Claims for Patent: 12,091,394

Summary for Patent: 12,091,394

Title:	Crystal modifications of odevixibat
Abstract:	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.
Inventor(s):	Robert Lundqvist, Ingvar Ymen, Martin Bohlin, Eva Byröd, Per-Göran Gillberg, Anna-Maria Tivert, Rikard Bryland, Jessica Elversson, Nils Ove Gustafsson, Ann-Charlotte Dahlquist
Assignee:	Eva Byroed Consulting AB , Tivert Konsult AB , Albireo AB
Application Number:	US17/744,429
Patent Claims:	1. A process for the preparation of crystal modification 1 of odevixibat, comprising the steps of: a) isolating crystals of 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; and b) drying the isolated crystals of odevixibat under vacuum or under a nitrogen flow to form crystal modification 1 of odevixibat. 2. The process according to claim 1, wherein crystal modification 1 of odevixibat has an XRPD pattern, obtained with CuKα1-radiation, with peaks at °2θ positions 5.6±0.2, 6.7±0.2 and 12.1±0.2. 3. The process according to claim 1, wherein crystal modification 1 of odevixibat has 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. 4. The process according to claim 1, wherein crystal modification 1 of odevixibat has an XRPD pattern, obtained with CuKα1-radiation, as shown in FIG. 1 . 5. The process according to claim 1, wherein crystal modification 2 of odevixibat is crystal modification 2A of odevixibat. 6. The process according to claim 5, wherein crystal modification 2A of odevixibat is isolated from a solution of odevixibat in a mixture of ethanol and water, acetone and water, 1,4-dioxane and water, DMF and water or 2-propanol and water. 7. The process according to claim 5, wherein crystal modification 2A of odevixibat is isolated from a solution of odevixibat in a mixture of ethanol and water. 8. The process according to claim 7, wherein the ethanol content in the solvent mixture is about 55 to about 75% (v/v). 9. The process according to claim 5, wherein crystal modification 2A of odevixibat has an XRPD pattern, obtained with CuKα1-radiation, with peaks at °2θ positions 5.0±0.2, 5.1±0.2 and 11.8±0.2. 10. The process according to claim 5, wherein crystal modification 2A of odevixibat has 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. 11. The process according to claim 5, wherein crystal modification 2A of odevixibat has an XRPD pattern, obtained with CuKα1-radiation, as shown in any one of FIGS. 6 to 9 . 12. The process according to claim 1, wherein crystal modification 2 of odevixibat is crystal modification 2B of odevixibat. 13. The process according to claim 12, wherein crystal modification 2B of odevixibat is isolated from a solution of odevixibat in a mixture of methanol and water or acetonitrile and water. 14. The process according to claim 12, wherein crystal modification 2B of odevixibat has an XRPD pattern, obtained with CuKα1-radiation, with peaks at °2θ positions 4.8±0.2, 5.1±0.2 and 11.6±0.2. 15. The process according to claim 12, wherein crystal modification 2B of odevixibat has 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. 16. The process according to claim 12, wherein crystal modification 2B of odevixibat has an XRPD pattern, obtained with CuKα1-radiation, as shown in FIGS. 10 or 11 . 17. The process according to claim 1, wherein crystal modification 2 of odevixibat is crystal modification 2C of odevixibat. 18. The process according to claim 17, wherein crystal modification 2C of odevixibat is isolated from a solution of odevixibat in a mixture of DMSO and water. 19. The process according to claim 17, wherein crystal modification 2C of odevixibat has 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. 20. The process according to claim 17, wherein crystal modification 2C of odevixibat has 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. 21. The process according to claim 17, wherein crystal modification 2C of odevixibat has an XRPD pattern, obtained with CuKα1-radiation, as shown in FIG. 12 . 22. The process according to claim 1, wherein the isolated odevixibat is dried under a vacuum of less than 5 mbar. 23. The process according to claim 1, wherein crystal modification 1 of odevixibat has a crystallinity of greater than about 99%. 24. A process for the preparation of crystal modification 1 of odevixibat, comprising the steps of: a) preparing a saturated solution of odevixibat in a mixture of water and ethanol; b) adding an excess of odevixibat to the saturated solution so as to obtain a slurry comprising crystals of odevixibat; c) maintaining stirring of the slurry at a temperature of about 20 to about 25° C. for a period of at least 24 hours; d) recovering the crystals of odevixibat; e) optionally exposing the crystals of odevixibat to an ethanol/water atmosphere; and f) drying the crystals of odevixibat under vacuum or under a nitrogen flow to form crystal modification 1 of odevixibat. 25. A process for the preparation of crystal modification 1 of odevixibat, comprising the steps of: a) preparing a saturated solution of odevixibat in a mixture of water and ethanol; b) adding seed crystals to the saturated solution so as to obtain a slurry comprising crystals of odevixibat; c) maintaining stirring of the slurry at a temperature of about 20 to about 25° C. for a period of at least 24 hours; d) recovering the crystals of odevixibat; e) optionally exposing the crystals of odevixibat to an ethanol/water atmosphere; and f) drying the crystals of odevixibat under vacuum or under a nitrogen flow to form crystal modification 1 of odevixibat. 26. The process according to claim 25, wherein the seed crystals are of crystal modification 1. 27. Crystal modification 1 of odevixibat, prepared by a process comprising the steps of: a) isolating crystals of 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; and b) drying the isolated crystals of odevixibat under vacuum or under a nitrogen flow to form crystal modification 1 of odevixibat.