WO2022017549A2 - Réactif et procédé utilisés pour une analyse de structure chirale moléculaire du médicament ibuprofène - Google Patents

Réactif et procédé utilisés pour une analyse de structure chirale moléculaire du médicament ibuprofène Download PDF

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Publication number
WO2022017549A2
WO2022017549A2 PCT/CN2021/119472 CN2021119472W WO2022017549A2 WO 2022017549 A2 WO2022017549 A2 WO 2022017549A2 CN 2021119472 W CN2021119472 W CN 2021119472W WO 2022017549 A2 WO2022017549 A2 WO 2022017549A2
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WIPO (PCT)
Prior art keywords
ibuprofen
ion
chiral structure
reagent
chiral
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PCT/CN2021/119472
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English (en)
Chinese (zh)
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WO2022017549A3 (fr
Inventor
方向
戴新华
江游
彭涛
徐福兴
古连城
吴芳玲
丁传凡
Original Assignee
中国计量科学研究院
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Priority claimed from CN202010703682.8A external-priority patent/CN114034759B/zh
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Publication of WO2022017549A2 publication Critical patent/WO2022017549A2/fr
Publication of WO2022017549A3 publication Critical patent/WO2022017549A3/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
    • G01N27/622—Ion mobility spectrometry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/38—Diluting, dispersing or mixing samples
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
    • G01N27/622—Ion mobility spectrometry
    • G01N27/623—Ion mobility spectrometry combined with mass spectrometry

Definitions

  • the invention relates to the technical field of analysis and testing, in particular to a reagent and a method for analyzing the molecular chiral structure of drug ibuprofen.
  • Molecules are the most basic building blocks of the material world, and chirality is one of the basic properties of molecules.
  • a chiral molecule refers to a molecule that has two stereoisomers that are both physical and mirror images of each other, one of which is called a left-handed body, and the other is called a right-handed body.
  • the left-handed body and the right-handed body are like the left hand and the right hand of a human being, they are symmetrical, but they cannot be superimposed.
  • Ibuprofen is a common antipyretic and analgesic drug, belonging to non-steroidal anti-inflammatory drugs. Clinically, it is widely used for analgesic and anti-inflammatory effects.
  • Ibuprofen molecule is a chiral molecule, its molecule contains a chiral molecule, its molecular formula and structural formula are:
  • the molecular formula is:
  • a common method for molecular analysis of chiral drugs is to first separate molecules containing two or more chiral structures, that is, chiral drug resolution.
  • Commonly used separation methods are: chiral high performance liquid chromatography, chiral capillary electrophoresis, chiral gas chromatography, chiral thin layer chromatography, circular dichroism, nuclear magnetic resonance and supercritical fluid chromatography. Then, perform structural analysis on the separated molecular system containing only a single chiral structure to obtain its chiral properties, that is, it belongs to left-handed or right-handed.
  • Another method for analyzing the structure of chiral molecules is the so-called derivatization, that is, using chiral molecules with different structures and other molecules, such as different reactivity or reaction processes of chiral reagents, to produce different product molecules, and then Different reaction products were analyzed to obtain the structure and content information of the original chiral molecules.
  • the existing methods for analyzing the structure of chiral molecules must first separate or derivatize the chiral molecules before they can be analyzed.
  • Mass spectrometry is the most commonly used molecular or atomic mass analysis technology. It can quickly analyze the mass-to-charge ratio or mass information of different atoms or molecules, but for chiral molecules with exactly the same mass-to-charge ratio and molecular mass Powerless.
  • the ion mobility spectrometry technique can analyze molecules with different structures, such as isomers. Its working principle and process are: firstly generate ions of the sample to be analyzed, and then introduce these ions into the ion mobility spectrum. Mobility spectroscopy was performed under low vacuum conditions. In the ion mobility spectrum, the sample ions do directional motion under the action of the electric field, and continuously collide with the inactive working gases in the mobility spectrum, such as nitrogen, argon, etc.
  • the purpose of the present invention is to overcome the defects of the prior art, and to provide a reagent and method for analyzing the molecular chiral structure of the drug ibuprofen.
  • the technical scheme for realizing the object of the present invention is: a reagent for analyzing the molecular chiral structure of drug ibuprofen, the reagent comprises ibuprofen molecule mixed with solvent, gamma cyclodextrin and divalent calcium ion-containing reagent. compound.
  • the concentration of the ibuprofen molecule in the above technical solution is 10 -12 to 1 mol/liter
  • the concentration of the gamma cyclodextrin is 10 -12 to 1 mol/liter
  • the concentration of the compound containing divalent calcium ions is 10 -12 to 1 mol/liter.
  • the concentration is 10 ⁇ 12 to 1 mol/liter
  • the relative ratio between the ibuprofen molecule, the gamma cyclodextrin and the compound containing divalent calcium ions is not limited.
  • the ibuprofen molecule described in the above technical solution has two chiral structures of left-handed R and right-handed S.
  • the compound containing divalent calcium ions described in the above technical solution is one of salts containing calcium ions, alkalis containing calcium ions, and complexes containing calcium ions.
  • the gamma cyclodextrins described in the above technical solutions also include derivatives of gamma cyclodextrins.
  • the solvent described in the above technical solution is two or more of water, methanol, ethanol, ether, acetonitrile and acetone.
  • a method for analyzing the molecular chiral structure of drug ibuprofen comprising the following steps:
  • S3 measure the ion collision cross section of the monovalent positive ion of ibuprofen-gamma cyclodextrin-calcium ion, or use the experimental device of ion mobility spectrometry to measure the monovalent positive ion of ibuprofen-gamma cyclodextrin-calcium ion
  • the ion mobility spectrum of the ions can obtain the chiral structure information of the ibuprofen molecule.
  • the ion source is one of an electrospray ionization ion source, a laser-assisted desorption ionization ion source, and a desorption electrospray ionization ion source.
  • the mixture of ibuprofen-gamma cyclodextrin-calcium ion is in liquid state or in solid state prepared from liquid state according to experimental analysis.
  • the experimental device described in the above technical solution is one of the ion mobility spectrum and the composite experimental device including the ion mobility spectrum.
  • the present invention has following positive effect:
  • the present invention provides a new reagent and method for analyzing the molecular chiral structure of ibuprofen, which simply combines the molecular sample of ibuprofen with ⁇ -cyclodextrin, a compound containing calcium ions (Ca 2+ ).
  • the method provided by the present invention can also obtain information on their relative contents.
  • the method for analyzing the chiral structure of the ibuprofen molecule provided by the present invention is simple, does not require pre-chiral separation or derivatization of the ibuprofen chiral molecule, and the chemical samples used are easy to obtain, cheap and free of charge. Poisonous and harmless. Compared with the commonly used methods, it has many advantages.
  • Figure 1 is the molecular structural formula of ibuprofen, the position of the chiral carbon is shown in the figure,
  • Fig. 2 is a schematic diagram of the molecular structure of cyclodextrin
  • FIG. 3 is a schematic diagram showing the results of ion mobility spectra of two chiral molecule samples of ibuprofen and ⁇ CD ( ⁇ -cyclodextrin), a compound containing calcium ions (Ca 2+ ) obtained in Example 1 of the present invention.
  • the experimental device used in the present invention is a commercial ion mobility spectrometry-mass spectrometry instrument.
  • the TIMS-TOFMS instrument produced by Bruke Company analyzes the chiral structure of the ibuprofen molecule, and the experimental result is shown in FIG. 3 . It is clear from the experimental results that ibuprofen molecules with different chiral structures can be easily distinguished.
  • the used compound containing calcium ions can be salts containing calcium ions, such as: CaCl 2 , Ca(NO 3 ) 2 , CaSO 4 calcium halide (except F), calcium nitrate, calcium chlorate, perchloric acid Calcium, calcium bicarbonate, calcium dihydrogen phosphate, calcium gluconate, calcium hydrogen phosphate, calcium lactate, etc., it can also be an alkali containing calcium ions, such as Ca(OH) 2 , or a complex containing ions, etc. Compounds that can give Ca 2+ in aqueous solutions.
  • the used ⁇ -cyclodextrin refers to a common chemical reagent whose molecular formula is: C 48 H 80 O 40 , its molecular weight is 1297.12, and has the molecular structure shown in FIG. 2 .
  • ESI electrospray ionization
  • the obtained mass spectrum signal intensity and ion mobility spectrum signal intensity are related to the concentration of the sample in the solution, according to the ion mobility spectrum intensity corresponding to a certain chiral 3-aminomethyl-5-methylhexanoic acid molecule , the content of such chiral ibuprofen molecules contained in the solution can be calculated, that is, quantitative analysis can be realized.
  • a solution of suitable concentration can be prepared according to needs, that is, the concentration of calcium chloride (CaCl 2 ), ⁇ -cyclodextrin ( ⁇ CD) and ibuprofen molecules in the solution can be determined according to the needs of the experiment.
  • concentration of each compound in the mixed solution may be the same or different.
  • the type and relative content of the solvent used in the solution can be prepared according to the needs, that is, it can be a mixture of acetonitrile and methanol, or a mixture of water, acetonitrile and methanol, or water, methanol, ethanol, Mixing of any two or more reagents in common reagents such as acetonitrile, propionitrile, formic acid, acetone, etc., and the ratio of each reagent in the mixed solution is not limited, which is determined according to experimental needs.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pathology (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Electrochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • Molecular Biology (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un réactif et un procédé utilisés pour une analyse de structure chirale moléculaire du médicament ibuprofène ; ledit réactif comprend des molécules d'ibuprofène mélangées avec un solvant, la gamma-cyclodextrine et des composés contenant des ions calcium divalents. L'invention consiste à : d'abord, combiner un échantillon de molécule chirale d'ibuprofène et la gamma-cyclodextrine (γ-CD) ; formuler un composé contenant des ions calcium dans une solution ; ensuite, utiliser un appareil de génération d'ions, par exemple, un appareil d'ionisation par électronébulisation, pour préparer et produire les ions monovalents complexes de « ibuprofène – γ-CD – ions calcium » ; enfin, utiliser un appareil de spectrométrie de mobilité ionique apte à mesurer la section transversale des collisions ioniques pour mesurer les spectres de mobilité ionique des ions monovalents du complexe de « ibuprofène – γ-CD – ions calcium » contenant différentes molécules chirales d'ibuprofène, pour obtenir les caractéristiques de structure chirale de la molécule d'ibuprofène contenue dans l'échantillon. Le réactif et le procédé analytiques selon la présente invention sont simples, précis et présentent des avantages tels qu'une vitesse d'analyse rapide, sont plus simples que les procédés existants d'analyse de chiralité de molécules d'ibuprofène.
PCT/CN2021/119472 2020-07-21 2021-09-18 Réactif et procédé utilisés pour une analyse de structure chirale moléculaire du médicament ibuprofène WO2022017549A2 (fr)

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CN202010703682.8A CN114034759B (zh) 2020-07-21 一种用于药物布洛芬分子手性结构分析的试剂和方法
CN202010703682.8 2020-07-21

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Cited By (1)

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CN114702609A (zh) * 2022-04-02 2022-07-05 崔凯 伽马环糊精的制备方法

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WO2007134446A1 (fr) * 2006-05-23 2007-11-29 The University Of Western Ontario Criblage a haut debit d'exces enantiomere (ee)
JP2010054216A (ja) * 2008-08-26 2010-03-11 Iwate Prefectural Univ キラル識別又は光学純度測定方法
EP2419851B1 (fr) * 2009-04-15 2019-03-13 Micromass UK Limited Procédé et système pour estimer la superficie de section d'une molécule et prédire à partir de celle-ci la mobilité ionique
CN107764891B (zh) * 2017-10-16 2020-03-13 杭州先导医药科技有限责任公司 一种恩替卡韦手性异构体的区分测定方法
CN107764890B (zh) * 2017-10-16 2019-12-17 杭州先导医药科技有限责任公司 一种依折麦布对映异构体的区分检测方法
CN112834314B (zh) * 2020-07-21 2023-03-31 常州磐诺仪器有限公司 一种用于药物布洛芬分子手性结构分析的试剂及其方法

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* Cited by examiner, † Cited by third party
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CN114702609A (zh) * 2022-04-02 2022-07-05 崔凯 伽马环糊精的制备方法

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