vedomostiregmedРегуляторные исследования и экспертиза лекарственных средствRegulatory Research and Medicine Evaluation3034-30623034-3453Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/1991-2919-2020-10-1-63-76vedomostiregmed-262Research ArticleМЕТОДИЧЕСКИЕ МАТЕРИАЛЫMETHODICAL APPROACHESПроблема проявления динамических процессов при решении задачи подтверждения подлинности органических соединений методом ЯМР-спектроскопииThe Problem of Dynamic Process Manifestation in Identification of Organic Compounds by NMR Spectroscopyhttps://orcid.org/0000-0002-9133-0835КузьминаН. Е.Kuz’minaN. E.

Кузьмина Наталия Евгеньевна - доктор химических наук.

Петровский бульвар, д. 8, стр. 2, Москва, 127051

Natalia E. Kuz’mina - Dr. Sci. (Chem.).

8/2 Petrovsky Blvd, Moscow 127051

 

KuzminaN@expmed.ruhttps://orcid.org/0000-0003-1310-4477МоисеевС. В.MoiseevS. V.

Моисеев Сергей Владимирович - кандидат химических наук, доцент.

Петровский бульвар, д. 8, стр. 2, Москва, 127051

 

Sergey V. Moiseev - Cand. Sci. (Chem.).

8/2 Petrovsky Blvd, Moscow 127051

MoiseevSV@expmed.ruhttps://orcid.org/0000-0001-8752-5245ЛутцеваА. И.LuttsevaA. I

Лутцева Анна Ивановна - кандидат фармацевтических наук.

Петровский бульвар, д. 8, стр. 2, Москва, 127051

Anna I. Luttseva - Cand. Sci. (Pharm.).

8/2 Petrovsky Blvd, Moscow 127051

Lutceva@expmed.ruФедеральное государственное бюджетное учреждение “Научный центр экспертизы средств медицинского применения” Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation2020140120201016376Copyright © Кузьмина Н.Е., Моисеев С.В., Лутцева А.И., 20202020Кузьмина Н.Е., Моисеев С.В., Лутцева А.И.Kuz’mina N.E., Moiseev S.V., Luttseva A.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.vedomostincesmp.ru/jour/article/view/262

Зависимость числа, формы и положения линий в ЯМР-спектре от динамических процессов создает определенные трудности при подтверждении подлинности фармацевтической субстанции методом ЯМР-спектроскопии.

Цель работы

Цель работы: рассмотреть примеры проявления внутримолекулярных динамических процессов, отрицательно влияющих на процедуру идентификации органического соединения методом ЯМР, и показать возможности и ограничения способов их снижения.

Материалы и методы

Материалы и методы: для иллюстрации отрицательных эффектов динамических процессов использованы ЯМР-спектры 1Н и 13С лекарственных субстанций: бусерелина ацетат, валсартан, гозерелина ацетат, йопромид, клопидогрела гидросульфат, омепразол, пророксан, рисперидон, трипторелина ацетат, эналаприла малеат. Пространственное строение конформеров устанавливали на основе данных 1Н-1Н ROESY экспериментов. Квантово-химический расчет геометрических и термодинамических характеристик различных конформеров проведен методом РМ3, электронных – АМ1 с использованием программы HyperChem.

Результаты

Результаты: рассмотрены наиболее часто встречающиеся в экспертной практике внутримолекулярные динамические процессы: пирамидальная инверсия конфигурации атома азота в гетероциклическом соединении (рисперидон, пророксан, клопидогрел), вращение фрагментов молекул вокруг амидной связи (валсартан, йопромид, эналаприл), прототропные перегруппировки (бусерелин, гозерелин, омепразол, трипторелин). Изменение скорости обмена объяснено с позиции изменения системы внутри- и межмолекулярных невалентных взаимодействий.

Выводы

Выводы: показано, что использование традиционных приемов увеличения скорости динамических процессов (увеличение температуры и смена растворителя) не всегда позволяет устранить отрицательные эффекты внутримолекулярных превращений. Ограничения в применении способов нивелирования спектральных проявлений динамических процессов связаны с сильными внутримолекулярными невалентными взаимодействиями, которые препятствуют переводу скорости динамического процесса в область быстрого обмена. Проявление динамических процессов необходимо учитывать экспертам и производителям при подтверждении подлинности фармацевтических субстанций методом ЯМР-спектроскопии.

The number, shape and position of NMR spectral lines depend on dynamic processes, and this creates certain difficulties in identification of pharmaceutical substances by NMR spectroscopy. The aim of the paper was to study instances of manifestation of intramolecular dynamic processes that affect identification of organic compounds by NMR, and to illustrate the potential of the methods used for their reduction, as well as associated problems.

Materials and methods

Materials and methods: 1H and 13C spectra of the following pharmaceutical substances: «buserelin acetate», «valsartan», «goserelin acetate», «iopromide», «clopidogrel hydrogensulfate», «omeprazole», «proroxan», «risperidone», «triptorelin acetate», and «enalapril maleate» were used to demonstrate negative effects of dynamic processes. The spatial structures of conformers were established by 1H-1H ROESY experiments. The quantum-chemical calculation of geometric and thermodynamic characteristics of different conformers was carried out by the PM3 method, and electronic characteristics—by the AM1 method with the help of the HyperChem software.

Results

Results: the authors analysed intramolecular dynamic processes which are most commonly encountered in expert work: pyramidal inversion of nitrogen in a heterocyclic compound (risperidone, proroxan, clopidogrel), rotation of molecular fragments around the amide bond (valsartan, iopromide, enalapril), prototropic rearrangements (buserelin, goserelin, omeprazole, triptorelin). The change in exchange rates was explained from the perspective of the change in the system of intra- and intermolecular nonvalent interactions.

Conclusions

Conclusions: the use of traditional methods for increasing the rate of dynamic processes (increasing the temperature and changing the solvent) does not always eliminate the negative effects of intramolecular transformations. Methods of smoothing the spectral manifestations of dynamic processes have limited application due to strong intramolecular nonvalent interactions which prevent the conversion of the dynamic process rate into fast exchange. Experts and manufacturers should take into account the manifestation of dynamic processes during identification of pharmaceutical substances by NMR spectroscopy.

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