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Clindamycin isomer, analytical preparation method and application thereof

A technology of clindamycin and isomers, applied in the field of pharmaceutical analytical chemistry and analytical chemistry, can solve the problems of lack of understanding of importance, little consideration of the adverse effects of impurities on drug safety, and insufficient consideration of impurity limits, etc. question

Inactive Publication Date: 2013-05-29
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] 2. Reaction raw materials that exist due to incomplete reaction, reaction initial complexes, synthetic intermediate products, by-products and other substances related to the synthesis process;
[0023] 5. Except for degradation products and toxic impurities, the impurities that have been controlled in the raw materials are generally no longer controlled in the preparation;
From the analysis of new drug declarations in recent years, there are many problems in the research and limit determination of impurities, mainly as follows: some drug research units do not have a deep understanding of the importance of impurity research; the control of impurities in standards is not enough Comprehensive and accurate; considerations are not comprehensive when formulating impurity limits, and the adverse effects of impurities on drug safety are rarely considered; even when the content of impurities is obviously beyond the range allowed by normal processes, no attention is paid to the current prescription and process. Necessary optimization to reduce impurity limit

Method used

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  • Clindamycin isomer, analytical preparation method and application thereof
  • Clindamycin isomer, analytical preparation method and application thereof
  • Clindamycin isomer, analytical preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] LC-MS Determination of Clindamycin API and Crude Products

[0079] Liquid-mass spectrometer: HPLC Waters 2486, MS Waters micromass ZQ 4000. Chromatographic column: Diamonsil C 18 (5 μ 250 × 4.6mm); mobile phase is acetonitrile-tetrahydrofuran-water-formic acid (18%: 3%: 79%: 0.2%), ammonia water adjusts the pH value to 5.45; column temperature is room temperature; detection Wavelength 210nm; flow rate 1.0mL / min, split into mass spectrometer. The mass spectrometry conditions are electrospray ionization source positive ion (ESI+) detection mode; source temperature 80°C; cone voltage 35v.

[0080] LC-MS detection of raw materials

[0081] Take the mobile phase of the raw material medicine with batch number 090303×7 and dissolve it into a solution with a concentration of 2 mg / mL, and the injection volume is 20 μL. LC-MS detection results such as figure 1 shown.

[0082] Six related substances except clindamycin in clindamycin hydrochloride API were detected by liqu...

Embodiment 2

[0118] Structural identification of target impurity-clindamycin isomer shown in formula II

[0119] The obtained pure products of clindamycin isomers were determined by high-resolution mass spectrometry, and then determined by nuclear magnetic resonance hydrogen spectrum, carbon spectrum and two-dimensional spectrum DEPT, HMBC, HMQC, COZY and NOESY The structure of isomers. The instruments used are Micromass Q-TOF mass spectrometer and American Varian nuclear magnetic resonance spectrometer (400MHz). The following structural formula is the structure of clindamycin, and Table 4 is the data of clindamycin nuclear magnetic resonance spectrum.

[0120]

[0121] Table 4. Clindamycin 1 H-NMR spectrum, 13 C-NMR spectrum, HMQC spectrum, COZY spectrum,

[0122] NOESY spectral attribution

[0123]

[0124] There are four chiral centers in the structure of clindamycin, and their configurations are 6S, 7S, 1’S, 3’R.

[0125] Impurity 2-Structure Identification of Clindamyc...

Embodiment 3

[0141] Antibacterial experiment of clindamycin hydrochloride and impurity 2 of the present invention

[0142] The tests used to determine the effectiveness of antibacterial drugs in inhibiting bacterial growth in vitro are called bacteriostatic tests. In this experiment, the antibacterial activity of clindamycin isomers with an apparent content of more than 0.1% in clindamycin hydrochloride raw materials was investigated. Antibacterial activity control of raw materials.

[0143] Preparation of the test solution

[0144] Clindamycin hydrochloride (090303×7 batches, Zhejiang Tiantai Pharmaceutical Co., Ltd.): 1.091mg, dissolved in 1mL water;

[0145] Impurity 2: 1.200mg, dissolved in 0.5mL water;

[0146] Experimental strain

[0147] Staphylococcus aureus (Gram-positive bacteria), Bacillus subtilis (bacteria), Candida albicans (fungi); provided by the Department of Biology, Shanghai Pharmaceutical Industry Research Institute.

[0148] Preparation of culture medium ...

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Abstract

The invention provides a clindamycin isomer which has a structure shown in the formula II. The invention further provides an analytical preparation method of the clindamycin isomer. The method is characterized in that the clindamycin raw materials are analyzed and the clindamycin isomer is separated and prepared from the raw materials. The method comprises the following steps of: a) determining the clindamycin raw materials by the LC-MS (liquid chromatography-mass spectrometry) method, and determining the clindamycin isomer in the raw materials according to relative retaining time and / or molecular weight of analyzed components; b) determining conditions of column chromatography according to the relative retaining time and / or molecular weight of the clindamycin isomer, obtained in the step a, and enriching analyzed components corresponding to the relative retaining time and / or molecular weight by positive phase silica gel column chromatography; and c) determining condition of the preparation liquid phase method according to chromatographic retention behavior displayed by the relative retaining time of the clindamycin isomer, obtained in the step a, and collecting the analyzed components corresponding to the relative retaining time by the liquid phase method.

Description

technical field [0001] The present invention relates to the field of analytical chemistry, in particular to the field of pharmaceutical analytical chemistry, in particular to clindamycin isomers, their analytical preparation methods and applications. Background technique [0002] Clindamycin hydrochloride is a semi-synthetic derivative obtained by replacing the 7-hydroxyl of lincomycin hydrochloride with a chlorine atom. The antibacterial spectrum is the same as that of lincomycin, and its antibacterial activity is 4-8 times stronger than that of lincomycin. It is widely used in the treatment of infections caused by Gram-positive cocci such as Staphylococcus aureus and various anaerobic bacteria. [0003] Clindamycin hydrochloride and its injection have many adverse reactions in clinical application. The adverse effects of drugs in clinical use are not only related to the pharmacological activity of the drug itself, but also have a lot to do with the impurities in the drug....

Claims

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Application Information

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IPC IPC(8): C07H15/16A61K31/7056G01N30/88G01N27/64G01N24/08A61P31/04
Inventor 李悦孙秋实吴彤许卓妮
Owner SHANGHAI INST OF PHARMA IND
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