A comprehensive spectroscopic study of the polymorphs of diflunisal and their phase transformations

Anuradha R Pallipurath; Francesco Civati; Juraj Sibik; Clare Crowley; J Axel Zeitler; Patrick McArdle; Andrea Erxleben

doi:10.1016/j.ijpharm.2017.06.020

A comprehensive spectroscopic study of the polymorphs of diflunisal and their phase transformations

Int J Pharm. 2017 Aug 7;528(1-2):312-321. doi: 10.1016/j.ijpharm.2017.06.020. Epub 2017 Jun 8.

Authors

Anuradha R Pallipurath¹, Francesco Civati², Juraj Sibik³, Clare Crowley⁴, J Axel Zeitler³, Patrick McArdle⁵, Andrea Erxleben⁶

Affiliations

¹ School of Chemistry, National University of Ireland, Galway, Ireland; Department of Chemistry, University of Bath, Claverton Down, Bath BA2 1AY, UK.
² School of Chemistry, National University of Ireland, Galway, Ireland.
³ Department of Chemical Engineering and Biotechnology, Pembroke Street, Cambridge CB2 3RA, UK.
⁴ Materials and Surface Science Institute, Department of Chemical and Environmental Sciences, University of Limerick, Ireland.
⁵ School of Chemistry, National University of Ireland, Galway, Ireland. Electronic address: p.mcardle@nuigalway.ie.
⁶ School of Chemistry, National University of Ireland, Galway, Ireland. Electronic address: andrea.erxleben@nuigalway.ie.

PMID: 28603011
DOI: 10.1016/j.ijpharm.2017.06.020

Abstract

Understanding phase transitions in pharmaceutical materials is of vital importance for drug manufacturing, processing and storage. In this paper we have carried out comprehensive high-resolution spectroscopic studies on the polymorphs of the non-steroidal anti-inflammatory drug diflunisal that has four known polymorphs, forms I-IV (FI-FIV), three of which have known crystal structures. Phase transformations during milling, heating, melt-quenching and exposure to high relative humidity were investigated using Raman and terahertz spectroscopy in combination with differential scanning calorimetry and X-ray powder diffraction. The observed phase transformations indicate the stability order FIII>FI>FII, FIV. Furthermore, crystallization experiments from the gas phase and from solution by fast evaporation of different solvents were carried out. Fast evaporation of an ethanolic solution below 70°C was identified as a reliable and convenient method to obtain the somewhat elusive FII in bulk quantities.

Keywords: Diflunisal; Diflunisal (PubChem CID: 3059); Phase transformation; Polymorphs; Terahertz spectroscopy.

MeSH terms

Anti-Inflammatory Agents, Non-Steroidal / analysis*
Calorimetry, Differential Scanning
Crystallization
Diflunisal / analysis*
Spectrum Analysis, Raman
X-Ray Diffraction

Substances

Anti-Inflammatory Agents, Non-Steroidal
Diflunisal