Interplay between Thermodynamics and Kinetics on Polymorphic Appearance in the Solution Crystallization of an Enantiotropic System, Gestodene

The development of rational pharmaceutical polymorph control systems from crystallization requires the experimental manipulation of both thermodynamic and kinetic factors. Herein, we discuss the interplay between thermodynamics and kinetics on the formation mechanism responsible for concomitant polymorphs and their subsequent phase transformations. The polymorphic system studied is gestodene, which exhibits two enantiotropic polymorphs, I and II. The thermodynamic stability in ethanol is I > II above 18.5 °C and I < II below. At low supersaturation (1.09 to 1.25), plate-like crystals corresponding to form I become the dominant polymorph at T ≥ 19 °C, while at T ≤ 17 °C, needle-like solids corresponding to form II predominate. Solution crystallization at 5 ≤ T ≤ 25 °C and high supersaturation (1.36 to 1.81) results in concomitant polymorphs of forms I and II. The assessments of nucleation and growth kinetics indicate that at lower supersaturations, both nucleation and growth rates of the stable form are higher than that of the metastable one, while at higher supersaturations, the reverse occurs. It is therefore concluded that at lower supersaturations the stable form is favored by both thermodynamics and kinetics and at higher supersaturations concomitant polymorphism is the result of a balance between these competing driving forces. A semiempirical model that displays the influence of initial supersaturation and crystallization temperature on the relative nucleation rate of the two forms was derived and could be used to predict the polymorphic form resulting from nucleation with good accuracy. As the solvent-mediated polymorphic transformation kinetics between forms I and II is relatively fast at 5, 10, 30, and 35 °C, it can reasonably be expected that one can use a slurrying procedure to obtain the pure stable form when concomitant polymorphs appear at conditions of relatively high supersaturations.