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Pharmaceutical analysis method for efficiently measuring bazedoxifene acetate and impurities of bazedoxifene acetate

A bazedoxifene acetate, high performance liquid chromatography technology, applied in the directions of analysis materials, measuring devices, material separation, etc., can solve the problems of too long analysis time, ineffective separation, single gradient change procedure, etc., and achieves high sensitivity, The effect of quality control guarantee and good versatility

Active Publication Date: 2016-12-07
QILU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of the above method is that the buffer solution with a fixed pH value is used as the mobile phase, the gradient change program is single, and the analysis time of some examples is too long. Impurity mixed system

Method used

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  • Pharmaceutical analysis method for efficiently measuring bazedoxifene acetate and impurities of bazedoxifene acetate
  • Pharmaceutical analysis method for efficiently measuring bazedoxifene acetate and impurities of bazedoxifene acetate
  • Pharmaceutical analysis method for efficiently measuring bazedoxifene acetate and impurities of bazedoxifene acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] 1. Chromatographic conditions

[0060] Instrument: High Performance Liquid Chromatography—UV Detector

[0061] Chromatographic column: use octadecylsilane bonded silica gel as filler (Xbridge C18, 4.6×150mm, 3.5μm);

[0062] Mobile phase A: phosphate buffer with a pH value of 8.0-acetonitrile (61:39); wherein, the phosphate buffer with a pH value of 8.0 adjusts the pH by adding an appropriate amount of 10% phosphoric acid solution to a 0.01mol / L dipotassium hydrogen phosphate solution Values ​​up to 8.0 are obtained.

[0063] Mobile phase B: 0.5% phosphoric acid aqueous solution-acetonitrile (10:90);

[0064] gradient elution procedure

[0065]

[0066] Flow rate: 1.0ml / min; Column temperature: 40°C; Detection wavelength: 220nm; Injection volume: 10μl

[0067] 2. Validation of analytical methods:

[0068] (1) System suitability / impurity location

[0069] System suitability solution: take bazedoxifene acetate, impurity SST, impurity NOH, impurity SQJ, impurity N...

Embodiment 2

[0083] The preparation of embodiment 2 impurity compound QNA

[0084]

[0085] 6.0 g of compound BN and 3.4 g of compound SM2 were dissolved in 100 mL of acetonitrile, and the mixture was stirred at room temperature for 24 h. After the reaction was completed, suction filtration was performed, and the obtained filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography to obtain 2.0 g of impurity QNA;

[0086] ESI(+): m / z 882.39;

[0087] [M+1] + ; 1 H NMR: (400MHz, DMSO-d6) δ = 11.5-11.6 (s, 1H), 7.623 (d, 2H, J = 8.4Hz), 7.491 (dd, 4H, J = 1.6Hz, J = 7.2Hz), 7.434-7.320(m,8H),7.235(d,1H,J=9.2Hz),7.156-7.099(m,5H),6.902(d,2H,J=8.4Hz),6.839-6.811(m,3H) ,5.206(s,2H),5.157(d,4H,J=12.0Hz),4.681(s,2H),4.524-4.499(m,4H),3.602-3.400(m,6H),3.250-3.200(m ,2H),3.1-3.2(s,4H),2.175(s,3H),1.943-1.883(m,2H),1.812(s,6H),1.682-1.638(m,2H),1.559(s,6H ).

Embodiment 3

[0088] The preparation of embodiment 3 impurity compound QNP

[0089]

[0090] Disperse 1.0 g of compound QNA in a mixed system of 20 mL of ethanol and 5 mL of ethyl acetate, add 0.1 g of 10% palladium carbon under nitrogen protection, replace the reaction system with hydrogen for 3 times, and stir the mixture at room temperature until TLC shows that the reaction is complete, and the reaction liquid suction filtration, the filter cake was washed with 30ml ethyl acetate, the organic phases were combined, and the solvent was evaporated to dryness to obtain a crude product, which was purified by chromatographic column chromatography to obtain 0.5g impurity compound QNP;

[0091] ESI(+): m / z 702.20;

[0092] [M] + ; 1 H NMR: (400MHz,DMSO-d6)δ=11.360(d,1H,J=6.4Hz),9.862(s,1H),8.798(s,1H),7.585(d,2H,J=8.8Hz), 7.186(d, 2H, J=8.4Hz), 7.093(dd, 3H, J=2.0Hz, J=8.8Hz), 6.914-6.820(m, 7H), 6.607(dd, 1H, J=2.4Hz, J =8.8Hz), 5.142(s, 2H), 4.635(s, 2H), 4.471(s, 2H), 3.580-3.436(m, 8H),...

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Abstract

The invention provides a pharmaceutical analysis method for efficiently measuring bazedoxifene acetate and impurities of the bazedoxifene acetate and belongs to the technical field of pharmaceutical analysis. A chromatographic column with octadecylsilane chemically bonded silica as filling agent serves as a solid phase, a mixed solution of phosphate buffer solution and acetonitrile serves as a mobile phase A, a mixed solution of phosphoric acid and acetonitrile serves as a mobile phase B, effective separation can be achieved in a gradient elution mode, and the content of bazedoxifene acetate and the impurities of the bazedoxifene acetate can be effectively measured.

Description

technical field [0001] The invention belongs to the technical field of drug analysis, and specifically discloses a drug analysis method for efficiently determining related substances of bazedoxifene acetate. The analytical method can effectively separate and determine bazedoxifene-related impurities, and can be used as an important part of the quality control of bazedoxifene acetate. Background technique [0002] Bazedoxifene acetate, chemical name 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methanol Base-1H-indol-5-alcohol acetate has the structural formula shown in formula I. [0003] [0004] Bazedoxifene acetate is a selective estrogen receptor modulator developed by European Ligand company partner Wyeth in 1997. It was launched in Spain (trade name Conbriza) and Japan (trade name Viviant) in 2010. The drug can compete with Sexually inhibits the binding of estradiol to estrogen receptors, has estrogen agonist activity on bones, and can significantly r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/88G01N30/74G01N30/06
CPCG01N30/06G01N30/74G01N30/88
Inventor 马超高永宏王永智李殿庆
Owner QILU PHARMA CO LTD
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