(277b) Leveraging Mechanistic Understanding of Impurity Rejection during Crystallization for Rational Process Design

The control of impurities in the chemical synthesis of a new drug substance is a requirement in registering pharmaceuticals with worldwide regulatory agencies. Crystallization is an essential tool in controlling the purity profile of a drug substance and its intermediates. An overview of the various mechanisms of impurity incorporation during crystallization will be discussed along with remediation strategies. A case study will be provided on the replacement of chromatography with crystallization during the development of a second generation commercial manufacturing route for Ceftolozane, the cephalosporin antibiotic found in Zerbaxa. The implementation of a crystallization based purification process for Ceftolozane, replacing a chromatography/nanofiltration/diafiltration sequence, resulted in a more productive, greener, and more portable manufacturing process. Another case study will be presented on limiting substrate concentration on product crystals during a reactive crystallization via engineering design.