Metastable phase diagram, mobility, and kinetic stability of amorphous mixtures of two mutually compatible APIs
DSC, dielectric spectroscopy, and optical microscopy, are employed to analyze the equilibrium and out-of-equilibrium binary phase diagram of two antifungal azole compounds, fluconazole (FLZ) and econazole (ECZ), to study the physical stability of co-amorphous formulations that may allow co-administr...
| Autores: | , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2026 |
| País: | España |
| Institución: | Universitat Politècnica de Catalunya (UPC) |
| Repositorio: | UPCommons. Portal del coneixement obert de la UPC |
| Idioma: | inglés |
| OAI Identifier: | oai:dnet:upcommonspor::ffeeda7d426484d34c788b812a25cfb1 |
| Acceso en línea: | https://hdl.handle.net/2117/460708 https://dx.doi.org/10.1016/j.ijpx.2026.100525 |
| Access Level: | acceso abierto |
| Palabra clave: | Amorphous solid solutions Glass transition temperature Eutectic amorphous mixtures Relaxation dynamics Physical stability of glasses Formulation pre-development |
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| dc.title.none.fl_str_mv |
Metastable phase diagram, mobility, and kinetic stability of amorphous mixtures of two mutually compatible APIs |
| title |
Metastable phase diagram, mobility, and kinetic stability of amorphous mixtures of two mutually compatible APIs |
| spellingShingle |
Metastable phase diagram, mobility, and kinetic stability of amorphous mixtures of two mutually compatible APIs Noor, Wahi Amorphous solid solutions Glass transition temperature Eutectic amorphous mixtures Relaxation dynamics Physical stability of glasses Formulation pre-development |
| title_short |
Metastable phase diagram, mobility, and kinetic stability of amorphous mixtures of two mutually compatible APIs |
| title_full |
Metastable phase diagram, mobility, and kinetic stability of amorphous mixtures of two mutually compatible APIs |
| title_fullStr |
Metastable phase diagram, mobility, and kinetic stability of amorphous mixtures of two mutually compatible APIs |
| title_full_unstemmed |
Metastable phase diagram, mobility, and kinetic stability of amorphous mixtures of two mutually compatible APIs |
| title_sort |
Metastable phase diagram, mobility, and kinetic stability of amorphous mixtures of two mutually compatible APIs |
| dc.creator.none.fl_str_mv |
Noor, Wahi Romanini, Michela|||0000-0002-1685-855X Villalobos Ramos, Laia Talukder, Bijori Tamarit Mur, José Luis|||0000-0002-7965-0000 Macovez, Roberto|||0000-0001-5026-9372 |
| author |
Noor, Wahi |
| author_facet |
Noor, Wahi Romanini, Michela|||0000-0002-1685-855X Villalobos Ramos, Laia Talukder, Bijori Tamarit Mur, José Luis|||0000-0002-7965-0000 Macovez, Roberto|||0000-0001-5026-9372 |
| author_role |
author |
| author2 |
Romanini, Michela|||0000-0002-1685-855X Villalobos Ramos, Laia Talukder, Bijori Tamarit Mur, José Luis|||0000-0002-7965-0000 Macovez, Roberto|||0000-0001-5026-9372 |
| author2_role |
author author author author author |
| dc.subject.none.fl_str_mv |
Amorphous solid solutions Glass transition temperature Eutectic amorphous mixtures Relaxation dynamics Physical stability of glasses Formulation pre-development |
| topic |
Amorphous solid solutions Glass transition temperature Eutectic amorphous mixtures Relaxation dynamics Physical stability of glasses Formulation pre-development |
| description |
DSC, dielectric spectroscopy, and optical microscopy, are employed to analyze the equilibrium and out-of-equilibrium binary phase diagram of two antifungal azole compounds, fluconazole (FLZ) and econazole (ECZ), to study the physical stability of co-amorphous formulations that may allow co-administration and a faster dissolution of the poorly soluble ECZ compound. The two crystalline APIs form a eutectic equilibrium phase diagram with eutectic point at Te = 351.1 ± 0.5 K and eutectic molar fraction of FLZ of xFLZ,e = 0.22 ± 0.01. While amorphous FLZ has a strong tendency to crystallize, amorphous ECZ is kinetically stable during at least several weeks even as a supercooled liquid. Amorphous ECZ is found to display faster kinetic dissolution profile in water compared with crystalline ECZ. The glass transition (Tg) of the liquid mixtures depends linearly on composition, increasing by 4 K for every 10% increase in xFLZ. The molecular mobility determined by dielectric spectroscopy is characterized by a single structural relaxation and a single Johari-Goldstein relaxation at all compositions, testifying the structural and dynamic homogeneity of the amorphous mixtures. The equimolar supercooled liquid mixture and FLZ-rich mixtures phase-separate over few days or weeks, with the FLZ-rich phase recrystallizing into bundles of rod-like crystallites surrounded by an almost pure amorphous ECZ matrix. The amorphous mixture at the eutectic composition remains instead kinetically stable during 6 months above Tg, and for at least 10 months in the glass state below Tg. Mixtures that have ECZ molar fractions of 0.9 or higher are kinetically the most stable ones (they remain amorphous during more than 14 months at room temperature) despite having the fastest molecular mobility both in the supercooled liquid and glassy phases. Their high kinetic stability is likely due to lower supercooling and lower supersaturation, leading to lower thermodynamic driving force, and to the dilution of the recrystallizing FLZ compound. These results help shed light on the stability of binary amorphous mixtures. |
| publishDate |
2026 |
| dc.date.none.fl_str_mv |
2026 2026-06-01 2026 2026-04-17 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2117/460708 https://dx.doi.org/10.1016/j.ijpx.2026.100525 |
| url |
https://hdl.handle.net/2117/460708 https://dx.doi.org/10.1016/j.ijpx.2026.100525 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.relation.none.fl_str_mv |
Agencia Estatal de Investigación http://doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023 PID2023-146623NB-I00 ABORDANDO EL DESORDEN: LA FISICA EN EL APROVECHAMIENTO DE LA ENERGIA |
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open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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openAccess |
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application/pdf |
| dc.publisher.none.fl_str_mv |
Elsevier |
| publisher.none.fl_str_mv |
Elsevier |
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reponame:UPCommons. Portal del coneixement obert de la UPC instname:Universitat Politècnica de Catalunya (UPC) |
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Universitat Politècnica de Catalunya (UPC) |
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UPCommons. Portal del coneixement obert de la UPC |
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UPCommons. Portal del coneixement obert de la UPC |
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1869425210619330560 |
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Metastable phase diagram, mobility, and kinetic stability of amorphous mixtures of two mutually compatible APIsNoor, WahiRomanini, Michela|||0000-0002-1685-855XVillalobos Ramos, LaiaTalukder, BijoriTamarit Mur, José Luis|||0000-0002-7965-0000Macovez, Roberto|||0000-0001-5026-9372Amorphous solid solutionsGlass transition temperatureEutectic amorphous mixturesRelaxation dynamicsPhysical stability of glassesFormulation pre-developmentDSC, dielectric spectroscopy, and optical microscopy, are employed to analyze the equilibrium and out-of-equilibrium binary phase diagram of two antifungal azole compounds, fluconazole (FLZ) and econazole (ECZ), to study the physical stability of co-amorphous formulations that may allow co-administration and a faster dissolution of the poorly soluble ECZ compound. The two crystalline APIs form a eutectic equilibrium phase diagram with eutectic point at Te = 351.1 ± 0.5 K and eutectic molar fraction of FLZ of xFLZ,e = 0.22 ± 0.01. While amorphous FLZ has a strong tendency to crystallize, amorphous ECZ is kinetically stable during at least several weeks even as a supercooled liquid. Amorphous ECZ is found to display faster kinetic dissolution profile in water compared with crystalline ECZ. The glass transition (Tg) of the liquid mixtures depends linearly on composition, increasing by 4 K for every 10% increase in xFLZ. The molecular mobility determined by dielectric spectroscopy is characterized by a single structural relaxation and a single Johari-Goldstein relaxation at all compositions, testifying the structural and dynamic homogeneity of the amorphous mixtures. The equimolar supercooled liquid mixture and FLZ-rich mixtures phase-separate over few days or weeks, with the FLZ-rich phase recrystallizing into bundles of rod-like crystallites surrounded by an almost pure amorphous ECZ matrix. The amorphous mixture at the eutectic composition remains instead kinetically stable during 6 months above Tg, and for at least 10 months in the glass state below Tg. Mixtures that have ECZ molar fractions of 0.9 or higher are kinetically the most stable ones (they remain amorphous during more than 14 months at room temperature) despite having the fastest molecular mobility both in the supercooled liquid and glassy phases. Their high kinetic stability is likely due to lower supercooling and lower supersaturation, leading to lower thermodynamic driving force, and to the dilution of the recrystallizing FLZ compound. These results help shed light on the stability of binary amorphous mixtures.We acknowledge support from the Spanish Ministry of Science, Innovation and Universities under the “María deMaeztu” Program for Units of Excellence (Grant No. CEX2023-001300-M). This work was funded by the same Ministry under Grant No. MCIN/AEI/10.13039/ 501100011033, and under Project No. PID2023-146623NB-I00, cofi- nanced also by the European Union European Regional Development Fund (FEDER). We acknowledge support from the Generalitat de Cata- lunya (Grant No. 2021SGR-00343). J.-Ll. Tamarit is grateful to the ICREA Academia program. M. Romanini is a Serra Húnter fellow. The authors are grateful to Lourdes Franco of the Universitat Politècnica de Catalunya - BarcelonaTech for her help with microscopy experiments.Elsevier20262026-06-0120262026-04-17journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/2117/460708https://dx.doi.org/10.1016/j.ijpx.2026.100525reponame:UPCommons. Portal del coneixement obert de la UPCinstname:Universitat Politècnica de Catalunya (UPC)InglésengAgencia Estatal de Investigación http://doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023 PID2023-146623NB-I00 ABORDANDO EL DESORDEN: LA FISICA EN EL APROVECHAMIENTO DE LA ENERGIAopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:dnet:upcommonspor::ffeeda7d426484d34c788b812a25cfb12026-05-27T15:37:01Z |
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15,812429 |