(409e) Formation of Solid Solutions As a Key Impurity Retention Mechanism in Solution Crystallization in the Presence of Structurally Similar Impurities

The main purpose of crystallization is to purify the product by removing undesired impurities. In pharmaceutical industry, crystallizations at different steps in the synthesis are relied upon to control the final quality of the active pharmaceutical ingredient (API). During these operations, the main challenge often stems from dealing with structurally similar impurities, which tend to be difficult to remove. Presented herein is an investigation into how this type of challenging impurities are purged mechanistically in the crystallization, using pharmaceutical case studies. Through these examples, it is shown that formation of substitutional solid solutions is the underlying mechanism for impurity retention. Impurities molecularly replace the product molecules in the crystal lattice during the crystallization. This lattice incorporation entrapment occurs unevenly during the crystallization resulting in a gradient in impurity levels throughout the material. A mathematic framework combined with a previously reported SLIP test is used to elucidate this varying impurity entrapment through a so-called material impurity distribution (MID). The impurity levels are seen in many cases to change by an order of 20 across the material. The effect of the entrapment can also be observed in the physical properties of the material, e.g. by a significant reduction in crystallinity, increase in solubility and earlier onset melting event.