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Comparison and Combination of Organic Solvent Nanofiltration and Adsorption Processes: A Mathematical Approach for Mitigation of Active Pharmaceutical Ingredient Losses during Genotoxin Removal.

ABSTRACT: Active pharmaceutical ingredients (API) are synthesized using highly reactive reagents, catalysts, and solvents. Some of those persist as impurities in the final product and are genotoxic or carcinogenic. The conventional processes used for API purification and isolation are able to achieve the limits imposed by regulatory agencies, but at the expense of significant API losses. Here we report the development of a model to aid in the decision of which dedicated purification process, membrane or adsorption, is most suitable for removal of genotoxic impurities (GTIs), according with a small set of key intrinsic parameters. A hybrid process was developed, combining these two unit operations, to be applied when the use of OSN or adsorption alone result on non-acceptable API losses. Membrane solute rejection and solvent flux was used as parameter for OSN. In the case of adsorption, two isotherm models, Langmuir and Freundlich, were considered. The effect of the recirculation stream and amount of adsorber used on the hybrid process was investigated. Case studies were experimentally validated, confirming that combining the two unit operations can reduce API loss from 24.76% in OSN to 9.76% in a hybrid process. Economic and environmental analyses were performed.

SUBMITTER: Ferreira F

PROVIDER: S-EPMC7231377 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Comparison and Combination of Organic Solvent Nanofiltration and Adsorption Processes: A Mathematical Approach for Mitigation of Active Pharmaceutical Ingredient Losses during Genotoxin Removal.

Ferreira Flávio F Resina Leonor L Esteves Teresa T Ferreira Frederico Castelo FC

Membranes 20200416 4

Active pharmaceutical ingredients (API) are synthesized using highly reactive reagents, catalysts, and solvents. Some of those persist as impurities in the final product and are genotoxic or carcinogenic. The conventional processes used for API purification and isolation are able to achieve the limits imposed by regulatory agencies, but at the expense of significant API losses. Here we report the development of a model to aid in the decision of which dedicated purification process, membrane or a ...[more]

PMID: 32316155

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Project description:Washing is a key step in pharmaceutical isolation to remove the unwanted crystallization solvent (mother liquor) from the active pharmaceutical ingredient (API) filter cake. This study looks at strategies for optimal wash solvent selection, which minimizes the dissolution of API product crystals while preventing the precipitation of product or impurities. Selection of wash solvents to avoid both these phenomena can be challenging but is essential to maintain the yield, purity, and particle characteristics throughout the isolation process. An anti-solvent screening methodology has been developed to quantitatively evaluate the propensity for precipitation of APIs and their impurities of synthesis during washing. This is illustrated using paracetamol (PCM) and two typical impurities of synthesis during the washing process. The solubility of PCM in different binary wash solutions was measured to provide a basis for wash solvent selection. A map of wash solution composition boundaries for precipitation for the systems investigated was developed to depict where anti-solvent phenomena will take place. For some crystallization and wash solvent combinations investigated, as much as 90% of the dissolved PCM and over 10% of impurities present in the PCM saturated mother liquor were found to precipitate out. Such levels of uncontrolled crystallization during washing in a pharmaceutical isolation process can have a drastic effect on the final product purity. Precipitation of both the product and impurities from the mother liquor can be avoided by using a solvent in which the API has a solubility similar to that in the mother liquor; for example, the use of acetonitrile as a wash solvent does not result in precipitation of either the PCM API or its impurities. However, the high solubility of PCM in acetonitrile would result in noticeable dissolution of API during washing and would lead to agglomeration during the subsequent drying step. Contrarily, the use of n-heptane as a wash solvent for a PCM crystal slurry resulted in the highest amount of precipitation among the solvent pairs evaluated. This can be mitigated by designing a multi-stage washing strategy where wash solutions of differing wash solvent concentrations are used to minimize step changes in solubility when the mother liquor and the wash solvent come into contact.

Project description:Glycolipid biosurfactants are the most prominent group of microbial biosurfactants, comprising rhamnolipids, sophorolipids and mannosylerythritol lipids (MELs). Usually, large amounts of hydrophobic substrates (e.g., vegetable oils) are used to achieve high titers (~200 g/L) of a crude product of low purity at values limited to 50-60%, contaminated with unconsumed triacylglycerol and residual free fatty acids and monoacylglycerides. The methods reported for the removal of these contaminants use a mixture of organic solvents, compromising solvent recyclability and increasing final process costs. This study reports, for the first time, an innovative downstream method for MELs, in which 90% of the triacylglycerols are separated from the crude MEL mixture in a first stage and the other lipid derivatives (free fatty acids, mono- and diacylglycerols) are removed by organic solvent nanofiltration (OSN). Three commercially available membranes (GMT-oNF-2, PuraMEm-600 and DuramMem-500) and several homemade membranes, casted from 22, 24 or 26% (w/v) polybenzimidazole (PBI) solutions, were assessed for crude MELs purification by diafiltration. A final purity of 87-90% in the MELs was obtained by filtering two diavolumes of methanol or ethyl acetate solutions through a PBI 26% membrane, resulting in MELs losses of 14.7 ± 6.1% and 15.3 ± 2.2%, respectively. Higher biosurfactant purities can be archived using the PBI 26% membrane at higher DV, but at the cost of higher product losses. Namely, in MeOH, the use of 6 DV leads to losses of 32% for MELs and 18% for sophorolipids. To obtain MELs at reagent grade with purities equal or higher than 97%, a two-sequential cascade filtration approach was implemented using the commercial membrane, GMT-oNF. In such a process, MELs with 98% purity was obtained at the cost of 11.6% MELs losses. Finally, decoloration, important in some applications, was successfully assessed using activated carbon. Overall, this study reports a unique solution for microbial biosurfactants production with minimal product losses, enabling solvent recycling and potentially reducing costs.

Dataset Information

Comparison and Combination of Organic Solvent Nanofiltration and Adsorption Processes: A Mathematical Approach for Mitigation of Active Pharmaceutical Ingredient Losses during Genotoxin Removal.

Publications

Comparison and Combination of Organic Solvent Nanofiltration and Adsorption Processes: A Mathematical Approach for Mitigation of Active Pharmaceutical Ingredient Losses during Genotoxin Removal.

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