Analysis of hydrogen sulfide gas from a pharmaceutical drug formulation by cryofocused headspace gas chromatography

Abstract

A sulfurous odour generated in formulations of pioglitazone, a drug candidate that was under development as an antidiabetic agent, was determined to be owing to hydrogen sulfide. The odour was produced in granulations containing citric acid as an excipient. Odour generation was exacerbated at high temperature and humidity. The maximum concentration of H₂S detected was 340 ppb, measured in the headspace over an aqueous, granulated 1 + 1 pioglitazone–citric acid mixture which had been stressed for 30 d at 50 °C and 100% relative humidity. The principal mechanism of degradation is believed to involve initial liberation of carbonyl sulfide from the 2,4-thiazolidinedione ring followed by acid-catalysed reaction with trace water to form carbon dioxide and hydrogen sulfide. Static headspace GC (SHGC) with cryofocusing was used to identify and quantify hydrogen sulfide. The principal means of detection was electrolytic conductivity. Complementary qualitative assessments were provided by a lead acetate test and by odour appraisal. the high adsorptivity of H₂S produces a nonlinear response–concentration curve that approximates a sigmoidal shape response. The detection limit in the headspace over a sample is ≈ 5 ppb, close to the odour threshold for H₂S in air (≈ 2 ppb). A relative standard deviation (S_r) of 23.6% was obtained at a concentration of 23 ppb, where losses could occur owing to adsorption; at 92 ppb an S_r of 2.0% was attained. Cathodic stripping voltammetry (CSV) was investigated as an alternate technique to SHGC for the determination of H₂S, but CSV suffered an interference generated in situ in the alkaline solution required for analysis.