Choline chloride–malic acid Natural Deep Eutectic Solvent containing hydrophobic drugs: Insights into solubility and permeability behavior in digestive tract models

Abstract

This study evaluated the biopharmaceutical performance of six BCS Class II drugs with diverse physicochemical properties, formulated in a Natural Deep Eutectic Solvent (NaDES) composed of choline chloride and malic acid (1:1 M ratio). The selected APIs included weak bases (domperidone, cinnarizine, olanzapine), weak acids (nimesulide, flurbiprofen), and a pH-independent compound (carbamazepine). Solubility assessments revealed a 5- to 70-fold increase in API solubility in NaDES compared to biorelevant digestive media. In vitro dilution studies in FaSSGF and FaSSIF demonstrated that NaDES facilitated the formation of supersaturated drug solutions at critical pH levels, particularly for carbamazepine and weakly basic APIs with log P ≤ 4. Conversely, cinnarizine (log P > 5.5) failed to maintain the supersaturated state, likely due to its pronounced hydrophobicity and limited hydrogen bonding capacity with the NaDES components. Under gastric conditions, weakly acidic APIs approached their solubility limits; however, all API + NaDES formulations exhibited superior solubilization kinetics compared to conventional solid dosage forms. Permeability studies using biomimetic Permeapad® barriers in PBS, FaSSIF and FeSSIF confirmed enhanced performance for neutral and basic drugs, but not for acidic ones. These findings highlight the potential of choline chloride-malic acid NaDES as a green and effective drug delivery platform. Nevertheless, its ability to improve bioavailability is highly dependent on the molecular characteristics of each API + NaDES system. Upon dilution in biorelevant media, performance is governed by a delicate interplay of hydrogen bonding, hydrophobic interactions and competition with solubilizing agents present in gastrointestinal fluids.

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