Patent EA-005294-B1 (EA)
Title: Polymorphic forms/hydrates of n-[4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-ylpropoxy)-quinazolin-6-yl]-acrylamide dihydrochloride
Inventor: BARTH HUBERT
IPC: A61P15/00
Filed: 2001-06-15
Abstract: 1. Polymorphic forms/hydrates of N-[4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide dihydrochloride corresponding to the following formula 2. Form A of the dihydrochloride according to Claim 1 containing about 3 mol of water. 3. Form B of the dihydrochloride according to claim 1 as polymorphic compound to form A according to Claim 2 also with about 3 mole of water. 4. Form H of the dihydrochloride according to Claim 1 containing about 7 mole of water. 5. Form M of the dihydrochloride according to Claim 1 containing about 1 mole of water. 6. Form A of the dihydrochloride according to Claim 1 and 2, characterised by diffraction peaks 2theta in the X-ray powder diagram at 8.7760 degree , 23.2083 degree , 28.8604 degree , 37.2905 degree . 7. Form A of the dihydrochloride according to claim 6 additionally characterised by a differential scanning calorimetry diagram according to Fig. Ib. 8. Form B of the dihydrochloride according to claim 1 and 3 as polymorphic compound of form A according to Claim 2, characterised by diffraction peaks 2theta in the X-ray powder diagram at 11.0986 degree , 19.0075 degree , 25.5280 degree . 9. Form B of the dihydrochloride according to claim 8 additionally characterised by a differential scanning calorimetry diagram according to Fig. IIb. 10. Form H of the dihydrochloride according to claim 1 and 4, characterised by diffraction peaks 2theta in the X-ray powder diagram at 7.4267 degree , 12.0027 degree , 24.9997 degree , 35.1642 degree . 11. Form H of the dihydrochloride according to claim 10, additionally characterised by a differential scanning calorimetry diagram according to Fig. IIIb. 12. Form M of the dihydrochloride according to claim 1 and 5, characterised by diffraction peaks 2theta in the X-ray powder diagram at 4.8985 degree , 9.7296 degree , 27.1578 degree , 35.7101 degree . 13. Form M of the dihydrochloride according to claim 12, additionally characterised by a differential scanning calorimetry diagram according to Fig. IVb. 14. Process for the preparation of the form A of the dihydrochloride according to Claim 2 from the free base N-[4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide made available in the usual way and aqueous hydrochloric acid, characterised in that the reaction is carried out in a mixture of 20 parts absolute ethanol and 1 part of water for the formation of the form M and the formed form M is crystallised out from a mixture of 10 parts absolute ethanol and 1 part of water. 15. Process for the preparation of the form B of the dihydrochloride according to claim 3 as polymorphous compound to form A according to claim 2, characterised in that the form A obtained according to Claim 14 is crystallised from water and the crystals obtained are dried in suitable way. 16. Process for the preparation of the form B of the dihydrochloride according to claim 3 as polymorphic compound to form A according to claim 2 by preparation of the dihydrochloride from the free base N-[4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide made available in usual known way and hydrochloric acid in water as well as suitable drying of the dihydrochloride obtained. 17. Process for the preparation of the form H of the dihydrochloride according to Claim 4 by dissolving in absolute ethanol of the form B obtained according to the process according to claim 15 or 16 and leaving the ethanol to evaporate at room temperature. 18. Process for the preparation of the form H of the dihydrochloride according to Claim 4 by dissolving and crystallising of the form A obtained according to claim 14 or of the form B obtained according to claim 15 or 16 in or from 1N hydrochloric acid and suitable drying of the crystals obtained. 19. Process for the preparation of the form M of the dihydrochloride according to claim 5 from the free base N-[4-(3-chloro-4-fluorophenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide made available in usual known manner and aqueous hydrochloric acid, characterised in that the reaction is carried out in a mixture of 20 parts absolute ethanol and 1 part of water. 20. Form A of the dihydrochloride according to claim 2 obtainable according to the process according to claim 14. 21. Form B of the dihydrochloride according to claim 3 obtainable according to the process according to claim 15 or 16. 22. Form H of the dihydrochloride according to claim 4 obtainable according to the process according to claim 17 or 18. 23. Form M of the dihydrochloride according to claim 5 obtainable according to the process according to Claim 19. 24. Use of one of the dihydrochloride forms A, B, H and/or M according to one of Claims 1 to 13 or 19 to 23, possibly together with usual carriers or adjuvants, for the preparation of a medicament with irreversible tyrosine kinase inhibition action.