Crystalline forms of zofenopril calcium
View Patent ↗The present invention relates to two novel crystalline forms of zofenopril calcium, to processes for their preparation and their use in pharmaceutical compositions.
1. A process for preparing zofenopril calcium, comprising the steps of:
(a) dissolving a salt of zofenopril in a water miscible organic solvent;
(b) mixing the solution obtained in step (a) with an aqueous solution of a calcium salt; and
(c) isolating the zofenopril calcium with the proviso that the salt of zofenopril in step (a) is not an amine salt.
2. A process according to claim 1 , wherein the process is for preparing a polymorphic form of zofenopril calcium, wherein the zofenopril calcium isolated in step (c) is the polymorphic form, and wherein the polymorphic form is characterised by:
(i) an XRPD spectrum comprising at least six of the following 2θ peaks: 4.2, 4.8, 9.6, 17.5, 18.0, 19.3, 19.9, 20.6 and 24.4±0.2 degrees 2θ; and/or
(ii) a differential scanning calorimetry (DSC) with an endothermic peak at about 255° C.; and/or
(iii) a TGA trace substantially as shown in FIG. 3 .
3. A process according to claim 2 , wherein the polymorphic form is characterised by an XRPD spectrum substantially as shown in FIG. 1 .
4. A process according to claim 2 , wherein the polymorphic form is characterised by a DSC trace substantially as shown in FIG. 2 .
5. A process according to claim 2 , wherein the polymorphic form comprises less than 10%, less than 5%, less than 1%, less than 0.5%, or less than 0.1% of zofenopril calcium in other polymorphic or amorphous forms.
6. A process according to claim 1 , wherein the water miscible organic solvent is an alcohol, an ether, a cyclic ether, a ketone or an amide.
7. A process according to claim 6 , wherein the water miscible organic solvent is an alcohol.
8. A process according to claim 7 , wherein the alcohol is a straight-chain, branched or cyclic C 1 to C 6 alcohol.
9. A process according to claim 8 , wherein the alcohol is selected from methanol, ethanol, propanol, isopropanol, n-butanol or mixtures thereof.
10. A process according to claim 6 , wherein the water miscible organic solvent is a cyclic ether.
11. A process according to claim 10 , wherein the cyclic ether is selected from tetrahydrofuran and dioxane or mixtures thereof.
12. A process according to claim 6 , wherein the water miscible organic solvent is an amide.
13. A process according to claim 12 , wherein the amide is selected from N,N-dimethylformamide, formamide and N,N-dimethylacetamide or mixtures thereof.
14. A process according to claim 1 , wherein the zofenopril salt in step (a) is a metal salt.
15. A process according to claim 14 , wherein the metal salt is a potassium, sodium, lithium, calcium, magnesium or aluminium salt.
16. A process according to claim 15 , wherein the metal salt is a potassium salt.
17. A process according to claim 1 , wherein the calcium salt in step (b) is selected from the fluoride, chloride, bromide, iodide, oxide, hydroxide, carbonate, nitrate, sulfate or acetate salts.
18. A process according to claim 17 , wherein the calcium salt is calcium chloride.
19. A process according to claim 1 , wherein steps (a) and (b) are carried out at a temperature of up to 60° C.
20. A process according to claim 1 , wherein the process is carried out at a temperature of from 20° C. to 30° C.