Direct Visualization of Drug–Polymer Phase Separation in Ritonavir–Copovidone Amorphous Solid Dispersions Using in situ Synchrotron X-ray Fluorescence Imaging of Thin Films
Abstract
Amorphous solid dispersions (ASDs) are new formulations currently being used in pharmaceutical industry. The ASDs, in which amorphous drug and polymeric excipients are intimately mixed at a molecular level, exhibit dramatically enhanced solubility and dissolution characteristics relative to their crystalline drug counterparts. In the process of achieving an ever-increasing drug loading (DL), it is noticed however, that the drug release profile deteriorates significantly beyond a certain DL. As an example, a ritonavir-copovidone ASD achieves continuous and full drug release when DL ≤ 25 wt%. The release drops at 30 wt% and when DL > 30 wt% there is virtually no drug release, behaving like a pure amorphous drug. In this communication, the dissolution behavior of ASD thin films has been investigated by in situ synchrotron X-ray fluorescence (XRF) imaging to elucidate the mechanism for the unique change in extent of drug release as a function of DL. It is found that the drug release profile correlates well with the amorphous-amorphous phase separation (AAPS) onset. At a lower drug loading (up to 20 wt%), it takes more than 12 hours for AAPS to happen while in sharp contrast, it only needs less than 10 minutes for DL > 30 wt%. Duringmore »
- Authors:
-
- AbbVie Inc., North Chicago, IL (United States)
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division
- OSTI Identifier:
- 1579933
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Molecular Pharmaceutics
- Additional Journal Information:
- Journal Volume: 16; Journal Issue: 11; Journal ID: ISSN 1543-8384
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY; phase separation; amorphous solid dispersion; release profile; synchrotron; X-ray fluorescence imaging
Citation Formats
Shi, Chenyang, Li, Luxi, Zhang, Geoff G. Z., and Borchardt, Thomas B. Direct Visualization of Drug–Polymer Phase Separation in Ritonavir–Copovidone Amorphous Solid Dispersions Using in situ Synchrotron X-ray Fluorescence Imaging of Thin Films. United States: N. p., 2019.
Web. doi:10.1021/acs.molpharmaceut.9b00651.
Shi, Chenyang, Li, Luxi, Zhang, Geoff G. Z., & Borchardt, Thomas B. Direct Visualization of Drug–Polymer Phase Separation in Ritonavir–Copovidone Amorphous Solid Dispersions Using in situ Synchrotron X-ray Fluorescence Imaging of Thin Films. United States. https://doi.org/10.1021/acs.molpharmaceut.9b00651
Shi, Chenyang, Li, Luxi, Zhang, Geoff G. Z., and Borchardt, Thomas B. Wed .
"Direct Visualization of Drug–Polymer Phase Separation in Ritonavir–Copovidone Amorphous Solid Dispersions Using in situ Synchrotron X-ray Fluorescence Imaging of Thin Films". United States. https://doi.org/10.1021/acs.molpharmaceut.9b00651. https://www.osti.gov/servlets/purl/1579933.
@article{osti_1579933,
title = {Direct Visualization of Drug–Polymer Phase Separation in Ritonavir–Copovidone Amorphous Solid Dispersions Using in situ Synchrotron X-ray Fluorescence Imaging of Thin Films},
author = {Shi, Chenyang and Li, Luxi and Zhang, Geoff G. Z. and Borchardt, Thomas B.},
abstractNote = {Amorphous solid dispersions (ASDs) are new formulations currently being used in pharmaceutical industry. The ASDs, in which amorphous drug and polymeric excipients are intimately mixed at a molecular level, exhibit dramatically enhanced solubility and dissolution characteristics relative to their crystalline drug counterparts. In the process of achieving an ever-increasing drug loading (DL), it is noticed however, that the drug release profile deteriorates significantly beyond a certain DL. As an example, a ritonavir-copovidone ASD achieves continuous and full drug release when DL ≤ 25 wt%. The release drops at 30 wt% and when DL > 30 wt% there is virtually no drug release, behaving like a pure amorphous drug. In this communication, the dissolution behavior of ASD thin films has been investigated by in situ synchrotron X-ray fluorescence (XRF) imaging to elucidate the mechanism for the unique change in extent of drug release as a function of DL. It is found that the drug release profile correlates well with the amorphous-amorphous phase separation (AAPS) onset. At a lower drug loading (up to 20 wt%), it takes more than 12 hours for AAPS to happen while in sharp contrast, it only needs less than 10 minutes for DL > 30 wt%. During AAPS amorphous drug accumulates on the surface of the film which prevents further dissolution from the interior of the ASD. The current study provides a mechanistic understanding of the confounding drug release profile of ASDs as a function of DL, and opens the door for studying drug-excipient (e.g. polymer, surfactant) interactions via XRF imaging in the future.},
doi = {10.1021/acs.molpharmaceut.9b00651},
journal = {Molecular Pharmaceutics},
number = 11,
volume = 16,
place = {United States},
year = {Wed Sep 25 00:00:00 EDT 2019},
month = {Wed Sep 25 00:00:00 EDT 2019}
}
Web of Science
Works referenced in this record:
Pharmaceutical Applications of Solid Dispersion Systems
journal, September 1971
- Chiou, Win Loung; Riegelman, Sidney
- Journal of Pharmaceutical Sciences, Vol. 60, Issue 9
Solid dispersion of poorly water‐soluble drugs: Early promises, subsequent problems, and recent breakthroughs
journal, October 1999
- Serajuddin, Abu T. M.
- Journal of Pharmaceutical Sciences, Vol. 88, Issue 10
Ritonavir–PEG 8000Amorphous Solid Dispersions: In vitro and In vivo Evaluations
journal, March 2004
- Law, Devalina; Schmitt, Eric A.; Marsh, Kennan C.
- Journal of Pharmaceutical Sciences, Vol. 93, Issue 3
Solubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals
journal, July 2011
- Babu, N. Jagadeesh; Nangia, Ashwini
- Crystal Growth & Design, Vol. 11, Issue 7
Amorphous pharmaceutical solids: preparation, characterization and stabilization
journal, May 2001
- Yu, Lian
- Advanced Drug Delivery Reviews, Vol. 48, Issue 1
Insights into the Dissolution Mechanism of Ritonavir–Copovidone Amorphous Solid Dispersions: Importance of Congruent Release for Enhanced Performance
journal, January 2019
- Indulkar, Anura S.; Lou, Xiaochun; Zhang, Geoff G. Z.
- Molecular Pharmaceutics, Vol. 16, Issue 3
Understanding the Tendency of Amorphous Solid Dispersions to Undergo Amorphous–Amorphous Phase Separation in the Presence of Absorbed Moisture
journal, September 2011
- Rumondor, Alfred C. F.; Wikström, Håkan; Van Eerdenbrugh, Bernard
- AAPS PharmSciTech, Vol. 12, Issue 4
Phase Separation Kinetics in Amorphous Solid Dispersions Upon Exposure to Water
journal, April 2015
- Purohit, Hitesh S.; Taylor, Lynne S.
- Molecular Pharmaceutics, Vol. 12, Issue 5
Water-induced phase separation of miconazole-poly (vinylpyrrolidone-co-vinyl acetate) amorphous solid dispersions: Insights with confocal fluorescence microscopy
journal, August 2017
- Saboo, Sugandha; Taylor, Lynne S.
- International Journal of Pharmaceutics, Vol. 529, Issue 1-2
Insights into Nano- and Micron-Scale Phase Separation in Amorphous Solid Dispersions Using Fluorescence-Based Techniques in Combination with Solid State Nuclear Magnetic Resonance Spectroscopy
journal, April 2017
- Purohit, Hitesh S.; Ormes, James D.; Saboo, Sugandha
- Pharmaceutical Research, Vol. 34, Issue 7
Understanding the Impact of Water on the Miscibility and Microstructure of Amorphous Solid Dispersions: An AFM–LCR and TEM–EDX Study
journal, March 2017
- Li, Na; Gilpin, Christopher J.; Taylor, Lynne S.
- Molecular Pharmaceutics, Vol. 14, Issue 5
Mechanisms of murine cerebral malaria: Multimodal imaging of altered cerebral metabolism and protein oxidation at hemorrhage sites
journal, December 2015
- Hackett, Mark J.; Aitken, Jade B.; El-Assaad, Fatima
- Science Advances, Vol. 1, Issue 11
MicroXRF tomographic visualization of zinc and iron in the zebrafish embryo at the onset of the hatching period
journal, January 2016
- Bourassa, Daisy; Gleber, Sophie-Charlotte; Vogt, Stefan
- Metallomics, Vol. 8, Issue 10
Biological applications of X-ray fluorescence microscopy: exploring the subcellular topography and speciation of transition metals
journal, April 2007
- Fahrni, Christoph J.
- Current Opinion in Chemical Biology, Vol. 11, Issue 2
Microplankton trace element contents: implications for mineral limitation of mesozooplankton in an HNLC area
journal, January 2016
- Baines, Stephen B.; Chen, Xi; Vogt, Stefan
- Journal of Plankton Research, Vol. 38, Issue 2
Spatial distribution of metals within the liver acinus and their perturbation by PCB126
journal, September 2017
- Klaren, William D.; Vine, David; Vogt, Stefan
- Environmental Science and Pollution Research, Vol. 25, Issue 17