Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

<!DOCTYPE html> <html lang="en-US" xml:lang="en-US"> <head> <meta charset="utf-8"> <meta name="viewport" content="width=device-width, initial-scale=1.0"> <title> Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality | ADMET and DMPK </title> <link rel="icon" href="https://pub.iapchem.org/ojs/public/journals/4/favicon_en_US.jpg"> <meta name="generator" content="Open Journal Systems 3.3.0.13"> <link rel="schema.DC" href="http://purl.org/dc/elements/1.1/" /> <meta name="DC.Creator.PersonalName" content="Alex Avdeef"/> <meta name="DC.Creator.PersonalName" content="Elisabet Fuguet"/> <meta name="DC.Creator.PersonalName" content="Antonio Llinàs"/> <meta name="DC.Creator.PersonalName" content="Clara Ràfols"/> <meta name="DC.Creator.PersonalName" content="Elisabeth Bosch"/> <meta name="DC.Creator.PersonalName" content="Gergely Völgyi"/> <meta name="DC.Creator.PersonalName" content="Tatjana Verbić"/> <meta name="DC.Creator.PersonalName" content="Elena Boldyreva"/> <meta name="DC.Creator.PersonalName" content="Krisztina Takács-Novák"/> <meta name="DC.Date.created" scheme="ISO8601" content="2016-06-29"/> <meta name="DC.Date.dateSubmitted" scheme="ISO8601" content="2016-05-08"/> <meta name="DC.Date.issued" scheme="ISO8601" content="2016-06-29"/> <meta name="DC.Date.modified" scheme="ISO8601" content="2020-09-28"/> <meta name="DC.Description" xml:lang="en" content="This commentary addresses data quality in equilibrium solubility measurement in aqueous solution. Broadly discussed is the “gold standard” shake-flask (SF) method used to measure equilibrium solubility of ionizable drug-like molecules as a function of pH. Many factors affecting the quality of the measurement are recognized. Case studies illustrating the analysis of both solution and solid state aspects of solubility measurement are presented. Coverage includes drug aggregation in solution (sub-micellar, micellar, complexation), use of mass spectrometry to assess aggregation in saturated solutions, solid state characterization (salts, polymorphs, cocrystals, polymorph creation by potentiometric method), solubility type (water, buffer, intrinsic), temperature, ionic strength, pH measurement, buffer issues, critical knowledge of the pKa, equilibration time (stirring and sedimentation), separating solid from saturated solution, solution handling and adsorption to untreated surfaces, solubility units, and tabulation/graphic presentation of reported data. The goal is to present cohesive recommendations that could lead to better assay design, to result in improved quality of measurements, and to impart a deeper understanding of the underlying solution chemistry in suspensions of drug solids."/> <meta name="DC.Format" scheme="IMT" content="application/pdf"/> <meta name="DC.Format" scheme="IMT" content="application/msword"/> <meta name="DC.Format" scheme="IMT" content="application/msword"/> <meta name="DC.Identifier" content="292"/> <meta name="DC.Identifier.pageNumber" content="117-178"/> <meta name="DC.Identifier.DOI" content="10.5599/admet.4.2.292"/> <meta name="DC.Identifier.URI" content="https://pub.iapchem.org/ojs/index.php/admet/article/view/292"/> <meta name="DC.Language" scheme="ISO639-1" content="en"/> <meta name="DC.Rights" content="Copyright (c) 2016 ADMET & DMPK"/> <meta name="DC.Rights" content=""/> <meta name="DC.Source" content="ADMET and DMPK"/> <meta name="DC.Source.ISSN" content="1848-7718"/> <meta name="DC.Source.Issue" 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Spain and Serra-Húnter Program, Generalitat de Catalunya, Barcelona, Spain </span> </li> <li> <span class="name"> Antonio Llinàs </span> <span class="affiliation"> RIA iMED DMPK, AstraZeneca R&D, Gothenburg, Sweden </span> </li> <li> <span class="name"> Clara Ràfols </span> <span class="affiliation"> Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain </span> </li> <li> <span class="name"> Elisabeth Bosch </span> <span class="affiliation"> Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain </span> </li> <li> <span class="name"> Gergely Völgyi </span> <span class="affiliation"> Semmelweis University, Dept. of Pharmaceutical Chemistry, H-1092 Budapest, Högyes E. u.9, Hungary </span> </li> <li> <span class="name"> Tatjana Verbić </span> <span class="affiliation"> Faculty of Chemistry, University of Belgrade, Dept. of Analytical Chemistry, Studentski trg 12-16, Belgrade 11158, Serbia </span> </li> <li> <span class="name"> Elena Boldyreva </span> <span class="affiliation"> Institute of Solid State Chemistry and Mechanochemistry SB RAS, Kutateladze, 18, Novosibirsk, 630128 Russia </span> </li> <li> <span class="name"> Krisztina Takács-Novák </span> <span class="affiliation"> Semmelweis University, Dept. of Pharmaceutical Chemistry, H-1092 Budapest, Högyes E. u.9, Hungary </span> </li> </ul> </section> <section class="item doi"> <h2 class="label"> DOI: </h2> <span class="value"> <a href="https://doi.org/10.5599/admet.4.2.292"> https://doi.org/10.5599/admet.4.2.292 </a> </span> </section> <section class="item abstract"> <h2 class="label">Abstract</h2> <p>This commentary addresses data quality in equilibrium solubility measurement in aqueous solution. Broadly discussed is the “gold standard” shake-flask (SF) method used to measure equilibrium solubility of ionizable drug-like molecules as a function of pH. Many factors affecting the quality of the measurement are recognized. Case studies illustrating the analysis of both solution and solid state aspects of solubility measurement are presented. Coverage includes drug aggregation in solution (sub-micellar, micellar, complexation), use of mass spectrometry to assess aggregation in saturated solutions, solid state characterization (salts, polymorphs, cocrystals, polymorph creation by potentiometric method), solubility type (water, buffer, intrinsic), temperature, ionic strength, pH measurement, buffer issues, critical knowledge of the pK<sub>a</sub>, equilibration time (stirring and sedimentation), separating solid from saturated solution, solution handling and adsorption to untreated surfaces, solubility units, and tabulation/graphic presentation of reported data. The goal is to present cohesive recommendations that could lead to better assay design, to result in improved quality of measurements, and to impart a deeper understanding of the underlying solution chemistry in suspensions of drug solids.</p> </section> <div class="item downloads_chart"> <h3 class="label"> Downloads </h3> <div class="value"> <canvas class="usageStatsGraph" data-object-type="Submission" data-object-id="292"></canvas> <div class="usageStatsUnavailable" data-object-type="Submission" data-object-id="292"> Download data is not yet available. </div> </div> </div> </div> <div class="entry_details"> <div class="item galleys"> <h2 class="pkp_screen_reader"> Downloads </h2> <ul class="value galleys_links"> <li> <a class="obj_galley_link pdf" href="https://pub.iapchem.org/ojs/index.php/admet/article/view/292/pdf"> PDF </a> </li> </ul> </div> <div class="item published"> <section class="sub_item"> <h2 class="label"> Published </h2> <div class="value"> <span>29-06-2016</span> </div> </section> </div> <div class="item citation"> <section class="sub_item citation_display"> <h2 class="label"> How to Cite </h2> <div class="value"> <div id="citationOutput" role="region" aria-live="polite"> <div class="csl-bib-body"> <div class="csl-entry">Avdeef, A., Fuguet, E., Llinàs, A., Ràfols, C., Bosch, E., Völgyi, G., Verbić, T., Boldyreva, E., & Takács-Novák, K. (2016). Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality. <i>ADMET and DMPK</i>, <i>4</i>(2), 117–178. https://doi.org/10.5599/admet.4.2.292</div> </div> </div> <div class="citation_formats"> <button class="cmp_button citation_formats_button" aria-controls="cslCitationFormats" aria-expanded="false" data-csl-dropdown="true"> More Citation Formats </button> <div id="cslCitationFormats" class="citation_formats_list" aria-hidden="true"> <ul class="citation_formats_styles"> <li> <a aria-controls="citationOutput" href="https://pub.iapchem.org/ojs/index.php/admet/citationstylelanguage/get/acm-sig-proceedings?submissionId=292&publicationId=223" data-load-citation data-json-href="https://pub.iapchem.org/ojs/index.php/admet/citationstylelanguage/get/acm-sig-proceedings?submissionId=292&publicationId=223&return=json" > ACM </a> </li> <li> <a aria-controls="citationOutput" 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Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality | ADMET and DMPK