(324a) Prevalence of Impurity Retention Mechanisms in Pharmaceutical Crystallizations

Purity control in pharmaceutical industry is primarily achieved through the unit operation of crystallization. Several types of theoretical impurity purge mechanisms have been proposed in literature that can explain how impurities can be retained in the solid phase with the product. However, the frequency of these presumed mechanisms and their importance in real industrial crystallizations have never been reported. Presented in this talk is the outcome of a joint investigation by Boehringer-Ingelheim (Ridgefield, CT), Merck & Co., Inc. (Rahway, NJ) and Rowan University on the occurrence of impurity retention mechanisms in solution crystallization[1]. The underlying impurity retention mechanism for a total of 52 product-impurity pairs have been determined using the so-called SLIP test[2]. 31 of these systems come from real pharmaceutical industrial crystallizations from 2017 to 2022 where impurity retention issues were observed in crystallizations. They include both intermediates and APIs and were observed in early to late-stage projects, as well as for marketed products. The remaining 21 of cases have been produced using generic compounds where structurally similar compounds have been spiked in to simulate impurities.

48 of the investigated examples can be explained by only two classes of impurity retention mechanisms. The most common mechanism at 79% of cases related to when the impurity is miscible in the solid state with the product and forms one solid solution phase, or in some cases two solid solution phases (one where the impurity is the minor component, and the second phase where the product is the minor component). This outcome was found across the board, independent of pharmaceutical company, academia or type of compound. The second most common impurity retention mechanism at 21%, related to when phase-pure impurities crystallized during the cycle time of the process, resulting in a physical mixture with the product. These can be further separated into SLIP 1 (17%) or SLIP 2 (4%) mechanisms². In no case were solvent inclusion, agglomeration, surface adsorption or co-crystals identified as the responsible mechanism. The reasons for the results are discussed based on a thermodynamic assessment including ternary phase diagrams, practical scale-up constraints, and a critical assessment on the theoretical impurity retention mechanisms.

[1] Nordstrom, Sirota, Hartmanshenn, Kwok, Paolello, Li, Abeyta, Bramante, Madrigal, Behre, Capellades, Org. Proc. Res. & Dev., 2023

[2] Nordstrom, Linehan, Teerakapibal, Li, Cryst. Growth. Des. 2019, 19, 1336-1346