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EP-4403223-B1 - CRYSTAL FORMS

EP4403223B1EP 4403223 B1EP4403223 B1EP 4403223B1EP-4403223-B1

Inventors

  • CHEN, SHUANG
  • GATES, BRADLEY D.
  • SHEIKH, AHMAD Y.

Dates

Publication Date
20260513
Application Date
20150605

Claims (20)

  1. A crystalline form of Compound I, wherein said crystalline form is a hydrate of Compound I; and has characteristic peaks in its PXRD pattern at values of two theta (° 2θ) of 8.4, 8.9, 11.1, 12.2, 14.5, 15, 15.9, 17.4, 17.8, and 22.2, when tested using a diffractometer that is operated with a copper anode tube at 40 kV and 30 mA and a germanium monochromator to provide monochromatic Cu-K α radiation with a wavelength of 1.54178 Å, with the respective peak positions being ± 0.2° 2θ.
  2. The crystalline form of claim 1, wherein said crystalline form has characteristic peaks in its PXRD pattern at values of two theta (° 2θ) of 8.4, 8.9, 10.2, 11.1, 12.2, 12.5, 13.2, 13.7, 14.5, 15, 15.5, 15.9, 17.4, 17.8, 19.6, 19.9, 21.1, 22.2, 22.7, and 23.9, with the respective peak positions being ± 0.2° 2θ.
  3. The crystalline form of claim 2, wherein said crystalline form has characteristic peaks in its PXRD pattern at values of two theta (° 2θ) of 6.7, 8.4, 8.9, 9.9, 10.2, 11.1, 12.2, 12.5, 13.2, 13.7, 14.5, 15, 15.5, 15.9, 17.4, 17.8, 18.1, 18.9, 19, 19.6, 19.9, 21.1, 21.8, 22.2, 22.7, 22.8, 23.2, 23.9, 24.6, and 25.1, with the respective peak positions being ± 0.2° 2θ.
  4. A crystalline form of Compound I, wherein said crystalline form is a trimethanol solvate of Compound I; and has characteristic peaks in its PXRD pattern at values of two theta (° 2θ) of 8.2, 10.9, 14.1, 14.3, 14.9, 15.5, 15.8, 17.5, 21.8, and 22.2, when tested using a diffractometer that is operated with a copper anode tube at 40 kV and 30 mA and a germanium monochromator to provide monochromatic Cu-K α radiation with a wavelength of 1.54178 Å, with the respective peak positions being ± 0.2° 2θ.
  5. The crystalline form of claim 4, wherein said crystalline form has characteristic peaks in its PXRD pattern at values of two theta (° 2θ) of 8.2, 8.7, 10.9, 14.1, 14.3, 14.6, 14.9, 15.5, 15.8, 17.3, 17.5, 18.7, 19.7, 20.7, 21.4, 21.8, 22.2, 22.8, 23.5, and 23.7 with the respective peak positions being ± 0.2° 2θ.
  6. The crystalline form of claim 5, wherein said crystalline form has characteristic peaks in its PXRD pattern at values of two theta (° 2θ) of 6.4, 8.2, 8.7, 10.1, 10.9, 12, 12.3, 13, 13.4, 14.1, 14.3, 14.6, 14.9, 15.2, 15.5, 15.8, 17.3, 17.5, 18, 18.7, 19.4, 19.7, 20.2, 20.7, 20.9, 21.4, 21.8, 22.2, 22.8, 23.1, 23.5, 23.7, 24.2, 25, 25.4, 26.5, and 26.8 with the respective peak positions being ± 0.2° 2θ.
  7. A crystalline form of Compound I, wherein said crystalline form is a Dimethanol monohydrate of Compound I; and has characteristic peaks in its PXRD pattern at values of two theta (° 2θ) of 8.4, 8.8, 11.1, 14.4, 15, 15.8, 17.4, 17.7, 22.2, and 23.8, when tested using a diffractometer that is operated with a copper anode tube at 40 kV and 30 mA and a germanium monochromator to provide monochromatic Cu-K α radiation with a wavelength of 1.54178 Å, with the respective peak positions being ± 0.2° 2θ.
  8. The crystalline form of claim 7, wherein said crystalline form has characteristic peaks in its PXRD pattern at values of two theta (° 2θ) of 8.4, 8.8, 10.2, 11.1, 12.2, 13.2, 13.6, 14.4, 15, 15.4, 15.8, 17.4, 17.7, 18.8, 19.8, 21, 22.2, 22.7, 23.2, and 23.8 with the respective peak positions being ± 0.2° 2θ.
  9. The crystalline form of claim 8, wherein said crystalline form has characteristic peaks in its PXRD pattern at values of two theta (° 2θ) of 6.6, 8.4, 8.8, 9.8, 10.2, 11.1, 12.2, 12.4, 13.2, 13.6, 14.4, 15, 15.4, 15.8, 17.4, 17.7, 18.1, 18.8, 19.5, 19.8, 20.7, 21, 21.7, 22.2, 22.7, 23.2, 23.8, 24.5, 25, 26.8, and 27.4 with the respective peak positions being ± 0.2° 2θ.
  10. A crystalline form of Compound I, wherein said crystalline form is a Desolvate of Compound I; and has characteristic peaks in its PXRD pattern at values of two theta (° 2θ) of 8.4, 9.1, 11.2, 14.5, 15.1, 15.6, 16, 16.3, 17.5, and 17.9, when tested using a diffractometer that is operated with a copper anode tube at 40 kV and 30 mA and a germanium monochromator to provide monochromatic Cu-K α radiation with a wavelength of 1.54178 Å, with the respective peak positions being ± 0.2° 2θ.
  11. The crystalline form of claim 10, wherein said crystalline form has characteristic peaks in its PXRD pattern at values of two theta (° 2θ) of 8.4, 9.1, 10.2, 11.2, 12.3, 13.3, 14.5, 15.1, 15.6, 16, 16.3, 17, 17.5, 17.9, 18.2, 19, 19.4, 20, 21.2, and 24, with the respective peak positions being ± 0.2° 2θ.
  12. The crystalline form of claim 11, wherein said crystalline form has characteristic peaks in its PXRD pattern at values of two theta (° 2θ) of 6.7, 8.4, 9.1, 9.6, 9.9, 10.2, 11.2, 12.3, 13.3, 13.7, 14.5, 15.1, 15.6, 16, 16.3, 17, 17.5, 17.9, 18.2, 19, 19.4, 20, 20.9, 21.2, 21.9, 22.4, 22.8, 23.3, 24, 24.6, 25.1, 25.6, 27, and 27.8, with the respective peak positions being ± 0.2° 2θ.
  13. A crystalline form of Compound I according to any of claims 1 to 12, wherein said crystalline form has characteristic peaks in its PXRD pattern as described in any one of Figures 1-4, when tested using a diffractometer that is operated with a copper anode tube at 40 kV and 30 mA and a germanium monochromator to provide monochromatic Cu-K α radiation with a wavelength of 1.54178 Å.
  14. A composition, comprising Compound I in a crystalline form according to any one of claims 1-13.
  15. A process for making a pharmaceutical composition comprising Compound I, comprising dissolving a crystalline form according to any one of claims 1-13.
  16. The process of claim 15, comprising dissolving the crystalline form in a volatile solvent, thereby forming a solution.
  17. The process of claim 16, wherein the solution further comprises an excipient.
  18. The process of claim 16 or 17, wherein the solution further comprises a pharmaceutically acceptable surfactant.
  19. The process of claim 17 or 18, further comprising spray drying or freeze drying the solution to remove the solvent, thereby forming a solid dispersion comprising Compound I and the excipient.
  20. The process of claim 15, comprising dissolving the crystalline form in a hydrophilic polymer excipient in a molten or rubbery state, thereby forming a solution or melt.

Description

FIELD OF THE INVENTION The present invention relates to crystalline polymorphs of Compound I, pharmaceutical compositions comprising the same, and methods of using the same to prepare pharmaceutical compositions. BACKGROUND The hepatitis C virus (HCV) is an RNA virus belonging to the Hepacivirus genus in the Flaviviridae family. The enveloped HCV virion contains a positive stranded RNA genome encoding all known virus-specific proteins in a single, uninterrupted, open reading frame. The open reading frame comprises approximately 9500 nucleotides and encodes a single large polyprotein of about 3000 amino acids. The polyprotein comprises a core protein, envelope proteins E1 and E2, a membrane bound protein p7, and the non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B. HCV infection is associated with progressive liver pathology, including cirrhosis and hepatocellular carcinoma. Chronic hepatitis C may be treated with peginterferon-alpha in combination with ribavirin. Substantial limitations to efficacy and tolerability remain as many users suffer from side effects, and viral elimination from the body is often inadequate. Therefore, there is a need for new drugs to treat HCV infection. BRIEF DESCRIPTION OF THE DRAWINGS The drawings are provided for illustration, not limitation. Figure 1 shows experimental PXRD pattern of crystalline Form I of Compound I.Figure 2 depicts experimental PXRD pattern of Compound I trimethanol solvate.Figure 3 describes experimental PXRD of Compound I dimethanol monohydrate.Figure 4 shows experimental PXRD of Compound I desolvate. DETAILED DESCRIPTION The present invention features crystalline polymorphs of Compound I ( ). Compound 1 is a potent HCV protease inhibitor and is described in U.S. Patent Application Publication No. 2012/0070416. A crystalline form of Compound I can be used to modulate/improve the physicochemical properties of the compound, including but not limited to solid state properties (e.g., crystallinity, hygroscopicity, melting point, or hydration), pharmaceutical properties (e.g., solubility/dissolution rate, stability, or compatibility), as well as crystallization characteristics (e.g., purity, yield, or morphology). In one aspect, the invention features a crystalline form of Compound I which has characteristic peaks in the powder X-ray diffraction (PXRD) pattern as shown in Figure 1. In another aspect, the invention features a crystalline form of Compound I which has characteristic peaks in the powder X-ray diffraction (PXRD) pattern at values of two theta (° 2θ) as shown in Table 1a. The relative intensity, as well as the two theta value, of each peak in Tables 1a, 2a, 3a and 4a, as well as Figures 1-4, may change or shift under certain conditions, although the crystalline form is the same. One of ordinary skill in the art should be able to readily determine whether a given crystalline form is the same crystalline form as described in one of Figures 1-4 or Tables 1a, 2a, 3a and 4a by comparing their PXRD data. In yet another aspect, the invention features a crystalline form of Compound I which has characteristic peaks in the powder X-ray diffraction (PXRD) pattern at values of two theta (° 2θ) of 8.4, 8.9, 11.1, 12.2, 14.5, 15, 15.9, 17.4, 17.8, and 22.2. In yet another aspect, the invention features a crystalline form of Compound I which has characteristic peaks in the powder X-ray diffraction (PXRD) pattern at values of two theta (° 2θ) of 8.4, 8.9, 10.2, 11.1, 12.2, 12.5, 13.2, 13.7, 14.5, 15, 15.5, 15.9, 17.4, 17.8, 19.6, 19.9, 21.1, 22.2, 22.7, and 23.9. In yet another aspect, the invention features a crystalline form of Compound I which has characteristic peaks in the powder X-ray diffraction (PXRD) pattern at values of two theta (° 2θ) of 6.7, 8.4, 8.9, 9.9, 10.2, 11.1, 12.2, 12.5, 13.2, 13.7, 14.5, 15, 15.5, 15.9, 17.4, 17.8, 18.1, 18.9, 19, 19.6, 19.9, 21.1, 21.8, 22.2, 22.7, 22.8, 23.2, 23.9, 24.6, and 25.1. In yet another aspect, the invention features a crystalline form of Compound I which has characteristic peaks in the powder X-ray diffraction (PXRD) pattern as shown in Figure 2. In yet another aspect, the invention features a crystalline form of Compound I which has characteristic peaks in the powder X-ray diffraction (PXRD) pattern at values of two theta (° 2θ) as shown in Table 2a. In yet another aspect, the invention features a crystalline form of Compound I which has characteristic peaks in the powder X-ray diffraction (PXRD) pattern at values of two theta (° 2θ) of 8.2, 10.9, 14.1, 14.3, 14.9, 15.5, 15.8, 17.5, 21.8, and 22.2. In yet another aspect, the invention features a crystalline form of Compound I which has characteristic peaks in the powder X-ray diffraction (PXRD) pattern at values of two theta (° 2θ) of 8.2, 8.7, 10.9, 14.1, 14.3, 14.6, 14.9, 15.5, 15.8, 17.3, 17.5, 18.7, 19.7, 20.7, 21.4, 21.8, 22.2, 22.8, 23.5, and 23.7. In yet another aspect, the invention features a crystalline form of Compound I which has character