Abstract
Continuous crystallization using Mixed Suspension-Mixed Product Removal (MSMPR) crystallizers has been demonstrated as a feasible method for implementing continuous separations in pharmaceutical manufacturing processes. This work conducts a steady-state process modeling and simulation study of the continuous cooling crystallization of cyclosporine, comparing processes with and without solids recycle for their technoeconomic viability. The model describes population balance equations, crystallization kinetics, and process mass balances to compare attainable crystallization and plantwide yields of different process configurations. Total cost components using an established economic analysis methodology are compared for varying numbers of crystallizers, operating temperatures, total crystallizer cascade residence times and API feed concentrations. Economic analyses and the calculation of normalized cost components with respect to total crystallizer volumes identify the process without recycle as the most economically viable option, achieving the lowest total costs and low E-factors for pharmaceutical processes. The sensitivity of total costs to the selected total residence times for economic analyses highlights the need for rigorous comparison methodologies. This work identifies the need for technoeconomic optimization studies of continuous crystallization processes to establish the optimal design of manufacturing campaigns prior to further development.
Highlights
Continuous pharmaceutical manufacturing (CPM) has been established as a promising new paradigm with the potential for significant technoeconomic benefits for the pharmaceutical industry.[1]
The results show that the considered active pharmaceutical ingredients (APIs) feed concentration has a significant impact on the attained yield; this is an important variable due to potential fluctuations in feed composition to a continuous crystallization process
The present study implements a technoeconomic analysis of two different configurations for the continuous crystallization of cyclosporine: with and without solids recycle, based on experimental demonstrations.[53,54]
Summary
Continuous pharmaceutical manufacturing (CPM) has been established as a promising new paradigm with the potential for significant technoeconomic benefits for the pharmaceutical industry.[1] While the current batch manufacturing methods have advantages such as specific product recall, flexible equipment usage and well-established analytical methods for quality control, they imply large material inventories, significant intermediate storage and poor mixing and heat transfer efficiencies.[2−4] Various demonstrations of continuous flow syntheses,[5−7] product formulation stages[8] and fully end-to-end production campaigns[9−13] show the initiative of academic and industrial researchers to facilitate the transition toward continuous methods. Systematic investigation of continuous crystallization processes for pharmaceutical manufacturing is required to realize the attainable benefits compared to existing batch methods
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