Crystalline forms of govorestat

Abstract

The application relates to crystalline polymorphs of Govorestat, processes for preparation thereof, and pharmaceutical compositions thereof.

Description

CRYSTALLINE FORMS OF GOVORESTATCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to Indian Provisional Patent Application No. 202411030891 filed on April 17, 2024, and Indian Provisional Patent Application No. 202411046807 filed on June 18, 2024. The entire disclosures of the foregoing applications are incorporated by reference herein.FIELD OF THE DISCLOSURE

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

[0003] Govorestat, 2-(4-Oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4- dihydrothieno[3,4-d]pyridazin-l-yl)acetic acid, has the following chemical structure:

[0004] Govorestat is an investigational Aldose Reductase Inhibitor (ARI) being developed for the treatment of several rare diseases; including: Galactosemia, and sorbitol dehydrogenase deficiency. Govorestat is also under investigation for the treatment of Phosphomannomutase 2 Deficiency, a congenital disorder of glycosylation (PMM2-CDG). The compound is described in International Publication No. WO2017 / 223179.

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

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

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

[0008] The present disclosure provides crystalline polymorphs of Govorestat, in embodiments crystalline polymorphs of Govorestat, processes for preparation thereof, and pharmaceutical compositions thereof.These crystalline forms can be used to prepare other solid state forms of Govorestat and salts thereof.

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

[0010] The present disclosure provides said crystalline forms of Govorestat for use in medicine, including for the treatment of Galactosemia, and sorbitol dehydrogenase deficiency.In embodiment, the present disclosure provides crystalline forms of Govorestat for treating multiple rare diseases, including Galactosemia, Sorbitol Dehydrogenase (SORD) Deficiency and Phosphomannomutase 2 Deficiency.

[0011] The present disclosure also encompasses the use of said crystalline polymorphs of Govorestat for the preparation of pharmaceutical compositions and / or formulations.

[0012] In another aspect, the present disclosure provides pharmaceutical compositions comprising said crystalline Govorestat according to the present disclosure.

[0013] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining said crystalline polymorphs of Govorestat with at least one pharmaceutically acceptable excipient.

[0014] The crystalline polymorphs of Govorestat as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorphs of Govorestat may be used as medicaments, such as for the treatment of Galactosemia, and sorbitol dehydrogenase deficiency.

[0015] The present disclosure also provides methods for the treatment of patients with Galactosemia or sorbitol dehydrogenase deficiency by administering a therapeutically effective amount of said crystalline polymorph of Govorestat of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from Galactosemia or sorbitol dehydrogenase deficiency or otherwise in need of the treatment.

[0016] The present disclosure also provides uses of crystalline polymorphs of Govorestat of the present disclosure or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g., Galactosemia, and sorbitol dehydrogenase deficiency.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Govorestat Form G1.

[0018] FIG. 2 shows a characteristic X-ray powder diffraction pattern (XRPD) of Govorestat Form G2.

[0019] FIG. 3 shows a characteristic X-ray powder diffraction pattern (XRPD) of Govorestat Form G3.

[0020] FIG. 4 shows a characteristic X-ray powder diffraction pattern (XRPD) of Govorestat Form G4.

[0021] FIG. 5 shows a characteristic X-ray powder diffraction pattern (XRPD) of Govorestat Form G5.

[0022] FIG. 6 shows a characteristic solid state13C NMR spectrum of Govorestat- Form G1 (full screen).

[0023] FIG. 7 shows solid state13C NMR spectrum of Govorestat- Form G1 (0-100 ppm).

[0024] FIG. 8 shows solid state13C NMR spectrum of Govorestat- Form G1 (100-200ppm).

[0025] FIG. 9 shows a characteristic solid state13C NMR spectrum of Govorestat- Form G2 (full screen).

[0026] FIG. 10 shows solid state13C NMR spectrum of Govorestat- Form G2 (0-100 ppm).

[0027] FIG. 11 shows solid state13C NMR spectrum of Govorestat- Form G2 (100-200ppm).DETAILED DESCRIPTION OF THE DISCLOSURE

[0028] The present disclosure encompasses solid state forms of Govorestat, in embodiments crystalline polymorphs of Govorestat, processes for preparation thereof, and pharmaceutical compositions thereof.

[0029] Solid state properties of Govorestat and crystalline polymorphs thereof can be influenced by controlling the conditions under which Govorestat and crystalline polymorphs thereof are obtained in solid form.

[0030] The solid state forms of Govorestat as described in any aspect or embodiment of the present disclosure may be polymorphically pure, or substantially free of any other solid state (or polymorphic) forms.

[0031] 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. For example, polymorphically pure Govorestat means that the solid state form is substantially free of other solid state forms of Govorestat. Thus, a crystalline polymorph of Govorestat 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 ofGovorestat. In some embodiments of the disclosure, the described crystalline polymorph of Govorestat, salt or cocrystal may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more other crystalline polymorph of the same Govorestat.

[0032] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Govorestat 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.

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

[0034] As used herein, the term "isolated" in reference to crystalline polymorph of Govorestat of the present disclosure corresponds to a crystalline polymorph of Govorestat that is physically separated from the reaction mixture in which it is formed.

[0035] As used herein, unless stated otherwise, the XRPD measurements are taken using copper K a radiation wavelength 1.54184 A. XRPD peaks reported herein are optionally measured using CuK a radiation, = 1.54184 A, typically at a temperature of 25 ± 3°C.

[0036] As used herein, unless stated otherwise,BC NMR reported herein are measured at 11.7 T at a magic angle spinning frequency CDI72JI = 11 kHz, preferably at a temperature of at 280 K ± 3°C. Preferably, the13C scale is referenced to a-glycine.

[0037] 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.

[0038] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term "v / v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v / v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.

[0039] 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.

[0040] 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.

[0041] As used herein and unless indicated otherwise, the term "ambient conditions" refer to atmospheric pressure and a temperature of 22-24°C.

[0042] The solid state forms of Govorestat as described in any aspect or embodiment of the present disclosure may be chemically pure, or substantially free of any other compounds.

[0043] 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, 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) or less, 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, 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 or less, 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.

[0044] Thus, pure or purified Govorestat 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 Govorestat. Alternatively, pure or purified Govorestat, 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 Govorestat.

[0045] The present disclosure includes crystalline Govorestat. In any aspect or embodiment of the present disclosure, crystalline Govorestat may be anhydrous. Preferably, the present disclosure relates to crystalline Govorestat which is anhydrous. In any aspect or embodiment, the crystalline Govorestat may be polymorphically pure. Preferably, thecrystalline Govorestat may contain: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of amorphous Govorestat, for example, as measured by XRPD.

[0046] The present disclosure includes a crystalline polymorph of Govorestat designated Form Gl. The crystalline Form G1 of Govorestat 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 powder diffraction pattern having peaks at 17.8, 19.5, 23.3, 28.0 and 29.6 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0047] Crystalline Form Gl of Govorestat may be further characterized by an X-ray powder diffraction pattern having peaks at 17.8, 19.5, 23.3, 28.0 and 29.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, or four additional peaks selected from 6.6, 13.8, 20.2 and 24.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0048] Crystalline Form Gl of Govorestat may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 6.6, 13.8, 17.8, 19.5, 20.2, 23.3, 24.8, 28.0 and 29.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0049] Crystalline Form Gl of Govorestat according to any aspect or embodiment of the present disclosure may be additionally characterized by an XRPD pattern having an absence of peaks at any one or more of: 7.2 to 11 degrees 2-theta ± 0.2 degrees 2-theta; and / or 14.9 to 15.1 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively or additionally, crystalline Form Gl of Govorestat according to any aspect or embodiment of the present disclosure may be additionally characterized by an XRPD pattern having an absence of peaks at any one or more of: 2.8 to 6.2 degrees 2-theta ± 0.2 degrees 2-theta, 7.2 to 11.0 degrees 2-theta ± 0.2 degrees 2- theta; and / or 14.9 to 15.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0050] Crystalline Form Gl of Govorestat as described in any aspect or embodiment of the disclosure may be alternatively or additionally characterized by a solid state13C NMR spectrum with peaks at 39.9, 54.9, 118.9, 134.6, 158.5 and 167.2 ppm ± 0.2 ppm. Alternatively or additionally, crystalline Form Gl of Govorestat may be characterized by a solid state13C NMR spectrum having the following chemical shift absolute differences from a peak at 140.2 ppm ± 2 ppm of 100.3, 85.3, 21.3, 5.6, 18.3 and 27.0 ppm ± 0.1 ppm; optionally, Form Gl of Govorestat may be characterized by a solid state13C NMR spectrum substantially as depicted in any of Figures 6, 7 or 8, preferably Figure 6.

[0051] In any aspect or embodiment of the present disclosure, crystalline Form Gl of Govorestat may be isolated.

[0052] In any aspect or embodiment of the present disclosure, crystalline Form G1 of Govorestat may be anhydrous.

[0053] In any aspect or embodiment crystalline Form G1 of Govorestat may be polymorphically pure.

[0054] Crystalline Form G1 of Govorestat is stable under all tested stress conditions (e.g., under strong grinding, pressure of 2 tons, high humidity (up to 100% RH for 7 days) and at high temperature (up to 100°C).

[0055] In a further embodiment, the present disclosure includes a crystalline polymorph of Govorestat designated Form G2. The crystalline Form G2 of Govorestat 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 6.2, 7.1, 12.4, 14.2 and 18.7 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0056] Crystalline Form G2 of Govorestat may be further characterized by an X-ray powder diffraction pattern having peaks at 6.2, 7.1, 12.4, 14.2 and 18.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, or four additional peaks selected from 10.4, 26.7, 29.3 and 30.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0057] Crystalline Form G2 of Govorestat may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 6.2, 7.1, 10.4, 12.4, 14.2, 18.7, 26.7, 29.3 and 30.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0058] Crystalline Form G2 of Govorestat according to any aspect or embodiment of the present disclosure may be additionally characterized by an XRPD pattern having an absence of peaks at any one or more of: 8.8 to 9.9 degrees 2-theta ± 0.2 degrees 2-theta; 13.4 to 13.7 degrees 2-theta ± 0.2 degrees 2-theta; and / or 17.2 to 17.6 degrees 2-theta ± 0.2 degrees 2-theta

[0059] Crystalline Form G2 of Govorestat as described in any aspect or embodiment of the disclosure may be alternatively or additionally characterized by a solid state13C NMR spectrum with peaks at 36.2, 49.7, 124.7, 132.7, 149.8 and 155.9 ppm ± 0.2 ppm. Alternatively or additionally, crystalline Form G2 of Govorestat may be characterized by a solid state13C NMR spectrum having the following chemical shift absolute differences from a peak at 140.2 ppm ± 2 ppm of 104.0, 90.5, 15.5, 7.5, 9.6 and 15.7 ppm ± 0.1 ppm; optionally, Form G2 of Govorestat may be characterized by a solid state13C NMR spectrum substantially as depicted in any of Figures 9, 10 or 11, preferably Figure 9.

[0060] In any aspect or embodiment of the present disclosure, crystalline Form G2 of Govorestat may be isolated.

[0061] In any aspect or embodiment of the present disclosure, crystalline Form G2 of Govorestat may be anhydrous.

[0062] In any aspect or embodiment crystalline Form G2 of Govorestat may be polymorphically pure.

[0063] Crystalline Form G2 of Govorestat is stable under all tested stress conditions (e.g., under strong grinding, pressure of 2 tons, high humidity (up to 100% RH for 7 days) and at high temperature (up to 100°C).

[0064] In another embodiment, the present disclosure includes a crystalline polymorph of Govorestat designated Form G3. The crystalline Form G3 of Govorestat 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, 16.0, 18.9, 21.3 and 24.0 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0065] Crystalline Form G3 of Govorestat may be further characterized by an X-ray powder diffraction pattern having peaks at 9.8, 16.0, 18.9, 21.3 and 24.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, or three additional peaks selected from 14.0, 19.6 and 31.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0066] Crystalline Form G3 of Govorestat may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 9.8, 14.0, 16.0, 18.9, 19.6, 21.3, 24.0 and 31.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0067] In any aspect or embodiment of the present disclosure, crystalline Form G3 of Govorestat may be isolated.

[0068] In any aspect or embodiment of the present disclosure, crystalline Form G3 of Govorestat may be a solvate; in particular, N,N-Dimethylacetamide solvate.

[0069] In any aspect or embodiment crystalline Form G3 of Govorestat may be polymorphically pure.

[0070] In another embodiment, the present disclosure provides a crystalline polymorph of Govorestat designated Form G4. The crystalline Form G4 of Govorestat 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 6.2, 12.0, 16.9, 24.2 and 26.7 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0071] Crystalline Form G4 of Govorestat may be further characterized by an X-ray powder diffraction pattern having peaks at 6.2, 12.0, 16.9, 24.2 and 26.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, or four additional peaks selected from 4.4, 16.0, 18.4 and 20.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0072] Crystalline Form G4 of Govorestat may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 4.4, 6.2, 12.0, 16.0, 16.9, 18.4, 20.4, 24.2 and 26.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0073] In any aspect or embodiment of the present disclosure, crystalline Form G4 of Govorestat may be isolated.

[0074] In any aspect or embodiment of the present disclosure, crystalline Form G4 of Govorestat may be a solvate; in particular, aniline solvate.

[0075] In any aspect or embodiment crystalline Form G4 of Govorestat may be polymorphically pure.

[0076] In another embodiment, the present disclosure includes a crystalline polymorph of Govorestat designated Form G5. The crystalline Form G5 of Govorestat may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 5; an X-ray powder diffraction pattern having peaks at 4.6, 8.6, 12.1, 13.3 and 17.2 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0077] Crystalline Form G5 of Govorestat may be further characterized by an X-ray powder diffraction pattern having peaks at 4.6, 8.6, 12.1, 13.3 and 17.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, or four additional peaks selected from 6.4, 16.0, 17.7 and 20.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0078] Crystalline Form G5 of Govorestat may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 4.6, 6.4, 8.6, 12.1, 13.3, 16.0, 17.2, 17.7 and 20.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0079] In any aspect or embodiment of the present disclosure, crystalline Form G5 of Govorestat may be isolated.

[0080] In any aspect or embodiment crystalline Form G5 of Govorestat may be polymorphically pure.

[0081] The present disclosure provides the above described crystalline polymorph of Govorestat for use in the preparation of pharmaceutical compositions comprising Govorestat and / or solid state forms thereof.

[0082] The present disclosure also encompasses the use of crystalline polymorph of Govorestat of the present disclosure for the preparation of pharmaceutical compositions of the crystalline polymorph Govorestat.

[0083] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination ofthe crystalline polymorphs of Govorestat of the present disclosure with at least one pharmaceutically acceptable excipient.

[0084] Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid state form of Govorestat 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] In liquid pharmaceutical compositions of the present invention, Govorestat 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.

[0093] 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.

[0094] 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.

[0095] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0100] 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.

[0101] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] A pharmaceutical formulation of Govorestat can be administered. Govorestat may be formulated for administration to a mammal, in embodiments to a human, by injection. Govorestat 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.

[0107] The crystalline polymorph of Govorestat and the pharmaceutical compositions and / or formulations of Govorestat of the present disclosure can be used as medicaments, in embodiments for the treatment of patients with Galactosemia, and sorbitol dehydrogenase deficiency

[0108] The present disclosure also provides methods of treating of patients with Galactosemia and sorbitol dehydrogenase deficiency, by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Govorestat of the present disclosure, or at least one of the above pharmaceutical compositions and / or formulations, to a subject in need of the treatment.

[0109] 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

[0110] X-ray diffraction was performed on X-Ray powder diffractometer:Bruker D8 Advance; Copper Ka 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.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.

[0111] All X-Ray Powder Diffraction peak values are calibrated with regard to standard silicon spiking in the sample ssNMR method

[0112] The solid-state NMR spectra were measured at 11.7 T using a Bruker Avance III HD 500 US / WB NMR spectrometer (Karlsruhe, Germany, 2013) with a 4-mm probehead. The samples (as received) were placed into the 4-mm thin-wall ZrCb rotor.

[0113] The13C CP / MAS NMR spectra employing cross-polarization were acquired using the standard cross-polarization pulse scheme at spinning frequency of 11 kHz. The cross- polarization contact time was 2 ms, and the dipolar decoupling SPINAL64 was applied during the data acquisition. The spectral width was 300 ppm with the resonance offset of 100 ppm. The13C scale was referenced to a-glycine (176.03 ppm for13C). The ’H MAS NMR spectra employing a single-pulse excitation were measured at spinning frequency of 11 kHz using a ’H (90 degree) pulse of 4 ms and power level 88 W. The number of scans was 4 (NS=4). The ’H scale was referenced to a-glycine (8.5 ppm for NHL signal).

[0114] The ’H TI spin-lattice relaxation buildup spectra were recorded to optimize DI repetition delay using a variable repetition delay (Dl=0.5, 1, 2, 4, 8, 16, 32 and 64 s). The number of scans was 1 (NS=1) and the number of dummy scans used for saturation was 4 (DS=4).

[0115] The experiments were carried out with active cooling, keeping the samples at a constant temperature of 280K ± 3°C.EXAMPLESPreparation of starting materials

[0116] Govorestat can be prepared according to methods known from the literature, for example according to the disclosure in International Publication No. WO2017 / 223179.Example 1: Preparation of Govorestat -Form Gl:

[0117] Govorestat (1.0 g) was dissolved in a mixture of dichloromethane and methanol (about 1 : 1; 100 ml) at about 25°C. The clear solution was subjected to distillation under reduced pressure (below lOOmbar) at about 50°C by using rotary evaporator for about 2 hours. The obtained solid was analyzed by XRD- Form Gl of Govorestat was obtained, as shown in FIG. 1.Example 2: Preparation of Govorestat-Form G2

[0118] Govorestat (1.0 g) was dissolved in tetrahydrofuran (25 ml) at about 50-55°C. The clear solution was subjected to distillation under reduced pressure (below lOOmbar) at about 50-55°C by using rotary evaporator for about 1.5 hours. The obtained solid was analyzed by XRD- Form G2 of Govorestat was obtained, as shown in FIG. 2.Example 3: Preparation of Govorestat-Form G3

[0119] Govorestat (0.5 g) was dissolved in N,N-Dimethylacetamide (DMAc, 2.5 ml) at about 25°C. A clear solution was obtained and then methyl tert-butyl ether (MTBE,12.5 ml) was added at about 25°C. The reaction mixture was stirred at about 25°C for about 10 minutes. The obtained solid was filtered and washed with MTBE (0.5 ml x3) and dried under vacuum for 10-15 minutes. The solid was further dried in vacuum oven at about 60°C for 1 hour. The obtained solid was analyzed by XRD and designated as Form G3 of Govorestat; as shown in FIG. 3.Example 4: Preparation of Govorestat-Form G4

[0120] Govorestat (0.25 g) was dissolved in dimethyl sulfoxide (DMSO, 1.25 ml) at about 60°C. A clear solution was obtained and then aniline (6.25 ml) was added at about 25°C. The reaction mixture was maintained under stirring at about 25°C for about 2 hours. The obtained solid was filtered, washed with Aniline (0.5 ml x3) and dried under vacuum for 10-15 minutes. The obtained solid was analyzed by XRD and designated as Form G4 of Govorestat; as shown in FIG. 4.Example 5: Preparation of Govorestat-Form G5

[0121] Govorestat (0.5 g) was dissolved in 2-methyl THF (40 ml) and dimethyl sulfoxide (0.5 ml) at about 80°C. A clear solution was obtained and then butyronitrile (100 ml) was added at about 80°C. The reaction mixture was maintained under stirring at about 60°C for about 2 hours then cooled down to 25°C and maintained under stirring for additional 72 hours. The obtained solid was filtered and dried under vacuum for 10-15 minutes. Sample was further dried in air tray drier at 100°C for about 2 hours and then cooled down to room temperature. The obtained solid was analyzed by XRD and designated as Form G5 of Govorestat; as shown in FIG. 5.Example 6: Preparation of Govorestat-Form G2

[0122] Form G3 of Govorestat (0.1g) was charged in a petridish and dried under vacuum oven at about 100°C for about 1 hour. The sample was cooled down to room temperature and analyzed by XRD- Form G2 of Govorestat was obtained.Example 7: Preparation of Govorestat -Form Gl:

[0123] Govorestat (1.0 g) was dissolved in a mixture of dichloromethane and methanol (1: 1 vohvol, 100 ml) at about 25°C. The clear solution was subjected to distillation under reduced pressure (at below 100 mbar) at about 50°C by using rotary evaporator for about 2 hours. Following the distillation, the obtained solid was analyzed by XRD (Form Gl of Govorestat was obtained).Example 8 - Stability testing of Forms Gl and G2Storage stability at different relative humidities

[0124] Samples of Govorestat Forms Gl and G2 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:

[0125] These results demonstrate that Forms Gl and G2 of Govorestat are stable after exposure to high and low relative humidity conditions for at least 7 days.

[0126] Samples of Govorestat Forms G1 and G2 were subjected to conditions of different relative humidities at different temperatures. XRPD analysis was performed on the samples after 6 months. The results are shown in Table 2 below:Table 2

[0127] The results demonstrate that Forms G1 and G2 of Govorestat are stable after exposure to high and low relative humidity at different temperatures for at least 6 months, indicating that these crystalline forms have excellent storage stability.Grinding experiments

[0128] Samples of Govorestat were subjected to strong grinding, and to solvent drop grinding in water, ethanol and isopropanol. Grinding was carried out on the samples alone, or in the presence of ethanol, water or isopropanol. In these experiments, about 20 mg of the sample is placed in a mortar and ground with a pestle for 2 minutes. The solvent, when used, as added to the crystalline material before grinding, in a volume of 10 microlitres. XRPD analysis performed on each of the samples after the grinding experiment, confirmed no change in the starting material (Table 3):Table 3

[0129] The results demonstrate that Forms G1 and G2 of Govorestat are resistant to polymorphic changes and are highly suitable for preparing pharmaceutical formulations.Thermal Stability

[0130] Samples of Forms G1 and G2 of Govorestat were subjected to heating up to 100°C for 30 minutes. XRPD analysis of the sample confirmed no change in the starting material (Table 4):Table 4

[0131] Accordingly, Forms G1 and G2 of Govorestat are stable to high temperature, further demonstrating the stability of these solid state forms.

Claims

CLAIMS1. Crystalline Govorestat.

2. Crystalline Govorestat designated Form Gl, which is characterized by data including at least one of:(a) an X-ray powder diffraction pattern substantially as depicted in Figure 1; or(b) an X-ray powder diffraction pattern having peaks at 17.8, 19.5, 23.3, 28.0 and 29.6 degrees 2-theta ± 0.2 degrees 2-theta.

3. The crystalline Govorestat according Claim 2, which is further characterized by an X- ray powder diffraction pattern having any one, two, three, or four additional peaks selected from 6.6, 13.8, 20.2 and 24.8 degrees 2-theta ± 0.2 degrees 2-theta.

4. The crystalline Govorestat according to Claims 2 or 3, which is characterized by an XRPD pattern having peaks at 6.6, 13.8, 17.8, 19.5, 20.2, 23.3, 24.8, 28.0 and 29.6 degrees 2- theta ± 0.2 degrees 2-theta.

5. The crystalline Govorestat according to any of Claims 2, 3, or 4 which is substantially free of any other solid state form of Govorestat.

6. Crystalline Govorestat designated Form G2, which is characterized by data including at least one of:(a) an X-ray powder diffraction pattern substantially as depicted in Figure 2; or(b) an X-ray powder diffraction pattern having peaks at 6.2, 7.1, 12.4, 14.2 and 18.7 degrees 2-theta ± 0.2 degrees 2-theta.

7. The crystalline Govorestat according Claim 6, which is further characterized by an X- ray powder diffraction pattern having any one, two, three, or four additional peaks selected from 10.4, 26.7, 29.3 and 30.4 degrees 2-theta ± 0.2 degrees 2-theta.

8. The crystalline Govorestat according to Claims 6 or 7, which is characterized by an XRPD pattern having peaks at 6.2, 7.1, 10.4, 12.4, 14.2, 18.7, 26.7, 29.3 and 30.4 degrees 2- theta ± 0.2 degrees 2-theta.

9. The crystalline Govorestat according to any of Claims 6, 7, or 8 which is substantially free of any other solid state form of Govorestat.

10. Use of the crystalline Govorestat according to any of Claims 1-9 for preparing pharmaceutical compositions of Govorestat.

11. A pharmaceutical composition comprising the crystalline Govorestat according to any of Claims 1-9, and at least one pharmaceutically acceptable excipient.

12. Use of the crystalline Govorestat according to any of Claims 1-9 for the preparation of a pharmaceutical composition and / or formulation.

13. A process for preparing the pharmaceutical composition according to Claim 11, comprising combining the crystalline Govorestat according to any of Claims 1-9 with at least one pharmaceutically acceptable excipient.

14. The crystalline Govorestat according to any of Claims 1-9, or a pharmaceutical composition according to Claim 11, for use as a medicament.

15. The crystalline Govorestat according to and of Claims 1 to 9, or a pharmaceutical composition according to Claim 11, for use as a medicament for treating rare Galactosemia, Sorbitol Dehydrogenase (SORD) Deficiency and Phosphomannomutase 2 Deficiency.

16. A method of treating rare diseases, including Galactosemia, Sorbitol Dehydrogenase (SORD) Deficiency and Phosphomannomutase 2 Deficiency, comprising administering a therapeutically effective amount of the crystalline Govorestat according to any of Claims 1-9, or a pharmaceutical composition according to Claim 11, to a subject in need of the treatment.

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