Explaining the Release Mechanism of Ritonavir/PVPVA Amorphous Solid Dispersions

Abstract

In amorphous solid dispersions (ASDs), an active pharmaceutical ingredient (API) is dissolved on a molecular level in a polymeric matrix. The API is expected to be released from the ASD upon dissolution in aqueous media. However, a series of earlier works observed a drastic collapse of the API release for ASDs with high drug loads (DLs) compared to those with low DLs. This work provides a thermodynamic analysis of the release mechanism of ASDs composed of ritonavir (RIT) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA). The observed release behavior is, for the first time, explained based on the quantitative thermodynamic phase diagram predicted by PC-SAFT. Both liquid–liquid phase separation in the dissolution medium, as well as amorphous phase separation in the ASD, could be linked back to the same thermodynamic origin, whereas they had been understood as different phenomena so far in the literature. Furthermore, it is illustrated that upon release, independent of DL, both phenomena occur simultaneously for the investigated system. It could be shown that the non-congruent release of the drug and polymer is observed when amorphous phase separation within the ASD has taken place to some degree prior to dissolution. Nanodroplet formation in the dissolution medium could be explained as the liquid–liquid phase separation, as predicted by PC-SAFT.

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

“…4,5,31,32 It was proposed that its origin stems from rapid, water-induced amorphous−amorphous phase separation (AAPS) at the surface. 12,32 Moreover, Han and co-workers argued that the same mechanism is responsible for generating the drug-rich nanoparticle phase. 32 In essence, the phase separation process generates a hydrophilic (aqueous) and a hydrophobic (insoluble) phase.…”

“…The formation of a drug-rich layer on the surface of a dissolving ASD is a common observation and is thought to be largely responsible for the catastrophic reduction in the drug and polymer release rate above the LoC. ,,, It was proposed that its origin stems from rapid, water-induced amorphous–amorphous phase separation (AAPS) at the surface. , Moreover, Han and co-workers argued that the same mechanism is responsible for generating the drug-rich nanoparticle phase . In essence, the phase separation process generates a hydrophilic (aqueous) and a hydrophobic (insoluble) phase.…”

“…ASDs are molecular mixtures of a drug and a polymer and have unique release properties. Studies as early as 1965 provided evidence that ASDs can generate a nanoparticle phase upon dissolution, with recent studies demonstrating that the process underlying the nanoparticle formation is liquid–liquid phase separation (LLPS). , It has also been confirmed that the nanoparticle phase contains amorphous drug, and the particles are typically on the order of a few hundred nanometers. − Rapid equilibration has been observed between these nanoparticles and the aqueous environment, leading to sustained supersaturation during drug absorption, which is thought to contribute to improved bioavailability. , …”

An isocratic RP-HPLC-UV method for simultaneous quantification of tizanidine and lidocaine: application to in vitro release studies of a subcutaneous implant

“…VCM is a technology that can be used for pre-formulation studies of implants and solid amorphous polymer-drug dispersions without using hot-melt extrusion. [63][64][65][66][67][68] This allows the use of small samples. In this case the pre-mixture of drugs with an organic solvent will mimic the mixing of the drugs and polymers within the barrel of a hotmelt extruder.…”

Dissolution Mechanisms of Amorphous Solid Dispersions: Application of Ternary Phase Diagrams To Explain Release Behavior

“…Despite recent progress, the connection between intermolecular interactions and the release behavior of ASD is mostly qualitative. Progress toward quantitative approaches was made by Krummnow et al, who provided a thermodynamic analysis of the release mechanism of ASDs composed of ritonavir and PVPVA based on the quantitative thermodynamic phase diagram of the ritonavir–PVPVA–water system predicted by Perturbed Chain Statistical Associating Fluid Theory (PC-SAFT). PC-SAFT − is a thermodynamic model that is capable of describing various intermolecular interactions (e.g., hydrogen bonding, van der Waals attraction, or electrostatic interactions) in small molecules such as water, solvents, or gases in medium-sized chemically complex active pharmaceutical ingredients (APIs), high-molecular-weight polymers, and mixtures thereof.…”