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Evaluation of the use of Classical Nucleation Theory for predicting intestinal crystalline precipitation of two weakly basic BSC class II drugs
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
2014 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 53, 17-27 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this work was to evaluate an in vitro-in silico approach for prediction of small intestinal crystalline precipitation and drug absorption of two weakly basic model BCS class II drugs, AZD0865 and mebendazole. The crystallization rates were investigated in an in vitro method using simulated gastric and intestinal media, and the result was modeled by using Classical Nucleation Theory (CNT). The effect of varying in vitro parameters (initial drug concentration, rate of mixing gastric and intestinal fluid, stirring and filtration) on the interfacial tension gamma, being a key parameter in CNT, was investigated. The initial drug concentration had the most significant effect on gamma for both substances tested, although gamma is a fundamental parameter independent of concentration according to CNT. In the subsequent in silico prediction of drug absorption, by use of a Compartmental and Transit intestinal model, an empirical approach was used where gamma was allowed to vary with simulated small intestinal concentrations. The in silico predictions were compared to published human in vivo plasma drug concentration data for different doses of AZD0865 and dog intestinal drug concentrations, amount precipitated in intestine and plasma concentrations for mebendazole. The results showed that lack of significant crystallization effects on absorption in man of the model drug AZD0865 up to doses of 4 mg/kg could be predicted which was in accordance with in vivo data. Mebendazole intestinal precipitation in canines was also well described by the model, where mean predicted amount precipitated was 136% (range 111-164%) of measured solid amount, and mean predicted intestinal concentration was 94% (range 59-147%) of measured concentration. In conclusion, the in vitro-in silico approach can be used for predictions of absorption effects of crystallization, but the model could benefit from further development work on the theoretical crystallization model and in vitro experimental design.

Place, publisher, year, edition, pages
2014. Vol. 53, 17-27 p.
Keyword [en]
Precipitation, In silico prediction, Absorption, Crystallization, Classical Nucleation Theory, In vitro-in vivo correlations
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-222725DOI: 10.1016/j.ejps.2013.12.004ISI: 000331506800003OAI: oai:DiVA.org:uu-222725DiVA: diva2:713043
Available from: 2014-04-17 Created: 2014-04-14 Last updated: 2014-04-17Bibliographically approved

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Lennernäs, Hans
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