(284c) Technoeconomic MINLP Optimisation of M.S.M.P.R. Cascades for Continuous Crystallisation of Melitracen Hydrochloride, an Antidepressant API

Continuous crystallisation is an emerging field of research due to its potential to enhance process flexibility, efficiency and product quality consistency compared to current batch techniques.¹ Development of robust continuous crystalliser designs is imperative for continuous pharmaceutical manufacturing (CPM) campaigns, which have received significant attention from academic, industry and regulatory bodies in the past decade.² Crystallisation is a key unit operation in pharmaceutical manufacturing given the significant quantity of solid dosage forms in pharmaceutical products.³ Mixed suspension, mixed product removal (MSMPR) crystallisers are a widely studied continuous design for their simple operation, low maintenance requirements, avoidance of rapid fouling typical of continuous tubular designs and ease of adaptation from existing stirred tank designs. A variety of experimental and theoretical studies have already investigated the design, simulation and optimisation of steady-state and dynamic operations of MSMPR crystallisers for different active pharmaceutical ingredients (APIs) and other pharmaceutically relevant compounds.⁴ Rapid screening of candidate flowsheet configurations of MSMPR cascades for different APIs can facilitate process development towards end-to-end CPM.⁵

Mixed Integer Nonlinear Programming (MINLP) has been widely implemented in various applications to rapidly screen for optimal design configurations.⁶ Mixed integer problems contain both continuous decision variables, e.g., unit operating and design parameters) as well as integer (binary or otherwise) decision variables, e.g., denoting existence of a unit operation or deciding recycle stream feed location. Optimisation of MSMPR cascades has yet to be implemented for pharmaceutical process design.

Melitracen HCl is a tricyclic antidepressant API available as single drug preparations and also in combinative therapies. The continuous crystallisation of the API in MSMPR crystallisers was recently demonstrated,⁷ facilitating its process modelling and optimisation. Existing work investigates the effects of different MSMPR design and operating parameters on crystal size for a maximum of two MSMPRs, showing significant variation in process performance and crystal product attributes when varying the number of implemented crystallisers.⁷ Investigating the effect of longer cascades and implementing recycle variations can further improve crystallisation yields in MSMPR design.⁸ Economic considerations are equally important as meeting specific product attributes when designing crystallisation processes, especially when the effect of production scale is considered.⁹

This work implements MINLP optimisation of MSMPR cascades for continuous melitracen crystallisation to screen for cost optimal flowsheet configurations subject to constraints on crystal product attributes. The MINLP superstructure for MSMPR cascades considers varying numbers of implemented crystallisers and recycle options, including considerations of constrained recycle crystal size distributions. The steady-state process model describes the crystallisation process by simultaneous solution of population balances, crystallisation kinetics and mass balance equations. The MINLP optimisation problem is solved at different plant capacities. Minimum total cost components, optimal flowsheet configurations and crystallisation yields and crystal product average sizes and distributions are compared for different problem instances.

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