Comparison of the hydrophilicity of water-soluble poly(2-alkyl-2-oxazoline)s, poly(2-alkyl-2-oxazine)s and poly(2,4-dialkyl-2-oxazoline)s

Abstract

Poly(cyclic imino ether)s (PCIEs) including poly(2-alkyl-2-oxazoline)s (POx), poly(2-alkyl-2-oxazine)s (POz) and poly(2,4-dialkyl-2-oxazoline)s (PdOx) are a rapidly emerging polymer class for use in biomedical and therapeutic applications due to the biocompatibility and “stealth-like” properties of their water-soluble homologues similar to poly(ethylene glycol) (PEG). The physico-chemical properties of PCIE can be easily “tuned” via appropriate monomer selection resulting for example in polymers ranging from water-soluble to water-insoluble. To date, studies focussing on the hydrophilicity of PCIEs have been limited to the well-known POx, with minimal comparison to POz and especially PdOx. In this study, the effect of degree of hydrophilicity for water-soluble POx, POz, and PdOx systems were assessed for the first time under one testing regime. Specifically, a library of 20 PCIEs was created, consisting of 10 different polymers each synthesised at two different degrees of polymerisation (DP = 20, 50). The hydrophilicity of each polymer was assessed by turbidimetry, high-performance liquid chromatography (HPLC), octanol–water partition coefficient (log K_OW), surface tension, and ¹H NMR relaxometry. Additionally, log K_OW was compared against in silico predictive techniques and hydrophilciity trends seen to correlate between the two techniques, though the predictive software utilised could not accurately predict log K_OW for long polymer chains. This investigation lead to the elucidation of hydrophilicity trends stemming from molar mass, side chain length, backbone spacing, and additional backbone functionality for the case of PdOx. More specifically, hydrophilicity followed a POz > PdOx > POx trend when comparing between structural isomers, and a POx > POz > PdOx trend when comparing between polymers with the same 2-side chain. The knowledge resulting from this study can be utilised for the future design of smart, solubility-tailored PCIE systems for a range of biomedical applications.