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Phase Behavior of Ritonavir Amorphous Solid Dispersions during Hydration and Dissolution.
Pharm Res. 2017 Dec; 34(12):2842-2861.PR

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.

Authors+Show Affiliations

Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, 47907, USA.Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, 47907, USA. lstaylor@purdue.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28956218

Citation

Purohit, Hitesh S., and Lynne S. Taylor. "Phase Behavior of Ritonavir Amorphous Solid Dispersions During Hydration and Dissolution." Pharmaceutical Research, vol. 34, no. 12, 2017, pp. 2842-2861.
Purohit HS, Taylor LS. Phase Behavior of Ritonavir Amorphous Solid Dispersions during Hydration and Dissolution. Pharm Res. 2017;34(12):2842-2861.
Purohit, H. S., & Taylor, L. S. (2017). Phase Behavior of Ritonavir Amorphous Solid Dispersions during Hydration and Dissolution. Pharmaceutical Research, 34(12), 2842-2861. https://doi.org/10.1007/s11095-017-2265-5
Purohit HS, Taylor LS. Phase Behavior of Ritonavir Amorphous Solid Dispersions During Hydration and Dissolution. Pharm Res. 2017;34(12):2842-2861. PubMed PMID: 28956218.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phase Behavior of Ritonavir Amorphous Solid Dispersions during Hydration and Dissolution. AU - Purohit,Hitesh S, AU - Taylor,Lynne S, Y1 - 2017/09/27/ PY - 2017/05/11/received PY - 2017/09/14/accepted PY - 2017/9/29/pubmed PY - 2018/7/31/medline PY - 2017/9/29/entrez KW - amorphous solid dispersion KW - amorphous-amorphous phase separation KW - dissolution KW - fluorescence spectroscopy KW - liquid-liquid phase separation SP - 2842 EP - 2861 JF - Pharmaceutical research JO - Pharm Res VL - 34 IS - 12 N2 - 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. SN - 1573-904X UR - https://www.unboundmedicine.com/medline/citation/28956218/Phase_Behavior_of_Ritonavir_Amorphous_Solid_Dispersions_during_Hydration_and_Dissolution_ L2 - https://doi.org/10.1007/s11095-017-2265-5 DB - PRIME DP - Unbound Medicine ER -