Organic solvent nanofiltration: A platform for removal of genotoxins from active pharmaceutical ingredients

Abstract

This paper discusses the use of organic solvent nanofiltration (OSN) as a general platform for the removal of genotoxic impurities (GTI) used as reactants or formed during the synthesis of active pharmaceutical ingredients (API) or their intermediates. The analyses carried out takes into account simple and easy available inputs, such as the molecular size of the API and GTIs. Results are discussed in terms of API losses and GTI removal, as well as final contamination levels. Boundaries are established for a quick assessment of the API/GTI separation in three categories (A) OSN provides a straight forward route for removal of GTIs from API post reactions, (B) OSN can be applied for a useful removal of GTI from API post reactions, and (C) OSN alone is not adequate removal of GTI form API and other technologies or new OSN membranes are required. For the intermediate category, case B, higher diavolumes may be required to reach low GTI toxicity thresholds leading to API losses with significant economic impact. Therefore, for this case, feasibility of OSN purification is also discussed on the basis of daily dose of an API and the corresponding GTI threshold limit. Nine APIs and eleven GTIs were selected as model compounds to be representative of the diversity of chemical reactions and compound structures produced by the Pharmaceutical Industry. The solubility of APIs in several solvents was evaluated and methyl ethyl ketone (MEK) and tetrahydrofuran (THF) were selected as model solvents for this study. These two polar solvents are usually used in industry due to their ability to dissolve APIs at high loads. However the very same dissolution power makes it difficult to develop polymeric OSN membranes stable to such solvents. Two available OSN membranes were selected on which the literature data available is scarce in order to complement the known data. Membrane rejections at two applied pressures were experimentally estimated and diafiltration was used to illustrate API/GTI potential separation. The methodology proposed here can be applied to other membranes, solvents, APIs and GTIs.