Explaining the Release Mechanism of Ritonavir/PVPVA Amorphous Solid Dispersions

In amorphous solid dispersions (ASDs), an active pharmaceutical ingredient (API) is dissolved on a molecular level in a polymeric matrix. The API is expected to be released from the ASD upon dissolution in aqueous media. However, a series of earlier works observed a drastic collapse of the API relea...

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Main Authors: Adrian Krummnow, Andreas Danzer, Kristin Voges, Stefanie Dohrn, Samuel O. Kyeremateng, Matthias Degenhardt, Gabriele Sadowski
Format: Article
Language:English
Published: MDPI AG 2022-09-01
Series:Pharmaceutics
Subjects:
Online Access:https://www.mdpi.com/1999-4923/14/9/1904
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author Adrian Krummnow
Andreas Danzer
Kristin Voges
Stefanie Dohrn
Samuel O. Kyeremateng
Matthias Degenhardt
Gabriele Sadowski
author_facet Adrian Krummnow
Andreas Danzer
Kristin Voges
Stefanie Dohrn
Samuel O. Kyeremateng
Matthias Degenhardt
Gabriele Sadowski
author_sort Adrian Krummnow
collection DOAJ
description In amorphous solid dispersions (ASDs), an active pharmaceutical ingredient (API) is dissolved on a molecular level in a polymeric matrix. The API is expected to be released from the ASD upon dissolution in aqueous media. However, a series of earlier works observed a drastic collapse of the API release for ASDs with high drug loads (DLs) compared to those with low DLs. This work provides a thermodynamic analysis of the release mechanism of ASDs composed of ritonavir (RIT) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA). The observed release behavior is, for the first time, explained based on the quantitative thermodynamic phase diagram predicted by PC-SAFT. Both liquid–liquid phase separation in the dissolution medium, as well as amorphous phase separation in the ASD, could be linked back to the same thermodynamic origin, whereas they had been understood as different phenomena so far in the literature. Furthermore, it is illustrated that upon release, independent of DL, both phenomena occur simultaneously for the investigated system. It could be shown that the non-congruent release of the drug and polymer is observed when amorphous phase separation within the ASD has taken place to some degree prior to dissolution. Nanodroplet formation in the dissolution medium could be explained as the liquid–liquid phase separation, as predicted by PC-SAFT.
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spelling doaj.art-a6f4f826bd9d43f4a239692d5477d9852023-11-23T18:22:43ZengMDPI AGPharmaceutics1999-49232022-09-01149190410.3390/pharmaceutics14091904Explaining the Release Mechanism of Ritonavir/PVPVA Amorphous Solid DispersionsAdrian Krummnow0Andreas Danzer1Kristin Voges2Stefanie Dohrn3Samuel O. Kyeremateng4Matthias Degenhardt5Gabriele Sadowski6Laboratory of Thermodynamics, Department of Biochemical and Chemical Engineering, TU Dortmund University, Emil-Figge-Str. 70, D-44227 Dortmund, GermanyLaboratory of Thermodynamics, Department of Biochemical and Chemical Engineering, TU Dortmund University, Emil-Figge-Str. 70, D-44227 Dortmund, GermanyAbbVie Deutschland GmbH & Co. KG, Global Pharmaceutical R&D, Knollstraße, D-67061 Ludwigshafen am Rhein, GermanyAbbVie Deutschland GmbH & Co. KG, Global Pharmaceutical R&D, Knollstraße, D-67061 Ludwigshafen am Rhein, GermanyAbbVie Deutschland GmbH & Co. KG, Global Pharmaceutical R&D, Knollstraße, D-67061 Ludwigshafen am Rhein, GermanyAbbVie Deutschland GmbH & Co. KG, Global Pharmaceutical R&D, Knollstraße, D-67061 Ludwigshafen am Rhein, GermanyLaboratory of Thermodynamics, Department of Biochemical and Chemical Engineering, TU Dortmund University, Emil-Figge-Str. 70, D-44227 Dortmund, GermanyIn amorphous solid dispersions (ASDs), an active pharmaceutical ingredient (API) is dissolved on a molecular level in a polymeric matrix. The API is expected to be released from the ASD upon dissolution in aqueous media. However, a series of earlier works observed a drastic collapse of the API release for ASDs with high drug loads (DLs) compared to those with low DLs. This work provides a thermodynamic analysis of the release mechanism of ASDs composed of ritonavir (RIT) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA). The observed release behavior is, for the first time, explained based on the quantitative thermodynamic phase diagram predicted by PC-SAFT. Both liquid–liquid phase separation in the dissolution medium, as well as amorphous phase separation in the ASD, could be linked back to the same thermodynamic origin, whereas they had been understood as different phenomena so far in the literature. Furthermore, it is illustrated that upon release, independent of DL, both phenomena occur simultaneously for the investigated system. It could be shown that the non-congruent release of the drug and polymer is observed when amorphous phase separation within the ASD has taken place to some degree prior to dissolution. Nanodroplet formation in the dissolution medium could be explained as the liquid–liquid phase separation, as predicted by PC-SAFT.https://www.mdpi.com/1999-4923/14/9/1904phase behaviorglass transitionreleaseamorphous phase separationliquid–liquid phase separation
spellingShingle Adrian Krummnow
Andreas Danzer
Kristin Voges
Stefanie Dohrn
Samuel O. Kyeremateng
Matthias Degenhardt
Gabriele Sadowski
Explaining the Release Mechanism of Ritonavir/PVPVA Amorphous Solid Dispersions
Pharmaceutics
phase behavior
glass transition
release
amorphous phase separation
liquid–liquid phase separation
title Explaining the Release Mechanism of Ritonavir/PVPVA Amorphous Solid Dispersions
title_full Explaining the Release Mechanism of Ritonavir/PVPVA Amorphous Solid Dispersions
title_fullStr Explaining the Release Mechanism of Ritonavir/PVPVA Amorphous Solid Dispersions
title_full_unstemmed Explaining the Release Mechanism of Ritonavir/PVPVA Amorphous Solid Dispersions
title_short Explaining the Release Mechanism of Ritonavir/PVPVA Amorphous Solid Dispersions
title_sort explaining the release mechanism of ritonavir pvpva amorphous solid dispersions
topic phase behavior
glass transition
release
amorphous phase separation
liquid–liquid phase separation
url https://www.mdpi.com/1999-4923/14/9/1904
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