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Phase Behavior of Ritonavir Amorphous Solid Dispersions during Hydration and Dissolution

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Abstract

Purpose

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).

Methods

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.

Results

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.

Conclusions

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.

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Abbreviations

ASD:

Amorphous solid dispersion

AAPS:

Amorphous-amorphous phase separation

AFM:

Atomic force microscopy

DSC:

Differential scanning calorimetry

DL:

Drug loading

HPMCAS:

Hydroxypropyl methylcellulose acetate succinate

LLPS:

Liquid-liquid phase separation

NTA:

Nanotracking analysis

PVP:

Polyvinylpyrrolidone

PVPVA:

Polyvinylpyrrolidone vinyl acetate

RH:

Relative humidity

RTV:

Ritonavir

UV-Vis:

Ultraviolet-visible

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ACKNOWLEDGMENTS AND DISCLOSURES

Financial support to HSP from Migliaccio/Pfizer graduate fellowship is greatly acknowledged. The authors would also like to thank the National Science Foundation through grant number EEC-0540855, and the National Institutes of Health through grant number R42 GM100657–03, for financial support.

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Authors and Affiliations

  1. Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, 47907, USA

    Hitesh S. Purohit & Lynne S. Taylor

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  1. Hitesh S. Purohit
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  2. Lynne S. Taylor
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Correspondence to Lynne S. Taylor.

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Purohit, H.S., Taylor, L.S. Phase Behavior of Ritonavir Amorphous Solid Dispersions during Hydration and Dissolution. Pharm Res 34, 2842–2861 (2017). https://doi.org/10.1007/s11095-017-2265-5

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