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A kind of impurity of polymyxin b sulfate and preparation method thereof

A technology of polymyxin sulfate and polymyxin, which is applied to the preparation methods of peptides, polymyxins, chemical instruments and methods, etc., can solve problems such as the increase of degraded impurity content, improve quality, and ensure safety and effectiveness. sexual effect

Active Publication Date: 2020-11-10
HANGZHOU ZHONGMEI HUADONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

During the purification of polymyxin B sulfate, the content of some degraded impurities will increase, or new degraded impurities will be generated, but there is no report on the single impurity of polymyxin B sulfate

Method used

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  • A kind of impurity of polymyxin b sulfate and preparation method thereof
  • A kind of impurity of polymyxin b sulfate and preparation method thereof
  • A kind of impurity of polymyxin b sulfate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1 Separation and Purification of Polymyxin B Sulfate Impurity D17

[0032] 1. Crude production of impurity D17

[0033] Polymyxin B sulfate was dissolved in 5% acetonitrile solution, prepared by Agilent SD-1 preparative liquid phase; chromatographic column C18 (5um, 20×250mm); mobile phase was acetonitrile: sodium sulfate solution 4.46g / L=20 : 80; detection wavelength 215nm; flow rate 25mL / min. Fractions were collected and enriched by C18 preparative chromatographic column. It was eluted with 80% acetonitrile, and the impurity crude extract solution was collected.

[0034] 2. Refining of impurity D17

[0035] The collected impurity crude extract solution was concentrated under reduced pressure at 35°C to remove acetonitrile. Put the concentrated solution on the preparative column for purification again, collect the fractions in which the content of impurity D17 is greater than 90%, enrich and desalt them, and obtain a concentrated solution of polymyxin B sul...

Embodiment 2

[0038] Example 2 Structural Identification of Polymyxin B Sulfate Impurity D17

[0039] Gained impurity D17 in embodiment 1 is detected through high-resolution mass spectrometry, and the results are as follows:

[0040] High resolution mass spectrum m / z of polymyxin B sulfate impurity: 1203.7587[M+H]+, 1225.7408[M+Na]+.

[0041] The obtained impurity D17 in embodiment 1 is carried out nuclear magnetic detection again, obtain proton nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum, the result is as follows:

[0042] 1 H NMR (600MHz, D2O) δ7.30(t, J=7.2Hz, 2H), 7.25(t, J=7.2Hz, 1H), 7.10(d, J=7.2Hz, 2H), 4.72(t, J =7.2Hz, 1H), 4.50(dd, J=9.0, 4.2Hz, 1H), 4.45(dd, J=9.6, 4.2Hz, 1H), 4.38(dd, J=9.0, 4.2Hz, 1H), 4.29 (d, J=4.2Hz, 1H), 4.23(dd, J=9.6, 3.0Hz, 1H), 4.20(dd, J=6.6, 4.2Hz, 1H), 4.14(dd, J=6.6, 4.2Hz, 1H), 4.00(t, J=7.8Hz, 1H), 3.91(dd, J=10.2, 4.2Hz, 1H), 3.90(m, 1H), 3.89(d, J=4.8Hz, 1H), 3.29( m, 2H), 3.13(m, 2H), 3.06(m, 1H), 3....

Embodiment 3

[0046] The investigation of the factor of impurity D17 produced by the degradation of polymyxin B sulfate of embodiment 3

[0047] 1. The influence of solution pH

[0048] Weigh 2.0g of the sample, dissolve it in 200ml of pure water, stir to dissolve it, and pack in 5ml per bottle. Take 4 bottles of samples without pH adjustment (pH 6.5) and samples with pH adjustment of 8.5, 8.8, 9.3, 9.8, and 10.3, respectively. Four samples at the same pH were degraded at 33°C for 20min, 1h, 2h, and 4h, respectively, and samples were taken for HPLC detection.

[0049] The chromatographic conditions are: Agilent 1260 high performance liquid chromatography;

[0050] Chromatographic column: Waters symmetry-C18 4.6mm×25cm;

[0051] Mobile phase: acetonitrile: sodium sulfate solution (4.46g / L)=20:80;

[0052] Flow rate: 1mL / min;

[0053] Column temperature: 30°C;

[0054] Detection wavelength: 215nm.

[0055] The content of impurity D17 was counted to obtain the content of D17 after degra...

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Abstract

The invention discloses an impurity D17 of polymyxin B sulfate and a separation and preparation method thereof. The growth of the impurity under different conditions of temperature and pH is investigated. The preparation method provides a guarantee to control the content of the impurity, optimize the industrial production of the polymyxin B sulfate and improve the quality of a medicine.

Description

technical field [0001] The invention belongs to the technical field of drug analysis and quality control, and in particular relates to an impurity of polymyxin B sulfate and a separation and preparation method thereof. Background technique [0002] Polymyxin sulfate, as an early non-ribosomal antibacterial drug, was widely used in the clinical treatment of Gram-negative bacteria, but was replaced because of its narrow antibacterial spectrum and obvious side effects. At present, as the infection rate of multi-drug resistant Gram-negative bacteria continues to increase worldwide, colistin sulfate has been paid attention to again as the last line of defense for the treatment of Gram-negative bacteria. According to the different chemical structures produced by different strains, there are more than 30 types of polymyxin sulfate, which are mainly divided into five subtypes: A, B, C, D, and E. The basic structures are all cyclic decapeptide sequences, including A heptapeptide rin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/62C07K1/14
CPCC07K7/62
Inventor 谭芳李清仲翔王雪峰许乐义
Owner HANGZHOU ZHONGMEI HUADONG PHARMA
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