WO2023105483A1 - Crystalline forms of a 5-aminopyrazole compound useful for treating hbv - Google Patents

Crystalline forms of a 5-aminopyrazole compound useful for treating hbv Download PDF

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Publication number
WO2023105483A1
WO2023105483A1 PCT/IB2022/061999 IB2022061999W WO2023105483A1 WO 2023105483 A1 WO2023105483 A1 WO 2023105483A1 IB 2022061999 W IB2022061999 W IB 2022061999W WO 2023105483 A1 WO2023105483 A1 WO 2023105483A1
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Prior art keywords
formula
compound
crystalline form
peaks
crystalline
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PCT/IB2022/061999
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French (fr)
Inventor
Dongmei QIANG
Zhixin ZONG
Nicole White
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Assembly Biosciences, Inc.
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Publication of WO2023105483A1 publication Critical patent/WO2023105483A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the invention relates to novel crystalline forms of a 5-aminopyrazole compound, as well as to pharmaceutical compositions comprising the same, and to methods for their production and use in the context of treating Hepatitis B.
  • HBV Hepatitis B
  • liver cancer hepatocellular carcinoma
  • the hepatitis virus particle is composed of a lipid envelope studded with surface protein (HBsAg) that surrounds the viral core.
  • the core is composed of a protein shell, or capsid, built of 120 core protein (Cp) dimers, which in turn contains the relaxed circular DNA (rcDNA) viral genome as well as viral and host proteins.
  • Cp core protein
  • rcDNA relaxed circular DNA
  • cccDNA covalently closed circular DNA
  • the cccDNA is the template for viral RNAs and thus viral proteins.
  • Cp assembles around a complex of full-length viral RNA (the so-called pregenomic RNA or pgRNA and viral polymerase (P). After assembly, P reverse transcribes the pgRNA to rcDNA within the confines of the capsid to generate the DNA- filled viral core.
  • nucleotide analogs e.g., entecavir
  • entecavir nucleotide analogs
  • nucleotide analogs The only FDA approved alternative to nucleotide analogs is treatment with interferon a or pegylated interferon a. Unfortunately, the adverse event incidence and profile of interferon a can result in poor tolerability, and many patients are unable to complete therapy. Moreover, only a small percentage of patients are considered appropriate for interferon therapy, as only a small subset of patients are likely to have a sustained clinical response to a course of interferon therapy. As a result, interferon-based therapies are used in only a small percentage of all diagnosed patients who elect treatment. [0006] Thus, current HBV treatments can range from palliative to watchful waiting. Nucleotide analogs suppress virus production, treating the symptom, but leave the infection intact. Interferon a has severe side effects and less tolerability among patients and is successful as a finite treatment strategy in only a small minority of patients.
  • W02020/086533 discloses 5-aminopyrazole compounds, and pharmaceutical compositions thereof, useful as modulators of HBV core protein, and methods of treating HBV infection.
  • novel crystalline solid forms useful for the treatment of HBV in a subject in need thereof.
  • novel crystalline solid forms of the compound 5-amino-7V-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5-hydroxy-5- (methylsulfonylmethyl)octahydro-pentalen-2-yl)-l-methyl-lH-pyrazole-4-carboxamide referred to herein as the “compound of Formula (I)” having the structural formula: Formula (I).
  • XRPD X-ray powder diffraction
  • Form B is a non-solvated crystalline form of Formula (I).
  • Form B has been determined to be thermodynamically stable at water activities ⁇ 0.5 at 25°C.
  • Form B was also shown to be stable in the solid state at high humidity levels (at both room temperature and at elevated temperature) despite data from slurry experiments suggesting that a different form, i.e., the hydrated crystalline form, Form A, is the most thermodynamically stable form at water activities >0.75 at 25° (see Example 1).
  • the data in Example 1 demonstrates that Form B is stable in the solid state during a dynamic vapor sorption (DVS) experiment wherein humidity levels reached 90% RH (see Figures 17-18).
  • Example 2 demonstrates that Form B in the solid state is stable for at least four weeks when exposed at both 40°C/75%RH (closed and open) and 70°C/75%RH (closed and open) conditions (see Table 34).
  • Form B also has other advantageous properties.
  • Form B has been found to be stable in the solid state both physically and chemically when stressed (oxidative or mechanical), under photostability conditions, and under long term and accelerated stability conditions (at 25°C/60%RH for 24 months and 40°C/75%RH for 6 months).
  • the present disclosure provides a crystalline form of a compound of Formula (I) wherein the form is Form A.
  • Form A is a hydrated crystalline form of a compound of Formula (I).
  • Form A has been determined to the most thermodynamically stable form at water activities >0.75 at 25°C.
  • the present disclosure provides a crystalline form of a compound of Formula (I) wherein the form is Form C.
  • Form C is a solvated crystalline form of a compound of Formula (I).
  • the present disclosure provides a crystalline form of a compound of Formula (I) wherein the form is Form D.
  • Form D is a crystalline 1,4-dioxane/water solvate of a compound of Formula (I).
  • the present disclosure provides a crystalline form of a compound of Formula (I) wherein the form is Form F.
  • Form F is a crystalline DMSO/water solvate of a compound of Formula (I).
  • the present disclosure provides a crystalline form of a compound of Formula (I) wherein the form is Form G.
  • Form G is a non-solvated crystalline form of a compound of Formula (I).
  • the present disclosure provides a crystalline form of a compound of Formula (I) wherein the form is Form H.
  • Form H is a non-solvated crystalline form of a compound of Formula (I).
  • the present disclosure provides a crystalline form of a compound of Formula (I) wherein the form is Form I.
  • Form I is a hydrated crystalline form of a compound of Formula (I).
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form of a compound of Formula (I): Formula (I) wherein the crystalline form is Form A, B, C, D, F, G, H or I, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides a method of treating HBV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of a compound of Formula (I): Formula (I) wherein the crystalline form is Form A, B, C, D, F, G, H or I.
  • the present invention provides a method of treating HBV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of a compound of Formula (I): Formula (I) wherein the crystalline form is Form A, B, C, D, F, G, H or I and a pharmaceutically acceptable carrier, diluent or excipient.
  • a crystalline form of a compound of Formula (I) for use in the treatment of HBV infection wherein the crystalline form is Form A, B, C, D, F, G, H or I.
  • a pharmaceutical composition comprising a crystalline form of a compound of Formula (I), and a pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of HBV infection, wherein the crystalline form is Form A, B, C, D, F, G, H or I.
  • a crystalline compound of Formula (I) or a pharmaceutical composition comprises a crystalline form a compound of Formula (I) in the manufacture of a medicament for treating HBV infection, wherein the crystalline form is Form A,
  • a crystalline compound of Formula (I) obtainable by the processes described herein, wherein the crystalline form is Form A, B, C, D, F, G, H or I.
  • Figure 1 Characterization Data of Input Material (compound of Formula (I), Mixture of Forms A and G): FT-Raman Spectrum
  • Figure 3 Characterization Data of Input Material (compound of Formula (I), Mixture of Forms A and G): DSC/TGA-IR Data
  • Figure 20 Characterization Data of Form C (2-butanone solvate): FT-Raman Spectrum
  • Figure 21 Characterization Data of Form C (2-butanone solvate): PXRD Pattern
  • Figure 28 Characterization Data of Form D (1,4-Dioxane/Water Solvate): DSC/TGA-IR Data
  • Figure 30 FT-Raman Spectral Overlay of Form E Initially and After Two Days at Ambient and Form A
  • Figure 31 Characterization Data of Form F (DMSO/Water Solvate): FT-Raman Spectrum
  • Figure 32 Characterization Data of Form F (DMSO/Water Solvate): PXRD Pattern
  • Figure 33 Characterization Data of Form F (DMSO/Water Solvate): DSC/TGA-IR
  • Figure 34 Characterization Data of Form F (DMSO/Water Solvate): PLM Image
  • Figure 35 Characterization Data of Form G (Non-Solvated): FT-Raman Spectrum
  • Figure 36 Characterization Data of Form G (Non-Solvated): PXRD Pattern
  • Figure 37 Characterization Data of Form G (Non-Solvated): DSC Data
  • Figure 38 Characterization Data of Form G (Non-Solvated): PLM Image
  • 39 Characterization Data of Form H (Non-Solvated): FT-Raman Spectrum
  • 40 Characterization Data of Form H (Non-Solvated): PXRD Pattern
  • Figure 49 Overlay of pH 1 residue with Form A and B or parent and HC1 salt. *consistent with HC1 salt
  • Figure 50 IDR for compound of Formula (I) Form B in FaSSGF pH 1.6.
  • Figure 51 IDR for compound of Formula (I) Form B in FaSSIF V2 pH 6.5.
  • Figure 53 Overlay PXRD Diagram of milled and unmilled compound of Formula (I) Form B.
  • Figure 54 PLM of ball milling at 2 and 5 minute samples and unmilled compound of Formula (I) Form B.
  • Figure 55 DSC and TGA at 2 and 5 minute ball milling samples and unmilled compound of Formula (I) Form B.
  • FIG 56 Overlay PXRD of wet grinding samples and input material (compound of Formula (I) Form B).
  • Figure 57 PLM of grinding at 5 and 10 minute samples and input material (compound of Formula (I) Form B).
  • Figure 58 Overlay PXRD of compression sample with 10KN, 15 KN force and input material (compound of Formula (I) Form B).
  • Figure 59 PLM of Transmission of ground tablet with 10 kN and 15 kN Force.
  • Figure 60 Compaction PLM - Reflection of intact tablet with punch (10 kN force applied, left photograph; 15 kN force, right photograph).
  • Figure 61 DSC of 10 kN, 15 kN compression samples and input material (compound of Formula (I) Form B).
  • the terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds or pharmaceutical compositions of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, and the like).
  • the mammal treated in the methods of the disclosure is desirably a mammal in which treatment of HBV infection is desired.
  • modulation includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.
  • pharmaceutically acceptable include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carrier, diluent or excipient.
  • terapéuticaally effective amount refers to the amount of the subj ect compound that will elicit the biological or medical response of a tissue, system or animal, (e.g. mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the compounds or pharmaceutical compositions of the disclosure are administered in therapeutically effective amounts to treat a disease.
  • a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect.
  • treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, via disruption of HBV core protein assembly, that results in the improvement of the disease.
  • “Disruption” includes inhibition of HBV viral assembly and infection.
  • a “crystalline form” is a solid material wherein the constituents of the solid material are arranged in a highly ordered microscopic structure, thereby forming a crystal lattice which extends in all directions.
  • Crystalline forms can include anhydrous crystalline forms, solvated crystalline forms and/or hydrated crystalline forms.
  • Polymorphism is when a solid material can exist in more than one crystalline form.
  • amorphous refers to a solid material having no long-range order in the position of its molecules.
  • Amorphous solids are substances in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long-range order.
  • Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points.
  • an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid.
  • a “hydrate” is a compound that exists in a solid composition with water molecules.
  • the composition can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a “hydrate” refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein. Hydrates may be crystalline, wherein both the compound and water form part of the crystal lattice.
  • a “solvate” is a similar composition to a hydrate except that a solvent other that water replaces the water.
  • a solvent other that water replaces the water For example, methanol or ethanol can form an “alcoholate”, which can again be stoichiometric or non-stoichiometric.
  • a “solvate” refers to a solid form, i.e., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein.
  • Solvates may be crystalline, wherein both the compound and solvent form part of the crystal lattice.
  • anhydrous means the solid form of the compound does not have water incorporated into its structure.
  • an anhydrous crystalline form does not have water forming part of the crystal structure.
  • water content can be determined by either Karl Fischer Titration or Thermogravimetric Analysis (TGA).
  • an anhydrous solid form of the compound comprises less than about 1% by weight, such as less than about 0.5, about 0.4, about 0.3, about 0.2, about 0.1, about 0.05, or about 0.01% by weight of water.
  • un-solvated or non-solvated means the solid form of the compound does not have solvent(s) incorporated into its structure.
  • an un-solvated crystalline form does not have solvent(s) forming part of the crystal structure.
  • solvent content can be determined by Gas Chromatography (GC).
  • GC Gas Chromatography
  • an un-solvated or non-solvated solid form of the compound comprises less than about 1% by weight, such as less than about 0.5, about 0.4, about 0.3, about 0.2, about 0.1, about 0.05, or about 0.01% by weight of solvent.
  • composition where a composition is said to “consists essentially of’ a particular component, said composition suitably comprises at least 70 wt% of said component, suitably at least 80 wt% thereof, suitably at least 90 wt% thereof, suitably at least 95 wt% thereof, most suitably at least 99 wt% thereof.
  • a composition said to “consist essentially of’ a particular component consists of said component save for one or more trace components.
  • Active Pharmaceutical Ingredient means the Compound of Formula (I).
  • the “Compound of Formula (I)” refers to 5-amino-A-(3-chloro-4- fluorophenyl)-3-((2s,5s)-5-hydroxy-5-(methylsulfonylmethyl)octahydro-pentalen-2-yl)-l- methyl-lH-pyrazole-4-carboxamide.
  • the Compound of Formula (I) is an HBV core inhibitor whose synthesis and testing in an HBV viral load assay have been described in PCT International Publication WO 2020/086533.
  • the compound was referred to as AIA-227-2 in WO 2020/086533. It will be understood that the relative stereochemistry of AIA-227-2 was determined to be as depicted in Figure 2 of WO 2020/086533 and the Compound of Formula (I) may therefore also be shown as:
  • the present disclosure provides novel crystalline forms of a compound of a Formula (I): Formula (I) described and characterized herein as Forms A, B, C, D, F, G, H and I.
  • the present disclosure is also directed to pharmaceutical compositions comprising each crystalline form, and to methods for preparing such forms.
  • the present disclosure is further directed to the use of the crystalline forms in the treatment of HBV infections.
  • Powder X-ray diffraction is just one of several analytical techniques one may use to characterize and/or identify crystalline solid forms.
  • Spectroscopic techniques such as Raman may also be used to characterize and/or identify crystalline solid forms. These techniques may also be used to quantify the amount of one or more crystalline solid forms in a mixture.
  • a typical variability for a peak value associated with an FT-Raman measurement is in the order of plus or minus 2 cm' 1 .
  • Differential scanning calorimetry (DSC) may also be used to characterise and/or identity crystalline solid forms.
  • a typical variability for a value associated with a differential scanning calorimetry onset temperature is in the order of plus or minus 2°C.
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ⁇ 0.2°29; b) a Raman spectrum comprising at least one or two specific peaks selected from the peaks at wavenumbers of 770 and 1614 cm’ 1 ⁇ 2 cm’ 1 ; and c) a DSC thermogram comprising an endothermic event with an onset temperature of 195°C ⁇ 2°C.
  • XRPD X-ray powder diffraction
  • an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ⁇ 0.2°29 and further comprising at least one, two, three, four or five specific peaks selected from the peaks at 2-theta values of 9.9, 14.6, 15.1, 19.7 and 22.2°29 ⁇ 0.2°29.
  • XRPD X-ray powder diffraction
  • an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ⁇ 0.2°29 and further comprising a peak at a 2-theta value of 14.6°29 ⁇ 0.2°29.
  • XRPD X-ray powder diffraction
  • an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ⁇ 0.2°29 and further comprising a peak at a 2-theta value of 15.1°29 ⁇ 0.2°29.
  • XRPD X-ray powder diffraction
  • an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ⁇ 0.2°29 and further comprising peaks at 2-theta values of 9.9, 15.1, 19.7 and 22.2°29 ⁇ 0.2°29.
  • XRPD X-ray powder diffraction
  • an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ⁇ 0.2°29 and further comprising peaks at 2-theta values of9.9, 14.6, 15.1, 19.7 and 22.2°29 ⁇ 0.2°29.
  • XRPD X-ray powder diffraction
  • an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ⁇ 0.1°29.
  • XRPD X-ray powder diffraction
  • an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ⁇ 0.1°29 and further comprising a peak at a 2-theta value of 14.6°29 ⁇ 0.1°29.
  • XRPD X-ray powder diffraction
  • an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ⁇ 0.1°29 and further comprising a peak at a 2-theta value of 15.1°29 ⁇ 0.1°29.
  • XRPD X-ray powder diffraction
  • an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ⁇ 0.1°29 and further comprising the peaks at 2-theta values of 9.9, 15.1, 19.7 and 22.2°29 ⁇ 0.1°29.
  • XRPD X-ray powder diffraction
  • an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3 °29 ⁇ 0.1°29 and further comprising peaks at 2 theta values of 9.9, 14.6, 15.1, 19.7 and 22.2°29 ⁇ 0.1°29.
  • XRPD X-ray powder diffraction
  • an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising a peak at a 2-theta value of 13.2°29 ⁇ 0.2°29, suitably 13.2°29 ⁇ 0.1°29, and wherein Form B is un-solvated and anhydrous.
  • Form B comprises less than about 2% by weight solvent and/or water, such as less than about 1% by weight, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05% or less than about 0.01% by weight.
  • an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising a peak at 2-theta value of 16.4°29 ⁇ 0.2°29, suitably 16.4°29 ⁇ 0.1°29, and wherein Form B is un-solvated and anhydrous.
  • Form B comprises less than about 2% by weight solvent and/or water, such as less than about 1% by weight, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05% or less than about 0.01% by weight.
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ⁇ 0.2°29 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 1 in °29 ⁇ 0.2°29.
  • XRPD X-ray powder diffraction
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ⁇ 0.1°29; and further comprising at least two, five, ten, fifteen, twenty or twenty- five further peaks selected from the group consisting of the peaks in Table 1 in °29 ⁇ 0.1°29.
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising a peak at a 2-theta value of 13.2°29 ⁇ 0.2°29 (suitably, °29 ⁇ 0.1°29) and wherein Form B comprises less than about 0.5% by weight solvent and/or water.
  • XRPD X-ray powder diffraction
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a powder X-Ray diffraction pattern measured Cu Ka (X 1.5406 A) radiation substantially the same as shown in Figure 14.
  • the DSC thermogram further comprises an endothermic event with an onset temperature of 213°C ⁇ 2°C, suitably 213°C ⁇ 1°C.
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 195°C ⁇ 2°C, suitably 195°C ⁇ 1°C, and an endothermic event with an onset temperature of 213°C ⁇ 2°C, suitably 213°C ⁇ 1°C, and wherein the Form B is anhydrous and un-solvated.
  • Form B comprises less than about 2% by weight solvent and/or water, such as less than about 1% by weight, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05% or less than about 0.01% by weight.
  • the crystalline form is Form B.
  • particle size distribution is determined using laser diffraction.
  • particle size distribution is determine using laser diffraction using a wet dispersion of the compound of Formula (I).
  • the dispersion medium comprises water.
  • Form B is non-hygroscopic.
  • a substance is considered non- hygroscopic if the increase in mass is less than 0.2 per cent when the substance is exposed to 25°C/8%RH for 24 hours (for example, in accordance with the test procedure for “hygroscopicity” in Chapter 5.11 “Characters Section in Monographs”, European Pharmacopeia 6.0).
  • Form B is substantially pure.
  • Form B comprises less than about 2% by weight solvent and/or water, such as less than about 1% by weight, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05% or less than about 0.01% by weight.
  • suitable analytical techniques which can quantify the amount of solvent/water associated with a solid.
  • water content can be determined by Karl Fischer Titration.
  • Residual solvents can be determined by Gas Chromatography.
  • Thermogravimetric Analysis (TGA) can also quantify the amount of volatile material (i.e., solvent and water) associated with a solid (either surface bound or incorporated into the crystal structure).
  • Form B is anhydrous and un-solvated.
  • a crystalline form of a compound of Formula (I) of wherein the crystalline form is Form A and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising the peaks at 2-theta values of 11.1, 12.7, and 14.7°29 ⁇ 0.2°29; b) a Raman spectrum comprising at least one or two specific peaks selected from the peaks at wavenumbers of 1070 and 1390 cm' 1 ⁇ 2 cm' 1 ; c) a DSC thermogram comprising an endothermic event with an onset temperature of 213°C ⁇ 2°C; and d) comprising at least 2.5% by weight of water.
  • XRPD X-ray powder diffraction
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by an XRPD measured using Cu Ka (X 1.5406 A) radiation comprising the peaks at 2-theta values of 11.1, 12.7, and 14.7°29 ⁇ 0.1°29 and further comprising at least one, two or three specific peaks selected from the peaks at 2-theta values of 18.4, 22.1 and 22.8°29 ⁇ 0. 1°29.
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by an XRPD measured using Cu Ka (X 1.5406 A) radiation comprising the peaks at 2-theta values of 11.1, 12.7, 14.7, 18.7, 22.1 and 22.8°29 ⁇ 0.1°29.
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising peaks at 2-theta values of 11.1, 12.7, and 14.7°29 ⁇ 0.2°29 and further comprising at least five, ten, fifteen, or twenty peaks selected from the group consisting of the peaks in Table 3 in °29 ⁇ 0.2°29.
  • XRPD X-ray powder diffraction
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising peaks at 2-theta values of 11.1, 12.7, and 14.7°29 ⁇ 0.1°29 and further comprising at least five, ten, fifteen, or twenty peaks selected from the group consisting of the peaks in Table 3 in °29 ⁇ 0.1°29.
  • XRPD X-ray powder diffraction
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by a powder X-Ray diffraction pattern measured using Cu Ka (X 1.5406 A) radiation substantially the same as shown in Figure 8.
  • Form A is substantially pure.
  • a crystalline form of a compound of Formula (I) of wherein the crystalline form is Form C and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising a peak at a 2-theta value of 6.0°29 ⁇ 0.2°29; b) a Raman spectrum comprising peaks at wavenumbers of 747, 921 and 1129 cm' 1 ⁇ 2 cm' 1 ; c) a DSC thermogram comprising an endothermic event with an onset temperature of 194°C ⁇ 2°C; and d) comprising at least 2.5% by weight of solvent wherein the solvent is selected from 1,4-dixoane, 2-butanone and methyl acetate.
  • XRPD X-ray powder diffraction
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising a peak at a 2-theta value of 6.0°29 ⁇ 0.2°29 and further comprising at least five, ten, fifteen, twenty, twenty -five, or thirty peaks selected from the group consisting of the peaks in Table 5 in °29 ⁇ 0.2°29.
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C characterized by a powder X-Ray diffraction pattern measured Cu Ka (X 1.5406 A) radiation substantially the same as shown in Figure 21.
  • the crystalline form is Form C characterized by a Raman spectrum comprising peaks at wavenumbers of 747, 921 and 1129 cm' 1 ⁇ 1 cm' 1
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C characterized by a Raman spectrum comprising peaks at wavenumbers of 747, 921 and 1129 cm' 1 ⁇ 2 cm' 1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 6 in cm' 1 ⁇ 2 cm' 1 .
  • Form C is characterized by a Raman spectrum comprising peaks at wavenumbers of 747, 921 and 1129 cm' 1 ⁇ 1 cm' 1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 6 in cm' 1 ⁇ 1 cm' 1 .
  • a crystalline form of a compound of Formula (I) of wherein the crystalline form is Form D and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising the peaks at 2-theta values of 11.3, 20.1 and 21.2°20 ⁇ 0.2°29; b) a Raman spectrum comprising peaks at wavenumbers of 695 and 1640 cm' 1 ⁇ 2 cm' i.
  • XRPD X-ray powder diffraction
  • a DSC thermogram comprising an endothermic event with an onset temperature of 73°C ⁇ 2°C; d) a DSC thermogram comprising an endothermic event with an onset temperature of 193°C ⁇ 2°C; and e) comprising at least 5% by weight of 1,4-dixoane.
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form D characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form D characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form D characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form D characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (k 1.5406 A) comprising peaks at 2-theta values of 11.3, 20.1 and 21.2°20 ⁇ O.2°20 and further comprising at least five, ten, fifteen, twenty, or twenty-five peaks selected from the group consisting of the peaks in
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form D characterized by a powder X-Ray diffraction pattern measured Cu Ka (X 1.5406 A) radiation substantially the same as shown in Figure 27.
  • Form D is characterized by a Raman spectrum comprising peaks at wavenumbers of 695 and 1640 cm' 1 ⁇ 1 cm' 1 .
  • Form D is characterized by a Raman spectrum comprising peaks at wavenumbers of 695 and 1640 cm' 1 ⁇ 1 cm' 1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 8 in cm 4 ⁇ 1 cm' 1 .
  • a crystalline form of a compound of Formula (I) of wherein the crystalline form is Form F and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising a peak at a 2-theta value of 10.6°29 ⁇ 0.2°29; b) a Raman spectrum comprising peaks at wavenumbers of 1211, 1499 and 1528 cm' 1 ⁇ 2 cm' 1 ; c) a DSC thermogram comprising an endothermic event with an onset temperature of 103°C ⁇ 2°C; and d) comprising at least 5% by weight of DMSO and/
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising a peak at a 2-theta value of 10.6°29 ⁇ 0.2°29 and further comprising at least five, ten, fifteen, twenty, or twenty-five peaks selected from the group consisting of the peaks in Table 9 in °29 ⁇ 0.2°29.
  • XRPD X-ray powder diffraction
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F characterized by a powder X-Ray diffraction pattern measured Cu Ka (X 1.5406 A) radiation substantially the same as shown in Figure 32.
  • Form F is characterized by a Raman spectrum comprising peaks at wavenumbers of 1211, 1499 and 1528 cm' 1 ⁇ 1 cm' 1 .
  • Form F is characterized by a
  • Raman spectrum comprising peaks at comprising peaks at wavenumbers of 1211, 1499 and 1528 cm' 1 ⁇ 1 cm' 1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 10 in cm' 1 ⁇ 1 cm' 1 .
  • Table 10 - Raman shifts for Form F
  • a crystalline form of a compound of Formula (I) of wherein the crystalline form is Form G and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising peaks at 2-theta values of 13.6 and 14.7°29 ⁇ 0.2°29; b) a Raman spectrum comprising peaks at least one or two specific peaks selected from the peaks at wavenumbers of 663 and 1648 cm' 1 ⁇ 2 cm' 1 ; and c) a DSC thermogram comprising an endothermic event with an onset temperature of 212°C ⁇ 2°C.
  • XRPD X-ray powder diffraction
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form G characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form G characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form G characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form G characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising peaks at 2-theta values of 13.6 and 14.7°29 ⁇ 0.2°29 and further comprising at least five, ten, fifteen, twenty or twenty-five peaks selected from the group consisting of the peaks in Table 11 in °29 ⁇ 0.2°29.
  • XRPD X-ray powder diffraction
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form G characterized by a powder X-Ray diffraction pattern measured Cu Ka (X 1.5406 A) radiation substantially the same as shown in Figure 36.
  • Form G is characterized by a Raman spectrum comprising peaks at wavenumbers of 663 and 1648 cm' 1 ⁇ 1 cm' 1 .
  • Form G is characterized by a Raman spectrum comprising peaks at wavenumbers of 663 and 1648 cm' 1 ⁇ 1 cm' 1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 12 in cm 4 ⁇ 1 cm' 1 .
  • Form G comprises less than 2% by weight solvent and/or water, such as less than 1% by weight, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than
  • a crystalline form of a compound of Formula (I) of wherein the crystalline form is Form H and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising the peaks at 2-theta values of 4.7 and 9.5°29 ⁇ 0.2°29; b) a Raman spectrum comprising at least one, two or three specific peaks selected from the peaks at wavenumbers of 795, 1255 and 1314 cm' 1 ⁇ 2 cm' 1 ; and c) a DSC thermogram comprising an endothermic event with an onset temperature of 211°C ⁇ 2°C.
  • XRPD X-ray powder diffraction
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form H characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form H characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form H characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form H characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising peaks at 2-theta values of 4.7 and 9.5°29 ⁇ 0.2°29 and further comprising at least five, ten, fifteen, twenty or twenty -five thirty peaks selected from the group consisting of the peaks in Table 13 in °29 ⁇ 0.2°29.
  • XRPD X-ray powder diffraction
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form H characterized by a powder X-Ray diffraction pattern measured Cu Ka (X 1.5406 A) radiation substantially the same as shown in Figure 40.
  • Form H is characterized by a Raman spectrum comprising peaks at wavenumbers of 795, 1255 and 1314 cm' 1 ⁇ 1 cm' 1 .
  • Form H is characterized by a Raman spectrum comprising peaks at wavenumbers of 795, 1255 and 1314 cm' 1 ⁇ 1 cm' 1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 14 in cm' 1 ⁇ 1 cm' 1 .
  • Form H comprises less than 2% by weight solvent and/or water, such as less than 1% by weight, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1% by weight.
  • Form H is anhydrous and un-solvated.
  • a crystalline form of a compound of Formula (I) of wherein the crystalline form is Form I and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising the peaks at 2-theta values of 14.2, 16.6 and 16.9°29 ⁇ 0.2°29; b) a Raman spectrum comprising a peak at a wavenumber of 586 cm' 1 ⁇ 2 cm' 1 ; and c) a DSC thermogram comprising an endothermic event with an onset temperature of 166°C ⁇ 2°C.
  • XRPD X-ray powder diffraction
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by an XRPD measured using Cu Ka (X
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X 1.5406 A) comprising peaks at 2-theta values of 14.2, 16.6 and 16.9°29 ⁇ 0.2°29 and further comprising at least five, ten, fifteen, twenty or twenty-five peaks selected from the group consisting of the peaks in Table 15 in °29 ⁇ 0.2°29.
  • XRPD X-ray powder diffraction
  • a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by a powder X-Ray diffraction pattern measured Cu Ka (X 1.5406 A) radiation substantially the same as shown in Figure 44.
  • Form I is characterized by a Raman spectrum comprising a peak at 586 cm' 1 ⁇ 1 cm' 1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 16 in cm' 1 ⁇ 1 cm' 1 .
  • the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, yet more conveniently greater than about 90% and preferably greater than 95%, 98% or 99% by weight.
  • Form A is pure or substantially pure.
  • substantially pure means that the solid state form of the compound of Formula (I) contains about 20% by weight or less, or about 15% by weight or less, or about 10% by weight or less, or about 5% by weight or less, or about 2% by weight or less, or about 1% by weight or less, or about 0.5 by weight or less of any impurities or other solid forms of the compound of Formula (I), including alternative crystalline forms, hydrates, solvates or amorphous forms, for example as measured by XRPD.
  • substantially pure Form A described herein would be understood to contain greater than about 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 95% by weight, greater than 98% by weight, greater than 99% by weight, greater than 99.5% by weight of the crystalline Form A of the compound of Formula (I).
  • Form A wherein when Form A is analyzed by a solid-state technique, such as by X-Ray Powder diffraction and/or Raman spectroscopy, no other solid forms (amorphous and/or other crystalline forms) are detected.
  • a crystalline form of a compound of Formula (I) essentially consisting of Form A.
  • a crystalline form of a compound of Formula (I) consisting of Form A there is provided.
  • Form B is pure or substantially pure.
  • the term “substantially pure” means that the solid state form of the compound of Formula (I) contains about 20% by weight or less, or about 15% by weight or less, or about 10% by weight or less, or about 5% by weight or less, or about 2% by weight or less, or about 1% by weight or less, or about 0.5 by weight or less of any impurities or other solid forms of the compound of Formula (I), including alternative crystalline forms, hydrates, solvates or amorphous forms, for example as measured, for example by XRPD.
  • substantially pure Form B described herein would be understood to contain greater than about 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 95% by weight, greater than 98% by weight, greater than 99% by weight, greater than 99.5% by weight of the crystalline Form B of the compound of Formula (I).
  • Form B wherein when Form B is analyzed by a solid-state technique, such as by X-Ray Powder diffraction and/or Raman spectroscopy, no other solid forms (amorphous and/or other crystalline forms) are detected.
  • a crystalline form of a compound of Formula (I) essentially consisting of Form B.
  • Form C, Form D, Form F, Form G, Form H or Form I is pure or substantially pure.
  • substantially pure means that the solid state form of the compound of Formula (I) contains about 20% by weight or less, or about 15% by weight or less, or about 10% by weight or less, or about 5% by weight or less, or about 2% by weight or less, or about 1% by weight or less, or about 0.5 by weight or less of any impurities or other solid forms of the compound of Formula (I), including alternative crystalline forms, hydrates, solvates or amorphous forms, for example as measured, for example by XRPD.
  • substantially pure Form C, Form D, Form F, Form G, Form H or Form I described herein would be understood to contain greater than about 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 95% by weight, greater than 98% by weight, greater than 99% by weight, greater than 99.5% by weight of the crystalline Form C, Form D, Form F, Form G, Form H or Form I of the compound of Formula (I).
  • Form C, Form D, Form F, Form G, Form H or Form I wherein when Form C, Form D, Form F, Form G, Form H or Form I is analyzed by a solid state technique, such as by X-Ray Powder diffraction and/or Raman spectroscopy, no other solid forms (amorphous and/or other crystalline forms) are detected.
  • a crystalline form of a compound of Formula (I) essentially consisting of Form C, Form D, Form F, Form G, Form H or Form I.
  • a crystalline form of a compound of Formula (I) consisting of Form C, Form D, Form F, Form G, Form H or Form I.
  • the present disclosure provides novel pharmaceutical compositions comprising a crystalline form of the compound of Formula (I), and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present disclosure provides pharmaceutical compositions comprising a crystalline compound of Formula (I) as disclosed herein formulated together with one or more pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form A, B, C, D, F, G, H or I.
  • a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B; and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) wherein the crystalline form is pure or substantially pure Form B; and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition comprising a compound of Formula (I) wherein the compound of Formula (I) consists essentially of crystalline Form B.
  • a pharmaceutical composition comprising a compound of Formula (I) wherein the compound of Formula (I) consists of crystalline Form B.
  • a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A; and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) wherein the crystalline form is pure or substantially pure Form A; and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition comprising a compound of Formula (I) wherein the compound of Formula (I) consists essentially of crystalline Form A.
  • a pharmaceutical composition comprising a compound of Formula (I) wherein the compound of Formula (I) consists of crystalline Form A.
  • a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C, Form D, Form F, Form G, Form H or Form I; and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) wherein the crystalline form is pure or substantially pure Form C, Form D, Form F, Form G, Form H or Form I; and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition comprising a compound of Formula (I) wherein the compound of Formula (I) consists essentially of crystalline Form C, Form D, Form F, Form G, Form H or Form I. In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) wherein the compound of Formula (I) consists of crystalline Form C, Form D, Form F, Form G, Form H or Form I.
  • the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, yet more conveniently greater than about 90% and preferably greater than 95%, 98% or 99% by weight.
  • compositions include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • parenteral e.g., subcutaneous, intramuscular, intradermal, or intravenous
  • rectal vaginal, or aerosol administration
  • disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.
  • compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more compounds of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
  • the active ingredient may be compounded, for example, with the non-toxic, pharmaceutically acceptable carriers for any form suitable for use.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
  • the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g., tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
  • a pharmaceutical carrier e.g., tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium ste
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells.
  • the pharmaceutical composition is a unit dose form comprising about 10 mg to about 500 mg, such as about 50 mg to 400mg, about 50 mg to about 300 mg, about 100 mg to 300 mg, about 75 mg to about 200 mg, about 75 mg to about 150 mg, about 80 mg to about 120 mg, or about 100 mg of a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A, Form B, Form C, Form D, Form F, Form G, Form H or Form I.
  • the crystalline form is Form B.
  • the pharmaceutical composition is a unit dose form comprising about 10 mg to about 50 mg, such as about 15 mg to about 40 mg, about 20 mg to about 30 mg, or about 25 mg of a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A, Form B, Form C, Form D, Form F, Form G, Form H or Form I.
  • the crystalline form is Form B.
  • kits for use by a e.g. a consumer in need of HBV infection treatment include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent HBV infection.
  • the instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art.
  • kits could advantageously be packaged and sold in single or multiple kit units.
  • An example of such a kit is a so-called blister pack.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material.
  • the packaging process recesses are formed in the plastic foil.
  • the recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . “etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this.
  • a method for treating a hepatitis B infection in a patient in need thereof comprising administering to a subject or patient a therapeutically effective amount of a crystalline form of a compound of Formula (I).
  • a method for treating a hepatitis B infection in a patient in need thereof comprising administering to a subject or patient a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of a compound of Formula (I), and a pharmaceutically acceptable carrier, diluent or excipient.
  • the crystalline form is Form A, B, C, D, F, G, H or I.
  • the crystalline form is Form A or B, conveniently Form B.
  • a crystalline form of a compound of Formula (I) for use in the treatment of HBV infection is provided.
  • the crystalline form is Form A, B, C, D, F, G, H or I.
  • the crystalline form is Form A or B, conveniently Form B.
  • a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) , and a pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of HBV infection.
  • the crystalline form is Form A, B, C, D, F, G, H or I.
  • the crystalline form is Form A or B, conveniently Form B.
  • a crystalline form of a compound of Formula (I) or the use of a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) for the treatment of hepatitis B infection is provided.
  • the crystalline form is Form A, B, C, D, F, G, H or I.
  • the crystalline form is Form A or B, conveniently Form B.
  • a crystalline compound of Formula (I) or the use of a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) in the manufacture of a medicament for treating hepatitis B infection is provided.
  • the crystalline form is Form A, B, C, D, F, G, H or I.
  • the crystalline form is Form A or B, conveniently Form B.
  • the appropriate dosage is expected to vary depending on, for example, the mode of administration, and the nature and severity of the infection to be treated as well as the specific infection to be treated and is within the purview of the treating physician.
  • an indicated administration dose may be in the range between about 0.1 to about 1000 pg/kg body weight.
  • the administration dose of the compound may be less than 400 pg/kg body weight.
  • the administration dose may be less than 200 pg/kg body weight.
  • the administration dose may be in the range between about 0.1 to about 100 pg/kg body weight.
  • the therapeutically effective amount of a crystalline form of a compound of Formula (I) is about 10 mg to about 500 mg, such as about 50 mg to 400mg, about 50 mg to about 300 mg, about 100 mg to 300 mg, about 75 mg to about 200 mg, about 75 mg to about 150 mg, about 80 mg to about 120 mg, or about 100 mg, wherein the crystalline form is Form A, Form B, Form C, Form D, Form F, Form G, Form H or Form I.
  • the crystalline form is Form B.
  • the therapeutically effective amount of a crystalline form of a compound of Formula (I) is about 10 mg to about 50 mg, such as about 15 mg to about 40 mg, about 20 mg to about 30 mg, or about 25 mg, wherein the crystalline form is Form A, Form B, Form C, Form D, Form F, Form G, Form H or Form I.
  • the crystalline form is Form B.
  • the dose may be conveniently administered once daily, or in divided doses up to, for example, twice daily or four times a day.
  • the pharmaceutical composition is administered daily, such as once daily.
  • the subject in need of treatment with a crystalline Compound of Formula (I) according to the present invention or a pharmaceutical composition comprising a crystalline Compound of Formula (I) according to the present invention is treatment naive and HBeAg (hepatitis B e-antigen) positive prior to treatment.
  • the subject in need of treatment with a crystalline Compound of Formula (I) according to the present invention or a pharmaceutical composition comprising a crystalline Compound of Formula (I) according to the present invention is virologically suppressed and HBeAg positive prior to treatment.
  • the subject in need of treatment with a crystalline Compound of Formula (I) according to the present invention or a pharmaceutical composition comprising a crystalline Compound of Formula (I) according to the present invention is virologically suppressed and HBeAg negative prior to treatment.
  • the subject in need of treatment with a crystalline Compound of Formula (I) according to the present invention or a pharmaceutical composition comprising a crystalline Compound of Formula (I) according to the present invention is virologically suppressed for at least 1, 2, 3, 4, 5, or 6 months prior to treatment.
  • the subject in need of treatment with a crystalline Compound of Formula (I) or a pharmaceutical composition comprising a crystalline Compound of Formula (I) according to the present invention is virologically suppressed for at least 1, 2, 3, 4, 5, or 6 months prior to treatment and the subject has previously been treated with a nucleos(t)ide inhibitor.
  • the subject in need of treatment with a crystalline Compound of Formula (I) or a pharmaceutical composition comprising a crystalline Compound of Formula (I) according to the present invention has previously been treated with a nucleos(t)ide inhibitor for at least 2 months, prior to treatment with a composition of the present invention.
  • the crystalline form of Compound of Formula (I) of the present invention or the pharmaceutical composition comprising the crystalline form of Compound of Formula (I) of the present invention is administered to the subject for a treatment period of at least 12 weeks (such as at least 24 weeks, 28 weeks, 32 weeks, 40 weeks, 12 months, 18 months, 24 months or 36 months).
  • the crystalline form of Compound of Formula (I) of the present invention or the pharmaceutical composition comprising the crystalline form of Compound of Formula (I) of the present invention is administered to the subject until the subject has a reduction in HBeAg and/or HBsAg (hepatitis B surface antigen).
  • the HBeAg positive subject has sustained loss of ⁇ 0.11 PEI units/mL.
  • the subject has a reduction of HBsAg to ⁇ 100 lU/mL.
  • the subject after at least 12 weeks of daily administration of the crystalline form of Compound of Formula (I) of the present invention or the pharmaceutical composition comprising the crystalline form of Compound of Formula (I) of the present invention, the subject has a reduction in HBV DNA or HBV RNA.
  • a compound of the present disclosure may be administered by any conventional route, in particular: enterally, topically, orally, nasally, e.g., in the form of tablets or capsules, via suppositories, or parenterally, e.g. in the form of injectable solutions or suspensions, for intravenous, intra-muscular, sub-cutaneous, or intra-peritoneal injection.
  • Suitable formulations and pharmaceutical compositions will include those formulated in a conventional manner using one or more physiologically acceptable carriers or excipients, and any of those known and commercially available and currently employed in the clinical setting.
  • the compounds may be formulated for oral, buccal, topical, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either orally or nasally).
  • compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). Tablets may be coated by methods well known in the art.
  • pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegr
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Preparations may also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.
  • the pharmaceutical composition is a tablet.
  • a disclosed compound may also be formulated for parenteral administration by injection e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain additives such as suspending, stabilizing and/or dispersing agents.
  • the compound may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • Compounds may also be formulated for rectal administration as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • a subject or patient can further have HBV infection-related co-morbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected with HBV.
  • HBV infection-related co-morbidities i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected with HBV.
  • Contemplated herein are disclosed crystalline forms of the Compound of Formula (I) of the present invention or pharmaceutical compositions comprising the crystalline form of the Compound of Formula (I) of the present invention in combination with at least one other agent that has previously been shown to treat these HBV- infection-related conditions.
  • a disclosed compound may be administered as part of a combination therapy in conjunction with one or more antivirals including nucleoside analogs, interferon a, and other assembly effectors, for instance heteroaryldihydropyrimidines (HAPs) such as methyl 4-(2- chi oro-4-fluorophenyl)-6-methyl-2-(pyri din-2 -yl)-l,4-dihydropyrimidine-5-carboxylate (HAP- 1).
  • HAPs heteroaryldihydropyrimidines
  • a method of treating hepatitis B in a subject in need thereof comprising administering a therapeutically effective amount of a crystalline form of Compound of Formula (I) according to the present invention or a pharmaceutical composition comprising a crystalline form of Compound of Formula (I) according to the present invention, to the subject and co-administering to the subject a therapeutically effective amount of an additional therapeutic agent.
  • the additional therapeutic agent is selected from one or more of the following agents: i. HBV capsid assembly promoters (for example, GLS4, BAY 41-4109, AT- 130, DVR-23 (e.g., as depicted below),
  • HBV capsid assembly promoters for example, GLS4, BAY 41-4109, AT- 130, DVR-23 (e.g., as depicted below)
  • NVR 3-778, NVR1221 (by code); and N890 (as depicted below):
  • CpAMs core protein allosteric modulators
  • Nucleoside analogs interfering with viral polymerase such as entecavir (Baraclude), Lamivudine, (Epivir-HBV), Telbivudine (Tyzeka, Sebivo), Adefovir dipivoxil (Hepsera), Tenofovir (Viread), Tenofovir alafenamide (Vemlidy), Tenofovir disoproxil fumarate (TDF), Tenofovir alafenamide fumarate (TAF), prodrugs of tenofavir (e.g.
  • ASPINs Active Site Polymerase Inhibitor Nucleotides
  • Viral entry inhibitors such as Myrcludex B and related lipopeptide derivatives
  • HBsAg secretion inhibitors such as REP 9AC’ and related nucleic acid-based amphipathic polymers, HBF-0529 (PBHBV-001), PBHBV-2-15 as depicted below: and BM601 as depicted below:
  • Disruptors of nucleocapsid formation or integrity such as NZ-4/W28F : vii.
  • cccDNA formation inhibitors such as BSBI-25, CCC-0346, or CCC-0975 (as depicted below): viii. HBc directed transbodies such as those described in Wang Y, et al, Transbody against hepatitis B virus core protein inhibits hepatitis B virus replication in vitro, Int. Immunopharmacol (2014), located at //dx.doi.org/10.1016/j.intimp.2015.01.028; antiviral core protein mutant (such as Cpl83-V124W and related mutations as described in WO/2013/010069, W02014/074906, each incorporated by reference); ix.
  • HBc directed transbodies such as those described in Wang Y, et al, Transbody against hepatitis B virus core protein inhibits hepatitis B virus replication in vitro, Int. Immunopharmacol (2014), located at //dx.doi.org/10.1016/j.intimp.2015.01.0
  • RNAi for example ALN-HBV, VIR-2218, ARC-520, JNJ- 3989, TKM-HBV, AB-729, ddRNAi
  • antisense ISIS-HBV/Bepirovirsen
  • nucleic acid based polymer REP 2139-Ca
  • Immunostimulants such as Interferon alpha 2a (Roferon), Intron A (interferon alpha 2b), Pegasys® (pegylated interferon alpha 2a), Pegylated IFN 2b, IFN lambda la and PEG IFN lambda la, Wellferon, Roferon, Infergen, lymphotoxin beta agonists such as CBE11 and BS1); xi. Non-Interferon Immune enhancers such as Thymosin alpha- 1 (Zadaxin) and Interleukin-7 (CYT107); xii. TLR-7/9 agonists such as GS-9620, CYT003, or Resiquimod; xiii.
  • Cyclophilin Inhibitors such as NVP018, OCB-030, SCY-635, Alisporivir, NIM811 and related cyclosporine analogs; xiv. Vaccines such as GS-4774, TG1050, JNJ-0535, VBI-2601, GSK3528869A, VTP-300, FP- 02.2, CVI-HBV-002, VVX001 and Core antigen vaccine; xv. Second mitochondria-derived activator of caspases (SMAC) mimetics such as birinapant ,or other lAP-antagonists; xvi.
  • SMAC Second mitochondria-derived activator of caspases
  • Epigenetic modulators such as KMT inhibitors (EZH1/2, G9a, SETD7, Suv39 inhibitors), PRMT inhibitors, HDAC inhibitors, SIRT agonists, HAT inhibitors, WD antagonists (e.g. OICR-9429), PARP inhibitors, APE inhibitors, DNMT inhibitors, LSD1 inhibitors, JMJD HDM inhibitors, and Bromodomain antagonists; xvii. Kinase inhibitors such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, and ATM & ATR kinase inhibitors; xviii. STING Agonists; xix.
  • Antibodies such as VIR-3434), therapeutic proteins, gene therapy, and biologies directed against viral components or interacting host proteins.
  • the disclosure provides a method of treating a HBV infection in a patient in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A, B, C, D, F, G, H or I, and one or more other HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBF viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists.
  • HBV capsid assembly promoters HBF viral polymerase interfering nucleosides
  • the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A, B, C, D, F, G, H or I, and administering another HBV capsid assembly promoter.
  • the first and second amounts together comprise a pharmaceutically effective amount.
  • the first amount, the second amount, or both may be the same, more, or less than effective amounts of each compound administered as monotherapies.
  • Therapeutically effective amounts of a disclosed compound and antiviral may be co-administered to the subject, i.e., administered to the subject simultaneously or separately, in any given order and by the same or different routes of administration.
  • it may be advantageous to initiate administration of a disclosed compound first for example one or more days or weeks prior to initiation of administration of the antiviral.
  • additional drugs may be given in conjunction with the above combination therapy.
  • the method further comprises co-administering to the subject a therapeutically effective amount of a nucleos(t)ide inhibitor.
  • the nucleos(t)ide inhibitor is selected from entecavir, tenofovir, tenofovir alafenamide, and tenofovir disoproxil fumarate.
  • the nucleos(t)ide inhibitor is administered orally.
  • the nucleos(t)ide inhibitor is administered daily, such as once daily.
  • the method further comprises co-administering to the subject a therapeutically effective amount of pegylated interferon alpha, such as pegylated interferon alpha-2a.
  • the pegylated interferon alpha is administered by subcutaneous injection.
  • the pegylated interferon alpha is administered weekly, such as once weekly.
  • the therapeutically effective amount of the pegylated interferon alpha is about 100 to 300 pg, such as about 180 pg.
  • the method further comprises co-administering to the subject a therapeutically effective amount of an siRNA inhibitor of HBV.
  • the siRNA inhibitor is administered by subcutaneous injection. In a convenient embodiment, the siRNA inhibitor is administered once every 4-12 weeks, such as once every 8 weeks. In a convenient embodiment, the therapeutically effective amount of the siRNA inhibitor is about 20 to 100 mg, such as about 60 mg.
  • the method further comprises co-administering to the subject a therapeutically effective amount of an ASPIN.
  • the ASPIN is administered orally.
  • the ASPIN is administered daily, such as once daily.
  • the therapeutically effective amount of the ASPIN is about 10 to 100 mg, such as about 25 mg or about 50 mg.
  • a method of treating hepatitis B in a subject in need thereof comprising administering a therapeutically effective amount of crystalline form of the Compound of Formula (I) according to the present invention or a pharmaceutical composition comprising the crystalline form for the Compound of Formula (I) according to the present invention, to the subject and co-administering to the subject a therapeutically effective amount of a nucleos(t)ide inhibitor (such as entecavir); and co-administering to the subject a therapeutically effective amount of pegylated interferon alpha (such as pegylated interferon alpha- 2a).
  • a nucleos(t)ide inhibitor such as entecavir
  • pegylated interferon alpha such as pegylated interferon alpha- 2a
  • a method of treating hepatitis B in a subject in need thereof comprising administering a therapeutically effective amount of crystalline form of the Compound of Formula (I) according to the present invention or a pharmaceutical composition comprising the crystalline form for the Compound of Formula (I) according to the present invention, to the subject, and co-administering to the subject a therapeutically effective amount of a nucleos(t)ide inhibitor (such as entecavir); and co-administering to the subject a therapeutically effective amount of an siRNA inhibitor of HBV.
  • a nucleos(t)ide inhibitor such as entecavir
  • a method of treating hepatitis B in a subject in need thereof comprising administering a therapeutically effective amount of crystalline form of the Compound of Formula (I) according to the present invention or a pharmaceutical composition comprising the crystalline form for the Compound of Formula (I) according to the present invention, to the subject, and co-administering to the subject a therapeutically effective amount of a nucleos(t)ide inhibitor (such as entecavir); and co-administering to the subject a therapeutically effective amount of an ASPIN.
  • a nucleos(t)ide inhibitor such as entecavir
  • the process to prepare Form B comprises the steps of: a) providing a slurry of Compound of Formula (I) in methanol; b) stirring the mixture from step a) at an elevated temperature; c) cooling the mixture; d) stirring the mixture from step c); e) optionally, filtering the mixture from step d) and/or washing the solids with methanol; and f) optionally, isolating the solids from step e) and drying under vacuum.
  • step a) comprises providing at least about 0.05 kg/kg of Compound of Formula(I) in methanol, such as at least about 0.01 kg/kg, at least about 1 kg/kg, at least about 2 kg/kg, at least about 3 kg/kg, or at least about 4 kg/kg.
  • the compound of Formula (I) is provided in methanol at a concentration of about 5 kg/kg.
  • Form I of the Compound of Formula (I) is provided in methanol in step a).
  • Compound of Formula (I) in step a) has been purified by column chromatography.
  • step b) comprises stirring the mixture for at least about 2 hours, such as at least about 4 hours, at least about 6 hours, at least about 8 hours, or at least 10 hours.
  • step b) comprises stirring the mixture for between about 7 to about 13 hours, such as between about 8 and about 12 hours.
  • step b) comprises stirring the mixture at an elevated temperature of at least about 50°C, such as at least about 55°C, at least about 60°C, at least about 65°C, at least about 70°C, or at least about 75°C.
  • the elevated temperature is between about 55°C and about 75°C, such as between about 60°C and about 70°C.
  • step c) comprises cooling the mixture to less than about 40°C, such as less than about 35°C.
  • step c) comprises cooling the mixture to between about 25°C and about 35°C.
  • step d) comprises stirring the mixture for at least about 1 hour, such as at least about 2 hours, or at least about 4 hours.
  • step d) comprises stirring the mixture for between about 3 to about 9 hours, such as between about 4 and about 8 hours.
  • the process to prepare Form B comprises the steps of: i. providing Compound of Formula (I) in a first solvent at an elevated temperature; ii. cooling the mixture from step i.; iii. optionally, isolating the solids from step ii.; and iv. optionally drying the solids from step iii. under reduced pressure and/or elevated temperature.
  • step i. comprises providing at least about 0.05 mg/mL of Compound of formula (I) in the first solvent, such as such as at least 0.1 mg/mL or at least 0.15 mg/mL.
  • the Compound of Formula (I) has a solubility of at least 0.5 mg/g in the first solvent at 60°C, such as at least 1 mg/mL, at least 2 mg/mL or at least 3 mg/mL.
  • the first solvent comprises ethanol, methanol, water, acetone, isopropyl alcohol, tetrahydrofuran or DMSO, or a mixture thereof.
  • the first solvent comprises methanol, ethanol and water.
  • the first solvent comprises acetone, isopropyl alcohol and water.
  • the first solvent comprises acetone, ethanol and water.
  • the first solvent comprises tetrahydrofuran, ethanol and water.
  • the first solvent comprises ethanol and water.
  • the first solvent comprises ethanol, THF or DMSO, or a mixture thereof.
  • the first solvent comprises ethanol.
  • the first solvent is a mixture of ethanol and DMSO.
  • the volume ratio of ethanol to DMSO is between about 4: 1 and about 1 :4, such as between about 3 : 1 and about 1 :3, such as between about 3 : 1 and about 1 : 1, such as between about 3 : 1 and about 2: 1.
  • the volume ratio of ethanol to DMSO is about 3 :2.
  • the elevated temperature in step i. is at least 30 °C, such as at least 35 °C or at least 40 °C.
  • step i. comprises adding Form B of the Compound of Formula (I) to the mixture. In one embodiment, at least 0.001 equivalents of Form B is added.
  • step i. comprises stirring the mixture for at least 30 minutes, such as at least 1 hour.
  • step i. comprises:
  • step I. comprises providing at least about 0.05 mg/mL of Compound of Formula (I) in the first solvent, such as such as at least 0.1 mg/mL or at least 0.15 mg/mL.
  • the Compound of formula (I) has a solubility of at least 0.5 mg/g in the first solvent at 60°C, such as at least 1 mg/mL, at least 2 mg/mL or at least 3 mg/mL.
  • the first solvent comprises ethanol, methanol, water, acetone, isopropyl alcohol, tetrahydrofuran or DMSO, or a mixture thereof.
  • the first solvent comprises methanol, ethanol and water.
  • the first solvent comprises acetone, isopropyl alcohol and water.
  • the first solvent comprises acetone, ethanol and water.
  • the first solvent comprises tetrahydrofuran, ethanol and water.
  • the first solvent comprises ethanol and water.
  • the first solvent comprises ethanol or DMSO, or a mixture thereof.
  • the first solvent comprises ethanol.
  • the first solvent is a mixture of ethanol and DMSO.
  • the volume ratio of ethanol to DMSO is between about 4: 1 and about 1 :4, such as between about 3 : 1 and about 1 :3, such as between about 3 : 1 and about 1 :1, such as between about 3 : 1 and about 2: 1.
  • the volume ratio of ethanol to DMSO is about 3 :2.
  • the first elevated temperature is greater than the second elevated temperature.
  • the first elevated temperature is at least 50°C, such as at least 55°C. In one embodiment, the first elevated temperature is between about 55 °C to about 70 °C.
  • the second elevated temperature is at least 30 °C, such as at least 35 °C or 40 °C. In one embodiment, the second elevated temperature is less than 50°C. In one embodiment, the second elevated temperature is between about 40 °C to about 50 °C.
  • step II. comprises adding Form B of the Compound of Formula (I) to the mixture. In one embodiment, at least 0.001 equivalents of Form B is added.
  • step I. comprises stirring the mixture for at least 30 minutes.
  • step II. comprises stirring the mixture for at least 30 minutes, such as at least 1 hour.
  • step ii. comprises cooling the mixture to less than 25°C, such as less than 20°C, or such as less than 15°C. In one embodiment, step ii. comprises cooling the mixture to between 8°C and 10°C.
  • step ii. comprises cooling the mixture over a period of at least 1 hour, such as at least 2 hours.
  • step ii. the mixture in step ii. is stirred for at least 10 minutes, such as at least 30 minutes. In one embodiment, step ii. further comprises stirring the cooled mixture for at least 1 hour, such as at least 2, 4, 8, 10, 12, 18 or 20 hours.
  • step ii. further comprises adding a second solvent prior to the mixture being cooled.
  • the second solvent is an anti-solvent.
  • the compound of Formula (I) has a solubility of less than 10 mg/mL in the second solvent at 25°C, such as less than 7.5 mg/mL or less than 6 mg/mL.
  • the compound of Formula (I) has a solubility of less than 20 mg/mL in the second solvent at 50°C, such as less than 15 mg/mL.
  • Form B of the compound of Formula (I) has a solubility of less than 10 mg/mL in the second solvent at 25°C, such as less than 7.5 mg/mL or less than 6 mg/mL.
  • Form B of the compound of Formula (I) has a solubility of less than 20 mg/mL in the second solvent at 50°C, such as less than 15 mg/mL.
  • the second solvent comprises ethanol, methanol or isopropyl alcohol. [0297] In one embodiment, the second solvent comprises ethanol.
  • the second solvent is added to the mixture from step i. over a period of at least 1 hour, such as at least 2 hours.
  • At least 10 volumes of the second solvent is added to the mixture in step ii.
  • the solids are isolated in step iii. using a centrifuge.
  • the solids in step iv. are dried at an elevated temperature of between about 50°C to about 60°C.
  • TGA-IR Thermogravimetric analysis interfaced with infrared spectrophotometer
  • FT-Raman Spectroscopy Raman spectra were collected with a Nicolet NXR9650 or NXR 960 spectrometer (Thermo Electron) equipped with 1064 nm Nd:YVO4 excitation laser, InGaAs and liquid-N2 cooled Ge detectors, and a MicroStage. All spectra were acquired at 4 cm' 1 resolution, 64 scans, using Happ-Genzel apodization function and 2-level zero-filling.
  • PLM Polarized-Light Microscopy
  • Configuration on the incidental beam side variable divergence slits (10 mm irradiated length), 0.04 rad Soller slits, fixed anti-scatter slit (0.50°), and 10 mm beam mask.
  • Configuration on the diffracted beam side variable anti-scatter slit (10 mm observed length) and 0.04 rad Soller slit. Samples were mounted flat on zero-background Si wafers.
  • Powder X-Ray Diffraction (PXRD) Bruker: PXRD diffractograms were acquired on a Bruker D8 Advance system (SN:2631) using Cu Ka (X 1.5406 A) (40 kV/40 mA) radiation and a step size of 0.03° 20 and LynxEye detector.
  • Configuration on the diffracted beam side anti-scatter slit (8 mm) and 2.5 deg. Soller slit. Samples were mounted flat on zerobackground Si wafers.
  • DSC Differential Scanning Calorimetry
  • TGA thermograms were obtained with a TA Instruments Q50 thermogravimetric analyzer under 40 mL/min N2 purge in Pt or Al pans. TGA thermograms of initial crystallization experiments samples were obtained at 15 °C/min, unless noted otherwise. TGA thermograms of input and scaled-up material were obtained at 10 °C/min, unless noted otherwise.
  • TGA-IR Thermogravimetric Analysis with IR Off-Gas Detection
  • Dynamic Vapor Sorption Moisture-sorption was obtained on a Surface Measurement Systems DVS-Advantage (SN: P22F00054) using the following sorption/desorption isotherms at 25 °C:
  • Adsorption Cycle 1 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, and 90 %RH
  • Desorption Cycle 1 90%, 80%, 75%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, and 0 %R
  • the input material was determined to be a mixture of forms designated Forms A and G.
  • Form A is a hydrate that was obtained from water and many organic/aqueous solvent mixtures.
  • the characterization data for Form A are shown in Figures 7-10.
  • DSC analysis of Form A showed a broad dehydration endotherm at 90.3 °C, immediately followed by an exotherm and at least two small endotherms, followed by a sharp melting/decomposition endotherm at 212.6 °C.
  • TGA-IR analysis in Figure 9 showed 3.0 % weight loss of water (0.8 eq) between 25-129 °C, indicating a hydrated form.
  • Form B is non-solvated and characterization data for Form B are shown in Figures 13-18.
  • DSC analysis of Form B showed a large, sharp endotherm at 194.6 °C followed by an exotherm and a second sharp endotherm at 212.3 °C.
  • TGA analysis of Form B in Figure 15 showed negligible (0.03 %) weight loss between 21-188 °C, indicating a non-solvated form.
  • DVS analysis in Figures 17-18 showed Form B to be non-hygroscopic ( ⁇ 0.1 % moisture increase from 0 to 90 % RH), and PXRD showed no change in form post-DVS analysis.
  • PLM shows that Form B is a white crystalline powders consisting of loose agglomeration of needle-like irregular shaped particles ( ⁇ 80 mm) and some large, agglomerated particles, see Figure 16.
  • Form B was scaled up to provide material for competitive ripening and water activity studies.
  • the input material (300.7 mg, mixture of Form A and G) was combined with methanol (5.0mL).
  • the suspension was stirred at 40°C for 0.5 h, then seeded with Form B ( ⁇ 1 mg).
  • the suspension was stirred and temperature-cycled from 40 °C - 5 °C for 20 h.
  • the solids were isolated by vacuum filtration and air dried for 1.5 h. The yield was 231.0 mg of Form B.
  • Form B seed was obtained from the temperature-cycled ripening of API slurries between 40 °C - 5 °C ( 1 hour at each temperature) for three days as described above.
  • Form B was scaled up to provide material for biorelevant solubility studies.
  • the input material (403. Omg, mixture of Forms A and G) was combined with methanol (6.0 mL). The suspension was stirred at 40°C for 2 h, then seeded with Form B ( ⁇ 1 mg) after 30 m at 40 °C. The suspension was stirred and slow-cooled (0.5 °C/min) to 20 °C, then mixed at 20 °C for 1 h. The solids were isolated by vacuum filtration and air-dried for 2 h. The yield was 325.9 mg (81%) of Form B .
  • Form C is a class of solvates, determined to be structurally similar by FT-Raman and PXRD analyses. These solvates are deemed isostructural solvates. Isostructural solvates have the same crystal structure but not necessarily the same cell dimensions or chemical composition. Isostructural solvates can exhibit variability in thermal properties and solvent content.
  • Figure 19 shows a PXRD overlay for three samples of Form C (1,4-dioxane solvate (top), methyl acetate solvate (middle), and 2-butanone solvate (bottom)).
  • Form D (1,4-Dioxane/Water Solvate)
  • Form D is a 1,4-dioxane/water solvate.
  • the characterization data for Form D are shown in Figures 26-29.
  • DSC analysis of Form D showed a broad desolvation endotherm at 73.3 °C, an endotherm at 192.6 °C immediately followed by an exotherm, and a large, sharp melting/decomposition endotherm at 213.3 °C.
  • TGA-IR analysis of Form D in Figure 28 showed 10.1 % weight loss of 1,4-dioxane and water between 36-94 °C, indicating a solvated form.
  • Form E is an unstable form obtained from two slurry -ripening experiments involving THF/water mixtures.
  • the isolated Form E solids converted to Form A within two days at ambient conditions.
  • FT-Raman was the only analysis conducted for Form E before solid-state form conversion occurred.
  • Figure 30 shows an FT-Raman spectral overlay of Form E initially and after two days at ambient and Form A.
  • Form F is a DMSO/water solvate.
  • the characterization data for Form F are shown in Figures 31-34.
  • DSC analysis of Form F showed a broad desolvation endotherm at 103.4 °C, a broad, shallow endotherm at 133.4 °C, and a large, sharp melting/decomposition endotherm at 212.3 °C.
  • TGA-IR analysis of Form F in Figure 33 showed 13.1 % weight loss of DMSO and water between 81-132 °C, indicating a solvated form.
  • Form G is a non-solvated form, was not observed from the crystallization experiments described above but obtained by either heating Form A or the input material (mixture of Forms A and G) to 150 °C (beyond the dehydration endotherm and initial exotherm) and cooling to RT.
  • the characterization data for Form G are shown in Figures 35-38. DSC analysis of Form G showed a small, shallow exotherm at 158.2 °C followed by a sharp melting/decomposition endotherm at 211.7 °C. Form G was found to be stable at ambient conditions for > 11 days. Form G was scaled up by heating the input material (mixture of Forms A and G) to 150 °C to provide material for competitive ripening and water activity studies.
  • Form H is a non-solvated form, was not observed from the crystallization experiments described above, but obtained by either heating Form A or the input material (mixture of Forms A and G) to 190 °C (beyond the small, second exotherm) and cooling to RT.
  • the characterization data for Form H are shown in Figures 39-42. DSC analysis of Form H showed a single sharp melting/decomposition endotherm at 210.9 °C. Form H was found to be stable at ambient for > 6 days. Form H was scaled up by heating input material (mixture of Forms A and G) to 190 °C to provide material for competitive ripening and water activity studies.
  • Form I (Hydrate 2) [0332] Form I, a hydrate that may entrap solvent, was obtained from an evaporative experiment.
  • PLM Polarized-Light Microscopy
  • Configuration on the incidental beam side variable divergence slits (10 mm irradiated length), 0.04 rad Soller slits, fixed anti-scatter slit (0.50°), and 10 mm beam mask.
  • Configuration on the diffracted beam side variable anti-scatter slit (10 mm observed length) and 0.02 rad Soller slit. Samples were mounted flat on zero-background Si wafers.
  • HPLC High-Performance Liquid Chromatography
  • FaSSIF, FeSSIF and FaSSGF powders were purchased from Biorelevant.com.
  • the solubility was monitored by HPLC analyses at 0.5, 2 and 24 hours, and results showed that solubility values in FaSSGF media were slightly higher at 24 hours than at 0.5 and 2 hours.
  • Presence of surfactants in fed-state simulated intestinal fluid (FeSSIF) and fasted-state simulated intestinal fluid (FaSSIF) did result in enhanced kinetic solubility in those media indicating a potential positive food effect in oral formulations of Compound of Formula (I) Form B.
  • Table 28 Composition of FaSSGF pH1.6, FaSSIF-V2 pH6.5, FeSSIF-V2 pH5.8 4 Table was obtained from Biorelevant.com. The sodium comes from sodium chloride; chloride comes from sodium chloride and hydrochloric acid. Table 29 - Kinetic solubility of Form B Lot 103133-SU-005 in FASSGF pH1.6, FaSSIF V2 pH 6.5 and FeSSIF V2 pH5.8 media.
  • the pKa of Compound of Formula (I) was assessed by UV spectral shift method with the Pion PULSE instrument.
  • Compound of Formula (I) solutions utilized a cosolvent system from 30- 47%.
  • Approximately 2 mg of Compound of Formula (I) was dissolved in 0.5 mL of DMSO.
  • a volume of 80 pL of this stock solution was transferred to a 25-mL sampling vial and placed on the PULSE autosampler. Titrations were performed in triplicate from pH 2-11.5 with cosolvent concentrations from 29.6% to 47.4%.
  • the measured pKa was determined by the difference in molar absorptivity between the ionized and unionized API between wavelengths of 280-320nm.
  • the pKa of Compound of Formula (I) in cosolvent-free media was then determined by the extrapolation of the Yasuda-Shedlovsky plot, which was derived from the measured pKa in the presence of a known percentage of cosolvent.
  • the extrapolated pKa in cosolvent-free media was determined to be 2.02 + 0.055 and 10.38 ⁇ 0.192.
  • the higher pKa might have been affected by experimental noise in presence of cosolvent in higher pH range.
  • the partition and distribution coefficients were determined through potentiometric titration by first determining the pKa of Compound of Formula (I), which is then used to extrapolate Log P from the potentiometric shift in the presence of octanol.
  • the log P was determined based on the shift of pKa in the presence of octanol and extrapolated Log D at different pH values.
  • the data indicate that the log P of Compound of Formula (I) is 2.24 ⁇ 0.23.
  • precipitation was observed in the assay vial after titration and hence the results obtained may be affected by the precipitation.
  • Oxidative stress was performed at RT (protected from light) for 24 hours for solution samples in pH 1, BRB pH 6, and pH 10 with 40% acetonitrile as a co-solvent, and 0.1% hydrogen peroxide.
  • An aliquot of 4.0 mL of the stock solution (0.25 mg/mL) was transferred into a 10.0 mL volumetric flask then buffer added to the flask making a final concentration of 0.1 mg/mL.
  • Final solvent composition was 40:60 v/v acetonitrile/buffer for both control sample (without hydrogen peroxide) and oxidative sample (with 0.1% hydrogen peroxide).
  • the volumetric flasks were sealed with a Parafilm.
  • Solution photo stability was determined by exposing solutions in pH 1, BRB pH 6, and pH 10 at 0.1 mg/mL with approximately 40% v/v acetonitrile as a co-solvent at 1 x ICH (as defined by ICH Q1B, approximately 7.5 hours at 765 W/m2 which is equivalent to exposure for 1.2 million lux-hours of visible light and >200 W-h/m2 (-72 J/cm2)).
  • ICH Q1B as defined by ICH Q1B, approximately 7.5 hours at 765 W/m2 which is equivalent to exposure for 1.2 million lux-hours of visible light and >200 W-h/m2 (-72 J/cm2)
  • Stability data have been collected on a representative batch (from a GMP manufacture) of Compound of Formula (I), Form B.
  • Form B was stored in a double lined polyethylene bag (twist tied) in a fibre drum at 25 °C/60%RH for 24 months and the accelerated condition of 40 °C/75%RH for 6 months. There was no change in the polymorphic form when analyzed by XRPD during these stability studies.
  • Form B About 15-20mg was transferred into a mortar, followed by addition of pure water to wet the powder to a porridge-like consistency. The mixture was hand ground with a pestle for 5 minutes. About 5mg sample was transferred for PXRD and PLM. Grinding was continued for the rest of the sample in the mortar for additional 5 min. Samples were collected again for PXRD and PLM. The result of wet grinding was similar to dry ball milling.
  • the final drug loading was 80% of Compound of Formula (I) Form B + 20 % of 10 % HPMC (E5) (Wt/Wt).
  • the wet granules were dried over night at ⁇ 45°C in an oven.
  • the purity and the XRPD for the dried granules at initial (upon drying), 2-week and 4-week open storage at 40 °C/75%RH were obtained.
  • Results of wet granulation simulation is summarized in Table 35. No significant changes were observed in the physical appearance, PXRD, and chemical assays by HPLC for wet granulation simulation stability samples exposed at 40 °C/75 %RH (open) condition for up to 4 weeks.
  • Phase compatibility screening was intended to collect preliminary data on the stability of Compound of Formula (I) Form B in the presence of excipients.
  • Three sets of ten binary samples were prepared, for initial, two week and 4 week time points, either as 1 : 1 or 1 : 10 mixture of Compound of Formula (I) Form B and excipient.
  • Each binary mixture was vortexed as dry blends for one minute and then stirred vigorously with spatula to achieve the intimate blending of the components.
  • the binary mixtures, along with excipient placebos were set up in sealed containers and stored at 40 °C for up to four weeks. All samples were analyzed at initial, two weeks and four- weeks time points by HPLC and PXRD.
  • Compound of Formula (I) was synthesized according to the synthetic procedures outlined in WO 2020/086533. After reaction completion and work-up, the crude Compound of Formula (I) was a solution in 2-methyl-THF. The solvent was removed in vacuo, and the crude product was preadsorbed on to silica gel and loaded onto a silica gel column. The column was eluted starting with THF:n-heptane 1 : 1.5 v/v and subsequently the polarity of the solvent composition was increased. The product-containing fractions were combined, and the solvent was removed in vacuo. The material isolated from the column chromatography was dissolved in THF and the solution was concentrated to 2-5 relative volumes.
  • 0.2 g of the sample was weighted into a 100 mL beaker, 2 mL ultrapure water and 5 drops of Tween 80 were added, stir and wet the sample with a glass rod, then add ultrapure water to 20 mL, stir until the sample is evenly dispersed.
  • Table 37 Particle size distribution analysis performed on Form B after isolation. These values are a mean of 3 measurements per method.
  • the vessel was rinsed with THF (364 L, 20x, 22.5 volumes). The rinse was transferred to reactor 1. The reactor was degassed. 2. To catalyst preparation tank 1 (120 L, SS304L) was charged 5% Pt/C(3.2 kg, 0.20x, 0.024 eq). The tank was degassed. To the tank was charged THF (109.2 L, 6. Ox, 6.7 volumes). The suspension was transferred to reactor 1. The catalyst tank was rinsed with THF (36.4 L, 2. Ox, 2.2 volumes). The rinse was transferred to reactor 1. The reactor was degassed.
  • Reactor 1 was filled with hydrogen gas and evacuated. The fill and evacuation sequence was repeated. The reactor was filled with hydrogen gas (0.0 to 0.2 MPa). The process temperature was adjusted (5 °C to 25 °C, target 10 °C). The reaction mixture was stirred at that temperature until completion (20 to 25 hours).
  • IPC NMT 0.30% 5-Amino-N-(3- chloro-4-fluorophenyl)-3-((3aS, 5S,6aR)-5-hydroxy-5-((methylsulfonyl)methyl)-l- 3a,4,5,6,6a-hexahydropentalen-2-yl)-l-methyl-lH-pyrazole-4-carboxamide.
  • the mixture was filtered through filter Nutsche filter (DN600, SS316L) and polish filter (10 inch, SS316L) to storage tanks 1 and 2 (1000 L, SS316L).
  • the reaction vessel was rinsed with THF (112.3 L, 6.2x, 6.9 volumes) and the rinse was filtered to the storage tanks. The filtrate was tested for purity and assay.
  • the wet cake was transferred to a stainless steel tray dryer and dried at 45 °C to 55 °C and pressure NMT -80 kPa until the Loss on drying was NMT 7.0% (drying time approximately 17 hours).
  • the dried material was tested for residual Pt (Report).
  • the dried material (24.1 kg) was stored in double PE bags.
  • the process temperature was adjusted (58 °C to 68 °C). The mixture was stirred for 30 - 60 minutes. The process temperature was adjusted (43 °C to 48 °C) over 2 to 3 hours (5 °C to 10 °C per hour). The mixture was seeded with Compound of Formula (I) Form B (0.24 kg, O.Olx). The mixture was stirred for 1 to 2 hours. To the mixture was added EtOH (520.9 L, 17. lx, 21.6 volumes) over 4 to 6 hours. The mixture was stirred for 1 to 2 hours. The mixture was sampled, and the crystallized product was tested for purity and crystalline form. The process temperature was adjusted (8 °C to 10 °C) over approximately 4 hours. The mixture was stirred for 24 hours.
  • the mother liquor was assayed every 3 hours. After 24 hours the mixture was sampled and the solid was tested for purity and crystalline form. The solid was collected in centrifuge (SS-Halar). The solid was washed with EtOH (48.2 L, 1.6x, 2.0 volumes). The crystallized wet cake (23.2 kg) was tested for LOD (loss on drying), impurities, residual Pd (NMT 100 ppm), residual Pt (NMT 100 ppm), and crystal form (Form B).
  • the wet cake was transferred to dryer 1 (GL) and then dried at 50 °C to 60 °C and NMT - 80 kPa for 17 hours until residual EtOH and DMSO met the limits (NMT 5000 ppm EtOH, NMT 5000 ppm DMSO).
  • the dried material was also tested for crystalline form (Form B).
  • the dried Compound of Formula (I) Form B (21.7 kg) was sieved, packaged into double PE bags inside a fiber drum (570 mm x 380 mm), and stored at NMT 25 °C.

Abstract

The present disclosure provides, in part, novel crystalline forms of a 5-aminopyrazole compound useful for treatment of Hepatitis B (HBV), methods for preparing such forms and pharmaceutical compositions comprising the crystalline forms. Provided herein are novel crystalline solid forms useful for the treatment of HBV in a subject in need thereof. Specifically, provided herein are novel crystalline solid forms of the compound 5-amino-N-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5-hydroxy-5-(methylsulfonylmethyl)octahydro-pentalen-2-yl)-1-methyl-1 H-pyrazole-4-carbo xamide (compound of Formula (I) as referred herein).

Description

CRYSTALLINE FORMS OF A 5-AMINOPYRAZOLE COMPOUND USEFUL FOR TREATING HBV
[0001] The invention relates to novel crystalline forms of a 5-aminopyrazole compound, as well as to pharmaceutical compositions comprising the same, and to methods for their production and use in the context of treating Hepatitis B.
BACKGROUND
[0002] Hepatitis B (HBV) causes viral hepatitis that can further lead to chronic liver disease and increase the risk of liver cirrhosis and liver cancer (hepatocellular carcinoma). Worldwide, about 2 billion people have been infected with HBV, around 360 million people are chronically infected, and every year HBV infection causes more than one half million deaths. HBV can be spread by body fluids: from mother to child, by sex, and via blood products. Children bom to HBV-positive mothers may also be infected, unless vaccinated at birth.
[0003] The hepatitis virus particle is composed of a lipid envelope studded with surface protein (HBsAg) that surrounds the viral core. The core is composed of a protein shell, or capsid, built of 120 core protein (Cp) dimers, which in turn contains the relaxed circular DNA (rcDNA) viral genome as well as viral and host proteins. In an infected cell, the genome is found as a covalently closed circular DNA (cccDNA) in the host cell nucleus. The cccDNA is the template for viral RNAs and thus viral proteins. In the cytoplasm, Cp assembles around a complex of full-length viral RNA (the so-called pregenomic RNA or pgRNA and viral polymerase (P). After assembly, P reverse transcribes the pgRNA to rcDNA within the confines of the capsid to generate the DNA- filled viral core.
[0004] At present, chronic HBV is primarily treated with nucleotide analogs (e.g., entecavir) that suppress the virus while the patient remains on treatment, but do not eliminate the infection, even after many years of treatment. Once a patient starts taking nucleotide analogs, most must continue taking them or risk the possibility of a life-threatening immune response due to viral rebound. Further, nucleotide therapy may lead to the emergence of antiviral drug resistance.
[0005] The only FDA approved alternative to nucleotide analogs is treatment with interferon a or pegylated interferon a. Unfortunately, the adverse event incidence and profile of interferon a can result in poor tolerability, and many patients are unable to complete therapy. Moreover, only a small percentage of patients are considered appropriate for interferon therapy, as only a small subset of patients are likely to have a sustained clinical response to a course of interferon therapy. As a result, interferon-based therapies are used in only a small percentage of all diagnosed patients who elect treatment. [0006] Thus, current HBV treatments can range from palliative to watchful waiting. Nucleotide analogs suppress virus production, treating the symptom, but leave the infection intact. Interferon a has severe side effects and less tolerability among patients and is successful as a finite treatment strategy in only a small minority of patients.
[0007] There is a clear on-going need for more effective treatments for HBV infections, including a class of compounds referred to as core inhibitors or core modulators. In particular, W02020/086533 discloses 5-aminopyrazole compounds, and pharmaceutical compositions thereof, useful as modulators of HBV core protein, and methods of treating HBV infection.
[0008] The present invention was devised with the foregoing in mind.
SUMMARY
[0009] Provided herein are novel crystalline solid forms useful for the treatment of HBV in a subject in need thereof. Specifically, provided herein are novel crystalline solid forms of the compound 5-amino-7V-(3-chloro-4-fluorophenyl)-3-((2s,5s)-5-hydroxy-5- (methylsulfonylmethyl)octahydro-pentalen-2-yl)-l-methyl-lH-pyrazole-4-carboxamide (referred to herein as the “compound of Formula (I)”) having the structural formula:
Figure imgf000004_0001
Formula (I).
[0010] The synthesis of the compound of Formula (I) was first disclosed in International PCT Publication, W02020/086533 (named as compound AIA-227-2). The present disclosure relates to certain novel solid forms of the compound of Formula (I), which possess promising and advantageous solid-state and/or biopharmaceutical properties.
[0011] In a first aspect, the present disclosure provides a crystalline form of a compound of Formula (I):
Figure imgf000005_0001
Formula (I) wherein the crystalline form is Form B and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (< = 1.5406 A) comprising peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.2°29; b) a Raman spectrum comprising at least one or two specific peaks selected from the peaks at wavenumbers of 770 and 1614 cm’1 ± 2 cm’1; and c) a DSC thermogram comprising an endothermic event with an onset temperature of 195°C ± 2°C.
[0012] Form B is a non-solvated crystalline form of Formula (I). Advantageously, Form B has been determined to be thermodynamically stable at water activities <0.5 at 25°C. Surprisingly, Form B was also shown to be stable in the solid state at high humidity levels (at both room temperature and at elevated temperature) despite data from slurry experiments suggesting that a different form, i.e., the hydrated crystalline form, Form A, is the most thermodynamically stable form at water activities >0.75 at 25° (see Example 1). The data in Example 1 demonstrates that Form B is stable in the solid state during a dynamic vapor sorption (DVS) experiment wherein humidity levels reached 90% RH (see Figures 17-18). Furthermore, Example 2 demonstrates that Form B in the solid state is stable for at least four weeks when exposed at both 40°C/75%RH (closed and open) and 70°C/75%RH (closed and open) conditions (see Table 34).
[0013] Form B also has other advantageous properties. For example, Form B, has been found to be stable in the solid state both physically and chemically when stressed (oxidative or mechanical), under photostability conditions, and under long term and accelerated stability conditions (at 25°C/60%RH for 24 months and 40°C/75%RH for 6 months).
[0014] Additionally, slurry experiments performed in biorelevant media have demonstrated that residue solids remain as Form B, confirming no change in the crystalline form.
[0015] For a pharmaceutical product it is critical that the desired form can be consistently manufactured and remains stable throughout the formulation process and upon storage. This helps ensure the end user, i.e., the patient, receives the intended form and amount of the API and therefore the promised therapeutic benefit. Furthermore, from a manufacturing efficiency perspective (cost and time) it is also important the manufacturing process routinely delivers the intended form in a manner such that it can be used to provide a consistent product.
[0016] In another aspect, further crystalline forms of a compound of Formula (I) are provided.
[0017] In one embodiment, the present disclosure provides a crystalline form of a compound of Formula (I) wherein the form is Form A. Form A is a hydrated crystalline form of a compound of Formula (I). Advantageously, Form A has been determined to the most thermodynamically stable form at water activities >0.75 at 25°C.
[0018] In a further embodiment, the present disclosure provides a crystalline form of a compound of Formula (I) wherein the form is Form C. Form C is a solvated crystalline form of a compound of Formula (I).
[0019] In a further embodiment, the present disclosure provides a crystalline form of a compound of Formula (I) wherein the form is Form D. Form D is a crystalline 1,4-dioxane/water solvate of a compound of Formula (I).
[0020] In a further embodiment, the present disclosure provides a crystalline form of a compound of Formula (I) wherein the form is Form F. Form F is a crystalline DMSO/water solvate of a compound of Formula (I).
[0021] In a further embodiment, the present disclosure provides a crystalline form of a compound of Formula (I) wherein the form is Form G. Form G is a non-solvated crystalline form of a compound of Formula (I).
[0022] In a further embodiment, the present disclosure provides a crystalline form of a compound of Formula (I) wherein the form is Form H. Form H is a non-solvated crystalline form of a compound of Formula (I).
[0023] In a further embodiment, the present disclosure provides a crystalline form of a compound of Formula (I) wherein the form is Form I. Form I is a hydrated crystalline form of a compound of Formula (I).
[0024] In another aspect, the present disclosure provides a pharmaceutical composition comprising a crystalline form of a compound of Formula (I):
Figure imgf000006_0001
Formula (I) wherein the crystalline form is Form A, B, C, D, F, G, H or I, and a pharmaceutically acceptable carrier, diluent or excipient.
[0025] In a further aspect, the present invention provides a method of treating HBV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of a compound of Formula (I):
Figure imgf000007_0001
Formula (I) wherein the crystalline form is Form A, B, C, D, F, G, H or I.
[0026] In a further aspect, the present invention provides a method of treating HBV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of a compound of Formula (I):
Figure imgf000007_0002
Formula (I) wherein the crystalline form is Form A, B, C, D, F, G, H or I and a pharmaceutically acceptable carrier, diluent or excipient.
[0027] In another aspect, there is provided a crystalline form of a compound of Formula (I) for use in the treatment of HBV infection, wherein the crystalline form is Form A, B, C, D, F, G, H or I.
[0028] In another aspect, there is provided a pharmaceutical composition comprising a crystalline form of a compound of Formula (I), and a pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of HBV infection, wherein the crystalline form is Form A, B, C, D, F, G, H or I. [0029] In another aspect, there is provided the use of a crystalline form of a compound of Formula (I) or the use of a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) for the treatment of HBV infection, wherein the crystalline form is Form
A, B, C, D, F, G, H or I.
[0030] In another aspect, there is provided the use of a crystalline compound of Formula (I) or a pharmaceutical composition comprises a crystalline form a compound of Formula (I) in the manufacture of a medicament for treating HBV infection, wherein the crystalline form is Form A,
B, C, D, F, G, H or I.
[0031] In another aspect, there is provided a process to prepare a crystalline compound of Formula (I) wherein the crystalline form is Form A, B, C, D, F, G, H or I.
[0032] In another aspect, there is provided a crystalline compound of Formula (I) obtainable by the processes described herein, wherein the crystalline form is Form A, B, C, D, F, G, H or I.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 : Characterization Data of Input Material (compound of Formula (I), Mixture of Forms A and G): FT-Raman Spectrum
Figure 2: Characterization Data of Input Material (compound of Formula (I), Mixture of Forms A and G): PXRD Pattern
Figure 3: Characterization Data of Input Material (compound of Formula (I), Mixture of Forms A and G): DSC/TGA-IR Data
Figure 4: Characterization Data of Input Material (compound of Formula (I), Mixture of Forms A and G): PLM Image
Figure 5: DSC of Input material (compound of Formula (I), Mixture of Forms A and G) With Inset View
Figure 6: PXRD Pattern Overlay of Forms A-D and F-I of compound of Formula (I)
Figure 7: Characterization Data of Form A (Hydrate 1): FT-Raman Spectrum
Figure 8: Characterization Data of Form A (Hydrate 1): PXRD Pattern
Figure 9: Characterization Data of Form A (Hydrate 1): DSC/TGA-IR Data
Figure 10: Characterization Data of Form A (Hydrate 1): PLM Image
Figure 11 : TGA-IR Data for Two Form A Samples
Figure 12: DSC Data for Two Form A Samples
Figure 13: Characterization Data of Form B (Non-Solvated): FT-Raman Spectrum
Figure 14: Characterization Data of Form B (Non-Solvated): PXRD Pattern
Figure 15: Characterization Data of Form B (Non-Solvated): DSC/TGA-IR Data Figure 16: Characterization Data of Form B (Non-Solvated): PLM Image
Figure 17: Characterization Data of Form B (Non-Solvated): DVS Isotherm Plot
Figure 18: Characterization Data of Form B (Non-Solvated): DVS Mass Plot
Figure 19: PXRD Pattern Overlay for Three Form C Samples
Figure 20: Characterization Data of Form C (2-butanone solvate): FT-Raman Spectrum Figure 21 : Characterization Data of Form C (2-butanone solvate): PXRD Pattern
Figure 22: Characterization Data of Form C (2-butanone solvate): DSC/TGA-IR Data Figure 23: Characterization Data of Form C (2-butanone solvate): PLM Image
Figure 24: DSC and TGA-IR Data for Form C (methyl acetate solvate)
Figure 25: DSC and TGA-IR Data for Form C (1,4-dioxane solvate)
Figure 26: Characterization Data of Form D (1,4-Dioxane/Water Solvate): FT-Raman Spectrum
Figure 27: Characterization Data of Form D (1,4-Dioxane/Water Solvate): PXRD Pattern
Figure 28: Characterization Data of Form D (1,4-Dioxane/Water Solvate): DSC/TGA-IR Data
Figure 29: Characterization Data of Form D (1,4-Dioxane/Water Solvate): PLM Image
Figure 30: FT-Raman Spectral Overlay of Form E Initially and After Two Days at Ambient and Form A
Figure 31 : Characterization Data of Form F (DMSO/Water Solvate): FT-Raman Spectrum Figure 32: Characterization Data of Form F (DMSO/Water Solvate): PXRD Pattern Figure 33: Characterization Data of Form F (DMSO/Water Solvate): DSC/TGA-IR Data Figure 34: Characterization Data of Form F (DMSO/Water Solvate): PLM Image Figure 35: Characterization Data of Form G (Non-Solvated): FT-Raman Spectrum
Figure 36: Characterization Data of Form G (Non-Solvated): PXRD Pattern Figure 37: Characterization Data of Form G (Non-Solvated): DSC Data Figure 38: Characterization Data of Form G (Non-Solvated): PLM Image Figure 39: Characterization Data of Form H (Non-Solvated): FT-Raman Spectrum Figure 40: Characterization Data of Form H (Non-Solvated): PXRD Pattern
Figure 41 : Characterization Data of Form H (Non-Solvated): DSC Data
Figure 42: Characterization Data of Form H (Non-Solvated): PLM Image
Figure 43: Characterization Data of Form I (Hydrate 2): FT-Raman Spectrum
Figure 44: Characterization Data of Form I (Hydrate 2): PXRD Pattern
Figure 45: Characterization Data of Form I (Hydrate 2): DSC/TGA-IR Data Figure 46: Characterization Data of Form I (Hydrate 2): PLM Image Figure 47: PXRD of Form J
Figure 48: PXRD of Form K
Figure 49: Overlay of pH 1 residue with Form A and B or parent and HC1 salt. *consistent with HC1 salt
Figure 50: IDR for compound of Formula (I) Form B in FaSSGF pH 1.6.
Figure 51 : IDR for compound of Formula (I) Form B in FaSSIF V2 pH 6.5.
Figure 52: Equation - Log P/D calculation formula.
Figure 53 : Overlay PXRD Diagram of milled and unmilled compound of Formula (I) Form B.
Figure 54: PLM of ball milling at 2 and 5 minute samples and unmilled compound of Formula (I) Form B.
Figure 55: DSC and TGA at 2 and 5 minute ball milling samples and unmilled compound of Formula (I) Form B.
Figure 56: Overlay PXRD of wet grinding samples and input material (compound of Formula (I) Form B).
Figure 57: PLM of grinding at 5 and 10 minute samples and input material (compound of Formula (I) Form B)..
Figure 58: Overlay PXRD of compression sample with 10KN, 15 KN force and input material (compound of Formula (I) Form B).
Figure 59: PLM of Transmission of ground tablet with 10 kN and 15 kN Force.
Figure 60: Compaction PLM - Reflection of intact tablet with punch (10 kN force applied, left photograph; 15 kN force, right photograph).
Figure 61 : DSC of 10 kN, 15 kN compression samples and input material (compound of Formula (I) Form B).
DETAILED DESCRIPTION
[0033] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure is provided, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.
Definitions
[0034] Unless the context requires otherwise, throughout this specification and claims, the words “comprise,” “comprising” and the like are to be construed in an open, inclusive sense; the words “a,” “an,” and the like are to be considered as meaning at least one and are not limited to just one; and the term “about” is to be construed as meaning plus or minus 10%. Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context.
[0035] The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds or pharmaceutical compositions of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, and the like). The mammal treated in the methods of the disclosure is desirably a mammal in which treatment of HBV infection is desired.
[0036] The term “modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.
[0037] The term “pharmaceutically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.
[0038] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, fillers, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
[0039] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carrier, diluent or excipient.
[0040] The term “therapeutically effective amount” or “effective amount” as used herein refers to the amount of the subj ect compound that will elicit the biological or medical response of a tissue, system or animal, (e.g. mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds or pharmaceutical compositions of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect. [0041] The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, via disruption of HBV core protein assembly, that results in the improvement of the disease. “Disruption” includes inhibition of HBV viral assembly and infection.
[0042] A “crystalline form” is a solid material wherein the constituents of the solid material are arranged in a highly ordered microscopic structure, thereby forming a crystal lattice which extends in all directions. Crystalline forms can include anhydrous crystalline forms, solvated crystalline forms and/or hydrated crystalline forms.
[0043] “Polymorphism” is when a solid material can exist in more than one crystalline form.
[0044] As used herein, the term “amorphous” refers to a solid material having no long-range order in the position of its molecules. Amorphous solids are substances in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long-range order. Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points. For example, an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid.
[0045] A “hydrate” is a compound that exists in a solid composition with water molecules. The composition can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a “hydrate” refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein. Hydrates may be crystalline, wherein both the compound and water form part of the crystal lattice.
[0046] A “solvate” is a similar composition to a hydrate except that a solvent other that water replaces the water. For example, methanol or ethanol can form an “alcoholate”, which can again be stoichiometric or non-stoichiometric. As the term is used herein a “solvate” refers to a solid form, i.e., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein. Solvates may be crystalline, wherein both the compound and solvent form part of the crystal lattice.
[0047] “Anhydrous” means the solid form of the compound does not have water incorporated into its structure. For example, an anhydrous crystalline form does not have water forming part of the crystal structure. The skilled person would be aware of techniques which can be used to quantify the amount of water associated with a solid. For example, water content can be determined by either Karl Fischer Titration or Thermogravimetric Analysis (TGA). Suitably, an anhydrous solid form of the compound comprises less than about 1% by weight, such as less than about 0.5, about 0.4, about 0.3, about 0.2, about 0.1, about 0.05, or about 0.01% by weight of water.
[0048] “Un-solvated” or “non-solvated” means the solid form of the compound does not have solvent(s) incorporated into its structure. For example, an un-solvated crystalline form does not have solvent(s) forming part of the crystal structure. The skilled person would be aware of techniques which can quantify the amount of solvent associated with a solid. For example, solvent content can be determined by Gas Chromatography (GC). Suitably, an un-solvated or non-solvated solid form of the compound comprises less than about 1% by weight, such as less than about 0.5, about 0.4, about 0.3, about 0.2, about 0.1, about 0.05, or about 0.01% by weight of solvent.
[0049] Herein, where a composition is said to “consists essentially of’ a particular component, said composition suitably comprises at least 70 wt% of said component, suitably at least 80 wt% thereof, suitably at least 90 wt% thereof, suitably at least 95 wt% thereof, most suitably at least 99 wt% thereof. Suitably, a composition said to “consist essentially of’ a particular component consists of said component save for one or more trace components.
[0050] Active Pharmaceutical Ingredient (API) means the Compound of Formula (I).
[0051] As used herein, the “Compound of Formula (I)” refers to 5-amino-A-(3-chloro-4- fluorophenyl)-3-((2s,5s)-5-hydroxy-5-(methylsulfonylmethyl)octahydro-pentalen-2-yl)-l- methyl-lH-pyrazole-4-carboxamide. The Compound of Formula (I) is an HBV core inhibitor whose synthesis and testing in an HBV viral load assay have been described in PCT International Publication WO 2020/086533. The compound was referred to as AIA-227-2 in WO 2020/086533. It will be understood that the relative stereochemistry of AIA-227-2 was determined to be as depicted in Figure 2 of WO 2020/086533 and the Compound of Formula (I) may therefore also be shown as:
Figure imgf000013_0001
[0052] The phrase "substantially as shown in Figure" refers to an X-ray powder diffraction pattern, Raman spectrum or DSC thermogram with at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95% or at least 99% of its features appearing in the Figure. Crystalline Forms of Compound of Formula (I)
[0053] In one aspect, the present disclosure provides novel crystalline forms of a compound of a Formula (I):
Figure imgf000014_0001
Formula (I) described and characterized herein as Forms A, B, C, D, F, G, H and I.
[0054] The present disclosure is also directed to pharmaceutical compositions comprising each crystalline form, and to methods for preparing such forms. The present disclosure is further directed to the use of the crystalline forms in the treatment of HBV infections.
[0055] There are a number of analytical methods one of ordinary skill in the art in solid-state chemistry can use to analyse solid forms. The term "analyse" as used herein means to obtain information about the solid-state structure of solid forms. For example, powder X-ray diffraction (XRPD) is a suitable technique for differentiating amorphous solid forms from crystalline solid forms and for characterizing and identifying particular crystalline solid forms of a compound.
[0056] Due to differences in instruments, samples, and sample preparation, peak values are often reported with the modifier "±0.2°29". This is common practice in the solid-state chemical arts because of the variation inherent in peak values. Variability in peak intensity is a result of how individual crystals are oriented in the sample container with respect to the external X-ray source (known as "preferred orientation"). This orientation effect does not provide structural information about the crystal.
[0057] Powder X-ray diffraction is just one of several analytical techniques one may use to characterize and/or identify crystalline solid forms. Spectroscopic techniques such as Raman may also be used to characterize and/or identify crystalline solid forms. These techniques may also be used to quantify the amount of one or more crystalline solid forms in a mixture. A typical variability for a peak value associated with an FT-Raman measurement is in the order of plus or minus 2 cm'1. Differential scanning calorimetry (DSC) may also be used to characterise and/or identity crystalline solid forms. A typical variability for a value associated with a differential scanning calorimetry onset temperature is in the order of plus or minus 2°C. [0058] It should be noted that unless noted otherwise, thermal data (DSC and TGA) presented herein were acquired using a heating rate of 15°C/min. Furthermore, DSC data was acquired using Aluminium crimped pans.
[0059] In a first aspect, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.2°29; b) a Raman spectrum comprising at least one or two specific peaks selected from the peaks at wavenumbers of 770 and 1614 cm’1 ± 2 cm’1; and c) a DSC thermogram comprising an endothermic event with an onset temperature of 195°C ± 2°C.
[0060] In one embodiment, there is provided an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.2°29 and further comprising at least one, two, three, four or five specific peaks selected from the peaks at 2-theta values of 9.9, 14.6, 15.1, 19.7 and 22.2°29 ± 0.2°29.
[0061] In one embodiment, there is provided an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.2°29 and further comprising a peak at a 2-theta value of 14.6°29 ± 0.2°29.
[0062] In one embodiment, there is provided an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.2°29 and further comprising a peak at a 2-theta value of 15.1°29 ± 0.2°29.
[0063] In one embodiment, there is provided an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.2°29 and further comprising peaks at 2-theta values of 9.9, 15.1, 19.7 and 22.2°29 ± 0.2°29.
[0064] In one embodiment, there is provided an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.2°29 and further comprising peaks at 2-theta values of9.9, 14.6, 15.1, 19.7 and 22.2°29 ± 0.2°29.
[0065] In one embodiment, there is provided an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.1°29. [0066] In one embodiment, there is provided an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.1°29 and further comprising at least one, two, three, four or five specific peaks selected from the peaks at 2-theta values of 9.9, 14.6, 15.1, 19.7 and 22.2°29 ± 0.1°29.
[0067] In one embodiment, there is provided an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.1°29 and further comprising a peak at a 2-theta value of 14.6°29 ± 0.1°29.
[0068] In one embodiment, there is provided an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.1°29 and further comprising a peak at a 2-theta value of 15.1°29 ± 0.1°29.
[0069] In one embodiment, there is provided an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.1°29 and further comprising the peaks at 2-theta values of 9.9, 15.1, 19.7 and 22.2°29 ± 0.1°29.
[0070] In one embodiment, there is provided an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3 °29 ± 0.1°29 and further comprising peaks at 2 theta values of 9.9, 14.6, 15.1, 19.7 and 22.2°29 ± 0.1°29.
[0071] In one embodiment, there is provided an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising a peak at a 2-theta value of 13.2°29 ± 0.2°29, suitably 13.2°29 ± 0.1°29, and wherein Form B is un-solvated and anhydrous. Suitably, Form B comprises less than about 2% by weight solvent and/or water, such as less than about 1% by weight, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05% or less than about 0.01% by weight.
[0072] In one embodiment, there is provided an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising a peak at 2-theta value of 16.4°29 ± 0.2°29, suitably 16.4°29 ± 0.1°29, and wherein Form B is un-solvated and anhydrous. Suitably, Form B comprises less than about 2% by weight solvent and/or water, such as less than about 1% by weight, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05% or less than about 0.01% by weight.
[0073] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.2°29 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 1 in °29 ± 0.2°29.
Table 1 - XRPD peak positions for Form B
Figure imgf000017_0001
[0074] In one embodiment, there is there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.1°29; and further comprising at least two, five, ten, fifteen, twenty or twenty- five further peaks selected from the group consisting of the peaks in Table 1 in °29 ± 0.1°29.
[0075] In one embodiment, there is there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising a peak at a 2-theta value of 13.2°29 ± 0.2°29 (suitably, °29 ± 0.1°29) and wherein Form B comprises less than about 2% by weight solvent and/or water, such as less than about 1% by weight, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05% or about 0.01% by weight.
[0076] In one embodiment, there is there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising a peak at a 2-theta value of 13.2°29 ± 0.2°29 (suitably, °29 ± 0.1°29) and wherein Form B comprises less than about 0.5% by weight solvent and/or water.
[0077] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a powder X-Ray diffraction pattern measured Cu Ka (X = 1.5406 A) radiation substantially the same as shown in Figure 14.
[0078] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a Raman spectrum comprising the peaks at wavenumbers of 770 and 1614 cm’1 ± 2 cm’1.
[0079] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a Raman spectrum comprising at least one or two specific peaks at wavenumbers of 770 and 1614 cm’1 ± 1 cm’1.
[0080] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a Raman spectrum comprising the peaks at wavenumbers of 770 and 1614 cm’1 ± 1 cm’1.
[0081] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a Raman spectrum comprising peaks at wavenumbers of 770 and 1614 cm’1 ± 2 cm’1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 2 in cm’1 ± 2 cm’1.
Table 2 - Raman shifts for Form B
Figure imgf000018_0001
Figure imgf000019_0001
[0082] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a Raman spectrum comprising peaks at wavenumbers of 770 and 1614 cm'1 ± 1 cm'1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 2 in cm4± 1 cm'1.
[0083] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a Raman spectrum substantially the same as shown in Figure 13.
[0084] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 213°C ± 2°C.
[0085] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 195°C ± 2°C.
[0086] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 195°C ± 2°C and an endothermic event with an onset temperature of 213°C ± 2°C.
[0087] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 195°C ± 1°C.
[0088] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 213°C ± 1°C.
[0089] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 195°C ± 1°C and an endothermic event with an onset temperature of 213°C ± 1°C. [0090] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a DSC thermogram comprising no thermal events between about 100 and about 150°C and an endothermic event with an onset temperature of 195°C ± 2°C, suitably 195°C ± 1°C. Suitably, the DSC thermogram further comprises an endothermic event with an onset temperature of 213°C ± 2°C, suitably 213°C ± 1°C.
[0091] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 195°C ± 2°C, suitably 195°C ± 1°C, and wherein the Form B is anhydrous and un-solvated. In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 195°C ± 2°C, suitably 195°C ± 1°C, and an endothermic event with an onset temperature of 213°C ± 2°C, suitably 213°C ± 1°C, and wherein the Form B is anhydrous and un-solvated.
[0092] Suitably, Form B comprises less than about 2% by weight solvent and/or water, such as less than about 1% by weight, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05% or less than about 0.01% by weight.
[0093] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 195°C ± 2°C, suitably 195°C ± 1°C, and wherein the Form B is anhydrous and un-solvated.
[0094] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a DSC thermogram comprising no thermal events between about 100 and about 150°C and an endothermic event with an onset temperature of 195°C ± 2°C, suitably 195°C ± 1°C.
[0095] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B characterized by a DSC thermogram substantially the same as Figure 15.
[0096] In one embodiment, there is provided a plurality of particles of the crystalline form of a compound of Formula (I). Suitably, the crystalline form is Form B.
[0097] In one embodiment, there is provided a plurality of particles of the crystalline form B of a compound of Formula (I) having a particle size distribution wherein 10% of the particles have a mean particle size of less than about 10 pm, 50% of the particles have a mean particle size of less than about 25 pm, and/or 90% of the particles have a mean particle size of less than about 65pm. [0098] In one embodiment, there is provided a plurality of particles of the crystalline form B of a compound of Formula (I) having a particle size distribution wherein 10% of the particles have a mean particle size less than about 10 pm, 50% of the particles have a mean particle size less than about 30 pm, and/or 90% of the particles have a mean particle size of less than about 70 pm. In one embodiment, there is provided a plurality of particles of the crystalline form B of a compound of Formula (I) having a particle size distribution wherein 10% of the particles have a mean particle size less than about 7 pm, 50% of the particles have a mean particle size less than about 20 pm, and/or 90% of the particles have a mean particle size of less than about 50 pm. In one embodiment, there is provided a plurality of particles of the crystalline form B of a compound of Formula (I) having a particle size distribution wherein 10% of the particles have a mean particle size less than about 5 pm, 50% of the particles have a mean particle size less than about 15 pm, and/or 90% of the particles have a mean particle size of less than about 35 pm.
[0099] In one embodiment, there is provided a plurality of particles of the crystalline form B of a compound of Formula (I) having a particle size distribution wherein 10% of the particles have a mean particle size less than about 10 pm, 50% of the particles have a mean particle size less than about 25 pm, and/or 90% of the particles have a mean particle size of less than about 75 pm. In one embodiment, there is provided a plurality of particles of the crystalline form B of a compound of Formula (I) having a particle size distribution wherein 10% of the particles have a mean particle size less than about 15 pm, 50% of the particles have a mean particle size less than about 40 pm, and/or 90% of the particles have a mean particle size of less than about 80 pm. In one embodiment, there is provided a plurality of particles of the crystalline form B of a compound of Formula (I) having a particle size distribution wherein 10% of the particles have a mean particle size less than about 7 pm, 50% of the particles have a mean particle size less than about 20 pm, and/or 90% of the particles have a mean particle size of less than about 75 pm. In one embodiment, there is provided a plurality of particles of the crystalline form B of a compound of Formula (I) having a particle size distribution wherein 10% of the particles have a mean particle size less than about 5 pm, 50% of the particles have a mean particle size less than about 10 pm, and/or 90% of the particles have a mean particle size of less than about 15 pm.
[0100] Preferably, particle size distribution is determined using laser diffraction. Suitably, particle size distribution is determine using laser diffraction using a wet dispersion of the compound of Formula (I). Suitably, the dispersion medium comprises water.
[0101] In one embodiment, Form B is non-hygroscopic. A substance is considered non- hygroscopic if the increase in mass is less than 0.2 per cent when the substance is exposed to 25°C/8%RH for 24 hours (for example, in accordance with the test procedure for “hygroscopicity” in Chapter 5.11 “Characters Section in Monographs”, European Pharmacopeia 6.0).
[0102] In one embodiment, Form B is substantially pure.
[0103] In one embodiment, Form B comprises less than about 2% by weight solvent and/or water, such as less than about 1% by weight, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05% or less than about 0.01% by weight. The skilled person would know of suitable analytical techniques which can quantify the amount of solvent/water associated with a solid. For example, water content can be determined by Karl Fischer Titration. Residual solvents can be determined by Gas Chromatography. Thermogravimetric Analysis (TGA) can also quantify the amount of volatile material (i.e., solvent and water) associated with a solid (either surface bound or incorporated into the crystal structure). Suitably, Form B is anhydrous and un-solvated.
[0104] In one embodiment, there is provided a crystalline form of a compound of Formula (I) of wherein the crystalline form is Form A and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising the peaks at 2-theta values of 11.1, 12.7, and 14.7°29 ± 0.2°29; b) a Raman spectrum comprising at least one or two specific peaks selected from the peaks at wavenumbers of 1070 and 1390 cm'1 ± 2 cm'1; c) a DSC thermogram comprising an endothermic event with an onset temperature of 213°C ± 2°C; and d) comprising at least 2.5% by weight of water.
[0105] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising the peaks at 2-theta values of 11.1, 12.7, and 14.7°29 ± 0.2°29 and further comprising at least one, two or three specific peaks selected from the peaks at 2-theta values of 18.4, 22.1 and 22.8°29 ± 0.2°29.
[0106] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising the peaks at 2-theta values of 11.1, 12.7, 14.7, 18.4, 22.1 and 22.8°29 ± 0.2°29.
[0107] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising the peaks at 2-theta values of 11.1, 12.7, and 14.7°29 ± 0.1°29. [0108] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising the peaks at 2-theta values of 11.1, 12.7, and 14.7°29 ± 0.1°29 and further comprising at least one, two or three specific peaks selected from the peaks at 2-theta values of 18.4, 22.1 and 22.8°29 ± 0. 1°29.
[0109] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising the peaks at 2-theta values of 11.1, 12.7, 14.7, 18.7, 22.1 and 22.8°29 ± 0.1°29.
[0110] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising peaks at 2-theta values of 11.1, 12.7, and 14.7°29 ± 0.2°29 and further comprising at least five, ten, fifteen, or twenty peaks selected from the group consisting of the peaks in Table 3 in °29 ± 0.2°29.
Table 3 - XRPD peak positions for Form A
Figure imgf000023_0001
[0111] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising peaks at 2-theta values of 11.1, 12.7, and 14.7°29 ± 0.1°29 and further comprising at least five, ten, fifteen, or twenty peaks selected from the group consisting of the peaks in Table 3 in °29 ± 0.1°29. [0112] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by a powder X-Ray diffraction pattern measured using Cu Ka (X = 1.5406 A) radiation substantially the same as shown in Figure 8.
[0113] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by a Raman spectrum comprising peaks at wavenumbers of 1070 and 1390 cm'1 ± 2 cm'1.
[0114] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by a Raman spectrum comprising at least one or two peaks at wavenumbers of 1070 and 1390 cm'1 ± 1 cm'1.
[0115] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by a Raman spectrum comprising peaks at wavenumbers of 1070 and 1390 cm'1 ± 1 cm'1.
[0116] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by a Raman spectrum comprising peaks at wavenumbers of 1070 and 1390 cm'1 ± 2 cm'1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 4 in cm'1 ± 2 cm'1.
Table 4 - Raman shifts for Form A
Figure imgf000024_0001
[0117] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by a Raman spectrum comprising peaks at wavenumbers of 1070 and 1390 cm'1 ± 1 cm'1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 4 in cm4± 1 cm'1.
[0118] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by a Raman spectrum substantially the same as shown in Figure 7.
[0119] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by a DSC thermogram comprising an endothermic with an onset temperature in the range of about 85 to about 105°C.
[0120] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by a DSC thermogram comprising an endothermic with an onset temperature in the range of 85 to 105°C and comprising an endothermic event with an onset temperature of 213°C ± 2°C.
[0121] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A characterized by a DSC thermogram substantially the same as Figure 9 or Figure 12.
[0122] In one embodiment, Form A is substantially pure.
[0123] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A and comprises at least 2.5% by weight of water, such as at least 3% by weight of water.
[0124] In one embodiment, there is provided a crystalline form of a compound of Formula (I) of wherein the crystalline form is Form C and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising a peak at a 2-theta value of 6.0°29 ± 0.2°29; b) a Raman spectrum comprising peaks at wavenumbers of 747, 921 and 1129 cm'1 ± 2 cm'1; c) a DSC thermogram comprising an endothermic event with an onset temperature of 194°C ± 2°C; and d) comprising at least 2.5% by weight of solvent wherein the solvent is selected from 1,4-dixoane, 2-butanone and methyl acetate. [0125] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising a peak at a 2-theta value of 6.0°29 ± O.l°20.
[0126] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising a peak at a 2-theta value of 6.0°29 ± 0.2°29 and further comprising at least one, two or three specific peaks selected from the peaks at 2-theta values of 7.6, 8.8 and 9.3°29 ± 0.2°29. Conveniently, Form C is characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising a peak at a 2-theta value of 6.0°29 ± 0.1°29 and further comprising at least one, two or three specific peaks selected from the peaks at 2-theta values of 7.6, 8.8 and 9.3°29 ± 0.1°29.
[0127] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising the peaks at 2-theta values of 6.0, 7.6, 8.8 and 9.3°29 ± 0.2°29. Conveniently, Form C is characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising the peaks at 2-theta values of 6.0, 7.6, 8.8 and 9.3°29 ± 0.1°29.
[0128] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising a peak at a 2-theta value of 6.0°29 ± 0.2°29 and further comprising at least five, ten, fifteen, twenty, twenty -five, or thirty peaks selected from the group consisting of the peaks in Table 5 in °29 ± 0.2°29. Conveniently, Form C is characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising a peak at a 2-theta value of 6.0°29 ± 0.1°29 and further comprising at least five, ten, fifteen, twenty, twenty-five, or thirty peaks selected from the group consisting of the peaks in Table 5 in °29 ± 0.1°29.
Table 5 - XRPD peak positions for Form C
Figure imgf000026_0001
Figure imgf000027_0001
[0129] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C characterized by a powder X-Ray diffraction pattern measured Cu Ka (X = 1.5406 A) radiation substantially the same as shown in Figure 21. [0130] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C characterized by a Raman spectrum comprising peaks at wavenumbers of 747, 921 and 1129 cm'1 ± 2 cm'1. Conveniently the crystalline form is Form C characterized by a Raman spectrum comprising peaks at wavenumbers of 747, 921 and 1129 cm' 1 ± 1 cm'1 [0131] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C characterized by a Raman spectrum comprising peaks at wavenumbers of 747, 921 and 1129 cm'1 ± 2 cm'1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 6 in cm'1 ± 2 cm'1. Conveniently Form C is characterized by a Raman spectrum comprising peaks at wavenumbers of 747, 921 and 1129 cm'1 ± 1 cm'1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 6 in cm'1 ± 1 cm'1.
Table 6 - Raman shifts for Form C
Figure imgf000027_0002
Figure imgf000028_0001
[0132] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C characterized by a Raman spectrum substantially the same as shown in Figure 20.
[0133] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 214°C ± 2°C.
[0134] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 194°C ± 2°C and an endothermic event with an onset temperature of 214°C ± 2°C.
[0135] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C characterized by a DSC thermogram substantially the same as Figure 22, 24 or 25.
[0136] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C and comprises at least 3.0% by weight of methyl acetate.
[0137] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C and comprises at least 4.5% by weight of 2-butanone.
[0138] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C and comprises at least 6.5% by weight of 1,4-dioxane.
[0139] In one embodiment, there is provided a crystalline form of a compound of Formula (I) of wherein the crystalline form is Form D and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising the peaks at 2-theta values of 11.3, 20.1 and 21.2°20 ± 0.2°29; b) a Raman spectrum comprising peaks at wavenumbers of 695 and 1640 cm'1 ± 2 cm' i. c) a DSC thermogram comprising an endothermic event with an onset temperature of 73°C ± 2°C; d) a DSC thermogram comprising an endothermic event with an onset temperature of 193°C ± 2°C; and e) comprising at least 5% by weight of 1,4-dixoane.
[0140] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form D characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising peaks at 2-theta values of 11.3, 20.1 and 21.2°20 ± O.l°20.
[0141] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form D characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising peaks at 2-theta values of 11.3, 20.1 and 21.2°20 ± O.2°20 and further comprising at least one, two or three specific peaks selected from the peaks at 2-theta values of 17.5, 19.5 and 24.1°20 ± O.2°20. Conveniently Form D is characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising peaks at 2-theta values of 11.3, 20.1 and 21 ,2°20 ± 0.1 °20 and further comprising at least one, two or three specific peaks selected from the peaks at 2-theta values of 17.5, 19.5 and 24.1 °20 ± 0.1 °20.
[0142] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form D characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising peaks at 2-theta values of 11.3, 17.5, 19.5, 20.1, 21.2 and 24.1°20 ± O.2°20. Conveniently Form D is characterized by an XRPD measured using Cu Ka (k = 1.5406 A) radiation comprising peaks at 2-theta values of 11.3, 17.5, 19.5, 20.1, 21.2 and 24.1°20 ± O. l°20.
[0143] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form D characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (k = 1.5406 A) comprising peaks at 2-theta values of 11.3, 20.1 and 21.2°20 ± O.2°20 and further comprising at least five, ten, fifteen, twenty, or twenty-five peaks selected from the group consisting of the peaks in
[0144] Table 7 in °20 ± O.2°20. Conveniently Form D is characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising peaks at 2-theta values of 11.3, 20.1 and 21 ,2°20 ± 0.1 °20 and further comprising at least five, ten, fifteen, twenty or twenty -five peaks selected from the group consisting of the peaks in
[0145] Table 7 in °20 ± O.l°20. Table 7 - XRPD peak positions for Form D
Figure imgf000030_0001
[0146] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form D characterized by a powder X-Ray diffraction pattern measured Cu Ka (X = 1.5406 A) radiation substantially the same as shown in Figure 27.
[0147] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form D characterized by a Raman spectrum comprising peaks at wavenumbers of 695 and 1640 cm'1 ± 2 cm'1. Conveniently Form D is characterized by a Raman spectrum comprising peaks at wavenumbers of 695 and 1640 cm'1 ± 1 cm'1.
[0148] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form D characterized by a Raman spectrum comprising peaks at wavenumbers of 695 and 1640 cm'1 ± 2 cm'1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 8 in cm'1 ± 2 cm'1. Conveniently Form D is characterized by a Raman spectrum comprising peaks at wavenumbers of 695 and 1640 cm'1 ± 1 cm'1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 8 in cm4± 1 cm'1. Table 8 - Raman shifts for Form D
Figure imgf000031_0001
[0149] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form D characterized by a Raman spectrum substantially the same as shown in Figure 26.
[0150] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form D characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 73°C ± 2°C, an endothermic event with an onset temperature of 193°C ± 2°C, and/or an endothermic event with an onset temperature of 213°C ± 2°C.
[0151] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form D characterized by a DSC thermogram substantially the same as Figure 28.
[0152] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form D and comprises at least 7.5% by weight of 1,4-dioxane, such as at least 9% by weight. [0153] In one embodiment, there is provided a crystalline form of a compound of Formula (I) of wherein the crystalline form is Form F and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising a peak at a 2-theta value of 10.6°29 ± 0.2°29; b) a Raman spectrum comprising peaks at wavenumbers of 1211, 1499 and 1528 cm' 1 ± 2 cm'1; c) a DSC thermogram comprising an endothermic event with an onset temperature of 103°C ± 2°C; and d) comprising at least 5% by weight of DMSO and/or water.
[0154] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising a peak at a 2-theta value of 10.6°29 ± 0.1°29.
[0155] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising a peak at a 2-theta value of 10.6°29 ± 0.2°29 and further comprising at least one, two or three specific peaks selected from the peaks at 2-theta values of 14.1, 17.6 and 19.5°29 ± 0.2°29. Conveniently Form F is characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising a peak at a 2-theta value of 10.6°29 ± 0.1°29 and further comprising at least one, two or three specific peaks selected from the peaks at 2-theta values of 14.1, 17.6 and 19.5°29 ± 0.1°29.
[0156] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising peaks at 2-theta values of 10.6, 14.1, 17.6 and 19.5°29 ± 0.2°29. Conveniently Form F is characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising peaks at 2-theta values of 10.6, 14.1, 17.6 and 19.5°29 ± 0.1°29.
[0157] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising a peak at a 2-theta value of 10.6°29 ± 0.2°29 and further comprising at least five, ten, fifteen, twenty, or twenty-five peaks selected from the group consisting of the peaks in Table 9 in °29 ± 0.2°29. Conveniently Form F is characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising a peak at a 2-theta value of 10.6°29 ± 0.1°29 and further comprising at least five, ten, fifteen, twenty, or twenty-five peaks selected from the group consisting of the peaks in Table 9 in °29 ± 0.1°29. Table 9 - XRPD peak positions for Form F
Figure imgf000033_0001
[0158] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F characterized by a powder X-Ray diffraction pattern measured Cu Ka (X = 1.5406 A) radiation substantially the same as shown in Figure 32.
[0159] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F characterized by a Raman spectrum comprising peaks at wavenumbers of 1211, 1499 and 1528 cm'1 ± 2 cm'1. Conveniently Form F is characterized by a Raman spectrum comprising peaks at wavenumbers of 1211, 1499 and 1528 cm'1 ± 1 cm'1.
[0160] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F characterized by a Raman spectrum comprising peaks at comprising peaks at wavenumbers of 1211, 1499 and 1528 cm'1 ± 2 cm'1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 10 in cm'1 ± 2 cm'1. Conveniently Form F is characterized by a
Raman spectrum comprising peaks at comprising peaks at wavenumbers of 1211, 1499 and 1528 cm'1 ± 1 cm'1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 10 in cm'1 ± 1 cm'1. Table 10 - Raman shifts for Form F
Figure imgf000034_0001
[0161] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F characterized by a Raman spectrum substantially the same as shown in Figure 31.
[0162] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 212°C ± 2°C.
[0163] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F characterized by a DSC thermogram comprising endothermic event with an onset temperature of 103 °C ± 2°C and an endothermic event with an onset temperature of 212°C ± 2°C.
[0164] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F characterized by a DSC thermogram substantially the same as Figure 33. [0165] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form F and comprises at least 10% by weight of DMSO and/or water.
[0166] In one embodiment, there is provided a crystalline form of a compound of Formula (I) of wherein the crystalline form is Form G and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising peaks at 2-theta values of 13.6 and 14.7°29 ± 0.2°29; b) a Raman spectrum comprising peaks at least one or two specific peaks selected from the peaks at wavenumbers of 663 and 1648 cm'1 ± 2 cm'1; and c) a DSC thermogram comprising an endothermic event with an onset temperature of 212°C ± 2°C.
[0167] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form G characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising peaks at 2-theta values of 13.6 and 14.7°29 ± O.l°20.
[0168] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form G characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising peaks at 2-theta values of 13.6 and 14.7°29 ± 0.2°29 and further comprising at least one, two, three or four specific peaks selected from the peaks at 2-theta values of 12.8, 20.8, 25.8 and 27.6°29 ± 0.2°29. Conveniently Form G is characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising peaks at 2-theta values of 13.6 and 14.7°29 ± 0.1°29 and further comprising at least one, two, three or four specific peaks selected from the peaks at 2-theta values of 12.8, 20.8, 25.8 and 27.6°29 ± 0.1°29.
[0169] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form G characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising peaks at 2-theta values of 12.8, 13.6, 14.7, 20.8, 25.8 and 27.6°29 ± 0.2°29. Conveniently Form G is characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising peaks at 2-theta values of 12.8, 13.6, 14.7, 20.8, 25.8 and 27.6°29 ± 0.1°20.
[0170] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form G characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising peaks at 2-theta values of 13.6 and 14.7°29 ± 0.2°29 and further comprising at least five, ten, fifteen, twenty or twenty-five peaks selected from the group consisting of the peaks in Table 11 in °29 ± 0.2°29. Conveniently Form G is characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising peaks at 2-theta values of 13.6 and 14.7°29 ± 0.1°29 and further comprising at least five, ten, fifteen, twenty or twenty-five peaks selected from the group consisting of the peaks in Table 11 in °29 ± 0.1°29.
Table 11 - XRPD peak positions for Form G
Figure imgf000036_0001
[0171] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form G characterized by a powder X-Ray diffraction pattern measured Cu Ka (X = 1.5406 A) radiation substantially the same as shown in Figure 36.
[0172] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form G characterized by a Raman spectrum comprising at least one or two specific peaks selected from the peaks at wavenumbers of 663 and 1648 cm'1 ± 1 cm' i
[0173] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form G characterized by a Raman spectrum comprising peaks at wavenumbers of 663 and 1648 cm'1 ± 2 cm'1. Conveniently Form G is characterized by a Raman spectrum comprising peaks at wavenumbers of 663 and 1648 cm'1 ± 1 cm'1.
[0174] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form G characterized by a Raman spectrum comprising peaks at wavenumbers of 663 and 1648 cm'1 ± 2 cm'1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 12 in cm'1 ± 2 cm'1. Conveniently Form G is characterized by a Raman spectrum comprising peaks at wavenumbers of 663 and 1648 cm'1 ± 1 cm'1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 12 in cm4± 1 cm'1.
Table 12 - Raman shifts for Form G
Figure imgf000037_0001
[0175] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form G characterized by a Raman spectrum substantially the same as shown in Figure 35.
[0176] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form G characterized by a DSC thermogram substantially the same as Figure 37.
[0177] In one embodiment, Form G comprises less than 2% by weight solvent and/or water, such as less than 1% by weight, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than
0.1% by weight. Suitably, Form G is anhydrous and un-solvated. [0178] In one embodiment, there is provided a crystalline form of a compound of Formula (I) of wherein the crystalline form is Form H and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising the peaks at 2-theta values of 4.7 and 9.5°29 ± 0.2°29; b) a Raman spectrum comprising at least one, two or three specific peaks selected from the peaks at wavenumbers of 795, 1255 and 1314 cm'1 ± 2 cm'1; and c) a DSC thermogram comprising an endothermic event with an onset temperature of 211°C ± 2°C.
[0179] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form H characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising peaks at 2-theta values of 4.7 and 9.5°29 ± 0.1°29.
[0180] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form H characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising peaks at 2-theta values of 4.7 and 9.5°29 ± 0.2°29 and further comprising at least one, two or three specific peaks from the peaks at 2-theta values of 11.0, 14.7 and 22.0°29 ± 0.2°29. Conveniently Form H is characterized by an XRPD measured using Cu Ka ( = 1.5406 A) radiation comprising peaks at 2-theta values of 4.7 and 9.5°29 ± 0.1°29 and further comprising at least one, two or three specific peaks from the peaks at 2-theta values of 11.0, 14.7 and 22.0°29 ± 0.1°29.
[0181] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form H characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising peaks at 2-theta values of 4.7, 9.5, 11.0, 14.7 and 22.0°29 ± 0.2°29. Conveniently Form H is characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising peaks at 2-theta values of 4.7, 9.5, 11.0, 14.7 and 22.0°29 ± 0.1°29.
[0182] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form H characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising peaks at 2-theta values of 4.7 and 9.5°29 ± 0.2°29 and further comprising at least five, ten, fifteen, twenty or twenty -five thirty peaks selected from the group consisting of the peaks in Table 13 in °29 ± 0.2°29. Conveniently Form H is characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising peaks at 2-theta values of 4.7 and 9.5°29 ± 0.1°29 and further comprising at least five, ten, fifteen, twenty, or twenty-five peaks selected from the group consisting of the peaks in Table 13 in °29 ± 0.1°29. Table 13 - XRPD peak positions for Form H
Figure imgf000039_0001
[0183] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form H characterized by a powder X-Ray diffraction pattern measured Cu Ka (X = 1.5406 A) radiation substantially the same as shown in Figure 40.
[0184] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form H characterized by a Raman spectrum comprising at least one, two or three specific peaks selected from the peaks at wavenumbers of 795, 1255 and 1314 cm'1 ± 1 cm'1.
[0185] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form H characterized by a Raman spectrum comprising peaks at wavenumbers of 795, 1255 and 1314 cm'1 ± 2 cm'1. Conveniently Form H is characterized by a Raman spectrum comprising peaks at wavenumbers of 795, 1255 and 1314 cm'1 ± 1 cm'1.
[0186] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form H characterized by a Raman spectrum comprising peaks at wavenumbers of 795, 1255 and 1314 cm'1 ± 2 cm'1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 14 in cm'1 ± 2 cm'1. Conveniently Form H is characterized by a Raman spectrum comprising peaks at wavenumbers of 795, 1255 and 1314 cm'1 ± 1 cm'1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 14 in cm'1 ± 1 cm'1.
Table 14 - Raman shifts for Form H
Figure imgf000040_0001
[0187] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form H characterized by a Raman spectrum substantially the same as shown in Figure 39.
[0188] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form H characterized by a DSC thermogram substantially the same as Figure 41.
[0189] In one embodiment, Form H comprises less than 2% by weight solvent and/or water, such as less than 1% by weight, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1% by weight. Suitably, Form H is anhydrous and un-solvated. [0190] In one embodiment, there is provided a crystalline form of a compound of Formula (I) of wherein the crystalline form is Form I and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising the peaks at 2-theta values of 14.2, 16.6 and 16.9°29 ± 0.2°29; b) a Raman spectrum comprising a peak at a wavenumber of 586 cm'1 ± 2 cm'1; and c) a DSC thermogram comprising an endothermic event with an onset temperature of 166°C ± 2°C.
[0191] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising peaks at 14.2, 16.6 and 16.9°29 ± 0.1°29.
[0192] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising peaks at 14.2, 16.6 and 16.9°29 ± 0.2°29, further comprising at least one or two specific peaks from the peaks at 2-theta values of 11.4 and 13.1°29 ± 0.2°29.
[0193] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising peaks at 14.2, 16.6 and 16.9°29 ± 0.1°29, further comprising at least one or two specific peaks from the peaks at 2-theta values of 11.4 and 13.1°29 ± 0.1 °29.
[0194] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by an XRPD measured using Cu Ka (X =
1.5406 A) radiation comprising peaks at 11.4, 13.1, 14.2, 16.6 and 16.9°29 ± 0.2°29. Conveniently, Form I characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising peaks at 11.4, 13.1, 14.2, 16.6 and 16.9°29 ± 0.1°29
[0195] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising peaks at 2-theta values of 14.2, 16.6 and 16.9°29 ± 0.2°29 and further comprising at least five, ten, fifteen, twenty or twenty-five peaks selected from the group consisting of the peaks in Table 15 in °29 ± 0.2°29. Conveniently Form I is characterized by an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising peaks at 2-theta values of 14.2, 16.6 and 16.9°29 ± 0.1°29 and further comprising at least five, ten, fifteen, twenty or twenty-five peaks selected from the group consisting of the peaks in Table 15 in °29 ± 0.1 °29. Table 15 - XRPD peak positions for Form I
Figure imgf000042_0001
[0196] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by a powder X-Ray diffraction pattern measured Cu Ka (X = 1.5406 A) radiation substantially the same as shown in Figure 44.
[0197] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by a Raman spectrum comprising a peak at wavenumber of 586 cm'1 ± 1 cm'1. [0198] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by a Raman spectrum comprising a peak at 586 cm'1 ± 2 cm'1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 16 in cm'1 ± 2 cm'1. Conveniently Form I is characterized by a Raman spectrum comprising a peak at 586 cm'1 ± 1 cm' 1 and further comprising at least two, five, ten, fifteen, twenty or twenty-five further peaks selected from the group consisting of the peaks in Table 16 in cm'1 ± 1 cm'1.
Table 16 - Raman shifts for Form I
Figure imgf000042_0002
Figure imgf000043_0001
[0199] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by a Raman spectrum substantially the same as shown in Figure 43. [0200] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 208°C ± 2°C.
[0201] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 166°C ± 2°C and an endothermic event with an onset temperature of 208°C ± 2°C.
[0202] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I characterized by a DSC thermogram substantially the same as Figure 45. [0203] In one embodiment, there is provided a crystalline form of a compound of Formula (I) wherein the crystalline form is Form I and comprises at least 1.5% by weight of water. [0204] When it is stated herein that the specification relates to a crystalline form of a compound of Formula (I), the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, yet more conveniently greater than about 90% and preferably greater than 95%, 98% or 99% by weight.
[0205] In one embodiment, Form A is pure or substantially pure. As used herein, the term “substantially pure” means that the solid state form of the compound of Formula (I) contains about 20% by weight or less, or about 15% by weight or less, or about 10% by weight or less, or about 5% by weight or less, or about 2% by weight or less, or about 1% by weight or less, or about 0.5 by weight or less of any impurities or other solid forms of the compound of Formula (I), including alternative crystalline forms, hydrates, solvates or amorphous forms, for example as measured by XRPD. Thus, substantially pure Form A described herein would be understood to contain greater than about 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 95% by weight, greater than 98% by weight, greater than 99% by weight, greater than 99.5% by weight of the crystalline Form A of the compound of Formula (I). Suitably, there is provided Form A wherein when Form A is analyzed by a solid-state technique, such as by X-Ray Powder diffraction and/or Raman spectroscopy, no other solid forms (amorphous and/or other crystalline forms) are detected. Suitably, there is provided a crystalline form of a compound of Formula (I) essentially consisting of Form A. Suitably, there is provided a crystalline form of a compound of Formula (I) consisting of Form A.
[0206] In one embodiment, Form B is pure or substantially pure. As used herein, the term “substantially pure” means that the solid state form of the compound of Formula (I) contains about 20% by weight or less, or about 15% by weight or less, or about 10% by weight or less, or about 5% by weight or less, or about 2% by weight or less, or about 1% by weight or less, or about 0.5 by weight or less of any impurities or other solid forms of the compound of Formula (I), including alternative crystalline forms, hydrates, solvates or amorphous forms, for example as measured, for example by XRPD. Thus, substantially pure Form B described herein would be understood to contain greater than about 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 95% by weight, greater than 98% by weight, greater than 99% by weight, greater than 99.5% by weight of the crystalline Form B of the compound of Formula (I). Suitably, there is provided Form B wherein when Form B is analyzed by a solid-state technique, such as by X-Ray Powder diffraction and/or Raman spectroscopy, no other solid forms (amorphous and/or other crystalline forms) are detected. Suitably, there is provided a crystalline form of a compound of Formula (I) essentially consisting of Form B. Suitably, there is provided a crystalline form of a compound of Formula (I) consisting of Form B. [0207] In one embodiment, Form C, Form D, Form F, Form G, Form H or Form I is pure or substantially pure. As used herein, the term “substantially pure” means that the solid state form of the compound of Formula (I) contains about 20% by weight or less, or about 15% by weight or less, or about 10% by weight or less, or about 5% by weight or less, or about 2% by weight or less, or about 1% by weight or less, or about 0.5 by weight or less of any impurities or other solid forms of the compound of Formula (I), including alternative crystalline forms, hydrates, solvates or amorphous forms, for example as measured, for example by XRPD. Thus, substantially pure Form C, Form D, Form F, Form G, Form H or Form I described herein would be understood to contain greater than about 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 95% by weight, greater than 98% by weight, greater than 99% by weight, greater than 99.5% by weight of the crystalline Form C, Form D, Form F, Form G, Form H or Form I of the compound of Formula (I). Suitably, there is provided Form C, Form D, Form F, Form G, Form H or Form I wherein when Form C, Form D, Form F, Form G, Form H or Form I is analyzed by a solid state technique, such as by X-Ray Powder diffraction and/or Raman spectroscopy, no other solid forms (amorphous and/or other crystalline forms) are detected. Suitably, there is provided a crystalline form of a compound of Formula (I) essentially consisting of Form C, Form D, Form F, Form G, Form H or Form I. Suitably, there is provided a crystalline form of a compound of Formula (I) consisting of Form C, Form D, Form F, Form G, Form H or Form I.
Pharmaceutical Compositions and Kits
[0208] In another aspect, the present disclosure provides novel pharmaceutical compositions comprising a crystalline form of the compound of Formula (I), and a pharmaceutically acceptable carrier, diluent or excipient. In particular, the present disclosure provides pharmaceutical compositions comprising a crystalline compound of Formula (I) as disclosed herein formulated together with one or more pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form A, B, C, D, F, G, H or I.
[0209] In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) wherein the crystalline form is Form B; and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) wherein the crystalline form is pure or substantially pure Form B; and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) wherein the compound of Formula (I) consists essentially of crystalline Form B. In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) wherein the compound of Formula (I) consists of crystalline Form B.
[0210] In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A; and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) wherein the crystalline form is pure or substantially pure Form A; and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) wherein the compound of Formula (I) consists essentially of crystalline Form A. In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) wherein the compound of Formula (I) consists of crystalline Form A.
[0211] In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) wherein the crystalline form is Form C, Form D, Form F, Form G, Form H or Form I; and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) wherein the crystalline form is pure or substantially pure Form C, Form D, Form F, Form G, Form H or Form I; and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) wherein the compound of Formula (I) consists essentially of crystalline Form C, Form D, Form F, Form G, Form H or Form I. In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I) wherein the compound of Formula (I) consists of crystalline Form C, Form D, Form F, Form G, Form H or Form I.
[0212] When it is stated herein that the specification relates to a crystalline form of a compound of Formula (I), the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, yet more conveniently greater than about 90% and preferably greater than 95%, 98% or 99% by weight.
[0213] These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration. [0214] Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more compounds of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the non-toxic, pharmaceutically acceptable carriers for any form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
[0215] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these pre-formulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
[0216] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers.
[0217] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells.
[0218] In an embodiment, the pharmaceutical composition is a unit dose form comprising about 10 mg to about 500 mg, such as about 50 mg to 400mg, about 50 mg to about 300 mg, about 100 mg to 300 mg, about 75 mg to about 200 mg, about 75 mg to about 150 mg, about 80 mg to about 120 mg, or about 100 mg of a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A, Form B, Form C, Form D, Form F, Form G, Form H or Form I. Preferably, the crystalline form is Form B. [0219] In an embodiment, the pharmaceutical composition is a unit dose form comprising about 10 mg to about 50 mg, such as about 15 mg to about 40 mg, about 20 mg to about 30 mg, or about 25 mg of a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A, Form B, Form C, Form D, Form F, Form G, Form H or Form I. Preferably, the crystalline form is Form B.
[0220] Advantageously, the disclosure also provides kits for use by a e.g. a consumer in need of HBV infection treatment. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent HBV infection. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening. [0221] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . “etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.
Methods of Treatment [0222] In a further aspect, a method for treating a hepatitis B infection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a crystalline form of a compound of Formula (I). In another embodiment, a method for treating a hepatitis B infection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of a compound of Formula (I), and a pharmaceutically acceptable carrier, diluent or excipient. In one embodiment, the crystalline form is Form A, B, C, D, F, G, H or I. In one embodiment, the crystalline form is Form A or B, conveniently Form B.
[0223] In another aspect, there is provided a crystalline form of a compound of Formula (I) for use in the treatment of HBV infection. In one embodiment, the crystalline form is Form A, B, C, D, F, G, H or I. In one embodiment, the crystalline form is Form A or B, conveniently Form B.
[0224] In another aspect, there is provided a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) , and a pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of HBV infection. In one embodiment, the crystalline form is Form A, B, C, D, F, G, H or I. In one embodiment, the crystalline form is Form A or B, conveniently Form B.
[0225] In another aspect, there is provided the use of a crystalline form of a compound of Formula (I) or the use of a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) for the treatment of hepatitis B infection. In one embodiment, the crystalline form is Form A, B, C, D, F, G, H or I. In one embodiment, the crystalline form is Form A or B, conveniently Form B.
[0226] In another aspect, there is provided the use of a crystalline compound of Formula (I) or the use of a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) in the manufacture of a medicament for treating hepatitis B infection. Suitably, the crystalline form is Form A, B, C, D, F, G, H or I. In one embodiment, the crystalline form is Form A or B, conveniently Form B.
[0227] For use in accordance with this aspect, the appropriate dosage is expected to vary depending on, for example, the mode of administration, and the nature and severity of the infection to be treated as well as the specific infection to be treated and is within the purview of the treating physician. Usually, an indicated administration dose may be in the range between about 0.1 to about 1000 pg/kg body weight. In some cases, the administration dose of the compound may be less than 400 pg/kg body weight. In other cases, the administration dose may be less than 200 pg/kg body weight. In yet other cases, the administration dose may be in the range between about 0.1 to about 100 pg/kg body weight. In an embodiment, the therapeutically effective amount of a crystalline form of a compound of Formula (I) is about 10 mg to about 500 mg, such as about 50 mg to 400mg, about 50 mg to about 300 mg, about 100 mg to 300 mg, about 75 mg to about 200 mg, about 75 mg to about 150 mg, about 80 mg to about 120 mg, or about 100 mg, wherein the crystalline form is Form A, Form B, Form C, Form D, Form F, Form G, Form H or Form I. Preferably, the crystalline form is Form B.
[0228] In a convenient embodiment, the therapeutically effective amount of a crystalline form of a compound of Formula (I) is about 10 mg to about 50 mg, such as about 15 mg to about 40 mg, about 20 mg to about 30 mg, or about 25 mg, wherein the crystalline form is Form A, Form B, Form C, Form D, Form F, Form G, Form H or Form I. Preferably, the crystalline form is Form B. [0229] The dose may be conveniently administered once daily, or in divided doses up to, for example, twice daily or four times a day. In a convenient embodiment, the pharmaceutical composition is administered daily, such as once daily.
[0230] In an embodiment, the subject in need of treatment with a crystalline Compound of Formula (I) according to the present invention or a pharmaceutical composition comprising a crystalline Compound of Formula (I) according to the present invention is treatment naive and HBeAg (hepatitis B e-antigen) positive prior to treatment. In an embodiment, the subject in need of treatment with a crystalline Compound of Formula (I) according to the present invention or a pharmaceutical composition comprising a crystalline Compound of Formula (I) according to the present invention is virologically suppressed and HBeAg positive prior to treatment. In an embodiment, the subject in need of treatment with a crystalline Compound of Formula (I) according to the present invention or a pharmaceutical composition comprising a crystalline Compound of Formula (I) according to the present invention is virologically suppressed and HBeAg negative prior to treatment.
[0231] In an embodiment, the subject in need of treatment with a crystalline Compound of Formula (I) according to the present invention or a pharmaceutical composition comprising a crystalline Compound of Formula (I) according to the present invention is virologically suppressed for at least 1, 2, 3, 4, 5, or 6 months prior to treatment. In an embodiment, the subject in need of treatment with a crystalline Compound of Formula (I) or a pharmaceutical composition comprising a crystalline Compound of Formula (I) according to the present invention is virologically suppressed for at least 1, 2, 3, 4, 5, or 6 months prior to treatment and the subject has previously been treated with a nucleos(t)ide inhibitor. In an embodiment, the subject in need of treatment with a crystalline Compound of Formula (I) or a pharmaceutical composition comprising a crystalline Compound of Formula (I) according to the present invention has previously been treated with a nucleos(t)ide inhibitor for at least 2 months, prior to treatment with a composition of the present invention.
[0232] In an embodiment, the crystalline form of Compound of Formula (I) of the present invention or the pharmaceutical composition comprising the crystalline form of Compound of Formula (I) of the present invention is administered to the subject for a treatment period of at least 12 weeks (such as at least 24 weeks, 28 weeks, 32 weeks, 40 weeks, 12 months, 18 months, 24 months or 36 months). In an alternative embodiment, the crystalline form of Compound of Formula (I) of the present invention or the pharmaceutical composition comprising the crystalline form of Compound of Formula (I) of the present invention is administered to the subject until the subject has a reduction in HBeAg and/or HBsAg (hepatitis B surface antigen). In an embodiment, after at least 12 weeks of daily administration of the crystalline form of Compound of Formula (I) of the present invention or the pharmaceutical composition comprising the crystalline form of Compound of Formula (I) of the present invention, the HBeAg positive subject has sustained loss of <0.11 PEI units/mL. In an embodiment, after at least 12 weeks of daily administration of the crystalline form of Compound of Formula (I) of the present invention or the pharmaceutical composition comprising the crystalline form of Compound of Formula (I) of the present invention, the subject has a reduction of HBsAg to < 100 lU/mL. In an embodiment, after at least 12 weeks of daily administration of the crystalline form of Compound of Formula (I) of the present invention or the pharmaceutical composition comprising the crystalline form of Compound of Formula (I) of the present invention, the subject has a reduction in HBV DNA or HBV RNA.
[0233] A compound of the present disclosure may be administered by any conventional route, in particular: enterally, topically, orally, nasally, e.g., in the form of tablets or capsules, via suppositories, or parenterally, e.g. in the form of injectable solutions or suspensions, for intravenous, intra-muscular, sub-cutaneous, or intra-peritoneal injection. Suitable formulations and pharmaceutical compositions will include those formulated in a conventional manner using one or more physiologically acceptable carriers or excipients, and any of those known and commercially available and currently employed in the clinical setting. Thus, the compounds may be formulated for oral, buccal, topical, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either orally or nasally).
[0234] For oral administration, pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Preparations may also contain buffer salts, flavoring, coloring and sweetening agents as appropriate. Conveniently, the pharmaceutical composition is a tablet.
[0235] A disclosed compound may also be formulated for parenteral administration by injection e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain additives such as suspending, stabilizing and/or dispersing agents. Alternatively, the compound may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Compounds may also be formulated for rectal administration as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
Combinations
[0236] Also contemplated herein are methods that include administering a second active agent both independently and via compositions that include a second active agent. For example, in addition to being infected with HBV, a subject or patient can further have HBV infection-related co-morbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected with HBV. Contemplated herein are disclosed crystalline forms of the Compound of Formula (I) of the present invention or pharmaceutical compositions comprising the crystalline form of the Compound of Formula (I) of the present invention in combination with at least one other agent that has previously been shown to treat these HBV- infection-related conditions.
[0237] In some cases, a disclosed compound may be administered as part of a combination therapy in conjunction with one or more antivirals including nucleoside analogs, interferon a, and other assembly effectors, for instance heteroaryldihydropyrimidines (HAPs) such as methyl 4-(2- chi oro-4-fluorophenyl)-6-methyl-2-(pyri din-2 -yl)-l,4-dihydropyrimidine-5-carboxylate (HAP- 1).
[0238] Therefore, provided herein is a method of treating hepatitis B in a subject in need thereof, the method comprising administering a therapeutically effective amount of a crystalline form of Compound of Formula (I) according to the present invention or a pharmaceutical composition comprising a crystalline form of Compound of Formula (I) according to the present invention, to the subject and co-administering to the subject a therapeutically effective amount of an additional therapeutic agent.
[0239] In an embodiment, the additional therapeutic agent is selected from one or more of the following agents: i. HBV capsid assembly promoters (for example, GLS4, BAY 41-4109, AT- 130, DVR-23 (e.g., as depicted below),
Figure imgf000053_0001
MR-®
NVR 3-778, NVR1221 (by code); and N890 (as depicted below):
Figure imgf000053_0002
ii. Other core protein allosteric modulators (CpAMs) such as those disclosed in the following patent applications hereby incorporated by reference: W02014037480, WO2014184328, W02013006394, WO2014089296, W02014106019, WO2013102655, WO2014184350, WO2014184365, WO2014161888, WO2014131847, WO2014033176, WO2014033167, and W02014033170; iii. Nucleoside analogs interfering with viral polymerase, such as entecavir (Baraclude), Lamivudine, (Epivir-HBV), Telbivudine (Tyzeka, Sebivo), Adefovir dipivoxil (Hepsera), Tenofovir (Viread), Tenofovir alafenamide (Vemlidy), Tenofovir disoproxil fumarate (TDF), Tenofovir alafenamide fumarate (TAF), prodrugs of tenofavir (e.g. AGX-1009), L- FMAU (Clevudine), LB80380 (Besifovir):
Figure imgf000054_0001
and Active Site Polymerase Inhibitor Nucleotides (ASPINs), such as those disclosed in WO20 16099982; iv. Viral entry inhibitors such as Myrcludex B and related lipopeptide derivatives; v. HBsAg secretion inhibitors such as REP 9AC’ and related nucleic acid-based amphipathic polymers, HBF-0529 (PBHBV-001), PBHBV-2-15 as depicted below:
Figure imgf000054_0002
and BM601 as depicted below:
Figure imgf000054_0003
vi. Disruptors of nucleocapsid formation or integrity such as NZ-4/W28F :
Figure imgf000054_0004
vii. cccDNA formation inhibitors such as BSBI-25, CCC-0346, or CCC-0975 (as depicted below):
Figure imgf000054_0005
viii. HBc directed transbodies such as those described in Wang Y, et al, Transbody against hepatitis B virus core protein inhibits hepatitis B virus replication in vitro, Int. Immunopharmacol (2014), located at //dx.doi.org/10.1016/j.intimp.2015.01.028; antiviral core protein mutant (such as Cpl83-V124W and related mutations as described in WO/2013/010069, W02014/074906, each incorporated by reference); ix. Inhibitors of HBx-interactions such as RNAi, antisense and nucleic acid based polymers targeting HBV RNA, e.g., RNAi (for example ALN-HBV, VIR-2218, ARC-520, JNJ- 3989, TKM-HBV, AB-729, ddRNAi), antisense (ISIS-HBV/Bepirovirsen), or nucleic acid based polymer (REP 2139-Ca); x. Immunostimulants such as Interferon alpha 2a (Roferon), Intron A (interferon alpha 2b), Pegasys® (pegylated interferon alpha 2a), Pegylated IFN 2b, IFN lambda la and PEG IFN lambda la, Wellferon, Roferon, Infergen, lymphotoxin beta agonists such as CBE11 and BS1); xi. Non-Interferon Immune enhancers such as Thymosin alpha- 1 (Zadaxin) and Interleukin-7 (CYT107); xii. TLR-7/9 agonists such as GS-9620, CYT003, or Resiquimod; xiii. Cyclophilin Inhibitors such as NVP018, OCB-030, SCY-635, Alisporivir, NIM811 and related cyclosporine analogs; xiv. Vaccines such as GS-4774, TG1050, JNJ-0535, VBI-2601, GSK3528869A, VTP-300, FP- 02.2, CVI-HBV-002, VVX001 and Core antigen vaccine; xv. Second mitochondria-derived activator of caspases (SMAC) mimetics such as birinapant ,or other lAP-antagonists; xvi. Epigenetic modulators such as KMT inhibitors (EZH1/2, G9a, SETD7, Suv39 inhibitors), PRMT inhibitors, HDAC inhibitors, SIRT agonists, HAT inhibitors, WD antagonists (e.g. OICR-9429), PARP inhibitors, APE inhibitors, DNMT inhibitors, LSD1 inhibitors, JMJD HDM inhibitors, and Bromodomain antagonists; xvii. Kinase inhibitors such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, and ATM & ATR kinase inhibitors; xviii. STING Agonists; xix. Agents selected from Ribavirin, N-acetyl cysteine, NOV-205 (BAM205), Nitazoxanide (Alinia), Tizoxanide, SB 9200 Small Molecule Nucleic Acid Hybrid (SMNH), DV-601, Arbidol, and FXR agonists (such as GW 4064 and Fexaramin); xx. Antibodies (such as VIR-3434), therapeutic proteins, gene therapy, and biologies directed against viral components or interacting host proteins.
[0240] In some embodiments, the disclosure provides a method of treating a HBV infection in a patient in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A, B, C, D, F, G, H or I, and one or more other HBV agents each selected from the group consisting of HBV capsid assembly promoters, HBF viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists. In some embodiments, the disclosure provides a method of treating a hepatitis B infection in a patient in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of a compound of Formula (I) wherein the crystalline form is Form A, B, C, D, F, G, H or I, and administering another HBV capsid assembly promoter.
[0241] In some embodiments, the first and second amounts together comprise a pharmaceutically effective amount. The first amount, the second amount, or both may be the same, more, or less than effective amounts of each compound administered as monotherapies. Therapeutically effective amounts of a disclosed compound and antiviral may be co-administered to the subject, i.e., administered to the subject simultaneously or separately, in any given order and by the same or different routes of administration. In some instances, it may be advantageous to initiate administration of a disclosed compound first, for example one or more days or weeks prior to initiation of administration of the antiviral. Moreover, additional drugs may be given in conjunction with the above combination therapy.
[0242] In a convenient embodiment, the method further comprises co-administering to the subject a therapeutically effective amount of a nucleos(t)ide inhibitor. Conveniently, the nucleos(t)ide inhibitor is selected from entecavir, tenofovir, tenofovir alafenamide, and tenofovir disoproxil fumarate. In a convenient embodiment, the nucleos(t)ide inhibitor is administered orally. In a convenient embodiment, the nucleos(t)ide inhibitor is administered daily, such as once daily. [0243] In a convenient embodiment, the method further comprises co-administering to the subject a therapeutically effective amount of pegylated interferon alpha, such as pegylated interferon alpha-2a. In a convenient embodiment, the pegylated interferon alpha is administered by subcutaneous injection. In a convenient embodiment, the pegylated interferon alpha is administered weekly, such as once weekly. In a convenient embodiment, the therapeutically effective amount of the pegylated interferon alpha is about 100 to 300 pg, such as about 180 pg. [0244] In a convenient embodiment, the method further comprises co-administering to the subject a therapeutically effective amount of an siRNA inhibitor of HBV. In a convenient embodiment, the siRNA inhibitor is administered by subcutaneous injection. In a convenient embodiment, the siRNA inhibitor is administered once every 4-12 weeks, such as once every 8 weeks. In a convenient embodiment, the therapeutically effective amount of the siRNA inhibitor is about 20 to 100 mg, such as about 60 mg.
[0245] In a convenient embodiment, the method further comprises co-administering to the subject a therapeutically effective amount of an ASPIN. In a convenient embodiment, the ASPIN is administered orally. In a convenient embodiment, the ASPIN is administered daily, such as once daily. In a convenient embodiment, the therapeutically effective amount of the ASPIN is about 10 to 100 mg, such as about 25 mg or about 50 mg.
[0246] In an embodiment, there is provided a method of treating hepatitis B in a subject in need thereof, the method comprising administering a therapeutically effective amount of crystalline form of the Compound of Formula (I) according to the present invention or a pharmaceutical composition comprising the crystalline form for the Compound of Formula (I) according to the present invention, to the subject and co-administering to the subject a therapeutically effective amount of a nucleos(t)ide inhibitor (such as entecavir); and co-administering to the subject a therapeutically effective amount of pegylated interferon alpha (such as pegylated interferon alpha- 2a).
[0247] In an embodiment, there is provided a method of treating hepatitis B in a subject in need thereof, the method comprising administering a therapeutically effective amount of crystalline form of the Compound of Formula (I) according to the present invention or a pharmaceutical composition comprising the crystalline form for the Compound of Formula (I) according to the present invention, to the subject, and co-administering to the subject a therapeutically effective amount of a nucleos(t)ide inhibitor (such as entecavir); and co-administering to the subject a therapeutically effective amount of an siRNA inhibitor of HBV.
[0248] In an embodiment, there is provided a method of treating hepatitis B in a subject in need thereof, the method comprising administering a therapeutically effective amount of crystalline form of the Compound of Formula (I) according to the present invention or a pharmaceutical composition comprising the crystalline form for the Compound of Formula (I) according to the present invention, to the subject, and co-administering to the subject a therapeutically effective amount of a nucleos(t)ide inhibitor (such as entecavir); and co-administering to the subject a therapeutically effective amount of an ASPIN.
Process to prepare Form B
[0249] In one aspect, there is provided a process to prepare a crystalline form of compound of Formula (I) wherein the crystalline form is Form B.
[0250] In one embodiment, the process to prepare Form B comprises the steps of: a) providing a slurry of Compound of Formula (I) in methanol; b) stirring the mixture from step a) at an elevated temperature; c) cooling the mixture; d) stirring the mixture from step c); e) optionally, filtering the mixture from step d) and/or washing the solids with methanol; and f) optionally, isolating the solids from step e) and drying under vacuum.
[0251] In one embodiment, step a) comprises providing at least about 0.05 kg/kg of Compound of Formula(I) in methanol, such as at least about 0.01 kg/kg, at least about 1 kg/kg, at least about 2 kg/kg, at least about 3 kg/kg, or at least about 4 kg/kg. Suitably, the compound of Formula (I) is provided in methanol at a concentration of about 5 kg/kg.
[0252] In one embodiment, Form I of the Compound of Formula (I) is provided in methanol in step a).
[0253] In one embodiment, Compound of Formula (I) in step a) has been purified by column chromatography.
[0254] In one embodiment, step b) comprises stirring the mixture for at least about 2 hours, such as at least about 4 hours, at least about 6 hours, at least about 8 hours, or at least 10 hours. Suitably, step b) comprises stirring the mixture for between about 7 to about 13 hours, such as between about 8 and about 12 hours.
[0255] In one embodiment, step b) comprises stirring the mixture at an elevated temperature of at least about 50°C, such as at least about 55°C, at least about 60°C, at least about 65°C, at least about 70°C, or at least about 75°C. Suitably, the elevated temperature is between about 55°C and about 75°C, such as between about 60°C and about 70°C. [0256] In one embodiment, step c) comprises cooling the mixture to less than about 40°C, such as less than about 35°C. Suitably, step c) comprises cooling the mixture to between about 25°C and about 35°C.
[0257] In one embodiment, step d) comprises stirring the mixture for at least about 1 hour, such as at least about 2 hours, or at least about 4 hours. Suitably, step d) comprises stirring the mixture for between about 3 to about 9 hours, such as between about 4 and about 8 hours.
[0258] In another embodiment, the process to prepare Form B comprises the steps of: i. providing Compound of Formula (I) in a first solvent at an elevated temperature; ii. cooling the mixture from step i.; iii. optionally, isolating the solids from step ii.; and iv. optionally drying the solids from step iii. under reduced pressure and/or elevated temperature.
[0259] In one embodiment, step i. comprises providing at least about 0.05 mg/mL of Compound of formula (I) in the first solvent, such as such as at least 0.1 mg/mL or at least 0.15 mg/mL.
[0260] In one embodiment, the Compound of Formula (I) has a solubility of at least 0.5 mg/g in the first solvent at 60°C, such as at least 1 mg/mL, at least 2 mg/mL or at least 3 mg/mL.
[0261] In one embodiment, the first solvent comprises ethanol, methanol, water, acetone, isopropyl alcohol, tetrahydrofuran or DMSO, or a mixture thereof.
[0262] In one embodiment, the first solvent comprises methanol, ethanol and water.
[0263] In one embodiment, the first solvent comprises acetone, isopropyl alcohol and water.
[0264] In one embodiment, the first solvent comprises acetone, ethanol and water.
[0265] In one embodiment, the first solvent comprises tetrahydrofuran, ethanol and water.
[0266] In one embodiment, the first solvent comprises ethanol and water.
[0267] In one embodiment, the first solvent comprises ethanol, THF or DMSO, or a mixture thereof.
[0268] In one embodiment, the first solvent comprises ethanol.
[0269] In a preferred embodiment, the first solvent is a mixture of ethanol and DMSO. In one embodiment, the volume ratio of ethanol to DMSO is between about 4: 1 and about 1 :4, such as between about 3 : 1 and about 1 :3, such as between about 3 : 1 and about 1 : 1, such as between about 3 : 1 and about 2: 1. Conveniently, the volume ratio of ethanol to DMSO is about 3 :2.
[0270] In one embodiment, the elevated temperature in step i. is at least 30 °C, such as at least 35 °C or at least 40 °C.
[0271] Conveniently, the elevated temperature in step i. is at least 50 °C, such as at least 55 °C. [0272] In one embodiment, step i. comprises adding Form B of the Compound of Formula (I) to the mixture. In one embodiment, at least 0.001 equivalents of Form B is added.
[0273] In one embodiment, step i. comprises stirring the mixture for at least 30 minutes, such as at least 1 hour.
[0274] In one embodiment, step i. comprises:
I. providing Compound of Formula (I) in a first solvent at a first elevated temperature; and II. cooling the mixture from step II. to a second elevated temperature.
[0275] In one embodiment, step I. comprises providing at least about 0.05 mg/mL of Compound of Formula (I) in the first solvent, such as such as at least 0.1 mg/mL or at least 0.15 mg/mL.
[0276] In one embodiment, the Compound of formula (I) has a solubility of at least 0.5 mg/g in the first solvent at 60°C, such as at least 1 mg/mL, at least 2 mg/mL or at least 3 mg/mL.
[0277] In one embodiment, the first solvent comprises ethanol, methanol, water, acetone, isopropyl alcohol, tetrahydrofuran or DMSO, or a mixture thereof.
[0278] In one embodiment, the first solvent comprises methanol, ethanol and water.
[0279] In one embodiment, the first solvent comprises acetone, isopropyl alcohol and water.
[0280] In one embodiment, the first solvent comprises acetone, ethanol and water.
[0281] In one embodiment, the first solvent comprises tetrahydrofuran, ethanol and water.
[0282] In one embodiment, the first solvent comprises ethanol and water.
[0283] In one embodiment, the first solvent comprises ethanol or DMSO, or a mixture thereof.
[0284] In one embodiment, the first solvent comprises ethanol.
[0285] In one embodiment, the first solvent is a mixture of ethanol and DMSO. In one embodiment, the volume ratio of ethanol to DMSO is between about 4: 1 and about 1 :4, such as between about 3 : 1 and about 1 :3, such as between about 3 : 1 and about 1 :1, such as between about 3 : 1 and about 2: 1. Conveniently, the volume ratio of ethanol to DMSO is about 3 :2.
[0286] In one embodiment, the first elevated temperature is greater than the second elevated temperature.
[0287] In one embodiment, the first elevated temperature is at least 50°C, such as at least 55°C. In one embodiment, the first elevated temperature is between about 55 °C to about 70 °C.
[0288] In one embodiment, the second elevated temperature is at least 30 °C, such as at least 35 °C or 40 °C. In one embodiment, the second elevated temperature is less than 50°C. In one embodiment, the second elevated temperature is between about 40 °C to about 50 °C.
[0289] In one embodiment, step II. comprises adding Form B of the Compound of Formula (I) to the mixture. In one embodiment, at least 0.001 equivalents of Form B is added.
[0290] In one embodiment, step I. comprises stirring the mixture for at least 30 minutes. [0291] In one embodiment, step II. comprises stirring the mixture for at least 30 minutes, such as at least 1 hour.
[0292] In one embodiment, step ii. comprises cooling the mixture to less than 25°C, such as less than 20°C, or such as less than 15°C. In one embodiment, step ii. comprises cooling the mixture to between 8°C and 10°C.
[0293] In one embodiment, step ii. comprises cooling the mixture over a period of at least 1 hour, such as at least 2 hours.
[0294] In one embodiment, the mixture in step ii. is stirred for at least 10 minutes, such as at least 30 minutes. In one embodiment, step ii. further comprises stirring the cooled mixture for at least 1 hour, such as at least 2, 4, 8, 10, 12, 18 or 20 hours.
[0295] In one embodiment, step ii. further comprises adding a second solvent prior to the mixture being cooled. In one embodiment, the second solvent is an anti-solvent. Suitably, the compound of Formula (I) has a solubility of less than 10 mg/mL in the second solvent at 25°C, such as less than 7.5 mg/mL or less than 6 mg/mL. Suitably, the compound of Formula (I) has a solubility of less than 20 mg/mL in the second solvent at 50°C, such as less than 15 mg/mL. Suitably, Form B of the compound of Formula (I) has a solubility of less than 10 mg/mL in the second solvent at 25°C, such as less than 7.5 mg/mL or less than 6 mg/mL. Suitably, Form B of the compound of Formula (I) has a solubility of less than 20 mg/mL in the second solvent at 50°C, such as less than 15 mg/mL.
[0296] In one embodiment, the second solvent comprises ethanol, methanol or isopropyl alcohol. [0297] In one embodiment, the second solvent comprises ethanol.
[0298] In one embodiment, the second solvent is added to the mixture from step i. over a period of at least 1 hour, such as at least 2 hours.
[0299] In one embodiment, at least 10 volumes of the second solvent is added to the mixture in step ii.
[0300] In one embodiment, the solids are isolated in step iii. using a centrifuge.
[0301] In one embodiment, the solids in step iv. are dried at an elevated temperature of between about 50°C to about 60°C.
[0302] In another aspect, there is provided a crystalline compound of Formula (I) obtainable by the processes herein described, wherein the crystalline form is Form B.
EXAMPLES
The following abbreviations are used within this specification: API: Active pharmaceutical ingredient aw: Water activity
DMSO: Dimethyl sulfoxide
DSC: Differential scanning calorimetry eq: Equivalents
EtOAc: Ethyl acetate
EV : Evaporation
FT: Fourier Transform h: Hours
IPC: In process control
MeOH: Methanol
NMT : Not more than
PLM: Polarized light microscopy
PXRD: Powder X-ray diffraction
RC: Rapid cooling
RT : Room temperature (~22°C)
SU: Scale-up
TC: Temperature cycling
TGA: Thermogravimetric analysis
TGA-IR: Thermogravimetric analysis interfaced with infrared spectrophotometer
THF: Tetrahydrofuran vol: Volume
EXAMPLE 1: CRYSTAL FORMS OF COMPOUND OF FORMULA (I)
A. Instrumentation and Methods: [0303] FT-Raman Spectroscopy: Raman spectra were collected with a Nicolet NXR9650 or NXR 960 spectrometer (Thermo Electron) equipped with 1064 nm Nd:YVO4 excitation laser, InGaAs and liquid-N2 cooled Ge detectors, and a MicroStage. All spectra were acquired at 4 cm'1 resolution, 64 scans, using Happ-Genzel apodization function and 2-level zero-filling.
[0304] Polarized-Light Microscopy (PLM): The photomicrographs were collected using Olympus BX60 polarized-light microscope equipped with Olympus DP70 camera or equivalent.
[0305] Powder X-Ray Diffraction (PXRD) PANalytical: PXRD diffractograms were acquired on PANalytical X’Pert Pro diffractometer using Ni-filtered Cu Ka (X = 1.5406 A) (45 kV/40 mA) radiation and a step size of 0.03° 20 and X'celeratorTM RTMS (Real Time MultiStrip) detector. Configuration on the incidental beam side: variable divergence slits (10 mm irradiated length), 0.04 rad Soller slits, fixed anti-scatter slit (0.50°), and 10 mm beam mask. Configuration on the diffracted beam side: variable anti-scatter slit (10 mm observed length) and 0.04 rad Soller slit. Samples were mounted flat on zero-background Si wafers.
[0306] Powder X-Ray Diffraction (PXRD) Bruker: PXRD diffractograms were acquired on a Bruker D8 Advance system (SN:2631) using Cu Ka (X = 1.5406 A) (40 kV/40 mA) radiation and a step size of 0.03° 20 and LynxEye detector. Configuration on the incident beam side: Goebel mirror, mirror exit slit (0.2 mm), 2.5 deg Soller slits, beam knife. Configuration on the diffracted beam side: anti-scatter slit (8 mm) and 2.5 deg. Soller slit. Samples were mounted flat on zerobackground Si wafers.
[0307] Differential Scanning Calorimetry (DSC): DSC was conducted with a TA Instruments QI 00 or Q2000 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system under 40 mL/min N2 purge. DSC thermograms of samples from initial crystallization experiments were obtained at 15 °C/min in crimped Al pans, unless noted otherwise. DSC thermograms of input and scaled-up materials were obtained at 10 °C/min in crimped Al pans, unless noted otherwise.
[0308] Thermogravimetric Analysis (TGA): TGA thermograms were obtained with a TA Instruments Q50 thermogravimetric analyzer under 40 mL/min N2 purge in Pt or Al pans. TGA thermograms of initial crystallization experiments samples were obtained at 15 °C/min, unless noted otherwise. TGA thermograms of input and scaled-up material were obtained at 10 °C/min, unless noted otherwise.
[0309] Thermogravimetric Analysis with IR Off-Gas Detection (TGA-IR): TGA-IR was conducted with a TA Instruments Q5000 thermogravimetric analyzer interfaced to a Nicolet 6700 FT-IR spectrometer (Thermo Electron) equipped with an external TGAIR module with a gas flow cell and DTGS detector. TGA was conducted with 25 mL/min N2 flow and heating rate of 15 °C/min in Pt or Al pans. IR spectra were collected at 4 cm'1 resolution and 32 scans at each time point.
[0310] Dynamic Vapor Sorption (DVS): Moisture-sorption was obtained on a Surface Measurement Systems DVS-Advantage (SN: P22F00054) using the following sorption/desorption isotherms at 25 °C:
• Adsorption Cycle 1 : 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, and 90 %RH
• Desorption Cycle 1 : 90%, 80%, 75%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, and 0 %R
No drying step prior to Adsorption Cycle 1 was performed. Equilibrium masses were determined at each relative humidity condition. Equilibrium conditions criteria of 0.005% weight change, per 15 minutes interval with maximum equilibrium time of 240 minutes was utilized
B. Characterization of Input Material (Compound of Formula (I))
[0311] The characterization data of a sample of input crystalline material are presented in Figures 1-4. The input material was determined to be crystalline by PXRD and PLM analyses (see Figures
2 and 4). DSC analysis (note: the temperatures of transitions recorded via DSC analysis are reported as onset values) showed a broad dehydration endotherm at 89.3 °C, immediately followed by an exotherm at 119.7°C, followed by a small, shallow exotherm at 160.0 °C, and a sharp melting/ decomposition endotherm at 210.8 °C as shown in Figure 5. TGA-IR analysis in Figure
3 showed 4.8 % weight loss of water between 25-100°C, indicating a hydrated form. The input material was determined to be a mixture of forms designated Forms A and G.
Visual Solubility Assessment on Input Material
[0312] Solubility of the input crystalline material (Mixture of forms A and G) was assessed in 14 solvents at RT and 40°C. The input material exhibits low-to moderate solubility (400 mg/mL). The solubility data are summarized in Table 17. Table 17 - Solubility Estimates of Input material at RT and 40 °C
Figure imgf000065_0001
C. Methods to prepare Forms A, B, C, D, E, F, G, H and I.
A series of crystallization experiments were performed using the input material as characterized above (mixture of Forms A and G). The experiments performed were:
• Temperature-cycled ripening of API slurries between 40 °C - 5 °C (1 hour at each temperature) for three days (TC)
• Rapidly cooling clarified saturated solutions of API from 40 °C to 4 °C and holding at 4 °C for up to 4 days (RC) • Slow evaporation (loosened vial caps) of API solutions at RT for four days followed by fast evaporation (removed caps) for up to 20 days (EV).
Sample Analysis
[0313] All crystalline outputs were isolated and analyzed by FT-Raman spectroscopy. The samples were then sorted into groups based on FT-Raman spectral match. Representative samples from each of the groups were further analyzed by additional techniques as appropriate and as sample quantity permitted (PXRD, DSC, TGA, TGAIR, PLM). These data were used to support the group assignment shown in Table 18.
Table 18 - Summary of crystallization experiments and results
Figure imgf000065_0002
Figure imgf000066_0001
Figure imgf000067_0001
1 Insufficient solids for analysis
2 Solution after 24 days of evaporation
D. Characterization of Crystal Forms of Compound of Formula (I)
[0314] Characterization data and more detailed discussion of the forms observed from the crystallization experiments are summarized below. An overlay of the PXRD patterns of Forms A - I, except for transient Form E, is shown in Figure 6.
Form A (Hydrate 1)
[0315] Form A is a hydrate that was obtained from water and many organic/aqueous solvent mixtures. The characterization data for Form A are shown in Figures 7-10. DSC analysis of Form A showed a broad dehydration endotherm at 90.3 °C, immediately followed by an exotherm and at least two small endotherms, followed by a sharp melting/decomposition endotherm at 212.6 °C. TGA-IR analysis in Figure 9 showed 3.0 % weight loss of water (0.8 eq) between 25-129 °C, indicating a hydrated form.
[0316] Two Form A samples exhibited significant variability in water content (Figure 11) and DSC data (Figure 12). The first batch loses 3.0 % water (0.8 eq), while the second batch loses 8.5 % (2.5 eq) water. Despite the variability in thermal data, these Form A samples have very consistent PXRD patterns.
Form B (Non-Solvated)
[0317] Form B is non-solvated and characterization data for Form B are shown in Figures 13-18. DSC analysis of Form B showed a large, sharp endotherm at 194.6 °C followed by an exotherm and a second sharp endotherm at 212.3 °C. TGA analysis of Form B in Figure 15 showed negligible (0.03 %) weight loss between 21-188 °C, indicating a non-solvated form. DVS analysis in Figures 17-18 showed Form B to be non-hygroscopic (<0.1 % moisture increase from 0 to 90 % RH), and PXRD showed no change in form post-DVS analysis.
[0318] PLM shows that Form B is a white crystalline powders consisting of loose agglomeration of needle-like irregular shaped particles (<80 mm) and some large, agglomerated particles, see Figure 16.
[0319] Form B was scaled up to provide material for competitive ripening and water activity studies. The input material (300.7 mg, mixture of Form A and G) was combined with methanol (5.0mL). The suspension was stirred at 40°C for 0.5 h, then seeded with Form B (~1 mg). The suspension was stirred and temperature-cycled from 40 °C - 5 °C for 20 h. The solids were isolated by vacuum filtration and air dried for 1.5 h. The yield was 231.0 mg of Form B.
[0320] The Form B seed was obtained from the temperature-cycled ripening of API slurries between 40 °C - 5 °C ( 1 hour at each temperature) for three days as described above.
[0321] Form B was scaled up to provide material for biorelevant solubility studies. The input material (403. Omg, mixture of Forms A and G) was combined with methanol (6.0 mL). The suspension was stirred at 40°C for 2 h, then seeded with Form B (~1 mg) after 30 m at 40 °C. The suspension was stirred and slow-cooled (0.5 °C/min) to 20 °C, then mixed at 20 °C for 1 h. The solids were isolated by vacuum filtration and air-dried for 2 h. The yield was 325.9 mg (81%) of Form B .
Form C (Solvate Class 1)
[0322] Form C is a class of solvates, determined to be structurally similar by FT-Raman and PXRD analyses. These solvates are deemed isostructural solvates. Isostructural solvates have the same crystal structure but not necessarily the same cell dimensions or chemical composition. Isostructural solvates can exhibit variability in thermal properties and solvent content.
[0323] Figure 19 shows a PXRD overlay for three samples of Form C (1,4-dioxane solvate (top), methyl acetate solvate (middle), and 2-butanone solvate (bottom)).
[0324] The characterization data for Form C 2-butanone solvate are shown in Figures 20-23. DSC analysis of Form C showed a small exotherm immediately followed by a small endotherm at 120.3 °C, a small endotherm at 193.8 °C immediately followed by an exotherm, and a large, sharp melting/decomposition endotherm at 214.4 °C. TGA analysis of Form C in Figure 22 showed 4.7 % weight loss of 2-butanone (0.3 eq) between 80- 134 °C, indicating a solvated form.
[0325] DSC analysis of Form C methyl acetate solvate showed a small exotherm at 119.7 °C, a small endotherm at 193.1 °C immediately followed by an exotherm, and a large, sharp melting/decomposition endotherm at 214.2 °C. TGA analysis showed 3.2 % weight loss of methyl acetate (0.2 eq) between 75-125 °C. The thermal data is shown in Figure 24.
[0326] DSC analysis of Form C 1,4-dioxane solvate showed a small exotherm with onset at 111.4 °C, immediately followed by an endotherm at 112.1 °C, a small endotherm at 194.1 °C immediately followed by an exotherm, and a large, sharp melting/decomposition endotherm at 214.5 °C. TGA analysis showed 7.0 % weight loss of 1,4-dioxane (0.4 eq) between 82-127 °C. The thermal data is shown in Figure 25.
Form D (1,4-Dioxane/Water Solvate) [0327] Form D is a 1,4-dioxane/water solvate. The characterization data for Form D are shown in Figures 26-29. DSC analysis of Form D showed a broad desolvation endotherm at 73.3 °C, an endotherm at 192.6 °C immediately followed by an exotherm, and a large, sharp melting/decomposition endotherm at 213.3 °C. TGA-IR analysis of Form D in Figure 28 showed 10.1 % weight loss of 1,4-dioxane and water between 36-94 °C, indicating a solvated form.
Form E (Unstable Form)
[0328] Form E is an unstable form obtained from two slurry -ripening experiments involving THF/water mixtures. The isolated Form E solids converted to Form A within two days at ambient conditions. FT-Raman was the only analysis conducted for Form E before solid-state form conversion occurred. Figure 30 shows an FT-Raman spectral overlay of Form E initially and after two days at ambient and Form A.
Form F (DMSO/Water Solvate)
[0329] Form F is a DMSO/water solvate. The characterization data for Form F are shown in Figures 31-34. DSC analysis of Form F showed a broad desolvation endotherm at 103.4 °C, a broad, shallow endotherm at 133.4 °C, and a large, sharp melting/decomposition endotherm at 212.3 °C. TGA-IR analysis of Form F in Figure 33 showed 13.1 % weight loss of DMSO and water between 81-132 °C, indicating a solvated form.
Form G (Non-Solvated)
[0330] Form G, is a non-solvated form, was not observed from the crystallization experiments described above but obtained by either heating Form A or the input material (mixture of Forms A and G) to 150 °C (beyond the dehydration endotherm and initial exotherm) and cooling to RT. The characterization data for Form G are shown in Figures 35-38. DSC analysis of Form G showed a small, shallow exotherm at 158.2 °C followed by a sharp melting/decomposition endotherm at 211.7 °C. Form G was found to be stable at ambient conditions for > 11 days. Form G was scaled up by heating the input material (mixture of Forms A and G) to 150 °C to provide material for competitive ripening and water activity studies.
Form H (Non-Solvated)
[0331] Form H, is a non-solvated form, was not observed from the crystallization experiments described above, but obtained by either heating Form A or the input material (mixture of Forms A and G) to 190 °C (beyond the small, second exotherm) and cooling to RT. The characterization data for Form H are shown in Figures 39-42. DSC analysis of Form H showed a single sharp melting/decomposition endotherm at 210.9 °C. Form H was found to be stable at ambient for > 6 days. Form H was scaled up by heating input material (mixture of Forms A and G) to 190 °C to provide material for competitive ripening and water activity studies.
Form I (Hydrate 2) [0332] Form I, a hydrate that may entrap solvent, was obtained from an evaporative experiment.
The characterization data for Form I are shown in Figures 43-46. DSC analysis of Form I showed a small endotherm at 121.3 °C, a sharp endotherm at 165.7 °C, immediately followed by an exotherm, a small exotherm at 189.7 °C and a large, sharp melting/decomposition endotherm at 207.8 °C. TGA-IR analysis of Form I in Figure 45 showed 1.7 % weight loss of water (0.5 eq) between 26-143 °C and 0.6 % weight loss of acetone and water between 143-188 °C. The thermal data suggests that Form I could be a hydrate containing a small amount of trapped acetone. Four attempts to reproduce Form I using the Input material (mixture of Forms A and G), summarized in Table 19, were unsuccessful.
Table 19 - Attempts to Prepare Form I
Figure imgf000070_0001
Forms J and K (Unstable Forms)
[0333] Forms J and K, unstable forms that convert to Form I (Hydrate 2) within one day at ambient conditions, were observed during biorelevant solubility studies on a salt of Compound of Formula (I). The PXRD patterns for Forms J and K are shown in Figures 47 and 48, respectively. E. Competitive Ripening Studies
[0334] To determine their relative stabilities, competitive ripening studies were conducted at 25°C and 60°C between non-solvated Forms B, G and H in methanol, acetonitrile, and THF :EtOAc (1 :5). Seeds of Form I were included in the THF:EtOAc experiments. Form B was determined to be the most stable form after two days mixing at both temperatures in all three solvents.
[0335] Saturated solutions were prepared by combining an excess of Form B with the three solvents and stirring the 25 °C suspensions for 20 h and 60 °C suspensions for 4 h (to minimize evaporation at 60 °C). The suspensions were filtered at either 25 or 60 °C through 0.2 pm PTFE filters into separate vials containing 8-12 mg each of Forms B, G and H. Seeds of Form I were also included in the THF:EtOAc experiments. A portion of each suspension was isolated by vacuum -filtration and analyzed by PXRD after two days. As shown in Table 20 all six experiments showed complete conversion to Form B.
Table 20 - Competitive Ripening Results for Non-Solvated Forms B, G and H (with seeds of I)
Figure imgf000071_0001
F. Water Activity Studies
[0336] Water activity (“aw,” see G.M Wilson, J. Am. Chem. Soc. 86, 1964, 127-133; Bell G. et al Enzyme Microb. Technol., 1997, vol 20, May 1) studies were conducted at 25°C between nonsolvated Forms B, G, and H and hydrated Form A to determine their relative stabilities at aw 0.5, 0.75, and 1.0. Form B was determined to be the most stable form at aw 0.5, and Form A was determined to be the most stable form at aw > 0.75. [0337] Saturated solutions were prepared by combining an excess of Form B with methanol: water (80:20) and methanol: water (53:47), and an excess of input material (mixture of Forms A and G) with water. Each suspension was stirred at 25 °C for 20 h. The suspensions were filtered through 0.45 pm PVDF filters into separate vials containing ~5 mg each of Forms A, B, G, and H. A portion of each suspension was isolated by vacuum-filtration and analyzed by PXRD after two days. The results are summarized in Table 21.
Table 21- Results of Water Activity Studies of Forms A, B, G, and H at 25 °C
Figure imgf000072_0001
EXAMPLE 2: PHYSICOCHEMICAL CHARACTERIZATION OF COMPOUND OF FORMULA (I) FORM B
[0338] The objectives of this study were to further characterize the properties of Compound of Formula (I) Form B including determining the kinetic solubility in biorelevant media, intrinsic dissolution rate, pKa, log D/log P, solution-state stability and solid-state stability. Additional mechanical stress studies of Form B were performed to determine the impact of grinding, compression, milling and wet granulation on the form. The purity and API crystalline state were also evaluated on stability for up to four weeks at 40 °C/75 %RH.
A. Instrumentation and Methods:
[0339] Polarized-Light Microscopy (PLM): The photomicrographs were collected using Olympus BX60 polarized-light microscope equipped with Olympus DP70 camera or equivalent.
[0340] Powder X-Ray Diffraction (PXRD) PANalytical: PXRD diffractograms were acquired on PANalytical X’Pert Pro diffractometer using Nifiltered Cu Ka (k = 1.5406 A) (45 kV/40 mA) radiation and a step size of 0.03° 20 and X'celeratorTM RTMS (Real Time Multi-Strip) detector. Configuration on the incidental beam side: variable divergence slits (10 mm irradiated length), 0.04 rad Soller slits, fixed anti-scatter slit (0.50°), and 10 mm beam mask. Configuration on the diffracted beam side: variable anti-scatter slit (10 mm observed length) and 0.02 rad Soller slit. Samples were mounted flat on zero-background Si wafers.
[0341] High-Performance Liquid Chromatography (HPLC): HPLC analyses were conducted with an Agilent 1260 Infinity system equipped with a G131 IB Quad pump, G1329B Auto sampler, G4212B diode array detector, and Agilent 1290, model G1330B auto sampler thermostat. The stability assessments involved the methods described in [0342] Table 22 to Table 25.
Table 22 - HPLC Method for Stability Assessments
Figure imgf000073_0001
Table 23 - HPLC Method for Solubility Assessment
Figure imgf000073_0002
Table 24 - UPLC Method Parameters for Log P/Log D-Shake/Flask
Figure imgf000074_0001
Table 25 - Method Gradient Parameters for UPLC method of Table 24.
Figure imgf000074_0002
B. Preparation of Compound of Formula (I) Form B
[0343] The preparation of Compound of Formula (I) Form B was performed as follows. The input material (mixture of Forms A and G) was combined with methanol (49.0mL). The suspension was stirred at 40°C for 3 hours, then seeded with Form B after 30 minutes and 2 hours at 40°C. Heating was discontinued after 3 hours, and the flask was allowed to cool to RT (~22°C). The suspension was stirred at RT for 3 days. PXRD of an aliquot indicated the sample was Form
B. The solids were isolated by vacuum filtration and air dried for 3 hours. PXRD indicated the final sample was Form B. The yield was 2720.1 mg (82%).
C. Solubility Assessment
Solubility in Britton Robinson Buffer Media
[0344] The equilibrium solubility of Compound of Formula (I) Form B was determined by loading Form B at ~2.5 mg/mL in 7 aqueous media (0.1N HC1, Britton Robinson buffer (BRB) pH 2, 3, 5, 7, 9 and 11) at room temperature (RT). BRBs (0.1M ionic strength) were purchased commercially from RICCA. The solubility values were determined after the samples were stirred for three days. Results of HPLC analyses indicated the solubility values for Form B were high (300 pg/mL) in 0.1 N HC1 pHl and low (11 - 44 pg/mL) in the pH range from pH 2 to 11 at RT after three days. The final pH of the supernatant samples was also measured. The summary of equilibrium solubility assessments of Form B is shown in Table 26.
[0345] The undissolved material that remained following solubility measurements were analyzed by PXRD to confirm the solid-state form at the final time-point and the results are summarized in Table 26. The undissolved material remained the same form as that of the input material except for the pH 1 residue which was a mixture of Form A hydrate, Form B, and a HC1 salt as shown in Figure 49.
Table 26 - Equilibrium solubility of Form B
Figure imgf000075_0001
[0346] Equilibrium solubility of Form B was also tested in six liquid formulation media containing surfactant and solvent. The equilibrium solubility of Form B was determined by loading API at -10.4 mg/mL in 20% HP-Beta-CD in water and 10% Vitamin E TPGS in water, at -2.5 mg/mL in remaining aqueous media at room temperature (RT). The solubility values were determined after three days. Results of HPLC analyses indicated the solubility values were high, 3.68 and 3.57 mg/mL, in 20% HP-Beta-CD in water and 10% Vitamin E TPGS in water, respectively. Results also indicated the solubility values were low (0.03-0.04 mg/mL) in 10% propylene glycol in water and 10% PEG400 in water. The summary of equilibrium solubility assessments of Form B is shown in Table 27. The undissolved material that remained following solubility measurements was analyzed by PXRD to confirm the solid-state form at the final timepoint. PXRD analysis of all residues were consistent with the input material and confirmed no change in the crystalline form after dissolution test. Table 27 - Equilibrium solubility of Compound of Formula (I) Form B in six formulation relevant media
Figure imgf000076_0001
Solubility in GI Relevant Fluids [0347] The solubility of Compound of Formula (I) Form B was assessed at room temperature at
0.5, 2 and 24 hours in GI relevant media (pH 1.6 FASSGF, pH 6.5 FaSSIF V2 and pH 5.8 FeSSIF V2). The components of biorelevant media are listed in Table 28. FaSSIF, FeSSIF and FaSSGF powders were purchased from Biorelevant.com. The solubility was monitored by HPLC analyses at 0.5, 2 and 24 hours, and results showed that solubility values in FaSSGF media were slightly higher at 24 hours than at 0.5 and 2 hours. Presence of surfactants in fed-state simulated intestinal fluid (FeSSIF) and fasted-state simulated intestinal fluid (FaSSIF) did result in enhanced kinetic solubility in those media indicating a potential positive food effect in oral formulations of Compound of Formula (I) Form B. The summary of solubility in GI relevant fluids are shown in Table 29. The undissolved material that remained following solubility measurements at 24 hours was analyzed by PXRD to confirm the solid-state form. PXRD of the solids from FaSSGF, FaSSIF, and FeSSIF samples were consistent with Form B.
Table 28 - Composition of FaSSGF pH1.6, FaSSIF-V2 pH6.5, FeSSIF-V2 pH5.8
Figure imgf000077_0001
4Table was obtained from Biorelevant.com. The sodium comes from sodium chloride; chloride comes from sodium chloride and hydrochloric acid. Table 29 - Kinetic solubility of Form B Lot 103133-SU-005 in FASSGF pH1.6, FaSSIF V2 pH 6.5 and FeSSIF V2 pH5.8 media.
Figure imgf000078_0001
Determination of Intrinsic Dissolution Rate
[0348] The determination of the intrinsic dissolution rate was performed according to USP Chapter Intrinsic Dissolution in FaSSGF pH 1.6 and FaSSIF V2 pH6.5 solutions. Stationary disks with a diameter of 0.800 cm and a surface area of 0.5 cm2 for Form B were prepared with 3559 Newtons of compression force. The disks were prepared in triplicate and each disk was placed into flat bottom vessels containing 500 mL of FaSSGF pH 1.6 or FaSSIF V2 pH 6.5 media, using a Distek 2100A Dissolution bath, and Distek Circulator/heater (set to 37 °C), with a paddle speed of 100 RPM. Aliquots of the sample (2 mL) were pulled from dissolution media every 15 minutes starting at 30 minutes and then every 30 minutes at 60 minutes up to 180 minutes and analyzed by HPLC after filtration. Examples of intrinsic dissolution profile are presented in Figure 50 and Figure 51. The intrinsic dissolution rate of Form B in FaSSGF pH 1.6 and FaSSIF V2 pH 6.5 with 100 RPM paddle speed was calculated as 1.7 ± 0.0 pg/(min*cm2) and 0.4 ± 0.1 pg/(min*cm2), respectively. Furthermore, with 150 RPM of paddle speed the IDR of Form B in FaSSGF pH 1.6 and FaSSIF V2 pH 6.5 was calculated as 1.9 ± 0.1 pg/(min*cm2) and 0.4 ± 0.1 pg/(min*cm2), separately. There is no significant difference in IDR with different paddle speeds between 100 and 150 RPM as presented in Table 30 and Table 31. To eliminate the low solubility uncertainty at 30, 45, 60 and 90 min time points on the determined IDR values, the IDR diagrams were plotted with the 120, 150, and 180 min data only where the signals are significantly above the blank. The IDR value derived from the 120 - 180 min data was consistent as the IDR values from the plot using all time points. Therefore, the reported IDR values are deemed reliable within the error limits provided. By PXRD, there was no change in the physical form of the residual solids following the experiment. Table 30 - Intrinsic Dissolution Rate with 100 and 150 RPM in FaSSGF pH 1.6
Figure imgf000079_0001
Table 31 - Intrinsic Dissolution Rate with 100 and 150 RPM in FaSSIF V2 pH 6.5
Figure imgf000079_0002
Determination of pKa and Log D / Log P
[0349] The pKa of Compound of Formula (I) was assessed by UV spectral shift method with the Pion PULSE instrument. Compound of Formula (I) solutions utilized a cosolvent system from 30- 47%. Approximately 2 mg of Compound of Formula (I) was dissolved in 0.5 mL of DMSO. A volume of 80 pL of this stock solution was transferred to a 25-mL sampling vial and placed on the PULSE autosampler. Titrations were performed in triplicate from pH 2-11.5 with cosolvent concentrations from 29.6% to 47.4%. The measured pKa was determined by the difference in molar absorptivity between the ionized and unionized API between wavelengths of 280-320nm. The pKa of Compound of Formula (I) in cosolvent-free media was then determined by the extrapolation of the Yasuda-Shedlovsky plot, which was derived from the measured pKa in the presence of a known percentage of cosolvent. The extrapolated pKa in cosolvent-free media was determined to be 2.02 + 0.055 and 10.38 ± 0.192. The higher pKa might have been affected by experimental noise in presence of cosolvent in higher pH range.
[0350] The partition and distribution coefficients were determined through potentiometric titration by first determining the pKa of Compound of Formula (I), which is then used to extrapolate Log P from the potentiometric shift in the presence of octanol. The log P was determined based on the shift of pKa in the presence of octanol and extrapolated Log D at different pH values. The data indicate that the log P of Compound of Formula (I) is 2.24 ± 0.23. However, precipitation was observed in the assay vial after titration and hence the results obtained may be affected by the precipitation. In order to confirm the results obtained using the potentiometric method, avoiding the influence of precipitation, additional experiments were performed using the shake flask method. The Log P and Log D samples were mixed on a shaker overnight. Following shaking, the vials were equilibrated at room temperature for twenty-four hours. The aqueous and octanol layers were vialed neat and both were analyzed using the UPLC method. Log P and Log D were determined using the equation presented in Figure 52. The data suggested that Compound of Formula (I)has log P of 2.1 and the results were similar when compared to those obtained using the potentiometric method (Log P of 2.24 ± 0.23). The difference in the results could be due to the precipitation observed during the potentiometric titrations. However, during the shake flask procedure, there was no precipitation observed. For Log DpH 2 and Log DpH7.4, no precipitation occurred and Log D values were calculated to be 1.6 and 2.2, respectively. Table 32 is the summary of pka, Log P and Log D of Compound of Formula (I). Compound of Formula (I)was calculated to have two pKa species at 2.02 & 10.38 and a Log P value of around 2.2, indicating the molecule is lipophilic and will likely readily permeate.
Table 32 - Summary of pKa and Log P/D
Figure imgf000080_0001
D. Stability Assessment
API Solution-State Stability
[0351] Solution-state stability of the API (Form B) was assessed under the following conditions:
• Light-protected at room temperature, and 40 °C in pH 1 HC1, Britton Robinson buffers (BRB: 0.1 M) at pH 6, and 10 at Initial, 1 day and 7 days
• Oxidative stress with 0.1% hydrogen peroxide in pH 1, BRB pH 6, and 10 at RT (24 hours) protected from light
• 1 x ICH light exposure of samples in pH 1, BRB pH 6, and 10
[0352] For the light-protected samples in pH 1, Britton Robinson buffers (BRB; 0.1 M) at pH 6, and 10 at RT, and 40 °C, a stock solution were prepared at 0.25 mg/mL in 100% acetonitrile. An aliquot of the stock solution (4.0 mL) was transferred into a 10-mL clear volumetric flask, then buffer added to the flask making a final concentration of 0.1 mg/mL. Final solvent composition was 40:60 v/v acetonitrile/buffer. All stability samples were placed in a 40°C oven and in a container at ambient temperature in the lab for up to seven days with light protection. HPLC analysis were performed at Initial, Day 1, and Day 7 timepoints. [0353] All thermal stability samples were stable at both storage conditions after 7 days (total impurities were less than 1%). The results are presented in Table 33.
[0354] Oxidative stress was performed at RT (protected from light) for 24 hours for solution samples in pH 1, BRB pH 6, and pH 10 with 40% acetonitrile as a co-solvent, and 0.1% hydrogen peroxide. An aliquot of 4.0 mL of the stock solution (0.25 mg/mL) was transferred into a 10.0 mL volumetric flask then buffer added to the flask making a final concentration of 0.1 mg/mL. Final solvent composition was 40:60 v/v acetonitrile/buffer for both control sample (without hydrogen peroxide) and oxidative sample (with 0.1% hydrogen peroxide). The volumetric flasks were sealed with a Parafilm. The headspace for the control volumetric flask was purged with nitrogen for several minutes. Both volumetric flasks were stored in a container at ambient temperature for 24 hours. HPLC analyses were performed at Initial, 1 day and 7 days timepoints. The results as summarized in Table 33 indicated that slight degradation (-2.0 - 3.7% area) in pHl and 6 BR buffers and severe degradation in pH 10 BR buffer (-22.8 % area) were observed in the exposed sample, suggesting susceptibility to oxidative degradation.
[0355] Solution photo stability was determined by exposing solutions in pH 1, BRB pH 6, and pH 10 at 0.1 mg/mL with approximately 40% v/v acetonitrile as a co-solvent at 1 x ICH (as defined by ICH Q1B, approximately 7.5 hours at 765 W/m2 which is equivalent to exposure for 1.2 million lux-hours of visible light and >200 W-h/m2 (-72 J/cm2)). The HPLC results for the exposed samples were compared to control samples which were protected from light.
[0356] Results of the solution photo stability assessment indicated samples in pH 1 was stable; sample in BRB pH6 and 10 exposed to 1XICH light were slightly degraded (total impurities were 2.3 and 1.4% respectively).
Table 33 - Summary of Solution State Stability
Figure imgf000082_0001
*: Approximate time from sample preparation to injection time on LC.
**: Time prior to HPLC run start (actual age varies and is > 24 hours)
API Solid-State Photostability
[0357] Stability of the solid API Form B was assessed at an initial time point and after storage at the following conditions for two and four weeks:
• 40°C/75%RH (closed/opened) • 70°C/75%RH (closed/opened)
• Photo-stability 3 X ICH
[0358] Solid stability of Form Bat 40°C/75%RH, 70°C/75%RH and photostability at 3 x ICH condition (22.5 hours at 765 W/m2 with standard filter set) was assessed. The photostability was compared to control samples (protected from light exposure). [0359] Results of the solid-state stability and photostability assessment are summarized in [0360] Table 34. No significant changes were observed in the physical appearance, PXRD, and chemical assays by HPLC for stability samples exposed at both 40°C/75%RH (closed/open) and 70°C/75%RH closed/open conditions for up to 4 weeks.
[0361] For solid state photostability, no significant changes were observed in the physical appearance and impurity profile of Form B exposed to 3xICH light stress. These photostability samples showed no change in the PXRD patterns.
Table 34 - A Summary of Solid-State Stability and Photo Stability Assessment for Compound of Formula (I) Form B
Figure imgf000083_0001
Additional solid-state stability data
[0362] Stability data have been collected on a representative batch (from a GMP manufacture) of Compound of Formula (I), Form B. Form B was stored in a double lined polyethylene bag (twist tied) in a fibre drum at 25 °C/60%RH for 24 months and the accelerated condition of 40 °C/75%RH for 6 months. There was no change in the polymorphic form when analyzed by XRPD during these stability studies.
Mechanical Stress Studies
[0363] Mechanical stress studies of Compound of Formula (I) Form B were performed via ball milling, wet grinding, compaction, and wet granulation simulation. All mechanical stress samples were examined by PXRD, PLM, DSC and TGA. For wet granulation simulation sample, the purity check was performed by HPLC at initial, 2-weeks and 4-weeks storage at 40°/75%RH as well as physical form by PXRD. a. Ball Milling [0364] About 20 mg Compound of Formula (I) Form B was transferred into a stainless-steel milling jar (lOmL), followed by addition of two stainless-steel milling balls (7mm). Form B was ground at 16 Hz for 5 min. Sample fractions were collected at 2 mins and 5 mins for XRPD, PLM and thermal analysis. The ball milling study result indicated no significant pattern changes were observed in PXRD. However, there were some PXRD peak broadening observed in 5 -minute ground samples which may have been due to crystallite size reduction (Figure 53). PLM confirms particle size reduction (Figure 54). No amorphous was detected in dry milled material by PXRD and PLM, and DSC showed no clearly evident glass transition or exothermic crystallization event in dry ball milled material. (Figure 55). A possible very weak Tg was observed for 5-min dry ball milled sample but this could be instrumental artifact. b. Wet Grinding
[0365] About 15-20mg of Form B was transferred into a mortar, followed by addition of pure water to wet the powder to a porridge-like consistency. The mixture was hand ground with a pestle for 5 minutes. About 5mg sample was transferred for PXRD and PLM. Grinding was continued for the rest of the sample in the mortar for additional 5 min. Samples were collected again for PXRD and PLM. The result of wet grinding was similar to dry ball milling. No significant pattern change was observed, although there was a minor change at -15° 2theta for the 10-min wet grinding sample as shown in Figure 56; in PLM the particle size appears reduced by grinding in both 5 and 10 minute samples; the 5min sample appears two habits (one needle-like), but the needle habit is not seen in the 10-min sample as presented in Figure 57. c. Compression
[0366] Two compression samples were prepared with 10 kN and 15 kN force respectively. Two portions of ~60mg of Form B were transferred into separate stainless-steel dies (8mm diameter), followed by placing the stainless-steel punch on top of the powder. A force of lOkN (2248 lb) and 15kN (3372 lb) was applied to generate two tablets with 0.92 mm and 0.87 mm thickness, respectively. Then each sample was examined by PXRD, PLM and thermal as shown in Figures 58-61.
[0367] The results of compression samples indicated there were no pressure induced form changes or generation of amorphous material based on PXRD. The DSC diagram is similar to input API. It is possible that very weak Tg exist (or instrumental artifact) for 15 kN compaction sample. d. Wet Granulation Simulation - 80% of Compound of Formula (I) Form B+20% of
10% HPMCE5 [0368] To prepare 10% (w/v) HPMC in water HPMC (1 g) was transferred into a lOmL volumetric flask followed by addition of ~9 mL of pure water and sonicated for 10 minutes with heat on. Water was added to 10 mL and mixed well to obtain a foamy milk-looking suspension. After standing, the foam was on top (about 1 mL) and the lower portion was clear and viscous. The foam disappeared overnight on the bench. Then 10% HPMC (E5) solution was gradually added to Compound of Formula (I) Form B and triturated in a mortar/pestle for 2 minutes until a uniform mixture was obtained. The final drug loading was 80% of Compound of Formula (I) Form B + 20 % of 10 % HPMC (E5) (Wt/Wt). The wet granules were dried over night at ~45°C in an oven. The purity and the XRPD for the dried granules at initial (upon drying), 2-week and 4-week open storage at 40 °C/75%RH were obtained.
[0369] Results of wet granulation simulation is summarized in Table 35. No significant changes were observed in the physical appearance, PXRD, and chemical assays by HPLC for wet granulation simulation stability samples exposed at 40 °C/75 %RH (open) condition for up to 4 weeks.
Table 35 - A Summary of Wet Granulation Simulation Assessment for Compound of Formula (I)
Figure imgf000085_0001
E. Excipient Compatibility Assessment
[0370] Phase compatibility screening was intended to collect preliminary data on the stability of Compound of Formula (I) Form B in the presence of excipients. Three sets of ten binary samples were prepared, for initial, two week and 4 week time points, either as 1 : 1 or 1 : 10 mixture of Compound of Formula (I) Form B and excipient. Each binary mixture was vortexed as dry blends for one minute and then stirred vigorously with spatula to achieve the intimate blending of the components. The binary mixtures, along with excipient placebos were set up in sealed containers and stored at 40 °C for up to four weeks. All samples were analyzed at initial, two weeks and four- weeks time points by HPLC and PXRD.
No significant degradation was observed in all blend stability samples at 40°C/closed for up to 4 weeks. No physical form changes were observed in all compatibility samples as well.
EXAMPLE 3 - PREPARATION OF COMPOUND OF FORMULA (I) FORM B [0371] Compound of Formula (I) Form B can be prepared as follows:
Compound of Formula (I) was synthesized according to the synthetic procedures outlined in WO 2020/086533. After reaction completion and work-up, the crude Compound of Formula (I) was a solution in 2-methyl-THF. The solvent was removed in vacuo, and the crude product was preadsorbed on to silica gel and loaded onto a silica gel column. The column was eluted starting with THF:n-heptane 1 : 1.5 v/v and subsequently the polarity of the solvent composition was increased. The product-containing fractions were combined, and the solvent was removed in vacuo. The material isolated from the column chromatography was dissolved in THF and the solution was concentrated to 2-5 relative volumes. To the THF concentrate was added n-heptane (~3 relative volumes) and the resultant mixture was concentrated at <50 °C to 2-5 relative volumes. This n- heptane solvent swap was repeated twice. The resultant solids were filtered and washed with n- heptane to yield Form-I (purity 97.84%). MeOH (5 relative volumes) was added to the solids and the mixture was stirred for 8-12 hours at 60-70 °C. The batch temperature was adjusted to 25-35 °C and stirring was continued for 4-8 hours. The solids were then filtered and washed with MeOH, and the product was dried under vacuum at 50-60 °C for 10-12 hours to yield Compound of Formula (I) as Form-B (purity 99.10%).
[0372] Particle size analysis was performed on the isolated material and the material after milling using the following methodology.
A Malvern Mastersizer 3000 with Hydro EV was used.
0.2 g of the sample was weighted into a 100 mL beaker, 2 mL ultrapure water and 5 drops of Tween 80 were added, stir and wet the sample with a glass rod, then add ultrapure water to 20 mL, stir until the sample is evenly dispersed.
Table 36 - Particle size distribution analysis parameters
4, TEST CONDITION
Figure imgf000087_0001
The results are presented in Table 37.
Table 37 - Particle size distribution analysis performed on Form B after isolation. These values are a mean of 3 measurements per method.
Figure imgf000087_0002
EXAMPLE 4 - LARGE SCALE PREPARATION OF COMPOUND OF FORMULA (I) FORM B
[0373] Approximately 20 kg of Compound of Formula (I) Form B can be prepared as follows:
1. To pneumatic mixing tank 1 (500 L, SS3 16L) was charged THF (588 L, 32.3x, 36.3 volumes) followed by 5-Amino-N-(3-chloro-4-fluorophenyl)-3-((3aS, 5S,6aR)-5- hydroxy-5-((methylsulfonyl)methyl)-l-3a,4,5,6,6a-hexahydropentalen-2-yl)-l-methyl- lH-pyrazole-4 -carb oxami de (16. kg, l.Ox, 1.0 eq). The mixture was stirred for 10 to 30 minutes. The solution was transferred to reactor 1 (9000 L, SS316L). The vessel was rinsed with THF (364 L, 20x, 22.5 volumes). The rinse was transferred to reactor 1. The reactor was degassed. 2. To catalyst preparation tank 1 (120 L, SS304L) was charged 5% Pt/C(3.2 kg, 0.20x, 0.024 eq). The tank was degassed. To the tank was charged THF (109.2 L, 6. Ox, 6.7 volumes). The suspension was transferred to reactor 1. The catalyst tank was rinsed with THF (36.4 L, 2. Ox, 2.2 volumes). The rinse was transferred to reactor 1. The reactor was degassed.
3. Reactor 1 was filled with hydrogen gas and evacuated. The fill and evacuation sequence was repeated. The reactor was filled with hydrogen gas (0.0 to 0.2 MPa). The process temperature was adjusted (5 °C to 25 °C, target 10 °C). The reaction mixture was stirred at that temperature until completion (20 to 25 hours). IPC: NMT 0.30% 5-Amino-N-(3- chloro-4-fluorophenyl)-3-((3aS, 5S,6aR)-5-hydroxy-5-((methylsulfonyl)methyl)-l- 3a,4,5,6,6a-hexahydropentalen-2-yl)-l-methyl-lH-pyrazole-4-carboxamide.
4. The mixture was filtered through filter Nutsche filter (DN600, SS316L) and polish filter (10 inch, SS316L) to storage tanks 1 and 2 (1000 L, SS316L). The reaction vessel was rinsed with THF (112.3 L, 6.2x, 6.9 volumes) and the rinse was filtered to the storage tanks. The filtrate was tested for purity and assay.
5. The combined filtrates were transferred to reactor 2 (1000 L, GLSS) (the filtrates were added in portions to allow for distillation). The filtrate was concentrated at jacket temperature of NMT 50 °C and -70 to -90 kPa until 3 to 4 volumes remained.
6. EtOH (410.3 L, 12.8 volumes) was charged to reactor 2. The mixture was concentrated at jacket temperature NMT 50 °C and pressure -80 to -95 kPa until 3 to 4 volumes remained. The dilution and distillation sequence was repeated.
7. To reactor 2 was charged EtOH (324.0 L, 10.0 volumes). The mixture was sampled to determine the EtOH/THF ratio. The process temperature was adjusted (55 °C to 65 °C) and the slurry was stirred for 2 to 3 hours. The process temperature was adjusted (20 °C to 25 °C) at a cooling rate of approximately 5 °C to 10 °C per hour. The mixture was stirred for 12 hours (the mother liquor was assayed every 3 hours).
8. The mixture was filtered through Nutsche filter (DN800, SS-Halar). The filter cake was washed with EtOH (82.3 L, 2.5 volumes). The wet cake (37.1 kg) was tested for purity.
9. The wet cake was transferred to a stainless steel tray dryer and dried at 45 °C to 55 °C and pressure NMT -80 kPa until the Loss on drying was NMT 7.0% (drying time approximately 17 hours). The dried material was tested for residual Pt (Report). The dried material (24.1 kg) was stored in double PE bags.
10. To reactor 3 (300 L, Hastelloy) was charged crude compound of Formula (I) (from step 9.) (24.1 kg, l .Ox). To reactor 3 was charged DMSO (33.7 L, 1.5x, 1.4 volumes) followed by EtOH (50.6 L, 1.6x, 2.1 volumes). The process temperature was adjusted (58 °C to 68 C). The solution was transferred to pre-heated (58 °C to 68 °C) reactor 4 (2000 L, GLSS) (the solution was filtered through a 0.22 pm filter during the transfer from reactor 3 to reactor 4). To reactor 3 was charged DMSO (4.8 L, 0.20x, 0.2 volumes) followed by EtOH (7.3 L, 0.24x, 0.3 volumes). The rinse solvent was also transferred to reactor 4. The process temperature was adjusted (58 °C to 68 °C). The mixture was stirred for 30 - 60 minutes. The process temperature was adjusted (43 °C to 48 °C) over 2 to 3 hours (5 °C to 10 °C per hour). The mixture was seeded with Compound of Formula (I) Form B (0.24 kg, O.Olx). The mixture was stirred for 1 to 2 hours. To the mixture was added EtOH (520.9 L, 17. lx, 21.6 volumes) over 4 to 6 hours. The mixture was stirred for 1 to 2 hours. The mixture was sampled, and the crystallized product was tested for purity and crystalline form. The process temperature was adjusted (8 °C to 10 °C) over approximately 4 hours. The mixture was stirred for 24 hours. The mother liquor was assayed every 3 hours. After 24 hours the mixture was sampled and the solid was tested for purity and crystalline form. The solid was collected in centrifuge (SS-Halar). The solid was washed with EtOH (48.2 L, 1.6x, 2.0 volumes). The crystallized wet cake (23.2 kg) was tested for LOD (loss on drying), impurities, residual Pd (NMT 100 ppm), residual Pt (NMT 100 ppm), and crystal form (Form B). The wet cake was transferred to dryer 1 (GL) and then dried at 50 °C to 60 °C and NMT - 80 kPa for 17 hours until residual EtOH and DMSO met the limits (NMT 5000 ppm EtOH, NMT 5000 ppm DMSO). The dried material was also tested for crystalline form (Form B). The dried Compound of Formula (I) Form B (21.7 kg) was sieved, packaged into double PE bags inside a fiber drum (570 mm x 380 mm), and stored at NMT 25 °C.

Claims

88 CLAIMS:
1. A crystalline form of a compound of Formula (I):
Figure imgf000090_0001
Formula (I) wherein the crystalline form is Form B and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (A = 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.2°29; b) a Raman spectrum comprising at least one or two specific peaks selected from the peaks at wavenumbers of 770 and 1614 cm'1 ± 2 cm'1; and c) a DSC thermogram comprising an endothermic event with an onset temperature of 195°C ± 2°C.
2. The crystalline form of claim 1 wherein the form is characterized by: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (X = 1.5406 A) comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.2°29; and b) a Raman spectrum comprising at least one or two specific peaks selected from the peaks at wavenumbers of 770 and 1614 cm'1 ± 2 cm'1.
3. The crystalline form of any preceding claim wherein the form is characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising the peaks at 2-theta values of 13.2, 16.4 and 19.3°29 ± 0.2°29 and further comprising at least one, two, three, four, or five specific peaks selected from the peaks 9.9, 14.6, 15.1, 19.7 and 22.2°29 ± 0.2°29.
4. The crystalline form of any preceding claim wherein the form is characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising the peaks at 2-theta values of 9.9, 13.2, 14.6, 15.1, 16.4, 19.3, 19.7 and 22.2°29 ± 0.2°29. 89
5. The crystalline form of any preceding claim wherein the form is characterized by an XRPD measured using Cu Ka (X = 1.5406 A) radiation comprising at least two, five, ten, fifteen, twenty or twenty -five further peaks selected from the group consisting of the peaks in Table 1 in °20 ± 0.2°29.
6. The crystalline form of any preceding claim wherein the form is characterized by a powder X-Ray diffraction pattern measured Cu Ka (X = 1.5406 A) radiation substantially the same as shown in Figure 14.
7. The crystalline form of any preceding claim wherein the form is characterized by a Raman spectrum comprising peaks at the wavenumbers of 770 and 1614 cm'1 ± 2 cm'1.
8. The crystalline form of any preceding claim wherein the form is characterized by a Raman spectrum comprising peaks at the wavenumbers of 770 and 1614 cm'1 ± 1 cm'1.
9. The crystalline form of any preceding claim wherein the form is characterized by a Raman spectrum comprising at least two, five, ten, fifteen, twenty or twenty -five further peaks selected from the group consisting of the peaks in Table 2 in cm'1 ± 2 cm'1.
10. The crystalline form of any preceding claim wherein the form is characterized by a Raman spectrum substantially the same as shown in Figure 13.
11. The crystalline form of any preceding claim wherein the form is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 213°C ± 2°C.
12. The crystalline form of claim 11 wherein the form is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 195°C ± 2°C and an endothermic event with an onset temperature of 213°C ± 2°C.
13. The crystalline form of claim 12 wherein the form is characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 195°C ± 1°C and an endothermic event with an onset temperature of 213°C ± 1°C.
14. The crystalline form of any preceding claim wherein the form is characterized by a DSC thermogram substantially the same as Figure 15.
15. The crystalline form of any preceding claim wherein the form is non-hygroscopic.
16. The crystalline form of any preceding claim wherein the form is substantially pure.
17. The crystalline form of any preceding claim wherein the form comprises less than 2% by weight solvent and/or water.
18. A pharmaceutical composition comprising a crystalline form of a compound of Formula
(I):
Figure imgf000092_0001
Formula (I) wherein: the crystalline form is Form B according to any one of claims 1 to 17 and a pharmaceutically acceptable carrier, diluent or excipient.
19. A method of treating Hepatitis B (HBV) infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of a compound of Formula (I), wherein the crystalline form is Form B according to any one of claims 1 to 17 or the pharmaceutical compositions of claim 18.
20. The crystalline form of a compound of Formula (I) according to claims 1 to 17 or the pharmaceutical composition according to claim 18 for use in the treatment of HBV infection.
21. A process to prepare a crystalline compound of Formula (I):
Figure imgf000092_0002
Formula (I) wherein the crystalline form is Form B and the process comprises the steps of: a) providing at least about 0.05 kg/kg of Compound of Formula (I) in methanol; b) stirring the mixture from step a) at an elevated temperature; c) cooling the mixture; d) stirring the mixture from step c); e) optionally, filtering the mixture from step d) and/or washing the solids with methanol; and f) optionally, isolating the solids from step e) and drying under vacuum. 91
22. A crystalline compound of Formula (I):
Figure imgf000093_0001
Formula (I) obtainable by the process according to claim 21.
PCT/IB2022/061999 2021-12-10 2022-12-09 Crystalline forms of a 5-aminopyrazole compound useful for treating hbv WO2023105483A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6482939B1 (en) * 1998-04-07 2002-11-19 Smithkline Beecham Corporation Form vi 5,6-dichloro-2-(isopropylamino)-1-(β-l-ribofuranosyl)-1h-bezimimidazole
WO2021216660A1 (en) * 2020-04-22 2021-10-28 Assembly Biosciences, Inc. 5-membered heteroaryl carboxamide compounds for treatment of hbv

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6482939B1 (en) * 1998-04-07 2002-11-19 Smithkline Beecham Corporation Form vi 5,6-dichloro-2-(isopropylamino)-1-(β-l-ribofuranosyl)-1h-bezimimidazole
WO2021216660A1 (en) * 2020-04-22 2021-10-28 Assembly Biosciences, Inc. 5-membered heteroaryl carboxamide compounds for treatment of hbv

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