Computational polymorph screening reveals late-appearing and poorly-soluble form of rotigotine

The active pharmaceutical ingredient rotigotine—a dopamine agonist for the treatment of Parkinson’s and restless leg diseases—was known to exist in only one polymorphic form since 1985. In 2008, the appearance of a thermodynamically more stable and significantly less soluble polymorph led to a massive batch recall followed by economic and public health implications. Here, we carry out state-of-the-art computational crystal structure prediction, revealing the late-appearing polymorph without using any prior information. In addition, we predict a third crystalline form of rotigotine having thermodynamic stability between forms I and II. We provide quantitative description of the relative stability and solubility of the rotigotine polymorphs. Our study offers new insights into a challenging polymorphic system and highlights the robustness of contemporary computational crystal structure prediction during pharmaceutical development.