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Pyrrolo quinoline quinone (PQQ) disodium salt impurity separation and purification method

A technology for separation and purification, quinoline quinone, applied in the field of chemical drug impurity research

Active Publication Date: 2016-02-17
WEIFANG SHENGYU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Pyrrolo quinoline quinone (PQQ) disodium salt impurity separation and purification method
  • Pyrrolo quinoline quinone (PQQ) disodium salt impurity separation and purification method
  • Pyrrolo quinoline quinone (PQQ) disodium salt impurity separation and purification method

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Experimental program
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Effect test

Embodiment 1

[0052] Embodiment 1. The investigation of sample solubility

[0053] Since the preparative liquid chromatography requires a large injection volume, the sample concentration is too low to cause the injection volume to be too large, and the high-concentration solute is overloaded, and the peak expansion caused by the large volume can be avoided during the separation process. Therefore, it is necessary to find a suitable solvent to achieve a certain solubility in order to effectively separate on the preparative chromatographic column and obtain a certain amount of preparation.

[0054]Use deionized water, methanol, acetonitrile (CAN), 0.04M ammonium dihydrogen phosphate buffer solution (pH7.0) (Buffer) containing 10% tetrabutylammonium hydroxide (Buffer), Buffer / ACN (7:3), and investigate PQQ in Solubility in different solvents. The results are shown in the table below:

[0055]

[0056] When the 0.04M ammonium dihydrogen phosphate buffer solution (pH7.0) containing 10% tetr...

Embodiment 2

[0057] Embodiment 2. optimize preparation and separation conditions

[0058] The preparative chromatographic conditions in chemical synthesis are generally selected from the reference analytical column chromatographic conditions, and then expanded to the same type of preparative column separation. For the extraction and purification of unknown samples, analytical columns are usually used to explore the separation conditions, and then the separation is scaled up. In general, the separation degree of preparative chromatography should be greater than 1.25. Select the preparative chromatographic column, enlarge the injection volume, flow rate, etc. according to the scale of the preparation, and finally make appropriate adjustments in the preparative chromatography.

[0059] Preparative chromatography operates in the nonlinear range and belongs to nonlinear chromatography, while analytical chromatography is linear chromatography. Therefore, many concepts or parameters used in anal...

Embodiment 3

[0071] Example 3 The separation on the preparative column

[0072] Because this test is to obtain impurities with extremely low content, high value and difficult to separate. Therefore, columns with small particles (5 μm) and large inner diameters are used to optimize the separation by adjusting the relevant parameters in the separation equation. Due to the particularity of PQQ molecules, the separation curve changes during the gradual amplification process. We finally choose the column: GPC18 (5μm, 21.2×250mm), and slightly adjust the mobile phase: 0.04M containing 10% tetrabutylammonium hydroxide Ammonium dihydrogen phosphate buffer solution (pH7.0): ACN=75:25 (v / v); column temperature: room temperature; flow rate: 20mL / min; injection volume: 10mL; pressure: 1756psi; detection wavelength: 225nm.

[0073] 3.1 Selection of flow rate

[0074] The production yield increases with the increase of column length and mobile phase flow rate. Since we are using a column with small p...

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Abstract

The invention provides a pyrrolo quinoline quinone (PQQ) disodium salt impurity separation and purification method, belonging to the technical field of chemical drug impurity research. PQQ is a prothetic group of multiple oxidation-reduction enzymes, has remarkable effects in preventing and treating alcoholic fatty liver, is expected to become a novel liver injury prevention and cure drug, and has good clinical application prospect. Aiming at the impurity in the drug, quality control limit must be established according to the physiological activity itself; the method comprises effectively separating the impurity in the drug, thus ensuring drug quality and reducing untoward effects of the drug. Impurity separation and purification is the most key technology in drug research. PQQ synthesis by-product impurities are effectively separated to prepare a 100-mg impurity product, and high resolution mass spectrum (HRMS), infrared absorption spectrum (IR) and nuclear magnetic resonance spectrum (NMR) are adopted to confirm a chemical structural formula of the impurity and finally confirm a molecular formula, chemical construction and a chemical name of the impurity, thus providing a reliable basis for impurity limit formulation for reporting PQQ clinic medication.

Description

technical field [0001] A method for separating and purifying pyrroloquinoline quinone PQQ disodium salt impurities belongs to the technical field of chemical drug impurity research. Background technique [0002] In recent years, due to the influence of environmental factors and other factors, chemical liver injury has become more and more common. And chemical liver injury can easily develop into cirrhosis. At present, there is no clear treatment drug in the world. Therefore, safe and effective chemical liver injury prevention and treatment drugs are urgently needed. [0003] PQQ (pyrroloquinoline quinone, pyrroloquinoline quinone) is a prosthetic group of various oxidoreductases, widely exists in animals and plants, and plays an important role in the body because of its powerful function of scavenging free radicals. It can effectively prevent and treat liver damage caused by carbon tetrachloride, has a significant effect on the prevention and treatment of alcoholic fatty l...

Claims

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Application Information

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IPC IPC(8): G01N33/15G01N1/34
CPCG01N1/34G01N33/15
Inventor 胡名扬鲁秀强朱理伟
Owner WEIFANG SHENGYU PHARMA CO LTD
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