The perfect separation with optimal productivity, yield, and purity is very difficult to achieve. Despite its high selectivity, in crystallization unwanted impurities routinely contaminate a crystallization product. Awareness of the mechanism by which the impurity incorporates is key to understanding how to achieve crystals of higher purity. Here, we present a general workflow which can rapidly identify the mechanism of impurity incorporation responsible for poor impurity rejection during a crystallization. A series of four general experiments using standard laboratory instrumentation is required for successful discrimination between incorporation mechanisms. The workflow is demonstrated using four examples of active pharmaceutical ingredients contaminated with structurally related organic impurities. Application of this workflow allows a targeted problem-solving approach to the management of impurities during industrial crystallization development, while also decreasing resources expended on process development.
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