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Monte Carlo Studies of Drug Nucleation 1: Formation of Crystalline Clusters of Bicalutamide in Water

Journal article
Authors Rasmus Persson
Sture Nordholm
German Perlovich
Lennart Lindfors
Published in Journal of Physical Chemistry B
Volume 115
Issue 12
Pages 3062-3072
ISSN 1520-6106
Publication year 2011
Published at Department of Chemistry
Pages 3062-3072
Language en
Subject categories Other Chemistry Topics, Physical Chemistry


A computational method of predicting the effects of the metastability of drug solutions is sought. A simple extension of our in silicio approach to thermodynamic drug solubility is tested on the drug bicalutamide for which we performed vapor pressure measurements complementing earlier measurements of aqueous solubility and crystal−water interfacial tension. The free energy of formation of an N-cluster of the drug molecule is estimated semiempirically by use of an Einstein model of the crystal in which experiment supplies the crystal structure, enthalpy of sublimation, and Einstein frequency of vibration. The rigid drug clusters with N from 2 to 14 are extracted from the bulk crystal by minimization of either cluster energy or radius of gyration. The free energy of hydration is estimated by Monte Carlo simulation combined with simplified response theory based on the OPLS-AA/COMPASS force field for the drug−water interaction and the TIP4P water model. The results have been interpreted in terms of an apparent crystal−water interfacial tension according to classical nucleation theory. The energy-minimal and radius of gyration-minimal clusters seem to give very similar crystal−water interfacial tensions for both the monoclinic and the triclinic polymorph. The interfacial tension of the monoclinic polymorph is significantly higher (by around 20%) than that of the triclinic polymorph in accordance with experiment. For the triclinic polymorph a substantial overestimation of the interfacial tension compared to estimates from crystal nucleation experiments is found, mitigated somewhat by an empirical scaling of the simulated binding energies and free energies of hydration.

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