Congruent release of drug and polymer: A “sweet spot” in the dissolution of amorphous solid dispersions

Liquid-liquid phase separation (LLPS) occurs following amorphous solid dispersion (ASD) dissolution when the drug concentration exceeds the “amorphous solubility”, and is emerging as an important characteristic of formulations that may enhance the oral bioavailability of poorly soluble drugs. The purpose of this research was to identify criteria that impact the rate and extent of drug release and hence the occurrence or not of LLPS upon ASD dissolution.

Specifically, the effect of drug log P, phase behavior of the hydrated but undissolved ASD matrix and the relative dissolution rates of drug and polymer were studied as a function of drug loading, using nilvadipine (Nil) (ClogP = 3.04) and cilnidipine (Cil) (ClogP = 5.54) as model drugs. The model polymer was poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA). Nil-PVPVA and Cil-PVPVA ASDs with different drug loadings were prepared. Surface area normalized dissolution rates of both the drug and the polymer from ASD tablets were studied.

At a similar and relatively low drug loading (<20% w/w drug), dissolution of both Nil-PVPVA and Cil-PVPVA ASDs were found to switch from rapid, congruent (i.e. simultaneous) release of drug and polymer to incongruent release with slow release of drug. Only ASDs showing congruent release underwent LLPS, with the formation of amorphous drug-rich aggregates (~200 nm). Scanning electron microscopy (SEM) and micro-computed tomography (micro-CT) showed the presence of characteristic “pits” on the surface of partially dissolved, incongruently releasing ASD tablets.

These most likely arise due to faster polymer release in comparison to drug, whereby the drug-rich composition around these pits was confirmed by energy-dispersive X-ray (EDX) analysis and the surface drug enrichment on the compacts was confirmed by X-ray photoelectron spectroscopy (XPS). This study demonstrates two important findings, firstly, a link between congruent release of drug and polymer and the occurrence of LLPS and secondly, the switch between congruent and incongruent release of drug and polymer is a result of competitive kinetics between phase separation and the release rate of ASD components with minimal influence from drug hydrophobicity for two structural analogues. Continue on ASD