LC-HRMS and NMR study of the esterification pProducts of ibuprofen with solketal: Formation, isolation and identification

Abstract

Ibuprofen is a widely used non-steroidal anti-inflammatory drug dispensed in tablets, capsules, suspensions, oral solutions, creams, and gels. Ibuprofen's poor water solubility and gastrointestinal side-effects present ongoing formulation challenges. Alcoholic excipients are often employed to enhance solubility and minimise adverse effects. Solketal (1,2-isopropylidene glycerol), a ketal produced by the condensation of glycerol with acetone, offers further versatility as an excipient due to its free hydroxyl group, which enables esterification reactions with acidic active pharmaceutical ingredients like ibuprofen. Introducing any excipient, especially in direct contact with the active pharmaceutical ingredient, necessitates careful evaluation of potential drug–excipient interactions, as these can alter the drug's physicochemical properties and impact clinical performance. Chromatographic techniques coupled with mass spectrometry and nuclear magnetic resonance spectroscopy remain essential for identifying and characterising related and degradation products in pre-formulation studies. In this study, we investigated the esterification of ibuprofen with solketal to identify possible interaction products. Two major compounds were isolated and thoroughly characterised by MS and NMR, confirming their chemical structures: 1-mono-glycerol ester of ibuprofen and ibuprofen-solketal-ester, which contained a 1,3-dioxolane ring. This finding highlights the importance of comprehensive analytical evaluation of drug–excipient interactions during formulation development, as these can affect drug stability and performance.