Pharmaceutical polymorphism of a 5´-O-oxalatoyl prodrug of zidovudine (azidothymidine)

Autores
Kassuha, Diego Enrique; Bruno, Flavia Paola; Monti, Gustavo Alberto; Sperandeo, Norma Rebeca
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The importance of polymorphism in pharmaceuticals makes its study relevant. The aim of this study was to investigate the solid-state forms in which 3´-azido-2´,3´-dideoxi-5´-O-oxalatoyl-thymidinic acid (AZT-Ac), a zidovudine (AZT) prodrug with improved pharmacokinetic properties, may exist. Samples were prepared using different crystallization conditions, and characterized using powder X-ray diffraction, solid state nuclear magnetic resonance, differential scanning calorimetry, thermogravimetry and hot stage microscopy. Pharmaceutical relevant properties such as solid-state stability and intrinsic dissolution rate (IDR) at 37 °C in simulated gastric fluid (SGF) were also evaluated. AZT-Ac was found able to exist as a crystalline polymorph (AZT-Ac-C) and an amorphous phase (AZT-Ac-A), which were thoroughly characterized. At 40 °C/75% RH, AZT-Ac-A in part devitrified to AZT-Ac-C, and partially hydrolyzed to AZT after 7 and 14 days of storage, respectively. AZT-Ac-C was physically stable at 40 °C/75% RH but partly hydrolyzed to AZT after 14 days of storage. In SGF, AZT-Ac-C exhibited a linear ID profile and provided an ID rate of 0.494 mg/min/cm2 while AZT-Ac-A exhibited a nonlinear profile. Therefore, the crystalline form demonstrated advantages over the amorphous one in terms of solid state stability and IDR, but approaches to enhance its stability should be considered for further formulation of this prodrug.
Fil: Kassuha, Diego Enrique. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Cs. de la Alimentación, Bioquímicas y Farmacéuticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Bruno, Flavia Paola. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Laboratorio Fresenius Kabi; Argentina
Fil: Monti, Gustavo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Física Enrique Gaviola. Universidad Nacional de Córdoba. Instituto de Física Enrique Gaviola; Argentina. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina
Fil: Sperandeo, Norma Rebeca. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina
Materia
CRYSTALLIZATION
DIFFERENTIAL SCANNING CALORIMETRY
DRUGS
NUCLEAR MAGNETIC RESONANCE
NUCLEOSIDE INHIBITORS
X-RAY DIFFRACTIO
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
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CONICET Digital (CONICET)
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Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/137095
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/137095
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Pharmaceutical polymorphism of a 5´-O-oxalatoyl prodrug of zidovudine (azidothymidine)Kassuha, Diego EnriqueBruno, Flavia PaolaMonti, Gustavo AlbertoSperandeo, Norma RebecaCRYSTALLIZATIONDIFFERENTIAL SCANNING CALORIMETRYDRUGSNUCLEAR MAGNETIC RESONANCENUCLEOSIDE INHIBITORSX-RAY DIFFRACTIOhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1The importance of polymorphism in pharmaceuticals makes its study relevant. The aim of this study was to investigate the solid-state forms in which 3´-azido-2´,3´-dideoxi-5´-O-oxalatoyl-thymidinic acid (AZT-Ac), a zidovudine (AZT) prodrug with improved pharmacokinetic properties, may exist. Samples were prepared using different crystallization conditions, and characterized using powder X-ray diffraction, solid state nuclear magnetic resonance, differential scanning calorimetry, thermogravimetry and hot stage microscopy. Pharmaceutical relevant properties such as solid-state stability and intrinsic dissolution rate (IDR) at 37 °C in simulated gastric fluid (SGF) were also evaluated. AZT-Ac was found able to exist as a crystalline polymorph (AZT-Ac-C) and an amorphous phase (AZT-Ac-A), which were thoroughly characterized. At 40 °C/75% RH, AZT-Ac-A in part devitrified to AZT-Ac-C, and partially hydrolyzed to AZT after 7 and 14 days of storage, respectively. AZT-Ac-C was physically stable at 40 °C/75% RH but partly hydrolyzed to AZT after 14 days of storage. In SGF, AZT-Ac-C exhibited a linear ID profile and provided an ID rate of 0.494 mg/min/cm2 while AZT-Ac-A exhibited a nonlinear profile. Therefore, the crystalline form demonstrated advantages over the amorphous one in terms of solid state stability and IDR, but approaches to enhance its stability should be considered for further formulation of this prodrug.Fil: Kassuha, Diego Enrique. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Cs. de la Alimentación, Bioquímicas y Farmacéuticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bruno, Flavia Paola. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Laboratorio Fresenius Kabi; ArgentinaFil: Monti, Gustavo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Física Enrique Gaviola. Universidad Nacional de Córdoba. Instituto de Física Enrique Gaviola; Argentina. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; ArgentinaFil: Sperandeo, Norma Rebeca. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; ArgentinaOpen Science Publishers LLP2020-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/137095Kassuha, Diego Enrique; Bruno, Flavia Paola; Monti, Gustavo Alberto; Sperandeo, Norma Rebeca; Pharmaceutical polymorphism of a 5´-O-oxalatoyl prodrug of zidovudine (azidothymidine); Open Science Publishers LLP; Journal of Applied Pharmaceutical Science; 10; 3; 3-2020; 67-742231-3354CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://japsonline.com/abstract.php?article_id=3098&sts=2info:eu-repo/semantics/altIdentifier/doi/10.7324/JAPS.2020.103008info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:44:48Zoai:ri.conicet.gov.ar:11336/137095instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:44:48.45CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Pharmaceutical polymorphism of a 5´-O-oxalatoyl prodrug of zidovudine (azidothymidine)
title Pharmaceutical polymorphism of a 5´-O-oxalatoyl prodrug of zidovudine (azidothymidine)
spellingShingle Pharmaceutical polymorphism of a 5´-O-oxalatoyl prodrug of zidovudine (azidothymidine)
Kassuha, Diego Enrique
CRYSTALLIZATION
DIFFERENTIAL SCANNING CALORIMETRY
DRUGS
NUCLEAR MAGNETIC RESONANCE
NUCLEOSIDE INHIBITORS
X-RAY DIFFRACTIO
title_short Pharmaceutical polymorphism of a 5´-O-oxalatoyl prodrug of zidovudine (azidothymidine)
title_full Pharmaceutical polymorphism of a 5´-O-oxalatoyl prodrug of zidovudine (azidothymidine)
title_fullStr Pharmaceutical polymorphism of a 5´-O-oxalatoyl prodrug of zidovudine (azidothymidine)
title_full_unstemmed Pharmaceutical polymorphism of a 5´-O-oxalatoyl prodrug of zidovudine (azidothymidine)
title_sort Pharmaceutical polymorphism of a 5´-O-oxalatoyl prodrug of zidovudine (azidothymidine)
dc.creator.none.fl_str_mv Kassuha, Diego Enrique
Bruno, Flavia Paola
Monti, Gustavo Alberto
Sperandeo, Norma Rebeca
author Kassuha, Diego Enrique
author_facet Kassuha, Diego Enrique
Bruno, Flavia Paola
Monti, Gustavo Alberto
Sperandeo, Norma Rebeca
author_role author
author2 Bruno, Flavia Paola
Monti, Gustavo Alberto
Sperandeo, Norma Rebeca
author2_role author
author
author
dc.subject.none.fl_str_mv CRYSTALLIZATION
DIFFERENTIAL SCANNING CALORIMETRY
DRUGS
NUCLEAR MAGNETIC RESONANCE
NUCLEOSIDE INHIBITORS
X-RAY DIFFRACTIO
topic CRYSTALLIZATION
DIFFERENTIAL SCANNING CALORIMETRY
DRUGS
NUCLEAR MAGNETIC RESONANCE
NUCLEOSIDE INHIBITORS
X-RAY DIFFRACTIO
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The importance of polymorphism in pharmaceuticals makes its study relevant. The aim of this study was to investigate the solid-state forms in which 3´-azido-2´,3´-dideoxi-5´-O-oxalatoyl-thymidinic acid (AZT-Ac), a zidovudine (AZT) prodrug with improved pharmacokinetic properties, may exist. Samples were prepared using different crystallization conditions, and characterized using powder X-ray diffraction, solid state nuclear magnetic resonance, differential scanning calorimetry, thermogravimetry and hot stage microscopy. Pharmaceutical relevant properties such as solid-state stability and intrinsic dissolution rate (IDR) at 37 °C in simulated gastric fluid (SGF) were also evaluated. AZT-Ac was found able to exist as a crystalline polymorph (AZT-Ac-C) and an amorphous phase (AZT-Ac-A), which were thoroughly characterized. At 40 °C/75% RH, AZT-Ac-A in part devitrified to AZT-Ac-C, and partially hydrolyzed to AZT after 7 and 14 days of storage, respectively. AZT-Ac-C was physically stable at 40 °C/75% RH but partly hydrolyzed to AZT after 14 days of storage. In SGF, AZT-Ac-C exhibited a linear ID profile and provided an ID rate of 0.494 mg/min/cm2 while AZT-Ac-A exhibited a nonlinear profile. Therefore, the crystalline form demonstrated advantages over the amorphous one in terms of solid state stability and IDR, but approaches to enhance its stability should be considered for further formulation of this prodrug.
Fil: Kassuha, Diego Enrique. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Cs. de la Alimentación, Bioquímicas y Farmacéuticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Bruno, Flavia Paola. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Laboratorio Fresenius Kabi; Argentina
Fil: Monti, Gustavo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Física Enrique Gaviola. Universidad Nacional de Córdoba. Instituto de Física Enrique Gaviola; Argentina. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina
Fil: Sperandeo, Norma Rebeca. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacia; Argentina
description The importance of polymorphism in pharmaceuticals makes its study relevant. The aim of this study was to investigate the solid-state forms in which 3´-azido-2´,3´-dideoxi-5´-O-oxalatoyl-thymidinic acid (AZT-Ac), a zidovudine (AZT) prodrug with improved pharmacokinetic properties, may exist. Samples were prepared using different crystallization conditions, and characterized using powder X-ray diffraction, solid state nuclear magnetic resonance, differential scanning calorimetry, thermogravimetry and hot stage microscopy. Pharmaceutical relevant properties such as solid-state stability and intrinsic dissolution rate (IDR) at 37 °C in simulated gastric fluid (SGF) were also evaluated. AZT-Ac was found able to exist as a crystalline polymorph (AZT-Ac-C) and an amorphous phase (AZT-Ac-A), which were thoroughly characterized. At 40 °C/75% RH, AZT-Ac-A in part devitrified to AZT-Ac-C, and partially hydrolyzed to AZT after 7 and 14 days of storage, respectively. AZT-Ac-C was physically stable at 40 °C/75% RH but partly hydrolyzed to AZT after 14 days of storage. In SGF, AZT-Ac-C exhibited a linear ID profile and provided an ID rate of 0.494 mg/min/cm2 while AZT-Ac-A exhibited a nonlinear profile. Therefore, the crystalline form demonstrated advantages over the amorphous one in terms of solid state stability and IDR, but approaches to enhance its stability should be considered for further formulation of this prodrug.
publishDate 2020
dc.date.none.fl_str_mv 2020-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/137095
Kassuha, Diego Enrique; Bruno, Flavia Paola; Monti, Gustavo Alberto; Sperandeo, Norma Rebeca; Pharmaceutical polymorphism of a 5´-O-oxalatoyl prodrug of zidovudine (azidothymidine); Open Science Publishers LLP; Journal of Applied Pharmaceutical Science; 10; 3; 3-2020; 67-74
2231-3354
CONICET Digital
CONICET
url http://hdl.handle.net/11336/137095
identifier_str_mv Kassuha, Diego Enrique; Bruno, Flavia Paola; Monti, Gustavo Alberto; Sperandeo, Norma Rebeca; Pharmaceutical polymorphism of a 5´-O-oxalatoyl prodrug of zidovudine (azidothymidine); Open Science Publishers LLP; Journal of Applied Pharmaceutical Science; 10; 3; 3-2020; 67-74
2231-3354
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://japsonline.com/abstract.php?article_id=3098&sts=2
info:eu-repo/semantics/altIdentifier/doi/10.7324/JAPS.2020.103008
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Open Science Publishers LLP
publisher.none.fl_str_mv Open Science Publishers LLP
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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