Case-Based Thermal Safety Evaluation on a Pharmaceutical Process Using Dimethyl Sulfoxide as a Solvent

Abstract

A rupture disc burst was recorded when conducting a calorimetric test by sensitive detection of exothermic reaction. The tested sample was a reaction mixture from a hydroamination process containing the solvent dimethyl sulfoxide (DMSO). Subsequent investigation indicated that the event was caused by the strong autocatalytic decomposition of DMSO. The hazardous decomposition of DMSO that could be initiated by an inadvertent contact with substances involved in the process was studied. Furthermore, risk evaluation on the process thermal runaway was carried out based on the cooling failure scenario. In this particular case, although Stoessel criticality class 2 was assigned, the boiling point of DMSO could not serve as the safety barrier. On the basis of the thermal safety evaluation, the hydroamination process was safely scaled up in the Novartis pilot plant and successfully launched in a commercial production unit. This investigation highlights that every scale-up process involving DMSO as a solvent should be carefully evaluated owing to the potential safety concern caused by its autocatalytic behavior.