Analysis of the solvents involved in the manufacturing process is a longstanding regulatory requirement in the pharmaceutical
industry. According to the initial guidelines proposed by the International Conference on Harmonization (ICH) and by the United
States Pharmacopeia (USP, General Chapter <467>) and European Pharmacopeia (EP), manufacturing solvents must be carefully
regulated because they have varying levels of toxicity or environmental hazard and they have no therapeutic benefit (1–3).
The solvents are grouped into three classes:
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.
Class 3: Solvents with little or no toxicity. Required daily exposure limit of 5000 ppm. If only class 3 solvents are present,
they can be quantified by loss on drying, with quantitation by gas chromatography (GC) if the level exceeds 5000 ppm.
Table I: USP and ICH Class 1, 2, and 3 solvents with first and second dimension retention times and concentration limits
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There is also a fourth class of solvents for which there is not sufficient toxicological data to establish a requirement.
The class 1, 2, and 3 solvents and their maximum exposure limits are shown in Table I along with their comprehensive two-dimensional
GC (GC×GC) retention times using the separation conditions described in this article. Maximum daily exposure (MDE) is used
to determine the required concentration limit for an individual method. In United States Pharmacopeia (USP) method <467>,
Residual Solvents, the required concentration limit is determined from the MDE based upon a daily dosage of 10 g of the final
drug product (4). If the dosage is less than 10 g, the allowable detection limit in a method would be higher; if the dosage
is more than 10 g, the allowable detection limit is lower.
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.
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