Effects of moisture and residual solvent on the phase stability of orthorhombic paracetamol

Pharmaceutical Research
K KachrimanisUlrich J Griesser

Abstract

At high relative humidity (RH), orthorhombic paracetamol (form II) crystallized from ethanol transforms to monoclinic (form I) faster than such crystallized from the melt. The present study attempts to elucidate the reasons for this difference in stability. The transformation of form II was investigated by powder X-ray diffraction, optical microscopy, gravimetric moisture sorption, thermogravimetry, and vibrational spectroscopy. Solution-grown form II was found to be always contaminated with form I nuclei but still transforms much faster than corresponding physical mixtures of the pure forms in high RH, at a rate that is depending on the RH and the size of the crystals. A 0.1-0.6% w/w mass loss, inversely related to the initial monoclinic content, was observed during transformation of solution-grown form II, and was found to be due to residual ethanol that could not be removed by grinding, indicating incorporation by a solid solution mechanism. Moisture triggers the growth of existing form I nuclei but it exerts a weaker effect on nucleation, and the presence of residual ethanol greatly accelerates the transformation.

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Citations

Jun 15, 2011·Pharmaceutical Research·Andrey G OgienkoTatiana N Drebushchak
Jun 25, 2010·Journal of Pharmaceutical Sciences·John R G SanderLeonard R MacGillivray
Nov 7, 2009·Journal of Pharmaceutical Sciences·Harry G Brittain
Sep 25, 2010·Journal of Pharmaceutical and Biomedical Analysis·Boris Zimmermann, Goran Baranović
Jun 2, 2015·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Roman D OparinMichael G Kiselev
Aug 12, 2014·Molecular Pharmaceutics·Yi Gao, Kenneth W Olsen
Sep 15, 2016·Drug Development and Industrial Pharmacy·Ioannis Nikolakakis, Kyriakos Kachrimanis
Nov 6, 2014·Angewandte Chemie·Dejan-Krešimir BučarWilliam Jones

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