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Dissolution Rate and Apparent Solubility of Poorly Soluble Drugs in Biorelevant Dissolution Media
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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2010 (English)In: Molecular pharmaceutics, ISSN 1543-8384, Vol. 7, no 5, 1419-1430 p.Article in journal (Refereed) Published
Abstract [en]

A series of poorly soluble BCS class II compounds with "grease ball" characteristics were assessed for solubility and dissolution rate in biorelevant dissolution media (BDM) with the purpose of investigating which molecular structures gain most in solubility when dissolved under physiologically relevant conditions. The compounds were studied in four media (simulated intestinal fluid in fasted (FaSSIF pH 6.5) and fed state (FeSSIF pH 5.0), and their corresponding blank buffers (FaSSIF(blk) and FeSSIFblk)) at a temperature of 37 degrees C. The experimental results were used to analyze which molecular characteristics are of importance for the solubility in BDM and for in silico modeling using multivariate data analysis. It was revealed that a majority of the compounds exhibited a higher dissolution rate and higher solubility in the FaSSIF and FeSSIF than in their corresponding blank buffers. Compounds which were neutral or carried a positive charge were more soluble in FeSSIF than FaSSIF. The acidic compounds displayed clear pH dependency, although the higher concentration of solubilizing agents in FeSSIF than FaSSIF also improved the solubility. Five of the ten compounds were upgraded to BCS class I when dissolved in FaSSIF or FeSSIF, i.e., the maximum dose of these compounds given orally was soluble in 250 mL of these BDMs. Lipophilicity as described by the log D-oct value was identified as a good predictor of the solubilization ratio (R-2 = 0.74), and computed molecular descriptors were also shown to successfully predict the solubilities in BDM for this data set. To conclude, the physiological solubility of "grease ball" molecules may be largely underestimated in in vitro solubility assays unless BDM is used. Moreover, the results herein indicate that the improvement obtained in BDM may be possible to predict from chemical features alone.

Place, publisher, year, edition, pages
2010. Vol. 7, no 5, 1419-1430 p.
Keyword [en]
Poor solubility, dissolution rate, biorelevant dissolution media, FaSSIF, FeSSIF, apparent BCS, physicochemical properties, molecular features, solvation limited
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-134347DOI: 10.1021/mp100049mISI: 000282304200006OAI: oai:DiVA.org:uu-134347DiVA: diva2:372418
Available from: 2010-11-25 Created: 2010-11-24 Last updated: 2016-04-27Bibliographically approved
In thesis
1. Experimental and Computational Predictions of Drug Solubility in Human Gastrointestinal Fluids
Open this publication in new window or tab >>Experimental and Computational Predictions of Drug Solubility in Human Gastrointestinal Fluids
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aqueous solubility of a drug is viewed as a pivotal property for its oral absorption since only dissolved molecules can permeate the gut wall and reach the systemic circulation. The fluids in the intestine, however, do not only consist of water and therefore poor water solubility may not necessarily imply a poor solubility in the intestinal fluids and resulting low bioavailability. This thesis addresses the determination of drug solubility and dissolution rates in biorelevant dissolution media (BDM) with the aim of applying these methods to the early stages of drug discovery, where there is a need to reduce the volume of the medium and the amount of solid drug used in testing. The thesis also addresses the need for computational methods for predicting solubility in intestinal fluids and, hence, allowing in silico screening of drugs yet to be synthesized. The apparent solubility and dissolution behavior of large series of lipophilic and other diverse compounds in BDM were studied using a miniaturized method developed herein. The media used in the experimental design provided an opportunity to assess the effects of charge, solubilization in mixed lipid aggregates, and ethanol in BDM. Highly lipophilic and uncharged drugs were efficiently solubilized by aggregates in the BDM while solubilization was decreased with charge. The decrease was more pronounced for negatively charged drugs. The solubility of anionic and neutral drugs was significantly increased by the addition of ethanol to the medium and absorption simulations showed that intake of alcohol could lead to increased plasma concentrations of neutral compounds. Statistical models based on calculated molecular descriptors that accurately predicted the apparent solubility in fasted-state simulated intestinal fluid and in aspirated human intestinal fluid were also developed. In summary, the work undertaken in this thesis has resulted in new experimental and computational models for assessment of the dissolution and solubility of poorly water-soluble compounds in BDM. The models are applicable in the early discovery and development phases for predicting physiologically relevant solubility and the effects thereof on drug absorption.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 68 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 187
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
urn:nbn:se:uu:diva-221249 (URN)978-91-554-8913-7 (ISBN)
Public defence
2014-05-23, B42, Biomedicinskt centrum – BMC, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2014-04-28 Created: 2014-03-27 Last updated: 2016-04-12Bibliographically approved

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Fagerberg, Jonas H.Bergström, Christel A. S.
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