CN116413354A - Dibutylamine detection method in a kind of tetrabutylammonium bromide - Google Patents

Abstract

The invention belongs to the technical field of medicine analysis, in particular relates to a dibutylamine detection method in tetrabutylammonium bromide, and provides a convenient, efficient and accurate detection method for detecting the dibutylamine content in tetrabutylammonium bromide, so that the medicine safety is effectively ensured, the quality control of the tetrabutylammonium bromide is convenient, efficient and accurate.

Description

Dibutylamine detection method in a kind of tetrabutylammonium bromide

technical field

The invention belongs to the technical field of drug analysis, in particular to a method for testing dibutylamine in tetrabutylammonium bromide.

Background technique

Tetrabutylammonium bromide is an excellent phase transfer catalyst, which can make the reactants transform between the organic phase and the aqueous phase, and also has the ability to change the solvation degree of the particles, increase the reaction speed and increase the ion reactivity, etc. As an efficient phase transfer catalyst in organic synthesis, it is used in alkylation reaction, redox reaction, ester hydrolysis, cyanide halide ion displacement reaction, condensation reaction, addition reaction, polymerization reaction, carbene cycloaddition reaction and In terms of elimination reactions, tetrabutylammonium bromide is used as a catalyst in the synthesis process of irbesartan, which may remain in the drug. Tetrabutylammonium bromide is also used in the synthesis of pharmaceutical intermediates such as benzyltriethylammonium chloride, ethyl cinnamate, pseudoionone, etc., and is also commonly used in the synthesis of organic drugs such as anti-infective drugs Bamcillin and Sultacillin Reacting. Tetrabutylammonium bromide has a wide range of applications, so its synthesis process has received extensive attention from the industry.

Dibutylamine is the starting material for the synthesis of tetrabutylammonium bromide, and it is a potential impurity in tetrabutylammonium bromide. It may remain in tetrabutylammonium bromide and may introduce groups of genotoxic impurities. It is necessary to control the content of amines from the source.

At present, there are few reports about the detection method of dibutylamine in tetrabutylammonium bromide. The present invention discloses the detection method of dibutylamine in tetrabutylammonium bromide for the first time, and solves the detection of dibutylamine in tetrabutylammonium bromide. Problem, provide a kind of convenient, efficient, accurate detection method, this method can detect the content of dibutylamine in tetrabutylammonium bromide, thereby effectively guarantee drug safety, be convenient to the quality control of tetrabutylammonium bromide.

Contents of the invention

The invention provides a high-performance liquid chromatography method for determining the content of dibutylamine in tetrabutylammonium bromide, and provides a convenient, efficient and accurate method for solving the detection problem of dibutylamine in tetrabutylammonium bromide. The detection method can detect the content of dibutylamine in tetrabutylammonium bromide, so as to effectively ensure the safety of medication and facilitate the quality control of tetrabutylammonium bromide. This method is convenient, efficient and accurate. , repeatability, specificity, and accuracy are in full compliance with the guiding principles of Chinese Pharmacopoeia method validation, and can be used for quality control of tetrabutylammonium bromide.

To achieve the above object, the present invention provides the following technical solutions:

A kind of dibutylamine detection method in tetrabutylammonium bromide, described detection method comprises the following steps:

(1) Prepare solutions, prepare blank solution, reference solution and test solution respectively.

(2) Determination method: Determination of dibutylamine in tetrabutylammonium bromide by high performance liquid phase method, after the system is stable, enter blank solution, reference solution and test solution respectively, and record the chromatogram;

The chromatographic conditions are as follows:

Chromatographic column: octadecylsilane bonded silica gel as filler, detection wavelength: 265nm; flow rate: 1.0±0.1ml/min; column temperature: 30±2°C; injection volume: 20μl, mobile phase with phosphoric acid solution: Acetonitrile system was used as mobile phase, and gradient elution was adopted.

Further, the blank solution: take an appropriate amount of 9-fluorenylmethyl chloroformate and place it in a volumetric flask, measure an appropriate amount of sodium tetraborate solution, put it in the same bottle, shake it up, ultrasonically, dissolve it with a diluent and dilute to Scale, shake well; the reference solution: take an appropriate amount of chloroformic acid-9-fluorenylmethyl ester and place it in a volumetric flask, take an appropriate amount of dibutylamine, and measure an appropriate amount of sodium tetraborate solution, put them in the same bottle, shake well, Ultrasound, dissolve with diluent and dilute to the scale, shake well; the test solution: take an appropriate amount of tetrabutylammonium bromide sample, take an appropriate amount of chloroformic acid-9-fluorenylmethyl ester, and measure an appropriate amount of sodium tetraborate solution. In the bottle, shake well, sonicate, dissolve with diluent and dilute to the mark, shake well; the diluent is purified water: acetonitrile = 1:3 (V/V), and the mobile phase is: mobile phase A: 0.1% phosphoric acid solution; mobile phase B: acetonitrile; the chromatographic column is Water Nove-pak C18; 4μm, 3.9×150mm or equivalent chromatographic column.

Further, the gradient elution is:

Dibutylamine inspection method in described tetrabutylammonium bromide also comprises the method verification before detection, and this method verification is according to the chromatographic condition of formal detection, and assay result is:

The invention discloses a detection method for dibutylamine in tetrabutylammonium bromide, and provides a convenient, efficient and accurate detection method for solving the detection problem of dibutylamine in tetrabutylammonium bromide, which can detect Dibutylamine in tetrabutylammonium bromide, thus effectively ensuring drug safety.

Description of drawings

Fig. 1 is the spectrum of dibutylamine blank solution in tetrabutylammonium bromide

Fig. 2 is the test solution collection of dibutylamine in tetrabutylammonium bromide

Fig. 3 is dibutylamine reference solution collection of books in tetrabutylammonium bromide

Fig. 4 is the selective solution collection of dibutylamine in tetrabutylammonium bromide

Detailed ways

The present invention is further illustrated by the following examples, but not as a limitation of the present invention.

Example 1:

(1) Prepare the solution:

Diluent: purified water: acetonitrile = 1:3 (V/V);

Blank solution: Take a 10ml volumetric flask, weigh about 200mg of chloroformic acid-9-fluorenylmethyl ester, measure 1.0ml of sodium tetraborate solution (pH9.18), put it in the same bottle, shake well, ultrasonicate for 5min, and use diluent Dissolve and dilute to the mark, shake well;

Dibutylamine stock solution: take about 25mg of dibutylamine, accurately weigh it, put it in a 25ml volumetric flask, dilute to the mark with diluent, and shake well; accurately measure 1.0ml, put it in a 20ml volumetric flask, and dilute with diluent to scale, shake well. (Concentration: 50μg/ml)

Reference solution: Take a 10ml volumetric flask, weigh about 200mg of chloroformic acid-9-fluorenylmethyl ester, accurately measure 1.0ml of dibutylamine stock solution, measure 1.0ml of sodium tetraborate solution (pH9.18), and place the In the bottle, shake well, sonicate for 5min, dissolve with diluent and dilute to the mark, shake well. (dibutylamine concentration: 5 μg/ml).

Test solution: take a 10ml volumetric flask, weigh about 100mg of tetrabutylammonium bromide sample, weigh about 200mg of 9-fluorenylmethyl chloroformate, measure 1.0ml of sodium tetraborate solution (pH9.18), and place the In the bottle, shake well, sonicate for 5min, dissolve with diluent and dilute to the mark, shake well. (Tetrabutylammonium bromide concentration: 10mg/ml)

Dibutylamine positioning solution (reference solution): Take a 10ml volumetric flask, weigh about 200mg of 9-fluorenylmethyl chloroformate, accurately measure 1.0ml of dibutylamine stock solution, and measure sodium tetraborate solution (pH9.18 ) 1.0ml, put it in the same bottle, shake well, ultrasonicate for 5min, dissolve with diluent and dilute to the mark, shake well. (dibutylamine concentration: 5μg/ml)

Diluent positioning solution: Take an appropriate amount of diluent and put it in the sample injection vial.

Dibutylamine positioning solution (without derivatization reagent): Take a 10ml volumetric flask, accurately measure 1.0ml of dibutylamine stock solution, put it in the bottle, shake well, dilute to the mark with diluent, and shake well. (dibutylamine concentration: 5μg/ml)

Selective solution: take a 10ml volumetric flask, weigh about 100mg of tetrabutylammonium bromide sample, weigh about 200mg of 9-fluorenylmethyl chloroformate, accurately measure 1.0ml of dibutylamine stock solution, and measure sodium tetraborate Solution (pH9.18) 1.0ml, placed in the same bottle, shake well, ultrasonic 5min, dissolve with diluent and dilute to the mark, shake well. (dibutylamine concentration: 5μg/ml, tetrabutylammonium bromide concentration: 10mg/ml)

Test solution (a): take a 10ml volumetric flask, weigh about 200mg of chloroformic acid-9-fluorenylmethyl ester, accurately measure 1.0ml of dibutylamine stock solution, and measure 1.0ml of sodium tetraborate solution (pH9.18). Put it in the bottle, shake it well, sonicate it for 5 minutes, dissolve it with the diluent and dilute it to the mark, and shake it evenly.

LOQ solution: According to the S/N value of the spectrum obtained from the test solution (a), adjust the dilution ratio to S/N≥10 of dibutylamine. Prepare 6 copies in the same way.

LOD solution: Accurately measure 3.0ml of LOQ solution, put it in a 10ml volumetric flask, dilute to the mark with diluent, and shake well.

Linear-50% solution: Take a 10ml volumetric flask, precisely pipette 5.0ml of dibutylamine stock solution into the bottle, dilute to the mark with diluent, and shake well. Take another 10ml volumetric flask, weigh about 200mg of 9-fluorenylmethyl chloroformate, accurately measure 1.0ml of the above solution, and measure 1.0ml of sodium tetraborate solution (pH9.18), put them in the same bottle, shake well, Sonicate for 5 minutes, dissolve and dilute to the mark with diluent, and shake well. (dibutylamine concentration: 2.5μg/ml)

Linear-80% solution: take a 10ml volumetric flask, precisely pipette 4.0ml of dibutylamine stock solution into the bottle, dilute to the mark with diluent, and shake well. Take another 10ml volumetric flask, weigh about 200mg of 9-fluorenylmethyl chloroformate, accurately measure 2.0ml of the above solution, and measure 1.0ml of sodium tetraborate solution (pH9.18), put them in the same bottle, shake well, Sonicate for 5 minutes, dissolve and dilute to the mark with diluent, and shake well. (dibutylamine concentration: 4.0μg/ml)

Linear-100% solution: Take a 10ml volumetric flask, weigh about 200mg of chloroformic acid-9-fluorenylmethyl ester, accurately measure 1.0ml of dibutylamine stock solution, and measure 1.0ml of sodium tetraborate solution (pH9.18). Put it in the bottle, shake it well, sonicate it for 5 minutes, dissolve it with the diluent and dilute it to the mark, and shake it evenly. (dibutylamine concentration: 5μg/ml)

Linear-120% solution: Take a 10ml volumetric flask, precisely pipette 4.0ml of dibutylamine stock solution into the bottle, dilute to the mark with diluent, and shake well. Take another 10ml volumetric flask, weigh about 200mg of 9-fluorenylmethyl chloroformate, accurately measure 3.0ml of the above solution, and measure 1.0ml of sodium tetraborate solution (pH9.18), put them in the same bottle, shake well, Sonicate for 5 minutes, dissolve and dilute to the mark with diluent, and shake well. (dibutylamine concentration: 6.0μg/ml)

Linear-150% solution: Take a 10ml volumetric flask, precisely pipette 5.0ml of dibutylamine stock solution into the bottle, dilute to the mark with diluent, and shake well. Take another 10ml volumetric flask, weigh about 200mg of 9-fluorenylmethyl chloroformate, accurately measure 3.0ml of the above solution, and measure 1.0ml of sodium tetraborate solution (pH9.18), put them in the same bottle, shake well, Sonicate for 5 minutes, dissolve and dilute to the mark with diluent, and shake well. (dibutylamine concentration: 7.5μg/ml)

The chromatographic conditions are as follows:

test methods:

After the system is stable, inject 1 injection of blank solution, 5 injections of reference solution, and 1 injection of test solution, and record the chromatogram.

Result (ppm) = (R _u /R _s ) × (C _s /C _u )

Wherein: R _u : the peak area of dibutylamine in the test solution;

R _s : the average peak area of dibutylamine in the 5-pin reference solution;

C _s : the concentration of dibutylamine in the reference solution (μg/ml);

C _u : concentration (g/ml) of the test solution.

Example 2: System Suitability

The system suitability is realized by examining the RSD of the peak area of dibutylamine in the 5-pin reference solution. It is required that the RSD of the peak area of dibutylamine in the 5-pin reference solution should meet the acceptable standard. After the system is stable, enter the blank 1 needle of solution, 5 needles of reference solution, and record the chromatogram.

Example 3: Specificity

Specificity is achieved by determining whether the blank solution interferes with the detection of dibutylamine; the resolution between dibutylamine and adjacent component peaks in the selective solution, and the recovery rate of dibutylamine before and after sample addition. It is required that the blank solution should not interfere with the detection of dibutylamine; the separation between dibutylamine and adjacent peak components in the selective solution and the recovery rate of dibutylamine before and after sample addition should meet the acceptable standard.

选择性目的是为考察在加入四丁基溴化铵样品前后，对二丁胺检测是否产生影响，要求加入四丁基溴化铵样品前后，二丁胺的回收率应在80.0%～120.0%之间。

The purpose of selectivity is to investigate whether the detection of dibutylamine is affected before and after the addition of tetrabutylammonium bromide samples. It is required that the recovery rate of dibutylamine should be between 80.0% and 120.0% before and after adding tetrabutylammonium bromide samples. between.

实施例4：精密度

Example 4: Precision

The repeatability is realized by determining the RSD of the determination results of dibutylamine in 6 test solutions, and it is required that the RSD of the determination results of dibutylamine in the 6 test solutions should meet the acceptable standard.

Example 5: Limits of quantitation and detection limits

The limit of quantification and limit of detection are achieved by detecting the ratio of the response signal to noise. The signal-to-noise ratio (S/N) of the limit of quantification is ≥10, and the signal-to-noise ratio (S/N) of the limit of detection is ≥3; at this concentration level , repeated inspection of 6 parts of LOQ solutions, requiring 6 parts of LOQ solutions, the RSD of the peak area of dibutylamine should meet the acceptable standard, to prove that the determination of the limit of quantification has a certain precision.

Example 6: Linear

Select 6 concentration points within the concentration range of LOQ to 150% limit, draw a curve with the concentration as the abscissa and the peak area as the ordinate, and the square of the linear correlation coefficient R (R2) of the curve is required to meet the acceptable standard.

Example 6: Durability

Investigate the law of the test results changing with time after the reference solution and the test solution are placed at room temperature for 0 days, 1 day, and 2 days, and provide a basis for the storage time of the reference solution and the test solution during the test. Dibutylamine is required The recovery rate should meet the acceptance criteria.

Claims (3)

1. a dibutylamine detection method in tetrabutylammonium bromide, is characterized in that, described detection method comprises the following steps: (1) Prepare solutions, prepare blank solution, reference solution and test solution respectively; (2) Determination method: Determination of dibutylamine in tetrabutylammonium bromide by high performance liquid phase method, after the system is stable, enter blank solution, reference solution and test solution respectively, and record the chromatogram; The chromatographic conditions are as follows: Chromatographic column: octadecylsilane bonded silica gel as filler, detection wavelength: 265nm; flow rate: 1.0±0.1ml/min; column temperature: 30±2°C; injection volume: 20μl, mobile phase with phosphoric acid solution: Acetonitrile system was used as mobile phase, and gradient elution was adopted. 2. detection method according to claim 1, it is characterized in that, described blank solution: get chloroformic acid-9-fluorenyl methyl ester in right amount and be placed in volumetric flask, measure and take right amount sodium tetraborate solution, put in this bottle together , shake well, ultrasonically, dissolve with diluent and dilute to the scale, shake well; the reference solution: take an appropriate amount of 9-fluorenylmethyl chloroformate and place it in a volumetric flask, take an appropriate amount of dibutylamine, and measure tetraboric acid Appropriate amount of sodium solution, placed in the same bottle, shake well, ultrasonically, dissolve with diluent and dilute to the mark, shake well; said test solution: take appropriate amount of tetrabutylammonium bromide sample, take chloroformic acid-9-fluorenylmethyl For the appropriate amount of ester, measure an appropriate amount of sodium tetraborate solution, put it in the same bottle, shake well, ultrasonically dissolve it with a diluent and dilute to the mark, and shake well; the diluent is purified water: acetonitrile = 1:3 (V/ V), the mobile phase is: mobile phase A: 0.1% phosphoric acid solution; mobile phase B: acetonitrile; the chromatographic column is Water Nove-pakC18; 4μm, 3.9×150mm or equivalent chromatographic column. 3. detection method according to claim 2, is characterized in that, described gradient elution is:

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