Abstract
PurposeTo understand drug solubilization as a function of age and identify drugs at risk of altered drug solubility in pediatric patients. To assess the discrimination ability of the Abraham solvation parameters and age-related changes in simulated media composition to predict in vitro drug solubility differences between pediatric and adult gastrointestinal conditions by multivariate data analysis.MethodsDifferences between drug solubility in pediatric and adult biorelevant media were expressed as a % pediatric-to-adult ratio [Sp/Sa (%)]. Solubility ratios of fourteen poorly water-soluble drugs (2 amphoteric; 4 weak acids; 4 weak bases; 4 neutral compounds) were used in the analysis. Partial Least Squares Regression was based on Abraham solvation parameters and age-related changes in simulated gastrointestinal fluids, as well as their interactions, to predict the pediatric-to-adult solubility ratio.ResultsThe use of Abraham solvation parameters was useful as a theory-informed set of molecular predictors of drug solubility changes between pediatric and adult simulated gastrointestinal fluids. Our findings suggest that the molecular solvation environment in the fasted gastric state was similar in the pediatric age-groups studied, which led to fewer differences in the pediatric-to-adult solubility ratio. In the intestinal fasted and fed state, there was a high relative contribution of the physiologically relevant surfactants to the alteration of drug solubility in the pediatric simulated conditions compared to the adult ones, which confirms the importance of an age-appropriate composition in biorelevant media.ConclusionStatistical models based on Abraham solvation parameters were applied mostly to better understand drug solubility differences in adult and pediatric biorelevant media.
Highlights
Age-related developmental changes have the potential to affect the composition of gastrointestinal (GI) fluids, which can impact on the biorelevant solubility of drugs (1)
Interactions between the Abraham solvation parameters and BSs & LC were considered highly significant for identifying solubility changes in pediatric fasted intestinal fluids compared to that of adults
Previous work used this approach of a linear free energy relationship to predict the ratio of solubility enhancement (log(SE)) in Fasted state simulated intestinal fluid (FaSSIF) biorelevant medium when compared to solubility in a buffer solution for a series of apparently neutral drugs (2)
Summary
Age-related developmental changes have the potential to affect the composition of gastrointestinal (GI) fluids, which can impact on the biorelevant solubility of drugs (1). Compound solubility and dissolution are important variables regarding oral absorption, for poorly water-soluble drugs. The development of biorelevant media to study drug solubility and dissolution has been a landmark in biopharmaceutical research (2). Age-appropriate biorelevant media have been developed (1). Their use is fundamental for the in vitro assessment of oral drug performance of poorly-water soluble compounds, especially in younger population cohorts in comparison to adults.
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