Abstract
PurposeTo develop predictive models of apparent solubility (Sapp) of lipophilic drugs in fasted state simulated intestinal fluid (FaSSIF) and aspirated human intestinal fluid (HIF).MethodsMeasured 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.ResultsModest 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.ConclusionComputational 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.
Highlights
Modern drug discovery programs using high throughput screening and combinatorial chemistry continue to favor the selection of large and lipophilic new chemical entities (NCE)
Alternatives to human intestinal fluid (HIF) for dissolution testing and solubility measurements became available when Dressman and colleagues introduced fasted state simulated intestinal fluid (FaSSIF) in 1998 [11]
An additional criterion for this dataset was that corresponding solubility measurements were available in FaSSIF and that the same protocol had been used for solubility measurements in FaSSIF and HIF
Summary
Modern drug discovery programs using high throughput screening and combinatorial chemistry continue to favor the selection of large and lipophilic new chemical entities (NCE). This is in spite of their poor aqueous solubility [1,2,3,4], the increased awareness of related problems and the multitude of mnemonic rules for avoiding these compounds with low or variable absorption and pharmacokinetics [5,6,7]. Drugs with a partition coefficient between octanol and water (logP) greater than 3 have considerably higher apparent solubility (Sapp; the total concentration of drug dissolved in the lipid-containing dissolution medium) in BDM than in water or buffers [16,17,18,19]. Solubilization in lipid aggregates and molecular ionization as a response to the pH of the fluid can increase the Sapp in BDM of compounds several orders of magnitude compared to that observed in water
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