2019
DOI: 10.1002/aic.16738
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Technoeconomic Mixed Integer Nonlinear Programming (MINLP) optimization for design of Liquid‐Liquid Extraction (LLE) cascades in continuous pharmaceutical manufacturing of atropine

Abstract: Continuous Pharmaceutical Manufacturing (CPM) offers operational and economic benefits over the currently dominant methods implemented by industry. The demonstrated continuous flow synthesis of atropine facilitates modeling and optimization of its upstream continuous manufacturing. This study implements MINLP optimization of a continuous Liquid-Liquid Extraction (LLE) flowsheet superstructure for total cost minimization of an upstream atropine CPM plant. The steady-state process model considers reactor design … Show more

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Cited by 14 publications
(8 citation statements)
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“…For artemisinin, diphenhydramine and warfarin, the E-factor decreases (i.e., material efficiency improves) as plantwide recovery increases-this is expected, as waste quantities are lower when the plant API recovery is high for a specified plant API capacity. For atropine, the same trend is not observed; this is due to different quantities of separation solvent being used between design cases in order to attain total cost minima in the design cases [70]. For nevirapine, the different design cases correspond to different solvent recovery assumptions; evidently, as SR increases, the E-factor improves (i.e., decreases).…”
Section: Plant Design Performance Metricsmentioning
confidence: 89%
See 1 more Smart Citation
“…For artemisinin, diphenhydramine and warfarin, the E-factor decreases (i.e., material efficiency improves) as plantwide recovery increases-this is expected, as waste quantities are lower when the plant API recovery is high for a specified plant API capacity. For atropine, the same trend is not observed; this is due to different quantities of separation solvent being used between design cases in order to attain total cost minima in the design cases [70]. For nevirapine, the different design cases correspond to different solvent recovery assumptions; evidently, as SR increases, the E-factor improves (i.e., decreases).…”
Section: Plant Design Performance Metricsmentioning
confidence: 89%
“…In R-502, the aldol addition of formaldehyde (CH 2 O) to the tropine ester at 100 • C under basic conditions forms the API, accompanied by an undesired elimination of API to apoatropine via condensation [69]. A subsequent continuous LLE in a cascade of vessels is performed with either diethyl ether (Et 2 O), n-butyl acetate (BuOAc) or toluene (PhMe) for comparative evaluation purposes [70]. The CPM flowsheet for atropine is shown in Figure 15.…”
Section: Atropinementioning
confidence: 99%
“…Conventional batch equipment such as large batch reactors, crystallizers and mixer-settlers are replaced by smaller scale plug flow reactors (PFRs), mixed-suspension mixed-productremoval crystallisers (MSMPRs), and liquid-liquid separators, reducing footprint and enhancing process economies 6,9,10 .…”
Section: Introductionmentioning
confidence: 99%
“…Conventional batch equipment such as large batch reactors, crystallizers and mixersettlers are replaced by smaller scale plug flow reactors (PFRs), mixed-suspension mixed-product-removal crystallisers (MSMPRs), and liquid-liquid separators, reducing footprint and enhancing process economies. 6,9,10 Bubble columns have been shown to offer high rates of mass and heat transfer throughout, due to the intimate contact of the two phases and the enhanced mixing profiles provided by the bubble dynamics. [11][12][13][14][15] Also advantageous is their relative simplicity of installation, requiring no moving parts and easily introduced in most working fume hoods with suitable plumbing facilities.…”
Section: Introductionmentioning
confidence: 99%
“…Mixed Integer Nonlinear Programming (MINLP) has been widely implemented in various applications to rapidly screen for optimal design configurations of separation processes. Optimization of distillation column trains, adsorption cycles, , Liquid–Liquid Extraction (LLE) cascades, , chromatographic resolutions, and membrane separations have been covered extensively in the literature, showing promise of significant process improvements via MINLP optimization. Mixed integer problems contain both continuous decision variables (e.g., unit operating and design parameters), as well as integer (binary or otherwise) decision variables, such as denoting the existence of a unit operation or deciding stream allocation.…”
Section: Introductionmentioning
confidence: 99%