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.