Polymorphism of estramustine.

Abstract

As the solubility in water of the cytotoxic drug estramustine is less than 1 mg/L, polymorphism can have an impact on the bioavailability of orally administered drug. Therefore, the solid state characteristics of estramustine samples, crystallized from different solvents, were investigated by means of X-ray crystallography, thermal analysis, and IR spectroscopy. The DSC data indicated the existence of several phases. Four forms--A, B, C, and D--were confirmed. Phase A was obtained when crystallizing from solvents with a moderate or low dieletric constant (less than approximately 24). This form was an anhydrate and found to be the stable one. When crystallizing from methanol, metastable solvates, with approximately 0.5 mol for phase B or approximately 1 mol for form C, were precipitated. Both types were transformed to phase A during storage. This desolvation was accelerated by heating. Crystallizing from a mixture of acetone and water resulted in a monohydrate, form D, which was converted to the anhydrous type A upon heating. As forms B, C, and D were solvates which transformed to another crystal form upon desolvation, they were polymorphic solvates of the anhydrate, type A. Symmetry and unit cell dimensions of the stable form of estramustine (phase A) were determined by means of a single-crystal X-ray technique (orthorhombic, a = 23.90, b = 20.69, c = 8.76, space group P212121). In addition, the crystallographic parameters of form D were deduced from calculations based on powder diffraction data.