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Impurity analysis preparation method for clindamycin

A technology for clindamycin and impurity analysis, applied in the fields of analytical chemistry and pharmaceutical analytical chemistry, can solve the problems of reducing the limit of impurities, seldom considering the adverse effects of impurities on drug safety, and the control of impurities is not comprehensive and accurate.

Active Publication Date: 2013-05-29
浙江天台药业股份有限公司
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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. In addition to 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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  • Impurity analysis preparation method for clindamycin
  • Impurity analysis preparation method for clindamycin
  • Impurity analysis preparation method for clindamycin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] LC-MS Determination of Clindamycin API and Crude Products

[0089] Liquid-mass spectrometer: HPLC Waters 2486, MS Waters micromass ZQ 4000. Chromatographic column: Diamonsil C18 (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.

[0090] LC-MS detection of raw materials

[0091] 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.

[0092] Six related substances except clindamycin in clindamycin hydrochloride API were detected by liqui...

Embodiment 2

[0139] Structural identification of target impurities

[0140] The obtained pure products of the three target impurities were determined by high-resolution mass spectrometry, and then the structures of the three target impurities were determined by H-NMR, C-NMR and two-dimensional DEPT, HMBC, HMQC, COZY and NOESY spectra. 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.

[0141]

[0142] Clindamycin

[0143] Table 4. Clindamycin 1 H-NMR spectrum, 13 C-NMR spectrum, HMQC spectrum, COZY spectrum, NOESY spectrum assignment

[0144]

[0145] There are four chiral centers in the structure of clindamycin, and their configurations are 6S, 7S, 1’S, 3’R.

[0146] Structural identification of impurity 1

[0147] Instrument: Micromass Q-TOF mass spectro...

Embodiment 3

[0190] Bacteriostasis experiment of clindamycin hydrochloride and impurities 1, 2 and 3 of the present invention

[0191] 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 three related substances whose apparent content exceeds 0.1% in clindamycin hydrochloride bulk drug was investigated. active control.

[0192] Preparation of the test solution

[0193] Clindamycin hydrochloride (090303×7 batches, Zhejiang Tiantai Pharmaceutical Co., Ltd.): 1.091mg, dissolved in 1mL water;

[0194] Impurity 1 (i.e. 7-epiclindamycin): 1.049mg, dissolved in 0.5mL water;

[0195] Impurity 2: 1.200mg, dissolved in 0.5mL water;

[0196] Impurity 3: 1.139 mg, dissolved in 0.4 mL of water.

[0197] Experimental strain

[0198] Staphylococcus aureus (Gram-positive bacteria), Bacillus subtilis (bacteria), Candida albicans (fungi); provided by the Depar...

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Abstract

The invention provides an impurity analysis preparation method for clindamycin. The method is used for analyzing clindamycin materials and separating and preparing impurities from the materials, and comprises the following steps of: (a) measuring the clindamycin materials by an LC-MS (Liquid Chromatography-Mass Spectrometry) method, and determining one or more impurities in the materials according to the relative retention time and / or the molecular weight of the analyzed component; (b) determining the conditions of a column chromatography method according to the relative retention time and / or the molecular weight of one or more impurities, and gathering one or more impurities corresponding to the relative retention time and / or the molecular weight by the normal phase silica gel column chromatography method; and (c) determining the conditions of a preparative chromatography method according to the chromatographic retention behavior displayed by the relative retention time of one or more impurities in the step (a), and collecting one or more impurities corresponding to the retention time by the preparative chromatography method.

Description

technical field [0001] The invention relates to the field of analytical chemistry, in particular to the field of pharmaceutical analytical chemistry, in particular to an impurity analysis and preparation method of clindamycin. 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. [0004] Any substance...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02G01N30/08C07H15/16
CPCG01N30/88G01N2030/8872
Inventor 李悦孙秋实吴彤
Owner 浙江天台药业股份有限公司
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