Preparation of lamivudine form I
AssigneeMerck Sharp & Dohme Corp.
InventorsBenjamin Cohen, Christopher Wahl, Itzia Z. Arroyo, Aaron S. Cote
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Abstract
A thermodynamically controlled process for preparing Form I polymorph of lamivudine is described, wherein the process involves crystallizing Form I at a temperature of from about 0° C. to about 50° C. from a mixture which comprises (a) lamivudine or an acid salt thereof or both, (b) a solvent system comprising water and at least one organic solvent, and optionally (c) Form I seed; wherein, when a lamivudine acid salt is employed in the mixture, the crystallizing step is conducted in the presence of a base; and wherein the water activity of the solvent system is maintained in a range in which Form I is thermodynamically the most stable form of lamivudine.
Claims25
A thermodynamically controlled process for preparing Form I of lamivudine which comprises crystallizing Form I at a temperature T of from about 0° C. to about 50° C. from a mixture which comprises (a) lamivudine or an acid salt thereof or both, (b) a solvent system comprising water and at least one organic solvent, wherein the water activity of the solvent system is maintained in a range of from about Aw1 to about Aw2 during the crystallizing step, wherein Aw1=(0.00458×T)+0.506 and Aw2=(0.00316×T)+0.775, and optionally (c) Form I seed;
- wherein, when a lamivudine acid salt is employed in the mixture, the crystallizing step is conducted in the presence of a base;
- and wherein the water activity Aw of the solvent system is maintained in a range in which Form I is thermodynamically the most stable form of lamivudine;
- and provided that when the solvent system is a binary solvent system and the temperature T is in a range of from about 20° C. to about 30° C. and the mixture from which Form I is crystallized is a slurry of Form I and Form II in the binary solvent system and the process does not employ an acid salt of lamivudine, then the organic solvent in the binary system is other than ethyl acetate.
Dependencies are inferred from the claim text.