Crystalline forms of rosuvastatin calcium salt
Bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid] (also known as rosuvastatin) calcium salt and hydrates can exist in new crystal forms B and C. These crystal forms provide a higher diversity on crystalline materials to optimize manufacture, formulation and biological efficiency.
1. A crystalline hydrate form of bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å):
18.1 (m); 12.9 (w); 10.7 (vw); 9.5 (w); 8.6 (vs); 7.7 (w); 6.3 (vw); 5.56 (vw); 4.74 (w); 4.57 (w);
4.34 (vw); 4.24 (vw); 4.02 (vw); 3.87 (w); and 3.66 (vw);
hereinafter designated as form B.
2. A process for the preparation of crystalline form B of bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt and hydrates thereof according to claim 1 , which comprises
a) dissolving at ambient temperature a rosuvastatin calcium or a hydrate thereof in water containing an anionic surfactant;
b) removing water at ambient temperature to reduce the volume of water by 30% or more, relative to the volume used to dissolve rosuvastatin;
c) stirring the obtained suspension at ambient temperature for a time sufficient to produce said form B; and
d) filtering off the solid.
3. A process according to claim 2 , wherein the concentration of rosuvastatin in water in step a) ranges from 0.001 to 1 percent by weight.
4. A process according to claim 2 , wherein ambient temperature means a temperature range at room temperature, comprising 20 to 30° C.
5. A process according to claim 2 , wherein the anionic surfactant comprises organic compounds having hydrophilic acidic groups and hydrophobic carbon residues with 6 to 30 carbon atoms, and optionally hetero atoms such as oxygen, and salts thereof.
6. A process according to claim 5 , wherein the anionic surfactant comprises alkyl sulphates.
7. A process according to claim 6 , wherein the anionic surfactant comprises alkyl sulphates having formula C 8 -C 22 alkylOSO 3 H.
8. A process according to claim 2 , wherein the amount of anionic surfactant ranges from 0.001 to 0.5 percent by weight, relative to the amount of water.
9. A process according to claim 2 , wherein the phase equilibration in process step c) is carried out for a time period of hours to several days.