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Issue 28, 2015
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The reluctant polymorph: investigation into the effect of self-association on the solvent mediated phase transformation and nucleation of theophylline

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Abstract

Little is known concerning the pathway of the crystallization of the thermodynamically stable polymorph of theophylline, form IV. Here we study the reasons why the thermodynamically stable theophylline form IV can be obtained only by slow, solvent mediated phase transformation (SMPT) in specific solvents, and whether the presence of prenucleation aggregates affect the polymorphic outcome. Solution concentration, polymorphic composition and morphology were monitored over time during the transformation from form II to form IV in several solvents. NMR and FTIR spectroscopy were used to detect prenucleation molecular aggregates present in the solutions. It was determined that theophylline self-associates in solvents which are good H-bond donors and the presence of these aggregates hinder the nucleation and phase transformation. SMPT from form II to form IV is a nucleation-growth controlled polymorphic transformation, nucleation is most likely homogenous, and form IV crystals grow along the (001) plane, forming plate-like crystals.

Graphical abstract: The reluctant polymorph: investigation into the effect of self-association on the solvent mediated phase transformation and nucleation of theophylline

  • This article is part of the themed collection: Polymorphism
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Supplementary files

Article information


Submitted
17 Dec 2014
Accepted
15 Feb 2015
First published
17 Feb 2015

This article is Open Access

CrystEngComm, 2015,17, 5237-5251
Article type
Paper
Author version available

The reluctant polymorph: investigation into the effect of self-association on the solvent mediated phase transformation and nucleation of theophylline

R. Bobrovs, L. Seton and N. Dempster, CrystEngComm, 2015, 17, 5237
DOI: 10.1039/C4CE02484B

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