Polymorph screening and solubility characterization of lercanidipine hydrochloride

Detalhes bibliográficos
Autor(a) principal: Repin, Ilia Alekseevich
Data de Publicação: 2019
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Biblioteca Digital de Teses e Dissertações da USP
Texto Completo: http://www.teses.usp.br/teses/disponiveis/9/9139/tde-10122019-120541/
Resumo: The study of the polymorphism of lercanidipine hydrochloride (LRC) has revealed a significative impact on solubility with a strong dependence on buffer type, pH, and ionic strength. For the first time, unexpected changes in the solubility ratio between two polymorphic forms of LRC (forms I and II) depending on the media composition were identified, and its potential consequences to the pharmacokinetic performance were evaluated through physiologically based pharmacokinetic (PBPK) modeling using GastroPlus(TM); the results suggest that in cases of low stomach acidity, form II is potentially less bioavailable than form I. Phosphate buffer showed to promote less solubility variation in the concentration range of 0.01-0.1 mol·L-1 and favored solubility increase for both forms in the 2-3.5 pH range when compared to a citric acid buffer. Solid-state characterization of both polymorphs accompanied by polythermal solubility experiments carried out in ethanol and acetonitrile permitted to establish the thermodynamic relationship between the two polymorphs as monotropic. Furthermore, forced degradation was applied to determine thermal and photostability of each form, determining form I as the less chemically stable. Determination LRC form II crystalline structure was accomplished based on the successful obtainment of its single crystal, while structural data of LRC form I was estimated by applying single-value decomposition approach to its X-ray powder diffraction scans.
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spelling Polymorph screening and solubility characterization of lercanidipine hydrochlorideTriagem polimórfica e caracterização da solubilidade do cloridrato de lercanidipinoLercanidipine hydrochlorideLercanidipine hydrochloridePolymorphismPolymorphismSolid state characterizationSolid state characterizationSolubilitySolubilityThermodynamic propertiesThermodynamic propertiesThe study of the polymorphism of lercanidipine hydrochloride (LRC) has revealed a significative impact on solubility with a strong dependence on buffer type, pH, and ionic strength. For the first time, unexpected changes in the solubility ratio between two polymorphic forms of LRC (forms I and II) depending on the media composition were identified, and its potential consequences to the pharmacokinetic performance were evaluated through physiologically based pharmacokinetic (PBPK) modeling using GastroPlus(TM); the results suggest that in cases of low stomach acidity, form II is potentially less bioavailable than form I. Phosphate buffer showed to promote less solubility variation in the concentration range of 0.01-0.1 mol·L-1 and favored solubility increase for both forms in the 2-3.5 pH range when compared to a citric acid buffer. Solid-state characterization of both polymorphs accompanied by polythermal solubility experiments carried out in ethanol and acetonitrile permitted to establish the thermodynamic relationship between the two polymorphs as monotropic. Furthermore, forced degradation was applied to determine thermal and photostability of each form, determining form I as the less chemically stable. Determination LRC form II crystalline structure was accomplished based on the successful obtainment of its single crystal, while structural data of LRC form I was estimated by applying single-value decomposition approach to its X-ray powder diffraction scans.A investigação do polimorfismo do cloridrato de lercanidipina (LRC) revelou um impacto significativo na solubilidade com forte dependência do tipo de tampão, pH e força iônica. Pela primeira vez, mudanças inesperadas na relação de solubilidade entre duas formas polimórficas de LRC (formas I e II), dependendo da composição do meio, foram identificadas e suas conseqüências potenciais para o desempenho farmacocinético foram avaliadas através de modelagem farmacocinética (PBPK) usando GastroPlus(TM); os resultados sugerem que, em casos de baixa acidez estomacal, a forma II é potencialmente menos biodisponível que a forma I. O tampão fosfato mostrou promover menor variação de solubilidade na faixa de concentração de 0.01-0.1 mol·L-1 e aumento de solubilidade favorecido para ambas as formas em pH 2-3,5 quando comparado com um tampão de ácido cítrico. A caracterização em estado sólido de ambos os polimorfos e experimentos politermais de solubilidade realizados em etanol e acetonitrila permitiram estabelecer a relação termodinâmica de estabilidade entre os dois polimorfos como monotrópica. Além disso, a degradação forçada foi aplicada para determinar as propriedades térmicas e fotoestáveis de cada forma, determinando a forma I como menos quimicamente estável. A determinação da estrutura cristalina da forma II de LRC foi realizada com base na obtenção de seu monocristal, enquanto os dados estruturais da forma I de LRC foram estimados aplicando uma abordagem de decomposição de valor único para suas varreduras de difração de raios X.Biblioteca Digitais de Teses e Dissertações da USPAraujo, Gabriel Lima Barros deRepin, Ilia Alekseevich2019-10-18info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://www.teses.usp.br/teses/disponiveis/9/9139/tde-10122019-120541/reponame:Biblioteca Digital de Teses e Dissertações da USPinstname:Universidade de São Paulo (USP)instacron:USPLiberar o conteúdo para acesso público.info:eu-repo/semantics/openAccesseng2019-12-13T23:16:02Zoai:teses.usp.br:tde-10122019-120541Biblioteca Digital de Teses e Dissertaçõeshttp://www.teses.usp.br/PUBhttp://www.teses.usp.br/cgi-bin/mtd2br.plvirginia@if.usp.br|| atendimento@aguia.usp.br||virginia@if.usp.bropendoar:27212019-12-13T23:16:02Biblioteca Digital de Teses e Dissertações da USP - Universidade de São Paulo (USP)false
dc.title.none.fl_str_mv Polymorph screening and solubility characterization of lercanidipine hydrochloride
Triagem polimórfica e caracterização da solubilidade do cloridrato de lercanidipino
title Polymorph screening and solubility characterization of lercanidipine hydrochloride
spellingShingle Polymorph screening and solubility characterization of lercanidipine hydrochloride
Repin, Ilia Alekseevich
Lercanidipine hydrochloride
Lercanidipine hydrochloride
Polymorphism
Polymorphism
Solid state characterization
Solid state characterization
Solubility
Solubility
Thermodynamic properties
Thermodynamic properties
title_short Polymorph screening and solubility characterization of lercanidipine hydrochloride
title_full Polymorph screening and solubility characterization of lercanidipine hydrochloride
title_fullStr Polymorph screening and solubility characterization of lercanidipine hydrochloride
title_full_unstemmed Polymorph screening and solubility characterization of lercanidipine hydrochloride
title_sort Polymorph screening and solubility characterization of lercanidipine hydrochloride
author Repin, Ilia Alekseevich
author_facet Repin, Ilia Alekseevich
author_role author
dc.contributor.none.fl_str_mv Araujo, Gabriel Lima Barros de
dc.contributor.author.fl_str_mv Repin, Ilia Alekseevich
dc.subject.por.fl_str_mv Lercanidipine hydrochloride
Lercanidipine hydrochloride
Polymorphism
Polymorphism
Solid state characterization
Solid state characterization
Solubility
Solubility
Thermodynamic properties
Thermodynamic properties
topic Lercanidipine hydrochloride
Lercanidipine hydrochloride
Polymorphism
Polymorphism
Solid state characterization
Solid state characterization
Solubility
Solubility
Thermodynamic properties
Thermodynamic properties
description The study of the polymorphism of lercanidipine hydrochloride (LRC) has revealed a significative impact on solubility with a strong dependence on buffer type, pH, and ionic strength. For the first time, unexpected changes in the solubility ratio between two polymorphic forms of LRC (forms I and II) depending on the media composition were identified, and its potential consequences to the pharmacokinetic performance were evaluated through physiologically based pharmacokinetic (PBPK) modeling using GastroPlus(TM); the results suggest that in cases of low stomach acidity, form II is potentially less bioavailable than form I. Phosphate buffer showed to promote less solubility variation in the concentration range of 0.01-0.1 mol·L-1 and favored solubility increase for both forms in the 2-3.5 pH range when compared to a citric acid buffer. Solid-state characterization of both polymorphs accompanied by polythermal solubility experiments carried out in ethanol and acetonitrile permitted to establish the thermodynamic relationship between the two polymorphs as monotropic. Furthermore, forced degradation was applied to determine thermal and photostability of each form, determining form I as the less chemically stable. Determination LRC form II crystalline structure was accomplished based on the successful obtainment of its single crystal, while structural data of LRC form I was estimated by applying single-value decomposition approach to its X-ray powder diffraction scans.
publishDate 2019
dc.date.none.fl_str_mv 2019-10-18
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://www.teses.usp.br/teses/disponiveis/9/9139/tde-10122019-120541/
url http://www.teses.usp.br/teses/disponiveis/9/9139/tde-10122019-120541/
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv
dc.rights.driver.fl_str_mv Liberar o conteúdo para acesso público.
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Liberar o conteúdo para acesso público.
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.coverage.none.fl_str_mv
dc.publisher.none.fl_str_mv Biblioteca Digitais de Teses e Dissertações da USP
publisher.none.fl_str_mv Biblioteca Digitais de Teses e Dissertações da USP
dc.source.none.fl_str_mv
reponame:Biblioteca Digital de Teses e Dissertações da USP
instname:Universidade de São Paulo (USP)
instacron:USP
instname_str Universidade de São Paulo (USP)
instacron_str USP
institution USP
reponame_str Biblioteca Digital de Teses e Dissertações da USP
collection Biblioteca Digital de Teses e Dissertações da USP
repository.name.fl_str_mv Biblioteca Digital de Teses e Dissertações da USP - Universidade de São Paulo (USP)
repository.mail.fl_str_mv virginia@if.usp.br|| atendimento@aguia.usp.br||virginia@if.usp.br
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