Synthetic and natural polymers hold tremendous potential to improve therapeutic potency, bioavailability, stability, and safety through aiding the solubility of lipophilic drug candidates that may otherwise be clinically inaccessible. For the leading pharmaceutical delivery method (oral administration), one such approach involves maintaining drugs in an amorphous, nonequilibrium state using spray-dried dispersions (SDDs). However, few well-understood vehicles exist, and available formulations employ Edisonian approaches without regard to examining chemical, thermodynamic, and kinetic phenomena. Herein, we present a rational approach to study polymer-drug interactions with a multicomponent polymer platform, inspired by hydroxypropyl methylcellulose acetate succinate (an excipient increasingly utilized as a delivery vehicle). The controlled syntheses of these modular analogs were strategically defined with (i) hydroxypropyl, (ii) methoxy, (iii) acetyl, (iv) succinoyl, and (v) glucose groups to tune the amphiphilicity balance (i-v), ionization near gastrointestinal pH levels (iv), hydrogen bonding (i, iii, iv, v), and glass transition temperature (v). We examined how polymer architecture produces amorphous SDDs with a highly hydrophobic drug model (probucol, log P = 8.9). Dissolution experiments revealed dramatic differences in bioavailability as a function of polymeric chemical specificity. We identify chemically driven interactions as crucial ingredients for facilitating amorphous phase behavior and supersaturation maintenance. In particular, increasing the fraction of ionizable carboxylic acid moieties and selective deprotection of glucose acetates into hydroxyls established stabilizing ionic character and polar interactions. Our results show the utility of rationally designed polymer platforms, which we can precisely tune via monomer selection and functionality, as direct handles for elucidating important structure-property relationships in oral delivery.