Nonlinear Optimization via Explicit NRTL Model Solubility Prediction for Antisolvent Mixture Selection in Artemisinin Crystallization

Abstract

Continuous Pharmaceutical Manufacturing (CPM) has the potential to revolutionise the pharmaceutical industry, with many expected benefits in terms of cost, efficiency and quality. Process modelling and optimisation are valuable methodologies for comparative technoeconomic evaluations: this paper pursues total upstream CPM cost minimisation via two nonlinear optimisation methods. An explicit NRTL solubility estimation method has been used in order to analyse the potential performance of three binary antisolvent mixtures for the crystallisation of artemisinin. This Active Pharmaceutical Ingredient (API) is a key antimalarial substance and has been the focus of several CPM studies, including continuous chemistry and separation. Ethanol, acetone and ethyl acetate are the three antisolvents studied. Used as a binary antisolvent with toluene as the solvent, the composition of the binary antisolvent, the quantity of the binary antisolvent with respect to the process solvent, and the temperature the overall mixture is cooled to in the crystallisation process are formulated as the three key variables in a nonlinear optimisation problem. Two solvers are used, NOMAD and NLOPT-BOBYQA. Results show that they have very similar precision (<1 % difference), but that the latter is up to 66 % faster; NLOPT-BOBYQA was used for the majority of optimisation cases. Results show that for the size of the temperature gradient of the crystallisation has a much stronger effect on the total cost than the quantity of antisolvent used. Nearly pure antisolvent use (ethyl acetate followed by ethanol) is favoured as yielding the lowest total cost (for a single crystalliser). Considering multiple units, results indicate that higher API recovery, E-factor, and OpEx benefits can be achieved when using two crystallisers, but metrics are inferior with three or more. For sequential crystallisers of varying size, increasing the number of crystallisers also benefits OpEx, E-factor, and API recovery, but CapEx continues to increase, thereby promising technical but no economic benefits.

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

“…Due to its biological relevance, artemisinin, a tricyclic compound bearing a peroxide bridge, has been subject of extensive scientific investigations during the last decade [53][54][55][56][57][58][59][60][61][62][63]. In this context, Seeberger and co-workers successfully developed an ingenious continuous-flow process for the hemisynthesis of pure artemisinin from dihydroartemisinic acid (DHAA) [64,65].…”

Process Design and Optimization for the Continuous Manufacturing of Nevirapine, an Active Pharmaceutical Ingredient for HIV Treatment

“…19,20 Modelling and optimisation have also been implemented in the design of separation processes in pharmaceutical manufacturing, such as liquid-liquid extraction (LLE), [21][22][23] crystallisation [24][25][26][27][28][29][30] and chromatographic methods. 31 Identification of cost optimal plantwide designs is essential, 15 particularly end-to-end designs encompassing synthesis and purification/separation. Elucidating cost optimal designs for nevirapine CPM will further aid process development for this societally-important API.…”

“…Modeling and optimization methodologies can be used to establish optimal process design configurations. , Advanced theoretical methods have been previously implemented toward optimal pharmaceutical unit design and optimization of pharmaceutical manufacturing processes to elucidate optimal operation, analysis of synthetic pathways, − and life cycle assessments. , Modeling and optimization have also been implemented in the design of separation processes in pharmaceutical manufacturing, such as liquid–liquid extraction (LLE), − crystallization, − and chromatographic methods . Identification of cost-optimal plantwide designs is essential, particularly end-to-end designs encompassing synthesis and purification/separation.…”

“…Modeling and optimization methodologies can be used to establish optimal process design configurations. , Advanced theoretical methods have been previously implemented toward optimal pharmaceutical unit design and optimization of pharmaceutical manufacturing processes to elucidate optimal operation, analysis of synthetic pathways, − and life cycle assessments. , Modeling and optimization have also been implemented in the design of separation processes in pharmaceutical manufacturing, such as liquid–liquid extraction (LLE), − crystallization, − and chromatographic methods . Identification of cost-optimal plantwide designs is essential, particularly end-to-end designs encompassing synthesis and purification/separation. Elucidating cost-optimal designs for nevirapine CPM will further aid process development for this societally important API. , …”

Process modelling, simulation and technoeconomic optimisation for continuous pharmaceutical manufacturing of (S)-warfarin

“…Comparison of different conceptual separation process alternatives is essential for establishing cost-effective, materially efficient designs for upstream CPM configurations. Screening of candidate continuous LLE configurations for CPM of this API has yet to be conducted; process modelling, simulation and optimisation of continuous separation processes are valid alternatives to laborious experimental efforts for rapid design space investigation to elucidate technically feasible and economically viable processes (Jolliffe et al, 2018).…”