Separation of Active Pharmaceutical Ingredients (APIs) from Excipients in Pharmaceutical Formulations

Atwood, Jerry L.

doi:10.1021/acs.cgd.5b00317

Cited by 5 publications

(3 citation statements)

References 11 publications

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“…The slurry density, M i , is calculated from the population density (eq ). k v is the crystal volume shape factor − and ρ API is the API crystal density; values for all APIs are listed in Tables and .…”

Section: Process Modeling and Nonlinear Optimization Methodologymentioning

confidence: 99%

Technoeconomic Optimization of Continuous Crystallization for Three Active Pharmaceutical Ingredients: Cyclosporine, Paracetamol, and Aliskiren

Diab

Gerogiorgis

2018

Ind. Eng. Chem. Res.

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Mixed suspension, mixed product removal (MSMPR) crystallizers are widely implemented for the continuous crystallization of active pharmaceutical ingredients (APIs), allowing enhanced efficiency, flexibility, and product quality compared to currently dominant batch crystallizer designs. Establishing cost-effective continuous crystallization process configurations for societally and economically important APIs is essential to ensure the successful implementation of end-to-end continuous pharmaceutical manufacturing (CPM) campaigns. Process modeling and optimization allow rapid, systematic comparative technoeconomic evaluations. This paper pursues total cost minimization of different crystallizer configurations of three APIscyclosporine, paracetamol, and aliskiren hemifumaratewhose continuous MSMPR crystallization has been experimentally demonstrated. Nonlinear optimization for total cost minimization is implemented for one to three crystallizers for different plant API capacities with crystallizer temperatures and residence times as decision variables. Optimization results show that the optimal number of crystallizers is dependent on plant capacity; implementing one crystallizer is preferred for all three APIs at 102 kg year–1, while multiple crystallizer implementation is more cost-beneficial at increased capacities. These trends are observed due to the increasing dominance of operating expenditures on total costs at increased capacities, making the benefits of implementing more crystallizers (enhanced yields, reduced utility loads) worth the increased capital expenditures. Process modeling and optimization allows rapid technoeconomic evaluation of MSMPR crystallizer configurations for different APIs toward systematic selection of optimal continuous crystallizer designs for continuous manufacturing.

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Section: Process Modeling and Nonlinear Optimization Methodologymentioning

confidence: 99%

Technoeconomic Optimization of Continuous Crystallization for Three Active Pharmaceutical Ingredients: Cyclosporine, Paracetamol, and Aliskiren

Diab

Gerogiorgis

2018

Ind. Eng. Chem. Res.

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“…The slurry density in MSMPR i is calculated from the population density function as follows: k v is the crystal volume shape factor (= π/6 for spherical crystals, assumed constant for linear crystal growth) and ρ API is the API crystal density. A typical value of ρ API = 1.3 g cm –3 for solid APIs is assumed here due to the lack of physical property data for cyclosporine.…”

Section: Steady-state Process Model and Simulation Methodsmentioning

confidence: 99%

Technoeconomic Evaluation of Multiple Mixed Suspension-Mixed Product Removal (MSMPR) Crystallizer Configurations for Continuous Cyclosporine Crystallization

Diab

Gerogiorgis

2017

Org. Process Res. Dev.

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Continuous crystallization using Mixed Suspension-Mixed Product Removal (MSMPR) crystallizers has been demonstrated as a feasible method for implementing continuous separations in pharmaceutical manufacturing processes. This work conducts a steady-state process modeling and simulation study of the continuous cooling crystallization of cyclosporine, comparing processes with and without solids recycle for their technoeconomic viability. The model describes population balance equations, crystallization kinetics, and process mass balances to compare attainable crystallization and plantwide yields of different process configurations. Total cost components using an established economic analysis methodology are compared for varying numbers of crystallizers, operating temperatures, total crystallizer cascade residence times and API feed concentrations. Economic analyses and the calculation of normalized cost components with respect to total crystallizer volumes identify the process without recycle as the most economically viable option, achieving the lowest total costs and low E-factors for pharmaceutical processes. The sensitivity of total costs to the selected total residence times for economic analyses highlights the need for rigorous comparison methodologies. This work identifies the need for technoeconomic optimization studies of continuous crystallization processes to establish the optimal design of manufacturing campaigns prior to further development.

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“…After several days ageing, the analysis of the reaction mixture revealed the selective transformation of zinc oxide into Znox•2H 2 O, with retention of copper(II) oxide. The significant difference in density of zinc oxalate (2.2 g cm −3 ) and CuO (6.3 g cm −3 ) enabled the gravity-based separation [80] of the two materials by flotation in the heavy liquid diiodomethane (CH 2 I 2 , with density 3.32 g cm −3 ) (figure 5c). The broader applicability of such solvent-free separation was also demonstrated on binary mixtures of CuO and PbO, as well as ZnO and PbO.…”

Section: (B) Accelerated Ageing Synthesis Of Metal-organic Framework and Coordination Polymersmentioning

confidence: 99%

Geomimetic approaches in the design and synthesis of metal-organic frameworks

Huskić

Friščić

2019

Phil. Trans. R. Soc. A.

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The recent discovery of minerals with metal-organic framework (MOF) structures has challenged the view of MOFs as purely synthetic materials. At the same time, the application of geo-inspired synthetic methodologies, such as accelerated ageing and pseudomorphic replication, has enabled a cleaner, more environmentally friendly synthesis of MOFs from mineral-like feedstocks, as well as the assembly of materials with structure controlled at both micro- and meso-scales. These almost concomitant developments have highlighted the previously unknown relationships between geology and MOF chemistry. Here, we outline examples of MOF structures found in minerals, and note geologically inspired approaches to MOF synthesis, as a means to highlight how the emergent geomimetic concepts in MOF chemistry can lead to advances in the design and synthesis of MOFs. This article is part of the theme issue ‘Mineralomimesis: natural and synthetic frameworks in science and technology’.

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Separation of Active Pharmaceutical Ingredients (APIs) from Excipients in Pharmaceutical Formulations

Cited by 5 publications

References 11 publications

Technoeconomic Optimization of Continuous Crystallization for Three Active Pharmaceutical Ingredients: Cyclosporine, Paracetamol, and Aliskiren

Technoeconomic Optimization of Continuous Crystallization for Three Active Pharmaceutical Ingredients: Cyclosporine, Paracetamol, and Aliskiren

Technoeconomic Evaluation of Multiple Mixed Suspension-Mixed Product Removal (MSMPR) Crystallizer Configurations for Continuous Cyclosporine Crystallization

Geomimetic approaches in the design and synthesis of metal-organic frameworks

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