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See detailComputational polymorph screening reveals late-appearing and poorly-soluble form of rotigotine
Mortazavi, Majid; Hoja, Johannes; Aerts, Luc et al

in Communications Chemistry (2019), 2

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 ... [more ▼]

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. [less ▲]

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See detailReliable and practical computational description of molecular crystal polymorphs
Hoja, Johannes; Ko, Hsin-Yu; Neumann, Marcus A. et al

in Science Advances (2019), 5

Reliable prediction of the polymorphic energy landscape of a molecular crystal would yield profound insight into drug development in terms of the existence and likelihood of late-appearing polymorphs ... [more ▼]

Reliable prediction of the polymorphic energy landscape of a molecular crystal would yield profound insight into drug development in terms of the existence and likelihood of late-appearing polymorphs. However, the computational prediction of molecular crystal polymorphs is highly challenging due to the high dimensionality of conformational and crystallographic space accompanied by the need for relative free energies to within 1 kJ/mol per molecule. In this study, we combine the most successful crystal structure sampling strategy with the most successful first-principles energy ranking strategy of the latest blind test of organic crystal structure prediction methods. Specifically, we present a hierarchical energy ranking approach intended for the refinement of relative stabilities in the final stage of a crystal structure prediction procedure. Such a combined approach provides excellent stability rankings for all studied systems and can be applied to molecular crystals of pharmaceutical importance. [less ▲]

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