Insights into the degradation chemistry of tazarotene, a third generation acetylenic retinoid: LC-HRMS (Orbitrap), LC-MSn and NMR characterization of its degradation products, and prediction of their physicochemical and ADMET properties

Abstract Tazarotene is a prodrug that belongs to the acetylenic class of retinoids. The drug was subjected to hydrolytic, oxidative and photolytic stress testing to establish its comprehensive degradation chemistry. The drug proved to be unstable under acidic and basic hydrolytic conditions, yielding tazarotenic acid, which is a known major degradation product (DP) and an active metabolite. Additionally, two DPs each were generated upon interaction of drug and tazarotenic acid with HCl, used as an acid stressor. These were experimentally proven as pseudo DPs, as they did not originate when H2SO4 was employed as the stressor. The drug was also unstable under oxidative and photolytic conditions, yielding six DPs. All the products were separated on reversed phase (C18) column, while mobile phase composed of 10 mM ammonium formate (pH 3.5) and acetonitrile was run in a gradient mode. The separated DPs were subjected to LC-HRMS and LC-MSn studies for their initial characterization. Seven hydrolytic and oxidative DPs could be isolated using semi-preparative column and were subjected to extensive 1D (1H, 13C and DEPT-135) and 2D (COSY, HSQC and HMBC) NMR studies to confirm their structure. In total, five novel DPs were characterized, apart from two previously reported DPs, viz., tazarotenic acid and tazarotene sulfoxide, and four additional pseudo DPs. A complete degradation pathway of the drug was established. In silico ADMET properties of the drug and its DPs were evaluated using ADMET PredictorTM.