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Phase Behavior of Ritonavir Amorphous Solid Dispersions during Hydration and Dissolution.
Hitesh S Purohit1, Lynne S Taylor2
1Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, 47907, USA.
Pharmaceutical Research
|September 29, 2017
Summary
Phase transformations during ritonavir (RTV) amorphous solid dispersion (ASD) dissolution depend on formulation and storage. Liquid-liquid phase separation (LLPS) and nanodroplet formation occur, influenced by drug release rates and polymer interactions.
Area of Science:
- Pharmaceutical Sciences
- Materials Science
- Physical Chemistry
Background:
- Amorphous solid dispersions (ASDs) enhance the solubility and bioavailability of poorly soluble drugs.
- Understanding solid and solution state phase transformations is crucial for ASD performance.
- Ritonavir (RTV) is a model drug often formulated as ASDs.
Purpose of the Study:
- To investigate the interplay between solid and solution state phase transformations during ritonavir (RTV) amorphous solid dispersion (ASD) dissolution.
- To examine the influence of different polymers (PVP, PVPVA, HPMCAS) and drug loading on RTV ASD phase behavior.
- To elucidate the mechanisms of amorphous nanodroplet formation during dissolution.
Main Methods:
- Preparation of RTV ASDs with PVP, PVPVA, and HPMCAS via solvent evaporation at varying drug loadings.
- Assessment of ASD miscibility before and after high relative humidity (97% RH) exposure.
- Non-sink dissolution studies of fresh and moisture-exposed ASDs, monitoring RTV and polymer release.
- Utilized techniques: fluorescence spectroscopy, confocal imaging, SEM, AFM, DSC, and NTA for phase transformation monitoring.
Main Results:
- RTV-PVP and RTV-PVPVA ASDs showed moisture-induced amorphous-amorphous phase separation (AAPS), while RTV-HPMCAS ASDs remained miscible.
- Low drug loading PVP/PVPVA ASDs exhibited rapid release, leading to concentrations exceeding amorphous solubility, resulting in liquid-liquid phase separation (LLPS) and nanodroplet formation.
- High drug loading PVP/PVPVA ASDs and all RTV-HPMCAS ASDs showed LLPS upon dissolution, with the former attributed to extensive AAPS.
Conclusions:
- Ritonavir ASD dissolution is a balance between dissolution rate and matrix phase separation rate.
- LLPS occurred in polymer-controlled release ASDs, and only initially miscible ASDs led to LLPS.
- Fluorescence spectroscopy, confocal imaging, and SEM were key in understanding ASD phase behavior and nanodroplet generation mechanisms.
Keywords:
amorphous solid dispersionamorphous-amorphous phase separationdissolutionfluorescence spectroscopyliquid-liquid phase separationMore Related Videos
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