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Göteborgs universitets publikationer

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

Författare och institution:
Rasmus Persson (Institutionen för kemi); Sture Nordholm (Institutionen för kemi); German Perlovich (-); Lennart Lindfors (Institutionen för kemi)
Publicerad i:
J. Phys. Chem. B, 115 ( 12 ) s. 3062-3072
Artikel, refereegranskad vetenskaplig
Sammanfattning (abstract):
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.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
Kemi ->
Fysikalisk kemi
Kemi ->
Annan kemi
Postens nummer:
Posten skapad:
2011-03-31 10:36

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