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Investigation and Prediction of Small Intestinal Precipitation of Poorly Soluble Drugs: a Study Involving in silico, in vitro and in vivo Assessment
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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 [en]
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: urn:nbn:se:uu:diva-178053ISBN: 978-91-554-8408-8 (print)OAI: oai:DiVA.org:uu-178053DiVA: diva2:541907
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
List of papers
1. Nucleation and crystal growth in supersaturated solutions of a model drug
Open this publication in new window or tab >>Nucleation and crystal growth in supersaturated solutions of a model drug
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.

Keyword
Crystal nucleation, Crystal growth, Poorly soluble drugs, Classical nucleation theory
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-178050 (URN)10.1016/j.jcis.2008.05.034 (DOI)
Available from: 2012-07-25 Created: 2012-07-25 Last updated: 2017-12-07Bibliographically approved
2. Predicting intestinal precipitation: a case example for a basic BCS class II drug
Open this publication in new window or tab >>Predicting intestinal precipitation: a case example for a basic BCS class II drug
Show others...
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.

Keyword
absorption-biopharmaceutics classification system . gastrointestinal . in vitro/in vivo correlations (IVIVC) . precipitation
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-132389 (URN)10.1007/s11095-010-0213-8 (DOI)000281860900010 ()20717839 (PubMedID)
Available from: 2010-10-19 Created: 2010-10-19 Last updated: 2017-12-12Bibliographically approved
3.
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4. Evaluation of the use of Classical Nucleation Theory for predicting intestinal crystallization of two weakly basic BCS class II drugs
Open this publication in new window or tab >>Evaluation of the use of Classical Nucleation Theory for predicting intestinal crystallization of two weakly basic BCS class II drugs
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The aim of this work was to evaluate an in vitro-in silico approach for prediction of small intestinal crystallization of two weakly basic model BCS class II drugs, AZD0865 and mebendazole, and the effect crystallization would have on the absorption prediction of the drug. 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 g, being a key parameter in CNT, was investigated. The initial drug concentration had the most significant effect on g for both substances tested, although g is a fundamental parameter independent of concentration according to CNT. In the subsequent in silico prediction of drug absorption an empirical approach was used where g was predicted at expected in vivo small intestinal concentrations. The results showed that lack of crystallization effects on absorption in man of the model drug AZD0865 up to doses of 4 mg/kg could be predicted. Mebendazole intestinal precipitation in canines was also well described by the model, where mean predicted amount precipitated was 111% (range 41-166%) of measured solid amount, and mean predicted supersaturation was 106% (range 73-118%) of measured supersaturation. The plasma concentration of mebendazole after duodenal administration of a solution could not be predicted by the model with the same precision in the absence of measured intestinal drug concentrations as basis for estimating the g value. 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.

Keyword
precipitation, in silico prediction, absorption, biopharmaceutics classification system, crystallization, classical nucleation theory, in vitro-in vivo correlations
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-178052 (URN)
Available from: 2012-07-25 Created: 2012-07-25 Last updated: 2013-01-22

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