Plantwide Design and Economic Evaluation of Two Continuous Pharmaceutical Manufacturing (CPM) Cases: Ibuprofen and Artemisinin

Computers & Chemical Engineering

2018

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Continuous pharmaceutical manufacturing (CPM) is a promising new paradigm to produce active pharmaceutical ingredients (APIs), allowing reduced equipment dimensions, lower waste production and energy consumption, and safer operation in comparison to the industrially dominant batch methods. Rufinamide is an antiepileptic agent whose demonstrated continuous flow synthesis (featuring three reactions in flow) circumvents the accumulation of toxic and explosive organoazide intermediates. To ascertain the feasibility and viability of this continuous synthetic route, systematic process modelling and costing is required. This paper presents a technoeconomic analysis of the upstream continuous flow synthesis of rufinamide via steady-state process modelling and plantwide simulation. Reaction kinetics and Arrhenius parameters are estimated from previously published experimental data, and plug flow reactor (PFR) volumes are calculated towards rigorous plant costing. Continuous reactor and separator units have been designed, and the CPM flowsheet is compared vs. the batch production method, with respect to technical efficiency and profitability. Plantwide costing via an established economic analysis methodology has been pursued to enable a detailed comparison of cost items towards process scale-up, as well as motivate the need for further systematic optimisation.

Section: Crystallisation Designmentioning

confidence: 99%

Process modelling, simulation and technoeconomic evaluation of crystallisation antisolvents for the continuous pharmaceutical manufacturing of rufinamide

Diab

Computers & Chemical Engineering

2018

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“…Here, we expand on a previous publication (Jolliffe and Gerogiorgis, 2015b) and evaluate the cost saving potential of continuous crystallisation for API recovery (Fig. 6).…”

Section: Artemisinin Continuous Separation (Artemisinin Cpm1 Artemimentioning

confidence: 99%

Plantwide design and economic evaluation of two Continuous Pharmaceutical Manufacturing (CPM) cases: Ibuprofen and artemisinin

Jolliffe

Computers & Chemical Engineering

2016

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Increasing Research and Development (R&D) costs, growing competition from generic manufacturers and dwindling market introduction rates for novel drug products bolster the efforts of pharmaceutical firms to secure competitiveness by investigating Continuous Pharmaceutical Manufacturing (CPM). The present paper explores the CPM of two key Active Pharmaceutical Ingredients (APIs), ibuprofen and artemisinin: cost savings and material efficiency benefits are evaluated for CPM vs. batch processing, with two continuous options for each API. Capital Expenditure (CapEx) savings of up to 57.0% and 19.6% and corresponding Operating Expenditure (OpEx) savings of up to 51.6% and 29.3% have been determined for ibuprofen and artemisinin, respectively. Total projected cost savings for a 20-year plant lifetime can reach 54.5% and 20.1%, respectively. Environmental (E)-factors (mass of waste generated per unit mass of product) of 43.4 (for ibuprofen) and 12.2 (for artemisinin) have been computed, indicating environmental and material efficiency advantages for these conceptual continuous pharmaceutical processes.

“…[13][14][15][16][17][18][19]; and a section implementing the optimisation itself (Eqs. [20][21][22][23][24][25][26][27][28][29]. Two solvers were tested: the NOMAD solver and the NLOPT solver with the BOBYQA algorithm (NLOPT-BOBYQA), both implemented in MATLAB.…”

Section: Nlp Code and Structurementioning

confidence: 99%

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

Jolliffe

Diab

2017

Org. Process Res. Dev.

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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.