Quantitative Impurity Rejection Analysis for Crystallization

The analysis of impurity profiles is one of the most frequently performed activities in drug development. While mass-based quantification using a reference standard often provides the highest degree of accuracy, carrying this out on every impurity across the synthetic scheme can quickly become untenable when considering the often large number of impurities and the requirement for a synthesized and characterized reference standard. These labor-intensive activities are generally reserved for only selected impurities using a science- and risk-based approach, and approximations such as "purge factor" or "before and after peak area %" are often used in the remaining cases when a wider margin of error is acceptable. Presented herein is a simple mathematical framework to perform mass-based quantification for impurity rejection in silico using the principles of mass balance without the burdensome requirements of obtaining individual response factors or reference standards. This analysis is expected to provide useful guidance for process and analytical chemists.