Solid state forms of bulaxacin and bulaxacin salts

Abstract

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

Description

Technical Field

[0001] This disclosure covers the solid form of Brilaroxazine, which in the embodiments is a crystalline polymorph or salt of Brilaroxazine, particularly Brilaroxazine hydrochloride, its preparation methods, and pharmaceutical compositions thereof. Background Technology

[0002] Brirazacin, 6-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2H-benzo(b)(1,4)oxazin-3(4H)-one, has the following chemical structure:

[0003]

[0004] Brisarazazin is an orally bioavailable small molecule that has been developed for the treatment of schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension.

[0005] The compound is described in U.S. Patent No. 8,188,076.

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

[0007] Different salts and solid forms (including solvated forms) of active pharmaceutical ingredients (APIs) can possess different properties. These differences in the properties of different salts, solid forms, and solvates can provide a basis for improving formulations, for example, by promoting better processing or handling characteristics, altering the dissolution profile in a favorable direction, or improving stability (polymorphism and chemical stability) and shelf life. Differences in the properties of different salts and solid forms may also contribute to improving the final dosage form, for example, if they contribute to increased bioavailability. Different salts, solid forms, and solvates of APIs can also produce multiple polymorphs or crystalline forms, which in turn may provide more opportunities to evaluate variations in the properties and characteristics of solid APIs.

[0008] Discovering novel solid forms and solvates of pharmaceutical products can yield materials with desirable processing properties, such as ease of handling, processability, storage stability, and ease of purification, or serve as ideal intermediate crystal forms for easy conversion to other polymorphs. Novel solid forms of pharmaceutically useful compounds can also provide opportunities to improve the performance characteristics of pharmaceutical products. This expands the library of materials that formulation scientists can use for formulation optimization, for example, by providing products with different properties, including different crystal habits, higher crystallinity, or polymorphic stability, thereby offering better processing or handling characteristics, improved dissolution profiles, or longer shelf life (chemical / physical stability). At least for these reasons, there is a need for more solid forms (including solvated forms) of bromelain or bromelain salts, particularly bromelain hydrochloride. Summary of the Invention

[0009] This disclosure provides crystalline polymorphs or salts of bromerazine (particularly bromerazine hydrochloride), methods for their preparation, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other solid forms of bromerazine, salts of bromerazine, and their solid forms.

[0010] This disclosure also provides the use of the solid form of brurazacin and its salts, particularly brurazacin hydrochloride, in the preparation of other solid forms of brurazacin and / or brurazacin eutectics and / or salts, particularly brurazacin hydrochloride and its solid form.

[0011] This disclosure provides crystalline polymorphs of bromerazine and salts of bromerazine, particularly bromerazine hydrochloride, for pharmaceutical use, including for the treatment of schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary hypertension.

[0012] This disclosure also covers the use of crystalline polymorphs of brevicornin and salts of brevicornin, particularly the use of brevicornin hydrochloride of this disclosure in the preparation of pharmaceutical compositions and / or formulations.

[0013] On the other hand, this disclosure provides pharmaceutical compositions comprising crystalline polymorphs of brevicornu and salts of brevicornu (particularly brevicornu hydrochloride according to this disclosure).

[0014] This disclosure includes a method for preparing the above-described pharmaceutical composition. The method comprises mixing any one or a combination of a crystalline polymorph of bromerazine and a salt of bromerazine (particularly bromerazine hydrochloride) with at least one pharmaceutically acceptable excipient.

[0015] Crystalline polymorphs of brurazacin and its salts, particularly brurazacin hydrochloride as defined herein, and pharmaceutical compositions or formulations of brurazacin and its salts, particularly brurazacin hydrochloride, may be used as medicines, for example, for the treatment of schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary hypertension.

[0016] This disclosure also provides a method for treating schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary hypertension by administering a therapeutically effective amount of any one or a combination of crystalline polymorphs of bromerazine and salts of bromerazine, particularly the bromerazine hydrochloride of this disclosure, or at least one of the above-mentioned pharmaceutical compositions, to a subject suffering from or requiring treatment of schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary hypertension.

[0017] This disclosure also provides the use of crystalline polymorphs of bromerazine and salts of bromerazine, particularly the bromerazine hydrochloride of this disclosure, or at least one of the above-described pharmaceutical compositions in the manufacture of medicaments for treating, for example, schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary hypertension. Attached Figure Description

[0018] Figure 1 shows the characteristic X-ray powder diffraction pattern (XRPD) of B1 type of Brirazaqin.

[0019] Figure 2 shows the characteristic X-ray powder diffraction (XRPD) pattern of B2 type of Brirazacin.

[0020] Figure 3 shows the characteristic X-ray powder diffraction (XRPD) pattern of B3 type of Brirazacin.

[0021] Figure 4 shows the characteristic X-ray powder diffraction (XRPD) pattern of B4 type of Brirazacin.

[0022] Figure 5 shows the characteristic X-ray powder diffraction (XRPD) pattern of B5 type of Brirazacin.

[0023] Figure 6 shows the characteristic X-ray powder diffraction (XRPD) pattern of B6 type of Brirazacin.

[0024] Figure 7 shows the characteristic X-ray powder diffraction (XRPD) pattern of BR1 type Brirazazin hydrochloride.

[0025] Figure 8 shows the characteristic X-ray powder diffraction (XRPD) pattern of BR2 type Brirazazin hydrochloride.

[0026] Figure 9 shows the characteristic X-ray powder diffraction (XRPD) pattern of BR3 type Brirazazin hydrochloride.

[0027] Figure 10 shows the characteristic X-ray powder diffraction (XRPD) pattern of BR4 type Brirazazin hydrochloride.

[0028] Figure 11 shows the characteristic X-ray powder diffraction (XRPD) pattern of BR5 type Brirazazin hydrochloride.

[0029] Figure 12 shows the characteristic X-ray powder diffraction (XRPD) pattern of BR6 type Brirazazin hydrochloride.

[0030] Figure 13 shows the characteristic X-ray powder diffraction (XRPD) pattern of BR7 type Brirazazin hydrochloride.

[0031] Figure 14 shows the characteristic X-ray powder diffraction (XRPD) pattern of BHBr1 type of Brirazazin hydrobromide.

[0032] Figure 15 shows the characteristic X-ray powder diffraction (XRPD) pattern of amorphous brenrazan hydrochloride.

[0033] Figure 16a shows the solid form of BR1 type Brirazazin hydrochloride. 13 C10 NMR spectroscopy (full scan).

[0034] Figure 16b shows the solid form of BR1 type Brirazazin hydrochloride. 13 C NMR spectra (0 to 100 ppm).

[0035] Figure 16c shows the solid state of BR1 type Brirazazan hydrochloride. 13 C100 NMR spectrum (100 to 200 ppm).

[0036] Figure 17a shows the solid form of BR3 type Brirazazin hydrochloride. 13 C10 NMR spectroscopy (full scan).

[0037] Figure 17b shows the solid form of BR3 type Brirazazin hydrochloride. 13 C NMR spectra (0 to 100 ppm).

[0038] Figure 17c shows the solid form of BR3 type Brirazazin hydrochloride. 13 C100 NMR spectrum (100 to 200 ppm). Detailed Implementation

[0039] This disclosure covers the solid forms of bremrazoxan, including crystalline polymorphs of bremrazoxan and salts of bremrazoxan, particularly bremrazoxan hydrochloride, methods for their preparation, and pharmaceutical compositions thereof. In the examples, this disclosure provides bremrazoxan crystal forms designated as B1, B2, B3, B4, B5, and B6; bremrazoxan hydrochloride designated as BR1, BR2, BR3, BR4, BR5, BR6, and BR7; and bremrazoxan hydrobromide designated as BHBr1 (as defined herein).

[0040] The solid properties of brurazacin and its salts, especially brurazacin hydrochloride and its crystalline polymorphs, can be influenced by controlling the conditions under which solid forms of brurazacin and its salts, particularly brurazacin hydrochloride and its crystalline polymorphs, are obtained.

[0041] Solid form (or polymorph) may be referred to herein as polymorphically pure or substantially free of any other solid (or polymorph) form. As used herein, “substantially free of any other form” should be understood to mean, for example, by XRPD measurement, that the solid form contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other form of the target compound. Therefore, the crystalline polymorph of brevicornuin and its salts (especially brevicornuin hydrochloride) substantially free of any other solid form as described herein should be understood as containing more than about 80% (w / w), more than about 90% (w / w), more than about 95% (w / w), more than about 98% (w / w), more than about 99% (w / w), or about 100% of the target crystalline polymorph of brevicornuin and its salts (especially brevicornuin hydrochloride). In some embodiments of this disclosure, the crystalline polymorphs of brilaroxazine and its salts (including brilaroxazine hydrobromide and brilaroxazine hydrochloride, particularly brilaroxazine hydrochloride) may contain about 1% to about 20% (w / w), about 5% to about 20% (w / w), or about 5% to about 10% (w / w) of one or more other crystalline polymorphs of the same brilaroxazine and its salts (particularly brilaroxazine hydrochloride). Therefore, for example, a polymorphic pure brirasalicylin and its salts (including brirasalicylin hydrobromide and brirasalicylin hydrochloride, particularly brirasalicylin hydrochloride) as described in any aspect or embodiment herein 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 form of brirasalicylin and its salts (including brirasalicylin hydrobromide and brirasalicylin hydrochloride, particularly brirasalicylin hydrochloride).

[0042] For example, a polymorphic pure brurazazin and its salts (including brurazazin hydrobromide and brurazazin hydrochloride, particularly brurazazin hydrochloride) as described in any aspect or embodiment herein 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 form of brurazazin and its salts (particularly brurazazin hydrochloride). Therefore, crystalline polymorphs of polymorphic pure brurazazin and its salts (especially brurazazin hydrochloride) as described in any aspect or embodiment herein 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 form of brurazazin and its salts (including brurazazin hydrobromide and brurazazin hydrochloride, especially brurazazin hydrochloride). Alternatively, according to any aspect or embodiment of the invention, the crystalline polymorph of brevicornu and its salts, particularly brevicornu hydrochloride, may be polymorphically pure and may contain more than about 80% (w / w), more than about 90% (w / w), more than about 95% (w / w), more than about 98% (w / w), more than about 99% (w / w), or about 100% of the crystalline polymorph of brevicornu and its salts, including brevicornu hydrobromide and brevicornu hydrochloride, particularly brevicornu hydrochloride.

[0043] Depending on other crystalline polymorphs compared, the crystalline polymorphs of brevicornu and salts of brevicornu (including brevicornu hydrobromide and brevicornu hydrochloride, particularly brevicornu hydrochloride) of this disclosure may have advantageous properties selected from at least one of the following: chemical purity, fluidity, solubility, dissolution rate, morphology or crystal habit, stability (e.g., chemical stability and thermal and mechanical stability relative to polymorphic transformation), dehydration stability and / or storage stability, low residual solvent content, low degree of hygroscopicity, fluidity, and advantageous processing and handling characteristics (e.g., compressibility and bulk density).

[0044] Solid forms, such as crystalline or amorphous forms, may be characterized herein by graphical data that are “as shown in the figures” or “essentially as shown in the figures.” Such data include, for example, powder X-ray diffraction patterns and solid-state NMR spectra. It is well known that graphical data can provide additional technical information to further define the corresponding solid form (the so-called “fingerprint”) that cannot be described solely by numerical values ​​or peak positions. However, those skilled in the art will understand that the graphical representation of such data may vary slightly due to factors such as, but not limited to, variations in instrument response and sample concentration and purity, such as variations in relative peak intensities and peak positions, which are well known to those skilled in the art. Nevertheless, those skilled in the art can readily compare the graphical data in the figures herein with graphical data generated for unknown crystalline forms and confirm whether the two sets of graphical data represent the same crystalline form or two different crystalline forms. The crystal forms of brurazacin and its salts (including brurazacin hydrobromide and brurazacin hydrochloride, particularly brurazacin hydrochloride) mentioned herein, characterized by graphical data “as shown in the figure” or “essentially as shown in the figure,” should be understood to include any crystal form of brurazacin and its salts (including brurazacin hydrobromide and brurazacin hydrochloride, particularly brurazacin hydrochloride), characterized by minor variations in the graphical data compared to the figures that are well known to those skilled in the art.

[0045] As used herein, unless otherwise stated, the term "anhydrous" in connection with the crystalline form of brempaquinone and its salts (especially brempaquinone hydrochloride) refers to the crystalline form of brempaquinone and its salts (including brempaquinone hydrobromide and brempaquinone hydrochloride, especially brempaquinone hydrochloride) that contains no prescribed stoichiometric amount of water of crystallization (or other solvent). Furthermore, "anhydrous" form generally refers to, for example, no more than 1% (w / w) of water or organic solvent as measured by TGA.

[0046] Unless otherwise stated, the term "solvate" as used herein refers to a crystalline form in which a solvent is introduced into a crystalline structure. When the solvent is water, the solvate is usually referred to as a "hydrate". The solvent in a solvate may be present in stoichiometric or non-stoichiometric amounts.

[0047] As used herein, the term "isolated" in relation to crystalline polymorphs of brurazacin and its salts (including brurazacin hydrobromide and brurazacin hydrochloride, particularly brurazacin hydrochloride) of this disclosure corresponds to crystalline polymorphs of brurazacin and its salts (particularly brurazacin hydrochloride) that are physically separated from the reaction mixture in which they are formed.

[0048] As used herein, unless otherwise stated, XRPD measurements are performed using the copper Kα radiation wavelength. The XRPD peak measurements reported in this paper were performed using α-radiation of CuK. It is usually carried out at a temperature of 25±3℃.

[0049] As used herein, unless otherwise stated, the information reported herein is subject to legal interpretation. 13 C NMR is based on the magic angle spinning frequency (ω) at 125MHz. r / 2π = 11kHz is measured, preferably at a temperature of 293K ± 3℃.

[0050] In this document, a substance (e.g., a reaction mixture) may be characterized as being at or permitted to reach “room temperature” or “ambient temperature” (often abbreviated as “RT”). This means that the temperature of the substance is close to or equal to the temperature of the space in which it is located (e.g., a room or fume hood). Typically, room temperature is from about 20°C to about 30°C, or from about 22°C to about 27°C, or about 25°C.

[0051] The amount of solvent used in a chemical process (such as a reaction or crystallization) may be expressed herein as “vol” or “V”. For example, a substance may be expressed as suspended in 10 volumes (or 10 vol or 10 V) of solvent. In this context, the expression should be understood as the number of milliliters of solvent required per gram of suspended substance; for example, suspending 5 grams of substance in 10 volumes of solvent means that the amount of solvent required per gram of suspended substance is 10 milliliters, or 50 milliliters in this example. In another case, the term “v / v” may be used to indicate the number of volumes of solvent added to the mixture based on the volume of the liquid mixture. For example, adding solvent X (1.5 v / v) to 100 ml of the reaction mixture means that 150 mL of solvent X was added.

[0052] In this document, a process or step may be referred to as being performed “overnight.” This refers to a time interval, for example, during which the process or step may not be actively observed. This time interval is approximately 8 to approximately 20 hours, or approximately 10 to 18 hours, and in some cases, approximately 16 hours.

[0053] As used in this article, “reduced pressure” refers to pressure below atmospheric pressure. For example, a reduction is approximately 10 mbar to approximately 50 mbar.

[0054] As used herein, unless otherwise stated, the term "ambient conditions" refers to atmospheric pressure and a temperature of 22–24°C.

[0055] This disclosure includes a crystalline polymorph of brevicornu, designated B1. The B1 polymorph of brevicornu can be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 1; an X-ray powder diffraction pattern having peaks at 15.8°2θ (degrees 2-theta), 22.0°2θ, and 24.3°2θ ± 0.2°2θ; and combinations of these data.

[0056] The B1 crystal form of Brirazacin can also be characterized by X-ray powder diffraction patterns with peaks at 15.8°2θ, 22.0°2θ, and 24.3°2θ±0.2°2θ, and also with any one, two, three, four, or five additional peaks selected from 5.0°2θ, 7.5°2θ, 10.1°2θ, 18.2°2θ, and 26.9°2θ±0.2°2θ.

[0057] Alternatively, the B1 crystal form of Brirazacin can be characterized by an X-ray powder diffraction pattern having peaks at 5.0°2θ, 7.5°2θ, 10.1°2θ, 18.2°2θ, and 26.9°2θ±0.2°2θ. The B1 crystal form of Brirazacin can also be characterized by an X-ray powder diffraction pattern having peaks at 5.0°2θ, 7.5°2θ, 10.1°2θ, 18.2°2θ, and 26.9°2θ±0.2°2θ, and also having any one, two, three, or four additional peaks selected from 14.9°2θ, 20.9°2θ, 21.4°2θ, and 28.0°2θ±0.2°2θ.

[0058] The B1 crystal form of Brirazacin can be characterized by X-ray powder diffraction patterns with peaks at 5.0°2θ, 7.5°2θ, 10.1°2θ, 14.9°2θ, 18.2°2θ, 20.9°2θ, 21.4°2θ, 26.9°2θ and 28.0°2θ ± 0.2°2θ.

[0059] According to any aspect or embodiment of the invention, the B1 crystal form of brevicornuate can be characterized by any data described herein, and further characterized by XRPD spectra showing no peaks at 3.2°2θ to 4.4°2θ ± 0.2°2θ, and / or no peaks at 5.6°2θ to 6.8°2θ ± 0.2°2θ, and / or no peaks at 8.2°2θ to 9.7°2θ ± 0.2°2θ, and / or no peaks at 10.6°2θ to 12.0°2θ ± 0.2°2θ. According to any aspect or embodiment of the invention, the B1 crystal form of brevicornuate can be characterized by any data described herein, and further characterized by XRPD spectra showing no peaks in any one, two, three, or four of the aforementioned regions.

[0060] In one embodiment of this disclosure, the B1 crystal form of Brirazacin was isolated.

[0061] Brira saqin B1 crystal form can be in anhydrous form.

[0062] The B1 crystal form of Brirazacin can be characterized by each of the above characteristics individually or in all possible combinations, for example, an XRPD spectrum with peaks at 15.8°2θ, 22.0°2θ, and 24.3°2θ ± 0.2°2θ; an XRPD spectrum with peaks at 5.0°2θ, 7.5°2θ, 10.1°2θ, 18.2°2θ, and 26.9°2θ ± 0.2°2θ; an XRPD spectrum as shown in Figure 1; and combinations thereof.

[0063] The B1 crystal form of Brirazacin described in any aspect or embodiment of this disclosure may be polymorphically pure and preferably comprises: 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 form of Brirazacin.

[0064] This disclosure includes a crystalline polymorph of brevicornu, designated B2. The B2 crystalline form of brevicornu can be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 2; an X-ray powder diffraction pattern having peaks at 12.8°2θ, 15.8°2θ, and 20.8°2θ ± 0.2°2θ; and combinations of these data.

[0065] The B2 crystal form of Brirazacin can also be characterized by X-ray powder diffraction patterns with peaks at 12.8°2θ, 15.8°2θ, and 20.8°2θ±0.2°2θ, and also with any one, two, three, four, or five additional peaks selected from 8.5°2θ, 14.0°2θ, 17.2°2θ, 19.0°2θ, and 26.0°2θ±0.2°2θ.

[0066] Alternatively, the B2 crystal form of Brirazacin can be characterized by an X-ray powder diffraction pattern having peaks at 8.5°2θ, 14.0°2θ, 17.2°2θ, 19.0°2θ, and 26.0°2θ±0.2°2θ. The B2 crystal form of Brirazacin can also be characterized by an X-ray powder diffraction pattern having peaks at 8.5°2θ, 14.0°2θ, 17.2°2θ, 19.0°2θ, and 26.0°2θ±0.2°2θ, and also having any one, two, three, or four additional peaks selected from 10.1°2θ, 19.6°2θ, 24.3°2θ, and 26.9°2θ±0.2°2θ.

[0067] The crystalline form B2 of Brirazacin can be characterized by X-ray powder diffraction patterns with peaks at 8.5°2θ, 10.1°2θ, 14.0°2θ, 17.2°2θ, 19.0°2θ, 19.6°2θ, 24.3°2θ, 26.0°2θ, and 26.9°2θ ± 0.2°2θ.

[0068] According to any aspect or embodiment of the invention, the B2 crystal form of brevicornuate can be characterized by any data described herein, and further characterized by XRPD spectra showing no peaks at 3.2°2θ to 4.4°2θ ± 0.2°2θ, and / or no peaks at 5.6°2θ to 6.7°2θ ± 0.2°2θ, and / or no peaks at 9.1°2θ to 9.7°2θ ± 0.2°2θ, and / or no peaks at 10.6°2θ to 11.7°2θ ± 0.2°2θ. According to any aspect or embodiment of the invention, the B2 crystal form of brevicornuate can be characterized by any data described herein, and further characterized by XRPD spectra showing no peaks in any one, two, three, or four of the aforementioned regions.

[0069] In one embodiment of this disclosure, the B2 crystal form of Brirazacin was isolated.

[0070] Brira saqin B2 crystal form can be in anhydrous form.

[0071] The B2 crystal form of Brirazacin can be characterized by each of the above characteristics individually or in all possible combinations, for example, an XRPD spectrum with peaks at 12.8°2θ, 15.8°2θ, and 20.8°2θ ± 0.2°2θ; an XRPD spectrum with peaks at 8.5°2θ, 14.0°2θ, 17.2°2θ, 19.0°2θ, and 26.0°2θ ± 0.2°2θ; an XRPD spectrum as shown in Figure 2; and combinations thereof.

[0072] The B2 crystal form of Brirazacin described in any aspect or embodiment of this disclosure may be polymorphically pure and preferably comprises: 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 form of Brirazacin.

[0073] This disclosure includes the crystalline polymorph of brevicornu, designated B3. The B3 crystalline form of brevicornu can be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 3; an X-ray powder diffraction pattern having peaks at 9.7°2θ, 23.0°2θ, and 31.2°2θ ± 0.2°2θ; and combinations of these data.

[0074] The B3 crystal form of Brirazacin can also be characterized by X-ray powder diffraction patterns with peaks at 9.7°2θ, 23.0°2θ, and 31.2°2θ±0.2°2θ, and also with any one, two, three, four, or five additional peaks selected from 15.5°2θ, 23.4°2θ, 24.0°2θ, 26.3°2θ, and 31.7°2θ±0.2°2θ.

[0075] Alternatively, the B3 crystal form of Brirazacin can be characterized by an X-ray powder diffraction pattern having peaks at 15.5°2θ, 23.4°2θ, 24.0°2θ, 26.3°2θ, and 31.7°2θ±0.2°2θ. The B3 crystal form of Brirazacin can also be characterized by an X-ray powder diffraction pattern having peaks at 15.5°2θ, 23.4°2θ, 24.0°2θ, 26.3°2θ, and 31.7°2θ±0.2°2θ, and also having any one, two, or three additional peaks selected from 8.7°2θ, 13.9°2θ, and 31.2°2θ±0.2°2θ.

[0076] The B3 crystal form of Brirazacin is characterized by peaks in its X-ray powder diffraction pattern at 8.7°2θ, 13.9°2θ, 15.5°2θ, 23.4°2θ, 24.0°2θ, 26.3°2θ, 31.2°2θ, and 31.7°2θ ± 0.2°2θ.

[0077] In one embodiment of this disclosure, the B3 crystal form of Brirazacin was isolated.

[0078] Brira saqin B3 crystal form can be in anhydrous form.

[0079] According to any aspect or embodiment of the invention, the B3 crystal form of Brirazacin can be characterized by any data described herein, and further characterized by the absence of peaks in the XRPD spectrum at 4.0 to 7.5°2θ ± 0.2°2θ, and / or at 8.0°2θ to 8.3°2θ ± 0.2°2θ, and / or at 9.0 to 9.4°2θ ± 0.2°2θ, and / or at 10.0 to 10.5°2θ ± 0.2°2θ, and / or at 11.4°2θ to 11.8°2θ ± 0.2°2θ; and / or at 14.3°2θ to 14.6°2θ ± 0.2°2θ. According to any aspect or embodiment of the invention, the B3 crystal form of Brirazacin can be characterized by any data described herein, and further by XRPD spectra of any one, two, three, four, five or six peaks in the aforementioned regions.

[0080] The B3 crystal form of Brirazacin can be characterized by each of the above characteristics individually or in all possible combinations, for example, an XRPD pattern with peaks at 9.7°2θ, 23.0°2θ, and 31.2°2θ ± 0.2°2θ; an XRPD pattern with peaks at 15.5°2θ, 23.4°2θ, 24.0°2θ, 26.3°2θ, and 31.7°2θ ± 0.2°2θ; an XRPD pattern as shown in Figure 3; and combinations thereof.

[0081] The B3 crystal form of Brirazacin described in any aspect or embodiment of this disclosure may be polymorphically pure and preferably comprises: 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 form of Brirazacin.

[0082] This disclosure includes the crystalline polymorph of brevicornu, designated B4. The B4 crystalline form of brevicornu can be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 4; an X-ray powder diffraction pattern having peaks at 20.1°2θ, 23.2°2θ, and 24.3°2θ ± 0.2°2θ; and combinations of these data.

[0083] A further characteristic of the B4 crystal form of Brirazacin is that its X-ray powder diffraction pattern has peaks at 20.1°2θ, 23.2°2θ, and 24.3°2θ±0.2°2θ, and also has any one, two, three, four, or five additional peaks selected from 11.9°2θ, 14.7°2θ, 16.2°2θ, 21.9°2θ, and 25.1°2θ±0.2°2θ.

[0084] Alternatively, the B4 crystal form of Brirazacin can be characterized by an X-ray powder diffraction pattern having peaks at 11.9°2θ, 14.7°2θ, 16.2°2θ, 21.9°2θ, and 25.1°2θ±0.2°2θ. The B4 crystal form of Brirazacin can also be characterized by an X-ray powder diffraction pattern having peaks at 11.9°2θ, 14.7°2θ, 16.2°2θ, 21.9°2θ, and 25.1°2θ±0.2°2θ, and also having any one, two, three, or four additional peaks selected from 11.2°2θ, 24.3°2θ, 26.3°2θ, and 27.4°2θ±0.2°2θ.

[0085] The B4 crystalline form of Brirazacin can be characterized by X-ray powder diffraction patterns with peaks at 11.2°2θ, 11.9°2θ, 14.7°2θ, 16.2°2θ, 21.9°2θ, 24.3°2θ, 26.3°2θ, 25.1°2θ, and 27.4°2θ ± 0.2°2θ.

[0086] According to any aspect or embodiment of the invention, the B4 crystal form of Brirazacin can be characterized by any data described herein, and further characterized by the absence of peaks in the XRPD spectrum at 3.0°2θ to 8.0°2θ ± 0.2°2θ.

[0087] In one embodiment of the present invention, the B4 crystal form of Brirazacin was isolated.

[0088] Brira saqin B4 crystal form can be in anhydrous form.

[0089] The B4 crystal form of Brirazacin can be characterized by each of the above characteristics individually or in all possible combinations, for example, XRPD spectra with peaks at 20.1, 23.2, and 24.3°2θ±0.2°2θ; XRPD spectra with peaks at 11.9, 14.7, 16.2, 21.9, and 25.1°2θ±0.2°; XRPD spectra as shown in Figure 4; and combinations thereof.

[0090] The B4 crystal form of Brirazacin as described in any aspect or embodiment of this disclosure may be polymorphically pure and preferably comprises: 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 form of Brirazacin.

[0091] This disclosure includes the crystalline polymorph of brevicornu, designated B5. The B5 crystalline form of brevicornu can be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 5; an X-ray powder diffraction pattern having peaks at 15.5°2θ, 25.0°2θ, and 27.3°2θ ± 0.2°2θ; and combinations of these data.

[0092] The B5 crystal form of Brirazacin can also be characterized by X-ray powder diffraction patterns with peaks at 15.5°2θ, 25.0°2θ, and 27.3°2θ±0.2°2θ, and also with any one, two, three, four, or five additional peaks selected from 14.1°2θ, 16.1°2θ, 21.6°2θ, 23.4°2θ, and 26.1°2θ±0.2°2θ.

[0093] Alternatively, the B5 crystal form of Brirazacin can be characterized by an X-ray powder diffraction pattern having peaks at 14.1°2θ, 16.1°2θ, 21.6°2θ, 23.4°2θ, and 26.1°2θ±0.2°2θ. The B5 crystal form of Brirazacin can also be characterized by an X-ray powder diffraction pattern having peaks at 14.1°2θ, 16.1°2θ, 21.6°2θ, 23.4°2θ, and 26.1°2θ±0.2°2θ, and also having any one, two, three, or four additional peaks selected from 12.3°2θ, 25.0°2θ, 27.3°2θ, and 28.0°2θ±0.2°2θ.

[0094] The B5 crystal form of Brirazacin can be characterized by X-ray powder diffraction patterns with peaks at 12.3°2θ, 14.1°2θ, 16.1°2θ, 21.6°2θ, 23.4°2θ, 25.0°2θ, 27.3°2θ, 26.1°2θ, and 28.0°2θ ± 0.2°2θ.

[0095] According to any aspect or embodiment of the present invention, the B5 crystal form of brevicornuate can be characterized by any data described herein, and further characterized by XRPD spectra showing no peaks at 2.5°2θ to 4.5°2θ ± 0.2°2θ, and / or no peaks at 5.2°2θ to 6.0°2θ ± 0.2°2θ, and / or no peaks at 7.4°2θ to 8.0°2θ ± 0.2°2θ. According to any aspect or embodiment of the present invention, the B5 crystal form of brevicornuate can be characterized by any data described herein, and further characterized by XRPD spectra showing no peaks in any one, two, or three of the aforementioned regions.

[0096] In one embodiment of this disclosure, the B5 crystal form of Brirazacin was isolated.

[0097] Brirazacin B5 crystal form can be in anhydrous form.

[0098] The B5 crystal form of Brirazacin can be characterized by each of the above characteristics individually or in all possible combinations, for example, an XRPD pattern with peaks at 15.5°2θ, 25.0°2θ, and 27.3°2θ ± 0.2°2θ; an XRPD pattern with peaks at 14.1°2θ, 16.1°2θ, 21.6°2θ, 23.4°2θ, and 26.1°2θ ± 0.2°2θ; an XRPD pattern as shown in Figure 5; and combinations thereof.

[0099] The B5 crystal form of Brirazacin described in any aspect or embodiment of this disclosure may be polymorphically pure and preferably comprises: 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 form of Brirazacin.

[0100] This disclosure includes the crystalline polymorph of brevicornuin, designated as B6. The B6 crystalline form of brevicornuin can be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 6; an X-ray powder diffraction pattern having peaks at 8.8°2θ, 17.7°2θ, and 20.1°2θ ± 0.2°2θ; and combinations of these data.

[0101] The B6 crystal form of Brirazacin can also be characterized by X-ray powder diffraction patterns with peaks at 8.8°2θ, 17.7°2θ, and 20.1°2θ±0.2°2θ, and also with any one, two, three, four, or five additional peaks selected from 10.8°2θ, 18.4°2θ, 27.6°2θ, and 29.7°2θ±0.2°2θ.

[0102] Alternatively, the B6 crystal form of Brirazacin can be characterized by an X-ray powder diffraction pattern having peaks at 10.8°2θ, 18.4°2θ, 27.6°2θ, and 29.7°2θ±0.2°2θ. The B6 crystal form of Brirazacin can also be characterized by an X-ray powder diffraction pattern having peaks at 10.8°2θ, 18.4°2θ, 27.6°2θ, and 29.7°2θ±0.2°2θ, and also having any one, two, three, four, or five additional peaks selected from 14.5°2θ, 15.7°2θ, 18.9°2θ, 24.9°2θ, and 26.6°2θ±0.2°2θ.

[0103] The B6 crystal form of Brirazacin can be characterized by X-ray powder diffraction patterns with peaks at 10.8°2θ, 14.5°2θ, 15.7°2θ, 18.4°2θ, 18.9°2θ, 24.9°2θ, 26.6°2θ, 27.6°2θ, and 29.7°2θ ± 0.2°2θ.

[0104] According to any aspect or embodiment of the present invention, the B6 crystal form of brevicornuate can be characterized by any data described herein, and further characterized by XRPD spectra showing no peaks at 4.5°2θ to 8.2°2θ ± 0.2°2θ, and / or no peaks at 9.2°2θ to 10.2°2θ ± 0.2°2θ, and / or no peaks at 11.0°2θ to 12.0°2θ ± 0.2°2θ, and / or no peaks at 12.6°2θ to 13.5°2θ ± 0.2°2θ. According to any aspect or embodiment of the present invention, the B6 crystal form of brevicornuate can be characterized by any data described herein, and further characterized by XRPD spectra showing no peaks in any one, two, three, or four of the aforementioned regions.

[0105] In one embodiment of the present invention, the BB6 crystal form of Brirazacin was isolated.

[0106] Brira saqin B6 crystal form can be in anhydrous form.

[0107] The B6 crystal form of Brirazacin can be characterized by each of the above characteristics individually or in all possible combinations, for example, XRPD spectra with peaks at 8.8°2θ, 17.7°2θ, and 20.1°2θ ± 0.2°2θ; XRPD spectra with peaks at 10.8°2θ, 18.4°2θ, 27.6°2θ, and 29.7°2θ ± 0.2°2θ; XRPD spectra as shown in Figure 6, and combinations thereof.

[0108] The B6 crystal form of Brirazacin described in any aspect or embodiment of this disclosure may be polymorphically pure and preferably comprises: 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 form of Brirazacin.

[0109] This disclosure includes a crystalline polymorph of brurazazin hydrochloride, designated BR1. The BR1 polymorph of brurazazin hydrochloride can be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern essentially as shown in Figure 7; an X-ray powder diffraction pattern having peaks at 17.3°2θ, 21.5°2θ, and 25.7°2θ ± 0.2°2θ; and a solid-state X-ray powder diffraction pattern having peaks at 20.6 ppm, 42.4 ppm, 97.5 ppm, 122.2 ppm, 131.0 ppm, and 165.5 ppm ± 0.2 ppm ± 0.2 ppm. 13 C NMR spectrum; solid state 13 The reference peak at a distance of 116.7 ppm ± 2 ppm in the C NMR spectrum has the following absolute differences in chemical shift: 96.11 ppm, 74.31 ppm, 19.21 ppm, 5.49 ppm, 14.29 ppm, and 48.78 ppm ± 0.1 ppm; essentially the solid state shown in Figures 16a, 16b, or 16c. 13 C NMR spectra; and combinations of these data.

[0110] The BR1 crystal form of Brirazazin hydrochloride can also be characterized by X-ray powder diffraction patterns with peaks at 17.3°2θ, 21.5°2θ, and 25.7°2θ±0.2°2θ, and also with any one, two, three, four, or five additional peaks selected from 7.2°2θ, 16.4°2θ, 19.5°2θ, 22.4°2θ, and 24.7°2θ±0.2°2θ.

[0111] Alternatively, the BR1 crystal form of brurazazin hydrochloride can be characterized by an X-ray powder diffraction pattern having peaks at 7.2°2θ, 16.4°2θ, 19.5°2θ, 22.4°2θ, and 24.7°2θ±0.2°2θ. The BR1 crystallization of brurazazin hydrochloride can also be characterized by an X-ray powder diffraction pattern having peaks at 7.2°2θ, 16.4°2θ, 19.5°2θ, 22.4°2θ, and 24.7°2θ±0.2°2θ, and also having any one, two, three, or four additional peaks selected from 14.3°2θ, 14.9°2θ, 25.7°2θ, and 27.2°2θ±0.2°2θ.

[0112] The BR1 crystal form of brurazazin hydrochloride can be characterized by X-ray powder diffraction patterns with peaks at 7.2°2θ, 14.3°2θ, 14.9°2θ, 16.4°2θ, 19.5°2θ, 22.4°2θ, 24.7°2θ, 25.7°2θ, and 27.2°2θ ± 0.2°2θ.

[0113] According to any aspect or embodiment of the invention, the BR1 crystal form of brevicornuate hydrochloride can be characterized by any data described herein, and further characterized by XRPD spectra showing no peaks at 2.0°2θ to 3.0°2θ ± 0.2°2θ, and / or no peaks at 4.0°2θ to 6.5°2θ ± 0.2°2θ, and / or no peaks at 8.0°2θ to 10.5°2θ ± 0.2°2θ, and / or no peaks at 11.5°2θ to 13.0°2θ ± 0.2°2θ. The BR1 crystal form of brevicornuate hydrochloride according to any aspect or embodiment of the invention can be characterized by any data described herein, and further characterized by XRPD spectra showing no peaks in any one, two, three, or four of the aforementioned regions.

[0114] In one embodiment of this disclosure, the BR1 crystal form of brurazazin hydrochloride was isolated.

[0115] The BR1 crystal form of Brirazazin hydrochloride can be in anhydrous form.

[0116] The BR1 crystal form of brurazazin hydrochloride can be characterized by each of the above characteristics individually or in all possible combinations, for example, an XRPD spectrum with peaks at 17.3°2θ, 21.5°2θ, and 25.7°2θ ± 0.2°2θ; an XRPD spectrum with peaks at 7.2°2θ, 16.4°2θ, 19.5°2θ, 22.4°2θ, and 24.7°2θ ± 0.2°2θ; an XRPD spectrum as shown in Figure 7; and combinations thereof.

[0117] The BR1 crystal form of brurazazin hydrochloride described in any aspect or embodiment of this disclosure may be polymorphically pure and preferably comprises: 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 form of brurazazin hydrochloride.

[0118] This disclosure provides a method for preparing the BR1 type of brevicornuate hydrochloride, the method comprising crystallizing brevicornuate hydrochloride from acetone and diethyl ether. According to any aspect or embodiment, the method may include: (a) preparing a brevicornuate hydrochloride solution in a solvent containing acetone; (b) combining the solution with diethyl ether; and (c) optionally separating the BR1 type of brevicornuate hydrochloride crystals. The solution in step (a) can be prepared by reacting an acetone solution of brevicornuate with hydrochloric acid. Preferably, the reaction is carried out at the following temperatures: 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 any aspect or embodiment of the disclosed method, a method for preparing BR1 type brurazazin hydrochloride may include:

[0120] (i) Dissolve brevicornuate in acetone;

[0121] (ii) Add hydrochloric acid;

[0122] (iii) Add ether;

[0123] (iv) Separation of bromerazine hydrochloride; and

[0124] (v) Dry.

[0125] According to any aspect or embodiment of the disclosed method for preparing BR1 type brevicornuate hydrochloride, the amount of acetone used can be: about 30 ml to about 70 ml, about 40 ml to about 60 ml, or about 50 ml per gram of brevicornuate. The temperature at which the acetone is added can be: 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.

[0126] According to one aspect or embodiment of the method for preparing BR1 type brurazazin hydrochloride, a 2M HCl solution is preferably used as hydrochloric acid. The amount of hydrochloric acid used is preferably about 5 ml to about 30 ml, or about 10 ml to about 25 ml, or about 20 ml per gram of brurazazin.

[0127] In any aspect or embodiment of the disclosed method, hydrochloric acid may be added to the solution at the following temperatures: 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.

[0128] According to any aspect or embodiment of the disclosed method for preparing BR1 type brurazazine hydrochloride, the amount of diethyl ether used can be: 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 brurazazine. According to any aspect or embodiment of the disclosed method for preparing BR1 type brurazazine hydrochloride, the volume ratio of acetone to diethyl ether can 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 method, diethyl ether can be added at the following temperatures: 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.

[0129] In any aspect or embodiment of the disclosed method, the reaction mixture comprising bromerazine hydrochloride, acetone and diethyl ether may be stirred at a temperature of about 10°C to about 50°C, about 15°C to about 40°C, about 18°C ​​to about 30°C, about 23°C to about 28°C, or about 25°C for a period of about 6 hours to about 48 hours, about 10 hours to about 24 hours, about 12 hours to about 20 hours, about 14 hours to about 18 hours, or about 16 hours.

[0130] The method may also include separating the obtained bromelain hydrochloride by any suitable method (e.g., filtration, decantation, or centrifugation). Specifically, the product may be separated by vacuum filtration. After separation, the bromelain hydrochloride may be dried. Drying may be carried out under vacuum for a time of approximately 5 minutes to 1 hour, or approximately 10 minutes to approximately 25 minutes, or approximately 15 minutes.

[0131] According to any aspect or embodiment of the disclosed method for preparing the BR1 form of brurazazin hydrochloride, the method may further include combining the BR1 form of brurazazin with at least one pharmaceutically acceptable excipient to prepare a pharmaceutical composition.

[0132] This disclosure includes crystalline polymorphs of brurazazin hydrochloride, designated BR2. The BR2 polymorph of brurazazin hydrochloride can be characterized by data selected from one or more of the following: X-ray powder diffraction patterns substantially as shown in Figure 8; X-ray powder diffraction patterns having peaks at 10.0°2θ, 19.6°2θ, and 22.9°2θ ± 0.2°2θ; and combinations of these data.

[0133] The BR2 crystal form of brurazazin hydrochloride can also be characterized by X-ray powder diffraction patterns with peaks at 10.0°2θ, 19.6°2θ, and 22.9°2θ±0.2°2θ, and also with any one, two, three, four, or five additional peaks selected from 12.1°2θ, 17.7°2θ, 20.3°2θ, 25.0°2θ, and 25.4°2θ±0.2°2θ.

[0134] Alternatively, the BR2 crystal form of brurazazin hydrochloride can be characterized by an X-ray powder diffraction pattern having peaks at 12.1°2θ, 17.7°2θ, 20.3°2θ, 25.0°2θ, and 25.4°2θ±0.2°2θ. The BR2 crystallization of brurazazin hydrochloride can also be characterized by an X-ray powder diffraction pattern having peaks at 12.1°2θ, 17.7°2θ, 20.3°2θ, 25.0°2θ, and 25.4°2θ±0.2°2θ, and also having any one, two, three, or four additional peaks selected from 4.8°2θ, 14.7°2θ, 21.8°2θ, and 24.1°2θ±0.2°2θ.

[0135] The BR2 crystal form of brurazazin hydrochloride can be characterized by X-ray powder diffraction patterns with peaks at 4.8°2θ, 12.1°2θ, 14.7°2θ, 17.7°2θ, 20.3°2θ, 21.8°2θ, 24.1°2θ, 25.0°2θ, and 25.4°2θ ± 0.2°2θ.

[0136] According to any aspect or embodiment of the present invention, the BR2 crystal form of brevicornuate hydrochloride can be characterized by any data described herein, and further characterized by the absence of peaks in XRPD spectra at 3.0°2θ to 3.6°2θ ± 0.2°2θ, and / or at 5.4°2θ to 7.0°2θ ± 0.2°2θ, and / or at 8.4°2θ to 9.0°2θ ± 0.2°2θ. The BR2 crystal form of brevicornuate hydrochloride according to any aspect or embodiment of the present invention can be characterized by any data described herein, and further characterized by XRPD spectra showing no peaks in any one, two, or three of the aforementioned regions.

[0137] In one embodiment of this disclosure, the BR2 crystal form of brurazazin hydrochloride was isolated.

[0138] The BR2 crystal form of Brirazacin hydrochloride can be in hydrate form.

[0139] The BR2 crystal form of brurazazin hydrochloride can be characterized by each of the above characteristics individually or in all possible combinations, for example, an XRPD spectrum with peaks at 10.0°2θ, 19.6°2θ, and 22.9°2θ ± 0.2°2θ; an XRPD spectrum with peaks at 12.1°2θ, 17.7°2θ, 20.3°2θ, 25.0°2θ, and 25.4°2θ ± 0.2°2θ; an XRPD spectrum as shown in Figure 8; and combinations thereof.

[0140] The BR2 crystal form of brurazazin hydrochloride described in any aspect or embodiment of this disclosure may be polymorphically pure and preferably comprises: 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 form of brurazazin hydrochloride.

[0141] This disclosure includes a crystalline polymorph of brurazazin hydrochloride, designated BR3. The BR3 polymorph of brurazazin hydrochloride can be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern essentially as shown in Figure 9; an X-ray powder diffraction pattern with peaks at 12.8°2θ, 15.4°2θ, and 18.9°2θ ± 0.2°2θ; and a solid-state form with peaks at 22.7 ppm, 28.4 ppm, 59.3 ppm, 66.3 ppm, 119.5 ppm, and 155.3 ppm ± 0.2 ppm ± 0.2 ppm. 13 C NMR spectrum; solid state 13 The reference peak at a distance of 116.7 ppm ± 2 ppm in the C NMR spectrum has the following absolute differences in chemical shift: 94.01 ppm, 88.31 ppm, 50.41 ppm, 48.78 ppm, 2.79 ppm, and 38.59 ppm ± 0.1 ppm; essentially the solid state shown in Figures 17a, 17b, or 17c. 13 C NMR spectra; and combinations of these data.

[0142] The BR3 crystal form of Brirazazin hydrochloride can also be characterized by X-ray powder diffraction patterns with peaks at 12.8°2θ, 15.4°2θ, and 18.9°2θ±0.2°2θ, and additionally with any one, two, three, four, or five peaks selected from 16.1°2θ, 17.4°2θ, 22.6°2θ, 25.3°2θ, and 27.8°2θ±0.2°2θ.

[0143] Alternatively, the BR3 crystal form of brevicornuate can be characterized by an X-ray powder diffraction pattern having peaks at 16.1°2θ, 17.4°2θ, 22.6°2θ, 25.3°2θ, and 27.8°2θ±0.2°2θ. The BR3 crystal form of brevicornuate can also be characterized by an X-ray powder diffraction pattern having peaks at 16.1°2θ, 17.4°2θ, 22.6°2θ, 25.3°2θ, and 27.8°2θ±0.2°2θ, and also having any one, two, three, four, or five additional peaks selected from 19.8°2θ, 20.7°2θ, 21.8°2θ, 23.7°2θ, and 24.0°2θ±0.2°2θ.

[0144] The BR3 crystal form of brurazazin hydrochloride can be characterized by X-ray powder diffraction patterns with peaks at 16.1°2θ, 17.4°2θ, 19.8°2θ, 20.7°2θ, 21.8°2θ, 22.6°2θ, 23.7°2θ, 24.0°2θ, 25.3°2θ, and 27.8°2θ ± 0.2°2θ.

[0145] According to any aspect or embodiment of the present invention, the BR3 crystal form of brevicornuate hydrochloride can be characterized by any data described herein, and further characterized by the absence of peaks in XRPD spectra at 3.5°2θ to 9.5°2θ ± 0.2°2θ or 3.5°2θ to 10.5°2θ ± 0.2°2θ; and / or the absence of peaks in XRPD spectra at 12.0°2θ to 12.5°2θ ± 0.2°2θ; and / or the absence of peaks in XRPD spectra at 13.2°2θ to 13.7°2θ ± 0.2°2θ; and / or the absence of peaks in XRPD spectra at 14.3°2θ to 14.7°2θ ± 0.2°2θ. The BR3 crystal form of brevicornuate hydrochloride according to any aspect or embodiment of the present invention can be characterized by any data described herein, and further characterized by XRPD spectra showing no peaks in any one, two, three, or four of the aforementioned regions.

[0146] In one embodiment of the present invention, the BR3 crystal form of brurazazin hydrochloride was isolated.

[0147] The BR3 crystal form of Brirazazin hydrochloride can be in anhydrous form.

[0148] The BR3 crystal form of brurazazin hydrochloride can be characterized by each of the above characteristics individually or in all possible combinations, for example, an XRPD spectrum with peaks at 12.8°2θ, 15.4°2θ, and 18.9°2θ ± 0.2°2θ; an XRPD spectrum with peaks at 16.1°2θ, 17.4°2θ, 22.6°2θ, 25.3°2θ, and 27.8°2θ ± 0.2°2θ; an XRPD spectrum as shown in Figure 9; and combinations thereof.

[0149] The BR3 crystal form of brurazazin hydrochloride described in any aspect or embodiment of this disclosure may be polymorphically pure and preferably comprises: 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 form of brurazazin hydrochloride.

[0150] According to any aspect or embodiment, the BR3 form of brevicornuate hydrochloride can be prepared by crystallizing brevicornuate hydrochloride from isopropanol. The method preferably includes cooling a mixture of brevicornuate hydrochloride in isopropanol. Specifically, according to any aspect or embodiment of the method, a mixture of brevicornuate hydrochloride in isopropanol can be provided and heated, preferably to the following temperatures: about 60°C to about 90°C, about 65°C to about 85°C, about 70°C to about 80°C, or about 75°C to about 80°C. Heating can be carried out for a suitable period of time, preferably about 2 hours to about 24 hours, about 8 hours to about 22 hours, about 12 hours to about 20 hours, about 14 hours to about 18 hours, or about 16 hours. The mixture is then cooled. Preferably, it is cooled to the following temperatures: about 10°C to about 40°C, about 15°C to about 35°C, about 20°C to about 30°C, or about 25°C. The product can be separated from the cooled mixture, preferably by any suitable method, such as filtration, decantation, or centrifugation. Specifically, the product can be separated by vacuum filtration. After separation, the BR3 crystal form of brurazazin hydrochloride can be dried. Drying can be carried out under vacuum for approximately 5 minutes to 1 hour, or approximately 10 minutes to 25 minutes, or approximately 10 minutes to 15 minutes.

[0151] According to any aspect or embodiment of the disclosed method, the method for preparing BR3 type brurazazin hydrochloride may specifically include:

[0152] (i) Mix isopropanol with brevicornuate hydrochloride (preferably BR2 type);

[0153] (ii) Heating;

[0154] (iii) Cooling;

[0155] (iv) optional separation; and

[0156] (v) Drying optionally.

[0157] According to any aspect or embodiment of the method for preparing BR3 type brurazazin hydrochloride, the starting material is preferably BR2 type brurazazin hydrochloride. According to any aspect or embodiment of the disclosed method, isopropanol can be mixed with BR2 type brurazazin hydrochloride.

[0158] According to any aspect or embodiment of the method for preparing BR3 type brurazazin hydrochloride, the amount of isopropanol used may be: about 30 ml to about 80 ml, about 40 ml to about 60 ml, or about 50 ml per gram of BR2 type brurazazin hydrochloride. According to any aspect or embodiment, the isopropanol may be mixed with brurazazin hydrochloride at the following temperatures: 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.

[0159] In any aspect or embodiment of the disclosed method for preparing the BR3 crystal form of brevicornuate, the reaction mixture may be heated to the following temperatures: about 60°C to about 90°C, about 65°C to about 85°C, about 70°C to about 80°C, or about 75°C to about 80°C. In any aspect or embodiment of the disclosed method, the mixture may be stirred at the following heating temperatures: 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 within this temperature range preferably for about 2 hours to about 24 hours, about 8 hours to about 22 hours, about 12 hours to about 20 hours, about 14 hours to about 18 hours, or about 16 hours.

[0160] In any aspect or embodiment of the method disclosed in this invention, the mixture may be cooled. The cooling temperature may be: 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 separated, preferably by any suitable procedure, such as filtration, decantation, or centrifugation. Specifically, the product may be separated by vacuum filtration. After separation, bromelain hydrochloride may be dried. Drying may be carried out under vacuum, and the drying time may be: about 5 minutes to 1 hour, or about 10 minutes to about 25 minutes, or about 10 minutes to about 15 minutes.

[0161] Alternatively, the BR3 form of brevicornuate hydrochloride can be prepared by grinding brevicornuate hydrochloride in isopropanol, preferably the BR2 form of brevicornuate hydrochloride. According to any aspect or embodiment of the disclosed method, the method for preparing the BR3 crystal form of brevicornuate hydrochloride may include grinding a mixture comprising brevicornuate hydrochloride (preferably the BR2 form) and isopropanol. Preferably, the amount of isopropanol used is about 190 μl to 220 μl, or about 200 μl, per gram of brevicornuate hydrochloride; the grinding time is about 1 minute to about 5 minutes, or about 2 minutes to about 3 minutes.

[0162] Alternatively, this disclosure provides a further method for preparing the BR3 form of brurazazin hydrochloride, comprising crystallizing brurazazin hydrochloride from acetone and n-heptane. According to any aspect or embodiment, the method may include: (a) preparing a mixture of brurazazin hydrochloride in acetone; (b) combining the mixture with n-heptane; and (c) optionally separating the crystals of the BR3 form of brurazazin hydrochloride. The mixture in step (a) can be prepared by reacting an acetone solution of brurazazin with hydrochloric acid. Preferably, the reaction is carried out at temperatures 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 about 30 minutes to about 6 hours, about 30 minutes to about 4 hours, about 30 minutes to about 2 hours, or about 1 hour. In step (b), n-heptane may be mixed with the mixture of brurazazin hydrochloride in acetone. Optionally, n-heptane may be added at a temperature of about 18°C ​​to about 22°C, or about 20°C. The mixture may be stirred, preferably for about 2 hours to about 24 hours, about 8 hours to about 22 hours, about 12 hours to about 20 hours, about 14 hours to about 18 hours, or about 16 hours. The product may be separated by any suitable method, such as by filtration, decantation, or centrifugation, preferably by filtration. A method for preparing BR3 type brurazazin hydrochloride according to any aspect or embodiment of the disclosed method may include:

[0163] (i) Dissolve brevicornuate in acetone;

[0164] (ii) Add hydrochloric acid;

[0165] (iii) Optional cooling;

[0166] (iv) Add n-heptane;

[0167] (v) Optional cooling;

[0168] (vi) Separation of BR3 type brurazazin hydrochloride; and

[0169] (vii) Optional washing.

[0170] Specifically, the amount of acetone used can be approximately 30 ml to approximately 80 ml, approximately 40 ml to approximately 70 ml, or approximately 60 ml per gram of bromelain. The temperature at which acetone is added can be approximately 18°C ​​to approximately 55°C, approximately 20°C to approximately 50°C, approximately 23°C to approximately 40°C, approximately 23°C to approximately 30°C, or approximately 25°C.

[0171] According to one aspect or embodiment of the method for preparing BR3 type brurazazine hydrochloride, a 2M HCl solution is preferably used as hydrochloric acid, and the preferred amount used is about 5 to about 30 ml, or about 10 ml to about 25 ml, or about 20 ml per gram of brurazazine. In any aspect or embodiment of the disclosed method for preparing BR3 type brurazazine, hydrochloric acid can be added to the solution at a temperature of about 18°C ​​to about 55°C, about 20°C to about 50°C, about 23°C to about 40°C, about 23°C to about 30°C, or about 25°C, preferably for about 0.5 hours to about 3 hours, or about 1 hour. In any aspect or embodiment of the disclosed method for preparing BR3 type brurazazine, the reaction mixture can be cooled, preferably to about 20°C. In any aspect or embodiment of the disclosed method for preparing BR3 type brurazazine, n-heptane can be added, and the mixture can be stirred for about 3 hours to 0.5 hours, or about 1 hour. According to any aspect or embodiment of the disclosed method for preparing BR3 type brurazazine hydrochloride, the amount of n-heptane used may be: 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 brurazazine. According to any aspect or embodiment of the disclosed method for preparing BR3 type brurazazine 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 to about 1:2.9. In any aspect or embodiment of the disclosed method, the temperature at which the n-heptane is added may be: 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.

[0172] In any aspect or embodiment of the disclosed method for preparing BR3 type brurazazin hydrochloride, the reaction mixture may be cooled, preferably to a temperature of about 10°C. The mixture may be maintained at this temperature for about 10 hours to about 30 hours, or about 12 hours to about 25 hours, or about 16 hours.

[0173] The method may also include separating the obtained bromelain hydrochloride by any suitable procedure, such as filtration, decantation, or centrifugation. Specifically, the product may be separated by filtration.

[0174] In any aspect or embodiment of the disclosed method for preparing brurazacin hydrochloride crystal form BR3, the reaction mixture may be heated to 25°C before separation (preferably by filtration), and the BR3 form of brurazacin hydrochloride may be washed with n-heptane in an amount of about 5 ml to about 30 ml, or about 10 ml, per gram of brurazacin.

[0175] Alternatively, this disclosure provides a further method for preparing brevicornuin hydrochloride BR3 type, the method comprising crystallizing brevicornuin hydrochloride from methanol and acetone. According to any aspect or embodiment, the method may include: (a) preparing a methanol solution of brevicornuin hydrochloride; (b) combining the solution with acetone; and (c) optionally separating the crystallized brevicornuin hydrochloride BR3 type. The solution in step (a) can be prepared by dissolving brevicornuin 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 brevicornuin hydrochloride solution may be mixed with acetone. Preferably, the methanol solution of brevicornuin hydrochloride is added to acetone. The acetone may be cooled before addition, preferably to about -5°C to about 15°C, about -5°C to about 10°C, or about 0°C to about 5°C. The mixture can be stirred, preferably for a stirring time of about 30 minutes to about 4 hours, about 30 minutes to about 2 hours, or about 1 hour. The product can be separated by any suitable method, such as by filtration, decantation, or centrifugation, preferably by filtration. After separation, the BR3 form of brurazazin hydrochloride can be dried. Drying can be carried out under vacuum for a drying time of about 5 minutes to 1 hour, about 10 minutes to 25 minutes, or about 10 minutes to 15 minutes. The drying temperature is preferably about 18°C ​​to 30°C, about 20°C to 27°C, or about 25°C. A method for preparing the BR3 form of brurazazin hydrochloride according to any aspect or embodiment of the disclosed method may include:

[0176] (i) Dissolve brevicornuate in methanol;

[0177] (ii) Add acetone;

[0178] (iii) Optional separation of BR3 type of brurazazin hydrochloride; and

[0179] (iv) Dry as desired.

[0180] According to any aspect of the method for preparing BR3 type brurazazine hydrochloride, the amount of methanol used can be: 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 brurazazine. The temperature at which acetone is added can be: 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 example of the disclosed method for preparing BR3 type brurazazine hydrochloride, the amount of acetone used can be: 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 brurazazine. According to any aspect or example of the disclosed method for preparing BR3 type brurazazine hydrochloride, the volume ratio of acetone to methanol can be: about 1:1 to about 1:10, about 1:2 to about 1:8, about 1:4 to about 1:7, or about 1:6. In any aspect or embodiment of the disclosed method for preparing BR3 type brurazazin hydrochloride, the reaction mixture may be cooled, preferably to about 10°C. The mixture may be stirred, preferably for a stirring time of about 30 minutes to about 4 hours, about 30 minutes to about 2 hours, or about 1 hour.

[0181] The method may further include separating the obtained bromelain hydrochloride by any suitable method, such as filtration, decantation, or centrifugation. Specifically, the product may be separated by filtration. After separation, the bromelain hydrochloride may be dried. Drying may be carried out under vacuum for a time of approximately 5 minutes to 1 hour, or approximately 10 minutes to approximately 25 minutes, or approximately 10 minutes to approximately 15 minutes. Preferably, the drying temperature is approximately 18°C ​​to approximately 30°C, approximately 20°C to approximately 27°C, or approximately 25°C.

[0182] According to any aspect or embodiment of the disclosed method for preparing the BR3 form of brurazazin hydrochloride, the method may further include mixing the BR3 form of brurazazin with at least one pharmaceutically acceptable excipient to prepare a pharmaceutical composition.

[0183] This disclosure includes crystalline polymorphs of brurazazin hydrochloride, designated BR4. The BR4 polymorph of brurazazin hydrochloride can be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 10; an X-ray powder diffraction pattern having peaks at 6.0°2θ, 10.8°2θ, and 12.6°2θ ± 0.2°2θ; and combinations of these data.

[0184] The BR4 crystal form of brurazazin hydrochloride can also be characterized by X-ray powder diffraction patterns with peaks at 6.0°2θ, 10.8°2θ, and 12.6°2θ±0.2°2θ, and additionally with any one, two, three, four, or five peaks selected from 8.9°2θ, 18.7°2θ, 21.2°2θ, 24.5°2θ, and 27.1°2θ±0.2°2θ.

[0185] Alternatively, the BR4 crystal form of brurazazin hydrochloride can be characterized by an X-ray powder diffraction pattern with peaks at 8.9°2θ, 18.7°2θ, 21.2°2θ, 24.5°2θ, and 27.1°2θ±0.2°2θ. The BR4 crystallization of brurazazin hydrochloride can also be characterized by an X-ray powder diffraction pattern with peaks at 8.9°2θ, 18.7°2θ, 21.2°2θ, 24.5°2θ, and 27.1°2θ±0.2°2θ, and also with any one, two, or three additional peaks selected from 12.1°2θ, 21.8°2θ, and 25.6°2θ±0.2°2θ.

[0186] The BR4 crystal form of brurazazin hydrochloride can be characterized by X-ray powder diffraction patterns with peaks at 8.9°2θ, 12.1°2θ, 18.7°2θ, 21.2°2θ, 21.8°2θ, 24.5°2θ, 25.6°2θ, and 27.1°2θ ± 0.2°2θ.

[0187] According to any aspect or embodiment of the invention, the BR4 crystal form of brurazazin hydrochloride can be characterized by any data described herein, and further characterized by the absence of peaks in XRPD spectra at 3.5°2θ to 4.0°2θ ± 0.2°2θ, and / or at 4.5°2θ to 4.9°2θ ± 0.2°2θ, and / or at 6.3°2θ to 6.8°2θ ± 0.2°2θ, and / or at 9.3°2θ to 10.2°2θ ± 0.2°2θ, and / or at 11.0°2θ to 11.8°2θ ± 0.2°2θ, and / or at 13.0°2θ to 14.0°2θ ± 0.2°2θ. The BR4 crystal form of brurazazin hydrochloride according to any aspect or embodiment of this disclosure can be characterized by any data described herein, and further by XRPD spectra of any one, two, three, four, five or six peaks in the aforementioned regions.

[0188] In one embodiment of this disclosure, the BR4 crystal form of brurazazin hydrochloride was isolated.

[0189] The BR4 crystal form of Brirazazin hydrochloride can be in hydrate form.

[0190] The BR4 crystal form of brurazazin hydrochloride can be characterized by each of the above characteristics individually or in all possible combinations, for example, an XRPD spectrum with peaks at 6.0°2θ, 10.8°2θ, and 12.6°2θ ± 0.2°2θ; an XRPD spectrum with peaks at 8.9°2θ, 18.7°2θ, 21.2°2θ, 24.5°2θ, and 27.1°2θ ± 0.2°2θ; an XRPD spectrum as shown in Figure 10; and combinations thereof.

[0191] The BR4 crystal form of brurazazin hydrochloride described in any aspect or embodiment of this disclosure may be polymorphically pure and preferably comprises: 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 form of brurazazin hydrochloride.

[0192] This disclosure includes crystalline polymorphs of brurazazin hydrochloride, designated BR5. The BR5 polymorph of brurazazin hydrochloride can be characterized by data selected from one or more of the following: X-ray powder diffraction patterns substantially as shown in Figure 11; X-ray powder diffraction patterns having peaks at 5.4°2θ, 17.9°2θ, and 21.9°2θ ± 0.2°2θ; and combinations of these data.

[0193] The BR5 crystal form of Brirazazin hydrochloride can also be characterized by X-ray powder diffraction patterns with peaks at 5.4°2θ, 17.9°2θ, and 21.9°2θ±0.2°2θ, and additionally with any one, two, three, four, or five peaks selected from 14.2°2θ, 17.4°2θ, 19.8°2θ, 23.0°2θ, and 24.6°2θ±0.2°2θ.

[0194] Alternatively, the BR5 crystal form of brurazazin hydrochloride can be characterized by an X-ray powder diffraction pattern with peaks at 14.2°2θ, 17.4°2θ, 19.8°2θ, 23.0°2θ, and 24.6°2θ±0.2°2θ. The BR5 crystal form of brurazazin hydrochloride can also be characterized by an X-ray powder diffraction pattern with peaks at 14.2°2θ, 17.4°2θ, 19.8°2θ, 23.0°2θ, and 24.6°2θ±0.2°2θ, and also has any one, two, or three additional peaks selected from 7.0°2θ, 21.9°2θ, and 26.1°2θ±0.2°2θ.

[0195] The BR5 crystal form of Brirazazin hydrochloride can be characterized by X-ray powder diffraction patterns with peaks at 7.0°2θ, 14.2°2θ, 17.4°2θ, 19.8°2θ, 21.9°2θ, 23.0°2θ, 24.6°2θ, and 26.1°2θ ± 0.2°2θ.

[0196] According to any aspect or embodiment of the invention, the BR5 crystal form of brurazazin hydrochloride can be characterized by any data described herein, and further characterized by the absence of peaks in the XRPD spectrum at 4.0°2θ to 5.0°2θ ± 0.2°2θ.

[0197] In one embodiment of the present invention, the BR5 crystal form of brurazazin hydrochloride was isolated.

[0198] The BR5 crystal form of Brirazazin hydrochloride can be in anhydrous form.

[0199] The BR5 crystal form of brurazazin hydrochloride can be characterized by each of the above characteristics individually or in all possible combinations, for example, an XRPD spectrum with peaks at 5.4°2θ, 17.9°2θ, and 21.9°2θ ± 0.2°2θ; an XRPD spectrum with peaks at 14.2°2θ, 17.4°2θ, 19.8°2θ, 23.0°2θ, and 24.6°2θ ± 0.2°2θ; an XRPD spectrum as shown in Figure 11; and combinations thereof.

[0200] The BR5 crystal form of brurazazin hydrochloride described in any aspect or embodiment of this disclosure may be polymorphically pure and preferably comprises: 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 form of brurazazin hydrochloride.

[0201] This disclosure includes a crystalline polymorph of brurazazin hydrochloride, designated BR6. The BR6 polymorph of brurazazin hydrochloride can be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 12; an X-ray powder diffraction pattern having peaks at 12.0°2θ, 18.2°2θ, and 20.4°2θ ± 0.2°2θ; and combinations of these data.

[0202] The BR6 crystal form of brurazazin hydrochloride can also be characterized by X-ray powder diffraction patterns with peaks at 12.0°2θ, 18.2°2θ, and 20.4°2θ±0.2°2θ, and also with any one, two, three, four, or five additional peaks selected from 7.7°2θ, 13.2°2θ, 17.0°2θ, 18.9°2θ, and 23.0°2θ±0.2°2θ.

[0203] Alternatively, the BR6 crystal form of brurazazin hydrochloride can be characterized by an X-ray powder diffraction pattern having peaks at 7.7°2θ, 13.2°2θ, 17.0°2θ, 18.9°2θ, and 23.0°2θ±0.2°2θ. The BR6 crystal form of brurazazin hydrochloride can also be characterized by an X-ray powder diffraction pattern having peaks at 7.7°2θ, 13.2°2θ, 17.0°2θ, 18.9°2θ, and 23.0°2θ±0.2°2θ, and also having any one, two, or three additional peaks selected from 14.8°2θ, 19.7°2θ, and 24.9°2θ±0.2°2θ.

[0204] The BR6 crystal form of brurazazin hydrochloride can be characterized by X-ray powder diffraction patterns with peaks at 7.7°2θ, 13.2°2θ, 14.8°2θ, 17.0°2θ, 18.9°2θ, 19.7°2θ, 23.0°2θ, and 24.9°2θ ± 0.2°2θ.

[0205] According to any aspect or embodiment of the invention, the BR6 crystal form of brurazazin hydrochloride can be characterized by any data described herein, and further characterized by the absence of peaks in the XRPD spectrum at 4.0°2θ to 6.0°2θ ± 0.2°2θ.

[0206] In one embodiment of the present invention, the BR6 crystal form of brurazazin hydrochloride was isolated.

[0207] The BR6 crystal form of Brirazazin hydrochloride can be in anhydrous form.

[0208] The BR6 crystal form of brurazazin hydrochloride can be characterized by each of the above characteristics individually or in all possible combinations, for example, an XRPD spectrum with peaks at 12.0°2θ, 18.2°2θ, and 20.4°2θ ± 0.2°2θ; an XRPD spectrum with peaks at 7.7°2θ, 13.2°2θ, 17.0°2θ, 18.9°2θ, and 23.0°2θ ± 0.2°2θ; an XRPD spectrum as shown in Figure 12; and combinations thereof.

[0209] The BR6 crystal form of brurazazin hydrochloride described in any aspect or embodiment of this disclosure may be polymorphically pure and preferably comprises: 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 form of brurazazin hydrochloride.

[0210] This disclosure includes crystalline polymorphs of brurazazin hydrochloride, designated BR7. The BR7 polymorph of brurazazin hydrochloride can be characterized by data selected from one or more of the following: X-ray powder diffraction patterns substantially as shown in Figure 13; X-ray powder diffraction patterns having peaks at 9.3°2θ, 14.4°2θ, and 23.6°2θ ± 0.2°2θ; and combinations of these data.

[0211] The BR7 crystal form of brurazazin hydrochloride can also be characterized by X-ray powder diffraction patterns with peaks at 9.3°2θ, 14.4°2θ, and 23.6°2θ±0.2°2θ, and additionally with any one, two, three, four, or five peaks selected from 9.9°2θ, 16.7°2θ, 18.9°2θ, 22.5°2θ, and 33.6°2θ±0.2°2θ.

[0212] Alternatively, the BR7 crystal form of brurazazin hydrochloride can be characterized by X-ray powder diffraction patterns with peaks at 9.9°2θ, 16.7°2θ, 18.9°2θ, 22.5°2θ, and 33.6°2θ±0.2°2θ. The BR7 crystals of brurazazin hydrochloride can also be characterized by X-ray powder diffraction patterns with peaks at 9.9°2θ, 16.7°2θ, 18.9°2θ, 22.5°2θ, and 33.6°2θ±0.2°2θ, and also have any one, two, or three additional peaks selected from 7.3°2θ, 18.1°2θ, and 20.8°2θ±0.2°2θ.

[0213] The BR7 crystal form of brurazazin hydrochloride can be characterized by X-ray powder diffraction patterns with peaks at 7.3°2θ, 9.9°2θ, 16.7°2θ, 18.1°2θ, 18.9°2θ, 20.8°2θ, 22.5°2θ and 33.6°2θ ± 0.2°2θ.

[0214] In one embodiment of this disclosure, the BR7 crystal form of brurazazin hydrochloride was isolated.

[0215] The BR7 crystal form of Brirazazin hydrochloride can be in hydrate form, more preferably in dihydrate form.

[0216] The BR7 crystal form of brurazazin hydrochloride can be characterized by each of the above characteristics individually or in all possible combinations, for example, XRPD spectra with peaks at 9.3°2θ, 14.4°2θ, and 23.6°2θ ± 0.2°2θ; XRPD spectra with peaks at 9.9°2θ, 16.7°2θ, 18.9°2θ, 22.5°2θ, and 33.6°2θ ± 0.2°2θ; XRPD spectra as shown in Figure 13; and combinations thereof.

[0217] The BR7 crystal form of brurazazin hydrochloride described in any aspect or embodiment of this disclosure may be polymorphically pure and preferably comprises: 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 form of brurazazin hydrochloride.

[0218] This disclosure provides Brilaroxazine hydrobromide. Brilaroxazine hydrobromide is preferably in solid form, and more preferably in crystalline form. This disclosure includes crystalline polymorphs of Brilaroxazine hydrobromide, designated BHBr1. The BHBr1 crystalline form of Brilaroxazine hydrobromide can be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as shown in Figure 14; an X-ray powder diffraction pattern having peaks at 10.1°2θ, 11.9°2θ, and 16.4°2θ ± 0.2°2θ; and combinations of these data.

[0219] The BHBr1 crystal form of brevicornuate can also be characterized by X-ray powder diffraction patterns, which have peaks at 10.1°2θ, 11.9°2θ, and 16.4°2θ±0.2°2θ, and also have any one, two, three, four, or five additional peaks selected from 15.2°2θ, 17.0°2θ, 18.9°2θ, 21.2°2θ, and 25.0°2θ±0.2°2θ.

[0220] Alternatively, the BHBr1 crystal form of brevicornuate can be characterized by X-ray powder diffraction (XPD) patterns with peaks at 15.2°2θ, 17.0°2θ, 18.9°2θ, 21.2°2θ, and 25.0°2θ ± 0.2°2θ. The BHBr1 crystals of brevicornuate can also be characterized by X-ray powder diffraction (XPD) patterns with peaks at 15.2°2θ, 17.0°2θ, 18.9°2θ, 21.2°2θ, and 25.0°2θ ± 0.2°2θ, and additionally with one, two, three, or four additional peaks selected from 23.4°2θ, 24.2°2θ, 26.4°2θ, and 29.8°2θ ± 0.2°2θ.

[0221] The BHBr1 crystal form of brurazazin hydrobromide can be characterized by X-ray powder diffraction patterns with peaks at 15.2°2θ, 17.0°2θ, 18.9°2θ, 21.2°2θ, 23.4°2θ, 24.2°2θ, 25.0°2θ, 26.4°2θ, and 29.8°2θ ± 0.2°2θ.

[0222] The BHBr1 crystal form of brevicornuate according to any aspect or embodiment of the present invention can be characterized by any data described herein, and further characterized by XRPD spectra showing no peaks at 3.5°2θ to 5.0°2θ ± 0.2°2θ, and / or no peaks at 6.0°2θ to 9.0°2θ ± 0.2°2θ. According to any aspect or embodiment of the present invention, the BHBr1 crystal form of brevicornuate can be characterized by any data described herein, and further characterized by XRPD spectra showing no peaks in one or both of the aforementioned regions.

[0223] In one embodiment of the present invention, the BHBr1 crystal form of brurazazin hydrobromide was isolated.

[0224] Brirazaqin hydrobromide in BHBr1 form can be in anhydrous form.

[0225] The BHBr1 crystal form of brevicornuate can be characterized by each of the above characteristics individually or in all possible combinations, for example, XRPD spectra with peaks at 10.1°2θ, 11.9°2θ, and 16.4°2θ ± 0.2°2θ; XRPD spectra with peaks at 15.2°2θ, 17.0°2θ, 18.9°2θ, 21.2°2θ, and 25.0°2θ ± 0.2°2θ; XRPD spectra as shown in Figure 14; and combinations thereof.

[0226] The BHBr1 crystal form of bromerazine hydrobromide described in any aspect or embodiment of this disclosure may be polymorphically pure and preferably comprises: 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 form of bromerazine hydrobromide.

[0227] This disclosure provides crystalline polymorphs of the above-mentioned brurazacin and its salts, particularly brurazacin hydrochloride, for use in preparing pharmaceutical compositions comprising brurazacin and its salts, particularly brurazacin hydrochloride and / or its crystalline polymorphs.

[0228] This disclosure also covers: crystalline polymorphs of brurasaqin and brurasaqin salts of this disclosure, particularly brurasaqin hydrochloride for the preparation of pharmaceutical compositions of crystalline polymorphs of brurasaqin and brurasaqin salts, particularly the use of brurasaqin hydrochloride and / or its crystalline polymorphs.

[0229] This disclosure includes a method for preparing the above-described pharmaceutical composition. The method includes mixing any one or a combination thereof of bromerazine and its salts (particularly bromerazine hydrochloride) of this disclosure with at least one pharmaceutically acceptable excipient.

[0230] The pharmaceutical compositions or formulations disclosed herein comprise any one or a combination thereof in solid form of bromerazine and its salts, particularly the bromerazine hydrochloride of this disclosure. In addition to the active ingredient, the pharmaceutical formulations of this disclosure may also comprise one or more excipients. Excipients may be added to the formulation for various purposes.

[0231] Diluents increase the volume of solid pharmaceutical compositions and make pharmaceutical dosage forms containing said compositions easier for patients and caregivers to handle. Diluents used for solid compositions include, for example, microcrystalline cellulose (e.g., ), fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, glucose binder, dextrin, dextrose, calcium hydrogen phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethyl methacrylate (e.g.) ), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

[0232] Solid pharmaceutical compositions compressed into dosage forms, such as tablets, may contain excipients that function to help bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include gum arabic, alginate, carbomer (e.g., Carbopol), sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, and hydroxypropyl cellulose (e.g., [missing information]). ), hydroxypropyl methylcellulose (e.g.) ), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethyl methacrylate, povidone (e.g.) ), pregelatinized starch, sodium alginate and starch.

[0233] The dissolution rate of the compacted solid pharmaceutical composition in the patient's stomach can be increased by adding a disintegrant to the composition. Disintegrants include alginate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose (e.g., ...). ), colloidal silica, cross-linked sodium carboxymethyl cellulose, crospovidone (e.g., Guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, potassium polycrylamide, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., ) and starch.

[0234] Gliding agents can be added to improve the flowability of uncompacted solid compositions and increase dosage accuracy. Excipients that can be used as gliding agents include colloidal silica, magnesium trisilicate, powdered cellulose, starch, talc, and tricalcium phosphate.

[0235] When preparing dosage forms such as tablets by pressing a powdered composition, the composition is subjected to pressure from a punch and a die. Some excipients and active ingredients tend to adhere to the surfaces of the punch and die, which can lead to dents and other surface irregularities in the product. Lubricants can be added to the composition to reduce adhesion and facilitate the release of the product from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearoyl fumarate, stearic acid, talc, and zinc stearate.

[0236] Flavoring agents and flavor enhancers make the dosage form more acceptable to patients. Common pharmaceutical flavoring agents and flavor enhancers that can be used in the compositions disclosed herein include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0237] Solid and liquid compositions may also be stained with any pharmaceutically acceptable coloring agent to improve their appearance and / or facilitate patient identification of the product and unit dosage.

[0238] In the liquid pharmaceutical compositions of the present invention, zipalletinib and any other solid excipients may be dissolved or suspended in a liquid carrier, such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0239] Liquid pharmaceutical compositions may contain a variety of emulsifiers to uniformly disperse the active ingredient or other excipients insoluble in the liquid carrier throughout the composition. Emulsifiers that can be used in the liquid pharmaceutical compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, gum arabic, tragacanth, carrageenan, pectin, methylcellulose, carbomer, cetearyl alcohol, and cetyl alcohol.

[0240] The liquid pharmaceutical compositions of the present invention may further comprise thickeners to improve the palatability of the product and / or coat the gastrointestinal tract. Such thickeners include gum arabic, bentonite alginate, carbomer, calcium or sodium carboxymethyl cellulose, cetearyl alcohol, methylcellulose, ethylcellulose, guar gum gelatin, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, tragacanth starch, xanthan gum, and combinations thereof.

[0241] Various sweeteners such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0242] Various preservatives and chelating agents, such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid, can be added at safe intake levels to improve storage stability.

[0243] According to this disclosure, the liquid composition may also contain a buffer, such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate. Formulation scientists can easily determine the selection and amount of excipients based on experience and by referring to standard procedures and references in the field.

[0244] The various solid compositions disclosed herein include powders, granules, aggregates, and compacted compositions. Dosages include those suitable for oral, sublingual, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, and ocular administration. While the most suitable route of administration in any particular case depends on the nature and severity of the condition being treated, in some embodiments, the route of administration is oral. Dosages can be conveniently available in unit dosage forms and prepared by any method known in the pharmaceutical industry.

[0245] The various dosage forms include a variety of solid dosage forms, such as tablets, powders, capsules, suppositories, sachets, sugar tablets and lozenges, as well as liquid syrups, suspensions and elixirs.

[0246] The dosage form disclosed herein may be a capsule containing the composition, such as a powdered or granular solid composition disclosed herein, the capsule shell of which may be hard or soft. The capsule shell may be made of gelatin and may optionally contain plasticizers, such as glycerin and / or sorbitol, opacifiers, and / or colorants.

[0247] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0248] Compositions for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the various active ingredients and excipients in powder form are mixed, and then further mixed in the presence of a liquid, typically water, to agglomerate the powder into granules. The granules are sieved and / or ground, dried, and then sieved and / or ground to the desired particle size. The granules can then be tableted, or other excipients, such as glidants and / or lubricants, can be added before tableting.

[0249] The tableting composition can be prepared using conventional dry mixing methods. For example, the mixture of the active ingredient and excipient is compressed into blocks or tablets, and then pulverized into compacted granules. The compacted granules can then be compressed into tablets.

[0250] As an alternative to dry granulation, direct compression technology can be used to directly compress the mixed composition into a tablet form. Direct compression produces more uniform tablets without granules. Excipients particularly suitable for direct compression tableting include microcrystalline cellulose, spray-dried lactose, calcium hydrogen phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those skilled in the art with experience and skill in the specific formulation challenges of direct compression tableting.

[0251] The capsule fillings disclosed herein may include any of the mixtures and granules mentioned above in relation to tableting, but they do not undergo the final tableting step.

[0252] Pharmaceutical formulations of bromelain and its salts, particularly bromelain hydrochloride, can be administered. Brirasarqin and its salts (particularly bromelain hydrochloride) can be formulated for administration to mammals, and in this example, for administration to humans. Brirasarqin and its salts, particularly bromelain hydrochloride, can be formulated as, for example, viscous liquid solutions or suspensions, such as clear solutions for injection. The formulations may contain one or more solvents. Suitable solvents can be selected by considering their physical and chemical stability at various pH levels, viscosity (which would allow for injectability), flowability, boiling point, miscibility, and purity. Suitable solvents include USP alcohol, benzyl alcohol NF, benzyl benzoate USP, and castor oil USP. Additional substances can be added to the formulations, such as buffers, solubilizers, and antioxidants, including those disclosed in Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition.

[0253] The crystalline polymorphs of bromelain and bromelain salt, particularly bromelain hydrochloride, disclosed herein, as well as pharmaceutical compositions and / or formulations of bromelain and bromelain salt, particularly bromelain hydrochloride, can be used, in the embodiments, as medicaments for treating schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary hypertension.

[0254] This disclosure also provides methods for treating schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary hypertension by administering to a subject in need of treatment a therapeutically effective amount of any one or a combination thereof of crystalline polymorphs of bromerazine and salts of bromerazine (particularly bromerazine hydrochloride of this disclosure), or at least one of the above-described pharmaceutical compositions and / or preparations.

[0255] This disclosure has been described above with reference to specific preferred embodiments and exemplary examples. Those skilled in the art will understand that modifications can be made to the described and illustrated disclosure without departing from the spirit and scope of this disclosure. The examples are intended to aid in understanding this disclosure but are not intended, and should not be construed as limiting its scope in any way.

[0256] Powder X-ray diffraction ("XRPD")

[0257] X-ray diffraction was performed using an X-ray powder diffractometer.

[0258] Bruker D8 Advance diffractometer; CuK-rays Lynx eye detector; laboratory temperature 22 to 25°C; PMMA sample holder. Before analysis, the sample was gently ground into a fine powder using a mortar and pestle. The ground sample was placed into the cavity of the sample holder, and the sample surface was smoothed with a coverslip.

[0259] Measurement parameters:

[0260] Scan range: 2°2θ to 40°2θ;

[0261] Scan mode: Continuous;

[0262] Step size: 0.05°;

[0263] Step time: 0.5 seconds;

[0264] Sample rotation: 30 rpm; and

[0265] Sample holder: PMMA sample holder.

[0266] All X-ray powder diffraction peaks were calibrated based on the standard silicon spikes in the samples.

[0267] 13 CCP / MAS NMR method:

[0268] Solid-state NMR spectra were measured at 11.7 T using a Bruker Avance III HD 500US / WB NMR spectrometer equipped with a 3.2 mm probe (Karlsruhe, Germany, 2023). Standard pulsed acquisition was employed, with cross-polarized NMR spectra acquired at a rotational frequency of 15 kHz and room temperature (300 K). 13 CCP / MAS NMR spectra. Cyclic delay was 8 seconds, and cross-polarization contact time was 2 milliseconds. 13 The C-scale is based on α-glycine ( 13 (C = 176.03 ppm) was used as a reference. Frictional heat generation from rotating samples was offset by active cooling, and temperature calibration was performed using Pb(NO3)2. Prior to the study, the NMR spectrometer was fully calibrated, and all experimental parameters were carefully optimized. During standard optimization, the magic angle was set using KBr, and magnetic field homogeneity was optimized using an adamantane sample (resulting in a half-maximum linewidth Δυ1 / 2 less than 3.5 Hz within a 250 ms acquisition time).

[0269] Example

[0270] Preparation of starting materials

[0271] Brirazacin can be prepared according to methods known in the literature, such as U.S. Patent No. 8,188,076.

[0272] Example 1: Preparation of B1 type of Brirazazan

[0273] Brinarizine (0.02 g) was dissolved in dichloromethane (0.2 mL) at approximately 25 °C to obtain a clear solution. The clear solution was covered with a paraffin film with pinholes, and the solvent was slowly evaporated at approximately 22 °C to approximately 25 °C. After one hour, the solid was separated and analyzed by XRPD. Crystalline brinarizine, type B1, was obtained. The XRPD pattern is shown in Figure 1.

[0274] Example 2: Preparation of B2 type of brevicornuate

[0275] Brinarizine (0.02 g) was dissolved in methanol (2.5 mL) at about 25 °C to obtain a clear solution. Water (3 mL) was added to the clear solution at about 25 °C, resulting in a white precipitate. After standing for about 1 hour, the reaction mixture was filtered and washed with water (3 mL × 1). The resulting solid was dried under vacuum at about 22 °C to about 25 °C for about 10 min to about 15 min. The resulting solid was analyzed by XRPD. Crystalline brinarizine of type B2 was obtained. The XRPD pattern is shown in Figure 2.

[0276] Example 3: Preparation of B3 form of brevicornuate

[0277] Brinarizine (0.02 g) was dissolved in 2.5 mL of methanol at approximately 25 °C to obtain a clear solution. The clear solution was covered with a paraffin film with pinholes, and the solvent was slowly evaporated at a temperature of approximately 22 °C to approximately 25 °C. After 1 hour, the solid was separated and analyzed by XRPD. Crystalline brinarizine, type B3, was obtained. The XRPD pattern is shown in Figure 3.

[0278] Example 4: Preparation of B4 form of Brirazazan

[0279] Brinarizine (0.02 g) was dissolved in tetrahydrofuran (0.1 mL) at about 25 °C to obtain a clear solution. The clear solution was covered with a paraffin film with pinholes, and the solvent was slowly evaporated at a temperature of about 22 °C to about 25 °C. After 1 hour, the solid was separated and analyzed by XRPD. Crystalline brinarizine B4 was obtained. The XRPD pattern is shown in Figure 4.

[0280] Example 5: Preparation of B5 form of Brirazazan

[0281] 1 gram of bromerazine was dissolved in 20 mL of dichloromethane at approximately 25 °C. The solution was filtered through a 0.45 μm filter, and heptane (10 mL) was added at approximately 25 °C, resulting in the formation of a white precipitate. The reaction mixture was stirred at approximately 25 °C for approximately 2 hours. The reaction mixture was filtered and washed with heptane (3 mL × 2). The resulting solid was dried under vacuum at approximately 22 °C to approximately 25 °C for approximately 10 to approximately 15 minutes, and then dried in a vacuum desiccator at approximately 60 °C for approximately 24 hours. XRPD analysis was performed on the resulting solid. Crystalline bromerazine of type B5 was obtained. The XRPD pattern is shown in Figure 5.

[0282] Example 6: Preparation of B6 form of Brirazazan

[0283] Brinarizine (0.1 g) (B5 type) was placed in a 10 mL vial, and 5 mL of heptane (5 mL) was added at approximately 60 °C. The slurry was stirred at approximately 60 °C for approximately 48 hours. The reaction mixture was filtered and dried under vacuum at approximately 25 °C to 30 °C for approximately 20 to 30 minutes. After 48 hours, and 1 hour later, the solid was separated and analyzed by XRPD. Crystalline brinarizine (B4 type) was obtained. The XRPD pattern is shown in Figure 6.

[0284] Example 7: Preparation of BR1 type of Brirazazan hydrochloride

[0285] Brinarizine (0.1 g) was dissolved in acetone (5 mL) at about 25 °C. 2 mL of 2M HCl solution was added, followed by diethyl ether (30 mL) at about 25 °C. The reaction mixture was stirred at about 25 °C for about 16 hours. The reaction mixture was filtered and dried under vacuum for about 10 to 15 minutes. The resulting solid was analyzed by XRPD. Crystalline brerasarzine hydrochloride of type BR1 was obtained. The XRPD pattern is shown in Figure 7.

[0286] Example 8: Preparation of BR2 type of Brirazazan hydrochloride

[0287] Brinarizine (B1 type, 0.1 g) was suspended in a glass vial and dissolved in a pH 1.2 buffer solution (prepared with HCl) (5 mL) at approximately 25°C. The slurry was stirred for approximately 1 to 2 hours until it became very viscous. The slurry was stirred at approximately 25°C for approximately 16 hours, and a white solid was observed. The slurry was filtered and dried under vacuum for approximately 10 to 15 minutes. XRPD analysis of the resulting solid yielded crystalline brerasarzine hydrochloride of type BR2. The XRPD pattern is shown in Figure 8.

[0288] Example 9: Preparation of BR3 type of brurazazin hydrochloride

[0289] Brinarizine hydrochloride (BR2 type, 0.1 g) was placed in a glass vial at approximately 25°C. 5 mL of isopropanol was added, and the reaction mixture was heated to approximately 75°C to approximately 80°C and stirred at this temperature for approximately 16 hours. The reaction mixture was cooled to approximately 25°C, filtered, and dried under vacuum for approximately 10 to 15 minutes. The resulting solid was analyzed by XRPD. Crystalline brerasarzine hydrochloride of type BR3 was obtained. The XRPD pattern is shown in Figure 9.

[0290] Example 10: Preparation of BR3 type of brurazazin hydrochloride

[0291] Brinarizine hydrochloride (BR2 type, 0.1 g) was placed in a mortar and pestle. A few drops (approximately 20 μL) of isopropanol were added, and the mixture was ground for approximately 2 to 3 minutes. The resulting solid was subjected to XRPD analysis. The BR3 type of crystalline brerasarzine hydrochloride was then obtained.

[0292] Example 11: Preparation of BR4 type of Brirazazan hydrochloride

[0293] Brinarizine (0.3 g) was dissolved in dichloromethane (4.5 mL) at approximately 25 °C. An aqueous HCl solution (0.12 mL) was added to the brinarizine solution at approximately 25 °C, and the mixture was stirred for approximately 1 hour. The mixture was filtered and dried over approximately 15 minutes. The resulting solid was analyzed by XRPD. Crystalline brinarizine hydrochloride of type BR4 was obtained. The XRPD pattern is shown in Figure 10.

[0294] Example 12: Preparation of BR5 type of Brirazazan hydrochloride

[0295] Brinarizine (1.0 g) was dissolved in dichloromethane (15 mL) at about 25 °C. 0.48 mL of aqueous HCl solution was added dropwise at about 25 °C. The reaction mixture was stirred for about 1 hour. The mixture was filtered and dried under vacuum for about 15 to about 30 minutes. It was further dried in a vacuum tray dryer (VTD) at about 50 °C for about 10 hours. The sample was cooled to room temperature and maintained at about 25 °C. The resulting solid was analyzed by XRPD. Crystalline brinarizine hydrochloride of type BR5 was obtained. The XRPD pattern is shown in Figure 11.

[0296] Example 13: Preparation of BR6 type of Brirazazan hydrochloride

[0297] Brinarizine hydrochloride (BR2 type, 0.03 g) was suspended in a 9:1 methanol-water mixture (1 mL) at approximately 25 °C. The reaction mixture was stirred at approximately 25 °C for approximately 18 hours. The slurry was filtered and dried under vacuum for approximately 10 to 15 minutes. The resulting solid was analyzed by XRPD. Crystalline brerasarzine hydrochloride of type BR6 was obtained. The XRPD pattern is shown in Figure 12.

[0298] Example 14: Preparation of BR7 type of Brirazazan hydrochloride

[0299] Brinarizine (B1 type, 0.06 g) was placed in a 20 mL PTFE flask. Water (10 mL) and a 37% aqueous hydrochloric acid solution (0.048 mL) were added at 25 °C. The reaction vessel was sealed with a PTFE cap and placed in a stainless steel jacket, which was then tightened. The reaction mixture was placed in an oven and heated to 80 °C for 8 hours, then cooled to 25 °C and maintained for 16 hours. This cycle was repeated three times under sealed conditions. Finally, the reaction mixture was cooled to 25 °C. The mixture was filtered, and the resulting solid was aspirated dry for approximately 15 minutes. XRPD analysis was performed on the resulting solid. Crystalline brerasarzine hydrochloride of type BR7 was obtained. The XRPD pattern is shown in Figure 13.

[0300] Example 15: Preparation of BHBr1 type of brevicornuate

[0301] 0.2 g of bromerazine free base was dissolved in 6 mL of acetone at approximately 40 °C. IPA-HBr solution [(isopropanol (0.5 mL) and HBr aqueous solution (0.036 g, approximately 48%)] was added and maintained for approximately 1 hour, then cooled to approximately 10 °C at a rate of 1 °C per minute. The reaction mixture was maintained for approximately 2 hours. The reaction mixture was then cooled to room temperature and filtered. It was washed with MTBE (1 mL × 3 times) and blotted dry for approximately 15 minutes. The resulting solid was analyzed by XRPD to give bromerazine hydrobromide of the BHBr1 form. The XRPD spectrum is shown in Figure 14.

[0302] Example 16: Preparation of amorphous brérazozine hydrochloride

[0303] Brirazazan hydrochloride (0.1 g) was dissolved in dichloromethane (4 mL) at approximately 35 °C. The clear solution was distilled under high vacuum (below 100 mbar) on a rotary evaporator at approximately 35 °C for approximately 30 min to approximately 45 min. The solid was separated and analyzed by XRPD. Amorphous brirazazan hydrochloride was obtained. The XRPD pattern is shown in Figure 15.

[0304] Example 17: Preparation of BR3 type of Brirazazan hydrochloride

[0305] Brinarizine (1 g) was dissolved in 60 mL of acetone at about 25 °C. 2 M HCl aqueous solution (20 mL) was added to the reaction mixture. The reaction mixture was stirred at about 25 °C for about 1 hour, then cooled to about 20 °C. 175 mL of n-heptane was added and stirred for about 1 hour. The mixture was further cooled to about 10 °C and stirred for about 16 hours, then heated to about 25 °C, filtered, and washed with n-heptane (10 mL × 3). The resulting solid was analyzed by XRPD. BR3 type crystalline brinarizine hydrochloride was obtained. Example 18: Preparation of BR3 type brinarizine hydrochloride

[0306] Brirazazon hydrochloride (0.96 g) was dissolved in methanol (24 mL) at about 60 °C. The solution was filtered to obtain a clear solution, which was used as the stock solution. 0.5 mL of the stock solution was added to pre-cooled antisolvent (4 mL) acetone at a temperature of about 0 °C to 5 °C, and the reaction mixture was stirred at the same temperature for about 1 hour. The mixture was filtered at about 25 °C and dried under vacuum at about 25 °C for about 15 min to about 20 min. The resulting solid was analyzed by XRPD. BR3 type crystalline brirazazon hydrochloride was obtained.

[0307] Example 19: Preparation of B6 form of Brirazazan

[0308] Brinarizine (0.1 g) (B5 type) was placed in a 10 mL vial, and 5 mL of n-heptane (5 mL) was added at approximately 60 °C. The slurry was stirred at approximately 60 °C for approximately 48 hours. The reaction mixture was filtered and dried under vacuum at approximately 25 °C to 30 °C for approximately 20 to 30 minutes. The resulting solid was analyzed by XRPD. Crystalline brinarizine (B6 type) was obtained.

[0309] Example 20: Stability Study

[0310] Storage stability under different relative humidity

[0311] Samples of bromelain hydrochloride (BR1 and BR3 types) were placed at room temperature under different relative humidity conditions. XRPD analysis was performed on the samples after 7 days. The results are shown in Table 1 below:

[0312]

[0313] Table 1

[0314] These results demonstrate that BR1 and BR3 types of brurazazin hydrochloride are stable after exposure to high and low relative humidity for at least 7 days.

[0315] Grinding experiment

[0316] Samples of BR1 and BR3 types of brevicornuate hydrochloride were vigorously ground and then solvent-drop milled in water, ethanol, and isopropanol. Grinding could be performed alone or in the presence of ethanol, water, or isopropanol. In these experiments, approximately 20 mg of sample was placed in a mortar and ground with a pestle for 2 minutes. The solvent (when used) was added to the crystalline material prior to grinding in a volume of 10 μL. XRPD analysis was performed on each sample after the grinding experiments, confirming no change in the starting materials (Table 2).

[0317]

[0318] Table 2

[0319] The results showed that the BR1 and BR3 forms of brurazazin hydrochloride are not prone to polymorphism changes, making them very suitable for the preparation of pharmaceutical formulations.

[0320] thermal stability

[0321] Samples of bromelain hydrochloride (BR1 and BR3 types) were heated to 100°C for 30 minutes. XRPD analysis of the samples confirmed that the starting materials remained unchanged (Table 3).

[0322] Initial form Heat to 80℃ for 30 minutes Heat to 100℃ for 30 minutes BR1 type BR1 type BR1 type BR3 type BR3 type BR3 type

[0323] Table 3

[0324] Compression stability

[0325] Samples of BR1 and BR3 types of brurazazine hydrochloride were placed under a pressure of 2 tons for 1 minute. The Autopress hydraulic press was set to 2 tons. XRPD analysis was performed on the sample after 1 minute. The results are shown in Table 4 below:

[0326] Initial form Pressure / 2 tons, 1 minute BR1 type BR1 type BR3 type BR3 type

[0327] Therefore, the BR1 and BR3 types of brurazazine hydrochloride are stable under high pressure, making these products very suitable for pharmaceutical processing.

Claims

1. A crystalline brevicornuate hydrochloride.

2. The crystalline brevicornuate hydrochloride as described in claim 1, specified as BR1 type, characterized in that: Select from one or more of the following data: (a) X-ray powder diffraction pattern with peaks at 17.3°2θ, 21.5°2θ and 25.7°2θ±0.2°2θ±0.2°2θ; (b) X-ray powder diffraction pattern with peaks at 7.2°2θ, 16.4°2θ, 19.5°2θ, 22.4°2θ and 24.7°2θ ± 0.2°2θ; (c) X-ray powder diffraction pattern as shown in Figure 7; (d) Solid-state products with peaks at 20.6 ppm, 42.4 ppm, 97.5 ppm, 122.2 ppm, 131.0 ppm, and 165.5 ppm ± 0.2 ppm 13 C NMR spectrum; (e) Solid state 13 The C NMR spectrum shows the following absolute differences in chemical shifts at a distance of 116.7 ppm ± 2 ppm from the reference peak: 96.11 ppm, 74.31 ppm, 19.21 ppm, 5.49 ppm, 14.29 ppm and 48.78 ppm ± 0.1 ppm; (f) Solid state, essentially as shown in Figures 16a, 16b or 16c 13 C NMR spectrum; and (g) A combination of two or more of a, b, c, d, e and f.

3. The crystalline brevicornuate hydrochloride as described in any one of claims 1 or 2, characterized in that: An X-ray powder diffraction pattern having peaks at 17.3°2θ, 21.5°2θ, and 25.7°2θ±0.2°2θ, and also having one, two, three, four, or five additional peaks selected from 7.2°2θ, 16.4°2θ, 19.5°2θ, 22.4°2θ, and 24.7°2θ±0.2°2θ.

4. The crystalline brevicornuate hydrochloride as described in claim 1 or 2, characterized in that: An X-ray powder diffraction pattern having peaks at 7.2°2θ, 16.4°2θ, 19.5°2θ, 22.4°2θ and 24.7°2θ±0.2°2θ, and also having one, two, three or four additional peaks selected from 14.3°2θ, 14.9°2θ, 25.7°2θ and 27.2°2θ±0.2°2θ.

5. The crystalline brevicornuate hydrochloride as described in claim 1, 2, 3 or 4, characterized in that: X-ray powder diffraction pattern with peaks at 7.2°2θ, 14.3°2θ, 14.9°2θ, 16.4°2θ, 19.5°2θ, 22.4°2θ, 24.7°2θ, 25.7°2θ and 27.2°2θ.

6. The crystalline brevicornuate hydrochloride according to any one of claims 1, 2, 3, 4 or 5, characterized in that: X-ray powder diffraction pattern with peaks at 7.2°2θ, 14.3°2θ, 14.9°2θ, 16.4°2θ, 17.3°2θ, 19.5°2θ, 21.5°2θ, 22.4°2θ, 24.7°2θ, 25.7°2θ and 27.2°2θ.

7. The crystalline brevicornuate hydrochloride according to any one of claims 1, 2, 3, 4, 5 or 6, further characterized by an X-ray powder diffraction pattern with no peaks at 2.0°2θ to 3.0°2θ ± 0.2°2θ.

8. The crystalline brevicornuate hydrochloride according to any one of claims 1, 2, 3, 4, 5, 6 and 7, further characterized by an X-ray powder diffraction pattern with no peaks at 4.0°2θ to 6.5°2θ ± 0.2°2θ.

9. The crystalline brevicornuate hydrochloride according to any one of claims 1, 2, 3, 4, 5, 6, 7 or 8, further characterized by an X-ray powder diffraction pattern with no peaks at 8.0°2θ to 10.5°2θ ± 0.2°2θ.

10. The crystalline brevicornuate hydrochloride according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8 or 9, further characterized by an X-ray powder diffraction pattern with no peaks at 11.5°2θ to 13.0°2θ ± 0.2°2θ.

11. The crystalline brevicornuate hydrochloride according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, characterized in that: It is in anhydrous crystal form.

12. The crystalline brevicornuate hydrochloride as described in claim 1, specified as BR3 type, characterized in that: Select from one or more of the following data: (a) X-ray powder diffraction pattern with peaks at 12.8°2θ, 15.4°2θ and 18.9°2θ±0.2°2θ±0.2°2θ; (b) X-ray powder diffraction pattern with peaks at 16.1°2θ, 17.4°2θ, 22.6°2θ, 25.3°2θ and 27.8°2θ±0.2°2θ±0.2°2θ; (b) X-ray powder diffraction pattern as shown in Figure 9; (c) Solid-state products having peaks at 22.7 ppm, 28.4 ppm, 59.3 ppm, 66.3 ppm, 119.5 ppm, and 155.3 ppm ± 0.2 ppm 13 C NMR spectrum; (d) Solid state 13 The C NMR spectrum shows the following absolute difference in chemical shift from the reference peak at 116.7 ppm ± 2 ppm: 94.01ppm, 88.31ppm, 50.41ppm, 48.78ppm, 2.79ppm and 38.59ppm±0.1ppm; (e) Solid state, essentially as shown in Figures 17a, 17b or 17c 13 C NMR spectrum; and (f) A combination of two or more of a, b, c, d and e.

13. The crystalline brevicornuate hydrochloride according to any one of claims 1 or 12, characterized in that: An X-ray powder diffraction pattern having peaks at 12.8°2θ, 15.4°2θ, and 18.9°2θ±0.2°2θ, and also having one, two, three, four, or five additional peaks selected from 16.1°2θ, 17.4°2θ, 22.6°2θ, 25.3°2θ, and 27.8°2θ±0.2°2θ.

14. The crystalline brevicornuate hydrochloride as described in claim 1 or 12, characterized in that: An X-ray powder diffraction pattern having peaks at 16.1°2θ, 17.4°2θ, 22.6°2θ, 25.3°2θ, and 27.8°2θ±0.2°2θ, and also having one, two, three, four, or five additional peaks selected from 19.8°2θ, 20.7°2θ, 21.8°2θ, 23.7°2θ, and 24.0°2θ±0.2°2θ.

15. The crystalline brevicornuate hydrochloride according to claim 1, 12 or 14, characterized in that: X-ray powder diffraction pattern with peaks at 16.1°2θ, 17.4°2θ, 19.8°2θ, 20.7°2θ, 21.8°2θ, 22.6°2θ, 23.7°2θ, 24.0°2θ, 25.3°2θ and 27.8°2θ±0.2°2θ.

16. The crystalline brevicornuate hydrochloride according to any one of claims 1, 12, or 13, characterized in that: X-ray powder diffraction pattern with peaks at 12.8°2θ, 15.4°2θ, 16.1°2θ, 17.4°2θ, 18.9°2θ, 19.8°2θ, 20.7°2θ, 21.8°2θ, 22.6°2θ, 23.7°2θ, 24.0°2θ, 25.3°2θ and 27.8°2θ±0.2°2θ.

17. The crystalline brevicornuate hydrochloride according to any one of claims 1, 12, 13, 14, 15 or 16, characterized in that: It is in anhydrous crystal form.

18. The crystalline brevicornuate hydrochloride according to any one of claims 2 to 17, characterized in that: 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 Brirazazin hydrochloride.

19. The crystalline brevicornuate hydrochloride according to any one of claims 1 to 18, characterized in that: 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 brurazazin hydrochloride.

20. A pharmaceutical composition, characterized in that: It comprises crystalline brurazazin hydrochloride according to any one of claims 1 to 19.

21. The use of crystalline bromerazine hydrochloride according to any one of claims 1 to 19 in the preparation of pharmaceutical compositions and / or pharmaceutical formulations, preferably wherein the pharmaceutical formulation is an oral formulation.

22. A pharmaceutical preparation, characterized in that: The pharmaceutical composition comprises crystalline bromerazine hydrochloride according to any one of claims 1 to 19 or according to claim 20, and at least one pharmaceutically acceptable excipient.

23. A method for preparing a pharmaceutical preparation according to claim 22, characterized in that: include: The crystalline brenrazacin hydrochloride according to any one of claims 1 to 19 or the pharmaceutical composition according to claim 20 is combined with at least one pharmaceutically acceptable excipient.

24. Use of a crystalline bromerazine hydrochloride according to any one of claims 1 to 19, a pharmaceutical composition according to claim 20, or a pharmaceutical preparation according to claim 22, characterized in that: It is used as a drug.

25. Use of a crystalline bromerazine hydrochloride according to any one of claims 1 to 19, a pharmaceutical composition according to claim 20, or a pharmaceutical preparation according to claim 22, characterized in that: It is used to treat schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary hypertension.

26. A treatment method, characterized in that: This includes administering to a subject requiring treatment a therapeutically effective amount of crystalline bromerazine hydrochloride according to any one of claims 1 to 19, the pharmaceutical composition according to claim 20, or the pharmaceutical preparation according to claim 22.

27. Use of a crystalline bromerazine hydrochloride according to any one of claims 2 to 19, a pharmaceutical composition according to claim 20, or a pharmaceutical preparation according to claim 22, characterized in that: This is used to prepare drugs for the treatment of schizophrenia, schizoaffective disorder, idiopathic pulmonary fibrosis, and pulmonary hypertension.

28. Use of crystalline bromerazine hydrochloride according to any one of claims 2 to 19, characterized in that: Used to prepare another solid form of brurazacin hydrochloride, or another brurazacin salt or its solid form.

Images