ИСТИНА

Основной научной проблемой предлагаемых исследований является получение высокоточных структурных данных с помощью рентгеновской дифракции порошковых и мелкокристаллических образцов признанных или потенциальных фармацевтических субстанций – органических соединений сложного строения, для которых невозможно или крайне затруднительно получение структурной информации иными физико-химическими методами (например, с помощью монокристальной рентгеновской или электронной дифракции).

The development in many areas of chemistry, materials science, biology, pharmacology, and related interdisciplinary research requires reliable data about the atomic and molecular structure of the objects under study for these disciplines. The most important task in obtaining such data is to establish information on the molecular and crystal structure of various compounds forming functional materials or pharmaceutical compositions. Although a number of problems can be solved with laboratory diffractometric equipment, the possibilities of powder diffraction, more common than single crystal diffraction, to obtain accurate structural data, especially in cases where single crystal production is not possible, are limited. In the course of the project, it is planned to develop a methodology for providing a powder X-ray diffraction experiment involving quantum calculations to obtain high-precision data on the molecular and crystal structure of compounds. A number of solid forms of recognized active pharmaceutical ingredients, the crystal structure of which is still unknown or arises some doubts will be selected as study objects. Among those are ticagrelor (active against acute coronary syndrome, form III), sofosbuvir (medicinal product for the treatment of hepatitis C, form VII), tofacitinib (rheumatoid arthritis remedy), vandetanib and its salts (anticancer activity, brand name Caprelsa), palbociclib and its salts, free base and salts of osimertinib, dapagliflozin, salts of ibrutinib; including polymorphs, salts, solvates and co-crystals, as well as compositions based on them. As such compositions, it is intended to use inert substances included in the tablets (starch, silica and titanium, lactose monohydrate, cellulose). Such studies are fundamentally new and have not been provided before. To achieve the stated goals, it is planned to use synchrotron radiation from the "Belok" and "Structural Chemistry" stations of the Kurchatov National Research Center using powder samples cooled to low temperatures in order to increase the intensity of high-angle reflexes and to reduce thermal motion of atoms as well. Single crystal X-ray diffraction, laboratory powder X-ray diffraction, quantum chemical calculations, solid state NMR spectroscopy, DSC/TGA will be used as auxiliary methods. The use of additional techniques would allow preliminary research, independently prove the reliability of the structure solution and identify the factors responsible for structure stabilization. The research team has wide experience in solving similar problems, in particular, used to work on the development of a methodology for checking structural models obtained by solution and refinement of powder X-ray diffraction data measured on laboratory equipment using quantum chemical calculations and specific statistical processing of data. This technique in some aspects will be used to perform this study, but cannot be completely transferred to synchrotron diffraction data due to differences in the nature of the measurement and processing. During the RSF grant, 20-13-00241 participants demonstrated the skills of synthesis and crystallization of various salts, solvates and co-crystals of recognized active pharmaceutical ingredients and their inclusion compounds based on metal sulfides of a layered structure. Research on this project will reduce the optimization of the production of new drugs, identify the contributions of various factors to the accuracy of structural data obtained by powder X-ray diffraction and adapt methods for refining structural data for common refinement programs.