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Abstract
Two polymorphs of tolazamide, N-[(azepan-1-ylamino)carbonyl]-4-methylbenzenesulfonamide, a sulfonylurea anti-diabetic drug, have different densities and molecular packings. Polymorph II converts into polymorph I in the solid state on heating or via recrystallization if solvent-assisted. The effect of pressure on the two forms and the possibility of a transformation to a denser form on compression have been studied. No phase transitions have been observed in either of the forms in a pentane–isopentane mixture (when no recrystallization is possible). Polymorph II recrystallized partly into a denser polymorph I in methanol at 0.1 GPa, but the transformation stopped at an early stage. Solid state DFT calculations of the two forms as well as conformational landscape investigation in the gas phase were used to rationalize this result. The anisotropic pressure-induced strain of the two polymorphs has been compared in relation to changes in the hydrogen bond geometry and the behavior of stacking interactions.
Highlights
Regardless of the above discussed possible limitations of the employed theoretical model, in the context of this work it is important that the calculations confirm that polymorph I remains the more stable form across the entire studied pressure range. This means that no transformation of polymorph I into polymorph II should be expected, but that form II could transform into form I, if the transformation was not kinetically hindered. To facilitate this potential transformation, we have studied the effect of pressure on a tolazamide-II single crystal loaded into a diamond anvil cell (DAC) with a saturated solution of tolazamide in methanol as a pressuretransmitting fluid
This is in sharp contrast to the ease at which polymorph II transforms into polymorph I in solution, in the presence of solvent on grinding, or in the solid state on heating.[35]
Nucleation of phase I is hindered at ambient temperature, and the packing of molecules in polymorph II does not change even at 6 GPa
Summary
Such information will allow better prediction of solid-form landscapes and polymorphism.[30,31,32,33,34]. When crystallized from solution at ambient pressure, the nuclei of the two polymorphs, I and II, seem to be formed almost simultaneously, the crystals of form II grow much faster than those of form I. The irreversible II to I transformation has been detected in the solid state by single-crystal and powder X-ray diffraction and thermomicroscopy upon heating. This suggested that polymorph I must be the stable form both at ambient temperature and on heating up to the melting point. DSC revealed no thermal effects corresponding to this transition, so the polymorphs have been classified as isoenergetic,‡
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