(243d) Structured Approach to Optimize Pharmaceutical Crystallization Process for Optimal Impurity Rejection

Current pharmaceutical drug substance or API manufacturing processes routinely face the challenge of having to control numerous organic impurities simultaneously while also trying to optimize yield. In this talk, we will present an industrial case study for an API in development where we used a structured approach described recently [1] to identify the impurity rejection mechanism of several key impurities present in the process with the aim to support the building of the impurity control strategy. This more mechanistic rejection information is then used to help assess risks of the process and define and optimize the final isolation conditions. A self-consistent approach to data reconciliation from isothermal equilibration, crystallization hold studies and stepwise dissolution experiments will be discussed to aid in the mechanism determination.[2, 3] Based on the solubility limited rejection mechanism identified for several impurities we modified the crystallization process for optimal impurity rejection and process yield as a function of various process parameters using existing mass balance equations.[4, 5]

References

1. Urwin, S.J., et al., A structured approach to cope with impurities during industrial crystallization development. 2020. 24(8): p. 1443-1456.
2. Myerson, A., Handbook of industrial crystallization. 2002: Butterworth-Heinemann.
3. Moynihan, H.A. and D.J.R.a. Armstrong, Stepwise dissolution and composition determination of samples of multiple crystals using a dissolution medium containing aqueous alcohol and fluorocarbon phases. 2019. 9(37): p. 21405-21417.
4. Nordstrom, F.L., et al., Solubility-limited impurity purge in crystallization. J Crystal Growth Design, 2019. 19(2): p. 1336-1346.
5. Teerakapibal, R., et al., Material Impurity Distribution of Lattice-Incorporated Impurities in Salicylic Acid. J Crystal Growth Design, 2020. 20(3): p. 1716-1728.