Identification of residues in ethylene oxide sterilized hard gelatin capsule shells by gas chromatography-mass spectrometry and development of a simple gas chromatography-flame ionization detector method for the determination of residues

Abstract

Four toxic residues in gelatin capsule shells after ethylene oxide (EO) sterilization were identified by gas chromatography-mass spectrometer (GC-MS) and they were ethylene oxide, 2-chloroethanol, acetaldehyde, and 1,4-dioxane. The generation pathway and mechanism of the 2-chloroethanol, acetaldehyde, and 1,4-dioxane were further investigated. Additionally, a simple and rapid gas chromatography-flame ionization detector (GC-FID) method was established and fully validation including specificity, linearity, sensitivity, and accuracy were conducted according to ICH Q2 (R1) guidelines. The results showed good linearities with coefficients (r) higher than 0.9999 for four analytes. The limits of detection (LODs) of four analytes were in the range of 0.025-1.0 μg·mL −1 and the limits of quantitation (LOQs) were in the range of 0.05-2.0 μg·mL −1 . The recoveries of four impurities were ranged from 83.0 % to 114.9 %. The repeatability and inter-day precisions were in the ranges of 0.7-3.3%. This validated GC-FID method provided an approach for capsule manufacturers to routinely monitor residues in gelatin capsule shells, design and optimize the storage time after sterilization and judge whether it can be released from the factory after sterilization. It can also be used for enterprises and regulatory bodies to routinely control the quality of hard gelatin capsule shells.