Abstract
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.
Highlights
The consequences for the patients were dramatic as, for instance, Neupro® patches remained unavailable in the United States from 2008 to 2012, until the patch was properly reformulated to a stable amorphous matrix
We have demonstrated that a contemporary computational crystal structure predictions (CSP) method reveals the late-appearing polymorph of rotigotine, and is ΔH
The relative enthalpy (ΔH), free energy (ΔF), and solubility between Form I and II of rotigotine as obtained by our computational approach compared with experimental measurements capable of correctly describing complex polymorphic energy landscapes of pharmaceutically relevant compounds
Summary
The consequences for the patients were dramatic as, for instance, Neupro® patches remained unavailable in the United States from 2008 to 2012, until the patch was properly reformulated to a stable amorphous matrix. The new form has a much higher stability and much lower solubility with an instability of the amorphous formulation as the most striking effect[13] The likelihood of such a late-appearing polymorph can nowadays be assessed via computational molecular crystal structure predictions (CSP), which yield the thermodynamical stabilities for a variety of different crystal-packing arrangements[14]. We have recently shown that a combination of the most successful crystallographic space sampling from the latest blind test with a sophisticated firstprinciples energy-ranking approach yields excellent results across all target systems of that blind test[21] This approach can be applied to large and complex systems of pharmaceutical relevance. We highlight that the synergy between modern computational CSP and first-principles electronic-structure methods can be a viable approach to obtain invaluable insights into the drug development, and could have had a significant impact on the case of rotigotine
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