Crystal modifications of odevixibat
The present invention relates to crystal modifications of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (odevixibat), more specifically crystal modifications 1 and 2 of odevixibat. The invention also relates to a process for the preparation of crystal modification 1 of odevixibat, to a pharmaceutical composition comprising crystal modification 1, and to the use of this crystal modification in the treatment of various conditions as described herein.
1. A crystalline hydrate of odevixibat.
2. The hydrate according to claim 1 , which is a channel hydrate.
3. The hydrate according to claim 1 , which comprises from about 0 to about 2 moles of water associated with the crystal per mole of odevixibat.
4. The hydrate according to claim 1 , which is a sesquihydrate.
5. The hydrate according to claim 1 , having an XRPD pattern, obtained with CuKα1-radiation, with peaks at °2θ positions 5.6±0.2, 6.7±0.2 and/or 12.1±0.2.
6. The hydrate according to claim 5 , having an XRPD pattern, obtained with CuKα1-radiation, with specific peaks at °2θ positions 5.6±0.2, 6.7±0.2 and 12.1±0.2 and one or more of the characteristic peaks: 4.1±0.2, 4.6±0.2, 9.3±0.2, 9.4±0.2 and 10.7±0.2.
7. The hydrate according to claim 5 , having a crystallinity of greater than about 99%.
8. A mixed solvate of odevixibat, containing about two moles of water per mole of odevixibat.
9. The mixed solvate according to claim 8 , wherein the organic solvent is methanol, ethanol, 2-propanol, acetone, acetonitrile, 1,4-dioxane, DMF or DMSO.
10. The mixed solvate according to claim 8 , wherein the organic solvent is ethanol.
11. The mixed solvate according to claim 8 , having an XRPD pattern, obtained with CuKα1-radiation, with peaks at °2θ positions 5.0±0.2, 5.1±0.2 and/or 11.8±0.2.
12. The mixed solvate according to claim 11 , having an XRPD pattern, obtained with CuKα1-radiation, with peaks at °2θ positions 5.0±0.2, 5.1±0.2, 6.4±0.2, 6.6±0.2, 9.5±0.2 and 11.8±0.2.
13. The mixed solvate according to claim 8 , having an XRPD pattern, obtained with CuKα1-radiation, with peaks at °2θ positions 4.8±0.2, 5.1±0.2 and/or 11.6±0.2.
14. The mixed solvate according to claim 13 , having an XRPD pattern, obtained with CuKα1-radiation, with peaks at °2θ positions 4.8±0.2, 5.1±0.2, 6.2±0.2, 6.67±0.2, 9.5±0.2, 11.6±0.2 and 20.3±0.
15. The mixed solvate according to claim 8 , having an XRPD pattern, obtained with CuKα1-radiation, with peaks at °2θ positions 5.0±0.2, 6.2±0.2, 9.4±0.2 and/or 23.9±0.2.
16. The mixed solvate according to claim 15 , having an XRPD pattern, obtained with CuKα1-radiation, with peaks at °2θ positions 5.0±0.2, 6.2±0.2, 9.4±0.2 and 23.9±0.2 and one or more of the characteristic peaks: 11.5±0.2, 19.5±0.2 and 20.2±0.2.
17. A process for the preparation of crystal modification 1 of odevixibat, comprising isolating crystal modification 2 of odevixibat from a solution of odevixibat in a solvent mixture comprising water and an organic solvent selected from the group consisting of methanol, ethanol, 2-propanol, acetone, acetonitrile, 1,4-dioxane, DMF and DMSO.
18. The process according to claim 17 , wherein the crystal modification 2 of odevixibat is crystal modification 2A of odevixibat.
19. The process according to claim 17 , wherein crystal modification 2A of odevixibat is obtained from a mixture of water and ethanol.
20. The process according to claim 19 , wherein the ethanol content in the solvent mixture is about 55 to about 75% (v/v).