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Predicting intestinal precipitation: a case example for a basic BCS class II drug
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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2010 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 27, no 10, 2119-2130 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: To investigate the prediction accuracy of in vitro and in vitro/in silico methods for in vivo intestinal precipitation of basic BCS class II drugs in humans. METHODS: Precipitation rate of a model drug substance, AZD0865 (pKa = 6.1; log K(D) = 4.2), was investigated in vitro using simulated intestinal media, and calculations of the crystallization rates were made with a theoretical model. Human intestinal precipitation was estimated by analysis of pharmacokinetic data from clinical studies at different doses. RESULTS: All in vitro models predicted rapid drug precipitation, where the intestinal concentration of dissolved AZD0865 at the highest dose tested was expected to decrease to half after less than 20 min. However, there was no indication of precipitation in vivo in humans as there was a dose proportional increase in drug plasma exposure. The theoretical model predicted no significant precipitation within the range of expected in vivo intestinal concentrations. CONCLUSIONS: This study indicated that simple in vitro methods of in vivo precipitation of orally administered bases overpredict the intestinal crystalline precipitation in vivo in humans. Hydrodynamic conditions were identified as one important factor that needs to be better addressed in future in vivo predictive methods.

Place, publisher, year, edition, pages
2010. Vol. 27, no 10, 2119-2130 p.
Keyword [en]
absorption-biopharmaceutics classification system . gastrointestinal . in vitro/in vivo correlations (IVIVC) . precipitation
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-132389DOI: 10.1007/s11095-010-0213-8ISI: 000281860900010PubMedID: 20717839OAI: oai:DiVA.org:uu-132389DiVA: diva2:357734
Available from: 2010-10-19 Created: 2010-10-19 Last updated: 2013-01-22Bibliographically approved
In thesis
1. Investigation and Prediction of Small Intestinal Precipitation of Poorly Soluble Drugs: a Study Involving in silico, in vitro and in vivo Assessment
Open this publication in new window or tab >>Investigation and Prediction of Small Intestinal Precipitation of Poorly Soluble Drugs: a Study Involving in silico, in vitro and in vivo Assessment
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The main objectives of the present project were to increase the understanding of small intestinal precipitation of poorly soluble pharmaceutical drugs, investigate occurrence of crystalline small intestinal precipitation and effects of precipitation on absorption. The aim was to create and evaluate methods of predicting crystalline small intestinal drug precipitation using in vivo, in vitro and in silico models.

In vivo small intestinal precipitation from highly supersaturated solutions of two weakly basic model drugs, AZD0865 and mebendazole, was investigated in humans and canine models. Potential precipitation of AZD0865 was investigated by examining dose dependent increases in human maximum plasma concentration and total exposure, which turned out to be dose linear over the range investigated, indicating no significant in vivo precipitation. The small intestinal precipitation of mebendazole was investigated from drug concentrations and amount of solid drug present in dog jejunum as well as through the bioavailability after direct duodenal administration in dogs. It was concluded that mebendazole small intestinal precipitation was limited, and that intestinal supersaturation was measurable for up to 90 minutes.

In vitro precipitation methods utilizing simulated or real fasted gastric and intestinal fluids were developed in order to simulate the in vivo precipitation rate. The methods overpredicted in vivo precipitation when absorption of drug was not simulated. An in vitro-in silico approach was therefore developed, where the in vitro method was used for determining the interfacial tension (γ), necessary for describing crystallization in Classical Nucleation Theory (CNT). CNT was evaluated using a third model drug, bicalutamide, and could successfully describe different parts of the crystallization process of the drug. CNT was then integrated into an in silico absorption model. The in vivo precipitation results of AZD0865 and mebendazole were well predicted by the model, but only by allowing the fundamental constant γ to vary with concentration. Thus, the in vitro-in silico approach could be used for small intestinal precipitation prediction if the in vitro concentration closely matched in vivo small intestinal concentrations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 63 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 164
gastrointestinal precipitation, crystallization, crystal nucleation, crystal growth, classical nucleation theory, poorly soluble drugs, drug absorption, biopharmaceutics classification system, in vitro/in vivo correlations (IVIVC), in silico prediction, human intestinal fluid, dog intestinal fluid, simulated intestinal fluid
National Category
Pharmaceutical Sciences
Research subject
urn:nbn:se:uu:diva-178053 (URN)978-91-554-8408-8 (ISBN)
Public defence
2012-09-14, B42, BMC, Husarg. 3, Uppsala, 09:15 (English)
Available from: 2012-08-24 Created: 2012-07-25 Last updated: 2013-01-22Bibliographically approved

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