Application of Cyrene, a biodegradable, sustainably produced biosolvent for the quantitative analysis of residual production solvents in pharmaceuticals using headspace gas chromatography mass spectrometry

Abstract

In line with green chemistry and green analytical chemistry (GAC) principles, analysts are increasingly adopting sustainably produced chemicals and solvents. Dihydrolevoglucosenone, known commercially as Cyrene, is a biodegradable solvent derived from sustainable materials. It has a high boiling point and serves as a replacement for solvents like NMP and DMF. In headspace gas chromatography mass spectrometry (HS-GC–MS), high-boiling-point solvents such as DMSO and DMF are commonly used as diluents, standard method. This study introduces Cyrene as a diluent in chromatographic separation for analysing off-the-shelf pharmaceuticals for residual production solvents (RPS) and provides the first qualitative characterisation of such volatile and very volatile organic compounds (VOCs and VVOCs) in commercially sourced Cyrene.

The AGREEprep greenness score for the method using Cyrene was 0.14 points higher than for the method using DMSO, indicating alignment with GAC principles. HS-GC–MS analysis revealed numerous impurities in commercially sourced Cyrene. The analysis of RPS using Cyrene showed identical retention times for 21 out of 22 RPS tested analysed using Cyrene and DMSO as diluents. Additionally, Cyrene did not affect the peak symmetry of any RPS. Both HS-GC–MS methods demonstrated good linearity across a wide concentration range, with most RPS analysed using Cyrene showing lower detection and quantification limits. The methods enabled the identification and quantification of acetic acid and 1-propanol in two off-the-shelf pharmaceuticals. Using Cyrene, acetic acid and 1-propanol were quantified at 278.0 ± 4.0 mg l^-1 and 90.8 ± 9.5 mg l^-1, respectively, compared to 279.3 ± 3.3 mg l^-1 and 110.0 ± 6.8 mg l^-1 with DMSO. This demonstrates Cyrene's suitability as a replacement of unsustainably produced solvents in headspace analysis of RPS in the pharmaceutical industry.