Towards Continuous Primary Manufacturing Processes—Particle Design through Combined Crystallization and Particle Isolation

Abstract

Integrated continuous manufacturing processes of active pharmaceutical ingredients (API) provide key benefits concerning product quality control, scale-up capability, and a reduced time-to-market. Thereby, the crystallization step, which is used in approximately 90% of API productions, mainly defines the final API properties. This study focuses on the design and operation of an integrated small-scale process combining a continuous slug flow crystallizer (SFC) with continuous particle isolation using the modular continuous vacuum screw filter (CVSF). By selective adjustment of supersaturation and undersaturation, the otherwise usual blocking could be successfully avoided in both apparatuses. It was shown that, during crystallization in an SFC, a significant crystal growth of particles (Δd50,3≈ 220 µm) is achieved, and that, during product isolation in the CVSF, the overall particle size distribution (PSD) is maintained. The residual moistures for the integrated process ranged around 2% during all experiments performed, ensuring free-flowing particles at the CVSF outlet. In summary, the integrated setup offers unique features, such as its enhanced product quality control and fast start-up behavior, providing a promising concept for integrated continuous primary manufacturing processes of APIs.