(125f) Continuous Crystallization Development for the End-to-End Manufacturing of Ciprofloxacin HCl in Refrigerator-Sized Modules

Crystallization has recently gained an increased interest for continuous pharmaceutical manufacturing, particularly for the use of Mixed Suspension Mixed Product Removal (MSMPR) crystallizers for intermediate purification and isolation of Active Pharmaceutical Ingredients (APIs). The ability to sustain high suspension densities of crystals grown under known, stable kinetics, provides an advantage for ensuring consistent product quality in continuous operation.

This work was part of the development of an end-to-end process for Ciprofloxacin hydrochloride in compact, reconfigurable modules. The overall process is divided in four steps, namely: synthesis, workup, isolation, and formulation. This presentation will focus on the downstream modules for workup and isolation, including continuous precipitation of Ciprofloxacin base as an intermediate and the final separation of Ciprofloxacin hydrochloride monohydrate via continuous crystallization.

The process development milestones are described first, with particular focus on how the critical crystallization conditions were selected and the role of each MSMPR step on defining the drug substance’s critical quality attributes. Then, the workup and isolation parts of the end-to-end manufacturing campaign are described, with emphasis on how the MSMPR processes were integrated with fundamentally batch processes (e.g. filtration, drying), and how the implemented process controls ensured an extended continuous operation and a consistent drug substance quality.