rmjournalЭталоны. Стандартные образцыMeasurement Standards. Reference Materials2687-0886D. I. Mendeleyev Institute for Metrology10.20915/2077-1177-2023-19-3-31-43rmjournal-401Research ArticleСтандартные образцыReference materialsМетрологическое обеспечение в области изотермической калориметрии титрования: перспективы разработки стандартных образцовMetrological Support in the Field of Isothermal Titration Calorimetry: Prospects for the Development of Reference Materialshttps://orcid.org/0000-0003-0401-5405МишинаК. А.MishinaK. A.

Мишина Карина Андреевна –  инженер лаборатории эталонов и научных исследований в области калориметрии горения и особо чистых органических веществ для метрологических целей 

190005, г. Санкт-Петербург, Московский пр., 19 

Karina A. Mishina – Engineer of the Laboratory for Measurement Standards and Scientific Research in the field of Combustion Calorimetry and High-Purity Organic Substances for Metrological Purposes

19 Moskovsky ave., St. Petersburg, 190005

k.a.mishina@vniim.ruФГУП «Всероссийский научно-исследовательский институт метрологии им. Д. И. Менделеева»РоссияD. I. Mendeleyev Institute for MetrologyRussian Federation2023200720231933143Copyright © Мишина К.А., 20232023Мишина К.А.Mishina K.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.rmjournal.ru/jour/article/view/401

Изотермическая калориметрия титрования (ИТК) позволяет исследовать тепловые эффекты различных химических и физико-химических процессов, в том числе и процессов растворения. Данный метод является сравнительно новым. Поэтому активное расширение области его применения выявило ряд проблем. Например, в рассматриваемой статье поднимается проблема недостаточного метрологического обеспечения изотермических калориметров титрования, что приводит к несогласованности результатов, полученных на различных моделях калориметров, а также к их несоответствию литературным данным. Используемые в настоящее время электрическая и химическая процедуры калибровки калориметров не являются универсальными и имеют ряд ограничений при их применении. Целью настоящего исследования является выработка основных подходов к созданию сертифицированных стандартных образцов с аттестованным значением количества теплоты физико-химических взаимодействий с установленной метрологической прослеживаемостью к основным единицам SI.

В ходе выполнения исследования проведен анализ состояния метрологического обеспечения в области измерений ИТК, сформулированы основные требования к веществам – кандидатам на роль СО; оценена целевая неопределенность значения интегральной теплоты разведения растворов пропанола-1 путем анализа характеристик рабочих средств измерений, что позволило установить требования к методу измерений, применяемому для характеризации СО. Предложен и опробован метод определения аттестованного значения количества интегральной теплоты разведения, обеспечивающий прослеживаемость к государственному первичному специальному эталону единицы количества теплоты в области калориметрии растворения и реакций ГЭТ 133.

В перспективе для реализации проекта необходимо продолжение исследований с целью получения экспериментальных данных по характеризации, оценке однородности и стабильности материала СО, обработки полученных результатов и оценки неопределенности аттестованного значения, что позволит завершить разработку стандартных образцов.

Isothermal titration calorimetry (ITC) allows studying the thermal effects of various chemical and physicochemical processes, including dissolution processes. This method is relatively new. Therefore, the active expansion of the scope of its application has revealed a number of problems. For instance, the article raises the problem of insufficient metrological support for isothermal titration calorimeters, which leads to inconsistency of the results obtained on different models of calorimeters, as well as their inconsistency with literature data. The current electrical and chemical calibration procedures for calorimeters are not universal and have a number of limitations in their application.

The purpose of the research is to develop basic approaches to the creation of certified reference materials with a certified value of heat of physicochemical interactions with established metrological traceability to the base SI units.

In the course of the study, the analysis of the state of metrological support in the field of ITC measurements was carried out, the main requirements for candidate substances to RMs were formulated; the target uncertainty of the value of the integral heat of dilution of propanol-1 solutions was estimated by analyzing the characteristics of working measuring instruments, which made it possible to establish requirements for the measurement method applied to characterize RMs. A method for determining the certified value of the integral heat of dilution that provides traceability to the State primary special standard of the unit of heat in the field of dissolution calorimetry and reactions GET 133 has been proposed and tested.

In order to implement the project, it is necessary to continue research in order to obtain experimental data on the characterization, assessment of the homogeneity and stability of the material, processing the obtained results, and estimating the uncertainty of the certified value, which will make it possible to complete the development of reference materials.

изотермическая калориметрия титрованиянеопределенность измеренийхимическая калибровка ИКТстандартные образцыэталонisothermal titration calorimetrymeasurement uncertaintychemical calibration of ITCreference materialsstandardИсследование выполнено в рамках совершенствования государственного первичного специального эталона единицы количества теплоты в области калориметрии растворения и реакций ГЭТ 133-2012. Измерения были выполнены на оборудовании ФГУП «ВНИИМ им. Д. И. Менделеева».The study was carried out as part of the improvement of the State primary special standard of the unit of heat in the field of dissolution calorimetry and reactions GET 133-2012. The measurements were performed on the equipment of the D. I. Mendeleyev Institute for Metrology.ReferencesSarge S. M., Höhne G. W. H., Hemminger W. Calorimetry: fundamentals, instrumentation and applications. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA, 2014. 280 p. https://doi.org/10.1002/9783527649365Sarge S. M., Höhne G. W. H., Hemminger W. (2014) Calorimetry: fundamentals, instrumentation and applications. Weinheim: WileyVCH Verlag GmbH & Co. KGaA; 280 p. https://doi.org/10.1002/9783527649365Kabiri M., Unsworth L. Application of isothermal titration calorimetry for characterizing thermodynamic parameters of biomolecular interactions: peptide self-assembly and protein adsorption case studies // Biomacromolecules. 2014. Vol. 15. P. 3463–3473. https://doi.org/10.1021/bm5004515Kabiri M., Unsworth L. Application of isothermal titration calorimetry for characterizing thermodynamic parameters of biomolecular interactions: peptide self-assembly and protein adsorption case studies. Biomacromolecules. 2014;15:3463–3473. https://doi.org/10.1021/bm5004515Survey of the year 2008: applications of isothermal titration calorimetry / R. J. Falconer [et al.] // Journal of Molecular Recognition. 2010. Vol. 23, № 5. P. 395–413. https://doi.org/10.1002/jmr.1025Falconer R. J., Penkova A., Jelesarov I., Collins B. M. Survey of the year 2008: applications of isothermal titration calorimetry. Journal of Molecular Recognition. 2010;23(5):395–413. https://doi.org/10.1002/jmr.1025Falconer R. J., Collins B. M. Survey of the year 2009: applications of isothermal titration Calorimetry // Journal of Molecular Recognition. 2011. Vol. 24, № 1. P. 1–16. https://doi.org/10.1002/jmr.1073Falconer R. J., Collins B. M. Survey of the year 2009: applications of isothermal titration Calorimetry. Journal of Molecular Recognition. 2011;24(1):1–16. https://doi.org/10.1002/jmr.1073Prozeller D., Morsbach S., Landfester K. Isothermal titration calorimetry as a complementary method for investigating nanoparticle– protein interactions // Nanoscale. 2019. Vol. 11, № 41. P. 19265–19273. https://doi.org/10.1039/c9nr05790kProzeller D., Morsbach S., Landfester K. Isothermal titration calorimetry as a complementary method for investigating nanoparticle– protein interactions. Nanoscale. 2019;11(41):19265–19273. https://doi.org/10.1039/c9nr05790kWadso I., Goldberg R. N. Standards in isothermal microcalorimetry // Pure and Applied Chemistry. 2001. Vol. 73, № 10. P. 1625– 1639. https://doi.org/10.1351/pac200173101625Wadso I., Goldberg R. N. Standards in isothermal microcalorimetry. Pure and Applied Chemistry. 2001;73(10):1625–1639. https://doi.org/10.1351/pac200173101625The Ca2+–EDTA chelation as standard reaction to validate Isothermal Titration Calorimeter measurements (ITC) / C. Rafols [et al.] // Talanta. 2016. Vol. 154. P. 354–359. https://doi.org/10.1016/j.talanta.2016.03.075Rafols C. et al. The Ca2+–EDTA chelation as standard reaction to validate Isothermal Titration Calorimeter measurements (ITC). Talanta. 2016;154:354–359. https://doi.org/10.1016/j.talanta.2016.03.075Titration calorimetry standards and the precision of isothermal titration calorimetry data / L. Baranauskiene [et al.] // International Journal of Molecular Sciences. 2009. Vol. 10, № 6. P. 2752–2762. https://doi.org/10.3390/ijms10062752Baranauskiene L., Petrikaitė V., Matulienė J., Matulis D. Titration calorimetry standards and the precision of isothermal titration calorimetry data. International Journal of Molecular Sciences. 2009;10(6):2752–2762. https://doi.org/10.3390/ijms10062752Repeatability, precision, and accuracy of the enthalpies and Gibbs energies of a protein–ligand binding reaction measured by isothermal titration calorimetry / V. Paketurytė [et al.] // European Biophysics Journal. 2019. Vol. 48, № 11. P. 139–152. https://doi.org/10.1007/s00249–018–1341-zPaketurytė V., Linkuvienė V., Krainer G., Chen W. Y., Matulis D. Repeatability, precision, and accuracy of the enthalpies and Gibbs energies of a protein–ligand binding reaction measured by isothermal titration calorimetry. European Biophysics Journal. 2019;48(11):139–152. https://doi.org/10.1007/s00249–018–1341-zDean J. A. Lange’s handbook of chemistry. New York, USA: McGraw-Hill, 1999.Dean J. A. Lange’s handbook of chemistry. New York, USA: McGraw-Hill; 1999.Christensen J. J., Hansen L. D., Izatt R. M. Handbook of Proton Ionizations Heats. New York, USA: WileyInterscience, Hoboken, 1976.Christensen J. J., Hansen L. D., Izatt R. M. Handbook of Proton Ionizations Heats. New York, USA: WileyInterscience; 1976.The ABRF-MIRG’02 study: assembly state, thermodynamic, and kinetic analysis of an enzyme/inhibitor interaction / D. G. Myszka [et al.] // Journal of Biomolecular Techniques. 2003. Vol. 14, № 4. P. 247–269.Myszka D. G., Abdiche Y. N., Arisaka F., Byron O., Eisenstein E., Hensley P. The ABRF-MIRG’02 study: assembly state, thermodynamic, and kinetic analysis of an enzyme/inhibitor interaction. Journal of Biomolecular Techniques. 2003;14(4):247–269.Calibration of nanowatt isothermal titration calorimeters with overflow reaction vessels / N. A. Demarse [et al.] // Analytical Biochemistry. 2011. Vol. 41, № 7. P. 247–255. https://doi.org/10.1016/j.ab.2011.06.014Demarse N. A., Quinn C. F., Eggett D. L., Russell D. J., Hansen L. D. et al. Calibration of nanowatt isothermal titration calorimeters with overflow reaction vessels. Analytical Biochemistry. 2011;417(2):247–255. https://doi.org/10.1016/j.ab.2011.06.014A multi-laboratory benchmark study of isothermal titration calorimetry (ITC) using Ca2+ and Mg2+ binding to EDTA / A. VelazquezCampoy [et al.] // European Biophysics Journal. 2021. Vol. 50, № 3–4. P. 429–451. https://doi.org/10.1007/s00249-021-01523-7Velazquez-Campoy A., Claro B., Abian O., Höring J., Bourlon L., Claveria-Gimeno R. A multi-laboratory benchmark study of isothermal titration calorimetry (ITC) using Ca2+ and Mg2+ binding to EDTA. European Biophysics Journal. 2021;50(3–4):429–451. https://doi.org/10.1007/s00249-021-01523-7Chemical calibration of isothermal titration calorimeters: An evaluation of the dilution of propan-1-ol into water as a test reaction using different calorimeters, concentrations, and temperatures / R. Adao [et al.] // Journal of Chemical Thermodynamics. 2012. Vol. 52. P. 57–63. https://doi.org/10.1016/j.jct.2011.12.018Adao R., Bai G. Y., Loh W., Bastos M. Chemical calibration of isothermal titration calorimeters: An evaluation of the dilution of propan-1-ol into water as a test reaction using different calorimeters, concentrations, and temperatures. Journal of Chemical Thermodynamics. 2012;52:57–63. https://doi.org/10.1016/j.jct.2011.12.018Kantonen S. A., Henriksen N. M., Gilson M. K. Evaluation and minimization of uncertainty in ITC binding measurements: Heat error, concentration error, saturation, and stoichiometry // Biochimica et Biophysica Acta. 2017. Vol. 1861, № 2. P. 485–498. https://doi.org/10.1016/j.bbagen.2016.09.002Kantonen S. A., Henriksen N. M., Gilson M. K. Evaluation and minimization of uncertainty in ITC binding measurements: Heat error, concentration error, saturation, and stoichiometry. Biochimica et Biophysica Acta. 2017;1861(2):485–498. https://doi.org/10.1016/j.bbagen.2016.09.002Bayesian analysis of isothermal titration calorimetry for binding thermodynamics / T. H. Nguyen [et al.] // PLOS ONE. 2018. Vol. 13, № 9. P. 1–26. https://doi.org/10.1371/journal.pone.0203224Nguyen T. H., Rustenburg A. S., Krimmer S. G., Zhang H., Clark J. D., Novick P. A. et al. Bayesian analysis of isothermal titration calorimetry for binding thermodynamics. PLOS ONE. 2018;13(9):1–26. https://doi.org/10.1371/journal.pone.0203224Hansen L. D., Quinn C. Obtaining precise and accurate results by ITC // European Biophysics Journal. 2019. Vol. 48, № 8. P. 825– 835. https://doi.org/10.1007/s00249-019-01399-8Hansen L. D., Quinn C. Obtaining precise and accurate results by ITC. European Biophysics Journal. 2019;48(8):825–835. https://doi.org/10.1007/s00249-019-01399-8Tellinghuisen J., Chodera J. D. Systematic errors in isothermal titration calorimetry: Concentrations and baselines // Analytical Biochemistry. 2011. Vol. 414, № 2. P. 297–299. https://doi.org/10.1016/j.ab.2011.03.024Tellinghuisen J., Chodera J. D. Systematic errors in isothermal titration calorimetry: Concentrations and baselines. Analytical Biochemistry. 2011;414(2):297–299. https://doi.org/10.1016/j.ab.2011.03.024Usually overlooked problems related with measurements of high-heat efects using power compensation isothermal titration calorimetry / Ž. Medoš [et al.] // Journal of Thermal Analysis and Calorimetry. 2021. Vol. 145. P. 87–96. https://doi.org/10.1007/s10973-020-09663-2Medoš Ž., Čobanov I., Bešter-Rogač M., Šarac B. Usually overlooked problems related with measurements of high-heat efects using power compensation isothermal titration calorimetry. Journal of Thermal Analysis and Calorimetry. 2021;145:87–96. https://doi.org/10.1007/s10973-020-09663-2Wadsö I. Needs for standards in isothermal microcalorimetry // Thermochimica Acta. 2000. Vol. 347, № 1–2. P. 73–77. https://doi.org/10.1016/S0040–6031(99)00418-9Wadsö I. Needs for standards in isothermal microcalorimetry. Thermochimica Acta. 2000;347(1–2):73–77. https://doi.org/10.1016/S0040–6031(99)00418-9Darnell A., SikkLy L., Porosk P. Uncertainty of small enthalpy effects measured by isothermal calorimetric titration // Journal of Chemical Metrology. 2021. Vol. 15, № 1. P. 25–37. https://doi.org/10.25135/jcm.57.21.03.1994Darnell A., SikkLy L., Porosk P. Uncertainty of small enthalpy effects measured by isothermal calorimetric titration. Journal of Chemical Metrology. 2021;15(1):25–37. https://doi.org/10.25135/jcm.57.21.03.1994Gherrou A., Buschmann H.-J., Schollmeyer E. Complex formation of crown ethers and cryptands with Ba2+ in the biphasic system chloroform/water studied by titration calorimetry // Thermochimica Acta. 2005. Vol. 425, № 1–2. P. 1–5. https://doi.org/10.1016/S0040–6031(03)00369-1Gherrou A., Buschmann H.-J., Schollmeyer E. Complex formation of crown ethers and cryptands with Ba2+ in the biphasic system chloroform/water studied by titration calorimetry. Thermochimica Acta. 2005;425(1–2):1–5. https://doi.org/10.1016/S0040–6031(03)00369-1Buschmann H. J., Mutihac R. C., Schollmeyer E. Complex formation of 18-crown-6 with metal cations and ammonium ions in dioxane– water mixtures // Thermochimica Acta. 2008. Vol. 472, № 1–2. P. 17–19. https://doi.org/10.1016/j.tca.2008.03.010Buschmann H. J., Mutihac R. C., Schollmeyer E. Complex formation of 18-crown-6 with metal cations and ammonium ions in dioxane–water mixtures. Thermochimica Acta. 2008;472(1–2):17–19. https://doi.org/10.1016/j.tca.2008.03.010Boyce S. E., Tellinghuisen J., Chodera J. D. Avoiding accuracy-limiting pitfalls in the study of protein-ligand interactions with isothermal titration Calorimetry // Preprint submitted to Analytical Biochemistry. 2015. https://doi.org/10.1101/023796Boyce S. E., Tellinghuisen J., Chodera J. D. Avoiding accuracy-limiting pitfalls in the study of protein-ligand interactions with isothermal titration Calorimetry. Preprint submitted to Analytical Biochemistry. 2015. https://doi.org/10.1101/023796Turnbull W. B., Daranas A. H. On the value of c: Can low affinity systems be studied by isothermal titration calorimetry? Journal of the American Chemical Society. 2003. Vol. 125, № 48. P. 14859–14866. https://doi.org/10.1021/ja036166sTurnbull W. B., Daranas A. H. On the value of c: Can low affinity systems be studied by isothermal titration calorimetry? Journal of the American Chemical Society. 2003;125(48):14859–14866. https://doi.org/10.1021/ja036166sImpact of protein and ligand impurities on ITC-derived protein–ligand thermodynamics / S. Grüner [et al.] // Biochimica et Biophysica Acta. 2014. Vol. 1840, № 9. P. 2843–2850. https://doi.org/10.1016/j.bbagen.2014.04.018Grüner S., Neeb M., Barandun L. J., Sielaff F., Hohn Ch. Impact of protein and ligand impurities on ITC-derived protein–ligand thermodynamics. Biochimica et Biophysica Acta 2014;1840(9):2843–2850. https://doi.org/10.1016/j.bbagen.2014.04.018Isothermal titration calorimetry for drug design: Precision of the enthalpy and binding constant measurements and comparison of the instruments / V. Linkuviene [et al.] // Analytical Biochemistry. 2016. Vol. 515. P. 61–64. https://doi.org/10.1016/j.ab.2016.10.005Linkuviene V., Krainer G., Chen W. Y., Matulis D. Isothermal titration calorimetry for drug design: Precision of the enthalpy and binding constant measurements and comparison of the instruments. Analytical Biochemistry. 2016;515:61–64. https://doi.org/10.1016/j.ab.2016.10.005

The authors declare that there are no conflicts of interest present.