Polymorphic forms
View Patent ↗Novel polymorphic forms of bosentan and processes for their preparation are disclosed. Further, pharmaceutical compositions comprising said polymorphic forms and the use of said compositions in the treatment of patients suffering from endothelin receptor mediated disorders, for example, cardiovascular disorders such as hypertension, pulmonary hypertension, ischemia, vasospasm and angina pectoris are disclosed.
1. Crystalline form 2 of bosentan characterized by:
(i) an X-ray diffraction pattern comprising at least five peaks selected from peaks at 2θ values 7.6, 13.6, 16.6, 16.9, 17.3, 18.6, 20.0, 20.3 and 23.0±0.2; and/or
(ii) a DSC comprising an endothermic peak at about 144° C.
2. A process for preparing the crystalline form 2 of bosentan as claimed in claim 1 , comprising the steps of:
(a) dissolving bosentan in one or more organic solvent(s),
(b) causing a crystalline solid to precipitate from the solution obtained in step (a), and
(c) isolating the crystalline solid obtained in step (b).
3. A process for preparing the crystalline form 2 of bosentan as claimed in claim 1 , comprising the steps of:
(a) heating bosentan in n-butanol to about 90° C.,
(b) cooling the solution obtained in step (a) to about 25° C. over about 60 minutes,
(c) filtering the solution obtained in step (b),
(d) adding n-hexane to the filtrate obtained in step (c) to precipitate a crystalline solid,
(e) isolating the crystalline solid obtained in step (d) by filtration, and
(f) air-drying the crystalline solid obtained in step (e) for about 12 hours.
4. A process for preparing the crystalline form 2 of bosentan as claimed in claim 1 , comprising the steps of:
(a) heating bosentan in 2-ethoxyethanol to about 45° C.,
(b) cooling the solution obtained in step (a) to about 10° C. over about 50 minutes,
(c) adding n-hexane and water to the solution obtained in step (b) to precipitate a crystalline solid,
(d) isolating the crystalline solid obtained in step (c) by filtration, and
(e) air-drying the crystalline solid obtained in step (d) for about 12 hours.
5. A process for preparing the crystalline form 2 of bosentan as claimed in claim 1 , comprising the steps of:
(a) heating bosentan in n-propyl acetate to about 80° C.,
(b) cooling the solution obtained in step (a) to about 25° C. to precipitate a crystalline solid,
(c) isolating the crystalline solid obtained in step (b) by filtration, and
(d) air-drying the crystalline solid obtained in step (c) for about 12 hours.
6. A process for preparing the crystalline form 2 of bosentan as claimed in claim 1 , comprising the steps of:
(a) heating bosentan in 2-methoxyethanol to about 45° C. or until a clear solution is obtained,
(b) cooling the solution obtained in step (a) to about 25° C.,
(c) adding water to the solution obtained in step (b) to precipitate a crystalline solid,
(d) isolating the crystalline solid obtained in step (c) by filtration, and
(e) air-drying the crystalline solid obtained in step (d) for about 12 hours.
7. Crystalline form 3 of bosentan characterized by:
(i) an X-ray diffraction pattern comprising at least five peaks selected from peaks at 2θ values 5.2, 7.5, 8.2, 9.3, 10.0, 18.1, 20.5, 21.5 and 25.0±0.2; and/or
(ii) a DSC comprising an endothermic peak at about 174° C. and an endothermic peak at about 246° C.
8. A process for preparing the crystalline form 3 of bosentan as claimed in claim 7 , comprising the steps of:
(a) dissolving bosentan in one or more organic solvent(s),
(b) causing a crystalline solid to precipitate from the solution obtained in step (a), and
(c) isolating the crystalline solid obtained in step (b).
9. Crystalline form 4 of bosentan characterized by:
(i) an X-ray diffraction pattern comprising at least five peaks selected from peaks at 2θ values 5.7, 6.4, 9.5, 15.6, 16.6, 21.2, 21.5, 27.4 and 31.8±0.2;
(ii) a DSC comprising an endothermic peak at about 210° C.
10. A process for preparing the crystalline form 4 of bosentan as claimed in claim 9 , comprising the steps of:
(a) dissolving bosentan in one or more organic solvent(s),
(b) causing a crystalline solid to precipitate from the solution obtained in step (a), and
(c) isolating the crystalline solid obtained in step (b).
11. Amorphous bosentan.
12. A process for preparing amorphous bosentan as claimed in claim 11 , comprising the steps of:
(a) dissolving bosentan in one or more organic solvent(s),
(b) causing an amorphous solid to precipitate from the solution obtained in step (a), and
(c) isolating the amorphous solid obtained in step (b).
13. A method of treating hypertension, ischemia, vasospasm, angina pectoris, and pulmonary arterial hypertension comprising administering a therapeutically effective amount of bosentan crystalline form 2 as claimed in claim 1 to a subject in need thereof.
14. A method of treating hypertension, ischemia, vasospasm, angina pectoris, and pulmonary arterial hypertension comprising administering a therapeutically effective amount of bosentan crystalline form 3 as claimed in claim 7 to a subject in need thereof.
15. A method of treating hypertension, ischemia, vasospasm, angina pectoris, and pulmonary arterial hypertension comprising administering a therapeutically effective amount of bosentan crystalline form 4 as claimed in claim 9 to a subject in need thereof.
16. A method of treating hypertension, ischemia, vasospasm, angina pectoris, and pulmonary arterial hypertension comprising administering a therapeutically effective amount of amorphous bosentan as claimed in claim 11 to a subject in need thereof.