| Anti-solvent precipitation is widely used in pharmaceutical industry. Generally, it involves two sequential processes: mixing and crystallization. Classical crystallization theory is based on the assumption that solution is homogeneously mixed before nucleation. However, in many anti-solvent precipitation cases this assumption may not be true. The quality of the mixing process will directly affect the further crystallization process. Viscous, aqueous, low molecular weight PEG300 solutions are mainly used as the solvent in our study of anti-solvent precipitation of pharmaceutical compounds because of PEG300's environmental benign property. Water is generally the anti-solvent. Some experimental observations have led to the idea that quasi-emulsions form in the "mixed" solution. The quasi-emulsion may consist of drops of solute dissolved in the viscous solvent and an interfacial layer of "precipitated" solute molecules surrounded by the continuous anti-solvent liquid. General conditions to form such quasi-emulsions are proposed based on Taylor's droplet deformation theory and a spontaneous emulsification mechanism with emphasis on the viscosity difference between solvent and anti-solvent. A precipitation mechanism involving quasi-emulsions is then developed to explain some unusual results in our crystal nucleation and growth studies. Based on the quasi-emulsion model, mixing effects on the polymorph crystallization are predicted and experimentally verified with several pharmaceutical compounds. These predicted results, in return, prove the quasi-emulsion model. Recommendations for further research are proposed. |
