Integrated Continuous Crystallization–-Spherical Agglomeration (CCSA) Process for the Intensified Manufacturing of Atorvastatin Calcium

Abstract

This study applies an innovative two-stage continuous manufacturing process for atorvastatin calcium (ASC), focusing on the integration of process intensification through spherical agglomeration. The integrated continuous crystallization–spherical agglomeration (CCSA) process significantly improves the crystallization of active pharmaceutical ingredients (APIs), traditionally focused on downstream processing efficiency. The method integrates continuous crystallization with spherical agglomeration in a two-stage continuous mixed suspension mixed product removal (MSMPR) system. This integration enables the decoupling of nucleation and growth mechanisms from agglomeration, facilitating the continuous production of ASC with optimized physical and processing properties. The intensified system not only enhances particle size and morphology but also significantly improves the downstream processing efficiency, such as filtration, drying, and tableting, while maintaining or enhancing the drug molecule’s efficacy. It also allows for bypassing certain downstream unit operations, such as granulation, that are generally bottleneck processes in ASC manufacturing. The versatility of this approach is evident in its ability to tailor the properties of ASC for maximum bioavailability and processing efficiency, marking a significant advancement in the implementation of process intensification in ASC manufacturing via a novel spherical agglomeration route combined with continuous manufacturing.