Evaluating pediatric and adult simulated fluids solubility: Abraham solvation parameters and multivariate analysis.

PURPOSE: To 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. METHODS: Differences 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. RESULTS: The 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. CONCLUSION: Statistical models based on Abraham solvation parameters were applied mostly to better understand drug solubility differences in adult and pediatric biorelevant media.

How Predictable Are Human Stratum Corneum Lipid/Water Partition Coefficients? Assessment and Useful Correlations for Dermal Absorption.

Partition coefficients between human stratum corneum lipids and water (Ksclip/w) are collected or deduced from a variety of sources in a manner that approximately doubles the available data compared to the current state-of-the-art model (Hansen et al., Adv Drug Deliv Rev. 2013;65(2):251-264). An additional datum for water itself in porcine SC that considerably extends the molecular size and lipophilicity range of the data set is considered. The data are analyzed in terms of an extended linear free energy relationship involving octanol/water partition coefficients, Abraham solvation parameters, and a secondary, power law molecular weight dependence. The optimum fit to log Ksclip/w for the full data set reduces the standard error of prediction from 0.50 for a Hansen-like model to 0.39; corresponding multiplicative errors in Ksclip/w are reduced from a factor of 3.1 to one of 2.5. The difference in performance is driven by the water datum, which requires a more complex dependence on molecular size than that afforded by Abraham parameters. In the absence of the water value, the Hansen-like model, which does not include a dependence on molecular size, is essentially optimum. A comparison is presented to fluid-phase phospholipid-water systems, which have a demonstrably different structure-property relationship.

Characterization of a dicationic imidazolium-based ionic liquid as a gas chromatography stationary phase.

Here we report the characteristics of a new synthesized ionic liquid, 1,9-di(N-naphthalen-2-ylimidazolium)nonane bis[(trifluoromethyl)sulfonyl]imide ([C9(2NPTim)2][(NTf2)2]), as a stationary phase by inverse gas chromatography. The McReynolds constants demonstrated that the [C9(2NPTim)2][(NTf2)2] had an average polarity of 667 and polarity number P.N.=75, suggesting its polar nature. The solvation properties of the new stationary phase were determined by the calculation of Abraham solvation system constants, whereby the results showed that its major interactions with the analytes included H-bond basicity (a), dipole-dipole (s) and dispersive (l) interactions. The activity coefficients (γ∞) and selectivities (SIJ∞) at infinite dilution were also determined for various polar and nonpolar organic solutes at different temperatures. The separation performance of the [C9(2NPTim)2][(NTf2)2] stationary phase was evaluated by GC separations of different analytes, including normal alkanes and aromatic compounds. The TGA results showed that the stationary phase had high thermal stability up to 420°C.