Process Intensification via End-to-End Continuous Manufacturing of Atorvastatin Calcium Using an Integrated, Modular Reaction-Crystallization-Spherical Agglomeration-Filtration-Drying Process

Abstract

Continuous manufacturing can show potential benefits over batch processing in lower turnaround times and smaller footprint in addition to higher productivity, adaptability, and consistent product quality. Although these possible benefits exist, there are also challenges in integrating the various technological steps into a coherent end-to-end continuous system, such as settling, clogging and breakage of particles during transfer, long filtration and drying times and large residence times needed to achieve desired product qualities. This study addresses these difficulties by creating and implementing an end-to-end continuous manufacturing process for atorvastatin calcium (ASC), a statin that is frequently used to treat hypercholesterolemia. The first end-toend integrated continuous, process involving reaction, crystallization, spherical agglomeration, filtration and drying is presented in this work. This approach uses a novel modular integrated continuous manufacturing system, which is developed to improve control over process parameters for the purpose of producing pharmaceutical compounds. Process intensification is achieved by a holistic integration of novel equipment design such as oscillatory flow crystallizers as well as innovative process development (spherical agglomeration). Both the product quality and the manufacturing efficiency are enhanced as a result. This study aims to ascertain the influence of crucial process parameters on the end product's quality through an extensive experimental investigation. Process variables, filtration and drying times, were changed, which offered information about how to best optimize the continuous manufacturing process for ASC with and without the spherical agglomeration step. This paper highlights the use of such methodologies in demonstrating the viability and benefits of a novel continuous end-to-end manufacturing process for ASC as it demonstrated significant improvements in cake yield, solvent retention, throughput and productivity and its potential for the future of intensified integrated continuous pharmaceutical manufacturing.