Partitioning behavior of caffeine, lamotrigine, clonazepam and oxcarbazepine in a biodegradable aqueous two-phase system comprising of polyethylene glycol dimethyl ether 250 and choline chloride/saccharose deep eutectic solvent

Abstract

Aqueous two-phase systems (ATPSs) are well-known as novel, green, non-toxic and sensitive pharmaceutical pretreatment systems, where they are necessary for drug extraction from plasma, serum or urine samples. In the search for new ATPSs, especially those that exemplify the above-mentioned characteristics, here, a systematic investigation of biodegradable ATPS containing polyethylene glycol dimethyl ether 250 and one natural deep eutectic solvent obtained from mixtures of choline chloride as hydrogen bond acceptor (HBA) and saccharose as hydrogen bond donor (HBD) with different molar ratio (i.e. 1:1, 2:1 and 4:1) was made by liquid-liquid equilibria and drug partitioning studies at T = (298.15, 308.15 and 318.15) K under atmospheric pressure (≈85 kPa). The salting-out strength of the natural deep eutectic solvent calculated from fitting solubility data with the effective excluded volume theory was used to explore the influences of temperature and HBA:HBD molar ratio on the phase separation in this ATPS; the trend showed that the biphasic region was expanded by enhancing HBA:HBD molar ratio as well as increasing temperature. The performance of this ATPS for partitioning caffeine, lamotrigine, clonazepam and oxcarbazepine was evaluated by computing their partition coefficients and extraction efficiencies with focusing on the absence or presence of HBD, HBA:HBD molar ratio, temperature, drug nature and mass fractions of natural deep eutectic solvent. In all conditions, the high hydrophobic drugs could be partitioned effectively into the top phase with a single step extraction efficiency up to 90% indicating a preferential interaction between drug and polymer enriched in this phase.