Isoenergetic Polymorphism: The Puzzle of Tolazamide as a Case Study

In the present case study of tolazamide we illustrate how many seemingly contradictory results that have been obtained from experimental observations and theoretical calculations can finally start forming a consistent picture: a “puzzle put together”. For many years, tolazamide was considered to have no polymorphs. This made this drug substance unique among the large family of sulfonylureas, which was known to be significantly more prone to polymorphism than many other organic compounds. The present work employs a broad and in‐depth analysis that includes the use of optical microscopy, single‐crystal and powder X‐ray diffraction, IR and Raman spectroscopies, DSC, semiempirical PIXEL calculations and DFT of three polymorphs of tolazamide. This case study shows how the polymorphs of a molecular crystal can be overlooked even if discovered serendipitously on one of numerous crystallizations, and how very different molecular packings can be practically isoenergetic but still crystallize quite selectively and transform one into another irreversibly upon heating. Previously overlooked polymorphs revealed: Two fundamental questions concerning polymorphism are addressed (see figure): Why can the polymorphs of a molecular crystal be overlooked? How can very different molecular packings be practically isoenergetic but still crystallize quite selectively and transform one into another on heating?