Enabling an HCV Treatment Revolution and the Frontiers of Solid Solution Formulation

McKelvey, Craig A.; Kesisoglou, Filippos

doi:10.1016/j.xphs.2018.11.003

Cited by 20 publications

(12 citation statements)

References 20 publications

(18 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Amorphous drugs offer increased transient solubility compared to their crystalline counterparts; however, this solubility advantage is often not sufficient to deliver high dose drugs [ 3 , 4 ]. Therefore, the dissolution advantage derived from polymer-controlled dissolution of amorphous solid dispersions (ASDs), where drug is molecularly dispersed in a hydrophilic polymer matrix, is gaining increased attention from drug product formulators and researchers [ 5 , 6 ]. The dissolution rate of a hydrophilic polymer is many times higher compared to that of a lipophilic drug.…”

Section: Introductionmentioning

confidence: 99%

“…Felodipine, a biopharmaceutical classification system class II drug, which has been extensively studied in ASD formulations, was chosen as the model drug [ 28 , 29 , 30 ]. Polyvinylpyrrolidone/vinyl acetate (PVPVA), a hydrophilic polymer, which has been widely utilized in marketed ASD-based pharmaceutical products, was selected as the model polymer [ 6 ]. TPGS, a pharmaceutically relevant surfactant present in commercial ASD formulations, Viekira Pak and Belsomra, was used to formulate ternary systems.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Exploring the Role of Surfactants in Enhancing Drug Release from Amorphous Solid Dispersions at Higher Drug Loadings

et al. 2021

View full text Add to dashboard Cite

To reduce the dosage size of amorphous solid dispersion (ASD)-based formulations, it is of interest to devise formulation strategies that allow increased drug loading (DL) without compromising dissolution performance. The aim of this study was to explore how surfactant addition impacts drug release as a function of drug loading from a ternary ASD, using felodipine as a model poorly soluble compound. The addition of 5% TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate, a surfactant) to felodipine-polyvinylpyrrolidone/vinyl acetate ASDs was found to facilitate rapid and congruent (i.e., simultaneous) release of drug and polymer at higher DLs relative to binary ASDs (drug and polymer only). For binary ASDs, good release was observed for DLs up to <20% DL; this increased to 35% DL with surfactant. Microstructure evolution in ASD films following exposure to 100% relative humidity was studied using atomic force microscopy coupled with nanoscale infrared imaging. The formation of discrete, spherical drug-rich domains in the presence of surfactant appeared to be linked to systems showing congruent and rapid release of drug and polymer. In contrast, a contiguous drug-rich phase was formed for systems without surfactant at higher DLs. This study supports the addition of surfactant to ASD formulations as a strategy to increase DL without compromising release. Furthermore, insights into the potential role of surfactant in altering ASD release mechanisms are provided.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploring the Role of Surfactants in Enhancing Drug Release from Amorphous Solid Dispersions at Higher Drug Loadings

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Amorphous solid dispersions (ASDs) are an increasingly popular formulation strategy to deliver poorly water-soluble drugs, treating conditions ranging from cancer, insomnia, HIV, HCV, and COVID-19. − Hot melt extrusion (HME) is one of the primary manufacturing routes to prepare ASDs. For thermally stable drug and polymer systems, HME offers solvent-free, high-throughput, continuous processing .…”

Section: Introductionmentioning

confidence: 99%

“…BCL is a biopharmaceutics classification system (BCS) Class 2 compound with low aqueous solubility and a melting point of 195 °C and is representative of the types of compounds processed by HME. PVPVA is the most common polymer used with ASDs processed by HME. , BCL was obtained as a micronized crystalline powder and recrystallized by several methods to yield particles of varying size distribution, morphology, and flowability. Hot melt extrusion processing of the recrystallized BCL, along with the as-received material, was performed in order to assess amorphization kinetics (crystal dissolution), guided by the BCL/PVPVA temperature–composition phase diagram.…”

Section: Introductionmentioning

confidence: 99%

Optimization of Amorphization Kinetics during Hot Melt Extrusion by Particle Engineering: An Experimental and Computational Study

Moseson

Eren

Altman

et al. 2021

Crystal Growth & Design

View full text Add to dashboard Cite

Hot melt extrusion (HME) to prepare amorphous solid dispersions (ASDs) at temperatures below the drug's melting point requires the crystalline drug to dissolve into the molten polymer. This requires an understanding of the drug's solubility in the molten polymer as well as amorphization (crystal dissolution) kinetics. The goal of this study was to identify drug crystal attributes which contribute to rapid amorphization during hot melt extrusion processing to form ASDs. Particle engineering approaches were used to recrystallize bicalutamide with different particle size distributions and defect density. These lots were then used to prepare ASDs by HME to monitor the amorphization kinetics. Particle size had the expected effect on the amorphization rate, and defect density was also observed to accelerate amorphization. A population balance model using dissolution and breakage phenomena was developed to investigate the dynamic evolution of crystal size distribution during a hot melt extrusion process, and parameter estimation was utilized to simulate the experimental HME results. Breakage kinetics were found to dominate the crystal dissolution process, synergistically accelerated by particles with high defect density. The findings have implications for particle engineering of crystals to enable the hot melt extrusion process, as well as improved process modeling through incorporating particle attributes.

show abstract

“…Molecules That Utilize Amorphous Solid Dispersion Formulations a and Associated Solubility, Dose, and Dose Number (Do)10,39 …”

mentioning

confidence: 99%

Dose Number as a Tool to Guide Lead Optimization for Orally Bioavailable Compounds in Drug Discovery

et al. 2022

Self Cite

View full text Add to dashboard Cite

Small molecule developability challenges have been well documented over the last two decades. One of these critical developability parameters is aqueous solubility. In general, more soluble compounds have improved oral absorption. While enabling formulation technologies exist to improve bioperformance for low solubility compounds, these are often more complex, expensive, and challenging to scale up. Therefore, to avoid these development issues, medicinal chemists need tools to rapidly profile and improve the physicochemical properties of molecules during discovery. Dose number (Do) is a simple metric to predict whether a compound will be reasonably absorbed based on solubility at an expected clinical dose and represents a valuable parameter to the medicinal chemist defining a clinical candidate. The goal of this mini-Perspective is to present the background of the Do equation and how it can be effectively used to rapidly predict oral absorption potential for molecules in the discovery space.

show abstract

Enabling an HCV Treatment Revolution and the Frontiers of Solid Solution Formulation

Cited by 20 publications

References 20 publications

Exploring the Role of Surfactants in Enhancing Drug Release from Amorphous Solid Dispersions at Higher Drug Loadings

Exploring the Role of Surfactants in Enhancing Drug Release from Amorphous Solid Dispersions at Higher Drug Loadings

Optimization of Amorphization Kinetics during Hot Melt Extrusion by Particle Engineering: An Experimental and Computational Study

Dose Number as a Tool to Guide Lead Optimization for Orally Bioavailable Compounds in Drug Discovery

Contact Info

Product

Resources

About