WO2021025969A1

WO2021025969A1 - Solid state forms of berotralstat

Info

Publication number: WO2021025969A1
Application number: PCT/US2020/044380
Authority: WO
Inventors: Anantha Rajmohan MUTHUSAMY; Sundara Lakshmi Kanniah; Vadivelan Rengasamy; Kirti MITTAL
Original assignee: Teva Pharmaceuticals International Gmbh; Teva Pharmaceuticals Usa, Inc.
Priority date: 2019-08-02
Filing date: 2020-07-31
Publication date: 2021-02-11

Abstract

The present disclosure relates to solid state forms of Berotralstat, pharmaceutically acceptable salts thereof, particularly Berotralstat dihydrochloride, processes for preparation thereof and pharmaceutical compositions thereof.

Description

SOLID STATE FORMS OF BEROTRALSTAT

FIELD OF THE INVENTION

[0001] The present disclosure relates to solid state forms of Berotralstat, pharmaceutically acceptable salts thereof, particularly Berotralstat dihydrochloride, processes for preparation thereof and pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION

[0002] Berotralstat has the chemical name l-[3-(aminomethyl)phenyl]-N-(5-{(R)-(3- cyanophenyl)[(cyclopropylmethyl)amino]methyl}-2-fluorophenyl)-3-(trifluoromethyl)-lH- pyrazole-5-carboxamide. Berotralstat has the following chemical structure:

[0003] Berotralstat is being developed for the treatment and prevention of hereditary angioedema.

[0004] Berotralstat is disclosed in International Publication No. WO 2015/134998. International Publication No. WO 2015/134998 discloses the preparation of Berotralstat dihydrochloride as a white solid by employing hydrogen chloride and methanol.

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

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

[0007] Discovering new solid state forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life.

[0008] For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Berotralstat.

SUMMARY OF THE INVENTION

[0009] The present disclosure relates to solid state forms of Berotralstat, its pharmaceutically acceptable salts thereof, particularly Berotralstat dihydrochloride, processes for preparation thereof, and pharmaceutical compositions comprising these solid state forms.

[0010] In embodiments, the present disclosure provides Berotralstat salt and crystalline forms thereof. In embodiments, the present disclosure provides crystalline forms of Berotralstat dihydrochloride designated as Form Bl, Form B2, Form B3 and/or Form B4 (defined herein). [0011] The present disclosure also provides uses of the solid state forms of Berotralstat and salts thereof, including Berotralstat dihydrochloride of the present disclosure, for preparing other solid state forms of Berotralstat and/or Berotralstat co-crystals and/or salts, and their solid state forms thereof.

[0012] The present disclosure also provides solid state forms of Berotralstat and salts thereof, including Berotralstat dihydrochloride of the present disclosure, for uses in the preparation of other solid state forms of Berotralstat and/or Berotralstat co-crystals and/or salts, and their solid state forms thereof. [0013] The present disclosure further provides processes for preparing other solid state forms of Berotralstat and/or Berotralstat co-crystals and/or salts, including Berotralstat dihydrochloride of the present disclosure and their solid state forms thereof.

[0014] In another embodiment, the present disclosure encompasses the described solid state forms of Berotralstat and salts thereof, including Berotralstat dihydrochloride of the present disclosure, in the preparation of pharmaceutical compositions and/or formulations, optionally for the treatment of hereditary angioedema.

[0015] In another embodiment, the present disclosure encompasses uses of the described solid state form of Berotralstat and salts thereof, including Berotralstat dihydrochloride of the present disclosure, for the preparation of pharmaceutical compositions and/or formulations.

[0016] The present disclosure further provides pharmaceutical compositions comprising any one or a combination of the solid state form of Berotralstat and salts thereof, including Berotralstat dihydrochloride according to the present disclosure.

[0017] In yet another embodiment, the present disclosure encompasses pharmaceutical formulations comprising any one or a combination of the described solid state forms of Berotralstat and salts thereof, including Berotralstat dihydrochloride of the present disclosure and at least one pharmaceutically acceptable excipient.

[0018] The present disclosure encompasses processes to prepare said pharmaceutical formulations of Berotralstat and salts thereof, including Berotralstat dihydrochloride, comprising combining any one or a combination of the described solid state forms at least one pharmaceutically acceptable excipient.

[0019] The solid state forms defined herein as well as the pharmaceutical compositions or formulations of the solid state form of Berotralstat and salts thereof, including Berotralstat dihydrochloride, can be used as medicaments, particularly for the treatment of hereditary angioedema.

[0020] The present disclosure also provides methods of treating hereditary angioedema, comprising administering a therapeutically effective amount of any one or a combination of the described solid state forms, or at least one of the herein described pharmaceutical compositions or formulations, to a subject suffering from hereditary angioedema.

[0021] The present disclosure also provides uses of the solid state forms of Berotralstat and salts thereof, including Berotralstat dihydrochloride of the present disclosure or at least one of the above pharmaceutical compositions or formulations, for the manufacture of medicaments for treating hereditary angioedema. BRIEF DESCRIPTION OF THE FIGURES

[0022] Figure 1 shows an X-ray powder diffractogram (XRPD) of form B1 of Berotralstat Dihydrochloride.

[0023] Figure 2 shows an X-ray powder diffractogram (XRPD) of form B2 of Berotralstat Dihydrochloride.

[0024] Figure 3 shows an X-ray powder diffractogram (XRPD) of amorphous form of Berotralstat Dihydrochloride.

[0025] Figure 4 shows an X-ray powder diffractogram (XRPD) of form B3 of Berotralstat Dihydrochloride.

[0026] Figure 5 shows an X-ray powder diffractogram (XRPD) of form B4 of Berotralstat Dihydrochloride.

[0027] Figure 6a shows ¹³C solid state NMR spectrum of form B4 of Berotralstat Dihydrochloride (full scan).

[0028] Figure 6b shows ¹³C solid state NMR spectrum of form B4 of Berotralstat Dihydrochloride (at the range of 0-100 ppm).

[0029] Figure 6c shows ¹³C solid state NMR spectrum of form B4 of Berotralstat Dihydrochloride (at the range of 100-200 ppm).

DETAILED DESCRIPTION OF THE INVENTION

[0030] The present disclosure relates to a solid state form of Berotralstat, its pharmaceutically acceptable salts thereof, particularly Berotralstat dihydrochloride, processes for preparation thereof and pharmaceutical compositions comprising this solid state form.

[0031] In embodiments, the present disclosure provides Berotralstat salt and crystalline forms thereof. In embodiments, the present disclosure provides crystalline form of Berotralstat dihydrochloride designated as Form Bl; Form B2, Form B3 and/or Form B4 (defined herein). [0032] The disclosure also relates to the conversion of the described solid state form of Berotralstat and salts thereof, including Berotralstat dihydrochloride, to other solid state forms of Berotralstat or Berotralstat co-crystals and/or salts.

[0033] The solid state form of Berotralstat and salts thereof, including Berotralstat dihydrochloride of the present disclosure, may have advantageous properties selected from at least one of: chemical or polymorphic purity, flowability, solubility, wettability, low hygroscopicity, low solvent (e.g. water) content, dissolution rate, bioavailability, morphology or crystal habit, stability - such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvents and advantageous processing and handling characteristics such as compressibility, or bulk density.

[0034] A crystal form may be referred to herein as being characterized by graphical data "as depicted in" a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called "fingerprint") which can not necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Berotralstat and salts thereof, including Berotralstat dihydrochloride referred to herein as being characterized by graphical data "as depicted in" a Figure will thus be understood to include any crystal forms of the Berotralstat and salts thereof, including Berotralstat dihydrochloride, characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0035] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to mean that the solid state forms form Bl, form B2, form B3 and form B4 of Berotralstat dihydrochloride contains about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or 0% of any other forms of the subject compound as measured, for example, by XRPD. Thus, the solid state forms form Bl, form B2, form B3 and form B4 of Berotralstat dihydrochloride described herein as is substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or 100% of the subject solid state form of Berotralstat dihydrochloride.

[0036] As used herein, unless stated otherwise, XRPD peaks reported herein are optionally measured using CuK _a radiation, l = 1.5418 A.

[0037] As used herein, the term "isolated" in reference to solid state forms of Berotralstat and salts thereof, including Berotralstat dihydrochloride of the present disclosure, corresponds to solid state form of Berotralstat and salts thereof, including Berotralstat dihydrochloride that is physically separated from the reaction mixture in which it is formed.

[0038] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to "room temperature", often abbreviated "RT." This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, about 22°C to about 27°C, or about 25°C.

[0039] As used herein, unless indicated otherwise, the term “elevated temperature” refers to any temperature above room temperature, preferably above about 20°C, and more preferably above about 25°C.

[0040] A process or step may be referred to herein as being carried out "overnight." This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, about 10 to about 18 hours, or about 16 hours.

[0041] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline Berotralstat and salts thereof, including Berotralstat dihydrochloride relates to a crystalline Berotralstat and salts thereof, including Berotralstat dihydrochloride which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form does not contain more than 1% (w/w) of either water or organic solvents as measured for example by TGA.

[0042] The term "solvate", as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0043] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of "volumes" or "vol" or "V." For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term "v/v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding methyl tert-butyl ether (MTBE) (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of MTBE was added.

[0044] As used herein, the term "reduced pressure" refers to a pressure of from about 10 pbar to 50 mbar.

[0045] The present disclosure includes a crystalline form of Berotralstat dihydrochloride designated as Form Bl. The crystalline Form B1 of Berotralstat dihydrochloride can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.2, 9.1, 18.1, 21.1, 21.8 and 22.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1; and combinations of these data.

[0046] Crystalline Form Blof Berotralstat dihydrochloride may be further characterized by the XRPD pattern having peaks at 5.2, 9.1, 18.1, 21.1, 21.8 and 22.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, or three additional peaks selected from 9.8, 23.6 and 24.9 degrees two theta ± 0.2 degrees two theta.

[0047] Crystalline Form Blof Berotralstat dihydrochloride may alternatively be characterized by the XRPD pattern having peaks at 5.2, 9.1, 9.8, 18.1, 21.1, 21.8, 22.6, 23.6, and 24.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0048] Crystalline Form Bl of Berotralstat dihydrochloride may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 5.2, 9.1, 18.1, 21.1, 21.8 and 22.6 degrees 2-theta ± 0.2 degrees 2-theta and an XRPD pattern as depicted in Figure 1.

[0049] In one embodiment of the present disclosure, crystalline Form Bl of Berotralstat dihydrochloride may be characterized as mixture of hydrate and acetonitrile solvate.

[0050] In one embodiment of the present disclosure, crystalline Form Bl of Berotralstat dihydrochloride may be characterized as a hydrate.

[0051] In one embodiment of the present disclosure, Form Bl of Berotralstat dihydrochloride is isolated.

[0052] In second embodiment Berotralstat dihydrochloride Form Bl can be isolated by crystallization.

[0053] The present disclosure includes a crystalline form of Berotralstat dihydrochloride designated as Form B2. The crystalline Form B2 of Berotralstat dihydrochloride can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 10.9, 14.2, 23.2, 24.5 and 33.2 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2; and combinations of these data. [0054] Crystalline Form B2 of Berotralstat dihydrochloride may be further characterized by the XRPD pattern having peaks at 10.9, 14.2, 23.2, 24.5 and 33.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, or four additional peaks selected from 8.9 19.7, 29.6 and 30.3 degrees two theta ± 0.2 degrees two theta.

[0055] Crystalline Form B2 of Berotralstat dihydrochloride may alternatively be characterized by the XRPD pattern having peaks at 8.9, 10.9, 14.2, 19.7, 23.2, 24.5, 29.6, 30.3, and 33.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0056] Crystalline Form B2 of Berotralstat dihydrochloride may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 10.9, 14.2, 23.2, 24.5 and 33.2 degrees 2-theta ± 0.2 degrees 2-theta and an XRPD pattern as depicted in Figure 2.

[0057] In one embodiment of the present disclosure, crystalline Form B2 of Berotralstat dihydrochloride may be characterized as a hydrate.

[0058] In one embodiment of the present disclosure, Form B2 of Berotralstat dihydrochloride is isolated.

[0059] In second embodiment Berotralstat dihydrochloride Form B2 can be isolated by crystallization.

[0060] The present disclosure includes a crystalline form of Berotralstat dihydrochloride designated as Form B3. The crystalline Form B3 of Berotralstat dihydrochloride can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.5, 8.7, 10.1, 15.3, 20.7 and 22.1 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 4; and combinations of these data.

[0061] Crystalline Form B3 of Berotralstat dihydrochloride may be further characterized by the XRPD pattern having peaks at 5.5, 8.7, 10.1, 15.3, 20.7 and 22.1 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, or four additional peaks selected from 9.2, 14.1, 21.2, 21.6 degrees two theta ± 0.2 degrees two theta.

[0062] Crystalline Form B3 of Berotralstat dihydrochloride may alternatively be characterized by the XRPD pattern having peaks at 5.5, 8.7, 9.2, 10.1, 14.1, 15.3, 20.7, 21.2,

21.6, and 22.1 degrees 2-theta.

[0063] Crystalline Form B3 of Berotralstat dihydrochloride may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 5.5, 8.7, 10.1, 15.3, 20.7 and 22.1 degrees 2-theta ± 0.2 degrees 2-theta and an XRPD pattern as depicted in Figure 4. [0064] In one embodiment of the present disclosure, crystalline Form B3 of Berotralstat dihydrochloride may be characterized as a hydrate. Typically, the water content in crystalline Form B3 of Berotralstat dihydrochloride is from about 2 % to about 6 % (w/w).

[0065] In one embodiment of the present disclosure, Form B3 of Berotralstat dihydrochloride is isolated.

[0066] The present disclosure includes a crystalline form of Berotralstat dihydrochloride designated as Form B4. The crystalline Form B4 of Berotralstat dihydrochloride can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 16.4, 20.6, 21.0, 21.4, 22.8 and 25.8 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 5; a solid state ¹³C NMR spectrum having peaks at 116.1, 132.0, 135.7, 155.5 and 157.5 ppm ± 0.2 ppm; a solid state ¹³C NMR spectrum having the following chemical shift absolute differences from a reference peak at 60.1 ppm ± 2 ppm of 56.0, 71.9, 75.6, 95.4 and 97.4 ppm ± 0.1 ppm; a solid state ¹³C NMR spectrum substantially as depicted in Figures 6a, 6b or 6c; and combinations of these data.

[0067] Crystalline Form B4 of Berotralstat dihydrochloride may be further characterized by the XRPD pattern having peaks at 16.4, 20.6, 21.0, 21.4, 22.8 and 25.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, or four additional peaks selected from 12.3,

14.1, 15.6 and 23.5 degrees two theta ± 0.2 degrees two theta.

[0068] Crystalline Form B4 of Berotralstat dihydrochloride may alternatively be characterized by the XRPD pattern having peaks at 12.3, 14.1, 15.6, 16.4, 20.6, 21.0, 21.4, 22.8, 23.5, and 25.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0069] Crystalline Form B4 of Berotralstat dihydrochloride according to any of the described embodiments may be further characterized by an XRPD pattern having an absence of any one, two, three or four peaks at: 17.1, 19.8, 25.2 and 26.5 degrees 2-theta ± 0.2 degrees 2-theta, and/or an absence of any one, two or three peaks at: 12.6, 13.7 and 33.4 degrees 2-theta ± 0.2 degrees 2- theta.

[0070] Crystalline Form B4 of Berotralstat dihydrochloride according to any of the described embodiments may be further characterized by an XRPD pattern having an absence of any one, two, three or four peaks at: 17.1, 19.8, 25.2 and 26.5 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form B4 of Berotralstat dihydrochloride according to any of the described embodiments may be further characterized by an XRPD pattern having an absence of a peak at 19.8 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form B4 of Berotralstat dihydrochloride according to any of the described embodiments may be further characterized by an XRPD pattern having an absence of peaks at 19.8 and 25.2 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form B4 of Berotralstat dihydrochloride according to any of the described embodiments may be further characterized by an XRPD pattern having an absence of peaks at 19.8, 25.2 and 26.5 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form B4 of Berotralstat dihydrochloride according to any of the described embodiments may be further characterized by an XRPD pattern having an absence of peaks at 17.1, 19.8, 25.2, and 26.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0071] Crystalline Form B4 of Berotralstat dihydrochloride according to any of the described embodiments may be further characterized by an XRPD pattern having an absence of any one, two or three peaks at: 12.6, 13.7 and 33.4 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form B4 of Berotralstat dihydrochloride according to any of the described embodiments may be further characterized by an XRPD pattern having an absence of a peak at 12.6 or 13.7 degrees 2- theta ± 0.2 degrees 2-theta, or by an absence of peaks at 12.6 and 13.7 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form B4 of Berotralstat dihydrochloride according to any of the described embodiments may be further characterized by an XRPD pattern having an absence of peaks at 12.6, 13.7 and 33.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0072] Crystalline Form B4 of Berotralstat dihydrochloride may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 16.4, 20.6, 21.0, 21.4, 22.8 and 25.8 degrees 2-theta ± 0.2 degrees 2-theta and an XRPD pattern as depicted in Figure 5.

[0073] In one embodiment of the present disclosure, crystalline Form B4 of Berotralstat dihydrochloride may be characterized as hydrate. In embodiments, Form B4 of Berotralstat dihydrochloride may be a monohydrate or a dihydrate. Typically, the water content in Crystalline Form B4 of Berotralstat dihydrochloride is from about 3 % to about 7.5 % (w/w), as measured by typical method such as TGA.

[0074] In one embodiment of the present disclosure, Form B4 of Berotralstat dihydrochloride is isolated.

[0075] In second embodiment Berotralstat dihydrochloride Form B4 can be isolated by crystallization.

[0076] The present disclosure further comprises a process for preparation of Form B4, comprising crystallization of Berotralstat dihydrochloride from water. The crystallization may comprise providing a solution of the Berotralstat dihydrochloride in water and cooling the solution to obtain a solid. The process for preparing crystalline Form B4 of Berotralstat dihydrochloride may further comprise isolating the said crystalline form. The isolation may be done, for example, by filtering the solid, for example by vacuum filtration; optionally washing; and drying.

[0077] In embodiments, the process includes the following steps:

(i) providing a mixture of Berotralstat dihydrochloride and water;

(ii) optionally heating the mixture;

(iii) cooling; and

(iv) optionally isolating Berotralstat dihydrochloride Form B4.

[0078] In any embodiment of the process, step (i) may be conducted at a temperature of about 18°C to about 40°C, or about 20°C to about 35°C , or about 25°C to about 30°C . In any embodiment of the process, the mixture may be heated. Step (ii) may comprise heating the mixture of Berotralstat dihydrochloride in water to a temperature of about 30°C to about 80°C, about 40°C to about 70°C, or about 50°C to about 70°C, or about 60°C. In any embodiment of this process, the water is typically used in an amount of 0.5 ml to about 10 ml, about 1 ml to about 10 ml, about 1 ml to about 5 ml, about 1 ml to about 3 ml, or about 1.0 to 2 ml or about 2 ml, per gram of Berotralstat dihydrochloride.

[0079] In any embodiment of the process, the solution may be cooled in step (ii), typically to a temperature of about -5°C to about 20°C , about -2°C to about 15°C , about 0°C to about 10°C, or about 0°C to about 5°C. The solution may be cooled over a period of about 5 minutes to 10 minutes, or about 10 minutes.

[0080] In any embodiment of the process, the cooled mixture may be optionally maintained, typically at the same temperature, for about 10 hours to about 20 hours, about 12 hours to about 18 hours or about 14 hours to about 16 hours.

[0081] The process may further include isolating the obtained form B4 of Berotralstat dihydrochloride, for example by vacuum filtration. In any embodiment of the process, the filtration under vacuum may be carried out at a temperature of about 5°C to about 45°C, about 10°C to about 40°C or about 15°C to about 35°C, or about 20°C to about 30°C, or about 25°C to about 30°C. Following isolation, the crystalline form B4 of Berotralstat dihydrochloride may be dried. The drying may be carried out during, e.g. filtration for the period of about 15 minutes to 1 hour, or about 20 minutes to about 30 minutes. Optionally or additionally, the form B4 of Berotralstat dihydrochloride may be dried under reduced pressure (such as in air tray dryer), typically at a temperature of about 20°C to about 60°C, about 25°C to about 55°C, about 30°C to about 50°C, or about 40°C. The drying may be carried out for any suitable time to remove the solvent, typically about 1 to about 10 hours, about 1.5 hours to about 8 hours, or about 2 hours to about 7 hours. [0082] In some embodiments, the isolated form B4 of Berotralstat dihydrochloride is dried under vacuum at a temperature of about 40°C, typically for a period of about 1 hour to about 8 hours, about 1 hour to about 5 hours, about 1 hour to about 3 hours, or about 2 hours.

[0083] The present disclosure further comprises a process for preparation of Form B4. The process may comprise crystallising Berotralstat dihydrochloride from a mixture, which may be a solution or a slurry, in a suitable solvent. Suitable solvents include dichloromethane, MTBE, or propyl acetate or toluene, optionally in combination with isopropanol. The process may comprise preparing Berotralstat dihydrochloride from Berotralstat free base in the suitable solvent. Thus, the mixture of Berotralstat dihydrochloride in this process may be prepared by reacting Berotralstat free base in the suitable solvent with HC1 (gas) in isopropanol (i.e. IPA-HCl). Typically about 1.8 to about 2.2 mole, or about 2 equivalents of HC1 is added. In embodiments, the HC1 (gas) in the isopropanol is about 5-20 % assay, or about 10-15% assay. In embodiments, about 0.5 ml to about 2 ml, about 0..8 ml to about 1.0 ml or about 0.8 ml to about 0.9 ml of IPA-HCl is added per g of Berotralstat free base.

[0084] Thus, this process may comprise:

(i) combining a mixture of Berotralstat in a suitable solvent with hydrogen chloride gas in isopropanol to form a reaction mixture;

(ii) optionally heating the reaction mixture;

(iii) optionally cooling the reaction mixture; and

(iv) optionally isolating Berotralstat dihydrochloride Form B4.

[0085] The process may comprise providing a mixture of the Berotralstat in the suitable solvent and adding HC1 in isopropanol (IPA-HCl) to form a mixture comprising Berotralstat dihydrochloride. The mixture of the Berotralstat in the suitable solvent may be in the form of a solution or a slurry. The process for preparing crystalline Form B4 of Berotralstat dihydrochloride may further comprise isolating the said crystalline form. The isolation may be done, for example, by filtering the solid, for example by vacuum filtration; optionally washing; and drying.

[0086] In any embodiment of the process, the mixture of Berotralstat in suitable solvent in step (i) may be prepared by combining Berotralstat in the suitable solvent, typically at a temperature of about 35°C to about 45°C, about 30°C to about 40°C, or about 25°C to about 30°C. In any embodiment of this process, the suitable solvent in step (i) may be dichloromethane, methyl tert-butyl ether MTBE, propyl acetate or toluene. The mixture may be in the form of a solution (e.g. with dichloromethane, MTBE and propyl acetate) or may be in the form of a slurry or suspension (e.g. with toluene). In any embodiment of this process, the suitable solvent in step (i) is typically used in an amount of about 5 ml to about 20ml, about 7 ml to about 15 ml, or about 10 ml, per gram of Berotralstat.

[0087] In any embodiment of this process, IPA-HCl in step (i) is typically used in an amount of about 1 mole eq. to 5 mole eq., about 1.5 m eq to about 3 mole eq, or about 2 mole eq. relative to Berotralstat free base. In any embodiment of the process, the mixture in step (ii) may be heated to a temperature of about 70°C to 80°C, or about 60°C to about 70°C, or about 50°C to about 60°C. The mixture may be stirred. In any embodiment, the mixture of step (ii) may be stirred at this temperature for period of about 2 hours to about 4 hours, or about 2 hours to about 3 hours.

[0088] In any embodiment of the process, the mixture may be cooled in step (iii), typically to a temperature of about 20°C to about 40°C, , or about 25°C to about 30°C. The mixture, comprising a suspension of Berotralstat dihydrochloride, may be maintained, typically at the same temperature, for about 12 hours to about 22 hours, about 15 hours to about 20 hours or about 17 hours to about 18 hours.

[0089] The process may further include isolating form B4 of Berotralstat dihydrochloride from the mixture, for example by vacuum filtration. In any embodiment of the process, the filtration under vacuum may be carried out at a temperature of about 5°C to about 45°C, about 10°C to about 40°C or about 15°C to about 35°C, or about 25°C to about 30°C. Following isolation, the crystalline form B4 of Berotralstat dihydrochloride may be dried. The drying may be carried out during e.g. filtration for the period of about 10 minutes to 1 hour, or about 15 minutes to about 30 minutes.

[0090] The process for preparing form B4 of Berotralstat dihydrochloride according to any embodiment described herein, may further comprise combining form B4 of Berotralstat dihydrochloride with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition or a pharmaceutical formulation.

[0091] The present disclosure also provides uses of the solid state forms of Berotralstat for preparing other solid state forms of Berotralstat and/or Berotralstat co-crystals and salts, and their solid state forms.

[0092] The present disclosure also provides solid state forms of Berotralstat and salts thereof including Berotralstat dihydrochloride of the present disclosure for uses in the preparation of other solid state forms of Berotralstat and/or co-crystals and salts, and their solid state forms. The present disclosure further encompasses processes for preparing other solid state forms of Berotralstat and salts thereof including Berotralstat dihydrochloride. The process includes preparing the solid state form and salts or co-crystal of the present disclosure, and converting it to other solid state forms of Berotralstat and/or Berotralstat co-crystals or salts.

[0093] In another embodiment, the present disclosure encompasses the above described solid state form of Berotralstat and salts thereof including Berotralstat dihydrochloride for use in the preparation of pharmaceutical compositions and/or formulations, optionally for the treatment of hereditary angioedema.

[0094] In another embodiment, the present disclosure encompasses the use of the above described solid state form of Berotralstat and salts thereof including Berotralstat dihydrochloride for the preparation of pharmaceutical compositions and/or formulations. The present disclosure also provides the solid state form of Berotralstat and salts thereof including Berotralstat dihydrochloride of the present disclosure for use in the preparation of pharmaceutical compositions and/or formulations.

[0095] The present disclosure further provides pharmaceutical compositions comprising any one or a mixture of the solid state form of Berotralstat, and salts thereof including Berotralstat dihydrochloride according to the present disclosure.

[0096] In yet another embodiment, the present disclosure encompasses pharmaceutical formulations comprising any one or a mixture of the solid state form of Berotralstat and salts thereof including Berotralstat dihydrochloride and at least one pharmaceutically acceptable excipient.

[0097] Pharmaceutical formulations of the present invention contain any one or a combination of the crystalline forms of Berotralstat and salts thereof including Berotralstat dihydrochloride of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[0098] Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0099] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch. [00100] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®), and starch.

[00101] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[00102] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. [00103] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[00104] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level. [00105] In liquid pharmaceutical compositions of the present disclosure, the active ingredient 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.

[00106] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[00107] Liquid pharmaceutical compositions of the present disclosure can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.

[00108] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[00109] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[00110] According to the present disclosure, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[00111] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present disclosure is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

[00112] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs. [00113] The dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.

[00114] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[00115] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.

[00116] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.

[00117] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

[00118] A capsule filling of the present invention can comprise any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[00119] In embodiments, a pharmaceutical formulation of Berotralstat is formulated for administration to a mammal, such as a human. Berotralstat can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection. The formulation can contain one or more solvents. A suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[00120] The present disclosure encompasses processes to prepare said formulations of Berotralstat and salts thereof including Berotralstat dihydrochloride comprising combining any one or a mixture of the solid state form of Berotralstat and salts thereof including Berotralstat dihydrochloride and at least one pharmaceutically acceptable excipient.

[00121] The solid state forms of Berotralstat and salts thereof including Berotralstat dihydrochloride as defined herein, as well as the pharmaceutical compositions or formulations thereof, at least can be used as medicaments, particularly for the treatment of hereditary angioedema.

[00122] The present disclosure also provides methods of treating of hereditary angioedema; comprising administering a therapeutically effective amount of any one or a mixture of the solid state form of Berotralstat and salts thereof including Berotralstat dihydrochloride of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from hereditary angioedema, or otherwise in need of the treatment.

[00123] The present disclosure also provides use of the solid state form of Berotralstat and salts thereof including Berotralstat dihydrochloride of the present disclosure, or at least one of the above pharmaceutical compositions or formulations for the manufacture of a medicament for treating hereditary angioedema.

[00124] Having described the disclosure with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The disclosure is further illustrated by reference to the following examples describing in detail the preparation of the composition and methods of use of the disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the disclosure.

Analytical Methods

X-ray powder diffraction method:

[00125] X-ray diffraction was performed on X-Ray powder diffractometer:

Bruker D8 Advance; CuK radiation (l = 1.5418 A); Lynx eye detector; laboratory temperature 22-25 °C; PMMA specimen holder ring. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.

Measurement parameters: Scan range: 2 - 40 degrees 2-theta; Scan mode: continuous; Step size: 0.05 degrees;

Time per step: 0.5 s; Sample spin: 30 rpm; Sample holder: PMMA specimen holder ring.

All X-Ray Powder Diffraction peak values are calibrated with regard to standard silicon spiking in the sample.

Solid state ¹³C-NMR method:

[00126] Solid-state NMR spectra were measured at 11.7 T using a Bruker Avance III HD 500 US/WB NMR spectrometer (Karlsruhe, Germany, 2013) with 3.2 mm probehead. The 13C CP/MAS NMR spectra employing cross-polarization were acquired using the standard pulse scheme at spinning frequency of 15 kHz and a room temperature (298 K). The recycle delay was 8 s and the cross-polarization contact time was 2 ms. The 13C scale was referenced to a-glycine (176.03 ppm for 13C). Frictional heating of the spinning samples was offset by active cooling, and the temperature calibration was performed with Pb(N03)2.The NMR spectrometer was completely calibrated and all experimental parameters were carefully optimized prior the investigation. Magic angle was set using KBr during standard optimization procedure and homogeneity of magnetic field was optimized using adamantane sample (resulting line-width at half-height Avi/2 was less than 3.5 Hz at 250 ms of acquisition time).

Procedure for Thermo Gravimetric Analysis (TGA)

[00127] Thermogravimetric analysis was conducted on a TA instrument Q500 thermogravimetric analyzer. About 5-15 mg sample was placed into a tared TGA crucible and placed into a TGA furnace. The furnace was heated under nitrogen at a heating rate of 10°C/min up to 250°C.

EXAMPLES

[00128] The starting material Berotralstat free base may be obtained according to reference example 1 or by any procedure described in the art.

Reference Example 1:

Preparation of Berotralstat free base

[00129] tert-butyl(R)-(3-(5-((5-((3-cyanophenyl)((cyclopropylmethyl)amino)methyl)-2- fluorophenyl)carbamoyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzyl)carbamate (6.9 gram, 0.0104 mole) and methanol (7 mL) were taken into the flask and stirred to get clear solution at temperature of about 25-30°C, then cooled to temperature of about 8-10°C. Methanolic HC1 (20.5g, 0.033mole) was slowly added over the period of 30 minutes, and stirred for the period of 1 to 3 hours at temperature of about 20-25°C. After completion of reaction, Reaction mass was cooled to 5-10°C, and dichloromethane (50mL) was added and cooled to 5-10°C. Aqueous ammonia solution (10 mL) was slowly added till 8-9 pH was obtained and stirred for 15-30 minutes at 5-10°C. The temperature was raised to 20-25°C and stirred for 15-30 minutes. The layers were separated and organic layer was distilled under vacuum at temperature of about 40- 45°C. The obtained solid was dried under vacuum at 40°C to give Berotralstat (5.45 gram). (Yield: 92.94%; HPLC Purity >98%)

Example 1: Preparation of Berotralstat dihydrochloride Form B1

[00130] Berotralstat (37.6 grams, 0.067 mole) and acetonitrile (370 mL) were taken into the reactor and stirred at the temperature of about 25-30°C to get clear solution. The obtained clear solution was cooled to temperature of about 22°C. Isopropyl alcohol hydrochloride (41 mL, 2.05 mole) was slowly added to the clear solution over a period of about 60 minutes, and stirred over a period of about 1 hour at temperature of about 20-25°C and a solid was formed. The obtained solid was filtered; then washed with acetonitrile (75 mL) followed by MTBE (200 mL). The washed solid was dried in VTD (Vacuum tray drier) under vacuum at temperature of about 20- 25°C for 4 hours. Crystalline Berotralstat dihydrochloride was obtained (0.05 gram). A sample was analyzed by XRPD. Form B1 was obtained. An XRPD pattern is shown in Figure 1.

Example 2: Preparation of Berotralstat dihydrochloride Amorphous [00131] Berotralstat (0.5 grams) was added into methanol (62.5 ml) at temperature of 25-30°C and was stirred for 10 minutes at the same temperature to obtain a clear solution. 0.95 ml of 30% aqueous hydrochloride is added to the clear solution and stirred for 10 minutes at same temperature and the solvent was distilled off under vacuum (less than 10 mbar) at temperature of about 25-30°C for 30 minutes to 35 minutes. The temperature was raised to about 60°C in 15 minutes to 20 minutes and distillation was continued at temperature of about 60°C for 10 minutes and a solid was obtained. The obtained solid was dried under vacuum at temperature of about 60°C for 30 minutes. A sample was analyzed by XRPD. Berotralstat dihydrochloride amorphous was obtained (0.05 gr). An XRPD pattern is shown in Figure 3.

Example 3: Preparation of Berotralstat dihydrochloride Form B2 [00132] Berotralstat dihydrochloride (Amorphous) 0.08 grams was added in 0.8 ml Acetonitrile into 2 ml vial at temperature of about 25-30°C. The temperature was slowly raised to about 60°C over a period of about 10 minutes to get the clear solution. The clear solution was crystallized spontaneously at the temperature of about 60°C while stirring. Then the vial was kept open for solvent evaporation at the temperature of about 25-30°C for the period of 18-20 hours, solid was scratched and dried in air tray drier at temperature of about 50°C for 3 hours. The solid was further dried at temperature of about 80°C of 18 hours in air tray drier and further dried at temperature of about 100°C for 5 hours in air tray drier. Crystalline Berotralstat dihydrochloride was obtained. A sample was analyzed by XRPD. Form B2 was obtained (0.05gm). An XRPD pattern is shown in Figure 2.

Example 4: Preparation of Berotralstat dihydrochloride Form B2 [00133] Berotralstat dihydrochloride (Amorphous) 0.1 grams was added in 1 ml acetonitrile into 2 ml vial at temperature of about 25-30°C. The temperature was slowly raised to about 60°C over a period of about 10 minutes to get the clear solution. The clear solution was crystallized spontaneously at the temperature of about 60°C and stirred for 10-20 minutes at same temperature. The obtained solid was filtered under vacuum at temperature of about 25-30°C and kept under suction for about 10 minutes at temperature of about 20-30°C, further dried at temperature of about 50°C for 1 hours in air tray dryer and further dried at temperature of about 100°C temperature for 5 hours in air tray dryer. Crystalline Berotralstat dihydrochloride was obtained. A sample was analyzed by XRPD. Form B2 was obtained (0.07 gram).

Example 5: Preparation of Berotralstat dihydrochloride Form B2 [00134] Berotralstat dihydrochloride (Amorphous) 0.3 grams was added in 3 ml acetonitrile into 5ml vial at 25-30°C. The temperature was slowly raised to about 60°C over a period of about 10 minutes to get the clear solution. The clear solution was cooled to temperature of about 0-5°C in 10 minutes under stirring, sticky mass was observed and the sticky mass was heated to temperature of about 60°C in 5 minutes and maintained for 20-30 minutes under stirring at same temperature. The solid was crystallized at temperature of about 60°C and stirred for 10-20 minutes at same temperature. The obtained solid was filtered under vacuum at temperature of about 25-30°C and kept under suction for about 30 minutes at temperature of about 20-30°C and further dried in vacuum tray dryer at temperature of about 20-30°C for 2 hours. Crystalline Berotralstat dihydrochloride was obtained (0.2 grams). A sample was analyzed by XRPD. Form B2 was obtained (0.07 grams).

Example 6: Preparation of Berotralstat dihydrochloride Form B3

[00135] Berotralstat dihydrochloride (Amorphous) about 1.6 to 2.0 grams was kept at temperature of about 60°C and Relative Humidity of about 95% to about 100% for the period of about 1 to 3 days. Crystalline Berotralstat dihydrochloride was obtained. A sample was analyzed by XRPD. Form B3 was obtained. An XRPD pattern is shown in Figure 4.

Example 7: Preparation of Berotralstat dihydrochloride Form B2

[00136] Berotralstat dihydrochloride 0.1 grams was dissolved in water at temperature of about 50°C to about 70°C and stirred for a period of about 10 minutes to 15 minutes at temperature of about 50°C to about 70°C. The obtained clear solution was cooled to temperature of about 25°C to about 30°C in a period of about 2 hours and kept for additional 23 hours to 41 hours at temperature of about 25°C to about 30°C with stirring. The obtained solid was filtered under vacuum at temperature of about 25°C to about 30°C and was dried under suction for a period of about 30 minutes. Crystalline Berotralstat dihydrochloride was obtained. A sample was analyzed by XRPD. Form B2 was obtained. The same procedure can be performed by using propyl alcohol or 1 -Butanol instead of water.

Example 8: Preparation of Berotralstat dihydrochloride Form B2

[00137] Berotralstat dihydrochloride (Form Bl) 0.07 grams was added in 1 ml of chloroform at a temperature of about 20 °C to about 30°C into 2ml vial and slurry was obtained. The obtained slurry was stirred for period of about 24 hours to about 7 days at a temperature of about 20 °C to about 30°C. The obtained solid was filtered under nitrogen blanket under vacuum at a temperature of about 20°C to about 30°C and was dried under suction for period of about 20 minutes. Crystalline Berotralstat dihydrochloride is obtained. A sample was analyzed by XRPD. Form B2 was obtained. The same procedure can be performed by using Isopropyl acetate or Nitromethane instead of Chloroform.

Example 9: Preparation of Berotralstat dihydrochloride Form B2

[00138] Berotralstat dihydrochloride (Form Bl) 0.07 grams was added in 1 ml of Ethyl

Formate at a temperature of about 20 °C to about 30°C into 2 ml vial and slurry was obtained.

The obtained slurry was stirred for period of about 24 hours to about 7 days at a temperature of about 60 °C to about 65°C. The obtained solid was filtered under nitrogen blanket under vacuum at a temperature of about 20°C to about 30°C and was dried under suction for period of about 20 minutes. Crystalline Berotralstat dihydrochloride is obtained. A sample was analyzed by XRPD. Form B2 was obtained. The same procedure can be performed by using Isopropyl acetate or Propionitrile instead of Ethyl Formate. Example 10: Preparation of Berotralstat dihydrochloride Form B2

[00139] Berotralstat dihydrochloride (Form Bl) 0.07 grams was added in 1 ml of Ethyl Formate at a temperature of about 20 °C to about 30°C into 2 ml vial and slurry was obtained. The obtained slurry was stirred for period of about 7 days at a temperature of about 0 °C to about 5°C. The obtained solid was filtered under nitrogen blanket under vacuum at a temperature of about 20°C to about 30°C and was dried under suction for period of about 20 minutes.

Crystalline Berotralstat dihydrochloride was obtained. A sample was analyzed by XRPD. Form B2 was obtained. The same procedure can be done by using Nitrom ethane instead of Ethyl Formate.

Example 11: Preparation of Berotralstat dihydrochloride Form B2 [00140] Berotralstat dihydrochloride (Amorphous) 0.07 grams was added in 1 ml of Ethyl Formate at a temperature of about 20 °C to about 30°C into 2 ml vial and slurry was obtained. The obtained slurry was stirred for period of about 24 hours to about 7 days at a temperature of about 20 °C to about 30°C. The obtained solid was filtered under nitrogen blanket under vacuum at a temperature of about 20°C to about 30°C and was dried under suction for period of about 20 minutes. Crystalline Berotralstat dihydrochloride was obtained. A sample was analyzed by XRPD. Form B2 was obtained. The same procedure can be done by using Nitromethane or Propionitrile instead of Ethyl Formate.

Example 12: Preparation of Berotralstat dihydrochloride Form B2 [00141] Berotralstat dihydrochloride (Amorphous) 0.07 grams was added in 1 ml of Ethyl Formate at a temperature of about 20 °C to about 30°C into 2 ml vial and slurry was obtained. The obtained slurry was stirred for period of about 24 hours to about 7 days at a temperature of about 60 °C to about 65°C. The obtained solid was filtered under nitrogen blanket under vacuum at a temperature of about 20°C to about 30°C and was dried under suction for period of about 20 minutes. Crystalline Berotralstat dihydrochloride was obtained. A sample was analyzed by XRPD. Form B2 was obtained. The same procedure can be done by using Nitromethane or Propionitrile instead of Ethyl Formate.

Example 13: Preparation of Berotralstat dihydrochloride Form B2 [00142] Berotralstat dihydrochloride (Amorphous) 0.07 grams was added in 1 ml of Ethyl Formate at a temperature of about 20 °C to about 30°C into 2 ml vial and slurry was obtained. The obtained slurry was stirred for period of about 7 days at a temperature of about 0°C to about 5°C. The obtained solid was filtered under nitrogen blanket under vacuum at a temperature of about 20°C to about 30°C and was dried under suction for period of about 20 minutes. Crystalline Berotralstat dihydrochloride was obtained. A sample was analyzed by XRPD. Form B2 was obtained. The same procedure can be done by using Nitromethane or Propionitrile instead of Ethyl Formate.

Example 14: Preparation of Berotralstat dihydrochloride Amorphous [00143] Berotralstat dihydrochloride (4.3 grams) and methanol (200.0 ml) was added in flask and was stirred for a period of about 10 minutes at temperature of about 25°C to about 30°C to obtain a clear solution. The solvent was distilled off under vacuum (less than 10 mbar) at temperature of about 60°C in a period of about 60 minutes. The obtained solid was dried at temperature of about 60°C for a period of about 2 hours under vacuum. A sample was analyzed by XRPD. Berotralstat dihydrochloride amorphous was obtained (4.34 grams).

Example 15: Preparation of Berotralstat dihydrochloride Form B4

[00144] Berotralstat dihydrochloride (0.728 grams) was added in 1.4 ml water into 5ml vial at temperature of about 25°C to about 30°C. The temperature was slowly raised to about 60°C in a period of about 5 minutes to about 10 minutes to get the clear solution. The clear solution was stirred at same temperature for period of less than 5 minutes, cooled down to temperature of about 0°C to about 5°C in a period of less than 10 minutes, and stirred for a period of about 14 hours to about 20 hours at same temperature. The obtained solid was filtered under vacuum at temperature of about 25°C to about 30°C and was kept for suction under vacuum for a period of about 30 minutes at same temperature and further dried at 40°C in air tray dryer for a period of about 2 hours. Crystalline Berotralstat dihydrochloride was obtained. A sample was analyzed by XRPD. Form B4 was obtained (0.635 grams). An XRPD Pattern is shown in Figure 5.

Example 16: Preparation of Berotralstat dihydrochloride Form B4

[00145] Berotralstat free base (100 mg) was dissolved in Dichloromethane (1.0 ml) at temperature of about 25°C to about 30°C and 2.0 mole eq. IPA-HCl was added to it. The reaction mass was stirred for period of 2 hours to 3 hours at temperature of about 50°C to about 60°C followed by stirring at 25°C to about 30°C for period of about 17 hours to about 18 hours. The obtained solid was filtered under vacuum at temperature of about 25°C to about 30°C for about 15 minutes to about 30 minutes Crystalline Berotralstat dihydrochloride was obtained. A sample was analyzed by XRPD. Form B4 was obtained.

Example 17: Preparation of Berotralstat dihydrochloride Form B4

[00146] Berotralstat free base (100 mg) was dissolved in MTBE (1.0 ml) at temperature of about 25°C to about 30°C and 2.0 mole eq. IPA-HCl was added to it. The reaction mass was stirred for period of 2 hours to 3 hours at temperature of about 50°C to about 60°C followed by stirring at 25°C to about 30°C for period of about 17 hours to about 18 hours. The obtained solid was filtered under vacuum at temperature of about 25°C to about 30°C for about 15minutes to about 30 minutes Crystalline Berotralstat dihydrochloride was obtained. A sample was analyzed by XRPD. Form B4 was obtained.

Example 18: Preparation of Berotralstat dihydrochloride Form B4

[00147] Berotralstat free base (100 mg) was dissolved in propyl acetate (1.0 ml) at temperature of about 25°C to about 30°C and 2.0 mole eq. IPA-HCl was added to it. The reaction mass was stirred for period of 2 hours to 3 hours at temperature of about 50°C to about 60°C followed by stirring at 25°C to about 30°C for period of about 17 hours to about 18 hours. The obtained solid was filtered under vacuum at temperature of about 25°C to about 30°C for about 15 minutes to about 30 minutes Crystalline Berotralstat dihydrochloride was obtained. A sample was analyzed by XRPD. Form B4 was obtained.

Example 19: Preparation of Berotralstat dihydrochloride Form B4

[00148] Berotralstat free base (100 mg) was added in toluene (1.0 ml) at temperature of about 25°C to about 30°C and 2.0 mole eq. IPA-HCl was added to it. The reaction mass was stirred for period of 2 hours to 3 hours at temperature of about 50°C to about 60°C followed by stirring at 25°C to about 30°C for period of about 17 hours to about 18 hours. The obtained solid was filtered under vacuum at temperature of about 25°C to about 30°C for about 15minutes to about 30 minutes Crystalline Berotralstat dihydrochloride was obtained. A sample was analyzed by XRPD. Form B4 was obtained.

Example 20: Preparation of Berotralstat dihydrochloride Form B4

[00149] Berotralstat dihydrochloride (600 mg) was dissolved in 1.2 ml of water at temperature of about 50°C to about 60°C into 2ml vial. The obtained clear solution cooled down to temperature of about 0°C to about 5°C in a period of 5-10 minutes and stirred for period of about 16 hours at same temperature. The obtained solid was filtered under nitrogen blanket under vacuum at temperature of about 20°C to about 30°C and kept for suction under vacuum for period of about for 20 minutes at 20-30°C temperature and followed by drying in air tray dryer at 40°C for period of about 7 hours. Crystalline Berotralstat dihydrochloride was obtained. A sample was analyzed by XRPD. Form B4 was obtained.

Example 21: Preparation of Berotralstat dihydrochloride Form B3

[00150] Berotralstat dihydrochloride (Amorphous) ( 800m g) was kept at temperature of about 60°C and Relative Humidity of about 95% to about 100% for the period of about for 18 hours to about 20 hours. The obtained wet compound was kept outside for period of about 4 hours to about 5 hours at temperature of about 25°C for drying. Crystalline Berotralstat dihydrochloride was obtained. A sample was analyzed by XRPD. Form B3 was obtained.

Example 22: Preparation of Berotralstat dihydrochloride Form B3

[00151] Berotralstat dihydrochloride (100 mg) was dissolved in acetonitrile (0.2 ml) at temperature of about 50°C to about 70°C and stirred for period of about 10 minutes to about 15 minutes at same temperature. The obtained clear solution was cooled to temperature of about 0°C to about 5°C and stirred for period of about 15 hours at same temperature. The obtained solid was filtered under vacuum at temperature of about 25°C to about 30°C under nitrogen atmosphere and kept under suction for period of about 30 minutes. Crystalline Berotralstat dihydrochloride was obtained. A sample was analyzed by XRPD. Form B3 was obtained.

Claims

Claims:

1. Crystalline Form B4 of Berotralstat dihydrochloride characterized by data selected from one or more of the following: a) an XRPD pattern having peaks at 16.4, 20.6, 21.0, 21.4, 22.8 and 25.8 degrees 2- theta ± 0.2 degrees 2-theta or an XRPD pattern having peaks at 16.5, 20.6, 21.0, 21.4, 22.8 and 25.8 degrees 2-theta ± 0.2 degrees 2-theta; b) an XRPD pattern as depicted in Figure 5; c) a solid state ¹³C NMR spectrum having peaks at 116.1, 132.0, 135.7, 155.5 and 157.5 ppm ± 0.2 ppm; d) a solid state ¹³C NMR spectrum having the following chemical shift absolute differences from a reference peak at 60.1 ppm ± 2 ppm of 56.0, 71.9, 75.6, 95.4 and 97.4 ppm ± 0.1 ppm; e) a solid-state 13C NMR spectrum substantially as depicted in Figures 6a, 6b or 6c; and f) combinations of two or more of a, b, c, d and e.

2. Crystalline Form B4 of Berotralstat dihydrochloride according to Claim 1, characterized by an XRPD pattern having peaks at 16.4, 20.6, 21.0, 21.4, 22.8 and 25.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, or four additional peaks selected from 12.3, 14.1, 15.6 and 23.5 degrees two theta ± 0.2 degrees two theta; or characterized by an XRPD pattern having peaks at: 12.3, 14.1, 15.6 16.4, 20.6, 21.0, 21.4, 22.8, 23.5 and 25.8 degrees 2-theta ± 0.2 degrees 2-theta.

3. Crystalline Form B4 of Berotralstat dihydrochloride according to Claim 1 or Claim 2, further characterized by an XRPD pattern having an absence of one, two, three, or four peaks at: 17.1, 19.8, 25.2, and 26.5 degrees 2-theta ± 0.2 degrees 2-theta.

4. Crystalline Form B4 of Berotralstat dihydrochloride according to any of Claims 1, 2 or 3, further characterized by an XRPD pattern having an absence of a peak at: 19.8 degrees 2- theta ± 0.2 degrees 2-theta.

5. Crystalline Form B4 of Berotralstat dihydrochloride according to any of Claims 1, 2, 3, or 4, further characterized by an XRPD pattern having an absence of one, two or three peaks at: 12.6, 13.7 and 33.4 degrees 2-theta ± 0.2 degrees 2-theta.

6. Crystalline Form B4 of Berotralstat dihydrochloride according to any of Claims 1 to 5, wherein said crystalline form is a hydrate form.

7. Crystalline Berotralstat dihydrochloride according to any of Claims 1 to 6, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Berotralstat dihydrochloride.

8. A pharmaceutical composition comprising crystalline Form B4 of Berotralstat dihydrochloride according to any of Claims 1 to 7.

9. Use of crystalline Form B4 of Berotralstat dihydrochloride according to any of Claims 1 to 7 for the preparation of a pharmaceutical composition and/or pharmaceutical formulation, preferably wherein the pharmaceutical formulation is oral formulation.

10. A pharmaceutical formulation comprising crystalline Form B4 of Berotralstat dihydrochloride according to any of Claims 1 to 7, or a pharmaceutical composition of Claim 8, with at least one pharmaceutically acceptable excipient.

11. A process for preparing the pharmaceutical formulation according to Claim 10, comprising combining crystalline Form B4 of Berotralstat dihydrochloride according to any of Claims 1 to 7 or a pharmaceutical composition of Claim 8, with at least one pharmaceutically acceptable excipient.

12. Crystalline Form B4 of Berotralstat dihydrochloride, according to any one of Claims 1 to 7, a pharmaceutical composition according to Claim 8, or a pharmaceutical formulation according to Claim 10, for use as a medicament.

13. Crystalline Form B4 of Berotralstat dihydrochloride, according to any of Claims 1 to 7, a pharmaceutical composition according to Claim 8, or a pharmaceutical formulation according to Claim 10, for use in the treatment of hereditary angioedema.

14. A method of treating hereditary angioedema, comprising administering a therapeutically effective amount of Crystalline Form B4 of Berotralstat dihydrochloride according to any one of Claims 1 to 7, a pharmaceutical composition according to Claim 8, or a pharmaceutical formulation according to Claim 10, to a subject in need of the treatment.

15. Crystalline Form B4 of Berotralstat dihydrochloride, according to any one of Claims 1 to 7, a pharmaceutical composition according to Claim 8, or a pharmaceutical formulation according to Claim 10, for the manufacture of a medicament for hereditary angioedema.

16. Use of crystalline Form B4 of Berotralstat dihydrochloride according to any one of Claims 1 to 7, in the preparation of another solid state form of Berotralstat dihydrochloride, or another Berotralstat salt or solid state form thereof.

17. A process for preparing a Berotralstat salt or a solid state form thereof comprising preparing crystalline Form B4 of Berotralstat dihydrochloride according to any one of Claims 1 to 7, and converting it to another Berotralstat salt or a solid state form thereof.