Braun, DE;
Vickers, M;
Griesser, UJ;
(2019)
Dapsone Form V: A Late Appearing Thermodynamic Polymorph of a Pharmaceutical.
Molecular Pharmaceutics
, 16
(7)
pp. 3221-3236.
10.1021/acs.molpharmaceut.9b00419.
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Abstract
Five anhydrate polymorphs (forms I–V) and the isomorphic dehydrate (Hy_{dehy}) of dapsone (4,4′-diaminodiphenyl sulfone or DDS) were prepared and characterized in an interdisciplinary experimental and computational study, elucidating the kinetic and thermodynamic stabilities, solid form interrelationships, and structural features of the known forms I–IV, the novel polymorph form V, and Hy_{dehy}. Calorimetric measurements, solubility experiments, and lattice energy calculations revealed that form V is the thermodynamically stable polymorph from absolute zero to at least 90 °C. At higher temperatures, form II, and then form I, becomes the most stable DDS solid form. The computed 0 K stability order (lattice energy calculations) was confirmed with calorimetric measurements as follows, V (most stable) > III > Hy_{dehy} > II > I > IV (least stable). The discovery of form V was complicated by the fact that the metastable but kinetically stabilized form III shows a higher nucleation and growth rate. By combining laboratory powder X-ray diffraction data and ab initio calculations, the crystal structure of form V (P2_{1} /c, Z′ = 4) was solved, with a high energy DDS conformation allowing a denser packing and more stable intermolecular interactions, rationalizing the formation of a high Z′ structure. The structures of the forms I and IV, only observed from the melt and showing distinct packing features compared to the forms II, III, and V, were derived from the computed crystal energy landscapes. Dehydration modeling of the DDS hydrate led to the Hydehy structure. This study expands our understanding about the complex crystallization behavior of pharmaceuticals and highlights the big challenge in solid form screening, especially that there is no clear end point.
| Type: | Article |
|---|---|
| Title: | Dapsone Form V: A Late Appearing Thermodynamic Polymorph of a Pharmaceutical |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1021/acs.molpharmaceut.9b00419 |
| Publisher version: | https://doi.org/10.1021/acs.molpharmaceut.9b00419 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | dapsone, polymorph, kinetic and thermodynamic stability, transformation, X-ray diffraction, thermal analysis, solution calorimetry, crystal structure prediction, lattice energy |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10085054 |
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