Ionizable drug self-associations and the solubility dependence on pH: detection of aggregates in saturated solutions using mass spectrometry (ESI-Q-TOF-MS/MS)

Fuguet i Jordà, Elisabet; Subirats i Vila, Xavier; Ràfols Llach, Clara; Bosch, Elisabeth; Avdeef, Alex

Ionizable drug self-associations and the solubility dependence on pH: detection of aggregates in saturated solutions using mass spectrometry (ESI-Q-TOF-MS/MS)

It is widely accepted that solubility-pH profiles of ionizable compounds follow the Henderson-Hasselbalch equation. However, several studies point out that compounds often undergo additional processes in saturated solutions, such as sub-micellar oligomerization, micellar aggregation, or drug-buffer...

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Detalles Bibliográficos
Autores:	Fuguet i Jordà, Elisabet, Subirats i Vila, Xavier, Ràfols Llach, Clara, Bosch, Elisabeth, Avdeef, Alex
Tipo de recurso:	artículo
Estado:	Versión aceptada para publicación
Fecha de publicación:	2021
País:	España
Institución:	Universidad de Barcelona
Repositorio:	Dipòsit Digital de la UB
OAI Identifier:	oai:diposit.ub.edu:2445/178187
Acceso en línea:	https://hdl.handle.net/2445/178187
Access Level:	acceso abierto
Palabra clave:	Espectrometria de masses Solubilitat Mass spectrometry Solubility

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spelling	Ionizable drug self-associations and the solubility dependence on pH: detection of aggregates in saturated solutions using mass spectrometry (ESI-Q-TOF-MS/MS)Fuguet i Jordà, ElisabetSubirats i Vila, XavierRàfols Llach, ClaraBosch, ElisabethAvdeef, AlexEspectrometria de massesSolubilitatMass spectrometrySolubilityIt is widely accepted that solubility-pH profiles of ionizable compounds follow the Henderson-Hasselbalch equation. However, several studies point out that compounds often undergo additional processes in saturated solutions, such as sub-micellar oligomerization, micellar aggregation, or drug-buffer complexation among others, which make the experimental profiles deviate from the behavior predicted by the Henderson-Hasselbalch equation. Often, the presence of additional processes is supported by the analysis of experimental data through solubility computer programs. However, the purpose of this work is to experimentally prove the aggregation phenomena for a series of bases for which deviations from the theoretical profile have been observed. To this end, five monoprotic bases (lidocaine, maprotiline, cyproheptadine, bupivacaine, and mifepristone) susceptible to form ionic aggregates in solution have been selected, and mass spectrometry has been the technique of choice to prove the presence of aggregation. High declustering potentials have been applied to prevent aggregates from forming in the ionization source of the mass spectrometer. In addition, haloperidol has been used as a negative control since according to its profile, it is not suspected to form ionic aggregates. In all instances, except for haloperidol, the analysis of the saturated solutions revealed the presence of mixed-charged dimers (aggregates formed by a neutral molecule and a charged one) and even trimers in the case of mifepristone and bupivacaine. For lidocaine, the most soluble of the compounds, the presence of neutral aggregates was also detected. These experiments support the hypothesis that the simple Henderson-Hasselbalch equation may explain the solubility-pH behavior of certain compounds, but it can be somewhat inaccurate in describing the behavior of many other substances.American Chemical Society2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/178187Articles publicats en revistes (Enginyeria Química i Química Analítica)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: https://doi.org/10.1021/acs.molpharmaceut.1c00131Molecular Pharmaceutics, 2021, vol. 18, num. 6, p. 2311-2321https://doi.org/10.1021/acs.molpharmaceut.1c00131(c) American Chemical Society , 2021info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1781872026-05-27T06:46:51Z
dc.title.none.fl_str_mv	Ionizable drug self-associations and the solubility dependence on pH: detection of aggregates in saturated solutions using mass spectrometry (ESI-Q-TOF-MS/MS)
title	Ionizable drug self-associations and the solubility dependence on pH: detection of aggregates in saturated solutions using mass spectrometry (ESI-Q-TOF-MS/MS)
spellingShingle	Ionizable drug self-associations and the solubility dependence on pH: detection of aggregates in saturated solutions using mass spectrometry (ESI-Q-TOF-MS/MS) Fuguet i Jordà, Elisabet Espectrometria de masses Solubilitat Mass spectrometry Solubility
title_short	Ionizable drug self-associations and the solubility dependence on pH: detection of aggregates in saturated solutions using mass spectrometry (ESI-Q-TOF-MS/MS)
title_full	Ionizable drug self-associations and the solubility dependence on pH: detection of aggregates in saturated solutions using mass spectrometry (ESI-Q-TOF-MS/MS)
title_fullStr	Ionizable drug self-associations and the solubility dependence on pH: detection of aggregates in saturated solutions using mass spectrometry (ESI-Q-TOF-MS/MS)
title_full_unstemmed	Ionizable drug self-associations and the solubility dependence on pH: detection of aggregates in saturated solutions using mass spectrometry (ESI-Q-TOF-MS/MS)
title_sort	Ionizable drug self-associations and the solubility dependence on pH: detection of aggregates in saturated solutions using mass spectrometry (ESI-Q-TOF-MS/MS)
dc.creator.none.fl_str_mv	Fuguet i Jordà, Elisabet Subirats i Vila, Xavier Ràfols Llach, Clara Bosch, Elisabeth Avdeef, Alex
author	Fuguet i Jordà, Elisabet
author_facet	Fuguet i Jordà, Elisabet Subirats i Vila, Xavier Ràfols Llach, Clara Bosch, Elisabeth Avdeef, Alex
author_role	author
author2	Subirats i Vila, Xavier Ràfols Llach, Clara Bosch, Elisabeth Avdeef, Alex
author2_role	author author author author
dc.subject.none.fl_str_mv	Espectrometria de masses Solubilitat Mass spectrometry Solubility
topic	Espectrometria de masses Solubilitat Mass spectrometry Solubility
description	It is widely accepted that solubility-pH profiles of ionizable compounds follow the Henderson-Hasselbalch equation. However, several studies point out that compounds often undergo additional processes in saturated solutions, such as sub-micellar oligomerization, micellar aggregation, or drug-buffer complexation among others, which make the experimental profiles deviate from the behavior predicted by the Henderson-Hasselbalch equation. Often, the presence of additional processes is supported by the analysis of experimental data through solubility computer programs. However, the purpose of this work is to experimentally prove the aggregation phenomena for a series of bases for which deviations from the theoretical profile have been observed. To this end, five monoprotic bases (lidocaine, maprotiline, cyproheptadine, bupivacaine, and mifepristone) susceptible to form ionic aggregates in solution have been selected, and mass spectrometry has been the technique of choice to prove the presence of aggregation. High declustering potentials have been applied to prevent aggregates from forming in the ionization source of the mass spectrometer. In addition, haloperidol has been used as a negative control since according to its profile, it is not suspected to form ionic aggregates. In all instances, except for haloperidol, the analysis of the saturated solutions revealed the presence of mixed-charged dimers (aggregates formed by a neutral molecule and a charged one) and even trimers in the case of mifepristone and bupivacaine. For lidocaine, the most soluble of the compounds, the presence of neutral aggregates was also detected. These experiments support the hypothesis that the simple Henderson-Hasselbalch equation may explain the solubility-pH behavior of certain compounds, but it can be somewhat inaccurate in describing the behavior of many other substances.
publishDate	2021
dc.date.none.fl_str_mv	2021
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion
format	article
status_str	acceptedVersion
dc.identifier.none.fl_str_mv	https://hdl.handle.net/2445/178187
url	https://hdl.handle.net/2445/178187
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	Versió postprint del document publicat a: https://doi.org/10.1021/acs.molpharmaceut.1c00131 Molecular Pharmaceutics, 2021, vol. 18, num. 6, p. 2311-2321 https://doi.org/10.1021/acs.molpharmaceut.1c00131
dc.rights.none.fl_str_mv	(c) American Chemical Society , 2021 info:eu-repo/semantics/openAccess
rights_invalid_str_mv	(c) American Chemical Society , 2021
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	American Chemical Society
publisher.none.fl_str_mv	American Chemical Society
dc.source.none.fl_str_mv	Articles publicats en revistes (Enginyeria Química i Química Analítica) reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona
instname_str	Universidad de Barcelona
reponame_str	Dipòsit Digital de la UB
collection	Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score	15,300719

Ionizable drug self-associations and the solubility dependence on pH: detection of aggregates in saturated solutions using mass spectrometry (ESI-Q-TOF-MS/MS)

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