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WO2024201244A1 - Formes à l'état solide de bavdégalutamide et leur procédé de préparation - Google Patents

Formes à l'état solide de bavdégalutamide et leur procédé de préparation Download PDF

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Publication number
WO2024201244A1
WO2024201244A1 PCT/IB2024/052772 IB2024052772W WO2024201244A1 WO 2024201244 A1 WO2024201244 A1 WO 2024201244A1 IB 2024052772 W IB2024052772 W IB 2024052772W WO 2024201244 A1 WO2024201244 A1 WO 2024201244A1
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bavdegalutamide
theta
crystalline
degrees
crystalline form
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Lorena KORDIC
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Assia Chemical Industries Ltd
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Assia Chemical Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present disclosure encompasses solid state forms of Bavdegalutamide, in embodiments crystalline polymorphs or salts or co-crystals of Bavdegalutamide, processes for preparation thereof, and pharmaceutical compositions thereof.
  • Bavdegalutamide is an investigational, oral PROTAC® protein degrader that targets the androgen receptor (AR), and it is developed for the treatment of metastatic castration resistant prostate cancer.
  • 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 ( 13 C) NMR spectrum.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • XRD X-ray diffraction
  • 13 C solid state
  • 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.
  • 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/physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Bavdegalutamide.
  • the present disclosure provides crystalline polymorphs of Bavdegalutamide, including salts or co-crystals of Bavdegalutamide, processes for preparation thereof, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other solid state forms of Bavdegalutamide, co-crystals of Bavdegalutamide, Bavdegalutamide salts and their solid state forms.
  • the present disclosure also provides uses of the said solid state forms of Bavdegalutamide in the preparation of other solid state forms of Bavdegalutamide or salts thereof.
  • the present disclosure provides crystalline polymorphs of Bavdegalutamide for use in medicine, including for the treatment of metastatic castration resistant prostate cancer.
  • the present disclosure also encompasses the use of crystalline polymorphs of Bavdegalutamide of the present disclosure for the preparation of pharmaceutical compositions and/or formulations.
  • the present disclosure provides pharmaceutical compositions comprising crystalline polymorphs of Bavdegalutamide according to the present disclosure.
  • the present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes includes combining any one or a combination of the crystalline polymorphs of Bavdegalutamide with at least one pharmaceutically acceptable excipient.
  • the crystalline polymorph of Bavdegalutamide as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorph of Bavdegalutamide may be used as medicaments, such as for the treatment of metastatic castration resistant prostate cancer.
  • the present disclosure also provides methods of treating metastatic castration resistant prostate cancer, by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Bavdegalutamide of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from metastatic castration resistant prostate cancer, or otherwise in need of the treatment.
  • the present disclosure also provides uses of crystalline polymorphs of Bavdegalutamide of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g. metastatic castration resistant prostate cancer.
  • Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of crystalline Bavdegalutamide: glutaric acid Form Gl;
  • Figure 2 shows a characteristic X-ray powder diffraction pattern (XRPD) of crystalline Bavdegalutamide: glutaric acid Form G2;
  • Figure 3 shows a characteristic X-ray powder diffraction pattern (XRPD) of crystalline Bavdegalutamide: citric acid Form Cl;
  • Figure 4 shows a characteristic X-ray powder diffraction pattern (XRPD) of crystalline Bavdegalutamide: citric acid Form C2;
  • Figure 5 shows a characteristic X-ray powder diffraction pattern (XRPD) of crystalline Bavdegalutamide mesylate Form Ml;
  • Figure 6 shows a characteristic X-ray powder diffraction pattern (XRPD) of crystalline Bavdegalutamide mesylate Form M2;
  • Figure 7 shows a characteristic X-ray powder diffraction pattern (XRPD) of crystalline Bavdegalutamide hydrochloride Form Hl;
  • Figure 8 shows a characteristic X-ray powder diffraction pattern (XRPD) of crystalline Bavdegalutamide hydrochloride Form H2;
  • Figure 9 shows a characteristic X-ray powder diffraction pattern (XRPD) of crystalline Bavdegalutamide hydrochloride Form H3;
  • Figure 10 shows a characteristic X-ray powder diffraction pattern (XRPD) of Bavdegalutamide Form LI ;
  • Figure 11 shows a characteristic XRPD of a Bavdegalutamide Amorphous Form
  • Figure 12a shows solid state 13 C NMR spectrum of crystalline Bavdegalutamide: glutaric acid Form G1 (Full scan);
  • Figure 12b shows solid state 13 C NMR spectrum of crystalline Bavdegalutamide: glutaric acid Form G1 (at the range of 0-100 ppm);
  • Figure 12c shows solid state 13 C NMR spectrum of crystalline Bavdegalutamide: glutaric acid Form G1 (at the range of 100-200 ppm);
  • Figure 13a shows solid state 13 C NMR spectrum of Bavdegalutamide Form LI (Full scan);
  • Figure 13b shows solid state 13 C NMR spectrum of Bavdegalutamide Form LI (at the range of 0-100 ppm);
  • Figure 13c shows solid state 13 C NMR spectrum of Bavdegalutamide Form LI (at the range of 100-200 ppm).
  • the present disclosure encompasses solid state forms of Bavdegalutamide, including crystalline polymorphs of Bavdegalutamide, processes for preparation thereof, and pharmaceutical compositions thereof.
  • Solid state properties of Bavdegalutamide and crystalline polymorphs thereof can be influenced by controlling the conditions under which Bavdegalutamide and crystalline polymorphs thereof are obtained in solid form.
  • the present disclosure provides crystalline Bavdegalutamide: glutaric acid Form Gl, crystalline Bavdegalutamide: glutaric acid Form G2, Bavdegalutamide: citric acid Form Cl, crystalline Bavdegalutamide: citric acid Form C2, crystalline Bavdegalutamide mesylate Form Ml , crystalline Bavdegalutamide mesylate Form M2, crystalline Bavdegalutamide hydrochloride Form Hl, crystalline Bavdegalutamide hydrochloride Form H2, crystalline Bavdegalutamide hydrochloride Form H3 and crystalline form of Bavdegalutamide designated as Form LI (defined herein).
  • a solid state form may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms.
  • 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.
  • a crystalline polymorph of Bavdegalutamide 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 Bavdegalutamide.
  • the described crystalline polymorph of Bavdegalutamide 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 Bavdegalutamide.
  • a crystalline polymorph of Bavdegalutamide, salts of Bavdegalutamide, or cocrystal of Bavdegalutamide may contain: about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other forms of salts of Bavdegalutamide, or cocrystal of Bavdegalutamide.
  • a crystalline polymorph of Bavdegalutamide, salts of Bavdegalutamide, or cocrystal of Bavdegalutamide, as described in any aspect or embodiment herein, which is polymorphically pure may contain: about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other forms of the Bavdegalutamide, salts of Bavdegalutamide, or cocrystal of Bavdegalutamide.
  • a crystalline polymorph of Bavdegalutamide, salts of Bavdegalutamide, or cocrystal of Bavdegalutamide as described in any aspect or embodiment herein, which is polymorphically pure may contain: about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other forms of Bavdegalutamide, salts of Bavdegalutamide, or cocrystal of Bavdegalutamide.
  • a crystalline polymorph of Bavdegalutamide, salts of Bavdegalutamide, or cocrystal of Bavdegalutamide may be polymorphically pure and may 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 Bavdegalutamide, salts of Bavdegalutamide, or cocrystal of Bavdegalutamide.
  • the crystalline polymorphs of Bavdegalutamide 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.
  • 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.
  • 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.
  • a crystal form of Bavdegalutamide referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Bavdegalutamide characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.
  • anhydrous in relation to crystalline forms of Bavdegalutamide, relates to a crystalline form of Bavdegalutamide 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.
  • solvate refers to a crystal form that incorporates a solvent in the crystal structure.
  • 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.
  • the term "isolated" in reference to crystalline polymorph of Bavdegalutamide of the present disclosure corresponds to a crystalline polymorph of Bavdegalutamide that is physically separated from the reaction mixture in which it is formed.
  • a thing e.g., a reaction mixture
  • 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.
  • room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25 °C.
  • the amount of solvent employed in a chemical process may be referred to herein as a number of “volumes” or “vol” or “V.”
  • a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent.
  • 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.
  • 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.
  • 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.
  • reduced pressure refers to a pressure that is less than atmospheric pressure.
  • reduced pressure is about 10 mbar to about 50 mbar.
  • ambient conditions refer to atmospheric pressure and a temperature of 22-24°C.
  • Co-Crystal or "Co-crystal” as used herein is defined as a crystalline material including two or more molecules in the same crystalline lattice and associated by non-ionic and non-covalent. Bonds.
  • the co-crystal includes two molecules which are in natural state.
  • the molar ratio between the active pharmaceutical ingredient (Bavdegalutamide) and the coformer (glutaric acid or citric acid) is between 1: 1.5 and 1.5: 1, preferably between 1: 1.25 and 1.25: 1, in other embodiments about 1: 1.
  • crystalline Bavdegalutamide glutaric acid is a distinct molecular species.
  • Crystalline Bavdegalutamide glutaric acid may be a co-crystal of Bavdegalutamide and glutaric acid.
  • crystalline Bavdegalutamide glutaric acid may be a salt.
  • the present disclosure further encompasses crystalline Bavdegalutamide: glutaric acid.
  • Crystalline Bavdegalutamide: glutaric acid may be a co-crystal of Bavdegalutamide and glutaric acid.
  • crystalline Bavdegalutamide: glutaric acid may be a salt.
  • the disclosure further encompasses a crystalline form of Bavdegalutamide and glutaric acid, designated as form Gl.
  • a crystalline form of Bavdegalutamide and glutaric acid designated as form Gl.
  • Crystalline Form G1 of Bavdegalutamide: glutaric acid is a co-crystal.
  • Crystalline Form Gl of Bavdegalutamide: glutaric acid wherein the Bavdegalutamide and glutaric acid are present in a molar ratio of 1:2.
  • Crystalline Form Gl of Bavdegalutamide glutaric acid may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1 ; an X-ray powder diffraction pattern having peaks at 7.8 and 20.5 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data; a solid state 13 C NMR spectrum having peaks at 56.42, 113.08, 129.34 and 133.88 ppm ⁇ 0.2 ppm; a solid state 13 C NMR spectrum having the following chemical shift absolute differences from a reference peak at 143.34 ppm ⁇ 0.2 ppm of 86.92, 30.26, 14.0 and 9.46 ppm ⁇ 0.1 ppm; a solid state 13 C NMR spectrum substantially as depicted in Figures 12a, 12b or 12c; and combinations of these data.
  • Crystalline Form G1 of Bavdegalutamide glutaric acid may be further characterized by an X-ray powder diffraction pattern having peaks at 7.8 and 20.5 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having an additional peak selected from 17.1 ⁇ 0.2 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Form G1 of Bavdegalutamide glutaric acid is isolated. According to any aspect or embodiment, crystalline Form G1 of Bavdegalutamide: glutaric acid may be substantially free of any other crystalline and/or amorphous forms of Bavdegalutamide: glutaric acid.
  • Crystalline Form G1 of Bavdegalutamide glutaric acid may be characterized by each of the above characteristics alone or by all possible combinations, e.g., an XRPD pattern having peaks at 7.8 and 20.5 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1 ; and combinations thereof.
  • the crystalline Form G1 of Bavdegalutamide glutaric acid according to any aspect or embodiment of the disclosure is obtainable in very high purity (for example: at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%, or about 100%), and provides a useful method for purification of Bavdegalutamide, i.e.
  • the disclosure further encompasses a crystalline form of Bavdegalutamide and glutaric acid, designated form G2.
  • Crystalline Form G2 of Bavdegalutamide glutaric acid may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2; an X-ray powder diffraction pattern having peaks at 9.1, 9.9 and 19.5 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline Form G2 of Bavdegalutamide glutaric acid may be further characterized by an X-ray powder diffraction pattern having peaks at 9.1, 9.9 and 19.5 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one or two additional peak selected from 17.1 and 21.1 ⁇ 0.2 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Form G2 of Bavdegalutamide glutaric acid is isolated. According to any aspect or embodiment, crystalline Form G2 of Bavdegalutamide: glutaric acid may be substantially free of any other crystalline and/or amorphous forms of Bavdegalutamide: glutaric acid.
  • Crystalline Form G2 of Bavdegalutamide glutaric acid may be characterized by each of the above characteristics alone or by all possible combinations, e.g., an XRPD pattern having peaks at 9.1, 9.9 and 19.5 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2; and combinations thereof.
  • crystalline Bavdegalutamide citric acid is a distinct molecular species.
  • Crystalline Bavdegalutamide citric acid may be a co-crystal of Bavdegalutamide and citric acid.
  • crystalline Bavdegalutamide citric acid may be a salt.
  • the present disclosure further encompasses crystalline Bavdegalutamide: citric acid.
  • Crystalline Bavdegalutamide: citric acid may be a co-crystal of Bavdegalutamide and citric acid.
  • crystalline Bavdegalutamide: citric acid may be a salt.
  • the disclosure further encompasses a crystalline form of Bavdegalutamide and citric acid, designated form Cl.
  • Crystalline Form Cl of Bavdegalutamide citric acid may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 3; an X-ray powder diffraction pattern having peaks at 4.6 and 18.9 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline Form Cl of Bavdegalutamide citric acid may be further characterized by an X-ray powder diffraction pattern having peaks at 4.6 and 18.9 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having an additional peak selected from 17.4 ⁇ 0.2 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Form Cl of Bavdegalutamide: citric acid is isolated.
  • crystalline Form Cl of Bavdegalutamide: citric acid may be substantially free of any other crystalline and/or amorphous forms of Bavdegalutamide: citric acid.
  • Crystalline Form Cl of Bavdegalutamide: citric acid may be characterized by each of the above characteristics alone or by all possible combinations, e.g., an XRPD pattern having peaks at 4.6 and 18.9 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 3; and combinations thereof.
  • the disclosure further encompasses a crystalline form of Bavdegalutamide and citric acid, designated form C2.
  • Crystalline Form C2 of Bavdegalutamide citric acid may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; an X-ray powder diffraction pattern having peaks at 5.5, 9.9, 18.6 and 21.1 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline Form C2 of Bavdegalutamide citric acid may be further characterized by an X-ray powder diffraction pattern having peaks at 5.5, 9.9, 18.6 and 21.1 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 17.0, 25.0 and 25.6 ⁇ 0.2 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Form C2 of Bavdegalutamide: citric acid is isolated. According to any aspect or embodiment, crystalline Form C2 of Bavdegalutamide: citric acid may be substantially free of any other crystalline and/or amorphous forms of Bavdegalutamide: citric acid.
  • Crystalline Form C2 of Bavdegalutamide citric acid may be characterized by each of the above characteristics alone or by all possible combinations, e.g., an XRPD pattern having peaks at 5.5, 9.9, 18.6 and 21.1 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 4; and combinations thereof.
  • the present disclosure includes a crystalline polymorph of Bavdegalutamide mesylate, designated Ml.
  • the crystalline Form Ml of Bavdegalutamide mesylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 5; an X-ray powder diffraction pattern having peaks at 6.3, 7.5, 18.3, 20.8 and 21.5 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline Form Ml of Bavdegalutamide mesylate may be further characterized by an X-ray powder diffraction pattern having peaks at 6.3, 7.5, 18.3, 20.8 and 21.5 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 14.9, 16.1, 17.5 and 20.1 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Form Ml of Bavdegalutamide mesylate is isolated.
  • crystalline Form Ml of Bavdegalutamide mesylate may be substantially free of any other crystalline and/or amorphous forms of Bavdegalutamide mesylate.
  • Crystalline Form Ml of Bavdegalutamide mesylate may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 6.3, 7.5, 18.3, 20.8 and 21.5 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 5, and combinations thereof.
  • the present disclosure includes a crystalline polymorph of Bavdegalutamide mesylate, designated M2.
  • the crystalline Form M2 of Bavdegalutamide mesylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 6; an X-ray powder diffraction pattern having peaks at 6.9, 9.1, 11.9, 19.1 and 23.8 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline Form M2 of Bavdegalutamide mesylate may be further characterized by an X-ray powder diffraction pattern having peaks at 6.9, 9.1, 11.9, 19.1 and 23.8 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 12.4, 12.7 and 25.5 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Form M2 of Bavdegalutamide mesylate is isolated. According to any aspect or embodiment, crystalline Form M2 of Bavdegalutamide mesylate may be substantially free of any other crystalline and/or amorphous forms of Bavdegalutamide mesylate.
  • Crystalline Form M2 of Bavdegalutamide mesylate may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 6.9, 9.1, 11.9, 19.1 and 23.8 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 6, and combinations thereof.
  • the present disclosure includes a crystalline polymorph of Bavdegalutamide hydrochloride, designated Hl.
  • the crystalline Form Hl of Bavdegalutamide hydrochloride may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 7; an X-ray powder diffraction pattern having peaks at 7.6, 16.6 and 21.7 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline Form Hl of Bavdegalutamide hydrochloride may be further characterized by an X-ray powder diffraction pattern having peaks at 7.6, 16.6 and 21.7 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 14.3, 19.1 and 29.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Form Hl of Bavdegalutamide hydrochloride is isolated. According to any aspect or embodiment, crystalline Form Hl of Bavdegalutamide hydrochloride may be substantially free of any other crystalline and/or amorphous forms of Bavdegalutamide hydrochloride.
  • Crystalline Form Hl of Bavdegalutamide hydrochloride may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.6, 16.6 and 21.7 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 7, and combinations thereof.
  • the present disclosure includes a crystalline polymorph of Bavdegalutamide hydrochloride, designated H2.
  • the crystalline Form H2 of Bavdegalutamide hydrochloride may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 8; an X-ray powder diffraction pattern having peaks at 3.6, 7.1, 23.5 and 26.1 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline Form H2 of Bavdegalutamide hydrochloride may be further characterized by an X-ray powder diffraction pattern having peaks at 3.6, 7.1, 23.5 and 26.1 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three additional peaks selected from 7.9, 11.7, 14.5 and 17.5 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Form H2 of Bavdegalutamide hydrochloride is isolated. According to any aspect or embodiment, crystalline Form H2 of Bavdegalutamide hydrochloride may be substantially free of any other crystalline and/or amorphous forms of Bavdegalutamide hydrochloride.
  • Crystalline Form H2 of Bavdegalutamide hydrochloride may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 3.6, 7.1, 23.5 and 26.1 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 8, and combinations thereof.
  • the present disclosure includes a crystalline polymorph of Bavdegalutamide hydrochloride, designated H3.
  • the crystalline Form H3 of Bavdegalutamide hydrochloride may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 9; an X-ray powder diffraction pattern having peaks at 8.9 and 25.4 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
  • Crystalline Form H3 of Bavdegalutamide hydrochloride may be further characterized by an X-ray powder diffraction pattern having peaks at 8.9 and 25.4 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three additional peaks selected from 11.6, 13.8, 17.1 and 17.9 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Form H3 of Bavdegalutamide hydrochloride is isolated. According to any aspect or embodiment, crystalline Form H3 of Bavdegalutamide hydrochloride may be substantially free of any other crystalline and/or amorphous forms of Bavdegalutamide hydrochloride.
  • Crystalline Form H3 of Bavdegalutamide hydrochloride may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.9 and 25.4 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 9, and combinations thereof.
  • the present disclosure includes a crystalline polymorph of Bavdegalutamide, designated LI.
  • the crystalline Form LI of Bavdegalutamide may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 10; an X-ray powder diffraction pattern having peaks at 4.5, 8.8 and 19.8 degrees 2-theta ⁇ 0.2 degrees 2-theta; a solid state 13 C NMR spectrum having peaks at 44.68, 64.46, 119.86 and 146.07 ppm ⁇ 0.2 ppm; a solid state 13 C NMR spectrum having the following chemical shift absolute differences from a reference peak at 142.86 ppm ⁇ 0.2 ppm of 98.81, 78.40, 23.0 and 133.4 ppm ⁇ 0.1 ppm; a solid state 13 C NMR spectrum substantially as depicted in Figures 13a, 13b or 13 c; and combinations of these data.
  • Crystalline Form LI of Bavdegalutamide may be further characterized by an X-ray powder diffraction pattern having peaks at 4.5, 8.8 and 19.8 degrees 2-theta ⁇ 0.2 degrees 2- theta, and also having any one, two, or three additional peaks selected from 12.0, 17.1 and 20.9 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form LI of Bavdegalutamide may be characterized by an X-ray powder diffraction pattern having peaks at 4.5, 8.8, 12.0, 17.1, 19.8 and 20.9 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • crystalline Form LI of Bavdegalutamide may be characterized by an X-ray powder diffraction pattern having peaks at 4.5, 8.8 and 19.8 degrees 2- theta ⁇ 0.2 degrees 2-theta, or an X-ray powder diffraction pattern having peaks at 4.5, 8.8 and 19.8 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having one, two, or three additional peaks selected from 12.0, 17.1 and 20.9 degrees two theta ⁇ 0.2 degrees two theta; or an XRPD pattern having peaks at: 4.5, 8.8, 12.0, 17.1, 19.8 and 20.9 degrees 2-theta ⁇ 0.2 degrees 2-theta; and in each case, wherein the XRPD pattern has at least one of the following:
  • crystalline Form LI of Bavdegalutamide may be characterized by a solid state 13 C NMR spectrum having peaks at 44.68, 64.46, 119.86 and 146.07 ppm ⁇ 0.2 ppm; and/or a solid state 13 C NMR spectrum having the following chemical shift absolute differences from a reference peak at 142.86 ppm ⁇ 0.2 ppm of 98.81, 78.40, 23.0 and 133.4 ppm ⁇ 0.1 ppm; and in each case, wherein the 13 C NMR spectrum has at least one of the following:
  • crystalline Form LI of Bavdegalutamide is isolated.
  • crystalline Form LI of Bavdegalutamide may be substantially free of any other crystalline and/or amorphous forms of Bavdegalutamide.
  • Crystalline Form LI of Bavdegalutamide may be hydrate form with water content from 2% to 4.3%.
  • Form LI of Bavdegalutamide may optionally be a monohydrate, or a sesquihydrate, or a dihydrate.
  • Crystalline Form LI of Bavdegalutamide may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 4.5, 8.8 and 19.8 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 10, and combinations thereof.
  • the present disclosure further comprises a process for preparation of Form LI of Bavdegalutamide.
  • the process may comprise slurrying amorphous Bavdegalutamide in a solvent mixture, preferably wherein the solvent mixture is methanol and water, for a sufficient time to form Bavdegalutamide Form LI; and optionally isolating the Form LI of Bavdegalutamide.
  • Form LI of Bavdegalutamide as described in any aspect or embodiment of the disclosure may be prepared by a process comprising: combining Bavdegalutamide in the solvent mixture to form a mixture, and maintaining the mixture for a sufficient time for prepare Form LI of Bavdegalutamide.
  • Form LI of Bavdegalutamide as described in any aspect or embodiment of the disclosure may be prepared by a process comprising:
  • the suspension in step (i) may be at a temperature of: about 5°C to about 35°C, about 10°C to about 30°C, or about 20°C to about 25°C.
  • the mixture of methanol and water may be used in an amount of: about 10 ml to about 30 ml, about 15 ml to about 25 ml, or about 19.9 ml, per gram of the Bavdegalutamide.
  • the mixture of methanol and water may comprise methanol and water in a vol/vol ratio of about: 1 : 1 to about 20: 1 , about 2: 1 to about 18: 1, about 4: 1 to about 16: 1, about 6:1 to about 14:1, about 7: 1 to about 12: 1, about 8:1 to about 10: 1, or about 9:1.
  • step (ii) may be carried out at a temperature of: 5°C to about 35°C, about 10°C to about 30°C, or about 20°C to about 25°C.
  • step (ii) comprises stirring the suspension for period of: about 48 hour to 100 hours, or about 60 hours to about 90 hours, or about 72 hours.
  • the Form LI of Bavdegalutamide may be isolated in step (iii) by any suitable method, such as by filtration, centrifuge or decantation, preferably by filtration at the temperature of about 5°C to about 35°C, about 10°C to about 30°C, or about 20°C to about 25 °C.
  • Form LI of Bavdegalutamide may be prepared by crystallising Bavdegalutamide from a mixture of acetone and tetrahydrofuran (THF) and an antisolvent.
  • the antisolvent may be water.
  • the crystallisation may comprise combining a solution of Bavdegalutamide in the solvent mixture of acetone and THF, with an antisolvent (preferably wherein the antisolvent is water).
  • Form LI of Bavdegalutamide according to any embodiment of the disclosure may be prepared by a process comprising:
  • the solution in step (a) may be prepared by dissolving Bavdegalutamide in acetone/THF mixture at temperature, preferably: 5°C to about 35°C, about 10°C to about 30°C, or about 20°C to about 25°C.
  • the mixture of acetone and THF may be used in an amount of: about 30 ml to about 70 ml, about 40 ml to about 60 ml, about 50 ml, per gram of Bavdegalutamide.
  • the mixture of THF and acetone may comprise THF and acetone in a vol/vol ratio of about: 10:1 to about 1: 10, about 5: 1 to about 1 :5, about 4: 1 to about 1 :2, about 3: 1 to about 1 :1, about 2.5:1 to about 1.5:1, about 2.2:1 to about 1.8:1, or about 2:1.
  • the water may be added a temperature of about 5°C to about 35°C, about 10°C to about 30°C, , or about 20°C to about 25°C.
  • the water may be preferably used in an amount of about 20 ml to about 200 ml, about 40 ml to about 150 ml, about 60 ml to about 130 ml, about 80 ml to about 120 ml, about 90 ml to about 110 ml, or about 100 ml, per gram of Bavdegalutamide.
  • the vol/vol ratio of water to mixture of acetone/THF may be: about 10: 1 to about 1 :5, about 5: 1 to about 1:3, about 4: 1 to about 1:2, about 3:1 to about 1: 1, about 2.5: 1 to about 1.5: 1, about 2.2: 1 to about 1.8: 1, or about 2: 1.
  • Step (b) may comprise adding the water to the solution of Bavdegalutamide in acetone/THF, or adding the solution of Bavdegalutamide in acetone/THF to the water.
  • step (b) adding water to the solution of Bavdegalutamide in acetone/THF.
  • the addition of the water to the solution of Bavdegalutamide in acetone/THF may be carried out in one portion, or portionwise, or dropwise.
  • the mixture following the combining of the solution of Bavdegalutamide in acetone/THF and water, the mixture may be maintained for a sufficient time to prepare Bavdegalutamide Form LI .
  • the mixture may be maintained preferably at a temperature of: about 5°C to about 35°C, about 10°C to about 30°C, or about 20°C to about 25°C, and preferably for a period of: about 1 to about 12 days, about 1 to about 10 days, about 1.5 to about 8 days, about 2 to about 6 days, or about 6 days.
  • the Bavdegalutamide Form LI may be isolated, preferably by any suitable process, such as by decantation, filtration or by centrifuge, preferably by filtration under vacuum at temperature of about 5°C to about 35°C, about 10°C to about 30°C, , or about 20°C to about 25°C.
  • the crystalline Form DF1 of Bavdegalutamide may be dried under suction.
  • the product may be dried over filter paper at room temperature (for example under suction), or may be dried in a vacuum at room temperature.
  • the above crystalline polymorphs can be used to prepare other crystalline polymorphs of Bavdegalutamide, Bavdegalutamide salts and their solid state forms.
  • the present disclosure encompasses a process for preparing other solid state forms of Bavdegalutamide, Bavdegalutamide salts, and their solid state forms thereof.
  • the process includes preparing any one of the crystalline polymorph of Bavdegalutamide by the processes of the present disclosure.
  • the present disclosure also encompasses the use of crystalline polymorphs of Bavdegalutamide of the present disclosure for the preparation of pharmaceutical compositions of crystalline polymorph Bavdegalutamide and/or crystalline polymorphs thereof.
  • the present disclosure includes processes for preparing the above mentioned pharmaceutical compositions.
  • the processes includes combining any one or a combination of the crystalline polymorphs of Bavdegalutamide of the present disclosure with at least one pharmaceutically acceptable excipient.
  • compositions of the present disclosure contain any one or a combination of the solid state forms of Bavdegalutamide of the present disclosure.
  • the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.
  • 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.
  • 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, hydroxy ethyl 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.
  • povidone e.g. Kollidon®, Plasdone®
  • pregelatinized starch sodium alginate, and starch.
  • 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.
  • alginic acid include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®),
  • 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.
  • 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.
  • 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.
  • 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.
  • Bavdegalutamide 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.
  • 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.
  • 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.
  • a viscosity enhancing agent 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.
  • Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.
  • 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.
  • 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.
  • a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.
  • 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.
  • Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.
  • 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.
  • compositions and dosage forms can be formulated into compositions and dosage forms according to methods known in the art.
  • a composition for tableting or capsule filling can be prepared by wet granulation.
  • 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.
  • a tableting composition can be prepared conventionally by dry blending.
  • 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.
  • 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.
  • 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.
  • a pharmaceutical formulation of Bavdegalutamide can be administered.
  • Bavdegalutamide may be formulated for administration to a mammal, in embodiments to a human, by injection.
  • Bavdegalutamide 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.
  • the crystalline polymorphs of Bavdegalutamide and the pharmaceutical compositions and/or formulations of Bavdegalutamide of the present disclosure can be used as medicaments, in embodiments in the treatment of metastatic castration resistant prostate cancer.
  • the present disclosure also provides methods of treating metastatic castration resistant prostate cancer by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Bavdegalutamide of the present disclosure, or at least one of the above pharmaceutical compositions and/or formulations, to a subject in need of the treatment. 1 [0133] 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.
  • the NMR spectrometer is always completely calibrated and all experimental parameters are carefully optimized prior the recording of the spectra.
  • Magic angle is set using KBr during the standard optimization procedure and homogeneity of magnetic field is optimized using adamantane sample (resulting line-width at half-height Dnl/2 was less than 3.5 Hz at 250 ms of acquisition time). Frictional heating of the spinning samples is compensated by active cooling, and the temperature calibration is performed with Pb(NOi)2.
  • Bavdegalutamide can be prepared according to methods known from the literature, for example International Publication Nos. WO 2018/71606, WO 2021231174 or WO2023025268.
  • Example 1 Preparation of Crystalline Bavdegalutamide: glutaric acid Form G1
  • Crystalline Bavdegalutamide glutaric acid Form G1 (300 mg) was dried in oven under vacuum at temperature of about 100°C for period of about 2 hours. The obtained solid was analyzed by XRPD. Crystalline Bavdegalutamide: glutaric acid Form G2 was obtained. An XRPD pattern is shown in Figure 2.
  • Bavdegalutamide base 800 mg was suspended in 2-propanol (15 mL) at room temperature.
  • Hydrochloride acid (6M water solution, 550 pL, 3.4 eq.) was added to the suspension at room temperature. Suspension was left to stir for period of about 5 days at room temperature and then it was filtered over blue ribbon filter paper. The obtained solid was analyzed by XRPD._Crystalline Bavdegalutamide hydrochloride form Hl was obtained. An XRPD pattern is shown in Figure 7.
  • Amorphous Bavdegalutamide base (503 mg) was suspended in methanol/water solvent mixture (9: 1, 10 mL) at room temperature for period of about 3 days. Suspension was filtrated off over blue ribbon filter paper under vacuum at temperature of about 20°C to about 25°C. The obtained solid was analyzed by XRPD. Crystalline Bavdegalutamide Form LI was obtained. An XRPD pattern is shown in Figure 10.
  • Bavdegalutamide base (1.013 g) was dissolved in dichloromethane/methanol solvent mixture (4: 1, 20 mL) at room temperature. Obtained solution was filtered off over black ribbon filter paper. Then it was fast evaporated on rotary evaporator. Obtained powder was dried at temperature of about 80°C for period of about 10 hours with vacuum and additionally on room temperature with vacuum for period of about 4 hours. The obtained solid was analyzed by XRPD. Amorphous form of Bavdegalutamide was obtained. An XRPD pattern is shown in Figure 11.
  • Bavdegalutamide base (100 mg) was dissolved in acetone/THF 1:2 (5 mL) at room temperature. Water (10 mL) was added dropwise to the solution at about 20°C to about 25°C. Obtained suspension was left to stir for 6 days at temperature of about 20°C to about 25 °C, and then it was filtrated off over blue ribbon filter paper under vacuum at temperature of about 20°C to about 25°C. The obtained solid was analyzed by XRPD. Crystalline Bavdegalutamide Form LI was obtained.
  • Form LI shows superior stability to exposure to typical solvents used in pharmaceutical processing.
  • Form LI is stable in all tested solvents in both the slurry and sauna experiments.
  • the solvents used in the tests are commonly employed for formulation manufacturing, e.g. wet granulation).
  • Crystalline Form LI of Bavdegalutamide characterized by data selected from one or more of the following: a) an XRPD patern having peaks at 4.5, 8.8 and 19.8 degrees 2-theta ⁇ 0.2 degrees 2-theta; b) an XRPD patern as depicted in Figure 10; c) a solid state 13 C NMR spectrum having peaks at 44.68, 64.46, 119.86 and 146.07 ppm ⁇ 0.2 ppm; d) a solid state 13 C NMR spectrum having the following chemical shift absolute differences from a reference peak at 142.86 ppm ⁇ 0.2 ppm of 98.81, 78.40, 23.0 and 133.4 ppm ⁇ 0.1 ppm; e) a solid-state 13 C NMR spectrum substantially as depicted in Figures 13a, 13b or 13 c; and f) combinations of two or more of: a, b, c, d, and e.
  • Crystalline Form LI of Bavdegalutamide according to Clause 1 which is characterized by an XRPD pattern having peaks at 4.5, 8.8 and 19.8 degrees 2-theta ⁇ 0.2 degrees 2- theta.
  • Crystalline Form LI of Bavdegalutamide according to Clause 1 or Clause 2 which is characterized by an XRPD patern having peaks at 4.5, 8.8 and 19.8 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having one, two, or three additional peaks selected from 12.0, 17.1 and 20.9 degrees two theta ⁇ 0.2 degrees two theta.
  • Crystalline Form LI of Bavdegalutamide according to any of Clauses 2, 3 or 4 which is characterized by an XRPD patern having an absence of peaks at 5.2 to 7.8 degrees 2- theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Form LI of Bavdegalutamide according to Clause 1 which is characterized by a solid state 13 C NMR spectrum having peaks at 44.68, 64.46, 119.86 and 146.07 ppm ⁇ 0.2 ppm.
  • Crystalline Form LI of Bavdegalutamide according to Clause 11 or Clause 12 which is characterized by a solid state 13 C NMR spectrum having the following chemical shift absolute differences from a reference peak at 142.86 ppm ⁇ 0.2 ppm of 98.81, 78.40, 23.0 and 133.4 ppm ⁇ 0.1 ppm.
  • Crystalline Form LI of Bavdegalutamide according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Bavdegalutamide.
  • a pharmaceutical composition comprising a crystalline Form LI of Bavdegalutamide according to any of Clauses 1 to 23.
  • a pharmaceutical formulation comprising a crystalline Form LI of Bavdegalutamide according to any of Clauses 1 to 23, or a pharmaceutical composition of Clause 24, and at least one pharmaceutically acceptable excipient.
  • a method of treating metastatic castration resistant prostate cancer comprising administering a therapeutically effective amount of a crystalline Form LI of Bavdegalutamide according to any one of Clauses 1 to 23, a pharmaceutical composition according to Clause 24, or a pharmaceutical formulation according to Clause 26, to a subject in need of the treatment.
  • Crystalline Form LI of Bavdegalutamide according to any one of Clauses 1 to 23, a pharmaceutical composition according to Clause 24, or a pharmaceutical formulation according to Clause 26, for the manufacture of a medicament for metastatic castration resistant prostate cancer.

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Abstract

La présente invention concerne des formes à l'état solide de bavdégalutamide, dans des modes de réalisation, des cocristaux ou des sels ou des polymorphes cristallins de bavdégalutamide, des procédés de préparation de ceux-ci, et des compositions pharmaceutiques à base de ceux-ci.
PCT/IB2024/052772 2023-03-24 2024-03-22 Formes à l'état solide de bavdégalutamide et leur procédé de préparation Pending WO2024201244A1 (fr)

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WO2018071606A1 (fr) 2016-10-11 2018-04-19 Arvinas, Inc. Composés et procédés pour la dégradation ciblée du récepteur des androgènes
WO2021231174A1 (fr) 2020-05-09 2021-11-18 Arvinas Operations, Inc. Procédés de fabrication d'un composé bifonctionnel, formes ultra-pures du composé bifonctionnel, et formes posologiques les comprenant
WO2023025268A1 (fr) 2021-08-27 2023-03-02 苏州晶云药物科技股份有限公司 Formes cristallines d'un composé de pyridazine carboxamide et leur procédé de préparation

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Publication number Priority date Publication date Assignee Title
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