Class 1: Solvents to be avoided because they are highly toxic or are especially hazardous to the environment. Required daily exposure limits are 2–1500 ppm.

Class 2: Solvents with moderate toxicity, including most common solvents used in synthetic processes. Required daily exposure limits are 20–4800 ppm.

Table I: USP and ICH Class 1, 2, and 3 solvents with first and second dimension retention times and concentration limits

Table I demonstrates the two challenges in developing a single comprehensive GC method for pharmaceutical solvents: there are about 60 compounds in classes 1–3 and the allowable concentration limits can range over three orders of magnitude (2–5000 ppm for a 10-g dose of the drug) within the same sample. While there has been considerable work and there are numerous residual solvents methods reported in the literature, a single comprehensive method encompassing both challenges in one run does not currently exist (5–9). Most methods were designed for individual problems and involve the separation of 3–10 solvents with run times of 10–30 min or more. The large number of compounds coupled with their varying chemistry necessitates the use of separations run on multiple columns of differing selectivity methods if a single method to separate all of them in a reasonable amount of time, as described in USP <467>, is desired.