Understanding Polymorph Selection of Sulfamerazine in Solution
CX Liu and FJ Cao and SA Kulkarni and GPF Wood and EE Santiso, CRYSTAL GROWTH & DESIGN, 19, 6925-6934 (2019).
Polymorphism can have a significant impact on important physical and chemical properties of pharmaceutical products. Empirical screening of polymorphs by using different solvent systems is often labor intensive and time-consuming and is not guaranteed to find the most favorable polymorph for the given application. On the other hand, molecular modeling is a useful tool to study how solvents affect polymorphism, as it provides molecular-level information on the factors governing nucleation, but a number of challenges still remain due to the time scales involved. In the present study we have used a combined modeling and experimental approach to study the nucleation of sulfamerazine in different solvents. Using the string method in collective variables with predefined order parameters, we obtained the nucleation energy barrier of two polymorphs of sulfamerazine in three solvents: acetonitrile, methanol, and water. The energy barrier obtained for form I is lower in all of these solvents than that of form II, which is consistent with our experimental PXRD results. This is a direct observation consistent with the Ostwald rule of stages and the Stranski/Totomanow conjecture. We also carried out crystallization induction time measurements and found that our model correctly ranks the nucleation rates in the solvents studied. Our approach provides a route for computational screening of solvents for crystallization of pharmaceutical compounds.
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