(427h) Developing a Crystallization Process for an Active Pharmaceutical Ingredient (API) with Retrograde Solubility

Retrograde solubility, in which the solubility of a compound decreases with increasing temperature is well known but rare, particularly for organic compounds. Many crystallization practitioners have no experience with it. When retrograde solubility is encountered, it entails both challenges and opportunities for process development. During initial process development of an API with retrograde solubility the inverse dependence on temperature was not recognized, despite a significant number of solubility data at two temperatures. Small differences between the low and high temperatures were reported, but none where the high temperature solubility was less than that at low temperature. An isothermal antisolvent-addition process was developed, but the final process volume and the volume increase upon antisolvent addition were both quite high to achieve the desired yield. Later process development discovered retrograde solubility in the two solvent/antisolvent systems of interest. Characterizing the actual temperature dependence of the solubility allowed development of a process incorporating temperature increase that uses significantly less solvent and deceases the initial to final volume difference for similar yield. Solubility measurement, molecular modeling, and calorimetry were and are being used to understand the causes of this retrograde solubility and inform process development.