Influence Factor Investigation on the Solution-Mediated Polymorphic Transformation of Baricitinib Phosphate

Baricitinib is the only once-daily oral selective Janus kinase (JAK1 and JAK2) inhibitor, currently in late-stage clinical development for inflammatory and autoimmune diseases. Two most developable forms of Baricitinib phosphate, form A and form X, were fully characterized using powder X-ray diffraction (PXRD), differential scanning calorimetry and thermogravimetric analysis. Furthermore, the solution-mediated polymorphic transformation from form A to form X was investigated by monitoring and identifying the transformation process through focused beam reflectance measurement probe combined with PXRD and UV/Vis spectrophotometer. The influence factors, such as system temperature, solvent composition, suspension density, stirring rate, and additives were studied. Results showed that higher temperature, larger mole fraction of acetonitrile, larger suspension density, faster stirring rate and some specific additives could accelerate the solution-mediated phase transformation process to some extent.