Residual solvent (revision 9)

Residual solvents are organic volatile chemicals used or produced in manufacture that remain in the finished substance. They are classified by toxicity: Class 1 solvents are to be avoided, Class 2 are limited to specified concentrations, and Class 3 are regarded as low-risk and controlled at a general limit.^[1]

In peptide manufacture the solvents of interest are those used in synthesis, cleavage and purification — dimethylformamide, dichloromethane, acetonitrile, methanol, trifluoroacetic acid and diethyl ether among them. Several fall in Class 2 and are limited accordingly.^[2]

Determination is by headspace gas chromatography, in which the sample is equilibrated in a sealed vial and the vapour above it sampled. The method is specific to the named solvents: a solvent not on the method's list is not looked for and will not be reported.^[2]

Limits for Class 2 solvents are derived from a permitted daily exposure and a maximum daily dose, so a concentration limit depends on how much substance is administered. A concentration expressed without reference to that basis cannot be assessed against a limit.^[1]

Dimethylformamide is the solvent most characteristic of peptide synthesis and is a Class 2 solvent with a comparatively low limit. Its persistence in a dried peptide depends on the drying regime and on whether an intermediate solvent exchange was performed, and it contributes to any loss-on-drying figure obtained on the same material.^[3][4]