Poly(2-oxazoline)- and Poly(2-oxazine)-Based Formulation Library Reveals Limits of Solubility Parameter-Based Drug-Polymer Compatibility Prediction

Abstract Four structurally related poly(2-oxazoline) (POx)- and poly(2-oxazine) (POzi)-based ABA triblock copolymers were evaluated across 21 poorly water-soluble drugs to assess whether Hansen solubility parameters (HSPs) predict polymer-specific formulation performance. HSPs were calculated using Hoftyzer-Van Krevelen (HnV) and Yamamoto molecular break (YMB) methods, with semi-empirical polymer HSPs derived from solvent−solubility profiles. The polymers showed drug-specific performance, with maximum loading capacities exceeding 40 wt % for four drugs and 30 wt % for another four drugs. However, Ra showed limited discriminatory power. Among 20 drugs with YMB-derived Ra values, the lowest-Ra polymer was experimentally best for only 4 (20%), while Ra-based and experimental within-drug pairwise rankings agreed in 59 of 119 comparisons (49.6%). Significant cross-drug correlations for two polymers were positive, opposite to the expected trend. Despite this limited predictive performance, the resulting formulation library provides a broad experimental platform for identifying polymer-drug combinations for subsequent application-specific preclinical development.