4.5 Article

Computational Prediction of Drug Solubility in Fasted Simulated and Aspirated Human Intestinal Fluid

Journal

PHARMACEUTICAL RESEARCH
Volume 32, Issue 2, Pages 578-589

Publisher

SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-014-1487-z

Keywords

biorelevant solubility; human intestinal fluid; simulated intestinal fluid; in silico; prediction

Funding

  1. Swedish Research Council [621-2008-3777, 621-2011-2445]
  2. Swedish Medical Products Agency

Ask authors/readers for more resources

Purpose To develop predictive models of apparent solubility (S-app) of lipophilic drugs in fasted state simulated intestinal fluid (FaSSIF) and aspirated human intestinal fluid (HIF). Methods Measured S-app 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 S-app 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 logD(pH) 6.5 were included in the models. Conclusion Computational models were developed, that reliably predicted S-app 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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.5
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available