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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

Loading plots for the FaSSIF and HIF models. a FaSSIF model loading plot and b with measured PhBph6.5 Sapp as additional descriptor. c HIF model loading plot and d experimentally determined PhBph6.5 Sapp as a_descriptor.
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Fig5: Loading plots for the FaSSIF and HIF models. a FaSSIF model loading plot and b with measured PhBph6.5 Sapp as additional descriptor. c HIF model loading plot and d experimentally determined PhBph6.5 Sapp as a_descriptor.

Mentions: All descriptors remaining after the variable selection were significant in either both or the last component. For the FaSSIF model these include: i) eigenvalues weighted by bond order (Eig04_EA(bo)) or edge degree (Eig04_AEA(ed)); ii) a spectral moment of order 6 from Burden matrix weighted by van der Waals volume; and iii) a second-component accessibility directional WHIM index weighted by van der Waals volume; all these descriptors negatively influenced the solubility. These descriptors are related to some extent to molecular size. Geary autocorrelation (GATS4s) and Morse signal 26(Mor26s), both weighted by intrinsic state and the frequency of N – O at a topological distance of 5 (F05[N-O]) correlated with a high Sapp in FaSSIF (Fig. 5a and b).Fig. 5


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)

Loading plots for the FaSSIF and HIF models. a FaSSIF model loading plot and b with measured PhBph6.5 Sapp as additional descriptor. c HIF model loading plot and d experimentally determined PhBph6.5 Sapp as a_descriptor.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig5: Loading plots for the FaSSIF and HIF models. a FaSSIF model loading plot and b with measured PhBph6.5 Sapp as additional descriptor. c HIF model loading plot and d experimentally determined PhBph6.5 Sapp as a_descriptor.
Mentions: All descriptors remaining after the variable selection were significant in either both or the last component. For the FaSSIF model these include: i) eigenvalues weighted by bond order (Eig04_EA(bo)) or edge degree (Eig04_AEA(ed)); ii) a spectral moment of order 6 from Burden matrix weighted by van der Waals volume; and iii) a second-component accessibility directional WHIM index weighted by van der Waals volume; all these descriptors negatively influenced the solubility. These descriptors are related to some extent to molecular size. Geary autocorrelation (GATS4s) and Morse signal 26(Mor26s), both weighted by intrinsic state and the frequency of N – O at a topological distance of 5 (F05[N-O]) correlated with a high Sapp in FaSSIF (Fig. 5a and b).Fig. 5

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