Issue 28, 2015

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

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

Supplementary files

Article information

Article type
Paper
Submitted
17 дек 2014
Accepted
15 фев 2015
First published
17 фев 2015
This article is Open Access
Creative Commons BY license

CrystEngComm, 2015,17, 5237-5251

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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