Effect of solution thermodynamics on the purification of two isomorphic steroids by solution crystallization

11α11α-Hydroxy-16α,17α-epoxyprogesterone (HEP) and 16α,17α-epoxy-progesterone (EP) are two isomorphic steroid pharmaceutical intermediates and form substitutional solid solution when crystallized from solution. In this paper, the crystallization process of HEP from different solution systems that comprise small amounts of EP was studied. The distribution coefficients of EP between crystal phase and solution phase were determined. The distribution of EP in two phases depends on the relative solubility of two steroids in the same solvent to a large extent. The crystal purity significantly increases with the increase of the relative solubility of the impurity (EP) to the primary solute (HEP) in the same solvent. The mixed solvent of toluene+chloroformtoluene+chloroform was found to afford great purity enhancement for the studied steroid system. A simple linear relationship was observed between the distribution coefficients and the relative solubilities in the toluene+chloroformtoluene+chloroform system.