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.
Highlights
Active pharmaceutical ingredients (APIs) available in the market are mostly synthesized in organic solvent media using highly reactive molecules
The results are discussed in terms of API losses and process solvent intensity
API losses below 10% were considered acceptable, between
Summary
Active pharmaceutical ingredients (APIs) available in the market are mostly synthesized in organic solvent media using highly reactive molecules. Low levels of reagents, fractions of catalysts or by-products are present as impurities in the intermediate or final API post-reaction stream. Some of these impurities have unwanted toxicities, including genotoxicity and carcinogenicity. Related API administration risks for patient’s health caused by the genotoxic impurities (GTIs) has become an increasing concern from pharmaceutical companies and regulatory authorities [1]. It is mandatory to ensure that GTI content on the final APIs is controlled below a Threshold of Toxicological Concern (TTC), established by regulatory authorities (1.5 μg/day) [2]
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