Planejamento e determinação estrutural de modificações cristalinas dos fármacos lamivudina e efavirenz

Detalhes bibliográficos
Ano de defesa: 2013
Autor(a) principal: Melo, Ariane Carla Campos de lattes
Orientador(a): Martins, Felipe Terra lattes
Banca de defesa: Martins, Felipe Terra, Ellena, Javier Alcides, Chagas, Rafael Pavão das
Tipo de documento: Dissertação
Tipo de acesso: Acesso aberto
dARK ID: ark:/38995/001300000f2c6
Idioma: por
Instituição de defesa: Universidade Federal de Goiás
Programa de Pós-Graduação: Programa de Pós-graduação em Química (IQ)
Departamento: Instituto de Química - IQ (RG)
País: Brasil
Palavras-chave em Português:
Modificações cristalinas
Farmaco
Lamivudina
Efavirenz
Polimorfo do cloridrato de Lamivudina
Área do conhecimento CNPq:
FARMACOLOGIA::FARMACOLOGIA GERAL
Link de acesso: http://repositorio.bc.ufg.br/tede/handle/tede/3219
Resumo: Lamivudine and Efavirenz are anti-HIV drug largely used as, respectively a non-nucleoside and a nucleoside reverse transcriptase inhibitor as part of antiretroviral therapies. During the tests to obtain co-crystals of efavirenz with lamivudine it was obtained a novel crystalline phase, the polymorph of the hydrochloride salt of lamivudine. The structural and conformational analysis of this crystal modification showed that this keeps similarities, in intramolecular and intermolecular level, respectively with lamivudine hydrochloride and lamivudine hydrochloride monohydrate. Based on the intermolecular analysis and packing efficiency is expected that the polymorph of the hydrochloride salt of lamivudine is more soluble than the anhydrous phase. There are few reports on efavirenz solid state structures and behaviors. Crystal engineering strategies have not been well-exploited for this drug. In this sense, we delineate our synthesis strategy from the structural comparison and possibility of formation of intermolecular interactions patterns similar to those observed in the cocrystal of efavirenz and 4,4’-bipyridine. Two 4,4’-bipyridine-like compounds whose heterocycles are spaced by either an ethylene and an ethane moiety were cocrystallized together with efavirenz into solid state forms isostructural with respect to that of the drug cocrystal with 4,4’-bipyridine. The formation of a three-molecule entity based mainly on the hydrogen bonding donation from two efavirenz molecules to both pyridyl nitrogens of each coformer unit was kept in the three efavirenz cocrystals. The introduction of spacer groups in the coformers has altered the pattern of weak non-classical hydrogen bonds of the type C— H· · ·O. This intriduction was also related to the formation of a π-π stacking interaction between pyridyl rings of the ethane-spaced conformer. Furthermore, a polymorphic form of efavirenz with only one molecule in the asymmetric unit is reported for the first time here. This polymorph crystallizes in the monoclinic system and space group C2, strictly similar to form
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spelling Martins, Felipe Terrahttp://lattes.cnpq.br/0466799995060671Martins, Felipe TerraEllena, Javier AlcidesChagas, Rafael Pavão dashttp://lattes.cnpq.br/7764204807506356Melo, Ariane Carla Campos de2014-09-30T15:24:53Z2013-08-02MELO, Ariane Carla Campos de. Planejamento e determinação estrutural de modificações cristalinas dos fármacos lamivudina e efavirenz. 2013. 117 f. Dissertação (Mestrado em Química) - Universidade Federal de Goiás, Goiânia, 2013.http://repositorio.bc.ufg.br/tede/handle/tede/3219ark:/38995/001300000f2c6Lamivudine and Efavirenz are anti-HIV drug largely used as, respectively a non-nucleoside and a nucleoside reverse transcriptase inhibitor as part of antiretroviral therapies. During the tests to obtain co-crystals of efavirenz with lamivudine it was obtained a novel crystalline phase, the polymorph of the hydrochloride salt of lamivudine. The structural and conformational analysis of this crystal modification showed that this keeps similarities, in intramolecular and intermolecular level, respectively with lamivudine hydrochloride and lamivudine hydrochloride monohydrate. Based on the intermolecular analysis and packing efficiency is expected that the polymorph of the hydrochloride salt of lamivudine is more soluble than the anhydrous phase. There are few reports on efavirenz solid state structures and behaviors. Crystal engineering strategies have not been well-exploited for this drug. In this sense, we delineate our synthesis strategy from the structural comparison and possibility of formation of intermolecular interactions patterns similar to those observed in the cocrystal of efavirenz and 4,4’-bipyridine. Two 4,4’-bipyridine-like compounds whose heterocycles are spaced by either an ethylene and an ethane moiety were cocrystallized together with efavirenz into solid state forms isostructural with respect to that of the drug cocrystal with 4,4’-bipyridine. The formation of a three-molecule entity based mainly on the hydrogen bonding donation from two efavirenz molecules to both pyridyl nitrogens of each coformer unit was kept in the three efavirenz cocrystals. The introduction of spacer groups in the coformers has altered the pattern of weak non-classical hydrogen bonds of the type C— H· · ·O. This intriduction was also related to the formation of a π-π stacking interaction between pyridyl rings of the ethane-spaced conformer. Furthermore, a polymorphic form of efavirenz with only one molecule in the asymmetric unit is reported for the first time here. This polymorph crystallizes in the monoclinic system and space group C2, strictly similar to formLamivudina e Efavirenz são fármacos anti-VIH utilizados respectivamente como um inibidor não nucleosídeo da transcriptase reversa e inibidor nucleosídeo da transcriptase reversa como parte de terapias anti-retrovirais. Durante os ensaios destinados a obtenção dos co-cristais de efavirenz com lamivudina obteve-se uma fase cristalina inédita, o polimorfo do cloridrato de lamivudina. As análises conformacionais e estruturais desta modificação cristalina revelaram que a mesma guarda semelhanças em nível intramolecular e intermolecular, respectivamente com o cloridrato de lamivudina e com o cloridrato monohidratado de lamivudina. Baseada na análise intermolecular e na eficiência do empacotamento espera-se que o polimorfo do cloridrato de lamivudina seja mais solúvel que a fase anidra. Existem poucos registros de comportamento e estruturas da fase sólida do efavirenz. Estratégias de engenharia de cristais não têm sido bem exploradas com esse fármaco. Nesse sentindo, delineamos nossa estratégia de síntese a partir da comparação estrutural e possibilidade de formação de padrões de interações intermoleculares similares àquelas observadas no cocristal de efavirenz com 4,4’ - bipiridina. Dois compostos semelhantes a 4,4’- bipiridina, BPE e BPA, cujos heterociclos são respectivamente separados por um grupo etileno respectivamente e um grupo etano cristalizaram com o efavirenz em formas sólidas isoestruturais aquela obtida com a 4,4’- bipiridina. A formação de uma entidade tri-molecular baseada principalmente em doações de ligações de hidrogênio de duas moléculas de efavirenz para ambos os nitrogênios piridinícos de cada unidade do co-cristalizante foi mantida nos três cocristais de efavirenz. A introdução de grupos espaçadores nos co-cristais alterou o padrão das ligações de hidrogênio do tipo C—H· · ·O. A introdução destes grupos também está relacionada com a formação de interações do tipo π-π entre os anéis de piridil do cocristalizante espaçado com etano. Além disso, uma forma polimórfica do fármaco efavirenz com apenas uma molécula na unidade assimétrica é relatada pela primeira vez aqui. Este polimorfo, forma V, cristaliza no sistema monoclínico e grupo espacial C2, e estritamente similar à forma V.Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPqapplication/pdfhttp://repositorio.bc.ufg.br/tede/retrieve/9094/Melo%2c%20Ariane%20Carla%20Campos%20de-2013-disserta%c3%a7%c3%a3o.pdf.jpgporUniversidade Federal de GoiásPrograma de Pós-graduação em Química (IQ)UFGBrasilInstituto de Química - IQ (RG)AAKEROY, C. B.; FASULO, M. E.; DESPER, J. Cocrystal or Salt: Does it Really Matter. Molecular Pharmaceutics, Washington, v.4, n.3, p. 317-322, maio. 2007. AFFONSO, F. O; CRIVELARO, G. M. 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Journal Chemistry Society, Cambridge, v.3, n.3, p.558-565, outubro. 2004. VIPPAGUNTA, S. R.; BRITTAIN, H. G.; GRANT, D. J. W. Crystalline solids. Advanced Drug Delivery Reviews, Amsterdam, v.48, p. 3–26, 2001. VISHWESHWAR, P.; MCMAHON, J, A.; BIS, J. A; ZAWOROTKO, M. J. Pharmaceutical Co-Crystals. Journal of Pharmaceutical Sciences, v.95, p.499-516, janeiro. 2005 WALES, D. Intermolecular Forces and Clusters I. New York: Springer, 2005, v. 115, p. 206. WYETH, C. J.; SCHMID, J.; BICKSLER, J. J. New hydrochloride salt of quinoline and its crystalline monohydrochloride salt useful for treating e.g. dementia, Alzheimer’s disease, schizophrenia and depression. WO2007146115-A2, 21 Dec. 2007. 99 YU, C. Amorphous pharmaceutical solids: preparation, characterization and stabilization. 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dc.title.por.fl_str_mv Planejamento e determinação estrutural de modificações cristalinas dos fármacos lamivudina e efavirenz
title Planejamento e determinação estrutural de modificações cristalinas dos fármacos lamivudina e efavirenz
spellingShingle Planejamento e determinação estrutural de modificações cristalinas dos fármacos lamivudina e efavirenz
Melo, Ariane Carla Campos de
Modificações cristalinas
Farmaco
Lamivudina
Efavirenz
Polimorfo do cloridrato de Lamivudina
FARMACOLOGIA::FARMACOLOGIA GERAL
title_short Planejamento e determinação estrutural de modificações cristalinas dos fármacos lamivudina e efavirenz
title_full Planejamento e determinação estrutural de modificações cristalinas dos fármacos lamivudina e efavirenz
title_fullStr Planejamento e determinação estrutural de modificações cristalinas dos fármacos lamivudina e efavirenz
title_full_unstemmed Planejamento e determinação estrutural de modificações cristalinas dos fármacos lamivudina e efavirenz
title_sort Planejamento e determinação estrutural de modificações cristalinas dos fármacos lamivudina e efavirenz
author Melo, Ariane Carla Campos de
author_facet Melo, Ariane Carla Campos de
author_role author
dc.contributor.advisor1.fl_str_mv Martins, Felipe Terra
dc.contributor.advisor1Lattes.fl_str_mv http://lattes.cnpq.br/0466799995060671
dc.contributor.referee1.fl_str_mv Martins, Felipe Terra
dc.contributor.referee2.fl_str_mv Ellena, Javier Alcides
dc.contributor.referee3.fl_str_mv Chagas, Rafael Pavão das
dc.contributor.authorLattes.fl_str_mv http://lattes.cnpq.br/7764204807506356
dc.contributor.author.fl_str_mv Melo, Ariane Carla Campos de
contributor_str_mv Martins, Felipe Terra
Martins, Felipe Terra
Ellena, Javier Alcides
Chagas, Rafael Pavão das
dc.subject.por.fl_str_mv Modificações cristalinas
Farmaco
Lamivudina
Efavirenz
Polimorfo do cloridrato de Lamivudina
topic Modificações cristalinas
Farmaco
Lamivudina
Efavirenz
Polimorfo do cloridrato de Lamivudina
FARMACOLOGIA::FARMACOLOGIA GERAL
dc.subject.cnpq.fl_str_mv FARMACOLOGIA::FARMACOLOGIA GERAL
description Lamivudine and Efavirenz are anti-HIV drug largely used as, respectively a non-nucleoside and a nucleoside reverse transcriptase inhibitor as part of antiretroviral therapies. During the tests to obtain co-crystals of efavirenz with lamivudine it was obtained a novel crystalline phase, the polymorph of the hydrochloride salt of lamivudine. The structural and conformational analysis of this crystal modification showed that this keeps similarities, in intramolecular and intermolecular level, respectively with lamivudine hydrochloride and lamivudine hydrochloride monohydrate. Based on the intermolecular analysis and packing efficiency is expected that the polymorph of the hydrochloride salt of lamivudine is more soluble than the anhydrous phase. There are few reports on efavirenz solid state structures and behaviors. Crystal engineering strategies have not been well-exploited for this drug. In this sense, we delineate our synthesis strategy from the structural comparison and possibility of formation of intermolecular interactions patterns similar to those observed in the cocrystal of efavirenz and 4,4’-bipyridine. Two 4,4’-bipyridine-like compounds whose heterocycles are spaced by either an ethylene and an ethane moiety were cocrystallized together with efavirenz into solid state forms isostructural with respect to that of the drug cocrystal with 4,4’-bipyridine. The formation of a three-molecule entity based mainly on the hydrogen bonding donation from two efavirenz molecules to both pyridyl nitrogens of each coformer unit was kept in the three efavirenz cocrystals. The introduction of spacer groups in the coformers has altered the pattern of weak non-classical hydrogen bonds of the type C— H· · ·O. This intriduction was also related to the formation of a π-π stacking interaction between pyridyl rings of the ethane-spaced conformer. Furthermore, a polymorphic form of efavirenz with only one molecule in the asymmetric unit is reported for the first time here. This polymorph crystallizes in the monoclinic system and space group C2, strictly similar to form
publishDate 2013
dc.date.issued.fl_str_mv 2013-08-02
dc.date.accessioned.fl_str_mv 2014-09-30T15:24:53Z
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.citation.fl_str_mv MELO, Ariane Carla Campos de. Planejamento e determinação estrutural de modificações cristalinas dos fármacos lamivudina e efavirenz. 2013. 117 f. Dissertação (Mestrado em Química) - Universidade Federal de Goiás, Goiânia, 2013.
dc.identifier.uri.fl_str_mv http://repositorio.bc.ufg.br/tede/handle/tede/3219
dc.identifier.dark.fl_str_mv ark:/38995/001300000f2c6
identifier_str_mv MELO, Ariane Carla Campos de. Planejamento e determinação estrutural de modificações cristalinas dos fármacos lamivudina e efavirenz. 2013. 117 f. Dissertação (Mestrado em Química) - Universidade Federal de Goiás, Goiânia, 2013.
ark:/38995/001300000f2c6
url http://repositorio.bc.ufg.br/tede/handle/tede/3219
dc.language.iso.fl_str_mv por
language por
dc.relation.program.fl_str_mv 663693921325415158
dc.relation.confidence.fl_str_mv 600
600
600
600
dc.relation.department.fl_str_mv 7826066743741197278
dc.relation.cnpq.fl_str_mv -3959484153940758247
dc.relation.sponsorship.fl_str_mv -2555911436985713659
dc.relation.references.por.fl_str_mv AAKEROY, C. B.; FASULO, M. E.; DESPER, J. Cocrystal or Salt: Does it Really Matter. Molecular Pharmaceutics, Washington, v.4, n.3, p. 317-322, maio. 2007. AFFONSO, F. O; CRIVELARO, G. M. Direito a vida ou direito a propriedade? - uma reflexão sobre o licenciamento compulsório dos medicamentos para tratamento da AIDS. Memorias Convención Internacional de Salud Pública. Cuba Salud 2012. La Habana 3-7 de Diciembre de 2012. ISBN 978-959-212- 811-8. AGUIAR, M. R. M. P.; GEMAL, A. L.; GIL, R. A. S. Caracterização de polimorfismo em fármacos por ressonância magnética nuclear no estado sólido. Química Nova, São Paulo, v.22, n.4, p. 553-564, Julho/agosto. 1999. ALTOMARE, A.; CASCARANO, G.; GIACOVAZZO, C.; GUAGLIARDI, A. Completion and refinement of crystal-structures with SIR92. Journal of Applied Crystallography, England v. 26, p. 343-350, 1993. ARAUJO, G. L. B.; PITALUGA, A. J.; ANTONIO, S. G.; SANTOS, C. O. P. Polimorfismo na produção de medicamentos. Revista de Ciências Farmacêuticas Básica e Aplicada, São Paulo, v. 33, n.3, p. 27-36, 2012. ARIGA, K.; KUNITAKE, T. Supramolecular Chemistry-Fundamentals and Applications. New York: Springer, 2006. p. 208. ARUNAN, E.; DESIRAJU, G, R.; KLEIN, R, A.; SADLEJ, J.; SCHEINER, S.; ALKORTA, I.; CLARY, D, C.; CRABTREE, R, H.; DANNENBERG, J, J.; HOBZA, P; KJAERGAARD, H, G.; LEGON, A, C.; MENNUCCI, B.; NESBITT, D, J. Definition of the hydrogen Bond. Pure Applied Chemistry, United States of American v. 83, n. 8, p. 1637–1641, Julho. 2011. ATKINS, P; JONES, L. Princípios De Química - Questionando A Vida Moderna e o Meio Ambiente. 5 ª Ed. São Paulo: Bookman, 2011. p. 1048. 90 BANERJEE, R.; BHATT, P. M.; RAVINDRA, N. V.; DESIRAJU, G. R. Saccharin salts of active pharmaceutical ingredients, their crystal structures, and, increased water solubilities. Crystal Growth Design, Washington, v.5, p.2299-2309. Setembro, 2005. BERGERHOFF, G.; BERNDT, M.; BRANDENBURG, K. 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