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Computational prediction of drug solubility in fasted simulated and aspirated human intestinal fluid.

Fagerberg JH, Karlsson E, Ulander J, Hanisch G, Bergström CA - Pharm. Res. (2014)

Bottom Line: Modest relationships between Sapp in PhBpH6.5 and FaSSIF (R(2) = 0.61) or HIF (R(2) = 0.62) were found.Accuracy improved when solubility in PhBpH6.5 was added as a descriptor (FaSSIF, R(2) = 0.76 and RMSETe of 0.65; HIF, R(2) = 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.If experimentally determined pH-dependent solubility values were available, this further improved the accuracy of the predictions.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Uppsala University, Biomedical Centre, P.O. Box 580, SE-751 23, Uppsala, Sweden.

ABSTRACT

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 (R(2) = 0.61) or HIF (R(2) = 0.62) were found. As expected, there was a stronger correlation obtained between FaSSIF and HIF (R(2) = 0.78). Computational models were developed using calculated descriptors alone (FaSSIF, R(2) = 0.69 and RMSEte of 0.77; HIF, R(2) = 0.84 and RMSEte of 0.81). Accuracy improved when solubility in PhBpH6.5 was added as a descriptor (FaSSIF, R(2) = 0.76 and RMSETe of 0.65; HIF, R(2) = 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.

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Related in: MedlinePlus

Correlation between HIF, FaSSIF and buffer pH 6.5 Sapp correlations. a FaSSIF and PhBpH6.5, b HIF and PhBpH6.5, and c HIF and FaSSIF. Light gray circles represent compounds with a predicted logDpH6.5 below 3. Gray circles denote compounds with logDpH6.5 between 3 and 4. Dark gray circles shows compounds with a logDpH6.5 above 4.
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Fig2: Correlation between HIF, FaSSIF and buffer pH 6.5 Sapp correlations. a FaSSIF and PhBpH6.5, b HIF and PhBpH6.5, and c HIF and FaSSIF. Light gray circles represent compounds with a predicted logDpH6.5 below 3. Gray circles denote compounds with logDpH6.5 between 3 and 4. Dark gray circles shows compounds with a logDpH6.5 above 4.

Mentions: The solubility values of the dataset revealed modest relationships between measured solubility in PhBpH6.5 and FaSSIF or HIF (R2:0.61 and R2:0.62, respectively, Fig. 2). The PhBpH6.5 and FaSSIF Sapp correlation was considerably weaker for the more lipophilic compounds (logDpH6.5 > 4) for which R2 decreased to 0.28. However, for compounds with a logDpH6.5 < 3, there was a strong correlation (R2: 0.82) The correlation between FaSSIF Sapp and HIF Sapp was also strong (R2: 0.78) but unaffected by lipophilicity (Fig. 2c). Under- or over-prediction of the solubility was not related to melting point or lipophilicity.Fig. 2


Computational prediction of drug solubility in fasted simulated and aspirated human intestinal fluid.

Fagerberg JH, Karlsson E, Ulander J, Hanisch G, Bergström CA - Pharm. Res. (2014)

Correlation between HIF, FaSSIF and buffer pH 6.5 Sapp correlations. a FaSSIF and PhBpH6.5, b HIF and PhBpH6.5, and c HIF and FaSSIF. Light gray circles represent compounds with a predicted logDpH6.5 below 3. Gray circles denote compounds with logDpH6.5 between 3 and 4. Dark gray circles shows compounds with a logDpH6.5 above 4.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4300419&req=5

Fig2: Correlation between HIF, FaSSIF and buffer pH 6.5 Sapp correlations. a FaSSIF and PhBpH6.5, b HIF and PhBpH6.5, and c HIF and FaSSIF. Light gray circles represent compounds with a predicted logDpH6.5 below 3. Gray circles denote compounds with logDpH6.5 between 3 and 4. Dark gray circles shows compounds with a logDpH6.5 above 4.
Mentions: The solubility values of the dataset revealed modest relationships between measured solubility in PhBpH6.5 and FaSSIF or HIF (R2:0.61 and R2:0.62, respectively, Fig. 2). The PhBpH6.5 and FaSSIF Sapp correlation was considerably weaker for the more lipophilic compounds (logDpH6.5 > 4) for which R2 decreased to 0.28. However, for compounds with a logDpH6.5 < 3, there was a strong correlation (R2: 0.82) The correlation between FaSSIF Sapp and HIF Sapp was also strong (R2: 0.78) but unaffected by lipophilicity (Fig. 2c). Under- or over-prediction of the solubility was not related to melting point or lipophilicity.Fig. 2

Bottom Line: Modest relationships between Sapp in PhBpH6.5 and FaSSIF (R(2) = 0.61) or HIF (R(2) = 0.62) were found.Accuracy improved when solubility in PhBpH6.5 was added as a descriptor (FaSSIF, R(2) = 0.76 and RMSETe of 0.65; HIF, R(2) = 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.If experimentally determined pH-dependent solubility values were available, this further improved the accuracy of the predictions.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Uppsala University, Biomedical Centre, P.O. Box 580, SE-751 23, Uppsala, Sweden.

ABSTRACT

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 (R(2) = 0.61) or HIF (R(2) = 0.62) were found. As expected, there was a stronger correlation obtained between FaSSIF and HIF (R(2) = 0.78). Computational models were developed using calculated descriptors alone (FaSSIF, R(2) = 0.69 and RMSEte of 0.77; HIF, R(2) = 0.84 and RMSEte of 0.81). Accuracy improved when solubility in PhBpH6.5 was added as a descriptor (FaSSIF, R(2) = 0.76 and RMSETe of 0.65; HIF, R(2) = 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.

Show MeSH
Related in: MedlinePlus