Understanding the stability of the amorphous form of darifenacin†

Abstract

Darifenacin (DAR) is a benzofuran derivative used in the treatment of an overactive bladder. In a neat solid phase it shows a propensity to exist in an amorphous form (DAR-A), and in this work we examined the molecular reasons standing behind this propensity. To that purpose we characterized structurally two solvated forms of DAR, a hydrate (DAR-H) and a toluene solvate (DAR-T), using single crystal X-ray diffraction and solid-state NMR spectroscopy, and conducted crystal structure prediction (CSP) calculations to compare the energetic stability of the solvated and non-solvated phases. DAR-A was found to show no preference towards particular intermolecular interactions (no local molecular ordering), a feature associated with a lower likelihood for spontaneous crystallization. The CSP landscape for neat crystal forms showed that the lowest energy structures were at the same time low density ones, a phenomenon not commonly observed for stable neat crystals. Many of these low energy structures contained voids, which is consistent with the experimental tendency of DAR to form solvated rather than neat crystal structures. Indeed, the solvated structures were found to be more energetically favourable, and this was associated with the presence of intermolecular interactions between DAR and solvent molecules, providing an energetic compensation for unfavourable conformational energies. The computational results were consistent with experimental observation of crystallization behaviour of DAR and indicate a low likelihood of ever finding a neat polymorphic form of DAR.