Explaining the Release Mechanism of Ritonavir/PVPVA Amorphous Solid Dispersions

Krummnow, Adrian; Danzer, Andreas; Voges, Kristin; Kyeremateng, Samuel O.; Degenhardt, Matthias; Sadowski, Gabriele

doi:10.3390/pharmaceutics14091904

Cited by 15 publications

(33 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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. , …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Deac

Indulkar

et al. 2022

Mol. Pharmaceutics

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Deac

Indulkar

et al. 2022

Mol. Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Preparation Of the Implant Devicementioning

confidence: 99%

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

Picco,

Anjani,

Donnelly

et al. 2024

Anal. Methods

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Deac,

Luebbert,

et al. 2024

Mol. Pharmaceutics

Self Cite

View full text Add to dashboard Cite

The use of amorphous solid dispersions (ASDs) in commercial drug products has increased in recent years due to the large number of poorly soluble drugs in the pharmaceutical pipeline. However, the release behavior of ASDs is complex and remains not well understood. Often, the drug release from ASDs is rapid and complete at lower drug loadings (DLs) but becomes slow and incomplete at higher DLs. The DL where release becomes hindered is termed the limit of congruency (LoC). Currently, there are no approaches to predict the LoC. However, recent findings show that one potential cause leading to the LoC is a change in phase morphology after water-induced phase separation at the ASD/solution interface. In this study, the phase behavior of ASDs in contact with aqueous solutions was described thermodynamically by constructing experimental and computational ternary phase diagrams, and these were used to predict morphology changes and ultimately the LoC. Experimental ternary phase diagrams were obtained by equilibrating ASD/ water mixtures over time. Computational ternary phase diagrams were obtained by Perturbed Chain Statistical Associating Fluid Theory (PC-SAFT). The morphology of the hydrophobic phase was studied with fluorescence confocal microscopy. It was demonstrated that critical point (plait point) composition approximately corresponded to the ASD DL, where the hydrophobic phase, formed during phase separation, became interconnected and hindered ASD release. This work provides mechanistic insights into the ASD release behavior and highlights the potential of in silico ASD design using phase diagrams.

show abstract

Explaining the Release Mechanism of Ritonavir/PVPVA Amorphous Solid Dispersions

Cited by 15 publications

References 37 publications

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

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

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

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

Contact Info

Product

Resources

About