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Glasdegib Dimaleate: Synthesis, Characterization and Comparison of Its Properties with Monomaleate Analogue

Glasdegib is a recently approved drug for the treatment of acute myeloid leukemia. It is formulated and marketed in monomaleate salt form. In our investigation, we were able to prepare a glasdegib dimaleate form, which could, in theory, exist in double-salt form or as a mixture of salt and co-crysta...

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Autores principales: Peklar, Boris, Perdih, Franc, Makuc, Damjan, Plavec, Janez, Cluzeau, Jérôme, Kitanovski, Zoran, Časar, Zdenko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9415664/
https://www.ncbi.nlm.nih.gov/pubmed/36015269
http://dx.doi.org/10.3390/pharmaceutics14081641
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author Peklar, Boris
Perdih, Franc
Makuc, Damjan
Plavec, Janez
Cluzeau, Jérôme
Kitanovski, Zoran
Časar, Zdenko
author_facet Peklar, Boris
Perdih, Franc
Makuc, Damjan
Plavec, Janez
Cluzeau, Jérôme
Kitanovski, Zoran
Časar, Zdenko
author_sort Peklar, Boris
collection PubMed
description Glasdegib is a recently approved drug for the treatment of acute myeloid leukemia. It is formulated and marketed in monomaleate salt form. In our investigation, we were able to prepare a glasdegib dimaleate form, which could, in theory, exist in double-salt form or as a mixture of salt and co-crystal species. Therefore, the obtained crystals of glasdegib dimaleate were characterized via (15)N ssNMR and single-crystal X-ray diffraction, which revealed that the obtained glasdegib dimaleate exists in double-salt form. This is a surprising finding based on the pK(a) values for glasdegib and maleic acid. Furthermore, we fully characterized the new dimaleate form using thermal analyses (DSC and TGA) and spectroscopy (IR and Raman). Finally, the physicochemical properties, such as solubility and chemical stability, of both forms were determined and compared.
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spelling pubmed-94156642022-08-27 Glasdegib Dimaleate: Synthesis, Characterization and Comparison of Its Properties with Monomaleate Analogue Peklar, Boris Perdih, Franc Makuc, Damjan Plavec, Janez Cluzeau, Jérôme Kitanovski, Zoran Časar, Zdenko Pharmaceutics Article Glasdegib is a recently approved drug for the treatment of acute myeloid leukemia. It is formulated and marketed in monomaleate salt form. In our investigation, we were able to prepare a glasdegib dimaleate form, which could, in theory, exist in double-salt form or as a mixture of salt and co-crystal species. Therefore, the obtained crystals of glasdegib dimaleate were characterized via (15)N ssNMR and single-crystal X-ray diffraction, which revealed that the obtained glasdegib dimaleate exists in double-salt form. This is a surprising finding based on the pK(a) values for glasdegib and maleic acid. Furthermore, we fully characterized the new dimaleate form using thermal analyses (DSC and TGA) and spectroscopy (IR and Raman). Finally, the physicochemical properties, such as solubility and chemical stability, of both forms were determined and compared. MDPI 2022-08-06 /pmc/articles/PMC9415664/ /pubmed/36015269 http://dx.doi.org/10.3390/pharmaceutics14081641 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
Peklar, Boris
Perdih, Franc
Makuc, Damjan
Plavec, Janez
Cluzeau, Jérôme
Kitanovski, Zoran
Časar, Zdenko
Glasdegib Dimaleate: Synthesis, Characterization and Comparison of Its Properties with Monomaleate Analogue
title Glasdegib Dimaleate: Synthesis, Characterization and Comparison of Its Properties with Monomaleate Analogue
title_full Glasdegib Dimaleate: Synthesis, Characterization and Comparison of Its Properties with Monomaleate Analogue
title_fullStr Glasdegib Dimaleate: Synthesis, Characterization and Comparison of Its Properties with Monomaleate Analogue
title_full_unstemmed Glasdegib Dimaleate: Synthesis, Characterization and Comparison of Its Properties with Monomaleate Analogue
title_short Glasdegib Dimaleate: Synthesis, Characterization and Comparison of Its Properties with Monomaleate Analogue
title_sort glasdegib dimaleate: synthesis, characterization and comparison of its properties with monomaleate analogue
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9415664/
https://www.ncbi.nlm.nih.gov/pubmed/36015269
http://dx.doi.org/10.3390/pharmaceutics14081641
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