While attempting to grow co-crystals from 1:1 solutions of sulfameter and carboxylic acids, researchers at Ferris State University were surprised to obtain, instead, crystals of a polymorph (form III) of sulfameter from experiments containing benzilic, hydrocinnamic, or 2-nitrobenzoic acids. Subsequently, questions were raised about the role that the carboxylic acids played in inducing growth of form III and about whether sulfameter could be induced to crystallize in form III even when adding a much smaller amount of carboxylic acid. Graph sets were used as a tool to analyze the hydrogen-bond connectivity in previously published crystal structures of sulfameter (forms I and III) and 1:1 aspirin-sulfameter cocrystal.  Insight gained from this analysis was applied in proposing a mechanism by which drug-acid association in solution might promote growth of form III. In an attempt to determine the smallest amount of acid required to induce the growth of form III from solution, crystals were initially grown by evaporation of solutions containing equal amounts of sulfameter and carboxylic acid. The experiment was repeated multiple times, each time cutting the amount of acid until 1/100<sup>th</sup> the molar quantity of drug was reached. The products were analyzed using infrared spectroscopy in order to determine which form of the drug had been obtained. It was discovered that under fast evaporation (2-4 days), the crystals obtained were usually a mixture of forms I and III, but under slow evaporation (9-24 days), pure crystals were the norm. It was surprising to find that form III appeared even when there was a hundred times more sulfameter than acid; although with trace amounts of acid, occasionally mixtures of form I and III appeared. Results of the graph set analyses, a proposed mechanism, and results from the crystallization experiments of sulfameter are reported.<br/>

Influencing polymorphism of sulfameter

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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