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Computational Prediction of Drug Solubility in Fasted Simulated and Aspirated Human Intestinal Fluid
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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2015 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 32, no 2, 578-589 p.Article in journal (Refereed) Published
Abstract [en]


To develop predictive models of apparent solubility (Sapp) of lipophilic drugs in fasted state simulated intestinal fluid (FaSSIF) and aspirated human intestinal fluid (HIF).


Measured Sapp values in FaSSIF, HIF and phosphate buffer pH 6.5 (PhBpH6.5) for 86 lipophilic drugs were compiled and divided into training (Tr) and test (Te) sets. Projection to latent structure (PLS) models were developed through variable selection of calculated molecular descriptors. Experimentally determined properties were included to investigate their contribution to the predictions.


Modest relationships between Sapp in PhBpH6.5 and FaSSIF (R2 = 0.61) or HIF (R2 = 0.62) were found. As expected, there was a stronger correlation obtained between FaSSIF and HIF (R2 = 0.78). Computational models were developed using calculated descriptors alone (FaSSIF, R2 = 0.69 and RMSEte of 0.77; HIF, R2 = 0.84 and RMSEte of 0.81). Accuracy improved when solubility in PhBpH6.5 was added as a descriptor (FaSSIF, R2 = 0.76 and RMSETe of 0.65; HIF, R2 = 0.86 and RMSETe of 0.69), whereas no improvement was seen when melting point (Tm) or logDpH 6.5 were included in the models.


Computational models were developed, that reliably predicted Sapp of lipophilic compounds in intestinal fluid, from molecular structures alone. If experimentally determined pH-dependent solubility values were available, this further improved the accuracy of the predictions.

Place, publisher, year, edition, pages
Springer, 2015. Vol. 32, no 2, 578-589 p.
Keyword [en]
biorelevant solubility, human intestinal fluid, simulated intestinal fluid, in silico, prediction
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Physical Chemistry
URN: urn:nbn:se:uu:diva-220867DOI: 10.1007/s11095-014-1487-zISI: 000349357700019PubMedID: 25186438OAI: diva2:708185
Swedish Research Council, 621-2008-3777Swedish Research Council, 621-2011-2445
Available from: 2014-03-27 Created: 2014-03-21 Last updated: 2015-03-19Bibliographically 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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