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Nucleation and crystal growth in supersaturated solutions of a model drug
Pharmaceutical and Analytical R&D, AstraZeneca R&D Mölndal, Sweden.
Department of Physical Chemistry, Lunds University.
2008 (English)In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 325, no 2, 404-413 p.Article in journal (Refereed) Published
Abstract [en]

The crystallization process in aqueous solutions of the drug bicalutamide and the effect of the polymer polyvinylpyrrolidone (PVP) have been studied. Results show that PVP decreased the crystallization rate significantly in a system with PVP concentrations as low as 0.01% (w/w), without changing the polymorph formed. The crystal habit was changed already at PVP concentrations as low as 0.001% (w/w). Measurements made with self-diffusion NMR indicated that the decrease in crystallization rate was not because of a reduced supersaturation due to bicalutamide binding to PVP in solution. Furthermore, in experiments designed to specifically study crystal nucleation, the same nucleation rate was found in the absence and presence of PVP. Instead, PVP adsorbes to the crystals formed in solution and by doing so, the crystal growth rate is reduced. This was confirmed in separate experiments using bicalutamide nanocrystals. By combining theories describing classical nucleation and crystal growth, with some modifications, a consistent description of several independent experiments performed in polymer-free systems was obtained. From these experiments a crystal-water interfacial tension of 22.1 mN/m was extracted. We also analyze the interfacial tension of other crystalline organic solids and find that it varies approximately as the logarithm of the solubility. This finding is discussed within the framework of the Bragg-Williams regular solution theory where we also compare with the tension of liquid alkanes.

Place, publisher, year, edition, pages
2008. Vol. 325, no 2, 404-413 p.
Keyword [en]
Crystal nucleation, Crystal growth, Poorly soluble drugs, Classical nucleation theory
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
URN: urn:nbn:se:uu:diva-178050DOI: 10.1016/j.jcis.2008.05.034OAI: oai:DiVA.org:uu-178050DiVA: diva2:541904
Available from: 2012-07-25 Created: 2012-07-25 Last updated: 2017-12-07Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 164
Keyword
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
Biopharmaceutics
Identifiers
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)
Opponent
Supervisors
Available from: 2012-08-24 Created: 2012-07-25 Last updated: 2013-01-22Bibliographically approved

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