A Capillary Gas Chromatographic Procedure for the Analysis of Nine Common Residual Solvents in Water-Insoluble Bulk Pharmaceuticals

Abstract

A direct-injection, split-mode capillary gas chromatographic procedure is developed for the analysis of nine solvents commonly used in the synthesis and purification of bulk pharmaceuticals. The nine solvents are methanol, methylene chloride, hexane, ethyl acetate, tetrahydrofuran, iso-octane, 1,4-dioxane, toluene, and dimethylformamide. The procedure is derived by modifying U.S. Pharmacopeia and European Pharmacopeia compendial methods. Modifications include raising injection temperature and revising temperature programming, leading to enhanced sensitivity and a shorter analysis time of 40 min. For each solvent, the procedure is validated for selectivity, linearity, recovery, precision, quantitation limit, and detection limit. All nine solvents are completely resolved. Determination coefficients (r2) are at least 0.998. Toluene has a linear response from 10 to 1000 ppm (with respect to a drug concentration of 100 mg/mL). All other solvents have linear responses from 20 to 2000 ppm. Recoveries range from 99.3 to 100.9%. Relative standard deviations for precision are not more than 2.8%. The quantitation limits (in ppm) are as follows: methanol, 8.6; methylene chloride, 95.3; hexane, 48.5; ethyl acetate, 23.5; tetrahydrofuran, 13.0; iso-octane, 24.0; 1,4-dioxane, 31.5; toluene, 10.0; and dimethylformamide, 14.9. Furthermore, a system suitability test is validated, and requirements are set. Finally, two drug substance samples are analyzed to show the suitability of the procedure, which can generally be used to determine any one or any combination of these nine residual solvents in water-insoluble bulk pharmaceuticals.