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 degrees 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.

Automated summary

A methodical development approach was used to purify ciprofloxacin hydrochloride hydrate in a portable manufacturing unit. Through experiments and modeling, a continuous two-stage crystallization process was optimized and controlled, resulting in increased purity and yield of ciprofloxacin hydrochloride hydrate. The system also met the assay and water content requirements specified by USP monograph for the first time.