(623a) Technoeconomic Evaluation of Cyclosporine Crystallisation Intensification Using a Cascade of M.S.M.P.R. Crystallisers

Continuous Pharmaceutical Manufacturing (CPM) has been recognised as a promising new production paradigm over the currently implemented batch methods, which imply high volumes of waste and inefficiencies [1]. Whilst the literature demonstrates many continuous flow syntheses of active pharmaceutical ingredients [2], technological innovation is required to realise the benefits of integrated end-to-end CPM processes, including purification and separation unit operations. Process systems engineering (PSE) methodologies allow the screening of candidate CPM processes for their feasibility and viability prior to committing to significant time and financial investments in experimentation and scaleup [3]. Recent efforts in modelling and optimisation of the upstream CPM of APIs have demonstrated the importance of conducting PSE studies in establishing economically viable separation processes [4], realising issues in modelling of particulate processes for solids handling in continuous operation [5] and establishing limitations attainable process improvements in pharmaceutical manufacturing [6].

Cyclosporine is an immunosuppressant drug for the prevention of organ transplant rejection. The continuous cooling crystallisation of cyclosporine has recently been investigated using continuous mixed suspension, mixed product removal (MSMPR) crystallisers, due to their broad applicability and ease of integration into existing pharmaceutical processes [7]. The effect of process configuration [8], mother liquor and solids recycle [9], number of stages [10] on crystallisation yields, purities and product size distributions have been studied to demonstrate the feasibility of continuous crystallisation of the API. Technoeconomic comparisons between batch and continuous crystallisation configurations for cyclosporine to validate the viability of continuous crystallisations are yet to be implemented.

The present paper work develops a steady-state process model for the continuous cooling crystallisation of 100 kg per annum of cyclosporine from acetone including a systematic technoeconomic comparison of various continuous process configurations with the batch method, with a focus on computationally exploring and demonstrating process intensification. The effect of the number of MSMPR stages and varying recycle considerations (mother liquor versus solids recycle) on attainable yields, process material efficiencies and costs are compared. Mother liquor recycle requires vacuum evaporation of solvent, whilst solids recycle uses gravity driven separation to allow recycle of concentrated slurry to MSMPR stages. The developed model simultaneously solves MSMPR mass balances, crystal population balances and crystallisation kinetics to calculated stage and overall crystallisation yields. Prediction of temperature-dependent cyclosporine solubilities in acetone uses a regressed surrogate polynomial established from published experimental data [11]. Temperature- and concentration-dependent growth and nucleation rates are computed on the basis of published kinetic parameters [10] for accurate calculation of attainable yields. Material efficiencies are quantified via popular green chemistry metrics, namely the process mass intensity (PMI) and the mass productivity (MP), which offer quantitative insight into process intensification potential, for each configuration considered. Unit volumes and material throughputs required to meet the plant API capacity are scaled to account for stage inefficiencies. Economic analyses are conducted via an established methodology for pharmaceutical manufacturing processes [12].

The continuous MSMPR crystallisation configurations investigated show potential for application in the CPM of cyclosporine from the calculated attainable material efficiencies and total costs. The sensitivity of process performance to various operating parameters has been explored as well, indicating the significance of rigorous design space investigation of CPM processes. Our work encourages subsequent technoeconomic studies and life cycle assessments (LCA) of the CPM of cyclosporine for further investigation of process feasibility and viability.

The present study exhibits the importance of conducting PSE studies of candidate continuous separation processes for CPM prior to further process development. We demonstrate the economic viability of CPM to facilitate the transition from batch methods, and quantify the potential intensification benefits of improved material efficiency of continuous separation processes in comparison to their batch counterparts. This study expedites further process modelling for the CPM of cyclosporine and other candidates, as well as optimisation of continuous separation processes to realise the full benefits of continuous operation in the pharmaceutical industry.

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