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Confirm the Structure of Drug to Find Whether the Structure of the Synthetic API is Correct

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The preparation and research links of APIs are at a key position in the chemical drug R&D process, and only the same structure of the prepared compounds can ensure that subsequent quality control studies, pharmacological and toxicological studies and clinical studies are meaningful. Through the structure of the synthesized APIs Confirmation can characterize whether the structure of the prepared intermediate or API is correct. Structural confirmation research refers to the use of physical and chemical methods to analyze the structure of the prepared compound, and infer or verify the structure of the compound based on the obtained data and structural information.

Due to the diversity of the structure of chemical raw materials and the complexity of organic chemical reactions, sometimes only through the control of the preparation process during the preparation of the compound, the consistency of the structure between the batches of the obtained product cannot be guaranteed. Moreover, in compound synthesis, it is often difficult to generate the target compound in a single and quantitative manner according to the experimental design. Therefore, it is necessary to confirm the structure of the prepared product. Structural confirmation can provide sufficient test data and maps, and perform correct analysis to conclusively prove the structure of drug molecules. Whether it is new drug development or generic drug development, drug structure confirmation studies are required.

When confirming the structure of a drug, it is necessary to comprehensively consider the structural characteristics of the compound, the structural problems to be solved, the structural problems that can be solved by various methods, and the current known information of the compound. Framework structure, configuration, crystal water or crystal solvent, and crystal form confirmation are the main contents of structural confirmation.

Skeleton structure

The order and mode of connection between atoms in a molecule are the most basic structural features of organic compound molecules. The framework structure testing techniques include single crystal X-ray diffraction, elemental analysis (or high-resolution mass spectrometry), UV, IR, NMR, etc. The test items should be selected reasonably according to the characteristics of the compound skeleton structure and its complexity, the presence or absence of reference materials and references. For example, compounds with ultraviolet absorption can increase the ultraviolet spectrum for confirmation. Medicilon’s analytical testing platform has a professional and refined scientific research service team, with a total of 80 existing NMR, SFC, UPCC, ICP-MS, IC, LC-MS/MS, Prep-HPLC, DSC, TGA, etc. For more than equipment, the platform has introduced a classified registration sample management system, which implements automated management and clear fees, and mainly serves the fields of chemistry, medicine, and chemical engineering.


The relative position of each atom in space includes geometric isomerism and optical isomerism. Geometric isomers exist in double bonds and alicyclic compounds; these isomers have obvious differences in physical and chemical properties, and there are often obvious differences in physical and chemical constants. The confirmation of the configuration can be tested through physical and chemical constants, chiral resolution comparison analysis, etc., combined with the information provided by the skeleton structure study.

Crystal water or crystal solvent

Drug molecules combine with water and organic solvents through hydrogen bonds to form hydrates/solvates. Compounds containing different amounts of crystal water/crystal solvents may have different physical properties, which may affect the bioavailability of the drug. Clarify the crystal water/solvent content. Crystal water or crystal solvent can be confirmed by comparative tests such as element analysis, loss on drying and moisture inspection, infrared spectroscopy, and thermal analysis.

Confirmation of crystal form

Crystal form is an important characteristic of a compound. For example, polymorphic drugs, due to different crystal lattice structures, some physical and chemical properties (such as melting point, solubility, stability) may be different; and under different conditions, the crystal forms of the same compound Mutual transformation may occur. For example, for poorly soluble solid oral preparations, the crystal form of the raw material drug may affect some properties of the drug and thus may affect the efficacy. The crystal structure can be confirmed by comparative tests such as melting point, infrared spectrum, powder X-ray diffraction, and thermal analysis.

In order to verify that the synthesized compound is the target product tolvaptan, some researchers have used X-ray diffraction techniques to explore its crystal form. The method is to select suitable conditions to cultivate a single crystal suitable for single crystal X-ray diffraction analysis, and analyze the structure of the obtained single crystal data to obtain the three-dimensional structure information of the compound; at the same time, obtain the powder X-ray diffraction of the compound through the single crystal structure data simulation Theoretical spectrum, used for crystal formation research [1]. Results The results of single crystal X-ray diffraction structure analysis showed that the chemical structure and configuration of the synthesized tolvaptan were completely consistent with those reported in the literature; the theoretical powder X-ray diffraction pattern could be used as a crystal form control pattern, and further showed that tolvaptan There is polymorphism.

In short, drug structure confirmation research is the basis of drug research and development. However, due to the huge differences in drug structures and different preparation methods, a scientific, reasonable and feasible structure confirmation program can be effectively formulated according to the structural characteristics and preparation methods of the drug itself. Conduct structural studies of drugs.

[1] Tolvaptan’s structure confirmation and crystal form discussion [J].

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