Brilaroxazine Hydrochloride according to any of claims 2 to 17, which contains no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline form of Brilaroxazine Hydrochloride.

19. Crystalline Brilaroxazine Hydrochloride according to any of claims 1 to 18, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Brilaroxazine Hydrochloride.

20. A pharmaceutical composition comprising crystalline Brilaroxazine Hydrochloride according to any of claims 1 to 19.

21. Use of crystalline Brilaroxazine Hydrochloride according to any of claims 1 to 19 for the preparation of a pharmaceutical composition and / or pharmaceutical formulation, preferably wherein the pharmaceutical formulation is oral formulation.

22. A pharmaceutical formulation comprising crystalline Brilaroxazine Hydrochloride according to any of claims 1 to 19, or a pharmaceutical composition of claim 20, with at least one pharmaceutically acceptable excipient.

23. A process for preparing a pharmaceutical formulation according to claim 22, comprising combining crystalline Brilaroxazine Hydrochloride according to any of claims 1 to 19, or a pharmaceutical composition of claim 20, with at least one pharmaceutically acceptable excipient.

24. Crystalline Brilaroxazine Hydrochloride according to any one of claims 1 to 19, a pharmaceutical composition according to claim 20, or a pharmaceutical formulation according to claim 22, for use as a medicament.

25. Crystalline Brilaroxazine Hydrochloride according to any one of claims 1 to 19, a pharmaceutical composition according to claim 20, or a pharmaceutical formulation according to claim 22, for use in the treatment of Schizophrenia, Schizoaffective disorder, Idiopathic pulmonary fibrosis and Pulmonary arterial hypertension.

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

27. Crystalline Brilaroxazine hydrochloride, according to any one of claims 2 to 19, a pharmaceutical composition according to Claim 20, or a pharmaceutical formulation according to Claim 22, for the manufacture of a medicament for Schizophrenia, Schizoaffective disorder, Idiopathic pulmonary fibrosis and Pulmonary arterial hypertension.

28. Use of crystalline Brilaroxazine hydrochloride according to any one of claims 2 to 19, in the preparation of another solid state form of Brilaroxazine Hydrochloride, or another Brilaroxazine salt or solid state form thereof.

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