Thermodynamic Analysis of the Solubility of Isoniazid in (PEG 200+ Water) Cosolvent Mixtures from 278.15 K to 318.15 K

The solubility of drugs in cosolvent systems of pharmaceutical interest is of great importance for understanding and optimizing a large number of processes. Here, we report the solubility of isoniazid in nine (PEG 200 + water) cosolvent mixtures at nine temperatures (278.15, 283.15, 288.15, 293.15,...

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Autores:
Baracaldo-Santamaría, Daniela
Ospina, Carlos
Ortiz, Claudia
Cardenas, Rossember
Martinez, Fleming
Delgado, Daniel Ricardo Delgado
Tipo de recurso:
Article of journal
Fecha de publicación:
2022
Institución:
Universidad Cooperativa de Colombia
Repositorio:
Repositorio UCC
Idioma:
OAI Identifier:
oai:repository.ucc.edu.co:20.500.12494/46628
Acceso en línea:
https://hdl.handle.net/20.500.12494/46628
Palabra clave:
Isiniazid
Solubilidad
Cosolvencia
Termodinámica
PEG 200
Agua
Q1
isoniazid
Solubility
Cosolvent
Thermodynamics
PEG 200
Water
Rights
openAccess
License
Atribución – Sin Derivar
id COOPER2_c9e390444a896184dd0dbcdc35215578
oai_identifier_str oai:repository.ucc.edu.co:20.500.12494/46628
network_acronym_str COOPER2
network_name_str Repositorio UCC
repository_id_str
dc.title.spa.fl_str_mv Thermodynamic Analysis of the Solubility of Isoniazid in (PEG 200+ Water) Cosolvent Mixtures from 278.15 K to 318.15 K
title Thermodynamic Analysis of the Solubility of Isoniazid in (PEG 200+ Water) Cosolvent Mixtures from 278.15 K to 318.15 K
spellingShingle Thermodynamic Analysis of the Solubility of Isoniazid in (PEG 200+ Water) Cosolvent Mixtures from 278.15 K to 318.15 K
Isiniazid
Solubilidad
Cosolvencia
Termodinámica
PEG 200
Agua
Q1
isoniazid
Solubility
Cosolvent
Thermodynamics
PEG 200
Water
title_short Thermodynamic Analysis of the Solubility of Isoniazid in (PEG 200+ Water) Cosolvent Mixtures from 278.15 K to 318.15 K
title_full Thermodynamic Analysis of the Solubility of Isoniazid in (PEG 200+ Water) Cosolvent Mixtures from 278.15 K to 318.15 K
title_fullStr Thermodynamic Analysis of the Solubility of Isoniazid in (PEG 200+ Water) Cosolvent Mixtures from 278.15 K to 318.15 K
title_full_unstemmed Thermodynamic Analysis of the Solubility of Isoniazid in (PEG 200+ Water) Cosolvent Mixtures from 278.15 K to 318.15 K
title_sort Thermodynamic Analysis of the Solubility of Isoniazid in (PEG 200+ Water) Cosolvent Mixtures from 278.15 K to 318.15 K
dc.creator.fl_str_mv Baracaldo-Santamaría, Daniela
Ospina, Carlos
Ortiz, Claudia
Cardenas, Rossember
Martinez, Fleming
Delgado, Daniel Ricardo Delgado
dc.contributor.advisor.none.fl_str_mv Delgado, Daniel Ricardo
dc.contributor.author.none.fl_str_mv Baracaldo-Santamaría, Daniela
Ospina, Carlos
Ortiz, Claudia
Cardenas, Rossember
Martinez, Fleming
Delgado, Daniel Ricardo Delgado
dc.subject.spa.fl_str_mv Isiniazid
Solubilidad
Cosolvencia
Termodinámica
PEG 200
Agua
topic Isiniazid
Solubilidad
Cosolvencia
Termodinámica
PEG 200
Agua
Q1
isoniazid
Solubility
Cosolvent
Thermodynamics
PEG 200
Water
dc.subject.classification.spa.fl_str_mv Q1
dc.subject.other.spa.fl_str_mv isoniazid
Solubility
Cosolvent
Thermodynamics
PEG 200
Water
description The solubility of drugs in cosolvent systems of pharmaceutical interest is of great importance for understanding and optimizing a large number of processes. Here, we report the solubility of isoniazid in nine (PEG 200 + water) cosolvent mixtures at nine temperatures (278.15, 283.15, 288.15, 293.15, 298.15, 303.15, 308.15, and 318.15 K) determined by UV–vis spectrophotometry. From the solubility data, the thermodynamic solution, mixing, and transfer functions were calculated in addition to performing the enthalpy–entropy compensation analysis. The solubility of isoniazid depends on the concentration of PEG 200 (positive cosolvent effect) and temperature (endothermic process) reaching its maximum solubility in pure PEG 200 at 318.15 K and the lowest solubility in pure water at 278.15 K. The solution process is favored by the solution entropy and according to the enthalpy–entropy compensation analysis it is driven by entropy in mixtures rich in water and by enthalpy in mixtures rich in PEG 200.
publishDate 2022
dc.date.accessioned.none.fl_str_mv 2022-10-06T15:58:54Z
dc.date.available.none.fl_str_mv 2022-10-06T15:58:54Z
dc.date.issued.none.fl_str_mv 2022-09-05
dc.type.none.fl_str_mv Artículo
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dc.identifier.bibliographicCitation.spa.fl_str_mv Baracaldo-Santamaría, D.; Calderon-Ospina, C.A.; Ortiz, C.P.; Cardenas-Torres, R.E.; Martinez, F.; Delgado, D.R. Thermodynamic Analysis of the Solubility of Isoniazid in (PEG 200 + Water) Cosolvent Mixtures from 278.15 K to 318.15 K. Int. J. Mol. Sci. 2022, 23, 10190. https://doi.org/10.3390/ijms231710190
identifier_str_mv 1422-0067
10.3390/ijms231710190
Baracaldo-Santamaría, D.; Calderon-Ospina, C.A.; Ortiz, C.P.; Cardenas-Torres, R.E.; Martinez, F.; Delgado, D.R. Thermodynamic Analysis of the Solubility of Isoniazid in (PEG 200 + Water) Cosolvent Mixtures from 278.15 K to 318.15 K. Int. J. Mol. Sci. 2022, 23, 10190. https://doi.org/10.3390/ijms231710190
url https://hdl.handle.net/20.500.12494/46628
dc.relation.isversionof.spa.fl_str_mv https://www.mdpi.com/1422-0067/23/17/10190
dc.relation.ispartofjournal.spa.fl_str_mv International Journal of Molecular Sciences
dc.relation.references.spa.fl_str_mv Erwin, E.R.; Addison, A.P.; John, S.F.; Olaleye, O.A.; Rosell, R.C. Pharmacokinetics of isoniazid: The good, the bad, and the alternatives. Tuberculosis 2019, 116, S66–S70.
Nahid, P.; Dorman, S.E.; Alipanah, N.; Barry, P.M.; Brozek, J.L.; Cattamanchi, A.; Chaisson, L.H.; Chaisson, R.E.; Daley, C.L.; Grzemska, M.; et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin. Infect. Dis. 2016, 63, e147–e195.
Smieja, M.; Marchetti, C.; Cook, D.; Smaill, F. Isoniazid for preventing tuberculosis in non-HIV infected persons. Cochrane Database Syst. Rev. 1999, 1, CD001363.
Benator, D.; Bhattacharya, M.; Bozeman, L.; Burman, W.; Cantazaro, A.; Chaisson, R.; Gordin, F.; Horsburgh, C.R.; Horton, J.; Khan, A.; et al. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: A randomised clinical trial. Lancet 2002, 360, 528–534.
Soedarsono, S.; Jayanti, R.P.; Mertaniasih, N.M.; Kusmiati, T.; Permatasari, A.; Indrawanto, D.W.; Charisma, A.N.; Yuliwulandari, R.; Long, N.P.; Choi, Y.K.; et al. Development of population pharmacokinetics model of isoniazid in Indonesian patients with tuberculosis. Int. J. Infect. Dis. 2022, 117, 8–14.
Di, L.; Fish, P.V.; Mano, T. Bridging solubility between drug discovery and development. Drug Discov. Today 2012, 17, 486–495.
Delgado, D.R.; Martínez, F. Solution thermodynamics of sulfadiazine in some ethanol+water mixtures. J. Mol. Liq. 2013, 187, 99–105.
Delgado, D.R.; Martínez, F. Solubility and preferential solvation of sulfadiazine in methanol+water mixtures at several temperatures. Fluid Phase Equilibria 2014, 379, 128–138.
Delgado, D.R.; Martínez, F. Solubility and Solution Thermodynamics of Some Sulfonamides in 1-Propanol + Water Mixtures. J. Solut. Chem. 2014, 43, 836–852.
Delgado, D.R.; Martínez, F. Solubility and solution thermodynamics of sulfamerazine and sulfamethazine in some ethanol+water mixtures. Fluid Phase Equilibria 2013, 360, 88–96.
Delgado, D.R.; Almanza, O.A.; Martínez, F.; Peña, M.A.; Jouyban, A.; Acree, W.E. Solution thermodynamics and preferential solvation of sulfamethazine in (methanol + water) mixtures. J. Chem. Thermodyn. 2016, 97, 264–276.
Delgado, D.R.; Martínez, F. Solution Thermodynamics and Preferential Solvation of Sulfamerazine in Methanol + Water Mixtures. J. Solut. Chem. 2015, 44, 360–377.
Ortiz, C.P.; Cardenas-Torres, R.E.; Martínez, F.; Delgado, D.R. Solubility of Sulfamethazine in the Binary Mixture of Acetonitrile + Methanol from 278.15 to 318.15 K: Measurement, Dissolution Thermodynamics, Preferential Solvation, and Correlation. Molecules 2021, 26, 7588.
Holguín, A.R.; Rodríguez, G.A.; Cristancho, D.M.; Delgado, D.R.; Martínez, F. Solution thermodynamics of indomethacin in propylene glycol+water mixtures. Fluid Phase Equilibria 2012, 314, 134–139.
Delgado, D.R.; Martínez, F. Preferential solvation of sulfadiazine, sulfamerazine and sulfamethazine in ethanol+water solvent mixtures according to the IKBI method. J. Mol. Liq. 2014, 193, 152–159.
Delgado, D.R.; Bahamón-Hernandez, O.; Cerquera, N.E.; Ortiz, C.P.; Martínez, F.; Rahimpour, E.; Jouyban, A.; Acree, W.E. Solubility of sulfadiazine in (acetonitrile + methanol) mixtures: Determination, correlation, dissolution thermodynamics and preferential solvation. J. Mol. Liq. 2021, 322, 114979.
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MDPI
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dc.publisher.place.spa.fl_str_mv Neiva
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spelling Delgado, Daniel RicardoBaracaldo-Santamaría, DanielaOspina, CarlosOrtiz, ClaudiaCardenas, RossemberMartinez, FlemingDelgado, Daniel Ricardo Delgado23/172022-10-06T15:58:54Z2022-10-06T15:58:54Z2022-09-051422-006710.3390/ijms231710190https://hdl.handle.net/20.500.12494/46628Baracaldo-Santamaría, D.; Calderon-Ospina, C.A.; Ortiz, C.P.; Cardenas-Torres, R.E.; Martinez, F.; Delgado, D.R. Thermodynamic Analysis of the Solubility of Isoniazid in (PEG 200 + Water) Cosolvent Mixtures from 278.15 K to 318.15 K. Int. J. Mol. Sci. 2022, 23, 10190. https://doi.org/10.3390/ijms231710190The solubility of drugs in cosolvent systems of pharmaceutical interest is of great importance for understanding and optimizing a large number of processes. Here, we report the solubility of isoniazid in nine (PEG 200 + water) cosolvent mixtures at nine temperatures (278.15, 283.15, 288.15, 293.15, 298.15, 303.15, 308.15, and 318.15 K) determined by UV–vis spectrophotometry. From the solubility data, the thermodynamic solution, mixing, and transfer functions were calculated in addition to performing the enthalpy–entropy compensation analysis. The solubility of isoniazid depends on the concentration of PEG 200 (positive cosolvent effect) and temperature (endothermic process) reaching its maximum solubility in pure PEG 200 at 318.15 K and the lowest solubility in pure water at 278.15 K. The solution process is favored by the solution entropy and according to the enthalpy–entropy compensation analysis it is driven by entropy in mixtures rich in water and by enthalpy in mixtures rich in PEG 200.The solubility of drugs in cosolvent systems of pharmaceutical interest is of great importance for understanding and optimizing a large number of processes. Here, we report the solubility of isoniazid in nine (PEG 200 + water) cosolvent mixtures at nine temperatures (278.15, 283.15, 288.15, 293.15, 298.15, 303.15, 308.15, and 318.15 K) determined by UV–vis spectrophotometry. From the solubility data, the thermodynamic solution, mixing, and transfer functions were calculated in addition to performing the enthalpy–entropy compensation analysis. The solubility of isoniazid depends on the concentration of PEG 200 (positive cosolvent effect) and temperature (endothermic process) reaching its maximum solubility in pure PEG 200 at 318.15 K and the lowest solubility in pure water at 278.15 K. The solution process is favored by the solution entropy and according to the enthalpy–entropy compensation analysis it is driven by entropy in mixtures rich in water and by enthalpy in mixtures rich in PEG 200.Introducción, Metodos, Análisis de resultados, Conclusiones, Referenciashttps://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0001402116https://orcid.org/0000-0002-4835-9739https://scienti.minciencias.gov.co/gruplac/jsp/visualiza/visualizagr.jsp?nro=00000000004151danielr.delgado@campusucc.edu.cohttps://scholar.google.com/citations?hl=es&user=OW0mejcAAAAJ&view_op=list_works&sortby=pubdate17Universidad Cooperativa de Colombia, Facultad de Ingenierías, Ingeniería Civil, NeivaMDPIIngeniería CivilNeivahttps://www.mdpi.com/1422-0067/23/17/10190International Journal of Molecular SciencesErwin, E.R.; Addison, A.P.; John, S.F.; Olaleye, O.A.; Rosell, R.C. Pharmacokinetics of isoniazid: The good, the bad, and the alternatives. Tuberculosis 2019, 116, S66–S70.Nahid, P.; Dorman, S.E.; Alipanah, N.; Barry, P.M.; Brozek, J.L.; Cattamanchi, A.; Chaisson, L.H.; Chaisson, R.E.; Daley, C.L.; Grzemska, M.; et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin. Infect. Dis. 2016, 63, e147–e195.Smieja, M.; Marchetti, C.; Cook, D.; Smaill, F. Isoniazid for preventing tuberculosis in non-HIV infected persons. Cochrane Database Syst. Rev. 1999, 1, CD001363.Benator, D.; Bhattacharya, M.; Bozeman, L.; Burman, W.; Cantazaro, A.; Chaisson, R.; Gordin, F.; Horsburgh, C.R.; Horton, J.; Khan, A.; et al. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: A randomised clinical trial. Lancet 2002, 360, 528–534.Soedarsono, S.; Jayanti, R.P.; Mertaniasih, N.M.; Kusmiati, T.; Permatasari, A.; Indrawanto, D.W.; Charisma, A.N.; Yuliwulandari, R.; Long, N.P.; Choi, Y.K.; et al. Development of population pharmacokinetics model of isoniazid in Indonesian patients with tuberculosis. Int. J. Infect. Dis. 2022, 117, 8–14.Di, L.; Fish, P.V.; Mano, T. Bridging solubility between drug discovery and development. Drug Discov. Today 2012, 17, 486–495.Delgado, D.R.; Martínez, F. Solution thermodynamics of sulfadiazine in some ethanol+water mixtures. J. Mol. Liq. 2013, 187, 99–105.Delgado, D.R.; Martínez, F. Solubility and preferential solvation of sulfadiazine in methanol+water mixtures at several temperatures. Fluid Phase Equilibria 2014, 379, 128–138.Delgado, D.R.; Martínez, F. Solubility and Solution Thermodynamics of Some Sulfonamides in 1-Propanol + Water Mixtures. J. Solut. Chem. 2014, 43, 836–852.Delgado, D.R.; Martínez, F. Solubility and solution thermodynamics of sulfamerazine and sulfamethazine in some ethanol+water mixtures. Fluid Phase Equilibria 2013, 360, 88–96.Delgado, D.R.; Almanza, O.A.; Martínez, F.; Peña, M.A.; Jouyban, A.; Acree, W.E. Solution thermodynamics and preferential solvation of sulfamethazine in (methanol + water) mixtures. J. Chem. Thermodyn. 2016, 97, 264–276.Delgado, D.R.; Martínez, F. Solution Thermodynamics and Preferential Solvation of Sulfamerazine in Methanol + Water Mixtures. J. Solut. Chem. 2015, 44, 360–377.Ortiz, C.P.; Cardenas-Torres, R.E.; Martínez, F.; Delgado, D.R. Solubility of Sulfamethazine in the Binary Mixture of Acetonitrile + Methanol from 278.15 to 318.15 K: Measurement, Dissolution Thermodynamics, Preferential Solvation, and Correlation. Molecules 2021, 26, 7588.Holguín, A.R.; Rodríguez, G.A.; Cristancho, D.M.; Delgado, D.R.; Martínez, F. Solution thermodynamics of indomethacin in propylene glycol+water mixtures. Fluid Phase Equilibria 2012, 314, 134–139.Delgado, D.R.; Martínez, F. Preferential solvation of sulfadiazine, sulfamerazine and sulfamethazine in ethanol+water solvent mixtures according to the IKBI method. J. Mol. Liq. 2014, 193, 152–159.Delgado, D.R.; Bahamón-Hernandez, O.; Cerquera, N.E.; Ortiz, C.P.; Martínez, F.; Rahimpour, E.; Jouyban, A.; Acree, W.E. Solubility of sulfadiazine in (acetonitrile + methanol) mixtures: Determination, correlation, dissolution thermodynamics and preferential solvation. J. Mol. Liq. 2021, 322, 114979.IsiniazidSolubilidadCosolvenciaTermodinámicaPEG 200AguaQ1isoniazidSolubilityCosolventThermodynamicsPEG 200WaterThermodynamic Analysis of the Solubility of Isoniazid in (PEG 200+ Water) Cosolvent Mixtures from 278.15 K to 318.15 KArtículohttp://purl.org/coar/resource_type/c_6501http://purl.org/coar/resource_type/c_2df8fbb1http://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articlehttp://purl.org/redcol/resource_type/ARTinfo:eu-repo/semantics/publishedVersionAtribución – Sin Derivarinfo:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2PublicationORIGINALThermodynamic Analysis of the Solubility of Isoniazid in (PEG 200 + Water) Cosolvent Mixtures from 278.15 K to 318.15 K.pdfThermodynamic Analysis of the Solubility of Isoniazid in (PEG 200 + Water) Cosolvent Mixtures from 278.15 K to 318.15 K.pdfArtículoapplication/pdf604413https://repository.ucc.edu.co/bitstreams/3b9ed9ff-07ce-4df6-8ff6-662d0700089f/downloadb06917dac731e906ad91371805fd48b4MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-81748https://repository.ucc.edu.co/bitstreams/b597b2f5-df74-4a97-b156-15ba6299bc98/download8a4605be74aa9ea9d79846c1fba20a33MD52THUMBNAILThermodynamic Analysis of the Solubility of Isoniazid in (PEG 200 + Water) Cosolvent Mixtures from 278.15 K to 318.15 K.pdf.jpgThermodynamic Analysis of the Solubility of Isoniazid in (PEG 200 + Water) Cosolvent Mixtures from 278.15 K to 318.15 K.pdf.jpgGenerated Thumbnailimage/jpeg5760https://repository.ucc.edu.co/bitstreams/f1c93b8e-0617-4ea4-9a19-131134fb8402/downloadc100baae0b921a3b6e2987a1a812f08bMD53TEXTThermodynamic Analysis of the Solubility of Isoniazid in (PEG 200 + Water) Cosolvent Mixtures from 278.15 K to 318.15 K.pdf.txtThermodynamic Analysis of the Solubility of Isoniazid in (PEG 200 + Water) Cosolvent Mixtures from 278.15 K to 318.15 K.pdf.txtExtracted texttext/plain60930https://repository.ucc.edu.co/bitstreams/b006c2f3-4f36-4d9e-a574-25b453974c22/download7d4fe4db624e9e5511199587d7db6a45MD5420.500.12494/46628oai:repository.ucc.edu.co:20.500.12494/466282024-08-20 16:22:38.378open.accesshttps://repository.ucc.edu.coRepositorio Institucional Universidad Cooperativa de Colombiabdigital@metabiblioteca.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