Dispersões sólidas e complexos de inclusão como estratégia para o incremento da solubilidade de amiodarona
Autor(a) principal: | |
---|---|
Data de Publicação: | 2016 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/17958 |
Resumo: | This study aimed to develop solid dispersions (SD) and inclusion complex (IC) using as carriers hydrophilic polymers (polyethylene glycol PEGs 1500, 4000 and 6000) and cyclodextrins (CDs) (β–cyclodextrin, metil-β-cyclodextrin and hydroxypropy-β-cyclodextrin), respectively, in order to verify the influence of each technological approach in the solubility of Amiodarone Hydrochloride (AMH). SD was prepared in the proportion AMH:PEGs of 1:1 and 1:10 (w/w) by the fusion and kneading techniques. IC were prepared by co-evaporation, freeze-drying and spray-drying methods, and the proportion AMD: CD of 1:1 (w/w) was used. For both approaches, AL-type solubility diagrams and thermodynamic approaches favorable to the formation of this new solid entity were obtained. The AMH solubility in different physiological media (acid buffer pH 1.2, acetate buffer pH 4.5 and phosphate buffer pH 6.8 and water) showed a strong dependence of its ionization due to the presence of amine chemical, which ionizes itself in a greater proportion in more acid means, below the AMH pKA (6.56). In order to characterize SD and CI, different techniques were used, such as X-Ray Diffraction (XRD), Forrier Transform Infrared Spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), Scanning Electronic Miscroscopy (SEM), Proton Nuclear Magnetic Resonance (RMN), determination of Specific Surface Area of the particles (SBET) and studies about Molecular Modeling (MM), as well as the determination of dissolution profiles between pure AMH and the solid products obtained. From the DRX, FT-IR and DSC analysis, it was possible to verify a strong interaction in a molecular level between AMH and the studied carriers. With the aid of SEM and SSA analysis, it was diagnosed a morphological alteration on the AMH crystals after the IC formation, as well as an increase of the superficial area of the particles in relation to pure AMH. For the determination of each portion of AMH molecule that is inside the cyclodextrin cavity, RMN and MM were used. RMN spectra showed strong evidence that the complexation process with methyl-β-cyclodextrin occurred by the lipophilic side, constituted by a diethylamide group. MM was used from an IC containing AMH and methyl-β-cyclodextrin in order to determine the binding energy, amount of charge transferred and the distances between the principal atoms. According to the results, it was determined a strong interaction between the diethylamide group of AMH with the methyl-β-cyclodextrin cavity, compounding a stable complex with the binding energy of 0.76 eV, confirming the results found by RMN. The obtained dissolution profiles showed to suffer a great influence of SD and CI, as well as the preparation methods of these products. It was also developed three formulations for the obtainment of immediate release tablets containing 10 mg de AMH complex with methyl-β-cyclodextrin by direct compression. The batches were submitted to tests of quality control, and the formulation 1 presented friability superior to 1.5%, which rendered this formulation improper for the execution of dissolution profiles and continuation of the studies. The tablets obtained from the F2 and F3 formulations presented satisfactory results in relation to the tests of variation of weigh, hardness, friability, disintegration time and AMH content. These two formulations were selected for the execution of dissolution profiles using water and acetate buffer pH 4.5. For both evaluated mediums, there was an increase in the dissolved amount of AMH from the tablets in relation to the pure AMH, demonstrating that IC can be useful strategies in the pharmacotechnical developments of new solid oral pharmaceutical ways. |
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Dispersões sólidas e complexos de inclusão como estratégia para o incremento da solubilidade de amiodaronaSolid dispersion and inclusion complex as strategy for the enhancement of amiodarone solubilityDispersão sólidaComplexo de inclusãoComprimidosPerfil de dissoluçãoCloridrato de amiodaronaSolid dispersionInclusion complexTabletsDissolution profileAmiodarone hydrochlorideCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAThis study aimed to develop solid dispersions (SD) and inclusion complex (IC) using as carriers hydrophilic polymers (polyethylene glycol PEGs 1500, 4000 and 6000) and cyclodextrins (CDs) (β–cyclodextrin, metil-β-cyclodextrin and hydroxypropy-β-cyclodextrin), respectively, in order to verify the influence of each technological approach in the solubility of Amiodarone Hydrochloride (AMH). SD was prepared in the proportion AMH:PEGs of 1:1 and 1:10 (w/w) by the fusion and kneading techniques. IC were prepared by co-evaporation, freeze-drying and spray-drying methods, and the proportion AMD: CD of 1:1 (w/w) was used. For both approaches, AL-type solubility diagrams and thermodynamic approaches favorable to the formation of this new solid entity were obtained. The AMH solubility in different physiological media (acid buffer pH 1.2, acetate buffer pH 4.5 and phosphate buffer pH 6.8 and water) showed a strong dependence of its ionization due to the presence of amine chemical, which ionizes itself in a greater proportion in more acid means, below the AMH pKA (6.56). In order to characterize SD and CI, different techniques were used, such as X-Ray Diffraction (XRD), Forrier Transform Infrared Spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), Scanning Electronic Miscroscopy (SEM), Proton Nuclear Magnetic Resonance (RMN), determination of Specific Surface Area of the particles (SBET) and studies about Molecular Modeling (MM), as well as the determination of dissolution profiles between pure AMH and the solid products obtained. From the DRX, FT-IR and DSC analysis, it was possible to verify a strong interaction in a molecular level between AMH and the studied carriers. With the aid of SEM and SSA analysis, it was diagnosed a morphological alteration on the AMH crystals after the IC formation, as well as an increase of the superficial area of the particles in relation to pure AMH. For the determination of each portion of AMH molecule that is inside the cyclodextrin cavity, RMN and MM were used. RMN spectra showed strong evidence that the complexation process with methyl-β-cyclodextrin occurred by the lipophilic side, constituted by a diethylamide group. MM was used from an IC containing AMH and methyl-β-cyclodextrin in order to determine the binding energy, amount of charge transferred and the distances between the principal atoms. According to the results, it was determined a strong interaction between the diethylamide group of AMH with the methyl-β-cyclodextrin cavity, compounding a stable complex with the binding energy of 0.76 eV, confirming the results found by RMN. The obtained dissolution profiles showed to suffer a great influence of SD and CI, as well as the preparation methods of these products. It was also developed three formulations for the obtainment of immediate release tablets containing 10 mg de AMH complex with methyl-β-cyclodextrin by direct compression. The batches were submitted to tests of quality control, and the formulation 1 presented friability superior to 1.5%, which rendered this formulation improper for the execution of dissolution profiles and continuation of the studies. The tablets obtained from the F2 and F3 formulations presented satisfactory results in relation to the tests of variation of weigh, hardness, friability, disintegration time and AMH content. These two formulations were selected for the execution of dissolution profiles using water and acetate buffer pH 4.5. For both evaluated mediums, there was an increase in the dissolved amount of AMH from the tablets in relation to the pure AMH, demonstrating that IC can be useful strategies in the pharmacotechnical developments of new solid oral pharmaceutical ways.O presente estudo teve como objetivo desenvolver dispersões sólidas (DS) e complexos de inclusão (CI) utilizando como carreadores os polímeros hidrofílicos (polietilenoglicois PEGs 1500, 4000 e 6000) e ciclodextrinas (CDs) (β-ciclodextrina, metil-β-ciclodextrina e hidroxipropil-β-ciclodextrina) respectivamente, com a finalidade de verificar a influência de cada abordagem tecnológica na solubilidade do Cloridrato de Amiodarona (AMH). DS foram preparadas nas proporções AMH:PEGs de 1:1 e 1:10 (p/p) pelos métodos de fusão e amassamento. Os CI foram preparados pelos métodos de coevaporação, freeze-drying e spray-drying utilizando a proporção AMH:CDs de 1:1 (p/p). Para ambas as abordagens, foram obtidos diagramas de solubilidades do tipo AL e propriedades termodinâmicas favoráveis as formações destas novas entidades sólidas. A solubilidade do AMH em diferentes meios fisiológicos (tampão ácido 1,2; tampão acetato pH 4,5; tampão fosfato pH 6,8 e água) demonstrou uma forte dependência da sua ionização devido à presença do grupo químico amina, o qual se ioniza em maior proporção em ambientes mais ácidos, ou seja, abaixo do pKa do AMH (6,56). Com a finalidade de caracterizar as DS e CI foram utilizadas diferentes técnicas como difração de raios-X (DRX), espectroscopia no infravermelho com transformada de Fourier (FT-IR), calorimetria exploratória diferencial (DSC), microscopia eletrônica de varredura (MEV), ressonância magnética nuclear do próton (RMN), determinação da área superficial específica das partículas (ASE), estudos de modelagem molecular (MM), assim como a determinação dos perfis de dissolução entre o AMH puro e os produtos sólidos obtidos. A partir das análises de DRX, FT-IR e DSC foi possível verificar uma forte interação em nível molecular entre o AMH e os carreadores estudados. Com o auxílio das análises de MEV e ASE foi constatada uma alteração morfológica dos cristais do AMH após a formação dos CI, assim como um aumento da área superficial das partículas em relação ao AMH puro. Para a determinação da porção da molécula do AMH que se encontra dentro da cavidade da ciclodextrina, foram utilizadas a RMN e a MM. Os espectros de RMN mostraram um forte indício de que o processo de complexação com a metil-β-ciclodextrina ocorreu pelo lado lipofílico, constituído por um grupo dietilamina. A MM foi realizada a partir do CI contendo AMH e metil-β-ciclodextrina com a finalidade de determinar as energias de ligação, quantidade de carga transferida e as distâncias entre os principais átomos. Conforme os resultados, constatou-se uma forte interação entre o grupo dietilamina do AMH com a cavidade da metil-β-ciclodextrina, formando um complexo estável com energia de ligação de 0,76 eV, confirmando assim os resultados encontrados por RMN. Os perfis de dissolução obtidos demonstraram sofrer grande influência do tipo de DS e CI, assim como dos métodos de preparo destes produtos. Também foram desenvolvidas 3 formulações para obtenção de comprimidos de liberação imediata contendo 10 mg de AMH complexado com metil-β-ciclodextrina por compressão direta. Os lotes foram submetidos aos ensaios de controle de qualidade, sendo que a formulação 1 apresentou friabilidade superior a 1,5%, tornando esta formulação imprópria para a realização dos perfis de dissolução e continuidade dos estudos. Os comprimidos obtidos a partir das formulações F2 e F3 apresentaram resultados satisfatórios em relação aos ensaios de variação de peso, dureza, friabilidade, tempo de desintegração e doseamento do AMH. Estas duas formulações foram selecionadas para realização dos perfis de dissolução utilizando água e tampão acetato pH 4,5. Para ambos os meios avaliados, houve um aumento na quantidade dissolvida de AMH a partir dos comprimidos em relação ao AMH puro, demonstrando que os CI podem ser estratégias uteis no desenvolvimento farmacotécnico de novas formas farmacêuticas sólidas orais.Universidade Federal de Santa MariaBrasilFarmacologiaUFSMPrograma de Pós-Graduação em Ciências FarmacêuticasCentro de Ciências da SaúdeRolim, Clarice Madalena Buenohttp://lattes.cnpq.br/2270654658839508Adams, Andréa Inês Hornhttp://lattes.cnpq.br/6872246935204149Mortari, Sergio Robertohttp://lattes.cnpq.br/7784609477475171Cardoso, Simone Gonçalveshttp://lattes.cnpq.br/3679502590339850Teixeira, Helder Ferreirahttp://lattes.cnpq.br/6652867749152426Rubim, Alexandre Machado2019-08-19T12:22:12Z2019-08-19T12:22:12Z2016-12-02info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://repositorio.ufsm.br/handle/1/17958porAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSM2022-06-01T11:38:00Zoai:repositorio.ufsm.br:1/17958Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2022-06-01T11:38Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.none.fl_str_mv |
Dispersões sólidas e complexos de inclusão como estratégia para o incremento da solubilidade de amiodarona Solid dispersion and inclusion complex as strategy for the enhancement of amiodarone solubility |
title |
Dispersões sólidas e complexos de inclusão como estratégia para o incremento da solubilidade de amiodarona |
spellingShingle |
Dispersões sólidas e complexos de inclusão como estratégia para o incremento da solubilidade de amiodarona Rubim, Alexandre Machado Dispersão sólida Complexo de inclusão Comprimidos Perfil de dissolução Cloridrato de amiodarona Solid dispersion Inclusion complex Tablets Dissolution profile Amiodarone hydrochloride CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Dispersões sólidas e complexos de inclusão como estratégia para o incremento da solubilidade de amiodarona |
title_full |
Dispersões sólidas e complexos de inclusão como estratégia para o incremento da solubilidade de amiodarona |
title_fullStr |
Dispersões sólidas e complexos de inclusão como estratégia para o incremento da solubilidade de amiodarona |
title_full_unstemmed |
Dispersões sólidas e complexos de inclusão como estratégia para o incremento da solubilidade de amiodarona |
title_sort |
Dispersões sólidas e complexos de inclusão como estratégia para o incremento da solubilidade de amiodarona |
author |
Rubim, Alexandre Machado |
author_facet |
Rubim, Alexandre Machado |
author_role |
author |
dc.contributor.none.fl_str_mv |
Rolim, Clarice Madalena Bueno http://lattes.cnpq.br/2270654658839508 Adams, Andréa Inês Horn http://lattes.cnpq.br/6872246935204149 Mortari, Sergio Roberto http://lattes.cnpq.br/7784609477475171 Cardoso, Simone Gonçalves http://lattes.cnpq.br/3679502590339850 Teixeira, Helder Ferreira http://lattes.cnpq.br/6652867749152426 |
dc.contributor.author.fl_str_mv |
Rubim, Alexandre Machado |
dc.subject.por.fl_str_mv |
Dispersão sólida Complexo de inclusão Comprimidos Perfil de dissolução Cloridrato de amiodarona Solid dispersion Inclusion complex Tablets Dissolution profile Amiodarone hydrochloride CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Dispersão sólida Complexo de inclusão Comprimidos Perfil de dissolução Cloridrato de amiodarona Solid dispersion Inclusion complex Tablets Dissolution profile Amiodarone hydrochloride CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
This study aimed to develop solid dispersions (SD) and inclusion complex (IC) using as carriers hydrophilic polymers (polyethylene glycol PEGs 1500, 4000 and 6000) and cyclodextrins (CDs) (β–cyclodextrin, metil-β-cyclodextrin and hydroxypropy-β-cyclodextrin), respectively, in order to verify the influence of each technological approach in the solubility of Amiodarone Hydrochloride (AMH). SD was prepared in the proportion AMH:PEGs of 1:1 and 1:10 (w/w) by the fusion and kneading techniques. IC were prepared by co-evaporation, freeze-drying and spray-drying methods, and the proportion AMD: CD of 1:1 (w/w) was used. For both approaches, AL-type solubility diagrams and thermodynamic approaches favorable to the formation of this new solid entity were obtained. The AMH solubility in different physiological media (acid buffer pH 1.2, acetate buffer pH 4.5 and phosphate buffer pH 6.8 and water) showed a strong dependence of its ionization due to the presence of amine chemical, which ionizes itself in a greater proportion in more acid means, below the AMH pKA (6.56). In order to characterize SD and CI, different techniques were used, such as X-Ray Diffraction (XRD), Forrier Transform Infrared Spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), Scanning Electronic Miscroscopy (SEM), Proton Nuclear Magnetic Resonance (RMN), determination of Specific Surface Area of the particles (SBET) and studies about Molecular Modeling (MM), as well as the determination of dissolution profiles between pure AMH and the solid products obtained. From the DRX, FT-IR and DSC analysis, it was possible to verify a strong interaction in a molecular level between AMH and the studied carriers. With the aid of SEM and SSA analysis, it was diagnosed a morphological alteration on the AMH crystals after the IC formation, as well as an increase of the superficial area of the particles in relation to pure AMH. For the determination of each portion of AMH molecule that is inside the cyclodextrin cavity, RMN and MM were used. RMN spectra showed strong evidence that the complexation process with methyl-β-cyclodextrin occurred by the lipophilic side, constituted by a diethylamide group. MM was used from an IC containing AMH and methyl-β-cyclodextrin in order to determine the binding energy, amount of charge transferred and the distances between the principal atoms. According to the results, it was determined a strong interaction between the diethylamide group of AMH with the methyl-β-cyclodextrin cavity, compounding a stable complex with the binding energy of 0.76 eV, confirming the results found by RMN. The obtained dissolution profiles showed to suffer a great influence of SD and CI, as well as the preparation methods of these products. It was also developed three formulations for the obtainment of immediate release tablets containing 10 mg de AMH complex with methyl-β-cyclodextrin by direct compression. The batches were submitted to tests of quality control, and the formulation 1 presented friability superior to 1.5%, which rendered this formulation improper for the execution of dissolution profiles and continuation of the studies. The tablets obtained from the F2 and F3 formulations presented satisfactory results in relation to the tests of variation of weigh, hardness, friability, disintegration time and AMH content. These two formulations were selected for the execution of dissolution profiles using water and acetate buffer pH 4.5. For both evaluated mediums, there was an increase in the dissolved amount of AMH from the tablets in relation to the pure AMH, demonstrating that IC can be useful strategies in the pharmacotechnical developments of new solid oral pharmaceutical ways. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-12-02 2019-08-19T12:22:12Z 2019-08-19T12:22:12Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/17958 |
url |
http://repositorio.ufsm.br/handle/1/17958 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Farmacologia UFSM Programa de Pós-Graduação em Ciências Farmacêuticas Centro de Ciências da Saúde |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Farmacologia UFSM Programa de Pós-Graduação em Ciências Farmacêuticas Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Manancial - Repositório Digital da UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Manancial - Repositório Digital da UFSM |
collection |
Manancial - Repositório Digital da UFSM |
repository.name.fl_str_mv |
Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
atendimento.sib@ufsm.br||tedebc@gmail.com |
_version_ |
1805922036310081536 |