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HPLC analysis method of bortezomib related substances

An analysis method and technology related to substances, applied in the direction of analysis of materials, material separation, measurement devices, etc., can solve problems such as large errors, affecting the quality of anti-tumor drug bortezomib, and difficulty in gasification

Active Publication Date: 2020-07-07
SIMCERE ZAIMING PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Since the isomeric impurities of SCR-3081 continue to participate in the reaction in the subsequent steps, a variety of corresponding impurities will be formed, which will affect the quality of the antineoplastic drug bortezomib. Therefore, it is necessary to establish an analysis method for SCR-3081 to control isomeric impurities. Constructive impurity content, improve the purity of the target product, and then improve the quality of bortezomib
[0007] At the same time, since (1R)-(S)-pinanediol-1-ammonium trifluoroacetate-3-methylbutane-1-boronate (SCR-3081) exists in the form of trifluoroacetate, it is difficult to Gasification, and the UV absorption of SCR-3081 and its isomer impurities SCR-5220 and SCR-5221 is very weak, and the general HPLC analysis method has poor resolution, low response and large error

Method used

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  • HPLC analysis method of bortezomib related substances
  • HPLC analysis method of bortezomib related substances
  • HPLC analysis method of bortezomib related substances

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 1) Chromatographic conditions:

[0038] Instrument: Agilent1260HPLC

[0039] Mobile phase: 10mmol / L of K 2 HPO 4 Buffer (adjust pH to 5.0 with phosphoric acid)-acetonitrile (volume ratio 55:45)

[0040] Column: OX-3 (4.6×150mm, 3μm)

[0041] Detection wavelength: 235nm

[0042] Column temperature: 25°C

[0043] Flow rate: 0.4ml / min

[0044] Injection volume: 5ul

[0045] 2) Sample preparation:

[0046] Take about 50 mg of (1R)-(S)-pinanediol-1-ammonium trifluoroacetate-3-methylbutane-1-boronate (SCR-3081), weigh it accurately, and place it in a 25ml measuring bottle , add 20 μl of benzoyl chloride and shake well, then add 50 μl of DBU (1,8-diazabicyclo[5,4,0]undec-7-ene), add 15ml of acetonitrile to dissolve by ultrasound, and react in a water bath at 50°C for 30 minutes. Allow to cool to room temperature, dilute to volume with methanol, shake well, filter, and take the filtrate as the test solution.

[0047] Accurately weigh 5 mg each of SCR-5220 and SCR-52...

Embodiment 2

[0051] 1) Chromatographic conditions:

[0052] Instrument: Agilent1260HPLC

[0053] Mobile phase: phosphate buffered saline (pH 3.0)-acetonitrile (volume ratio 65:35)

[0054] Column: OX-3 (4.6×150mm, 3μm)

[0055] Detection wavelength: 235nm

[0056] Column temperature: 20°C

[0057] Flow rate: 1.0ml / min

[0058] Injection volume: 5ul

[0059] 2) Sample preparation:

[0060]Take about 50 mg of (1R)-(S)-pinanediol-1-ammonium trifluoroacetate-3-methylbutane-1-boronate (SCR-3081), weigh it accurately, and place it in a 25ml measuring bottle , add 20, add benzoyl chloride and shake well after adding 50 acid chloride (1,8 diazabicyclo[5,4,0]undec-7-ene), add 15ml of acetonitrile to dissolve by ultrasound, at 60 React in a water bath at ℃ for 30 minutes, let cool to room temperature, dilute to the mark with methanol, shake well, filter, take the subsequent filtrate as the test solution.

[0061] Accurately weigh 5 mg each of SCR-5220 and SCR-5221 reference substances, put...

Embodiment 3

[0065] 1) Chromatographic conditions:

[0066] Instrument: Agilent1260HPLC

[0067] Mobile Phase: Phosphate Buffered Saline (pH 6.5)-Acetonitrile (40:60)

[0068] Column: OX-3 (4.6×150mm, 3μm)

[0069] Detection wavelength: 235nm

[0070] Column temperature: 30°C

[0071] Flow rate: 0.2ml / min

[0072] Injection volume: 5ul

[0073] 2) Sample preparation:

[0074] Take about 50 mg of (1R)-(S)-pinanediol-1-ammonium trifluoroacetate-3-methylbutane-1-boronate (SCR-3081), weigh it accurately, and place it in a 25ml measuring bottle , add 20 μl of benzoyl chloride, shake well, add 50 μl of DBU (1,8-diazabicyclo[5,4,0]undec-7-ene), add 15ml of acetonitrile to dissolve it by ultrasound, and react in a water bath at 45°C for 30 minutes. Allow to cool to room temperature, dilute to volume with methanol, shake well, filter, and take the filtrate as the test solution.

[0075] Accurately weigh 5 mg each of SCR-5220 and SCR-5221 reference substances, put them in a 25ml measuring ...

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Abstract

The invention discloses an HPLC analysis method of bortezomib related substances, which comprises the following steps: carrying out derivatization treatment on the bortezomib related substances by using benzoyl chloride to obtain a derivatization product; using a reversed-phase chiral chromatographic column, using a mobile phase as a mixed solution of a buffer salt solution containing phosphate and an organic solvent, and using a high performance liquid chromatography-ultraviolet detector to detect a derivatization product. The method is simple in derivatization operation, single in derivatization product and good in separation degree, so that the SCR-3081 and isomer impurities SCR-5220 and SCR-5221 of the SCR-3081 can be simply, conveniently, quickly and stably detected, and the product quality can be effectively controlled.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical analysis, in particular to an HPLC analysis method for related substances of (1R)-(S)-pinanediol-1-ammonium trifluoroacetate-3-methylbutane-1-boronate . Background technique [0002] (1R)-(S)-Pinanediol-1-ammonium trifluoroacetate-3-methylbutane-1-boronate (SCR-3081) is the raw material for the synthesis of bortezomib and an important pharmaceutical intermediate Body, the structural formula is shown in the following formula I: [0003] [0004] (1R)-(S)-Pinanediol-1-ammonium trifluoroacetate-3-methylbutane-1-boronate (SCR-3081) usually has 2 larger isomer impurities: SCR -5220 (SCR-3081 enantiomer) and SCR-5221 (SCR-3081 diastereomer). Among them, the structural formula of SCR-5220 is shown in the following formula II, and the structural formula of SCR-5221 is shown in the following formula III: [0005] [0006] Since the isomeric impurities of SCR-3081 continue to participate in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02G01N30/06G01N30/74
CPCG01N30/02G01N30/06G01N30/74G01N2030/067
Inventor 石海云廖明毅刘伟田森群李薇任晋生
Owner SIMCERE ZAIMING PHARM CO LTD