Effect of Low-Level Organic Impurities on Pharmaceutical Crystallization Kinetics and Impact on Physical Properties

The crystallization for current drug substance API manufacturing is usually designed to hit the major critical quality attributes, namely purity and physical properties. It has been well documented that impurities can alter crystallization kinetics to affect morphology, size and crystal form.[1-3] Many synthetic schemes have reactive crystallization for salt formation[4] as the final API isolation step where either a recrystallization is implemented to improve physical properties for downstream drug product processing. Herein, we present a case study where an API free acid is isolated for purity control followed by a final recrystallization for physical property improvement. We show how trace levels of impurities impact both the salt formation and recrystallization steps. We show how these impurities can directly influence the solid form landscape as well as deactivate the seed surface which leads to poor physical properties.  We also show the efficiency of spherical agglomeration[5] to improve physical properties for downstream drug product development.

References

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2. Rauls, M., et al., The influence of impurities on crystallization kinetics–a case study on ammonium sulfate. 2000. 213(1-2): p. 116-128.
3. Ottens, M., et al., Impurity effects on the crystallization kinetics of ampicillin. 2004. 43(24): p. 7932-7938.
4. McDonald, M.A., et al., Reactive crystallization: a review. 2021. 6(3): p. 364-400.
5. Pitt, K., et al., Particle design via spherical agglomeration: A critical review of controlling parameters, rate processes and modelling. 2018. 326: p. 327-343.