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EP-4349403-B1 - MONOHYDRATE AND CRYSTALLINE FORMS OF 6-[(3S,4S)-4-METHYL-1- (PYRIMIDIN-2-YLMETHYL)PYRROLIDIN-3-YL]-3-TETRAHYDROPYRAN-4-YL- 7H-IMID AZO [1,5- A] PYRAZIN-8-ONE

EP4349403B1EP 4349403 B1EP4349403 B1EP 4349403B1EP-4349403-B1

Inventors

  • BUTTAR, Suzanne
  • PITAK, Mateusz
  • PATTERSON, Adam Ross
  • STRATFORD, Samuel Alexander
  • SOVAGO, Ioana
  • XU, JUN
  • ZHOU, PENG
  • WEI, Haojuan
  • DAI, Kuangchu

Dates

Publication Date
20260506
Application Date
20190523

Claims (13)

  1. A monohydrate crystalline form of Compound 1 wherein the monohydrate crystalline form is MH2, having an XRPD pattern comprising peaks of 2θ angles at 9.0, 11.6, 15.0, 16.0, 18.6, 19.1, 20.4, and 20.6 degrees 2θ, each ±0.2 degrees 2θ.
  2. The monohydrate crystalline form of claim 1, having an XRPD pattern as shown in FIG. 7.
  3. The monohydrate crystalline form of claim 1, having an endothermic peak at 59.1°C (±5 °C) and at 184.7 °C (±5 °C) in a differential scanning calorimetry (DSC) thermogram.
  4. The monohydrate crystalline form of claim 1, having a DSC thermogram in accordance with FIG. 9.
  5. The monohydrate crystalline form of claim 1, exhibiting dehydration at 25°C to 100°C with a weight loss of 4.4% in a thermogravimetric analysis (TGA).
  6. The monohydrate crystalline form of claim 1, having a TGA in accordance with FIG. 9.
  7. The monohydrate crystalline form of any one of claims 1 to 6, wherein the monohydrate crystalline form is at least 95%, 96%, 97%, 98%, or 99% purified.
  8. A pharmaceutical composition comprising the monohydrate crystalline form in any one of claims 1 to 7, and a pharmaceutically acceptable excipient.
  9. The pharmaceutical composition of claim 8, wherein the monohydrate crystalline form is present in an amount of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% by weight.
  10. The pharmaceutical composition of claim 8 or 9, wherein the monohydrate crystalline form is present in an amount of at least 91% by weight.
  11. The pharmaceutical composition of any one of claims 8 to 10, wherein the pharmaceutical composition is in tablet or capsule form.
  12. The monohydrate crystalline form of any one of claims 1 to 7, for use in a method of inhibiting PDE9 activity in a patient.
  13. A process for preparing the monohydrate crystalline form of any one of claims 1 to 7 comprising: a. treating Compound 1 or the MH1 of Compound 1 with a first solvent system to obtain a suspension; b. filtering the suspension to obtain the solid; c. washing the solid with heptane; and d. drying to remove the solvent to get MH2; wherein the MH1 of Compound 1 is a monohydrate crystalline form having an XRPD pattern comprising peaks of 2θ angles at 9.1, 11.5, 16.2, 16.7, 18.2, 18.9, 19.8, 22.6, and 26.4 degrees 2θ, each ±0.2 degrees 2θ, and wherein the solvent is a mixture of water and ethyl acetate (EtOAc) or methyl acetate (MeOAc), selected from 2% (v/v) EtOAc / water, 2.7% (v/v) EtOAc / water, and 7.5% (v/v) MeOAc / water.

Description

REFERENCE TO RELATED APPLICATIONS The present application claims the benefit and priority to US Provisional Application No. 62/676,381 filed May 25, 2018, entitled MONOHYDRATE AND CRYSTALLINE FORMS OF 6-[(3S,4S)-4-METHYL-1-(PYRIMIDIN-2-YLMETHYL)PYRROLIDIN-3-YL]-3-TETRAHYDROPYRAN-4-YL-7H-IMIDAZO[1,5-A]PYRAZIN-8-ONE, and US Provisional Application No. 62/788,323 filed January 4, 2019, entitled MONOHYDRATE AND CRYSTALLINE FORMS OF 6-[(3S,4S)-4-METHYL-1-(PYRIMIDIN-2-YLMETHYL)PYRROLIDIN-3-YL]-3-TETRAHYDROPYRAN-4-YL-7H-IMIDAZO[1,5-A]PYRAZIN-8-ONE.. FIELD OF THE DISCLOSURE The present disclosure relates to polymorphic form MH2 of a cyclic guanylate monophosphate (cGMP)-specific phosphodiesterase type 9 inhibitor (hereinafter referred to as PDE9 inhibitor). Form MH1 does not form part of the invention. BACKGROUND Solids exist in either amorphous or crystalline forms. Polymorphism relates to various crystalline forms of a chemical substance. These crystalline forms have different characteristics in structures and physical properties, such as XRPD spectrum, IR spectrum, and melting point. A particular polymorph form may have advantages over other forms and more suitable for the manufacture and use of the drug substance 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one (Compound 1) is a PDE9 inhibitor disclosed in WO 2017/005786 for treating various diseases such as sickle cell disease. Improved forms of Compound 1 are desired, particularly with regard to enhanced solubility, oral bioavailability, and/or physical stability. SUMMARY OF THE DISCLOSURE The present disclosure provides polymorph forms of a PDE9 inhibitor: 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one (Compound 1), referred to herein as Form MH2 and comparative form MH1. The present disclosure also provides methods of making the polymorph forms, characterization of the polymorph forms, pharmaceutical compositions comprising the polymorph forms, and polymorph forms for use in a method of inhibiting PDE9 activity. One aspect of the disclosure provided herein comprises a monohydrate crystalline form of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one wherein, the monohydrate crystalline form is MH2, having an XRPD pattern comprising peaks of 2θ angles at about 9.0, 11.6, 15.0, 16.0, 18.6, 19.1, 20.4, or 20.6 degrees 2θ, each ±0.2 degrees 2θ. In some embodiments, the monohydrate crystalline form is MH2, having an XRPD pattern substantially as shown in FIG. 7. In some embodiments, the monohydrate crystalline form is MH2, having an endothermic peak at about 59.1°C (±5 °C) and at about 184.7 °C (±5 °C) in a differential scanning calorimetry (DSC) thermogram. In some embodiments, the monohydrate crystalline form is MH2, having a DSC thermogram substantially in accordance with FIG. 9. In some embodiments, the monohydrate crystalline form is MH2, exhibiting dehydration at about 25°C to about 100°C with a weight loss of about 4.4% in a thermogravimetric analysis (TGA). In some embodiments, the monohydrate crystalline form is MH2, having a TGA substantially in accordance with FIG. 9. In some embodiments, the monohydrate crystalline form is at least 95, 96, 97, 98, or 99% purified. Another aspect described herein comprises a pharmaceutical composition comprising a therapeutically effective amount of the monohydrate crystalline form as described above, and a pharmaceutically acceptable excipient. In some embodiments, the monohydrate crystalline form is present in an amount of at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% by weight. In some embodiments, the monohydrate crystalline form is present in an amount of at least about 91% by weight. Another aspect described herein comprises a pharmaceutical composition consisting essentially of the monohydrate crystalline form of any one of the embodiments described herein. Another aspect described herein comprises a pharmaceutical composition consisting essentially of the monohydrate crystalline form MH2 of any one of the embodiments described herein. In some embodiments, the composition is in tablet or capsule form. Another aspect described herein comprises a process for preparing a monohydrate crystalline form of Compound 1, comprising precipitating the monohydrate crystalline form from a solution comprising Compound 1 and a solvent selected from the group consisting of n-propyl acetate, isopropyl acetate, anisole, methylisobutyl ketone, cumene, isopropanol, 2-methyl tetrahydrofuran, and combinations thereof. In some embodiments, the solvent is n-propyl acetate. In some embodiments, the process further comprises cooling the solution. Another aspect described herein comprises a monohydrate crystalline form of Compound 1 prepared by the process of any one of the embodiments described herein. Another aspect desc