Detection method and application of brexpiprazole related substances

A related substance, epipiprazole technology, applied in the detection field of epipiprazole related substances, can solve the problems of long detection time, complicated gradient elution procedure, inability to detect 1-bromo-4-chlorobutane and the like , to achieve the effect of reliable method, low price and high practicability

Active Publication Date: 2021-05-28
LIVZON NEW NORTH RIVER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Patent CN109307716A and patent CN111912914A carried out accurate and effective separation and detection of related substances in ebiprazole, but both could not detect 1-bromo-4-chlorobutane
And the mobile phase used is buffer salt-acetonitrile system, the detection time is long, and the gradient elution procedure is complicated

Method used

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  • Detection method and application of brexpiprazole related substances
  • Detection method and application of brexpiprazole related substances
  • Detection method and application of brexpiprazole related substances

Examples

Experimental program
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Effect test

Embodiment 1

[0049] Specificity test: a method for detecting related substances of ebiprazole, comprising the steps of:

[0050] S1: Preparation of reference substance stock solution: take Intermediate 1, Intermediate 2, Intermediate 3 and 1-bromo-4-chlorobutane respectively, add solvent to make the concentration 0.25 mg / mL, and use it as a stock solution for later use;

[0051]S2: Preparation of resolution solution: Weigh 100 mg of ebiprazole reference substance into a 100 mL volumetric flask, and add 0.36 mL each of the above-mentioned intermediate 1, intermediate 2, and intermediate 3 and 0.96 mL of 1-bromo-4-chlorobutane mL, dissolved with a solvent and diluted to the mark, mixed well, as a resolution solution, in which the concentration of ebiprazole is 100 μg / mL, and the concentrations of Intermediate 1, Intermediate 2, and Intermediate 3 are 0.90μg / mL, the concentration of 1-bromo-4-chlorobutane is 2.40μg / mL;

[0052] S3: HPLC determination: chromatographic conditions are: WatersXb...

Embodiment 2

[0055] The detection method of embodiment 2 and embodiment 1 is identical, and difference is the chromatographic condition of S3, specifically:

[0056] S1: Prepare the resolution solution according to Example 1;

[0057] S2: HPLC determination: chromatographic conditions are: WatersXbridgeC18 chromatographic column: 4.6mm × 250mm, 5 μ m; mobile phase: acetonitrile (A): 0.05% perchloric acid water (B) = 30: 70 (v / v), Carry out isocratic elution, elution time is 40min; flow rate: 0.6mL / min; column temperature: 30°C; detection wavelength of ultraviolet detector: 215nm; injection volume: 10μL; Such as figure 2 shown.

[0058] From figure 2 It can be seen that the retention time of intermediate 1 is 4.484min, the retention time of intermediate 2 is 14.530min, the retention time of intermediate 3 is 5.660min, the retention time of 1-bromo-4-chlorobutane is 35.780min, and the retention time of ebiprazole is 8.213 min, the method can effectively separate the three intermediates...

Embodiment 3

[0060] The detection method of embodiment 3 and embodiment 1 is identical, and difference is the chromatographic condition of S3, specifically:

[0061] S1: Prepare the resolution solution according to Example 1;

[0062] S2: HPLC determination: chromatographic conditions are: WatersXbridgeC18 chromatographic column: 4.6mm × 250mm, 5 μ m; mobile phase: acetonitrile (A): 0.15% perchloric acid water (B) = 30: 70 (v / v), Carry out isocratic elution, elution time is 40min; flow rate: 0.6mL / min; column temperature: 30°C; detection wavelength of ultraviolet detector: 215nm; injection volume: 10μL; Such as image 3 shown.

[0063] From image 3 It can be seen that the retention time of intermediate 1 is 3.845min, the retention time of intermediate 2 is 12.613min, the retention time of intermediate 3 is 4.867min, the retention time of 1-bromo-4-chlorobutane is 31.757min, and the retention time of ebiprazole is 7.118 min, the method can effectively separate the three intermediates a...

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Abstract

The invention discloses a detection method and application of brexpiprazole related substances. According to the detection method of the brexpiprazole related substances, the brexpiprazole related substances such as an intermediate 7-hydroxy-1H-quinoline-2-ketone (intermediate 1), 7-(4-chlorobutoxy)-1H-quinoline-2-ketone (intermediate 2) and 1-(benzo [b] thiophene-4-yl) piperazine hydrochloride (intermediate 3) and an impurity 1-bromo-4-chlorobutane can be detected at one time; the separation degree is good, the detection time is short, and the elution procedure is simple. The method is applied to preparation of brexpiprazole, the quality of each intermediate can be controlled, and the product quality can be more effectively controlled.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical analytical chemistry, and in particular relates to a detection method and application of related substances of ebiprazole. Background technique [0002] Ebiprazole (Brexpiprazole), as a drug with a new multi-target mechanism of action, is an experimental serotonin-dopamine activity regulator, which can act on dopamine D2 and 5-HT2A receptors. The product was approved by the U.S. FDA on July 11, 2015, under the trade name Rexulti. Ebiprazole has unique pharmacological targeting, and has certain effects on the treatment of schizophrenia and the adjuvant treatment of severe depression. Compared with aripiprazole, ebiprazole shows higher affinity to dopamine receptors, but relatively lower affinity to H receptors and M1 receptors. It has shown good safety and tolerability in clinical trials. [0003] Various intermediates and impurities are involved in the synthesis of ebiprazole, including ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02G01N30/06
CPCG01N30/02G01N30/04G01N30/06G01N2030/042
Inventor 谢倩玲龚俊姜桥刘美霞黄穗
Owner LIVZON NEW NORTH RIVER PHARMA
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