Method for detecting chloride ions in benzenesulfonic acid

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a method for detecting chloride ions in benzenesulfonic acid. The analysis method for detecting the residual content of chloride ions in benzenesulfonic acid comprises the step of detecting a benzenesulfonic acid sample by adopting an ion chromatograph, a chromatographic column is an anion exchange chromatographic column, and a mobile phase is an aqueous solution of 8-20mmol / L sodium hydroxide. The method provided by the invention has better accuracy and sensitivity.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to a method for detecting chloride ions in benzenesulfonic acid, and more particularly to a method for detecting the content of chloride ions in benzenesulfonic acid using ion chromatography and the standard curve method. Background Art

[0002] As an important organic chemical raw material, benzenesulfonic acid is widely used in many industries such as pharmaceuticals, dyes, and detergents. During its production process, due to various factors such as raw material sources, synthesis processes, and reaction equipment, chloride ion impurities will inevitably be introduced. The presence of chloride ions will have many adverse effects on the properties and subsequent use of benzenesulfonic acid. For example, in some fine chemical synthesis reactions, chloride ions may act as catalyst poisons, reducing the reaction efficiency, or even changing the reaction path, resulting in a decrease in product quality; in scenarios involving the use of metal equipment, chloride ions have strong corrosiveness and can damage the passivation film on the metal surface, causing local corrosion phenomena such as pitting corrosion and crevice corrosion, seriously affecting the service life and safety of the equipment; in the preparation process of cisatracurium besylate injection, the auxiliary material benzenesulfonic acid is used, and it is necessary to accurately quantify the chloride ion content in benzenesulfonic acid to prevent the impact of excessive chloride ions on the safety of the product.

[0003] However, the benzenesulfonic acid system is relatively complex, and conventional chloride ion detection methods face many challenges when applied to benzenesulfonic acid. The traditional titration method is easily interfered by other acidic substances or impurities in benzenesulfonic acid, resulting in inaccurate detection results; the turbidimetry method is to react chloride ions in the test sample with silver nitrate to produce a precipitate, and then compare it with the sodium chloride standard solution. As long as the concentration is lower than the standard solution, the disadvantage of the turbidimetry method is that it has low accuracy requirements, and visual observation and comparison are used, and there are personnel differences in subjective judgment; when the turbidity is less than 4 NTU, the naked eye cannot observe.

[0004] Patent application CN118858523A provides a titration device and its titration method for detecting chloride ion content in concrete. It uses potassium chromate as an indicator and titrates with silver nitrate titrant to detect chloride ions. Its disadvantage is that the end point is judged by the naked eye of the operator to observe the color change, resulting in inconsistent end point judgment criteria for different operators and inaccurate detection of chloride ion content; the composition of concrete itself is complex, and the specificity of the titration method is insufficient; this patent also does not disclose the experimental data of its method verification.

[0005] Therefore, it is of great practical significance and urgent market demand to develop a more accurate, sensitive and applicable chloride ion detection method for the benzenesulfonic acid system. Summary of the Invention

[0006] In view of the above technical status quo, the present invention provides a method for more accurately and sensitively detecting chloride ions in benzenesulfonic acid. The method uses an ion chromatograph to detect a benzenesulfonic acid sample, and the chromatographic conditions are as follows:

[0007] Chromatographic column: an anion exchange chromatographic column,

[0008] Mobile phase: an aqueous solution of 8-20 mmol / L sodium hydroxide,

[0009] Column temperature: 25-35 °C,

[0010] Flow rate: 0.8-1.2 mL / min,

[0011] Injection volume: 25-75 μL.

[0012] As an illustrative example, the concentration of the aqueous sodium hydroxide solution can be 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or any real value within the range of 8-20 mmol / L;

[0013] As an illustrative example, the column temperature can be 25 °C, 26 °C, 27 °C, 28 °C, 29 °C, 30 °C, 31 °C, 32 °C, 33 °C, 34 °C, 35 °C or any real value within the range of 25-35 °C;

[0014] As an illustrative example, the flow rate can be 0.8, 0.9, 1.0, 1.1, 1.2 or any real value within the range of 0.8-1.2 mL / min;

[0015] As an illustrative example, the injection volume can be 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or any real value within the range of 25-75 μL.

[0016] In the present invention, as one of the implementation manners, the mobile phase of the chromatographic column is an aqueous solution of 10 mmol / L sodium hydroxide.

[0017] In the present invention, as one of the implementation manners, the chromatographic column includes Dionex IonPac TM AS11RFIC TM , 250×4 mm as the separation column.

[0018] In the present invention, as one of the implementation manners, the chromatographic column further includes Dionex IonPac TM AG11 RFIC TM , 50×4 mm as the pre-column.

[0019] In the present invention, as one of the implementation manners, the chromatographic column is Dionex IonPacTM AG11RFIC TM ,50×4mm as the pre-column; Dionex IonPac TM AS11 RFIC TM ,250×4mm as the separation column.

[0020] In the present invention, as one of the implementation schemes, the column temperature of the chromatographic column is 30 °C.

[0021] In the present invention, as one of the implementation schemes, the flow rate of the chromatographic column is 1.0 mL / min.

[0022] In the present invention, as one of the implementation schemes, the injection volume is 50 μL.

[0023] In the present invention, as one of the implementation schemes, the chromatographic conditions further include a running time of 10 min.

[0024] In the present invention, as one of the implementation schemes, the chromatographic conditions further include an isocratic elution condition.

[0025] In the present invention, as one of the implementation schemes, the method further includes: using an anion exchange chromatographic column, sodium hydroxide solution as the mobile phase, adopting the standard curve method, and accurately detecting the residual content of chloride ions in benzenesulfonic acid by ion chromatography, including the following steps:

[0026] (1) Prepare the linear solution: Take 40 mg of sodium chloride, accurately weigh it, transfer it to a 10 mL volumetric flask, add the diluent to make a 4 mg / mL solution as the stock solution. Accurately measure 1 mL of the above stock solution, transfer it to a 100 mL volumetric flask, add the diluent to the scale, and shake well to obtain the linear stock solution. Prepare the L1-L5 linear solutions according to the following table:

[0027] Linear solution Volume of linear stock solution taken (mL) Volumetric flask (mL) L1 0.5 10 L2 2.5 10 L3 5 10 L4 7.5 10 L5 10 10 ;

[0028] (2) Record the chromatogram, use the concentration as the abscissa (X) and the peak area as the ordinate (Y) for linear regression to obtain the linear regression equation of chloride ions and calculate the correlation coefficient (r) of the regression equation;

[0029] (3) Prepare the test solution: Accurately weigh 400 mg of the test sample benzenesulfonic acid, transfer it to a 10 mL volumetric flask, dissolve and dilute it to the scale with the diluent, and shake well to obtain it;

[0030] (4) Take 50 μL of the test solution and inject it into the chromatographic column;

[0031] (5) Record the chromatogram, substitute it into the linear regression equation of chloride ions y = ax + b, and calculate the chloride ion concentration x = (y - b) / a using the standard curve method;

[0032] Among them, the chromatographic conditions of the chromatographic column described in step (4) are as follows:

[0033] Chromatographic column:

[0034] Pre-column: Dionex IonPac TM AG11 RFIC TM (50×4mm);

[0035] Separation column: Dionex IonPac TM AS11 RFIC TM (250×4mm);

[0036] Mobile phase: Aqueous solution of 10 mmol / L sodium hydroxide;

[0037] Column temperature: 30°C;

[0038] Flow rate: 1.0 mL / min;

[0039] Sample injection volume: 50 μL;

[0040] Running time: 10 minutes.

[0041] In the present invention, as one of the implementation manners, the diluent is deionized water.

[0042] In the present invention, as one of the implementation manners, in step (6), the calculation formula for the chloride ion content is as follows:

[0043] Chloride ion content % = (A - b) / a * 10 / M * 100;

[0044] Among them,

[0045] A: Peak area of chloride ions in the test solution;

[0046] a: Slope of the linear regression equation;

[0047] b: Intercept of the linear regression equation;

[0048] 10: Dilution factor of the test sample;

[0049] M: Sampling amount of the test sample, mg.

[0050] Beneficial effects

[0051] 1. The present invention adopts the external standard method, which has higher sensitivity than the turbidimetry method in the pharmacopoeia, can accurately quantify, and has high precision; it has stronger specificity than the titration method and is not interfered by other similar substances in the sample; it has better reproducibility and is not affected by manual operation;

[0052] 2. The method of the present invention is more suitable for the detection of chloride ions in benzenesulfonic acid, with good specificity. The chloride ions can be effectively separated from benzenesulfonic acid, and the resolution is 2.1, achieving baseline separation. It has good linearity and can detect samples in a wide concentration range. It has good accuracy to ensure accurate test results. It has a low detection limit and can detect trace amounts of chloride ions in the sample. Description of the Drawings

[0053] Figure 1 : Specificity chromatogram of the diluent;

[0054] Figure 2 : Specificity chromatogram of the linear solution;

[0055] Figure 3 : Specificity chromatogram of the test solution;

[0056] Figure 4 : System suitability - 1 chromatogram;

[0057] Figure 5 : System suitability - 2 chromatogram;

[0058] Figure 6 : System suitability - 3 chromatogram;

[0059] Figure 7 : System suitability - 4 chromatogram;

[0060] Figure 8 : System suitability - 5 chromatogram;

[0061] Figure 9 : Chromatogram of linear L1 solution;

[0062] Figure 10 : Chromatogram of linear L2 solution;

[0063] Figure 11 : Chromatogram of linear L3 solution;

[0064] Figure 12 : Chromatogram of linear L4 solution;

[0065] Figure 13 : Chromatogram of linear L5 solution;

[0066] Figure 14 : Regression curve;

[0067] Figure 15 : Recovery rate 50% - 1 chromatogram;

[0068] Figure 16 : Recovery rate 50% - 2 chromatogram;

[0069] Figure 17 : Recovery rate 50% - 3 chromatogram;

[0070] Figure 18 : Spectrogram of 100% recovery rate - 1;

[0071] Figure 19 : Spectrogram of 100% recovery rate - 2;

[0072] Figure 20 : Spectrogram of 100% recovery rate - 3;

[0073] Figure 21 : Spectrogram of 150% recovery rate - 1;

[0074] Figure 22 : Spectrogram of 150% recovery rate - 2;

[0075] Figure 23 : Spectrogram of 150% recovery rate - 3;

[0076] Figure 24 : Detection limit spectrogram;

[0077] Figure 25 : Quantitation limit spectrogram;

[0078] Figure 26 : Precision - 1 spectrogram;

[0079] Figure 27 : Precision - 2 spectrogram;

[0080] Figure 28 : Precision - 3 spectrogram;

[0081] Figure 29 : Precision - 4 spectrogram;

[0082] Figure 30 : Precision - 5 spectrogram;

[0083] Figure 31 : Precision - 6 spectrogram. Detailed implementation manners

[0084] The following examples are used to further illustrate the present invention, but do not limit the effective scope of the present invention in any way.

[0085] Example 1 Chromatographic conditions and solution preparation

[0086] 1.1 Instruments and reagents

[0087] Instrument: Thermo Fisher ICS - 5000 ion chromatograph

[0088] Reagents: All reagents used are of chromatographic grade; benzenesulfonic acid (Finar)

[0089] 1.2.1 Mobile phase concentration screening

[0090] Prepare the mobile phase: Prepare sodium hydroxide solutions with different concentrations as the mobile phase (4, 8, 10, 15, 20, 25 mmol / L).

[0091] Prepare the test solution: Weigh accurately 400 mg of benzenesulfonic acid, take 5 mL of the linear stock solution, place them in the same 10 mL volumetric flask, dissolve with the diluent and dilute to the mark, shake well to obtain the solution.

[0092] According to the chromatographic conditions, use sodium hydroxide solutions with different concentrations as the mobile phase for screening.

[0093] Table 1-1 Screening of Mobile Phase Concentrations

[0094] Mobile phase concentration (mmol / L) Screening results 4 Baseline fluctuation, affecting the integration of the main peak 8 Resolution 2.4 10 Resolution 2.1 15 Resolution 1.8 20 Resolution 1.6 25 Resolution 1.3, unable to separate

[0095] It can be seen from the results in Table 1-1 above that when the mobile phase concentration is 8-10 mmol / L, the resolution is relatively high. Therefore, an aqueous solution of 8-10 mmol / L sodium hydroxide can be selected as the mobile phase.

[0096] 1.2.2 Chromatographic Conditions

[0097] Chromatographic column:

[0098] Pre-column: Dionex IonPac TM AG11 RFIC TM (50×4 mm);

[0099] Analytical column: Dionex IonPac TM AS11 RFIC TM (250×4 mm);

[0100] Mobile phase: Aqueous solution of 10 mmol / L sodium hydroxide;

[0101] Column temperature: 30 °C;

[0102] Flow rate: 1.0 mL / min;

[0103] Injection volume: 50 μL;

[0104] Running time: 10 minutes.

[0105] 1.3 Solution Preparation

[0106] Diluent: Deionized water.

[0107] Test solution: Weigh accurately 400 mg of this product, place it in a 10 mL volumetric flask, dissolve with the diluent and dilute to the mark, shake well to obtain the solution.

[0108] Linear solution: Weigh accurately 40 mg of sodium chloride, transfer it to a 10-mL volumetric flask, add diluent to prepare a solution with a concentration of 4 mg / mL as the stock solution. Accurately measure 1 mL of the above stock solution, transfer it to a 100-mL volumetric flask, add diluent to the mark, shake well, and use it as the linear stock solution. The preparation of the linear solution is shown in Table 1-2.

[0109] Table 1-2 Preparation Table of Linear Solution

[0110] Linear solution Volume of linear stock solution taken (mL) Volumetric flask (mL) L1 0.5 10 L2 2.5 10 L3 5 10 L4 7.5 10 L5 10 10

[0111] Example 2 Specificity Experiment

[0112] Inject the diluent, linear solution L3, and the test solution into the chromatograph respectively, record the chromatograms, and examine the specificity.

[0113] There is no significant chromatographic peak interference at or near the chloride ion peak in the diluent; in the test solution, there is no significant chromatographic peak interference at or near the elution peak of chloride ion, indicating that the specificity of this method is good. The original chromatograms are shown in the appendix Figures 1 - 3 。

[0114] Example 3 System Suitability Experiment

[0115] Inject the L3 linear solution continuously for 5 times. The RSD of the chloride ion peak area is 0.2%, indicating good system suitability. The determination results are shown in Table 2 below. The original chromatograms are shown in the appendix Figures 4 - 8 。

[0116] Table 2 System Suitability Results

[0117]

[0118] Example 4 Linearity Experiment

[0119] Weigh approximately 40 mg of sodium chloride, add diluent to prepare a solution with a concentration of approximately 4 mg / mL as the stock solution. Accurately measure 1 mL of the above stock solution, transfer it to a 100-mL volumetric flask, add diluent to the mark, shake well, and use it as the linear stock solution. Prepare L1 - L5 linear solutions according to Table 3. Chloride ion mass = (35.5 / 58.44) * weighed amount of sodium chloride. Molecular weight of sodium chloride: 58.44, chloride ion: 35.5.

[0120] Table 3 Preparation Table of Linear Solution

[0121] Number (Pipetting volume → volumetric flask) Chloride ion concentration approximately (μg / mL) L1 0.5 → 10 mL 1.27 L2 2.5 → 10 mL 6.39 L3 5.0 → 10 mL 12.78 L4 7.5 → 10 mL 19.17 L5 Linear stock solution 25.57

[0122] Record the chromatograms, with the concentration as the abscissa (X) and the peak area as the ordinate (Y), perform linear regression, and calculate the correlation coefficient (r) of the regression line. The original chromatograms are shown in the appendix Figures 9 - 13 。

[0123] Linear regression equation for chloride ion: y = 427.21x + 0.01, correlation coefficient R 2 = 1, and within the concentration range of 1.27 μg / mL to 25.57 μg / mL, the linear relationship is good. The regression curve is shown in the appendix Figure 14 .

[0124] Example 5 Recovery Experiment

[0125] Verify the concentration levels of 50% - 150%, prepare according to Table 4, and prepare 3 replicates for each concentration in parallel.

[0126] Table 4 Preparation Table of Recovery Solutions

[0127] Concentration level Sample (mg) Volume of linear stock solution added (mL) Volumetric flask volume (mL) R1-50％ 400 2.5 10 R2-100％ 400 5 10 R3-150％ 400 7.5 10

[0128] Inject the above-mentioned recovery solutions respectively, substitute the peak areas of the recovery samples into the linear equation to calculate the recovery rate. The measurement results are shown in Table 5 below, and the original chromatograms are shown in the appendix Figures 15 - 23 .

[0129] Table 5 Results of Recovery Tests

[0130]

[0131] As shown in Table 5 above, for 3 concentrations and 9 samples, the RSD of the recovery rate is good. When the content of the component to be measured is 0.01%, RSD%: 3.3, indicating that the accuracy of this method is good.

[0132] Example 6 Detection Limit and Quantification Limit Experiments

[0133] Take the linear solution L1 of sodium chloride, dilute it by 264 times, use the signal-to-noise ratio S / N = 3 as the detection limit, take the linear solution L1 of sodium chloride, dilute it by 79 times, use S / N = 10 as the quantification limit. The results are shown in Table 6 below, and the original chromatograms are shown in the appendix Figures 24 - 25 .

[0134] Table 6 Results of Detection Limit and Quantification Limit

[0135] Name Quantitation limit (μg / ml) Detection limit (μg / ml) Chloride ion 0.01662 0.0049

[0136] As shown in Table 6 above, the quantification limit concentration is: 0.01662 μg / mL, and the detection limit concentration is: 0.0049 μg / mL. It can detect chloride ions at a relatively low concentration.

[0137] Example 7 Precision Test

[0138] Prepare 6 test solution samples according to Table 7-1, inject them, record the chromatograms, and calculate the RSD of each content. The results are shown in Table 7-2 below, and the original chromatograms are shown in the appendix Figures 26 - 31 .

[0139] Table 7-1 Preparation of Precision Solutions

[0140] Precision level Benzenesulfonic acid sample (mg) Volumetric flask volume (mL) Precision - 1 406.92 10 Precision - 2 408.34 10 Precision - 3 404.24 10 Precision - 4 402.20 10 Precision - 5 404.56 10 Precision - 6 405.33 10

[0141] Table 7-2 Results of precision test

[0142] Name Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Sample 6 RSD (%) Chloride ion content % 0.0155 0.0161 0.0167 0.0151 0.0157 0.0170 4.4

[0143] As shown in Table 7 above, the average chloride ion content of 6 samples is: 0.01603%, RSD%: 4.4. This indicates that this method has good repeatability and can accurately detect.

[0144] Example 8 Durability experiment

[0145] Take linear solutions L1-L5 and the spiked solution with a recovery rate of 100%, and determine by the standard curve method. The column temperature is changed by ±5°C and the flow rate is changed by ±0.2 ml, and the content in the spiked solution with a recovery rate of 100% is investigated. The specific results are shown in Table 8.

[0146] Table 8 Results of durability test

[0147]

[0148]

[0149] As can be seen from Table 8 above, when the flow rate is 1.2 mL / min, 0.8 mL / min; and the column temperature is 35°C and 25°C, the system suitability R value is greater than 0.99, and the absolute value of the difference in results is 0.0002%, 0.0002%, 0.0006%, 0.0022%, all less than 0.005%. This method has good durability to changes in flow rate and column temperature.

[0150] Example 9 Sample test results

[0151] This method is used to detect different batches of benzenesulfonic acid samples. The sample test results are shown in Table 9:

[0152] Table 9 Table of sample test results

[0153] Sample batch number 255363520DR 27820D201AS 28837D203ES 27815D231LR Chloride ion % 0.012 0.0092 0.010 0.012

[0154] As shown in Table 9 above, even if the chloride ion content in benzenesulfonic acid is low, the method of the present invention can still effectively detect the chloride ion content, and this method has good accuracy, sensitivity and reproducibility.

Claims

1. A method for detecting chloride ions in benzenesulfonic acid, characterized in that, The method uses an ion chromatograph to detect benzenesulfonic acid samples, and the chromatographic conditions are as follows: Chromatographic column: Anion exchange chromatographic column, Mobile phase: Aqueous solution of 8 - 20 mmol / L sodium hydroxide, Column temperature: 25 - 35 °C, Flow rate: 0.8 - 1.2 mL / min, Injection volume: 25 - 75 μL.

2. The detection method according to claim 1, wherein The mobile phase is an aqueous solution of 10 mmol / L sodium hydroxide.

3. The method according to claim 1, wherein The chromatographic column includes Dionex IonPac TM AS11RFIC TM , 250×4 mm as the separation column.

4. The detection method according to claim 1, wherein The column temperature of the chromatographic column is 30 °C.

5. The detection method according to claim 1, wherein The flow rate of the chromatographic column is 1.0 mL / min.

6. The detection method according to claim 1, wherein The injection volume is 50 μL.

7. The detection method according to claim 1, wherein The chromatographic conditions further include a running time of 10 min.

8. The detection method according to claim 1, wherein, The chromatographic conditions also include an isocratic elution condition for the elution condition.

9. The method according to claim 1, wherein The chromatographic column also includes Dionex IonPac TM AG11RFIC TM , 50×4 mm as a guard column.

10. The detection method according to any one of claims 1 to 9, characterized in that, The method further includes: Using an anion exchange chromatographic column, with a sodium hydroxide solution as the mobile phase, adopting the standard curve method, and using ion chromatography to detect the residual content of chloride ions in benzenesulfonic acid, including the following steps: (1) Prepare a linear solution: Weigh 40 mg of sodium chloride accurately, transfer it to a 10 mL volumetric flask, add a diluent to make a 4 mg / mL solution as the stock solution. Accurately measure 1 mL of the above stock solution, place it in a 100 mL volumetric flask, add the diluent to the scale, and shake well to obtain the linear stock solution. Prepare L1 - L5 linear solutions according to the following table: ； (2) Record the chromatogram, with the concentration as the abscissa (X) and the peak area as the ordinate (Y), perform linear regression to obtain the linear regression equation of chloride ions, and calculate the correlation coefficient (r) of the regression equation; (3) Prepare the test solution: Weigh 400 mg of the test sample benzenesulfonic acid accurately, transfer it to a 10 mL volumetric flask, dissolve and dilute it to the scale with a diluent, and shake well to obtain it; (4) Take 50 μL of the test solution and inject it into the chromatographic column; (5) Record the chromatogram, substitute it into the chloride ion linear regression equation y = ax + b, and use the standard curve method to calculate the chloride ion concentration x = (y - b) / a; Among them, the chromatographic conditions of the chromatographic column in step (4) are: Chromatographic column: Pre-column: Dionex IonPac TM AG11 RFIC TM (50×4mm); Separation column: Dionex IonPac TM AS11 RFIC TM (250×4mm); Mobile phase: Aqueous solution of 10 mmol / L sodium hydroxide; Column temperature: 30 °C; Flow rate: 1.0 mL / min; Injection volume: 50 μL; Running time: 10 minutes.

11. The detection method according to claim 10, characterized in that The diluent is deionized water.

12. The detection method according to claim 11, wherein In step (6), the calculation formula for the chloride ion content is: Chloride ion content % = (A - b) / a * 10 / M * 100; Among them, A: The peak area of chloride ions in the test solution; a: The slope of the linear regression equation; b: The intercept of the linear regression equation; 10: The dilution factor of the test sample; M: The weighed amount of the test sample, mg.

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