(610b) A New Slurry Reactive Crystallization to Improve Process Robustness and Scalability

Authors: 
Derdour, L., GlaxoSmithKline
Several challenges were faced during the development of development of a drug candidate isolated as a salt. These challenges included high solvent levels entrapped in isolated solids, disproportionation and agglomeration. A root-cause analysis pointed to dimethyl sulfoxide (DMSO), a co-solvent utilized in the crystallization as the main cause for solvent entrapment and agglomeration. DMSO was introduced in the procedure because it enhances drastically the solubility of the drug allowing for a clarifying filtration to be performed at the final step. However, because of its low volatility, DMSO is removed at a slower pace during drying causing partial solubilization of crystal surfaces during drying followed by recrystallization. It is believed that this behavior causes solvent entrapment and agglomeration during drying. In order to address these issues, a study was conducted to identify an alternative co-solvent to DMSO. In this presentation, the development of two types of crystallizations, namely an anti-solvent crystallization and slurry-slurry reactive crystallization to address the issues mentioned above is described. In particular, a new slurry-slurry reactive crystallization, based on an approach recently reported (Derdour et al‡) was found to be superior in terms of improving process robustness and scalability. That procedure performed successfully when executed at industrial scale.

‡ Derdour L., Reckamp J.M. and Pink C., Development of a reactive slurry salt crystallization to improve solid properties and process performance and scalability, Chem Eng Res Des, 121, pp 207-2018, 2017