Engineering piroxicam crystals with targeted morphologies and polymorphs using organic additives: A comprehensive study of tablet performance and molecular mechanisms

Piroxicam is widely employed as a non-steroidal anti-inflammatory drug for the alleviation of inflammation and pain. However, its crystallization process is often accompanied by concomitant polymorphism, which poses challenges for production control. In this study, organic small molecules were utilized as additives to precisely regulate the polymorphic forms of piroxicam during cooling crystallization, enabling targeted modulation of the crystal morphology of Form I. Consequently, Form I sample with distinct morphologies and particle size distributions were successfully prepared. Through systematic comparison of the tablet properties of different crystal forms and different morphologies of piroxicam, it was found that the tablets prepared from the piroxicam crystals modified by organic small molecules such as citric acid and glutaric acid in the acetonitrile and ethyl acetate systems exhibited significantly superior key performance indicators such as hardness, angle of repose, and dissolution rate compared to commercial products. Notably, piroxicam Form I with a cuboid morphology was observed to display a dissolution rate approaching that of Form II. In addition, the mechanism of crystal form and morphology regulation was explained using molecular dynamics calculations. This study not only provides an effective approach for the co-regulation of crystal form and morphology in piroxicam, but also offers experimental evidence and process guidance for the production of high-performance tablet formulations.