By Fredrik Nordstrom, Ph.D.
Material and Analytical Sciences, Boehringer-Ingelheim, Ridgefield, CT, 06877
fredrik.nordstrom@boehringer-ingelheim.com

The decision for selecting and optimizing the synthetic route of a drug candidate is to a large degree dependent on the achievable purity of the active pharmaceutical ingredient (API). Crystallization is the most widely utilized unit operation to reject process-impurities. This is carried out throughout the chemical synthesis, often ranging from the regulatory starting material to the API, in sometimes more than one iteration. While impurities can be of very different chemical structure and origin, it was recently demonstrated that the formation of solid solutions between the product and impurity constitutes a large majority of impurity challenges in pharmaceutical crystallizations[1]. This stems from having structurally similar impurities exhibiting solid-state miscibility with the product and becoming incorporated in the crystal lattice of the product as the crystallization proceeds. A particularly challenging purification occurs when the product-impurity pair not only forms one solid solution but two, wherein the second solid phase is comprised of predominately the impurity and the product is the minor component. Presented in this talk is an industrial case study showing how a critical regioisomer impurity formed at 15% in the last synthetic step, generated a partially miscible solid solution system with the API. Two solid phases were formed in the crystallization, each with different solvent solubilities that were dependent on process volumes and impurity level. No other crystal forms of either API or regioisomer could be identified to break the solid-state miscibility and the present synthetic route offered significant advantages. To overcome this extraordinary challenge for the project team, a novel thermodynamic model was developed based on isosceles ternary phase diagrams for partially miscible systems. The solvi from the constructed T-X binary phase diagram in concert with experimental solvent solubilities were introduced into the model to screen and identify suitable solvent systems for effective purification. The selected solvents were then experimentally verified by reslurrying and recrystallization. Ultimately, a combined polish filtration and crystallization process was developed that removed the regioisomer from 15% to less than 0.5% in acceptable yield. The two-step process was executed under thermodynamic control to omit any kinetic variations. This work demonstrates how effective purification strategies can be successfully implemented based on mechanistic understanding of impurity purge in crystallization, to enable an economical and efficient chemical synthetic route. [1] Nordstrom, F. L., Sirota, E., Hartmanshenn, C., Kwok, T. T., Paolello, M., Li, H., Abeyta, V., Bramante, T., Madrigal, E., Behre, T., Capellades, G., Prevalence of impurity retention mechanisms in pharmaceutical crystallizations, Org. Proc. Res. & Dev, 2023, 27, 4, 723-741