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Study of Thermal Properties, Molecular Dynamics, and Physical Stability of Etoricoxib Mixtures with Octaacetylmaltose near the Glass Transition

In this paper, we thoroughly investigated the physical stability of the anti-inflammatory drug etoricoxib, which has been reported earlier to be resistant to recrystallization in its glassy and supercooled states at ambient pressure. Our unique application of the standard refractometry technique sho...

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Autores principales: Grzybowska, Katarzyna, Rams-Baron, Marzena, Łucak, Kinga, Grzybowski, Andrzej, Paluch, Marian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9456116/
https://www.ncbi.nlm.nih.gov/pubmed/36077212
http://dx.doi.org/10.3390/ijms23179794
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author Grzybowska, Katarzyna
Rams-Baron, Marzena
Łucak, Kinga
Grzybowski, Andrzej
Paluch, Marian
author_facet Grzybowska, Katarzyna
Rams-Baron, Marzena
Łucak, Kinga
Grzybowski, Andrzej
Paluch, Marian
author_sort Grzybowska, Katarzyna
collection PubMed
description In this paper, we thoroughly investigated the physical stability of the anti-inflammatory drug etoricoxib, which has been reported earlier to be resistant to recrystallization in its glassy and supercooled states at ambient pressure. Our unique application of the standard refractometry technique showed that the supercooled liquid of the drug was able to recrystallize during isothermal experiments in atmospheric conditions. This enabled us to determine the crystallization onset timescale and nucleation energy barrier of etoricoxib for the first time. As the physical instability of etoricoxib requires working out an efficient method for improving the drug’s resistance to recrystallization to maintain its amorphous form utility in potential pharmaceutical applications, we focused on finding a solution to this problem, and successfully achieved this purpose by preparing binary mixtures of etoricoxib with octaacetylmaltose. Our detailed thermal, refractometry, and molecular dynamics studies of the binary compositions near the glass transition revealed a peculiar behavior of the glass transition temperatures when changing the acetylated disaccharide concentration in the mixtures. Consequently, the anti-plasticization effect on the enhancement of physical stability could be excluded, and a key role for specific interactions in the improved resistance to recrystallization was expected. Invoking our previous results obtained for etoricoxib, the chemically similar drug celecoxib, and octaacetylmaltose, we formulated a hypothesis about the molecular mechanisms that may cause an impediment to crystal nuclei formation in the amorphous mixtures of etoricoxib with octaacetylmaltose. The most plausible scenario may rely on the formation of hydrogen-bonded heterodimers of the drug and excipient molecules, and the related drop in the population of the etoricoxib homodimers, which disables the nucleation. Nevertheless, this hypothesis requires further investigation. Additionally, we tested some widely discussed correlations between molecular mobility and crystallization properties, which turned out to be only partially satisfied for the examined mixtures. Our findings constitute not only a warning against manufacturing the amorphous form of pure etoricoxib, but also evidence for a promising outcome for the pharmaceutical application of the amorphous compositions with octaacetylmaltose.
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spelling pubmed-94561162022-09-09 Study of Thermal Properties, Molecular Dynamics, and Physical Stability of Etoricoxib Mixtures with Octaacetylmaltose near the Glass Transition Grzybowska, Katarzyna Rams-Baron, Marzena Łucak, Kinga Grzybowski, Andrzej Paluch, Marian Int J Mol Sci Article In this paper, we thoroughly investigated the physical stability of the anti-inflammatory drug etoricoxib, which has been reported earlier to be resistant to recrystallization in its glassy and supercooled states at ambient pressure. Our unique application of the standard refractometry technique showed that the supercooled liquid of the drug was able to recrystallize during isothermal experiments in atmospheric conditions. This enabled us to determine the crystallization onset timescale and nucleation energy barrier of etoricoxib for the first time. As the physical instability of etoricoxib requires working out an efficient method for improving the drug’s resistance to recrystallization to maintain its amorphous form utility in potential pharmaceutical applications, we focused on finding a solution to this problem, and successfully achieved this purpose by preparing binary mixtures of etoricoxib with octaacetylmaltose. Our detailed thermal, refractometry, and molecular dynamics studies of the binary compositions near the glass transition revealed a peculiar behavior of the glass transition temperatures when changing the acetylated disaccharide concentration in the mixtures. Consequently, the anti-plasticization effect on the enhancement of physical stability could be excluded, and a key role for specific interactions in the improved resistance to recrystallization was expected. Invoking our previous results obtained for etoricoxib, the chemically similar drug celecoxib, and octaacetylmaltose, we formulated a hypothesis about the molecular mechanisms that may cause an impediment to crystal nuclei formation in the amorphous mixtures of etoricoxib with octaacetylmaltose. The most plausible scenario may rely on the formation of hydrogen-bonded heterodimers of the drug and excipient molecules, and the related drop in the population of the etoricoxib homodimers, which disables the nucleation. Nevertheless, this hypothesis requires further investigation. Additionally, we tested some widely discussed correlations between molecular mobility and crystallization properties, which turned out to be only partially satisfied for the examined mixtures. Our findings constitute not only a warning against manufacturing the amorphous form of pure etoricoxib, but also evidence for a promising outcome for the pharmaceutical application of the amorphous compositions with octaacetylmaltose. MDPI 2022-08-29 /pmc/articles/PMC9456116/ /pubmed/36077212 http://dx.doi.org/10.3390/ijms23179794 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Grzybowska, Katarzyna
Rams-Baron, Marzena
Łucak, Kinga
Grzybowski, Andrzej
Paluch, Marian
Study of Thermal Properties, Molecular Dynamics, and Physical Stability of Etoricoxib Mixtures with Octaacetylmaltose near the Glass Transition
title Study of Thermal Properties, Molecular Dynamics, and Physical Stability of Etoricoxib Mixtures with Octaacetylmaltose near the Glass Transition
title_full Study of Thermal Properties, Molecular Dynamics, and Physical Stability of Etoricoxib Mixtures with Octaacetylmaltose near the Glass Transition
title_fullStr Study of Thermal Properties, Molecular Dynamics, and Physical Stability of Etoricoxib Mixtures with Octaacetylmaltose near the Glass Transition
title_full_unstemmed Study of Thermal Properties, Molecular Dynamics, and Physical Stability of Etoricoxib Mixtures with Octaacetylmaltose near the Glass Transition
title_short Study of Thermal Properties, Molecular Dynamics, and Physical Stability of Etoricoxib Mixtures with Octaacetylmaltose near the Glass Transition
title_sort study of thermal properties, molecular dynamics, and physical stability of etoricoxib mixtures with octaacetylmaltose near the glass transition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9456116/
https://www.ncbi.nlm.nih.gov/pubmed/36077212
http://dx.doi.org/10.3390/ijms23179794
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