Selected food additives for inhibiting the metastable polymorphic transformation of baricitinib: a novel and safe strategy

Polymorphism, a common phenomenon in solid-state drugs, poses significant challenges to clinical drug application while offering valuable opportunities for formulation alternatives. Metastable forms generally exhibit higher solubility and dissolution rates than their stable forms, making them attractive candidates for active pharmaceutical ingredients (APIs). However, the use of metastable forms may result in polymorphic transformation during manufacture and storage, which diminishes their bioavailability. Thus, improving the stability of metastable forms has emerged as a key challenge in expanding pharmaceutical applications. In this study, Baricitinib (BRT) was selected as a model drug. Its metastable Form II with higher solubility and dissolution rates could easily undergo rapid conversion to the stable Form I in solution. Previous studies have shown that introducing organic small-molecule additives can effectively inhibit polymorphic transformation. We found that saccharin (SAC) and L-malic acid (MA), both of which are Generally Recognized as Safe (GRAS) food additives, effectively suppressed the phase transformation from BRT Form II to Form I, whereas citric acid (CA) showed a negligible effect on the transformation process. Our study elucidates the multifunctional mechanisms and demonstrates a safe, practical strategy for stabilizing metastable crystal forms, thereby paving the way for their industrial application.