Spray dried dispersions (SDDs) of glipizide, a BCS Class II model drug, were prepared using various grades of hydroxypropyl methylcellulose acetate succinate (HPMCAS) and copovidone S-630 as carriers. The SDDs appeared as a single amorphous phase with up to 60% drug loading level as revealed by X-ray powder diffraction (XRPD), modulated differential scanning calorimetry (mDSC) and scanning electron microscopy (SEM). Supersaturated micro-dissolution testing of various SDDs in fasted state simulated intestinal fluid showed prolonged supersaturation state (up to 180 min) with solubility increases of 5.2–13.9 fold relative to crystalline drug under similar conditions. Solubility and stability characteristics of the most desirable SDDs in terms of relative dissolution AUCs (AUC(SDD)/AUC(crystalline)) and supersaturated concentration ratios (C180/Cmax) were determined. Results show that HPMCAS-based SDDs achieve a higher degree of supersaturation compared to Copovidone S-630 and that SDDs comprising HPMCAS-M and HPMCAS-H maintained stable supersaturated concentration. Dissolution data showed that SDD-loaded CR tablets provide stable supersaturated concentration within the hydrated matrix with increased rate and extent of drug dissolution over 24 h. Co-existence of HPMCAS and HPMC within the hydrating matrix showed strong suppression of drug crystallization and allowed achievement of zero-order and slow-first order release kinetics.