Effect of Hypromellose Acetate Succinate Substituents on Miscibility Behavior of Spray-dried Amorphous Solid Dispersions: Flory–Huggins Parameter Prediction and Validation

Abstract

• Theoretical predictions and validation of miscibility was investigated. • Gibbs-composition phase diagram predicts the composition dependent miscibility. • Substituent ratios have significant effect on miscibility and drug loading. • Higher succinoyl content leads to higher dissolution efficiency. • Non-polar drugs show higher miscibility with HG grade, but low dissolution. This study reports the impact of physicochemical properties of lipophilic drugs such as Fenofibrate (FBT), Itraconazole (ITZ), Efavirenz (EFV) and Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS) grades on the miscibility, dissolution, and stability of the spray dried Amorphous Solid Dispersions (ASDs). The miscibility between of the drugs and HPMCAS grades was predicted using solubility parameter-derived Flory-Huggins interaction parameter and later phase diagram was constructed to delineate the composition dependent miscibility. By varying the HPMCAS grade−drug combinations and loadings, the amorphicity of prepared ASDs was analyzed using Differential Scanning Calorimetry (DSC), X-Ray Diffraction (XRD) and in vitro dissolution experiments were conducted to measure apparent solubility and finally, investigate the interplay between substituent ratio and functionality. Interactions between the drugs and polymeric grades and drug concentration in polymer is crucial in determining the drug precipitation within the ASDs which is further supported by Fourier Transform Infrared Spectroscopy (FTIR). The dissolution efficiency and dissolution rate of the ASDs were dependent on the acetyl-succinoyl ratio in HPMCAS.