Solid state forms of lorundrostat and process thereof

Abstract

The present disclosure relates to Lorundrostat solid state forms, in embodiments crystalline polymorphs or salts of Lorundrostat, particularly Lorundrostat hydrobromide, processes for preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

Description

SOLID STATE FORMS OF LORUNDROSTAT AND PROCESS THEREOFFIELD OF THE INVENTION

[0001] The present disclosure relates to Lorundrostat solid state forms, in embodiments crystalline polymorphs or salts of Lorundrostat, particularly solid state forms of Lorundrostat HBr, processes for preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.BACKGROUND

[0002] Lorundrostat (MT-4129) which has the chemical name N-(4-acetamidocyclohexyl)- 2-[4-[5-(4-methylphenyl)-l,2,4-triazin-3-yl]piperazin-l-yl]acetamide is a highly selective potent aldosterone synthase inhibitor being developed for the treatment of uncontrolled hypertension and chronic kidney disease (CKD). Lorundrostat was designed to reduce aldosterone levels by inhibiting CYP11B2, the enzyme responsible for its production. As described in U.S. Patent No. 10,029,993 Lorundrostat has the following chemical structure:

[0003] Lorundrostat preparation is disclosed in U.S. Patent No. 10,029,993 (IntT Publication No. WO 2015163427) and Lorundrostat salts and polymorphs are described in U.S. Patent Application Publication No. 2023 / 0365513 (IntT Publication No. WO 2022059700).

[0004] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Lorundrostat, 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.

[0005] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms 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. Thesevariations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms 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.

[0006] Discovering new salts and solid state forms 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 salts or polymorphic forms. New polymorphic forms and new salts 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. For at least these reasons, there is a need for additional salts and solid state forms (including solvated forms) of Lorundrostat.SUMMARY OF THE INVENTION

[0007] The present disclosure relates to Lorundrostat solid state forms, crystalline polymorphs and salts thereof, to processes for preparation thereof, and to pharmaceutical compositions comprising solid state form thereof.

[0008] In particular, the present disclosure provides crystalline forms of Lorundrostat designated as Forms LI and L2 and Lorundrostat hydrobromide designated as Forms LHBrl, LHBr2, LHBr3, LHBr4, LHBr5, LHBr6, LHBr7, LHBr8 and amorphous Lorundrostat hydrobromide as well as crystalline Lorundrostat hydrochloride Forms LHC11 and LHC12 and crystalline Lorundrostat oxalate form Loxl (defined herein).

[0009] The present disclosure further provides process for preparing Lorundrostat and Lorundrostat hydrobromide and solid state forms or crystalline polymorphs thereof. The solid state forms of Lorundrostat and of Lorundrostat salts, particularly Lorundrostat HBr, Lorundrostat HC1 and Lorundrostat oxalate can be used to prepared other solid state forms of Lorundrostat, or other salts of Lorundrostat and their solid state forms.

[0010] In another aspect, the present disclosure encompasses the above described solid state forms or crystalline polymorphs of Lorundrostat and crystalline polymorphs of Lorundrostat hydrobromide, Lorundrostat hydrochloride and Lorundrostat oxalate for use in the preparation of pharmaceutical compositions and / or formulations, preferably for use in medicine, preferably for the treatment of uncontrolled hypertension and chronic kidney disease (CKD).

[0011] In another aspect, the present disclosure encompasses the use of any one of the abovedescribed solid state forms or crystalline polymorphs of Lorundrostat and Lorundrostat hydrobromide for the preparation of pharmaceutical compositions and / or formulations, preferably for use in medicine, preferably for treating uncontrolled hypertension and CKD. In yet another embodiment, the present disclosure encompasses pharmaceutical compositions comprising any one of the solid state forms or crystalline polymorphs of Lorundrostat and od Lorundrostat hydrobromide, Lorundrostat hydrochloride and Lorundrostat oxalate.

[0012] In a specific embodiment, the present disclosure encompasses pharmaceutical formulations comprising the solid-state forms or crystalline polymorphs of Lorundrostat and Lorundrostat hydrobromide, as well as Lorundrostat hydrochloride and Lorundrostat oxalate and at least one pharmaceutically acceptable excipient.

[0013] The present disclosure further encompasses processes to prepare said pharmaceutical formulations of Lorundrostat and Lorundrostat hydrobromide, as well as Lorundrostat hydrochloride or Lorundrostat oxalate comprising combining any one of the above described solid state forms or crystalline polymorphs of Lorundrostat and Lorundrostat hydrobromide, as well as Lorundrostat hydrochloride and Lorundrostat oxalate or pharmaceutical compositions comprising it, and at least one pharmaceutically acceptable excipient.

[0014] The solid state forms or crystalline polymorphs of Lorundrostat and Lorundrostat hydrobromide, as well as Lorundrostat hydrochloride and Lorundrostat oxalate as defined herein as well as the pharmaceutical compositions or formulations comprising it can be used as medicaments, particularly for treating uncontrolled hypertension and CKD, comprising administering a therapeutically effective amount of the solid state form of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from uncontrolled hypertension and CKD, or otherwise in need of the treatment.

[0015] The present disclosure also provides the uses of the solid-state forms or crystalline polymorphs of Lorundrostat and Lorundrostat hydrobromide, as well as Lorundrostat hydrochloride and Lorundrostat oxalate of the present disclosure, or at least one of the abovepharmaceutical compositions or formulations, for the manufacture of medicaments for treating uncontrolled hypertension and CKD.BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG. 1 shows an X-ray powder diffraction (XRPD) pattern for crystalline Lorundrostat Form LI .

[0017] FIG. 2 shows an XRPD pattern of crystalline Lorundrostat Form L2.

[0018] FIG. 3 shows an XRPD pattern of crystalline Lorundrostat hydrobromide Form LHBrl.

[0019] FIG. 4 shows an XRPD pattern of crystalline Lorundrostat hydrobromide Form LHBr2.

[0020] FIG. 5 shows an XRPD pattern of crystalline Lorundrostat hydrobromide Form LHBr3.

[0021] FIG. 6 shows an XRPD pattern of crystalline Lorundrostat hydrobromide Form LHBr4.

[0022] FIG. 7 shows an XRPD pattern of crystalline Lorundrostat hydrobromide Form LHBr5.

[0023] FIG. 8 shows an XRPD pattern of Amorphous Lorundrostat hydrobromide.

[0024] FIG. 9 shows an XRPD pattern of crystalline Lorundrostat hydrobromide FormLHBr6.

[0025] FIG. 10 shows an XRPD pattern of crystalline Lorundrostat hydrobromide Form LHBr7.

[0026] FIG. 11 shows an XRPD pattern of crystalline Lorundrostat hydrobromide Form LHBr8.

[0027] FIG. 12 shows an XRPD pattern of crystalline Lorundrostat hydrochloride Form LHC11.

[0028] FIG. 13 shows an XRPD pattern of crystalline Lorundrostat hydrochloride Form LHC12.

[0029] FIG. 14 shows an XRPD pattern of crystalline Lorundrostat oxalate Form Loxl.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0030] The present disclosure relates to solid state forms or crystalline polymorphs of Lorundrostat and Lorundrostat hydrobromide to processes for preparation thereof and to pharmaceutical compositions comprising at least one of, or combination of these solid stateforms. In particular, the present disclosure relates to solid state forms of Lorundrostat designated as Forms LI and L2 (defined herein) and Lorundrostat hydrobromide designated as Forms LHBrl, LHBr2, LHBr3, LHBr4, LHBr5, LHBr6, LHBr7, LHBr8 and amorphous Lorundrostat hydrobromide as well as crystalline Lorundrostat hydrochloride Forms LHC11 and LHC12 and crystalline Lorundrostat oxalate form Loxl (defined herein).

[0031] The Lorundrostat and Lorundrostat hydrobromide, as well as Lorundrostat hydrochloride and Lorundrostat oxalate, and their solid state forms, according to the present disclosure may have advantageous properties selected from at least one of: chemical or polymorphic purity, flowability, solubility, 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, adhesive tendencies and advantageous processing and handling characteristics such as compressibility, and bulk density.

[0032] A crystal form may be referred to herein as being characterized by graphical data “as depicted in” a FIG. 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 FIG.s 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.

[0033] A crystal form of Lorundrostat and Lorundrostat hydrobromide, as well as Lorundrostat hydrochloride and Lorundrostat oxalate, referred to herein as being characterized by graphical data “as depicted in” a FIG. will thus be understood to include any crystal form of Lorundrostat and Lorundrostat hydrobromide characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the FIG.

[0034] The solid-state forms or crystalline polymorphs of Lorundrostat and Lorundrostat hydrobromide, as well as Lorundrostat hydrochloride and Lorundrostat oxalate, as described in any aspect or embodiment of the present disclosure may be polymorphically pure, orsubstantially free of any other solid state forms of Lorundrostat and Lorundrostat hydrobromide, as well as Lorundrostat hydrochloride and Lorundrostat oxalate.

[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 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% (w / w) of any other forms of the subject compound as measured, for example, by XRPD. Thus, solid states of Lorundrostat and Lorundrostat hydrobromide described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the subject solid state form of Lorundrostat and Lorundrostat hydrobromide respectively. Accordingly, in some embodiments of the disclosure, the described solid-state form of Lorundrostat and Lorundrostat hydrobromide, as well as Lorundrostat hydrochloride and Lorundrostat oxalate, may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more solid state forms of Lorundrostat and / or Lorundrostat hydrobromide, Lorundrostat hydrochloride and Lorundrostat oxalate respectively.

[0036] The solid state forms or crystalline polymorphs of Lorundrostat and Lorundrostat hydrobromide, as well as Lorundrostat hydrochloride and Lorundrostat oxalate, as described in any aspect or embodiment of the present disclosure may be chemically pure, or substantially free of any other compounds.

[0037] A compound may be referred to herein as chemically pure or purified compound or as substantially free of any other compounds. As used herein, the terms “chemically pure” or “purified” or “substantially free of any other compounds” refer to a compound that is substantially free of any impurities including enantiomers of the subject compound, diastereomers or other isomers. A chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% (w / w) or less, about 5% (w / w) or less, about 4% (w / w) or less, about 3% (w / w) or less, about 2% (w / w) or less, about 1.5% (w / w) or less, about 1% (w / w), about 0.8% (w / w) or less, about 0.6% (w / w) or less about 0.4% (w / w) or less about 0.2% (w / w) or less or less, about 0.1% (w / w) or less or about 0% of any other compound as measured, for example, by HPLC. Alternatively, A chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% area percent orless, about 5% area percent or less, about 4% area percent or less, about 3% area percent or less, about 2% area percent or less, about 1.5% area percent or less, about 1% area percent or less, about 0.8% area percent or less, about 0.6% area percent or less, about 0.4% area percent or less, about 0.2% area percent or less, about 0.1% area percent or less, or about 0% of any other compound as measured by HPLC. Thus, pure or purified Lorundrostat and / or Lorundrostat hydrobromide, Lorundrostat hydrochloride and Lorundrostat oxalate described herein as substantially free of any compounds would be understood to contain greater than about 90% (w / w), greater than about 95% (w / w), greater than about 96% (w / w), greater than about 97% (w / w), greater than about 98% (w / w), greater than about 98.5% (w / w), greater than about 99% (w / w), greater than about 99.2%, (w / w) greater than about 99.4% (w / w), greater than about 99.6% (w / w), greater than about 99.8% (w / w), greater than about 99.9% (w / w), or about 100% of the subject Lorundrostat and Lorundrostat hydrobromide, Lorundrostat hydrochloride and Lorundrostat oxalate respectively. Alternatively, pure or purified Lorundrostat and Lorundrostat hydrobromide, Lorundrostat hydrochloride and Lorundrostat oxalate, described herein as substantially free of any compounds would be understood to contain greater than about 90% area percent, greater than about 95% area percent, greater than about 96% area percent, greater than about 97% area percent, greater than about 98% area percent, greater than about 98.5% area percent, greater than about 99% area percent, greater than about 99.2%, area percent, greater than about 99.4% area percent, greater than about 99.6% area percent, greater than about 99.8% area percent, greater than about 99.9% area percent, or about 100% of the subject Lorundrostat and Lorundrostat hydrobromide, Lorundrostat hydrochloride and Lorundrostat oxalate, respectively.

[0038] As used herein, unless stated otherwise, XRPD peaks reported herein are preferably measured using CuKa radiation, X = 1.5418 A, preferably, XRPD peaks reported herein are measured using CuK a radiation, k = 1.5418 A, at a temperature of 25 ± 3 °C.

[0039] As used herein, the term “isolated” in reference to solid state form of Lorundrostat and Lorundrostat hydrobromide, as well as Lorundrostat hydrochloride and Lorundrostat oxalate of the present disclosure corresponds to solid state form of Lorundrostat and Lorundrostat hydrobromide, Lorundrostat hydrochloride and Lorundrostat oxalate that is physically separated from the reaction mixture in which it is formed.

[0040] 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 thething is located. Typically, room temperature is from about 20 °C to about 30 °C, or about 22 °C to about 27 °C, or about 25 °C.

[0041] A process or step may be referred to herein as being carried out “overnight.” This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10 to about 18 hours, typically about 16 hours.

[0042] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline Lorundrostat and Lorundrostat hydrobromide 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 about 1% (w / w) of either water or organic solvents as measured for example by TGA, Karl Fischer or by other suitable technique.

[0043] 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.

[0044] 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 “N / N” 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.

[0045] As used herein the term non-hygroscopic in relation to crystalline Lorundrostat, refers to less than about 1.0% (w / w) absorption of water at about 25 °C and about 80% relative humidity (RH), as determined for example by TGA or other suitable technique.

[0046] As used herein, the term “reduced pressure” refers to a pressure of about 10 mbar to about 500 mbar.

[0047] Optionally, crystalline Lorundrostat hydrobromide according to any aspect or embodiment, may be a monohydrobromide salt.

[0048] As used herein, and unless indicated otherwise, the term “thermo-dynamical stability” in relation to solid state forms or crystalline polymorphs of Lorundrostat and salts thereof refers to resistance of the solid state form or crystalline polymorph to polymorphic conversion under certain conditions, for example, heating, melting or dissolving. In some embodiments, the term refers to less than about 20% (w / w), about 10% (w / w), about 5% (w / w), about 1% (w / w), about 0.5% (w / w), or about 0% (w / w) conversion of crystalline Lorundrostat to any other solid state form of Lorundrostat and salts thereof as measured by XRPD. In some embodiments, the conversion is about 1% (w / w) to about 20% (w / w), about 1% (w / w) to about 10% (w / w) or about 1% (w / w) to about 5% (w / w).

[0049] As used herein, the term “form A” or “crystalline Form A” in relation to Lorundrostat hydrobromide, relates to a crystalline form A of Lorundrostat hydrobromide as described in WO 2022059700.

[0050] The present disclosure comprises a crystalline Lorundrostat designated as Form LI. Lorundrostat crystalline Form LI can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 6.6, 12.2, 15.2, 16.1 and 18.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 1; or combinations of these data.

[0051] Crystalline Lorundrostat Form LI may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 6.6, 12.2, 15.2, 16.1 and 18.6 degrees two theta ± 0.2 degrees two theta; and also having one, two, three or four additional peaks selected from 10.1, 13.9, 19.9 and 23.2 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0052] According to any aspect or embodiment, crystalline Lorundrostat Form LI may be characterized by an XRPD pattern having peaks at 6.6, 12.2, 15.2, 16.1 and 18.6 degrees two theta ± 0.2 degrees two theta; and also having one additional peak selected from 10.1, 13.9, 19.9 and 23.2 degrees two theta ± 0.2 degrees two theta.

[0053] Crystalline Lorundrostat Form LI may alternatively be characterized by XRPD pattern having peaks at 6.6, 10.1, 12.2, 13.9, 15.2, 16.1, 18.6, 19.9 and 23.2 degrees two theta ± 0.2 degrees two theta.

[0054] Crystalline Lorundrostat Form LI may be characterized by each of the above characteristics alone / or by all possible combinations, e.g. by XRPD pattern having peaks at 6.6, 12.2, 15.2, 16.1 and 18.6 degrees two theta ± 0.2 degrees two theta and an XRPD pattern as depicted in FIG. 1, and combinations thereof.

[0055] Crystalline Lorundrostat Form LI may be characterized as anhydrous form.

[0056] The present disclosure comprises a crystalline form of Lorundrostat designated as Form L2. The crystalline Form L2 of Lorundrostat can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 8.2, 12.8, 16.6, 17.9 and 24.8 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 2; or combinations of these data.

[0057] Crystalline Lorundrostat Form L2 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 8.2, 12.8, 16.6, 17.9 and 24.8 degrees two theta ± 0.2 degrees two theta; and also having one, two or three additional peaks selected from 13.5, 21.1 and 22.4 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0058] According to any aspect or embodiment, crystalline Lorundrostat Form L2 may be characterized by an XRPD pattern having peaks at 8.2, 12.8, 16.6, 17.9 and 24.8 degrees two theta ± 0.2 degrees two theta; and also one peak selected from 13.5, 21.1 and 22.4 degrees two theta ± 0.2 degrees two theta.

[0059] Crystalline Lorundrostat Form L2 my alternatively be characterized by XRPD pattern having peaks at 8.2, 12.8, 13.5, 16.6, 17.9, 21.1, 22.4 and 24.8 degrees two theta ± 0.2 degrees two theta.

[0060] Crystalline Lorundrostat Form L2 may be characterized by each of the above characteristics alone / or by all possible combinations, e.g. by XRPD pattern having peaks at 8.2, 12.8, 16.6, 17.9 and 24.8 degrees two theta ± 0.2 degrees two theta; an XRPD pattern as depicted in FIG. 2, and combinations thereof.

[0061] Crystalline Lorundrostat Form L2 may be characterized as an formamide solvate.

[0062] The present disclosure comprises a solid-state forms of Lorundrostat hydrobromide, particularly crystalline forms of Lorundrostat hydrobromide. According to any aspect or embodiment, the crystalline forms of Lorundrostat hydrobromide are crystalline forms of Lorundrostat mono-hydrobromide.

[0063] The present disclosure comprises a crystalline Lorundrostat hydrobromide designated as Form LHBrl. Lorundrostat hydrobromide crystalline Form LHBrl can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 9.2, 10.3, 12.4, 27.9 and 28.5 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 3; or combinations of these data.

[0064] Crystalline Lorundrostat hydrobromide Form LHBrl may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 9.2, 10.3, 12.4, 27.9 and 28.5 degrees two theta ± 0.2 degrees two theta; and also having one, two, threeor four additional peaks selected from 15.7 19.4, 24.4 and 26.5 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0065] According to any aspect or embodiment, crystalline Lorundrostat hydrobromide Form LHBrl may be characterized by an XRPD pattern having peaks at 9.2, 10.3, 12.4, 27.9 and 28.5 degrees two theta ± 0.2 degrees two theta; and also having one additional peak selected from 15.7 19.4, 24.4 and 26.5 degrees two theta ± 0.2 degrees two theta.

[0066] Crystalline Lorundrostat hydrobromide Form LHBrl may alternatively be characterized by XRPD pattern having peaks at 9.2, 10.3, 12.4, 15.7, 19.4, 24.4, 26.5, 27.9 and 28.5 degrees two theta ± 0.2 degrees two theta.

[0067] Crystalline Lorundrostat hydrobromide Form LHBrl may be characterized by each of the above characteristics alone / or by all possible combinations, e.g. by XRPD pattern having peaks at 9.2, 10.3, 12.4, 27.9 and 28.5 degrees two theta ± 0.2 degrees two theta and an XRPD pattern as depicted in FIG. 3, and combinations thereof.

[0068] The present disclosure comprises a crystalline Lorundrostat hydrobromide designated as Form LHBr2. Lorundrostat hydrobromide crystalline Form LHBr2 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 10.7, 16.9, 18.4 and 24.8 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 4; or combinations of these data.

[0069] Crystalline Lorundrostat hydrobromide Form LHBr2 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 10.7, 16.9, 18.4 and 24.8 degrees two theta ± 0.2 degrees two theta; and also having one, two or three additional peaks selected from 13.8, 16.1 and 19.6 degrees two theta ± 0.2 degrees two theta.

[0070] According to any aspect or embodiment, crystalline Lorundrostat hydrobromide Form LHBr2 may be characterized by an XRPD pattern having peaks at 10.7, 16.9, 18.4 and 24.8 degrees two theta ± 0.2 degrees two theta; and also one additional peak selected from 13.8, 16.1 and 19.6 degrees two theta ± 0.2 degrees two theta. Crystalline Lorundrostat hydrobromide Form LHBr2 may alternatively be characterized by an XRPD pattern having peaks at 10.7, 13.8, 16.1, 16.9, 18.4, 19.6 and 24.8 degrees two theta ± 0.2 degrees two theta.

[0071] Crystalline Lorundrostat hydrobromide Form LHBr2 may be characterized by each of the above characteristics alone / or by all possible combinations, e.g. by XRPD pattern having peaks at 10.7, 16.9, 18.4 and 24.8 degrees two theta ± 0.2 degrees two theta and an XRPD pattern as depicted in FIG. 4, and / or combinations thereof.

[0072] Crystalline Lorundrostat hydrobromide Form LHBr2 according to any aspect or embodiment may be polymorphically pure. In particular, Form LHBr2 is substantially free ofany other crystalline forms of Lorundrostat hydrobromide. Particularly, Form LHBr2 according to any aspect or embodiment contains less than about 10%, less than about 5%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1%, or about 0% (w / w) of any other crystalline forms of Lorundrostat hydrobromide According to any aspect or embodiment of the present disclosure, crystalline Lorundrostat hydrobromide Form LHBr2 is substantially free of crystalline Lorundrostat hydrobromide Form A. Particularly, Form LHBr2 contains less than about 10%, less than about 5%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1%, or about 0% (w / w) of Lorundrostat hydrobromide Form A.

[0073] Crystalline Lorundrostat hydrobromide Form LHBr2 may be a hydrate form.

[0074] Crystalline Lorundrostat hydrobromide Form LHBr2 may have advantageous properties as described herein above. In particular, Form LHBr2 is stable in various stress conditions, including strong grinding, pressure of 2 tons, and heating up to 100 °C. In addition, Form LHBr2 is stable at relative humidity (RH) of about 20-60% at a temperature of about 25 °C for a period of at least 7 days. It is also stable at RH of about 60% at temperature of about 25 °C, and RH of about 75% at a temperature of about 40 °C, for a period of at least 6 months.

[0075] The present disclosure comprises a crystalline Lorundrostat hydrobromide designated as Form LHBr3. Lorundrostat hydrobromide crystalline Form LHBr3 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.2, 7.8, 12.4, 15.0 and 22.8 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 5; or combinations of these data.

[0076] Crystalline Lorundrostat hydrobromide Form LHBr3 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.2, 7.8, 12.4, 15.0 and 22.8 degrees two theta ± 0.2 degrees two theta; and also having one, two or three additional peaks selected from 9.9, 13.7 and 29.3 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0077] According to any aspect or embodiment, crystalline Lorundrostat hydrobromide Form LHBr3 may be characterized an XRPD pattern having peaks at 5.2, 7.8, 12.4, 15.0 and 22.8 degrees two theta ± 0.2 degrees two theta; and also having one additional peak selected from 9.9, 13.7 and 29.3 degrees two theta ± 0.2 degrees two theta.

[0078] Crystalline Lorundrostat hydrobromide Form LHBr3 may alternatively be characterized by XRPD pattern having peaks at 5.2, 7.8, 9.9, 12.4, 13.7, 15.0, 22.8 and 29.3 degrees two theta ± 0.2 degrees two theta.

[0079] Crystalline Lorundrostat hydrobromide Form LHBr3 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, 7.8, 12.4, 15.0 and 22.8 degrees two theta ± 0.2 degrees two theta and an XRPD pattern as depicted in FIG. 5, and combinations thereof.

[0080] The present disclosure comprises a crystalline Lorundrostat hydrobromide designated as Form LHBr4. Lorundrostat hydrobromide crystalline Form LHBr4 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.4, 13.2, 14.9, 17.1 and 25.5 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 6; or combinations of these data.

[0081] Crystalline Lorundrostat hydrobromide Form LHBr4 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.4, 13.2, 14.9, 17.1 and 25.5 degrees two theta ± 0.2 degrees two theta; and also having one, two or three additional peaks selected from 16.0, 21.8 and 27.1 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0082] According to any aspect or embodiment, crystalline Lorundrostat hydrobromide Form LHBr4 may be characterized by an XRPD pattern having peaks at 5.4, 13.2, 14.9, 17.1 and 25.5 degrees two theta ± 0.2 degrees two theta; and also having one additional peak selected from 16.0, 21.8 and 27.1 degrees two theta ± 0.2 degrees two theta.

[0083] Crystalline Lorundrostat hydrobromide Form LHBr4 may alternatively be characterized by XRPD pattern having peaks at 5.4, 13.2, 14.9, 16.0, 17.1, 21.8, 25.5 and 27.1 degrees two theta ± 0.2 degrees two theta.

[0084] Crystalline Lorundrostat hydrobromide Form LHBr4 may be characterized by each of the above characteristics alone / or by all possible combinations, e.g. by XRPD pattern having peaks at 5.4, 13.2, 14.9, 17.1 and 25.5 degrees two theta ± 0.2 degrees two theta and an XRPD pattern as depicted in FIG. 6, and combinations thereof.

[0085] Crystalline Lorundrostat hydrobromide Form LHBr4 may be characterized as N- Methyl Pyrrolidone solvate (NMP).

[0086] The present disclosure comprises a crystalline Lorundrostat hydrobromide designated as Form LHBr5. Lorundrostat hydrobromide crystalline Form LHBr5 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 7.7, 10.1, 14.3, 20.0 and 29.2 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 7; or combinations of these data.

[0087] Crystalline Lorundrostat hydrobromide Form LHBr5 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 7.7, 10.1,14.3, 20.0 and 29.2 degrees two theta ± 0.2 degrees two theta; and also having one, two or three additional peaks selected from 16.9, 24.8 and 27.6 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0088] According to any aspect or embodiment, crystalline Lorundrostat hydrobromide Form LHBr5 may be characterized an XRPD pattern having peaks at 7.7, 10.1, 14.3, 20.0 and 29.2 degrees two theta ± 0.2 degrees two theta; and also having one additional peak selected from 16.9, 24.8 and 27.6 degrees two theta ± 0.2 degrees two theta.

[0089] Crystalline Lorundrostat hydrobromide Form LHBr5 may alternatively be characterized by XRPD pattern having peaks at 7.7, 10.1, 14.3, 16.9, 20.0, 24.8, 27.6 and 29.2 degrees two theta ± 0.2 degrees two theta.

[0090] Crystalline Lorundrostat hydrobromide Form LHBr5 may be characterized by each of the above characteristics alone / or by all possible combinations, e.g. by XRPD pattern having peaks at 7.7, 10.1, 14.3, 20.0 and 29.2 degrees two theta ± 0.2 degrees two theta and an XRPD pattern as depicted in FIG. 7, and combinations thereof.

[0091] Crystalline Lorundrostat hydrobromide Form LHBr5 may be characterized as DMSO solvate.

[0092] The present disclosure comprises a crystalline Lorundrostat hydrobromide designated as Form LHBr6. Lorundrostat hydrobromide crystalline Form LHBr6 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 11.8, 15.7, 19.0, 23.7 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 9; or combinations of these data.

[0093] Crystalline Lorundrostat hydrobromide Form LHBr6 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 11.8, 15.7, 19.0, 23.7 and 26.0 degrees two theta ± 0.2 degrees two theta; and also having one, two, three or five additional peaks selected from 9.2, 19.5, 27.2 and 36.8 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0094] Crystalline Lorundrostat hydrobromide Form LHBr6 may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 11.8, 15.7, 19.0, 23.7 and 26.0 degrees two theta ± 0.2 degrees two theta; and also having one, two, three or four additional peaks selected from 9.2, 19.5, 27.2 and 36.8 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0095] According to any aspect or embodiment, crystalline Lorundrostat hydrobromide Form LHBr6 may be characterized by an XRPD pattern having peaks at 11.8, 15.7, 19.0, 23.7 and26.0 degrees two theta ± 0.2 degrees two theta; and also having one additional peak selected from 9.2, 19.5, 27.2 and 36.8 degrees two theta ± 0.2 degrees two theta.

[0096] Crystalline Lorundrostat hydrobromide Form LHBr6 may alternatively be characterized by XRPD pattern having peaks at 9.2, 11.8, 15.7, 19.0, 19.5, 23.7, 26.0, 27.2 and36.8 degrees two theta ± 0.2 degrees two theta.

[0097] Crystalline Lorundrostat hydrobromide Form LHBr6 may be a hydrate form.

[0098] Crystalline Lorundrostat hydrobromide Form LHBr6 may be characterized by each of the above characteristics alone / or by all possible combinations, e.g. by XRPD pattern having peaks at 11.8, 15.7, 19.0, 23.7 and 26.0 degrees two theta± 0.2 degrees two theta and an XRPD pattern as depicted in FIG. 9, and combinations thereof.

[0099] The present disclosure comprises a crystalline Lorundrostat hydrobromide designated as Form LHBr7. Lorundrostat hydrobromide crystalline Form LHBr7 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 7.5, 10.6, 13.7 and 34.7 degrees 2-theta ± 0.2 degrees 2-theta and also by the absence of peaks at 8.8, 18.1, 20.9, 23.8, and 24.3 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 10; or combinations of these data.

[0100] Crystalline Lorundrostat hydrobromide designated as Form LHBr7 may also be characterized an XRPD pattern having peaks at 7.5, 10.6, 13.7 and 34.7 degrees 2-theta ± 0.2 degrees 2-theta and also by the absence of peaks at 8.8 and 13.0.

[0101] Crystalline Lorundrostat hydrobromide Form LHBr7 may be further characterized by an XRPD pattern having peaks at 7.5, 10.6, 13.7 and 34.7 degrees two theta ± 0.2 degrees two theta and also by the absence of peaks at 8.8, 18.1, 20.9, 23.8, and 24.3 degrees 2-theta ± 0.2 degrees 2-theta; and also having one, two or three additional peaks selected from 11.3, 22.8 and 26.8 degrees two theta ± 0.2 degrees two theta. Crystalline Lorundrostat hydrobromide designated as Form LHBr7 may also be characterized an XRPD pattern having peaks at 7.5, 10.6, 13.7 and 34.7 degrees 2-theta ± 0.2 degrees 2-theta, and also by the absence of peaks at8.8 and 13.0; and also having one, two or three additional peaks selected from 11.3, 22.8 and26.8 degrees two theta ± 0.2 degrees two theta.

[0102] Crystalline Lorundrostat hydrobromide Form LHBr7 may be characterized by an XRPD pattern having peaks at 7.5, 10.6, 13.7 and 34.7 degrees two theta ± 0.2 degrees two theta and also by the absence of peaks at 8.8, 18.1, 20.9, 23.8, and 24.3 degrees 2-theta ± 0.2 degrees 2-theta; and also having one additional peak selected from 11.3, 22.8 and 26.8 degrees two theta ± 0.2 degrees two theta. Crystalline Lorundrostat hydrobromide designated as Form LHBr7 may also be characterized an XRPD pattern having peaks at 7.5, 10.6, 13.7 and 34.7degrees 2-theta± 0.2 degrees 2-theta, and also by the absence of peaks at 8.8 and 13.0; and also having one additional peak selected from 11.3, 22.8 and 26.8 degrees two theta ± 0.2 degrees two theta.

[0103] Crystalline Lorundrostat hydrobromide Form LHBr7 may be further characterized by an XRPD pattern having peaks at 7.5, 10.6, 11.3, 13.7, 22.8, 26.8 and 34.7 degrees two theta ± 0.2 degrees two theta and also by the absence of peaks at 8.8, 18.1, 20.9, 23.8, and 24.3 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Lorundrostat hydrobromide Form LHBr7 may be further characterized by an XRPD pattern having peaks at 7.5, 10.6, 11.3, 13.7, 22.8, 26.8 and 34.7 degrees two theta ± 0.2 degrees two theta and also by the absence of peaks at 8.8 and 13.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0104] Crystalline Lorundrostat hydrobromide Form LHBr7 may be a hydrate form.

[0105] Crystalline Lorundrostat hydrobromide Form LHBr7 may be characterized by each of the above characteristics alone / or by all possible combinations, e.g. by XRPD pattern having peaks at 7.5, 10.6, 13.7 and 34.7 degrees two theta ± 0.2 degrees two theta and also by the absence of peaks at 8.8, 18.1, 20.9, 23.8, and 24.3 degrees 2-theta ± 0.2 degrees 2-theta and by an XRPD pattern as depicted in FIG. 10.

[0106] Crystalline Lorundrostat hydrobromide Form LHBr7 according to any aspect or embodiment m polymorphically pure. In particular, Form LHBr7 is substantially free of any other crystalline form of Lorundrostat hydrobromide. Particularly, Form LHBr7 contains less than about 10%, less than about 5%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1%, or about 0% (w / w) of any other crystalline form of Lorundrostat hydrobromide. According to any aspect or embodiment of the disclosure, Form LHBr7 may be substantially free of crystalline Lorundrostat hydrobromide Form A. Particularly, Form LHBr7 contains less than about 10%, less than about 5%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1%, or about 0% (w / w) of Lorundrostat hydrobromide Form A.

[0107] Crystalline Lorundrostat hydrobromide Form LHBr7 may have advantageous properties as described herein above. In particular, Form LHBr7 is stable in various stress conditions, including strong grinding, pressure of 2 tons, and heating up to 100 °C. in addition, Form LHBr7 is stable at relative humidity (RH) of about 20-60% at temperature of about 25 °C for a period of at least 7 days, and stable at RH of about 60% at a temperature of about 25 °C for a period of at least 6 months.

[0108] The present disclosure comprises a crystalline Lorundrostat hydrobromide designated as Form LHBr8. Lorundrostat hydrobromide crystalline Form LHBr8 can becharacterized by data selected from one or more of the following: an XRPD pattern having peaks at 11.5, 12.2, 15.8, 16.5, 18.5 and 20.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 11; or combinations of these data.

[0109] Crystalline Lorundrostat hydrobromide Form LHBr8 may be further characterized by an XRPD pattern having peaks at 11.5, 12.2, 15.8, 16.5, 18.5 and 20.6 degrees two theta ± 0.2 degrees two theta, and also having one, two or three additional peaks selected from 14.1, 22.7 and 24.4 degrees two theta ± 0.2 degrees two theta.

[0110] According to any aspect or embodiment, crystalline Lorundrostat hydrobromide Form LHBr8 may be characterized by an XRPD pattern having peaks at 11.5, 12.2, 15.8, 16.5, 18.5 and 20.6 degrees two theta ± 0.2 degrees two theta, and also having one additional peak selected from 14.1, 22.7 and 24.4 degrees two theta ± 0.2 degrees two theta.

[0111] Crystalline Lorundrostat hydrobromide Form LHBr8 may be further characterized by an XRPD pattern having peaks at 11.5, 12.2, 14.1, 15.8, 16.5, 18.5, 20.6, 22.7 and 24.4 degrees two theta ± 0.2 degrees two theta.

[0112] Crystalline Lorundrostat hydrobromide Form LHBr8 may be an anhydrous form.

[0113] Crystalline Lorundrostat hydrobromide Form LHBr8 may be characterized by each of the above characteristics alone / or by all possible combinations, e.g. by XRPD pattern having peaks at 11.5, 12.2, 15.8, 16.5, 18.5 and 20.6 degrees 2-theta ± 0.2 degrees 2-theta and by an XRPD pattern as depicted in FIG. 11, and combinations thereof.

[0114] The present disclosure comprises amorphous Lorundrostat hydrobromide. Amorphous Lorundrostat hydrobromide can be characterized by data selected from one or more of the following: an XRPD pattern that does not include any crystalline peak; an XRPD pattern substantially as depicted in FIG. 8; or combinations of these data.

[0115] Amorphous Lorundrostat hydrobromide may be characterized by each of the above characteristics alone / or by all possible combinations, e.g. by XRPD pattern that does not contain any crystallin peak and an XRPD pattern as depicted in FIG. 8, and combinations thereof.

[0116] The present disclosure comprises a crystalline Lorundrostat hydrochloride designated as Form LHC11. Lorundrostat hydrochloride crystalline Form LHC11 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 7.6, 13.4, 21.0, 22.4, and 26.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 12; or combinations of these data.

[0117] Crystalline Lorundrostat hydrochloride crystalline Form LHC11 may be further characterized by an XRPD pattern having peaks at 7.6, 13.4, 21.0, 22.4, and 26.6 degrees twotheta ± 0.2 degrees two theta, and also having one, two or three additional peaks selected from 17.1, 17.8 and 19.5 degrees two theta ± 0.2 degrees two theta.

[0118] According to any aspect or embodiment, crystalline Lorundrostat hydrochloride crystalline Form LHC11 may be characterized by an XRPD pattern having peaks at 7.6, 13.4, 21.0, 22.4, and 26.6 degrees two theta ± 0.2 degrees two theta, and also having one additional peak selected from 17.1, 17.8 and 19.5 degrees two theta ± 0.2 degrees two theta.

[0119] Crystalline Lorundrostat hydrochloride crystalline Form LHC11 may be further characterized by an XRPD pattern having peaks at 7.6, 13.4, 17.1, 17.8, 19.5 21.0, 22.4, and 26.6 degrees two theta ± 0.2 degrees two theta.

[0120] The above Crystalline Lorundrostat hydrochloride crystalline Form LHC11 is typically a dihydrochloride salt; it may be a hydrate form.

[0121] Crystalline Lorundrostat hydrochloride crystalline Form LHC11 may be characterized by each of the above characteristics alone / or by all possible combinations, e.g. by XRPD pattern having peaks at 7.6, 13.4, 21.0, 22.4, and 26.6 degrees 2-theta ± 0.2 degrees 2-theta and by an XRPD pattern as depicted in FIG. 12, and combinations thereof.

[0122] The present disclosure comprises a crystalline Lorundrostat hydrochloride designated as Form LHC12. Lorundrostat hydrochloride crystalline Form LHC12 can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 9.4, 12.9, 14.4, 18.3 and 31.7 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 13; or combinations of these data.

[0123] Crystalline Lorundrostat hydrochloride crystalline Form LHC12 may be further characterized by an XRPD pattern having peaks at 9.4, 12.9, 14.4, 18.3 and 31.7 degrees two theta ± 0.2 degrees two theta, and also having one, two, three or four additional peaks selected from 15.9 19.9, 25.6 and 26.0 degrees two theta ± 0.2 degrees two theta.

[0124] According to any aspect or embodiment, crystalline Lorundrostat hydrochloride crystalline Form LHC12 may be characterized by an XRPD pattern having peaks at 9.4, 12.9, 14.4, 18.3 and 31.7 degrees two theta ± 0.2 degrees two theta, and also having one additional peak selected from 15.9 19.9, 25.6 and 26.0 degrees two theta ± 0.2 degrees two theta.

[0125] Crystalline Lorundrostat hydrochloride crystalline Form LHC12 may be further characterized by an XRPD pattern having peaks at 9.4, 12.9, 14.4, 15.9, 18.3, 19.9, 25.6, 26.0 and 31.7 degrees two theta ± 0.2 degrees two theta.

[0126] The above Crystalline Lorundrostat hydrochloride crystalline Form LHC12 is typically a mono-hydrochloride salt; it may be an anhydrous form.

[0127] Crystalline Lorundrostat hydrochloride crystalline Form LHC12 may be characterized by each of the above characteristics alone / or by all possible combinations, e.g. by XRPD pattern having peaks at 9.4, 12.9, 14.4, 18.3 and 31.7 degrees 2-theta ± 0.2 degrees 2-theta and by an XRPD pattern as depicted in FIG. 13, and combinations thereof.

[0128] The present disclosure comprises a crystalline Lorundrostat oxalate designated as Form Loxl. Lorundrostat oxalate crystalline Form Loxl can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.2, 11.8, 18.8, 21.0 and21.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in FIG. 14; or combinations of these data.

[0129] Crystalline Lorundrostat oxalate crystalline Form Loxl may be further characterized by an XRPD pattern having peaks at 5.2, 11.8, 18.8, 21.0 and 21.6 degrees two theta ± 0.2 degrees two theta, and also having one, two or three additional peaks selected from 16.6, 23.9,24.6 and 26.3 degrees two theta ± 0.2 degrees two theta.

[0130] Crystalline Lorundrostat oxalate crystalline Form Loxl may be further characterized by an XRPD pattern having peaks at 5.2, 11.8, 18.8, 21.0 and 21.6 degrees two theta ± 0.2 degrees two theta, and also having one, two, three, or four additional peaks selected from 16.6, 23.9, 24.6 and 26.3 degrees two theta ± 0.2 degrees two theta.

[0131] According to any aspect or embodiment, Lorundrostat oxalate crystalline Form Loxl may be characterized by an XRPD pattern having peaks at 5.2, 11.8, 18.8, 21.0 and 21.6 degrees two theta ± 0.2 degrees two theta, and also having one, additional peak selected from 16.6, 23.9, 24.6 and 26.3 degrees two theta ± 0.2 degrees two theta.

[0132] Crystalline Lorundrostat oxalate crystalline Form Loxl may be further characterized by an XRPD pattern having peaks at 5.2, 11.8, 16.6, 18.8, 21.0, 21.6, 23.9, 24.6 and 26.3 degrees two theta ± 0.2 degrees two theta.

[0133] The Crystalline Lorundrostat oxalate crystalline Form Loxl may be a hydrate form.

[0134] Crystalline Lorundrostat oxalate crystalline Form Loxl 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, 11.8, 18.8, 21.0 and 21.6 degrees 2-theta ± 0.2 degrees 2-theta and by an XRPD pattern as depicted in FIG. 14, and combinations thereof.

[0135] In another embodiment of the present disclosure, crystalline Lorundrostat Forms LI and L2, crystalline Lorundrostat hydrobromide Forms LHBrl, LHBr2, LHBr3, LHBr4, LHBr5, LHBr6, LHBr7, LHBr8 and amorphous Lorundrostat hydrobromide are polymorphically and chemically pure.

[0136] In yet another embodiment of the present disclosure, crystalline Lorundrostat hydrochloride Forms LHC11 and LHC12 and crystalline Lorundrostat oxalate form Loxl are polymorphically and chemically pure.

[0137] The present disclosure also relates to a crystalline Lorundrostat Forms LI and L2, crystalline Lorundrostat hydrobromide Forms LHBrl, LHBr2, LHBr3, LHBr4, LHBr5, LHBr6, LHBr7, LHBr8 and amorphous Lorundrostat hydrobromide as well as crystalline Lorundrostat hydrochloride Forms LHC11 and LHC12 and crystalline Lorundrostat oxalate form Loxl which are obtainable by any process as described herein. The said process can include the process set out in the examples herein below.

[0138] The present disclosure also relates to preparation of other solid state forms of Lorundrostat, and to preparation of additional Lorundrostat salts and their solid state form. The said process comprises preparation of any one or a combination of crystalline Lorundrostat Forms LI and L2, crystalline Lorundrostat hydrobromide Forms LHBrl, LHBr2, LHBr3, LHBr4, LHBr5, LHBr6, LHBr7, LHBr8 and amorphous Lorundrostat hydrobromide or crystalline Lorundrostat hydrochloride Forms LHC11 and LHC12 and crystalline Lorundrostat oxalate form Loxl as described herein and converting them to other form of Lorundrostat or to other salt of Lorundrostat.

[0139] The present disclosure also relates to a pharmaceutical composition comprising any one or a combination of crystalline Lorundrostat Forms LI and L2, crystalline Lorundrostat hydrobromide Forms LHBrl, LHBr2, LHBr3, LHBr4, LHBr5, LHBr6, LHBr7, LHBr8 and amorphous Lorundrostat hydrobromide or crystalline Lorundrostat hydrochloride Forms LHC11 and LHC12 and crystalline Lorundrostat oxalate form Lox las described herein, or any one or a combination of crystalline Lorundrostat Forms LI and L2, crystalline Lorundrostat hydrobromide Forms LHBrl, LHBr2, LHBr3, LHBr4, LHBr5, LHBr6, LHBr7, LHBr8 and amorphous Lorundrostat hydrobromide or crystalline Lorundrostat hydrochloride Forms LHC11 and LHC12 and crystalline Lorundrostat oxalate form Loxl which are obtainable by any process as described herein below.

[0140] The invention further comprises a process for preparing a pharmaceutical composition comprising any one or a combination of crystalline Lorundrostat Forms LI and L2, crystalline Lorundrostat hydrobromide Forms LHBrl, LHBr2, LHBr3, LHBr4, LHBr5, LHBr6, LHBr7, LHBr8 and amorphous Lorundrostat hydrobromide, or crystalline Lorundrostat hydrochloride Forms LHC11 and LHC12 and crystalline Lorundrostat oxalate form Loxl wherein the process comprises combining any one or a combination of crystalline Lorundrostat Forms LI and L2, crystalline Lorundrostat hydrobromide Forms LHBrl, LHBr2,LHBr3, LHBr4, LHBr5, LHBr6, LHBr7, LHBr8, amorphous Lorundrostat hydrobromide, crystalline Lorundrostat hydrochloride Forms LHC11 and LHC12 or crystalline Lorundrostat oxalate form Loxl with at least one pharmaceutically acceptable excipient. The invention further comprises a process for preparing crystalline Lorundrostat Forms LI and L2, crystalline Lorundrostat hydrobromide Forms LHBrl, LHBr2, LHBr3, LHBr4, LHBr5, LHBr6, LHBr7, LHBr8, amorphous Lorundrostat hydrobromide, crystalline Lorundrostat hydrochloride Forms LHC11 and LHC12 or crystalline Lorundrostat oxalate form Loxl as described herein below and further comprising combining any one or a combination of crystalline Lorundrostat LI and L2, crystalline Lorundrostat hydrobromide Forms LHBrl, LHBr2, LHBr3, LHBr4, LHBr5, LHBr6, LHBr7, LHBr8, amorphous Lorundrostat hydrobromide, crystalline Lorundrostat hydrochloride Forms LHC11 and LHC12 or crystalline Lorundrostat oxalate form Loxl with at least one pharmaceutically acceptable excipient.

[0141] The present disclosure also provides for processes for the preparation of the solid state forms of Lorundrostat and Lorundrostat hydrobromide. The said process can include the process set out in the examples herein below.

[0142] In another aspect, the present disclosure encompasses the above described solid state forms of Lorundrostat, Lorundrostat hydrobromide Lorundrostat hydrochloride and Lorundrostat oxalate for use in the preparation of pharmaceutical compositions and / or formulations, preferably for use in medicine, preferably for treating uncontrolled hypertension and CKD.

[0143] In another aspect, the present disclosure encompasses the use of the above described solid state forms of Lorundrostat, Lorundrostat hydrobromide, Lorundrostat hydrochloride and Lorundrostat oxalate for the preparation of pharmaceutical compositions and / or formulations, preferably for use in medicine, preferably for treating uncontrolled hypertension and CKD.

[0144] In yet another embodiment, the present disclosure encompasses pharmaceutical compositions comprising any one of the solid state forms of Lorundrostat, Lorundrostat hydrobromide, Lorundrostat hydrochloride and Lorundrostat oxalate.

[0145] In specific embodiment, the present disclosure encompasses pharmaceutical formulation comprising any one of the solid state forms of Lorundrostat, Lorundrostat hydrobromide, Lorundrostat hydrochloride and Lorundrostat oxalate and at least one pharmaceutically acceptable excipient.

[0146] The present disclosure further encompasses processes to prepare said pharmaceutical formulations of Lorundrostat, Lorundrostat hydrobromide, Lorundrostat hydrochloride and Lorundrostat oxalate comprising combining any one of the above describedsolid state forms of Lorundrostat, Lorundrostat hydrobromide, Lorundrostat hydrochloride and Lorundrostat oxalate or pharmaceutical compositions comprising them, and at least one pharmaceutically acceptable excipient.

[0147] The present disclosure comprises processes for preparing the above mentioned pharmaceutical compositions. The processes comprise combining any one of the above described crystalline polymorph of Lorundrostat, Lorundrostat hydrobromide, Lorundrostat hydrochloride and Lorundrostat oxalate of the present disclosure with at least one pharmaceutically acceptable excipient.

[0148] Pharmaceutical formulations of the present invention contain the crystalline polymorphs of Lorundrostat and Lorundrostat hydrobromide of the present invention, particularly crystalline Lorundrostat Forms LI and L2, crystalline Lorundrostat hydrobromide Forms LHBrl, LHBr2, LHBr3, LHBr4 and LHBr5, amorphous Lorundrostat hydrobromide crystalline Lorundrostat hydrochloride Forms LHC11 and LHC12 or crystalline Lorundrostat oxalate form Loxl. In addition to the active ingredient, the pharmaceutical formulations of the present invention can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[0149] Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] In liquid pharmaceutical compositions of the present invention, Lorundrostat and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0157] 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 presentinvention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0158] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and / or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.

[0159] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0160] 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.

[0161] According to the present invention, 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.

[0162] The solid compositions of the present invention 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 invention 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.

[0163] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0164] The dosage form of the present invention can be a capsule containing the composition, preferably 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.

[0165] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0166] 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, which 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] The solid state forms of Lorundrostat as defined herein as well as the pharmaceutical compositions or formulations comprising them can be used as medicaments, particularly for treating uncontrolled hypertension and CKD, comprising administering a therapeutically effective amount of the solid state form of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from uncontrolled hypertension and CKD, or otherwise in need of the treatment.

[0171] The present disclosure also provides the uses of the solid state form of Lorundrostat of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, for the manufacture of medicaments for treating uncontrolled hypertension and CKD.

[0172] Having described the disclosure with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of thespecification. 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

[0173] Powder X-ray Diffraction was performed on an X-Ray powder diffractometer Bruker D8 Advance; CuK radiation ( = 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.

[0174] 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 with silicon low background.

[0175] All X-Ray Powder Diffraction peak values are calibrated with regard to standard silicon spiking in the sample.EXAMPLES

[0176] Lorundrostat and Lorundrostat hydrobromide starting materials used in the examples below, can be obtained by any procedure described in the literature, for example using the syntheses procedure reported in U.S. patent No. 10,029,993 and U.S. Patent Application Publication No. 2023 / 0365513. Amorphous Lorundrostat hydrobromide can be prepared according to Examples 9 or 19 below.Example 1: Preparation of Lorundrostat Form LI

[0177] Lorundrostat (0.025g) was dissolved in a solvent mixture of dichloromethane and methanol (1 : 1, 2 ml) at 40 °C. The clear solution was cooled to 25 °C and maintained for 4 hours at 25 °C under stirring. The obtained solid was isolated by filtration and analyzed by XRPD to obtain Lorundrostat designated Form LI (FIG. 1).Example 2: Preparation of Lorundrostat Form L2

[0178] Lorundrostat (0.025g, form LI) was suspended in 1 ml of formamide at -10 °C. Mixture of aq. HBr (47%, 4 pl) and water (6 pl) were added to above suspension at -10 °C and kept for 18 hours under stirring. The reaction mass was heated to at about 25 °C and the reaction mass was isolated by filtration and analyzed by XRPD to obtain Lorundrostat designated Form L2 (FIG. 2).Example 3: Preparation of Lorundrostat hydrobromide Form LHBrl

[0179] Amorphous Lorundrostat Hydrobromide (0.03g) was suspended in n-heptane (2 ml) at 0-5 °C and maintained at 0-5 °C for 20 hours. The reaction mass was heated to about 25 °C, filtered, dried under vacuum for 20-25 minutes and analyzed by XRPD to obtain Lorundrostat hydrobromide designated Form LHBrl (FIG. 3).Example 4: Preparation of Lorundrostat hydrobromide Form LHBrl

[0180] Amorphous Lorundrostat hydrobromide (0.03g) was suspended in water (2 ml) at 0- 5 °C and maintained at 25 °C for 2 hours under stirring. The reaction mass was filtered, dried under vacuum for 20-25 minutes and analyzed by XRPD to obtain Lorundrostat hydrobromide designated Form LHBrl.Example 5: Preparation of Lorundrostat hydrobromide Form LHBrl

[0181] Lorundrostat hydrobromide Form LHBrl (0.05g) was dried in vacuum tray drier (VTD) at about 50-55 °C for 2 hours. The obtained solid was analyzed by XRD and designated as Lorundrostat Form LHBr2 (FIG. 4).Example 6: Preparation of Lorundrostat hydrobromide Form LHBr3

[0182] Amorphous Lorundrostat Hydrobromide (0.1g) was kept in a humidity chamber at 100%RH, 20-25 °C and for 2-days. The obtained solid was analyzed by XRPD and designated as Lorundrostat Form LHBr3 (FIG. 5).Example 7: Preparation of Lorundrostat hydrobromide Form LHBr4

[0183] Amorphous Lorundrostat hydrobromide (0.1g) was dissolved in N-Methyl Pyrrolidone (NMP, 0.3ml) at 25 °C. The solution was slowly cooled to 5 °C and maintained for 20 hours at about 5 °C under stirring. The solid was isolated by filtration and analyzed by XRPD to obtain Lorundrostat hydrobromide designated Form LHBr4 (FIG. 6).Example 8: Preparation of Lorundrostat hydrobromide Form LHBr5

[0184] Amorphous Lorundrostat hydrobromide (0.05g) was dissolved in 0.15 ml of dimethyl sulfoxide (DMSO) at 75 °C and the clear solution was sudden cooled to -10 °C to obtain precipitation. The reaction mass was heated to at about 25 °C and the obtained solid was isolated by filtration and analyzed by XRPD to obtain Lorundrostat hydrobromide designated Form LHBr5 (FIG. 7).Example 9: Preparation of amorphous Lorundrostat hydrobromide

[0185] Lorundrostat Hydrobromide (0.5) was dissolved in mixture of dichloromethane and Methanol (1 : 1, lOmL) at 50-55 °C. The clear solution was distilled under reduced pressure (below 50 mbar) by using rotary evaporator at 50-55 °C for 30-45 minutes. The obtained solid was isolated and analyzed by XRPD to obtain amorphous Lorundrostat hydrobromide (FIG. 8).Example 10: Preparation of Lorundrostat hydrobromide Form LHBr6

[0186] Lorundrostat Hydrobromide (0.1 g) was dissolved in ethanol water mixture (ratio 1 : 1, total volume 2 ml) at a temperature of about 65 °C. The obtained clear solution was cooled down to a temperature of about -10 °C over a period of about 1.5 hour. The clear solution maintained at a temperature of about -10 °C for about 36 hours, and during this time a solid was formed. The obtained white solid was filtered and vacuum-dried for about 10 minutes at a temperature of about 25 °C. The obtained white solid was analyzed by XRD and designated as Lorundrostat Form LHBr6. A PXRD pattern is shown in FIG. 9.

[0187] Form LHBr6 is a Hydrate of Lorundrostat Hydrobromide.Example 11: Preparation of Lorundrostat hydrobromide Form LHBr6

[0188] Lorundrostat Hydrobromide (Amorphous, 1 g) was dissolved in Acetone-water mixture (ratio, 80:20, total volume 18 ml) at a temperature of about 50 °C and a clear solution obtained. The clear solution was added into a pre-cooled isobutyl acetate (75ml) at a temperature of about 0 °C in a reactor. The reaction mixture was maintained under stirring at a temperature of about 0 °C for a period of about 18 hours. The obtained solid was filtered and vacuum-dried for a period of about 10-15 minutes. The solid was analyzed by XRD and designated as Form LHBr6.Example 12: Preparation of Lorundrostat hydrobromide Form LHBr7

[0189] Lorundrostat Hydrobromide (0.1 g) was dissolved in ethanol water mixture (ratio 1 : 1, total volume 2 ml) at a temperature of about 65 °C. The obtained clear solution was cooled down to a temperature of about -10 °C over a period of about 1.5 hour. The clear solution maintained at a temperature of about -10 °C for 36 hours, and during this time a solid was formed. The obtained white solid (LHBr6) was filtered and vacuum-dried at about 25 °C for about 10 minutes. Then, the product was dried under vacuum for about 2 hours at about 50 °C. The dry solid was analyzed by PXRD and designated as Lorundrostat Hydrobromide Form LHBr7. A PXRD pattern is shown in FIG. 10.

[0190] Form LHBr7 is a Hydrate of Lorundrostat Hydrobromide.Example 13: Preparation of Lorundrostat hydrobromide Form LHBr8

[0191] Lorundrostat Hydrobromide (0.4g, Amorphous) was dissolved in methanol (10 mL) at a temperature of about 55 °C and a clear solution was formed. The clear solution added into Vinyl acetate (50 mL) which was pre-kept at a temperature of about 55 °C and the reaction mass maintained at about 55 °C for a period of about 4 to about 5 hours. The obtained solid was filtered and dried in Vacuum tray drier at a temperature of about 50 °C for about 2 hours. The obtained solid analyzed by XRD and designated as Form LHBr8. A PXRD pattern is shown in FIG. 11.Example 14: Preparation of Lorundrostat hydrochloride Form LHC11

[0192] Lorundrostat (0.05g) was suspended in acetone in (3 ml) at a temperature of about 25-30 °C and then IPA.HC1 (18%) (0.04 ml, 2 mole) was added. The reaction mass was stirred at about 25-30 °C and was maintained for about 1 hour. The reaction mass was filtered and dried under vacuum at a temperature of about 25 °C for a period of about 20-25 minutes. Then, the solid was further dried at a temperature of about 60 °C in a vacuum tray drier for about 2 hours. The obtained solid was analyzed by XRD and designated as Form LHC11. A PXRD pattern is shown in FIG. 12.

[0193] Form LHC11 is crystalline DiHCl salt of Lorundrostat.Example 15: Preparation of Lorundrostat hydrochloride Form LHC12

[0194] Lorundrostat (0.05g) was suspended in acetone (3 ml) at a temperature of about 25- 30 °C and then IPA.HC1 (18%) (0.02ml, 1 mole) was added. The reaction mass was stirred at about 25-30 °C and was maintained for about 1 hour. The reaction mass was filtered and dried under vacuum at a temperature of about 25 °C for 20-25 minutes. Then, the solid was further dried at about 60 °C in a vacuum tray drier for about 2 hours. The obtained solid was analyzed by XRD and designated as Form LHC12. A PXRD pattern is shown in FIG. 13.

[0195] Form LHC12 is crystalline mono HC1 salt of Lorundrostat.Example 16: Preparation of Lorundrostat oxalate Form Loxl

[0196] Lorundrostat (0.05g) was suspended in acetone (3 ml) at a temperature of about 60 °C. Then, oxalic acid (l lmg, 1 mole) was added to the above reaction mass and the reaction mass was maintained at a temperature of about 60 °C for a period of about 20 hours. The reaction mass was maintained at room temperature until temperature was cooled down to about 25 °C and then filtered and dried under vacuum for about 20-25 minutes. Then, the solid was further dried at a temperature of about 60 °C in a vacuum tray drier for about 2 hours. Theobtained solid was analyzed by XRD and designated as Form Loxl . A PXRD pattern is shown in FIG. 14.

[0197] Form Loxl is crystalline oxalate salt of Lorundrostat.Example 17: Preparation of Lorundrostat hydrobromide Form LHBr2

[0198] Lorundrostat Hydrobromide salt (0.5g, Amorphous) was suspended in water (10 ml) at 5-10 °C. The reaction mass was maintained at a temperature of about 5-10 °C for 5 hours. The reaction mass was maintained at room temperature until temperature reached about 25 °C and then it was filtered and dried under vacuum for about 20-25 minutes. The obtained solid was analyzed by XRD Form LHBrl obtained. Then, the LHBrl was dried under vacuum for 2 hours at a temperature of 55 °C. The dry solid was analyzed by XRD, Lorundrostat Hydrobromide Form LHBr2 obtained.

[0199] Form LHBr2 obtained in this example is a hydrate form.Example 18: Preparation of Lorundrostat hydrobromide Form LHBr7

[0200] Lorundrostat hydrobromide (Amorphous, 1 g) was dissolved in Acetone-water (80:20) (18 ml) at a temperature of about 50 °C and a clear solution was formed. The clear solution was added into a pre-cooled isobutyl acetate (75ml) at a temperature of about 0 °C in a reactor. The reaction mixture was maintained under stirring at about 0 °C for about 18 hours. The obtained solid was filtered and suck-dried for 10-15 minutes. The solid was analyzed by XRD, Form LHBr6 obtained. Then, the LHBr6 was dried under vacuum for about 2 hours at about 50 °C. The dry solid was analyzed by XRD, Lorundrostat Hydrobromide Form LHBr7 obtained.

[0201] Form LHBr7 obtained in this example is a hydrate.Example 19: Preparation of amorphous Lorundrostat hydrobromide

[0202] Lorundrostat Hydrobromide (0.5 g) was dissolved in mixture of di chloromethane and Methanol (1 : 1, lOmL) at 50-55 °C. The clear solution was distilled under reduced pressure (below 50 mbar) by using rotary evaporator at 50-55 °C for 30-45 minutes. The obtained solid was isolated and analyzed by XRPD to obtain amorphous Lorundrostat hydrobromide (FIG. 8).

Claims

CLAIMS:

1. Crystalline Lorundrostat hydrobromide Form LHBr2, which is characterized by data selected from one or more of the following:(a) an XRPD pattern having characteristic peaks at 10.7, 16.9, 18.4 and 24.8 degrees 2-theta ± 0.2 degrees 2-theta;(b) an XRPD pattern as depicted in Figure 4; or(c) any combinations thereof.

2. The crystalline Lorundrostat hydrobromide Form LHBr2 according to Claim 1, which is characterised by an X-ray powder diffraction pattern having peaks at 10.7, 16.9, 18.4 and 24.8 degrees two theta ± 0.2 degrees two theta; and also having one, two or three additional peaks selected from 13.8, 16.1 and 19.6 degrees 2-theta ± 0.2 degrees 2- theta.

3. The crystalline Lorundrostat hydrobromide Form LHBr2 according to Claim 1 or Claim 2, which is characterized by an XRPD pattern having characteristic peaks at 10.7, 13.8, 16.1, 16.9, 18.4, 19.6 and 24.8 degrees 2-theta ± 0.2 degrees 2-theta.

4. The crystalline Lorundrostat hydrobromide Form LHBr2 according to any of Claim 1, Claim 2, or Claim 3, which is isolated.

5. The crystalline Lorundrostat hydrobromide Form LHBr2 according to any of Claim 1, Claim 2, Claim 3, or Claim 4, which is a hydrate form.

6. The crystalline Lorundrostat hydrobromide Form LHBr2 according to any of Claim 1, Claim 2, Claim 3, Claim 4, or Claim 5, 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 Lorundrostat hydrobromide.

7. The crystalline Lorundrostat hydrobromide Form LHBr2 according to any preceding claim, 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 Lorundrostat hydrobromide.

8. The crystalline Lorundrostat hydrobromide Form LHBr2 according to any preceding claim, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Lorundrostat hydrobromide.

9. Crystalline Lorundrostat hydrobromide Form LHBr7, which is characterized by data selected from one or more of the following:(a) an XRPD pattern having characteristic peaks at 7.5, 10.6, 13.7 and 34.7 degrees 2-theta ± 0.2 degrees 2-theta and also by the absence of peaks at 8.8, 18.1, 20.9, 23.8, and 24.3 degrees 2-theta ± 0.2 degrees 2-theta;(b) an XRPD pattern as depicted in Figure 10; or(c) any combinations thereof.

10. The crystalline Lorundrostat hydrobromide Form LHBr7 according to Claim 9, which is characterised by an X-ray powder diffraction pattern having peaks at 7.5, 10.6, 13.7 and 34.7 degrees 2-theta ± 0.2 degrees 2-theta and also by the absence of peaks at 8.8, 18.1, 20.9, 23.8, and 24.3 degrees 2-theta ± 0.2 degrees 2-theta; and also having one, two or three additional peaks selected from 11.3, 22.8 and 26.8 degrees 2-theta ± 0.2 degrees 2- theta.

11. The crystalline Lorundrostat hydrobromide Form LHBr7 according to Claim 9 or Claim 10, which is characterized by an XRPD pattern having characteristic peaks at 7.5, 10.6,11.3, 13.7, 22.8, 26.8 and 34.7 degrees two theta ± 0.2 degrees two theta and also by the absence of peaks at 8.8, 18.1, 20.9, 23.8, and 24.3 degrees 2-theta ± 0.2 degrees 2-theta.

12. The crystalline Lorundrostat hydrobromide Form LHBr7 according to any of Claim 9, Claim 10 or Claim 11, which is isolated.

13. The crystalline Lorundrostat hydrobromide Form LHBr7 according to any of Claim 9, Claim 10 or Claim 11 or Claim 12, which is a hydrate form.

14. The crystalline Lorundrostat hydrobromide Form LHBr7 according to any of Claim 9, Claim 10, Claim 11, Claim 12, or Claim 13, 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 Lorundrostat hydrobromide.

15. The crystalline Lorundrostat hydrobromide Form LHBr7 according to any of Claim 9, Claim 10, Cairn 11, Claim 12, Claim 13 or Claim 14 which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Lorundrostat hydrobromide.

16. Use of the crystalline Lorundrostat hydrobromide Forms LHBr2 or LHBr7 according to any of Claims 1-15 for the preparation of a pharmaceutical composition and / or formulation, preferably wherein the pharmaceutical formulation is a tablet or capsule.

17. A pharmaceutical composition comprising the crystalline Lorundrostat hydrobromide Forms LHBr2 or LHBr7 according to any of Claims 1-15.

18. A process for preparing the pharmaceutical composition according to Claim 17, comprising: combining the crystalline Lorundrostat hydrobromide Forms LHBr2 orLHBr7 according to any of Claims 1-15 with at least one pharmaceutically acceptable excipient.

19. The crystalline Lorundrostat hydrobromide Forms LHBr2 or LHBr7 according to any of Claims 1-15, or a pharmaceutical composition according to Claim 17, for use as a medicament.

20. The crystalline Lorundrostat hydrobromide Forms LHBr2 or LHBr7 according to any of Claims 1-15, or a pharmaceutical composition according to Claim 17, for use in the treatment of uncontrolled hypertension and / or chronic kidney disease (CKD).

21. A method of treating uncontrolled hypertension and / or chronic kidney disease (CKD), comprising: administering a therapeutically effective amount of the crystalline Lorundrostat hydrobromide Forms LHBr2 or LHBr7 according to any of Claims 1-15, or a pharmaceutical composition according to Claim 17, to a subject in need of the treatment.

22. Use of the crystalline Lorundrostat hydrobromide Forms LHBr2 or LHBr7 according to any of Claims 1-15 in the preparation of another solid-state form of Lorundrostat, Lorundrostat hydrobromide or other Lorundrostat salt.

23. A process for preparing a solid state form of Lorundrostat, Lorundrostat hydrobromide or other Lorundrostat salt comprising: preparing any one or a combination of the crystalline Lorundrostat hydrobromide Forms LHBr2 or LHBr7 according to any one of Claims 1-15, and converting it to another a solid state form thereof.

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