Solid state forms of nirogacestat dihydrochloride salt

Abstract

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

Description

SOLID STATE FORMS OF NIROGACESTAT DIHYDROCHLORIDE SALTCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, Indian Provisional Application No. 202411055130 filed July 19, 2024; Indian Provisional Application No. 202411063869 filed August 23, 2024; Indian Provisional Application No. 202411085127 filed November 6, 2024; Indian Provisional Application No. 202511007398 filed January 29, 2025, and Indian Provisional Application No. 202511065020 filed July 8, 2025. The entire contents of the foregoing applications are incorporated by reference herein.FIELD OF THE DISCLOSURE

[0002] The present disclosure encompasses solid state forms of Nirogacestat hydrochloride salt, in embodiments crystalline polymorphs of Nirogacestat hydrochloride sallt, processes for preparation thereof, and pharmaceutical compositions thereof.BACKGROUND OF THE DISCLOSURE

[0003] Nirogacestat, S)-2-(((S)-6,8-dif!uoro-l,2,3,4-tetrahydronaphthalen-2-yl)amino)-N- (l-(2-methyl-l-(neopentylamino) propan-2-yl)-lH-imidazol-4-yl)pentanamide, has the following chemical structure:

[0004] Nirogacestat (is a selective gamma secretase (GS) inhibitor with potential antitumor activity. In particular, it has been investigated as a monotherapy for patients with desmoid tumors. Nirogacestat is also under clinical investigation for the treatment of ovarian granulosa cell tumors (OvGCTs), Aggressive Fibromatosis (AF).

[0005] The compound is described in U.S. Patent No. 7,795,447. The entire contents of the foregoing patent are incorporated by reference herein. International Publication Nos. WO2021 / 029854 and WO2023 / 174390 disclose polymorphs of Nirogacestat dihydrobromide salt and amorphous Nirogacestat dihydrobromide salt. The entire contents of the foregoing publications are incorporated by reference herein.

[0006] International Publication No. WO2023 / 096954 discloses polymorphs of different salts of Nirogacestat; including crystalline form of Nirogacestat hydrochloride salt. The entire contents of the foregoing application are incorporated by reference herein.

[0007] International Publication No. WO2023 / 174390 discloses polymorphs of Nirogacestat dihydrobromide.

[0008] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (“XRD”) pattern, infrared absorption fingerprint, and solid state (13C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0009] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

[0010] Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical / physicalstability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Nirogacestat and of Nirogacestat salts.SUMMARY OF THE DISCLOSURE

[0011] The present disclosure provides crystalline polymorphs of Nirogacestat hydrochloride salt and Nirogacestat dihydrochloride salt, processes for preparation thereof, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other forms of Nirogacestat or of Nirogacestat salts.

[0012] The present disclosure provides crystalline polymorphs of Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride salt for use in the preparation of pharmaceutical compositions and / or formulations for use in medicine, in embodiment as an antitumor agent. In particular, as a monotherapy for patients with desmoid tumors, or for the treatment of ovarian granulosa cell tumors (OvGCTs) and Aggressive Fibromatosis (AF).

[0013] The present disclosure provides crystalline polymorphs of Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride salt for use in medicine, including as an antitumor agent (in particular; in patients suffering from desmoid tumors, or patients suffering from ovarian granulosa cell tumors (OvGCTs) and Aggressive Fibromatosis (AF).

[0014] The present disclosure also encompasses the use of crystalline polymorphs of Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride salt of the present disclosure for the preparation of pharmaceutical compositions and / or formulations.

[0015] In another aspect, the present disclosure provides pharmaceutical compositions comprising any one or a combination of the crystalline polymorphs of Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride salt according to the present disclosure.

[0016] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorphs of Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride salt with at least one pharmaceutically acceptable excipient.

[0017] The crystalline polymorphs of Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride salt as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorphs of Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride salt may be used as medicaments, such as for the treatment of desmoid tumors, or for the treatment of ovarian granulosa cell tumors (OvGCTs) and Aggressive Fibromatosis (AF).

[0018] The present disclosure also provides methods of treating desmoid tumors by administering a therapeutically effective amount of any one or a combination of the crystallinepolymorphs of Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride salt of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from desmoid tumors, or to a subject suffering from ovarian granulosa cell tumors (OvGCTs) and Aggressive Fibromatosis (AF). or otherwise in need of the treatment.

[0019] The present disclosure also provides uses of crystalline polymorphs of Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride salt of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating tumors, e.g., desmoid tumors, or ovarian granulosa cell tumors (OvGCTs), or Aggressive Fibromatosis (AF).BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1 shows a characteristic powder X-ray diffraction (“XRPD”) pattern of Nirogacestat hydrochloride salt-Form NHC12.

[0021] FIG. 2 shows a characteristic XRPD pattern of Nirogacestat hydrochloride salt- Form NHC13.

[0022] FIG. 3 shows a characteristic XRPD pattern of Nirogacestat hydrochloride salt- Form NHC14.

[0023] FIG. 4 shows a characteristic XRPD pattern of Nirogacestat hydrochloride salt- Form NHC15.

[0024] FIG. 5 shows a characteristic XRPD pattern of Nirogacestat hydrochloride salt- Form NHC11.

[0025] FIG. 6 shows a characteristic XRPD pattern of Nirogacestat dihydrochloride salt- Form NHC16.

[0026] FIG. 7 shows a characteristic XRPD pattern of Nirogacestat dihydrochloride salt- Form NHC17.

[0027] FIG. 8 shows a characteristic XRPD pattern of Nirogacestat R-mandelate salt-Form NM1.

[0028] FIG. 9 shows a characteristic XRPD pattern of Nirogacestat Di-p-toluyl D-tartaric acid salt (“Nirogacestat DTTA salt”)-Form 1.

[0029] FIG. 10 shows a characteristic XRPD pattern of Nirogacestat Dibenzoyl -L-tartaric acid salt (“Nirogacestat DBTA salt”)-Form 1.

[0030] Fig 11 shows a characteristic XRPD pattern of Nirogacestat dihydrochloride salt- Form NHC18.

[0031] Fig 12 shows a characteristic XRPD pattern of Nirogacestat dihydrochloride salt- Form NHC19.

[0032] Fig 13 shows a characteristic XRPD pattern of Nirogacestat dihydrochloride salt- Form NHC110.

[0033] Fig 14 shows a characteristic XRPD pattern of Nirogacestat dihydrochloride salt- Form NHC111.

[0034] Fig 15 shows a characteristic XRPD pattern of Nirogacestat dihydrochloride salt- Form NHC112.

[0035] Fig 16 shows a characteristic XRPD pattern of Nirogacestat dihydrochloride salt- Form NHC113.

[0036] Fig 17 shows a characteristic XRPD pattern of Nirogacestat- Form Nl.DETAILED DESCRIPTION OF THE DISCLOSURE

[0037] The present disclosure encompasses solid state forms of Nirogacestat salts, processes for preparation thereof, and pharmaceutical compositions thereof.

[0038] In particular, the present invention discloses solid state forms of Nirogacestat hydrochloride salt and Nirogacestat dihydrochloride salt; process for preparation thereof, and pharmaceutical compositions thereof.

[0039] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression “substantially free of any other forms” will be understood to mean that the solid state form contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. Thus, a crystalline polymorph of Nirogacestat hydrochloride salt described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the subject crystalline polymorph of Nirogacestat hydrochloride salt. In some embodiments of the disclosure, the described crystalline polymorph of Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more other crystalline polymorph of Nirogacestat and / or of Nirogacestat salt.

[0040] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate,morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and / or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density. In particular, crystalline Nirogacestat dihydrochloride salts of the present disclosure have excellent stability to storage and other conditions. Crystalline Nirogacestat dihydrochloride salts of the present disclosure may have good powder properties, such as flowability and compressibility.

[0041] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially 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 cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Nirogacestat salt referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be to include any crystal forms of Nirogacestat salts characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0042] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of Nirogacestat salt which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w / w), of either water or organic solvents as measured for example by TGA.

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

[0045] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature”, often abbreviated as “RT ” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0046] 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 solvent X (1.5 v / v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.

[0047] A process or step may be referred to herein as being carried out “overnight.” This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.

[0048] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.

[0049] As used herein and unless indicated otherwise, the term “ambient conditions” refer to atmospheric pressure and a temperature of 22-24°C.

[0050] As used herein, the term “hydrochloride salt” can be used to describe monohydrochloride, dihydrochloride or trihydrochloride salt.

[0051] The present disclosure includes a crystalline polymorph of Nirogacestat hydrochloride salt- designated NHC12. The crystalline Form NHC12 of Nirogacestat hydrochloride salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 1; an X-ray powderdiffraction pattern having peaks at 3.9, 8.5, 11.4, 15.1 and 15.7 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0052] Crystalline Form NHC12 of Nirogacestat hydrochloride salt may be further characterized by an X-ray powder diffraction pattern having peaks at 3.9, 8.5, 11.4, 15.1 and 15.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 5.9, 14.8, 20.2 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0053] In a further embodiment, the crystalline Form NHC12 of Nirogacestat hydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks at: 3.9, 5.9, 8.5, 11.4, 14.8, 15.1, 15.7, 20.2 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0054] Crystalline Form NHC12 of Nirogacestat hydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at any one, two or three of (a), (b) and / or (c): (a)4.4 to 4.5 degrees 2-theta ± 0.2 degrees 2-theta; (b) 10.3 to 10.6 degrees 2-theta ± 0.2 degrees 2-theta; and (c) 12.1 to 12.4 degrees 2-theta ± 0.2 degrees 2-theta. In particular, crystalline Form NHC12 of Nirogacestat hydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at: (a) alone; or (b) alone; or (c) alone; or (a) and (b) in combination; or (a) and (c) in combination; or (b) and (c) in combination; or (a), (b) and (c) in combination.

[0055] Crystalline Form NHC12 is hydrochloride salt; preferably, dihydrochloride salt.

[0056] In one embodiment of the present disclosure, crystalline Form NHC12 of Nirogacestat hydrochloride salt is isolated.

[0057] Crystalline Form NHC12 may be anhydrous.

[0058] In a further embodiment, the present disclosure includes a crystalline polymorph of Nirogacestat hydrochloride salt- designated NHC13. The crystalline Form NHC13 of Nirogacestat hydrochloride salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 2; an X-ray powder diffraction pattern having peaks at 8.7, 9.4, 20.7, 21.9 and 26.4 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0059] Crystalline Form NHC13 of Nirogacestat hydrochloride salt may be further characterized by an X-ray powder diffraction pattern having peaks at 8.7, 9.4, 20.7, 21.9 and26.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 10.3, 16.5 and 17.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0060] In a further embodiment, the crystalline Form NHC13 of Nirogacestat hydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks at: 8.7, 9.4, 10.3, 16.5, 17.7, 20.7, 21.9 and 26.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0061] Crystalline Form NHC13 is hydrochloride salt; preferably, dihydrochloride salt.

[0062] In one embodiment of the present disclosure, crystalline Form NHC13 of Nirogacestat hydrochloride salt is isolated.

[0063] Crystalline Form NHC13 may be a solvate; preferably 2-butanol and / or hydrate.

[0064] The present disclosure also discloses a crystalline polymorph of Nirogacestat hydrochloride salt- designated NHC14. The crystalline Form NHC14 of Nirogacestat hydrochloride salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 3; an X-ray powder diffraction pattern having peaks at 9.8, 10.9, 17.8, 18.2 and 27.5 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0065] Crystalline Form NHC14 of Nirogacestat hydrochloride salt may be further characterized by an X-ray powder diffraction pattern having peaks at 9.8, 10.9, 17.8, 18.2 and 27.5 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 9.1, 26.5 and 29.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0066] In a further embodiment, the crystalline Form NHC14 of Nirogacestat hydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks at: 9.1, 9.8, 10.9, 17.8, 18.2, 26.5, 27.5 and 29.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0067] Crystalline Form NHC14 is hydrochloride salt; preferably, dihydrochloride salt.

[0068] In one embodiment of the present disclosure, crystalline Form NHC14 of Nirogacestat hydrochloride salt is isolated.

[0069] Crystalline Form NHC14 may be anhydrous.

[0070] The present disclosure provides a crystalline polymorph of Nirogacestat hydrochloride salt- designated NHC15. The crystalline Form NHC15 of Nirogacestat hydrochloride salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 4; an X-ray powder diffraction pattern having peaks at 6.1, 7.2, 10.4, 13.2 and 22.9 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0071] Crystalline Form NHC15 of Nirogacestat hydrochloride salt may be further characterized by an X-ray powder diffraction pattern having peaks at 6.1, 7.2, 10.4, 13.2 and 22.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 8.4, 9.9 and 10.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0072] In a further embodiment, the crystalline Form NHC15 of Nirogacestat hydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks at: 6.1, 7.2, 8.4, 9.9, 10.4, 10.9, 13.2 and 22.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0073] Crystalline Form NHC15 of Nirogacestat hydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at either: 3.8 to 4.3 degrees 2-theta ± 0.2 degrees 2-theta, or at 3.8 to 5.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0074] Crystalline Form NHC15 is hydrochloride salt; preferably, dihydrochloride salt. In one embodiment of the present disclosure, crystalline Form NHC15 of Nirogacestat hydrochloride salt is isolated.

[0075] Crystalline Form NHC15 may be hydrate; preferably monohydrate.

[0076] The above crystalline polymorphs of Nirogacestat hydrochloride salt can be used to prepare other crystalline polymorphs of Nirogacestat, other Nirogacestat salts and solid state forms thereof.

[0077] In a further embodiment, the present invention discloses a crystalline polymorph of Nirogacestat dihydrochloride salt- designated NHC16. The crystalline Form NHC16 of Nirogacestat dihydrochloride salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 6; an X- ray powder diffraction pattern having peaks at 9.9, 18.5, 19.9, 25.4 and 28.3 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0078] Crystalline Form NHC16 of Nirogacestat dihydrochloride salt may be further characterized by an X-ray powder diffraction pattern having peaks at 9.9, 18.5, 19.9, 25.4 and 28.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 9.0, 22.0 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0079] In a further embodiment, the crystalline Form NHC16 of Nirogacestat dihydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks at: 9.0, 9.9, 18.5, 19.9, 22.0, 23.5, 25.4 and 28.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0080] Crystalline Form NHC16 of Nirogacestat hydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at any one, two or three of (a), (b) and / or (c): (a) 4.8 to 8.0 degrees 2-theta ± 0.2 degrees 2-theta; (b) 10.8 to 12.4 degrees 2-theta ± 0.2 degrees 2-theta; and (c) 13.6 to 14.4 degrees 2-theta ± 0.2 degrees 2-theta. In particular, crystalline Form NHC16 of Nirogacestat hydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and alsohaving an absence of peaks at: (a) alone; or (b) alone; or (c) alone; or (a) and (b) in combination; or (a) and (c) in combination; or (b) and (c) in combination; or (a), (b) and (c) in combination.

[0081] In one embodiment of the present disclosure, crystalline Form NHC16 of Nirogacestat dihydrochloride salt is isolated.

[0082] Crystalline Form NHC16 may be anhydrous.

[0083] The present disclosure also discloses a crystalline polymorph of Nirogacestat dihydrochloride salt- designated NHC17. The crystalline Form NHC17 of Nirogacestat dihydrochloride salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 7; an X-ray powder diffraction pattern having peaks at 9.6, 12.6, 17.2, 20.4 and 27.6 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0084] Crystalline Form NHC17 of Nirogacestat dihydrochloride salt may be further characterized by an X-ray powder diffraction pattern having peaks at 9.6, 12.6, 17.2, 20.4 and 27.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 4.6, 21.8, 24.3 and 29.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0085] In a further embodiment, the crystalline Form NHC17 of Nirogacestat dihydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks at: 4.6, 9.6, 12.6, 17.2, 20.4, 21.8, 24.3, 27.6 and 29.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0086] Crystalline Form NHC12 of Nirogacestat hydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at any one, two or three of (a), (b) and / or (c): (a) 3.5 to 4.0 degrees 2-theta ± 0.2 degrees 2-theta; (b) 5.1 to 5.6 degrees 2-theta ± 0.2 degrees 2- theta; (c) 6.7 to 7.3 degrees 2-theta ± 0.2 degrees 2-theta; and (d) 11.1 to 12.0 degrees 2-theta ± 0.2 degrees 2-theta. In particular, crystalline Form NHC17 of Nirogacestat hydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at: (a) alone; or (b) alone; or (c) alone; or (d) alone, or (a) and (b) in combination; or (a) and (c) in combination; or (a) and (d) in combination; or (b) and (c) in combination; or (b) and (d) in combination; or (a), (b) and (c) in combination; or (a), (b) and (d) in combination; or (a), (b), (c) and (d) in combination.

[0087] In one embodiment of the present disclosure, crystalline Form NHC17 of Nirogacestat dihydrochloride salt is isolated.

[0088] Crystalline Form NHC17 may be anhydrous.

[0089] In a further embodiment, the present invention discloses a crystalline polymorph of Nirogacestat dihydrochloride salt- designated NHC18. The crystalline Form NHC18 ofNirogacestat dihydrochloride salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 11; an X- ray powder diffraction pattern having peaks at 7.4, 14.6, 17.4, 19.2 and 31.9 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0090] Crystalline Form NHC18 of Nirogacestat dihydrochloride salt may be further characterized by an X-ray powder diffraction pattern having peaks at 7.4, 14.6, 17.4, 19.2 and 31.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 8.4, 11.0, 22.4 and 26.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0091] In a further embodiment, the crystalline Form NHC18 of Nirogacestat dihydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks at: 7.4, 8.4, 11.0, 14.6, 17.4, 19.2, 22.4, 26.4 and 31.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0092] In one embodiment of the present disclosure, crystalline Form NHC18 of Nirogacestat dihydrochloride salt is isolated.

[0093] Crystalline Form NHC18 may be methanol solvate.

[0094] In another embodiment, the present invention discloses a crystalline polymorph of Nirogacestat dihydrochloride salt- designated NHC19. The crystalline Form NHC19 of Nirogacestat dihydrochloride salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 12; an X- ray powder diffraction pattern having peaks at 8.7, 9.4, 15.8, 22.0 and 24.6 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0095] Crystalline Form NHC19 of Nirogacestat dihydrochloride salt may be further characterized by an X-ray powder diffraction pattern having peaks at 8.7, 9.4, 15.8, 22.0 and 24.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 14.7, 17.4, 18.3 and 20.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0096] In a further embodiment, the crystalline Form NHC19 of Nirogacestat dihydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks at: 8.7, 9.4, 14.7, 15.8, 17.4, 18.3, 20.8, 22.0 and 24.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0097] In one embodiment of the present disclosure, crystalline Form NHC19 of Nirogacestat dihydrochloride salt is isolated.

[0098] Crystalline Form NHC19 may be DMSO solvate.

[0099] In a further embodiment, the present invention discloses a crystalline polymorph of Nirogacestat dihydrochloride salt- designated NHC110. The crystalline Form NHC110 of Nirogacestat dihydrochloride salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 13; an X-ray powder diffraction pattern having peaks at 9.0, 9.5, 18.5, 21.8 and 26.9 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0100] Crystalline Form NHC110 of Nirogacestat dihydrochloride salt may be further characterized by an X-ray powder diffraction pattern having peaks at 9.0, 9.5, 18.5, 21.8 and 26.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 17.5, 18.0, 20.1 and 20.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0101] In a further embodiment, the crystalline Form NHC110 of Nirogacestat dihydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks at: 9.0, 9.5, 17.5, 18.0, 18.5, 20.1, 20.8, 21.8 and 26.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0102] In one embodiment of the present disclosure, crystalline Form NHC110 of Nirogacestat dihydrochloride salt is isolated.

[0103] Crystalline Form NHC110 may be t-butyl alcohol solvate or t-amyl alcohol solvate.

[0104] In a further embodiment, the present invention discloses a crystalline polymorph of Nirogacestat dihydrochloride salt- designated NHC111. The crystalline Form NHC111 of Nirogacestat dihydrochloride salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 14; an X- ray powder diffraction pattern having peaks at 9.3, 15.3, 17.7, 20.9 and 27.8 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0105] Crystalline Form NHC111 of Nirogacestat dihydrochloride salt may be further characterized by an X-ray powder diffraction pattern having peaks at 9.3, 15.3, 17.7, 20.9 and 27.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 10.8, 18.5, 21.4 and 26.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0106] In a further embodiment, the crystalline Form NHC111 of Nirogacestat dihydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks at: 9.3,10.8, 15.3, 17.7, 18.5, 20.9, 21.4, 26.9 and 27.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0107] In one embodiment of the present disclosure, crystalline Form NHC111 of Nirogacestat dihydrochloride salt is isolated.

[0108] Crystalline Form NHC111 p-cresol solvate.

[0109] In another embodiment, the present invention discloses a crystalline polymorph of Nirogacestat dihydrochloride salt- designated NHC112. The crystalline Form NHC112 of Nirogacestat dihydrochloride salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 15; an X- ray powder diffraction pattern having peaks at 6.9, 13.6, 14.9, 16.7, 18.9 and 21.3 degrees 2- theta ± 0.2 degrees 2-theta; and combinations of these data.

[0110] Crystalline Form NHC112 of Nirogacestat dihydrochloride salt may be further characterized by an X-ray powder diffraction pattern having peaks at 6.9, 13.6, 14.9, 16.7, 18.9 and 21.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 8.2, 17.4 and 23.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0111] In a further embodiment, the crystalline Form NHC112 of Nirogacestat dihydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks at: 6.9, 8.2, 13.6, 14.9, 16.7, 17.4, 18.9, 21.3 and 23.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0112] In one embodiment of the present disclosure, crystalline Form NHC112 of Nirogacestat dihydrochloride salt is isolated.

[0113] Crystalline Form NHC112 may be a solvated form; preferably: t-butanol, isobutanol, methyl-ethyl ketone or t-butyl acetate solvate; more preferably, t-butanol solvate.

[0114] In a further embodiment, the present invention discloses a crystalline polymorph of Nirogacestat dihydrochloride salt- designated NHC113. The crystalline Form NHC113 of Nirogacestat dihydrochloride salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 16; an X- ray powder diffraction pattern having peaks at 6.1, 7.2, 8.2, 10.4 and 16.1 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0115] Crystalline Form NHC113 of Nirogacestat dihydrochloride salt may be further characterized by an X-ray powder diffraction pattern having peaks at 6.1, 7.2, 8.2, 10.4 and 16.1 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 18.9, 21.4 and 24.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0116] In a further embodiment, the crystalline Form NHC113 of Nirogacestat dihydrochloride salt may be characterized by an X-ray powder diffraction pattern having peaks at: 6.1, 7.2, 8.2, 10.4, 16.1, 18.9, 21.4 and 24.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0117] In one embodiment of the present disclosure, crystalline Form NHC113 of Nirogacestat dihydrochloride salt is isolated.

[0118] Crystalline Form NHC113 may be 2,2,2-trifluoro ethanol solvate.

[0119] In another embodiment, the present disclosure provides a crystalline polymorph of Nirogacestat R-mandelate salt- designated NM1. The crystalline Form NM1 of Nirogacestat R-mandelate salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 8; an X-ray powder diffraction pattern having peaks at 6.1, 12.9, 17.8, 20.8 and 25.1 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data. Crystalline Form NM1 may be further characterized by an X-ray powder diffraction pattern having peaks at 6.1, 12.9, 17.8, 20.8 and 25.1 degrees2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 10.9, 14,4, 17.2 and 26.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0120] In a further embodiment, the crystalline Form NM1 of Nirogacestat mandelate salt may be characterized by an X-ray powder diffraction pattern having peaks at: 6.1, 10.9, 12.9, 14.4, 17.2, 17.8, 20.8, 25.1 and 26.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0121] In one embodiment of the present disclosure, crystalline Form NM1 of Nirogacestat mandelate is isolated.

[0122] In another embodiment the molar ratio of Nirogacestat : (R) mandelic acid is 1 : 1.

[0123] In another embodiment, the present disclosure provides a crystalline polymorph of Nirogacestat DTTA salt - designated Form 1. The crystalline Form 1 of Nirogacestat DTTA salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 9; an X-ray powder diffraction pattern having peaks at 5.0, 7.7, 12.5, 16.4 and 20.7 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data. Crystalline Form 1 may be further characterized by an X-ray powder diffraction pattern having peaks at 5.0, 7.7, 12.5, 16.4 and 20.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 10.2, 17.8 and 22.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0124] In a further embodiment, the crystalline Form 1 of Nirogacestat DTTA salt may be characterized by an X-ray powder diffraction pattern having peaks at: 5.0, 7.7, 10.2, 12.5, 16.4, 17.8, 20.7 and 22.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0125] In one embodiment of the present disclosure, crystalline Form 1 of Nirogacestat DTTA is isolated.

[0126] In another embodiment the molar ratio of Nirogacestat : Di-p-toluyl D-tartaric is 1 : 1.

[0127] In a further embodiment, the present disclosure provides a crystalline polymorph of Nirogacestat DBTA salt - designated Form 1. The crystalline Form 1 of Nirogacestat DBTA salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 10; an X-ray powder diffraction pattern having peaks at 6.6, 7.2, 10.1, 16.0 and 21.9 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data. Crystalline Form 1 may be further characterized by an X-ray powder diffraction pattern having peaks at 6.6, 7.2, 10.1, 16.0 and 21.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 13.3, 17.7, 23.6 and 26.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0128] In a further embodiment, the crystalline Form 1 of Nirogacestat DBTA salt may be characterized by an X-ray powder diffraction pattern having peaks at: 6.6, 7.2, 10.1, 13.3, 16.0, 17.7, 21.9, 23.6 and 26.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0129] In one embodiment of the present disclosure, crystalline Form 1 of Nirogacestat DBTA is isolated.

[0130] In another embodiment the molar ratio of Nirogacestat : Dibenzoyl- L-tartaric is 1 : 1.

[0131] The present disclosure includes a crystalline polymorph of Nirogacestat -designated Nl. The crystalline Form Nl of Nirogacestat may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 17; an X-ray powder diffraction pattern having peaks at 4.8, 6.0, 7.0, 15.2 and 17.8 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0132] Crystalline Form Nl of Nirogacestat may be further characterized by an X-ray powder diffraction pattern having peaks at 4.8, 6.0, 7.0, 15.2 and 17.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 11.9, 14.1 and 16.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0133] In a further embodiment, the crystalline Form Nl of Nirogacestat may be characterized by an X-ray powder diffraction pattern having peaks at: 4.8, 6.0, 7.0, 11.9, 14.1, 15.2, 16.5 and 17.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0134] In one embodiment of the present disclosure, crystalline Form Nl of Nirogacestat is isolated.

[0135] Crystalline Form Nl may be anhydrous.

[0136] The above crystalline polymorph of Nirogacestat can be used to prepare other crystalline polymorphs of Nirogacestat, other Nirogacestat salts and solid state forms thereof.

[0137] The present disclosure provides crystalline polymorphs of Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride salt for use in the preparation of pharmaceutical compositions.

[0138] The present disclosure also encompasses the use of the crystalline polymorphs of Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride salt of the present disclosure for the preparation of pharmaceutical compositions.

[0139] The present disclosure includes processes for preparing the above-mentioned pharmaceutical compositions. The processes include combining the crystalline polymorphs of Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride salt of the present disclosure with at least one pharmaceutically acceptable excipient.

[0140] Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid state forms of Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride salt 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0147] 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.

[0148] In liquid pharmaceutical compositions of the present invention, Nirogacestat salt, and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0149] 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.

[0150] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and / or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.

[0151] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0152] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxy anisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[0153] 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.

[0154] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

[0155] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0156] The dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and / or sorbitol, an opacifying agent and / or colorant.

[0157] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] A capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[0162] A pharmaceutical formulation of Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride salt can be administered. Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride salt may be formulated for administration to a mammal, in embodiments to a human, by injection. Nirogacestat hydrochloride salt 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.

[0163] The crystalline polymorphs of Nirogacestat hydrochloride salt and / or Nirogacestat dihydrochloride salt, and the pharmaceutical compositions and / or formulations of Nirogacestat hydrochloride salt of the present disclosure, can be used as medicaments.

[0164] The present disclosure also provides methods of treating tumors by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Nirogacestat hydrochloride salt of the present disclosure, or at least one of the above pharmaceutical compositions and / or formulations, to a subject in need of the treatment.

[0165] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way.Powder X-ray Diffraction (“XRPD”) method

[0166] X-ray diffraction was performed on X-Ray powder diffractometer:Bruker D8 Advance; CuKa radiation (k = 1.5418 A); Lynx eye detector; laboratory temperature 22-25 °C; PMMA specimen holder ring with silicon low background. 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 with silicon low background.

[0120] All X-Ray Powder Diffraction peak values are calibrated with regard to standard silicon spiking in the sample.EXAMPLESPreparation of starting materials

[0119] Nirogacestat can be prepared according to methods known from the literature, for example U.S. Patent No. US7795447.Example 1: Preparation of Nirogacestat hydrochloride salt- Form NHC12

[0121] Nirogacestat (Amorphous, 5.0 g) was dissolved in acetone (50 ml) at 25°C. Isopropyl alcohol hydrochloride solution (IPA-HC1, 18%, 1.2ml) was added and the reaction mixture was stirred for 18 hours. Heptane (125 ml) was added and the mixture was further stirred for 4 hours at 25°C. The obtained solid was filtered, washed with heptane (2ml x 3) and dried under vacuum for 15 minutes. The solid was analyzed by XRD and designated as Form NHC12 of Nirogacestat hydrochloride salt, as shown in FIG.l.Example 2: Preparation of Nirogacestat hydrochloride salt- Form NHC13

[0122] A stock solution of IPA-HC1 was prepared by adding IPA-HC1 (18%, 0.18 ml) to isopropyl alcohol (12 ml) at 25 °C.

[0123] Nirogacestat (Amorphous, 0.05 g) was dissolved in 2-butanol (1 ml) at about 25°C. HCl-stock solution (1 ml) was added and the obtained mixture was stirred for 18 hours. Heptane (5 ml) was added and the mixture was stirred for additional 2 hours. The obtainedsolid was filtered, washed with heptane (1ml x 3) and dried under vacuum for 15 minutes. The solid was analyzed by XRD and designated as Form NHC13 of Nirogacestat hydrochloride salt; as shown in FIG.2.Example 3: Preparation of Nirogacestat hydrochloride salt- Form NHC14

[0124] A stock solution of IPA-HC1 was prepared by adding IPA-HC1 (18%, 0.36 ml) in 12 ml isopropyl alcohol (12ml) at about 25°C.

[0125] Nirogacestat (amorphous, 0.1 g) was dissolved in 2-butanol (2 ml) at about 25°C. HCl-stock solution (1 ml) was added and the reaction mixture was stirred for 18 hours. Heptane (5 ml) was added and the mixture was stirred for additional 2 hours. The obtained solid was filtered, washed with heptane (1ml x 3) and dried under vacuum for 15 minutes. The sample was further dried in air tray dryer at about 130°C for about 30 minutes. The obtained solid was analyzed by XRD and designated as Form NHC14 of Nirogacestat hydrochloride salt; as shown in FIG. 3.Example 4: Preparation of Nirogacestat hydrochloride salt- Form NHC15

[0126] Nirogacestat (amorphous, 0.05 g) was dissolved in 1-pentanol (1 ml) at about 25°C. A stock solution of IPA-HC1 (as prepared in example 2, 1ml) was added and the reaction mixture was stirred for 18 hours. Heptane (5 ml) was added and the mixture was stirred for additional 2 hours. The obtained solid was filtered, washed with heptane (1ml x 3) and dried under vacuum for 15 minutes. The solid was analyzed by XRD and designated as Form NHC15 of Nirogacestat hydrochloride salt; as Shown in FIG. 4.Example 5: Preparation of Nirogacestat hydrochloride salt- Form NHC11

[0127] Nirogacestat (amorphous, 1.0 g) was dissolved in isopropyl acetate (10 ml) at about 25°C to obtain a clear solution. IPA-HC1 solution (18%, 0.07 ml) was added and the reaction was stirred for about 18 hours. Heptane (25ml) was added and the reaction mixture was stirred for additional 2 hours. The obtained solid was filtered, washed with heptane (2ml x 3) and dried under vacuum for about 15 minutes. The sample was further dried in a vacuum oven (60°C, 4 hours). The obtained solid was analyzed by XRD- Form NHC11 of Nirogacestat hydrochloride salt, as shown in FIG. 5.Example 6: Preparation of Nirogacestat dihydrochloride salt- Form NHC16

[0128] Nirogacestat-free base (Amorphous, 1.0 g) was dissolved in acetone (50 ml) at about 25°C. Aqueous solution of HC1 (37%, 0.375 ml) was added and the reaction mixture was stirred for about 24 hours at about 25°C. The obtained solid was filtered, washed with methyl tert-butyl ether (1ml x 3) and dried under vacuum for 15 minutes. The obtained solid was analyzed by XRD- Form NHC16 of Nirogacestat dihydrochloride salt, as shown in FIG. 6.Example 7: Preparation of Nirogacestat dihydrochloride salt- Form NHC17

[0129] Nirogacestat hydrochloride salt (NHC11, 0.05 g) was taken in a glass vial. Ethanol (1 ml) was added at about 25°C to obtain a slurry. Aqueous solution of HC1 (37%, 0.01 ml) was added and the mixture was stirred for about 24 hours at about 25°C. The obtained solid was filtered, washed with methyl tert-butyl ether (1ml x 2) and dried under vacuum for 15 minutes. The obtained solid was analyzed by XRD- Form NHC17 of Nirogacestat dihydrochloride salt, as shown in FIG. 7.Example 8: Preparation of Nirogacestat (R) mandelate salt- Form NM1

[0130] Nirogecestat (5.0 g) was dissolved in acetone (50 mL) and R-mandelic acid (2.30 g) was added at 20-30°C. The reaction mixture was heated to 55-60°C and stirred for 2 hours. The reaction was then cooled to 20-30°C and stirred for additional 2-4 hours. The obtained solid was filtered, dried at 50°C and analyzed by XRPD- Form NM1 of Nirogacestat (R) mandelate salt; as shown in FIG.8. HPLC Purity: 99.17 %.Example 9: Preparation of Nirogacestat DTTA salt - Form 1

[0131] Nirogacestat (0.5g) was dissolved in methanol (5.0 mL). Ditoluyl D- tartaric acid (0.46 g ) was added and the mixture was stirred for 2 to 4 hours at 20-30°C. The obtained solid was filtered, dried at 50°C (6-8 hours) and analyzed by XRD- Form 1 of Nirogacestat DTTA salt; as shown in FIG. 9.Example 10: Preparation of Nirogacestat DBTA salt- Form 1

[0132] Nirogacestat (0.5g) was dissolved in methanol (5.0 ml), Dibenzoyl -L- tartaric acid (0.44 g) was added and the reaction mixture was stirred for 15 to 24 h at 20-30°C. The obtained solid was filtered, dried at 50°C (6 to 8 hours) and analyzed by XRD- Form 1 of Nirogacestat DBTA salt; as shown in FIG. 10.Example 11: Preparation of Nirogacestat dihydrochloride salt- Form NHC18

[0133] Nirogacestat (amorphous, 1.0 g) was dissolved in methanol (1.4 mL) at about 60°C in a closed reaction vessel. IPA-HC1 solution (18%, 1.7 ml) was added and the mixture was further stirred at 60°C for 30 minutes. Acetone (30 ml) was added at 60°C. The reaction mixture was cooled to 25°C during 2 hours and stirred at 25°C for about 16 hours. The obtained solid was filtered and dried under vacuum tray drier at 60°C for 2 hours. The obtained solid was analyzed by XRD - Form NHC18 of Nirogacestat dihydrochloride salt; as shown in FIG. 11.Example 12: Preparation of Nirogacestat dihydrochloride salt- Form NHC19

[0134] Nirogacestat dihydrochloride salt (Form NHC18, 0.02 g) was dissolved in dimethyl sulfoxide (0.2mL) at 25°C. The clear solution (in a 1.5 mL vial) was kept inside a 5mL vial containing 2mL of acetone. The 5mL vial was closed and the vapors diffusion setup was keptat 25°C for 24 hours. The obtained solid was filtered and dried under vacuum for 10-15 minutes. The solid was further dried under vacuum tray drier at 60°C for 2 hours. The obtained solid was analyzed by XRD- Form NHC19 of Nirogacestat dihydrochloride salt; as shown in FIG. 12.Example 13: Preparation of Nirogacestat dihydrochloride salt- Form NHC110

[0135] Nirogacestat-free base (amorphous, 0.03 g) was dissolved in t-butyl alcohol (1 mL) at 60°C under stirring. IPA-HC1 solution (18%, 0.05ml) was added dropwise into the solution at 60°C, stirred for about 60 hours at the same temperature and filtered under vacuum. After drying (10-15 minutes), the obtained solid was analyzed by XRD- Form NHC110 of Nirogacestat dihydrochloride salt; as shown in FIG. 13.Example 14: Preparation of Nirogacestat dihydrochloride salt- Form NHC110

[0136] Nirogacestat-free base (amorphous, 0.03 g) was dissolved in t-amyl alcohol (1 mL) at 60°C under stirring. IPA-HC1 solution (18%, 0.05 ml) was added dropwise at 60°C under stirring and further stirred for about 60 hours at the same temperature. The reaction mixture was filtered under vacuum (at the same temperature), dried for 10-15 minutes and analyzed by XRD - Form NHC110 of Nirogacestat dihydrochloride salt.Example 15: Preparation of Nirogacestat dihydrochloride salt- Form NHC111

[0137] Nirogacestat dihydrochloride salt (Form NHC18, 0.02 g) was dissolved in p-cresol (0.45 ml) in a 1.5 mL vial at 60°C. The clear solution was cooled to 25°C and kept inside another 5 mL vial having 2 mL of ethyl acetate. The 5 mL vial was crimped and kept at 25°C for vapors diffusion. After 4 days, the obtained solid was filtered and dried at 25°C under vacuum for 15 minutes. The obtained solid was analyzed by XRD - Form NHC111 of Nirogacestat dihydrochloride salt; as shown in FIG. 14.Example 16: Preparation of Nirogacestat dihydrochloride salt- Form NHC112

[0138] Nirogacestat-free base (amorphous, 0.03 g) was dissolved in t-butyl acetate (ImL) at 60°C under stirring. IPA-HC1 solution (18%, 0.05 ml) was added drop wise into the solution at 60°C. The reaction mixture was stirred at 60°C during 24 hours. The reaction mixture was filtered and dried under vacuum for 10-15 minutes. The obtained solid was analyzed by XRD- Form NHC112 of Nirogacestat dihydrochloride salt; as shown in FIG. 15.Example 17: Preparation of Nirogacestat dihydrochloride salt- Form NHC113

[0139] Nirogacestat dihydrochloride salt (Form NHC18, 0.02 g) was taken in a 1.5 ml vial and dissolved in 2,2,2-trifluoroethanol (0.125 ml) at 60°C. The clear solution was cooled to 25°C and kept inside another 5 ml vial having 2 ml of ethyl acetate. The 5 ml vial was crimped and kept at 25°C for vapors diffusion. After 4 days, the obtained solid was filtered and driedunder vacuum at 25°C for 15 minutes. The obtained solid was analyzed by XRD and designated as Form NHC113 of Nirogacestat dihydrochloride salt; as shown in FIG. 16.Example 18: Preparation of Nirogacestat dihydrochloride salt- Form NHC12

[0140] Nirogacestat (2g, Form Nl) was dissolved in isopropyl acetate (10ml) at 25°C. The clear solution was heated to 70°C and stirred for 5-10 minutes. Seeds of Form NHC12 were added (about 0.1g) and after 5 minutes a solution of HC1 (1.48 ml of 14% HC1-IPA mixed in 20 ml isopropyl acetate) was added dropwise for 45minutes. The mixture was stirred Ih at 70°C and then another portion of the HC1 solution was added dropwise for 45minutes. After one hour, n-heptane (20 ml) was added to the reaction mixture and the mixture was stirred for 20 hours at 70°C. The reaction mass was cooled down to 25°C and filtered under vacuum. The residue was washed with n-heptane (5ml x 3) and dried during 30 minutes. The solid was further dried in a vacuum oven (60°C for 24 hours). The obtained solid was analyzed by XRPD- Form NHC12 of Nirogacestat dihydrochloride salt.Example 19: Preparation of Nirogacestat dihydrochloride salt- Form NHC15

[0141] Nirogacestat (5g, Form Nl) was dissolved in a mixture of IPA: methanol (3: 1; 25 ml) at about 25°C. The clear solution was heated up to 70°C and stirred for 5-10 minutes. A solution of HC1 (1.02 ml of 34% aq. HC1 mixed in IPA: methanol (3:1; 50ml)) was added dropwise for 15-20 minutes and the mixture was stirred for 1.5 hour at 70°C. A second portion of the HC1 solution was added dropwise during 15-20 and the mixture was stirred overnight at 70°C. The mixture was filtered, washed with heptane (10ml x 3) and dried for 30 minutes. The solid was further dried in a vacuum oven at (60°C for 6 hours) and analyzed by XRPD- Form NHC15 of Nirogacestat dihydrochloride salt.Example 20: Preparation of Nirogacestat dihydrochloride salt- Form NHC16

[0142] Nirogacestat (2g, amorphous) was dissolved in ethyl acetate (40 ml) at about 25°C to obtain a clear solution. Seeds of NHC16 (0.1g) were added at about 25°C and then a solution of HC1 (2.2 ml of 37% aq. HC1 mixed with 40 ml ethanol) was slowly added. The reaction mixture was stirred overnight at 25°C, filtered and dried for about 30 minutes. The obtained solid was further dried in vacuum oven at about 60°C for 18 hours and analyzed by XRPD- Form NHC16 of Nirogacestat dihydrochloride salt.Example 21: Preparation of Nirogacestat dihydrochloride salt- Form NHC17

[0143] Nirogacestat hydrochloride (1g, NHC11) was suspended in acetone (20 ml) at about 25°C. An aq. HC1 (37%, 50 microliter) was added and the reaction mixture was stirred overnight at 25°C. The mixture was filtered and dried for about 20 minutes. The obtained solidwas further dried in a vacuum oven (60°C for 6 hours) and analyzed by XRPD-Form NHC17 of Nirogacestat dihydrochloride salt.Example 22: Preparation of crystalline Nirogacestat - Form N1

[0144] Nirogacestat DBTA salt (100 g) was charged in ethyl acetate (1000 mL) and water (300 ml) into the reactor at 25±5°C. Aqueous solution of NaOH (5%; 31.3g in 600 ml water) was added into the above suspension to obtain a clear solution. The solution was stirred for 45 minutes at about 25°C, then the aqueous layer was removed, and the organic layer was left in the reactor .The organic solvent was distilled under vacuum at 55±5°C ( residual volume was less than 1.0 Vol with respect to Nirogacestat DBTA salt). Heptane (200 mL) was added at 55±5°C, and then the solvent was removed under vacuum at 55±5°C (residual volume was less than 1.0 Vol). Reaction mixture was cooled to about 25±5°C, then Heptane (500ml) was added and the mixture was stirred for about 30 minutes at about 25±5°C and filtered off. The obtained solid was dried under vacuum at about 55±5° for about 4-6 hours. The dried solid was analyzed by XRD and designated as Form N1 of Nirogacestat; as shown in Figure 17.Example 23: Stability StudiesStorage stability at different relative humidities

[0145] Samples of crystalline Nirogacestat dihydrochloride forms were subjected to conditions of different relative humidities at ambient temperature. XRPD analysis was performed on the samples after 7 days. The results are shown in Table 1 below:Table 1

[0146] These results demonstrate that all forms of crystalline Nirogacestat dihydrochloride are stable after exposure to extremes of high and low relative humidities for at least 7 days.Grinding experiments

[0147] Samples of crystalline Nirogacestat dihydrochloride forms were subjected to strong grinding, and to solvent drop grinding in ethanol and isopropanol. Grinding was carried out on the samples alone, or in the presence of water. In these experiments, about 20 mg of the sample is placed in a mortar and ground with a pestle for 2 minutes. The solvent, when used, as added to the crystalline material before grinding, in a volume of 10 microlitres. XRPD analysis performed on each of the samples after the grinding experiment. The results are summarized in Table 2.Table 2

[0148] The results demonstrate that all forms of crystalline Nirogacestat dihydrochloride are resistant to polymorphic transformation even when exposed to grinding with solvents, and hence crystalline Nirogacestat dihydrochloride is highly suitable for preparing pharmaceutical formulations.Stability to compression

[0149] Samples of crystalline Nirogacestat dihydrochloride were subjected to pressures of 2 tons (Atlas® Autopress hydraulic press, set to 2 tons). XRPD analysis was performed on the samples after 1 minute. The results are shown in Table 3 below:Table 3

[0150] The results show that all forms of crystalline Nirogacestat dihydrochloride are stable under high pressure conditions, making it highly suitable for pharmaceutical processing.

Claims

CLAIMS1. A crystalline Nirogacestat dihydrochloride salt.

2. The crystalline Nirogacestat dihydrochloride salt according to Claim 1, which is anhydrous.

3. The crystalline Nirogacestat dihydrochloride salt according to Claim 1, which is hydrate.

4. The crystalline Nirogacestat dihydrochloride salt according to any of Claims 1, 2 or 3, designated Form NHC12, which is characterized by data selected from at least one of: i) an X-ray powder diffraction pattern substantially as depicted in Figure 1; or ii) an X-ray powder diffraction pattern having peaks at 3.9, 8.5, 11.4, 15.1 and 15.7 degrees 2-theta ± 0.2 degrees 2-theta.

5. The crystalline Nirogacestat dihydrochloride salt according Claim 4, which is further characterized by an X-ray powder diffraction pattern having any one, two, three, or four additional peaks selected from 5.9, 14.8, 20.2 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta.

6. The crystalline Nirogacestat dihydrochloride salt according to any of Claims 1, 2, 3, 4 or 5, which is characterized by an XRPD pattern having peaks at 3.9, 5.9, 8.5, 11.4, 14.8, 15.1, 15.7, 20.2 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta.

7. The crystalline Nirogacestat dihydrochloride salt according to any of Claims 1, 2 or 3, designated Form NHC16, which is characterized by data selected from at least one of: i) an X-ray powder diffraction pattern substantially as depicted in Figure 6; or ii) an X-ray powder diffraction pattern having peaks at 9.9, 18.5, 19.9, 25.4 and 28.3 degrees 2-theta ± 0.2 degrees 2-theta.

8. The crystalline Nirogacestat dihydrochloride salt according Claim 7, which is further characterized by an X-ray powder diffraction pattern having any one, two, or three additional peaks selected from 9.0, 22.0 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.

9. The crystalline Nirogacestat dihydrochloride salt according to any of Claims 1, 2, 3, 7 or 8, which is characterized by an XRPD pattern having peaks at 9.0, 9.9, 18.5, 19.9, 22.0, 23.5, 25.4 and 28.3 degrees 2-theta ± 0.2 degrees 2-theta.

10. The crystalline Nirogacestat dihydrochloride salt according to any of Claims 1, 2, or 3, designated Form NHC17, which is characterized by data selected from at least one of: i) an X-ray powder diffraction pattern substantially as depicted in Figure 7; or ii) an X-ray powder diffraction pattern having peaks at 9.6, 12.6, 17.2, 20.4 and 27.6 degrees 2-theta ± 0.2 degrees 2-theta.

11. The crystalline Nirogacestat dihydrochloride salt according Claim 10, which is further characterized by an X-ray powder diffraction pattern having any one, two, three, or four additional peaks selected from 4.6, 21.8, 24.3 and 29.3 degrees 2-theta ± 0.2 degrees 2- theta.

12. The crystalline Nirogacestat dihydrochloride salt according to any of Claims 1, 2, 3, 10 or 11, which is characterized by an XRPD pattern having peaks at 4.6, 9.6, 12.6, 17.2,20.4, 21.8, 24.3, 27.6 and 29.3 degrees 2-theta ± 0.2 degrees 2-theta.

13. The crystalline Nirogacestat dihydrochloride salt according to any of Claims 1, 2 or 3, designated Form NHC15, which is characterized by data selected from at least one of: i) an X-ray powder diffraction pattern substantially as depicted in Figure 4; or ii) an X-ray powder diffraction pattern having peaks at 6.1, 7.2, 10.4, 13.2 and 22.9 degrees 2-theta ± 0.2 degrees 2-theta.

14. The crystalline Nirogacestat dihydrochloride salt according Claim 13, which is further characterized by an X-ray powder diffraction pattern having any one, two, or three additional peaks selected from 8.4, 9.9 and 10.9 degrees 2-theta ± 0.2 degrees 2-theta.

15. The crystalline Nirogacestat dihydrochloride salt according to any of Claims 1, 2, 3, 13 or 14, which is characterized by an XRPD pattern having peaks at 6.1, 7.2, 8.4, 9.9,10.4, 10.9, 13.2 and 22.9 degrees 2-theta ± 0.2 degrees 2-theta.

16. Use of the crystalline Nirogacestat dihydrochloride salt according to any of Claims 1-15 for preparing pharmaceutical compositions and / or formulations.

17. A pharmaceutical composition comprising the crystalline Nirogacestat dihydrochloride salt according to any of Claims 1-15, and at least one pharmaceutically acceptable excipient.

18. A process for preparing the pharmaceutical composition according to Claim 17, comprising combining the crystalline Nirogacestat dihydrochloride salt according to any of Claims 1-15 with at least one pharmaceutically acceptable excipient.

19. The crystalline Nirogacestat dihydrochloride salt according to any of Claims 1 to 15, or a pharmaceutical composition according to Claim 17, for use as a medicament.

20. The crystalline Nirogacestat dihydrochloride salt according to any of Claims 1 to 15, or a pharmaceutical composition according to Claim 17, for use as a medicament for treating tumors, particularly desmoid tumors, or ovarian granulosa cell tumors (OvGCTs), or Aggressive Fibromatosis (AF).

21. A method of treating tumors, particularly desmoid tumors, ovarian granulosa cell tumors (OvGCTs), or Aggressive Fibromatosis (AF), comprising administering atherapeutically effective amount of the crystalline Nirogacestat dihydrochloride salt according to any of Claims 1-15, or a pharmaceutical composition according to Claim 17, to a subject in need of the treatment.

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