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Experimental and Computational Predictions of Drug Solubility in Human Gastrointestinal Fluids
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 187
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-221249ISBN: 978-91-554-8913-7 (print)OAI: oai:DiVA.org:uu-221249DiVA: diva2:708230
Public defence
2014-05-23, B42, Biomedicinskt centrum – BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-04-28 Created: 2014-03-27 Last updated: 2016-04-12Bibliographically approved
List of papers
1. Dissolution Rate and Apparent Solubility of Poorly Soluble Drugs in Biorelevant Dissolution Media
Open this publication in new window or tab >>Dissolution Rate and Apparent Solubility of Poorly Soluble Drugs in Biorelevant Dissolution Media
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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.

Keyword
Poor solubility, dissolution rate, biorelevant dissolution media, FaSSIF, FeSSIF, apparent BCS, physicochemical properties, molecular features, solvation limited
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-134347 (URN)10.1021/mp100049m (DOI)000282304200006 ()
Available from: 2010-11-25 Created: 2010-11-24 Last updated: 2016-04-27Bibliographically approved
2. Ethanol Effects on Apparent Solubility of Poorly Soluble Drugs in Simulated Intestinal Fluid
Open this publication in new window or tab >>Ethanol Effects on Apparent Solubility of Poorly Soluble Drugs in Simulated Intestinal Fluid
2012 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 9, no 7, 1942-1952 p.Article in journal (Refereed) Published
Abstract [en]

Ethanol intake can lead to an unexpected and possibly problematic increase in the bioavailability of druglike compounds. In this work we investigated the effect of ethanol on the apparent solubility and dissolution rate of poorly soluble compounds in simulated intestinal fluid representing a preprandial state. A series of 22 structurally diverse, poorly soluble compounds were measured for apparent solubility and intrinsic dissolution rate (37 degrees C) in phosphate buffer pH 6.5 (PhB6.5) and fasted state simulated intestinal fluid (FaSSIF, pH 6.5) with and without ethanol at 5% v/v or 20% v/v. The obtained data were used to understand for which molecules ethanol results in an increased apparent solubility and, therefore, may increase the amount of drug absorbed. In FaSSIF(20%ethanol) 59% of the compounds displayed >3-fold higher apparent solubility than in pure FaSSIF, whereas the effects of 5% ethanol on solubility, in most cases, were negligible. Acidic and neutral compounds were more solubilized by the addition of ethanol than by lecithin/taurocholate aggregates, whereas bases showed a more substance-specific response to the additives in the buffer. The stronger solubilizing capacity of ethanol as compared to the mixed lipid aggregates in FaSSIF was further identified through Spearman rank analyses, which showed a stronger relationship between FaSSIF(20%ethanol) and PhB6.5,20%ethanol (r(S) of 0.97) than FaSSIF(20%ethanol) and FaSSIF (r(S) of 0.86). No relationships were found between solubility changes in media containing ethanol and single physicochemical properties, but multivariate data analysis showed that inclusion of ethanol significantly reduced the negative effect of compound lipophilicity on solubility. For this data set the higher concentration of ethanol gave a dose number (Do) <1 for 30% of the compounds that showed incomplete dissolution in FaSSIF. Significant differences were shown in the melting point, lipophilicity, and dose profiles between the compounds having a Do < 1 and Do > 1, with the latter having higher absolute values in all three parameters. In conclusion, this study showed that significant effects of ethanol on apparent solubility in the preprandial state can be expected for lipophilic compounds. The results herein indicate that acidic and neutral compounds are more sensitive to the addition of ethanol than to the mixed lipid aggregates present in the fasted intestine.

Keyword
apparent solubility, dissolution rate, ethanol, biorelevant dissolution medium, poorly soluble compounds, molecular properties, dose number
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-178097 (URN)10.1021/mp2006467 (DOI)000305917600009 ()
Available from: 2012-07-30 Created: 2012-07-27 Last updated: 2017-12-07Bibliographically approved
3. Concomitant intake of alcohol may increase the absorption of poorly soluble drugs
Open this publication in new window or tab >>Concomitant intake of alcohol may increase the absorption of poorly soluble drugs
2015 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 67, 12-20 p.Article in journal (Refereed) Published
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-220869 (URN)10.1016/j.ejps.2014.10.017 (DOI)000348257500002 ()25444841 (PubMedID)
Note

Title in Thesis list of papers: Concomitant Intake of Alcohol Increases the Absorption of Poorly Soluble Drugs Administered as Immediate Release Formulations

Available from: 2014-03-27 Created: 2014-03-21 Last updated: 2017-12-05Bibliographically approved
4. Computational Prediction of Drug Solubility in Fasted Simulated and Aspirated Human Intestinal Fluid
Open this publication in new window or tab >>Computational Prediction of Drug Solubility in Fasted Simulated and Aspirated Human Intestinal Fluid
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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]

Purpose

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

Methods

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.

Results

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.

Conclusion

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
Keyword
biorelevant solubility, human intestinal fluid, simulated intestinal fluid, in silico, prediction
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-220867 (URN)10.1007/s11095-014-1487-z (DOI)000349357700019 ()25186438 (PubMedID)
Funder
Swedish Research Council, 621-2008-3777Swedish Research Council, 621-2011-2445
Available from: 2014-03-27 Created: 2014-03-21 Last updated: 2017-12-05Bibliographically approved

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