Dissolution Mechanisms of Amorphous Solid Dispersions: Role of Drug Load and Molecular Interactions

Abstract

High drug load amorphous solid dispersions (ASDs) have been a challenge to formulate partially because drug release is inhibited at high drug loads. The maximum drug load prior to inhibition of release has been termed the limit of congruency (LoC) and has been most widely studied for copovidone (PVPVA)-based ASDs. The terminology was derived from the observation that below LoC, the polymer controlled the kinetics and the drug and the polymer released congruently, while above LoC, the release rates diverged and were impaired. Recent studies show a correlation between the LoC value and drug−polymer interaction strength, where a lower LoC was observed for systems with stronger interactions. The aim of this study was to investigate the causality between drug−PVPVA interaction strength and LoC. Four chemical analogues with diverse abilities to interact with PVPVA were used as model drugs. The distribution of the polymer between the dilute aqueous phase and the insoluble nanoparticles containing drug was studied with solution nuclear magnetic resonance spectroscopy and traditional separation techniques to understand the thermodynamics of the systems in a dilute environment. Polymer diffusion to and from ASD particles suspended in aqueous solution was monitored for drug loads above the LoC to investigate the thermodynamic driving force for polymer release. The surface composition of ASD compacts before and after exposure to buffer was studied with Fourier transform infrared spectroscopy to capture potential kinetic barriers to release. It was found that ASD compacts with drug loads above the LoC formed an insoluble barrier on the surface that was in pseudo-equilibrium with the aqueous phase and prevented further release of drugs and polymers during dissolution. The insoluble barrier contained a substantial amount of the polymer for the strongly interacting drug−polymer systems. In contrast, a negligible amount was found for the weakly interacting systems. This observation provides an explanation for the ability of strongly interacting systems to form an insoluble barrier at lower drug loads. The study highlights the importance of thermodynamic and kinetic factors on the dissolution behavior of ASDs and provides a potential framework for maximizing the drug load in ASDs.

Dissolution Mechanisms of Amorphous Solid Dispersions: A Close Look at the Dissolution Interface

“…This is consistent with associative phase separation behavior, where a substantial amount of polymer was detected in the hydrophobic phase of the PHPH-PVPVAwater system, as reported in Table 3 and in our previous study. 22 Moreover, the T g of this phase was substantially lower than that of neat PHPH or PVPVA, suggesting that it also contained a considerable amount of water. The distance between the onset of phase separation and glass/gel boundary visually decreased with an increase in drug loading, similar to the MePHPH-PVPVA ASDs.…”

“…This indicates segregative phase separation into a hydrophobic phase (blue domains) and a hydrophilic phase (red domains). 22 The morphology of the hydrophobic phase varies depending on drug loading. For 5% (Figure S2), 20% (Figure S3), and 30% DL (Figure 5), the blue domains are discrete particles with a diameter less than 1 μm.…”

“…14,16 The decline, referred to as the "falling-of-a-cliff" effect, has been attributed to the formation of an insoluble barrier on the surface of the ASD. 8,10,11,22 For MePHPH-PVPVA and PHPH-PVPVA ASDs, the formation of this barrier is dependent on morphology of the two phases following phase separation in the gel layer. Above the LoC, both ASDs generated continuous or semi-continuous hydrophobic phases (Figure 7 and Figures 9 and 10).…”

“…13 Hydrogen bonding increases the PVPVA distribution into the hydrophobic phase after phase separation, leading to a volumetrically larger hydrophobic phase. 22 Systems with preferential association of polymer in the hydrophobic phase have been termed associative phase separating systems. Conversely, systems where the polymer prefers to distribute into the hydrophilic phase are termed as segregative.…”

“…Typically, the composition of this barrier has been reported as drug-rich, 8,15 but can also contain polymer, 13,20,21 with amounts reported up to approximately 75% for a phenolic compound in an ASD with copovidone. 22 Irrespective of the composition, the surface barrier has a very low thermodynamic driving force for dissolution; hence, it prevents the release of drug and polymer. Han and coworkers proposed that the phase morphology, resulting from AAPS, determines if an ASD will release congruently or incongruently.…”