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Investigation of a suitable in vitro dissolution test for itraconazole-based solid dispersions.
Eur J Pharm Sci. 2016 Mar 31; 85:94-105.EJ

Abstract

The difficulty to find a relevant in vitro dissolution test to evaluate poorly soluble drugs is a well-known issue. One way to enhance their aqueous solubility is to formulate them as amorphous solid dispersions. In this study, three formulations containing itraconazole (ITZ), a model drug, were tested in seven different conditions (different USP apparatuses and different media). Two of the formulations were amorphous solid dispersions namely Sporanox®, the marketed product, and extrudates composed of Soluplus® and ITZ produced by hot melt extrusion; and the last one was pure crystalline ITZ capsules. After each test, a ranking of the formulations was established. Surprisingly, the two amorphous solid dispersions exhibited very different behavior depending primarily on the dissolution media. Indeed, the extrudates showed a better release profile than Sporanox® in non-sink and in biphasic conditions, whilst Sporanox® showed a higher release profile than the extrudates in sink and fasted simulated gastric conditions. The disintegration, dynamic light scattering and nuclear magnetic resonance results highlighted the presence of interaction between the surfactants and Soluplus®, which slowed down the erosion of the polymer matrix. Indeed, the negative charge of sodium dodecyl sulfate (SDS) and bile salts interacted with the surface of the extrudates that formed a barrier through which the water hardly diffused. Moreover, Soluplus® and SDS formed mixed micelles in solution in which ITZ interacts with SDS, but no longer with Soluplus®. Regarding the biphasic dissolution test, the interactions between the octanol dissolved in the aqueous media disrupted the polymer--ITZ system leading to a reduced release of ITZ from Sporanox®, whilst it had no influence on the extrudates. All together these results pointed out the difficulty of finding a suitable in vitro dissolution test due to interactions between the excipients that complicates the prediction of the behavior of these solid dispersions in vivo.

Authors+Show Affiliations

Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000, Liege, Belgium. Electronic address: jthiry@ulg.ac.be.Center for Education and Research on Macromolecules, University of Liege, Chemistry Department, B6a, Sart-Tilman, Liege, Belgium.Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000, Liege, Belgium.Center of Nuclear Magnetic Resonance (CREMAN), Department of Chemistry, University of Liege, 4000, Liege, Belgium.Center of Nuclear Magnetic Resonance (CREMAN), Department of Chemistry, University of Liege, 4000, Liege, Belgium.Center of Nuclear Magnetic Resonance (CREMAN), Department of Chemistry, University of Liege, 4000, Liege, Belgium.Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000, Liege, Belgium.Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000, Liege, Belgium.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26850682

Citation

Thiry, Justine, et al. "Investigation of a Suitable in Vitro Dissolution Test for Itraconazole-based Solid Dispersions." European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, vol. 85, 2016, pp. 94-105.
Thiry J, Broze G, Pestieau A, et al. Investigation of a suitable in vitro dissolution test for itraconazole-based solid dispersions. Eur J Pharm Sci. 2016;85:94-105.
Thiry, J., Broze, G., Pestieau, A., Tatton, A. S., Baumans, F., Damblon, C., Krier, F., & Evrard, B. (2016). Investigation of a suitable in vitro dissolution test for itraconazole-based solid dispersions. European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, 85, 94-105. https://doi.org/10.1016/j.ejps.2016.02.002
Thiry J, et al. Investigation of a Suitable in Vitro Dissolution Test for Itraconazole-based Solid Dispersions. Eur J Pharm Sci. 2016 Mar 31;85:94-105. PubMed PMID: 26850682.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Investigation of a suitable in vitro dissolution test for itraconazole-based solid dispersions. AU - Thiry,Justine, AU - Broze,Guy, AU - Pestieau,Aude, AU - Tatton,Andrew S, AU - Baumans,France, AU - Damblon,Christian, AU - Krier,Fabrice, AU - Evrard,Brigitte, Y1 - 2016/02/02/ PY - 2015/11/04/received PY - 2016/01/20/revised PY - 2016/02/01/accepted PY - 2016/2/7/entrez PY - 2016/2/7/pubmed PY - 2016/12/15/medline KW - Excipient-medium interactions KW - In vitro dissolution test KW - Itraconazole KW - Solid dispersions KW - Soluplus® KW - Sporanox® SP - 94 EP - 105 JF - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JO - Eur J Pharm Sci VL - 85 N2 - The difficulty to find a relevant in vitro dissolution test to evaluate poorly soluble drugs is a well-known issue. One way to enhance their aqueous solubility is to formulate them as amorphous solid dispersions. In this study, three formulations containing itraconazole (ITZ), a model drug, were tested in seven different conditions (different USP apparatuses and different media). Two of the formulations were amorphous solid dispersions namely Sporanox®, the marketed product, and extrudates composed of Soluplus® and ITZ produced by hot melt extrusion; and the last one was pure crystalline ITZ capsules. After each test, a ranking of the formulations was established. Surprisingly, the two amorphous solid dispersions exhibited very different behavior depending primarily on the dissolution media. Indeed, the extrudates showed a better release profile than Sporanox® in non-sink and in biphasic conditions, whilst Sporanox® showed a higher release profile than the extrudates in sink and fasted simulated gastric conditions. The disintegration, dynamic light scattering and nuclear magnetic resonance results highlighted the presence of interaction between the surfactants and Soluplus®, which slowed down the erosion of the polymer matrix. Indeed, the negative charge of sodium dodecyl sulfate (SDS) and bile salts interacted with the surface of the extrudates that formed a barrier through which the water hardly diffused. Moreover, Soluplus® and SDS formed mixed micelles in solution in which ITZ interacts with SDS, but no longer with Soluplus®. Regarding the biphasic dissolution test, the interactions between the octanol dissolved in the aqueous media disrupted the polymer--ITZ system leading to a reduced release of ITZ from Sporanox®, whilst it had no influence on the extrudates. All together these results pointed out the difficulty of finding a suitable in vitro dissolution test due to interactions between the excipients that complicates the prediction of the behavior of these solid dispersions in vivo. SN - 1879-0720 UR - https://www.unboundmedicine.com/medline/citation/26850682/Investigation_of_a_suitable_in_vitro_dissolution_test_for_itraconazole_based_solid_dispersions_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0928-0987(16)30032-X DB - PRIME DP - Unbound Medicine ER -