Deep eutectic solvents as green and sustainable diluents in headspace gas chromatography for the determination of trace level genotoxic impurities in pharmaceuticals.

Genotoxic impurities (GTIs) are potential carcinogens that need to be controlled down to ppm or lower concentration levels in pharmaceuticals under strict regulations. The static headspace gas chromatography (HS-GC) coupled with electron capture detection (ECD) is an effective approach to monitor halogenated and nitroaromatic genotoxins. Deep eutectic solvents (DESs) possess tunable physico-chemical properties and low vapor pressure for HS-GC methods. In this study, zwitterionic and non-ionic DESs have been used for the first time to develop and validate a sensitive analytical method for the analysis of 24 genotoxins at sub-ppm concentrations. Compared to non-ionic diluents, zwitterionic DESs produced exceptional analytical performance and the betaine : 7 (1,4- butane diol) DES outperformed the betaine : 5 (1,4-butane diol) DES. Limits of detection (LOD) down to the 5-ppb concentration level were achieved in DESs. Wide linear ranges spanning over 5 orders of magnitude (0.005-100 µg g-1) were obtained for most analytes with exceptional sensitivities and high precision. The method accuracy and precision were validated using 3 commercially available drug substances and excellent recoveries were obtained. This study broadens the applicability of HS-GC in the determination of less volatile GTIs by establishing DESs as viable diluent substitutes for organic solvents in routine pharmaceutical analysis.

Simultaneous determination of formic acid and formaldehyde in pharmaceutical excipients using headspace GC/MS.

Formic acid and its esters, as well as formaldehyde, are trace impurities that are often present in pharmaceutical excipients. These trace impurities can potentially react with amino and/or hydroxyl groups in drugs to form significant levels of degradants. To select the appropriate excipients for a stable formulation, a gas chromatography/mass spectrometry (GC/MS) method was developed and validated for the rapid screening of trace amounts of residual formic acid, its esters and formaldehyde in pharmaceutical excipients. Samples were dissolved or dispersed in acidified ethanol to convert formic acid and formaldehyde to ethyl formate and diethoxymethane, respectively. Identification was conducted using a GC/MS system under scan mode and quantified using a selected ion monitoring (SIM) mode. Evaluation of the mass spectra of ethyl formate and diethoxymethane in the samples indicated that the method is specific. The limits of quantitation of the method were 0.5 ppm for formic acid and 0.2 ppm for formaldehyde. The precision of the method was demonstrated by the acceptable R.S.D. (