ritonavir and vinyl-acetate

Formulating poorly soluble molecules as amorphous solid dispersions (ASDs) is an effective strategy to improve drug release. However, drug release rate and extent tend to rapidly diminish with increasing drug loading (DL). The poor release at high DLs has been postulated to be linked to the process of amorphous-amorphous phase separation (AAPS), although the exact connection between phase separation and release properties remains somewhat unclear. Herein, release profiles of ASDs formulated with ritonavir (RTV) and polyvinylpyrrolidone/vinyl acetate (PVPVA) at different DLs were determined using surface normalized dissolution. Surface morphologies of partially dissolved ASD compacts were evaluated with confocal fluorescence microscopy, using Nile red and Alexa Fluor 488 as fluorescence markers to track the hydrophobic and hydrophilic phases respectively. ASD phase behavior during hydration and release of components were also visualized in real time using a newly developed in situ confocal fluorescence microscopy method. RTV-PVPVA ASDs showed complete and rapid drug release below 30% DL, partial drug release at 30% DL and no drug release above 30% DL. It was observed that formation of discrete drug-rich droplets at lower DLs led to rapid and congruent release of both drug and polymer, whereas formation of continuous drug-rich phase at the ASD matrix-solution interface was the cause of poor release above certain DLs. Thus, the domain size and interconnectivity of phase separated drug-rich domains appear to be critical factors impacting drug release from RTV-PVPVPA ASDs.

Topics: Drug Liberation; Polymers; Povidone; Pyrrolidines; Ritonavir; Solubility; Vinyl Compounds

In this study, the lack of complete drug release from amorphous solid dispersions (ASDs), as observed in most published reports, was investigated. ASDs with 20% ritonavir were prepared by HME using polyvinylpyrrolidone vinyl acetate (PVPVA) alone and in combination with 10% poloxamer 407 or Span 20 as carriers. It was established by the film casting technique that ritonavir was molecularly dispersed in formulations, and accelerated stability testing confirmed that extrudates were physically stable. Dissolution of ASDs (100-mg ritonavir equivalent) was performed in 250 mL 0.01 N HCl (pH 2), pH 6.8 phosphate buffer and FeSSIF-V2. Drug concentrations were measured by filtration through 0.45-μm pores and in unfiltered media; the latter gave total amounts of drug present in dissolution media, both as solution and dispersion. Because of low solubility, ritonavir did not dissolve completely in aqueous media. Rather, it formed supersaturated solutions, and the excess drug dispersed in the oily amorphous form with low particle sizes that could crystallize with time. Due to higher drug solubility, the dissolved drug in FeSSIF-V2 was much higher than that in the phosphate buffer. Complete drug release could be observed by accounting for drug both in solution and as phase-separated dispersion. Thus, the present study provides a complete picture of in vitro drug dissolution and dispersion from ASDs.

Topics: Drug Compounding; Povidone; Ritonavir; Solubility; Surface-Active Agents; Vinyl Compounds

We demonstrate instrumentation and methods to enable fluorescence-detected photothermal infrared (F-PTIR) microscopy and then demonstrate the utility of F-PTIR to characterize the composition within phase-separated domains of model amorphous solid dispersions (ASDs) induced by water sorption. In F-PTIR, temperature-dependent changes in fluorescence quantum efficiency are shown to sensitively report on highly localized absorption of mid-infrared radiation. The spatial resolution with which infrared spectroscopy can be performed is dictated by fluorescence microscopy, rather than the infrared wavelength. Intrinsic ultraviolet autofluorescence of tryptophan and protein microparticles enabled label-free F-PTIR microscopy. Following proof of concept F-PTIR demonstration on model systems of polyethylene glycol (PEG) and silica gel, F-PTIR enabled the characterization of chemical composition within inhomogeneous ritonavir/polyvinylpyrrolidone-vinyl acetate (PVPVA) amorphous dispersions. Phase separation is implicated in the observation of critical behaviors in ASD dissolution kinetics, with the results of F-PTIR supporting the formation of phase-separated drug-rich domains upon water sorption in spin-cast films.

Topics: Fluorescence; Gels; Kinetics; Microscopy, Fluorescence; Polyethylene Glycols; Povidone; Ritonavir; Silicon Dioxide; Spectrophotometry, Infrared; Temperature; Vinyl Compounds

The aim of this research was to study the interplay of solid and solution state phase transformations during the dissolution of ritonavir (RTV) amorphous solid dispersions (ASDs).. RTV ASDs with polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) were prepared at 10-50% drug loading by solvent evaporation. The miscibility of RTV ASDs was studied before and after exposure to 97% relative humidity (RH). Non-sink dissolution studies were performed on fresh and moisture-exposed ASDs. RTV and polymer release were monitored using ultraviolet-visible spectroscopy. Techniques including fluorescence spectroscopy, confocal imaging, scanning electron microscopy (SEM), atomic force microscopy (AFM), differential scanning calorimetry (DSC) and nanoparticle tracking analysis (NTA) were utilized to monitor solid and the solution state phase transformations.. All RTV-PVP and RTV-PVPVA ASDs underwent moisture-induced amorphous-amorphous phase separation (AAPS) on high RH storage whereas RTV-HPMCAS ASDs remained miscible. Non-sink dissolution of PVP- and PVPVA-based ASDs at low drug loadings led to rapid RTV and polymer release resulting in concentrations in excess of amorphous solubility, liquid-liquid phase separation (LLPS) and amorphous nanodroplet formation. High drug loading PVP- and PVPVA-based ASDs did not exhibit LLPS upon dissolution as a consequence of extensive AAPS in the hydrated ASD matrix. All RTV-HPMCAS ASDs led to LLPS upon dissolution.. RTV ASD dissolution is governed by a competition between the dissolution rate and the rate of phase separation in the hydrated ASD matrix. LLPS was observed for ASDs where the drug release was polymer controlled and only ASDs that remained miscible during the initial phase of dissolution led to LLPS. Techniques such as fluorescence spectroscopy, confocal imaging and SEM were useful in understanding the phase behavior of ASDs upon hydration and dissolution and were helpful in elucidating the mechanism of generation of amorphous nanodroplets.

Topics: Crystallization; Cytochrome P-450 CYP3A Inhibitors; Delayed-Action Preparations; Drug Liberation; Excipients; HIV Protease Inhibitors; Humidity; Methylcellulose; Phase Transition; Povidone; Ritonavir; Solubility; Vinyl Compounds