Method for detecting related substances of flunarizine hydrochloride preparation

A technology of flunarizine hydrochloride and related substances, which is applied in the field of detection of related substances of flunarizine hydrochloride preparations, and can solve the problems of poor separation of impurities, small specifications, long detection time, etc.

Active Publication Date: 2020-04-07
CHIATAI QINGCHUNBAO PHARMA
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Problems solved by technology

[0008] The 2015 edition of the Chinese Pharmacopoeia and the European Pharmacopoeia include the detection methods for the related substances of flunarizine hydrochloride raw materials. Among them, the method of the 2015 edition of the Pharmacopoeia adopts isocratic elution, which cannot effectively separate the relevant impurities, and the sensitivity is not high.
The European Pharmacopoeia method only monitors the impurities that may be introduced by the synthesis of raw materials. The method has high requirements on the system, and the concentration of the test product is too high. However, the specifications of flunarizine hydrochloride in various dosage forms are relatively small, so this concentration is not applicable to the preparation
The existing literature Mei Dan et al. "Commercially Available Flunarizine Hydrochloride Capsules Quality Evaluation", the detection time is long, time-consuming, the separation effect of impurities is poor, the amount of information reflected is small, and the purpose of effectively controlling the quality of flunarizine hydrochloride cannot be achieved
The existing literature Li Jie et al. "Improvement of related substances and content determination methods of flunarizine hydrochloride" cannot effectively separate related impurities, and this method is only for flunarizine hydrochloride raw materials and not for preparations

Method used

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  • Method for detecting related substances of flunarizine hydrochloride preparation
  • Method for detecting related substances of flunarizine hydrochloride preparation
  • Method for detecting related substances of flunarizine hydrochloride preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1 standard curve, limit of quantitation and rate of recovery

[0054] 1. Standard curve

[0055] Diluent: methanol: pH3.5 phosphate buffer = 75:25, v / v.

[0056] Accurately weigh 15 mg of impurity A, 12 mg of 4,4-difluorobenzhydryl alcohol, and 35.4 mg of flunarizine hydrochloride (equivalent to 30 mg of flunarizine), and place them in a 100ml measuring bottle, dissolve and dilute to the mark with methanol, and shake well , to prepare impurity A stock solution, 4,4-difluorobenzhydryl alcohol stock solution, and flunarizine hydrochloride stock solution respectively.

[0057] Accurately measure an appropriate amount of each of the above-mentioned stock solutions, and dilute them with a diluent into impurity A solution, 4,4-difluorobenzhydryl alcohol solution and flunarizine hydrochloride solution with different concentration gradients, and carry out high performance liquid chromatography detection (same as Embodiment 2), with the linear solution concentration...

Embodiment 2

[0085] 1. Instruments: High performance liquid chromatography, Agilent 1260 / 1100 high performance liquid chromatography, Chem Station chromatography workstation, Mettler FE20pH meter, Mettler ME204 / XS205 analytical balance.

[0086] 2. Reagent: The test product is the contents of commercially available flunarizine hydrochloride capsules, and the standard product is flunarizine hydrochloride standard product; 7 impurity standard products: impurity A (1-[bis-(4-fluorophenyl ) methyl] piperazine), impurity B (1-[(4-fluorophenyl) phenylethyl]-4-[(2E)-3-phenylpropenyl] piperazine), impurity D (1-[ Bis-(4-fluorophenyl)methyl]-4-[(2Z)-3-phenylpropenyl]piperazine), trans-1-cinnamylpiperazine, 4,4-difluorobenzophenone , 4,4-difluorobenzhydryl alcohol, nitrogen oxides; methanol and acetonitrile are chromatographically pure, and the rest of the reagents are analytically pure.

[0087] Diluent: methanol: pH3.5 phosphate buffer = 75:25, v / v.

[0088] 3. Solution preparation

[0089] Tes...

Embodiment 3

[0111] Need testing solution: get commercially available flunarizine hydrochloride tablet and grind finely, accurately weighed to be equivalent to flunarizine 30mg, place in 50mL volumetric flask, add diluent (same as embodiment 2), 40kHz ultrasonic 10min dissolves And dilute to the mark, filter with 0.45μm filter membrane, take the filtrate, as the test solution, the concentration of flunarizine is 0.6mg / ml.

[0112] The mixed solution of the test product and each impurity standard: Take commercially available flunarizine hydrochloride tablets and grind finely, accurately weighed to be equivalent to 30 mg of flunarizine, place it in a 50mL volumetric flask, and accurately measure each impurity standard for storage Liquid is appropriate in the same measuring bottle, then diluent (same as embodiment 2), 40kHz ultrasonic 10min dissolves and is diluted to scale, 0.45 μm membrane filtration, gets filtrate, as the solution of need testing sample and each impurity standard item, cont...

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Abstract

The invention discloses a method for detecting related substances of a flunarizine hydrochloride preparation, which comprises the following steps: respectively taking a test solution, a contrast solution and an impurity mixed solution for high performance liquid chromatography detection, and respectively detecting the content of each impurity in the test solution at 210nm and 253nm, wherein peaksof the impurity A and 4, 4-difluorobenzhydrol are detected at 210 nm, and the impurity content is calculated according to an external standard method; and detecting other impurity peaks at 253nm, andcalculating the impurity content according to a self-contrast method. The method is easy to operate, short in analysis time, high in specificity and high in sensitivity, seven impurities can be effectively separated, the separation degree of two process impurities and five degradation impurities, the most difficult-to-separate impurity B and a main peak reaches 1.2 or above, and the separation degree of other impurities and adjacent peaks can all reach 1.5 or above.

Description

[0001] (1) Technical field [0002] The invention relates to a method for detecting impurities in medicines, in particular to a method for detecting related substances in flunarizine hydrochloride preparations. [0003] (2) Background technology [0004] Flunarizine is a selective calcium antagonist. Its main mechanism of action is to selectively block T and L-type calcium channels, reduce intracellular calcium levels, inhibit vascular smooth muscle contraction caused by calcium influx, and relieve vasospasm. It can prevent cell damage caused by intracellular pathological calcium overload caused by ischemia and other reasons, and has a wide range of effects on the nervous system. Clinically, it is mainly used for brain tissue ischemia and hypoxic diseases, and has achieved remarkable curative effect in preventing and treating peripheral vascular endothelial cell damage caused by ischemia and hypoxia. In addition, it is also used to reduce cell fragility caused by ischemia and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02G01N30/34
CPCG01N30/02G01N30/34G01N2030/047
Inventor 付玲珠丁嘉胤陈世友刘晓云张平
Owner CHIATAI QINGCHUNBAO PHARMA
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