Determination of ethylene oxide residues in sterilized ophthalmic active pharmaceutical ingredients via the full evaporation technique coupled to gas chromatography.

Ethylene oxide (EO) is primarily employed for terminal sterilization. While efforts are made to minimize its presence post-sterilization, residues such as EO, ethylene chlorohydrin (ECH), and acetaldehyde (AA) may persist. Due to their low concentrations, sensitive analytical techniques are required for their detection. Existing techniques are scarce and typically involve multiple sample preparation steps, usually starting with the search for a suitable solvent to dissolve the sample. In this study, a novel approach combining the full evaporation technique with headspace - gas chromatography - flame ionization detection (FET-HS-GC-FID) has been explored to quantify EO residues in six active pharmaceutical ingredients (APIs) for ophthalmic use. This method simplifies sample preparation and utilizes standard GC instrumentation without any modification. An equilibration temperature of 105 °C for 20 min was found sufficient to evaporate all the analytes. To avoid coelution of AA and EO, a BP5 (5 % phenyl - 95 % dimethylpolysiloxane) column was used. The limit of quantification (LOQ) for AA and EO was 0.05 ppm while for ECH it was 1.25 ppm. The method showed good linearity with the coefficient of determination (r2) equal to 0.9993 for AA, 0.9996 for EO and 0.9992 for ECH. Precision was acceptable with relative standard deviation (RSD) values below 2 %. The recovery ranged from 90 to 101 %. An interference in the chromatogram was observed for one out of six APIs. Time-mediated interactions between EO and the APIs were also evaluated. Sterilized samples were also used to test the applicability of the procedure. Quality assurance testing of the aeration process is crucial to verify its effectiveness throughout the aeration cycle. Compared to existing methods, the developed one offers easy sample preparation, less sample interference and saves solvent, cost, and time.