Impurity Purging through Systematic Process Development of a Continuous Two-Stage Crystallization

A methodical development approach was deployed in a novel portable manufacturing (Pharmacy on Demand) unit to purify ciprofloxacin hydrochloride hydrate within assay, water content, and impurity specifications described by the United States Pharmacopeia (USP) monograph and ICH Q3A­(R2) guidelines for new impurities in drug substances. A series of design-of-experiment (DOE) and one-factor at a time (OFAT) experiments led to the optimization and control of a continuous two-stage crystallization that increased both the purity and yield of ciprofloxacin hydrochloride hydrate. Additionally, a statistically significant linear model was derived in batch within a 20 °C range that tracked the level of a difficult-to-purge impurity in stage 1 of the purification. This model was tested in continuous flow and predicted the impurity removal within 5% accuracy. With parametric control of process parameters, determined by optimization and modeling work, continuous flow isolations produced an active pharmaceutical ingredient (API) which had no individual impurities above 0.07%, with an isolated yield of 74%. In addition, acceptance criteria for assay (between 98 and 102%) and water content (between 4.7 and 6.7%) were met per the USP monograph for ciprofloxacin hydrochloride hydrate for the first time in the novel POD system.