Method for detecting quinidine sulfate column passing process on line by potentiometric titration method

Abstract

The invention relates to a method for on-line detection of a quinidine sulfate column-passing process by potentiometric titration, which comprises the following steps: S1, taking the effluent of the quinidine sulfate column-passing process in different periods, adding an inert solvent, and then adding a diluent as a test liquid; s2, placing the test solution on a potentiometric titrator, titrating with a perchloric acid titration solution to obtain a titration curve, and when the titration curve has a second-stage jump, judging that a titration end point is reached, and stopping titration; s3, calculating the concentration of quinidine sulfate in the effluent according to the volume of the perchloric acid titration solution, and drawing a quinidine sulfate concentration-time curve; according to the method, a propionic acid-propionic anhydride diluent system is adopted, an inert solvent toluene is added, interference of dichloromethane and methanol contained in effluent of a column chromatography process on a potentiometric titration method is eliminated, a titration curve has secondary potential jump by optimizing a solvent ratio, a titration end point is marked by the secondary potential jump, and the titration accuracy is improved. And the detection is more convenient, rapid and accurate.

Description

Technical Field

[0001] This invention relates to the field of quality control technology for quinidine sulfate, and more particularly to a method for online detection of quinidine sulfate in column chromatography using potentiometric titration. Background Technology

[0002] Quinidine sulfate is the sulfate form of quinidine, an alkaloid extracted from cinchona bark. It is a white or off-white crystalline powder, odorless, and extremely bitter. Its sulfate form improves the drug's water solubility, making it easier to formulate into oral preparations. Classification: Class Ia antiarrhythmic drug. Source: It is the dextrorotatory stereoisomer of the antimalarial drug quinine. The chemical formula of quinidine sulfate is (C...). 20 H 24 N2O2)2·H2SO4, the compound structure is as follows: Figure 1 As shown.

[0003] Quinidine sulfate is primarily used for maintenance therapy after electrical cardioversion of atrial fibrillation or atrial flutter. It also has some efficacy against premature atrial contractions, paroxysmal supraventricular tachycardia, Wolff-Parkinson-White syndrome with supraventricular arrhythmias, premature ventricular contractions, and ventricular tachycardia, and can convert atrial fibrillation or atrial flutter. Quinidine sulfate is a cell membrane inhibitor, and its main mechanism of action is the inhibition of Na+. + Inflow also hinders K + Outflow and Ca 2+ Influx slows the rise rate of phase 0 of the action potential, reduces the slope of phase 4, prolongs the duration of the action potential and the effective refractory period, raises the threshold potential and reduces automaticity, conductivity and myocardial contractility, which is beneficial for eliminating reentrant excitation and ectopic rhythms.

[0004] In the early 19th century, scientists began isolating various alkaloids from cinchona bark. In 1820, French chemists Pierre Joseph Pelletier and Joseph Caventou first isolated pure quinine. During the extraction of quinine, they noticed a substance that was very similar to but distinct from quinine. This substance was named "quinidine," meaning "an alkaloid similar to quinine." As early as the 18th century, doctors reported that patients treating malaria with cinchona bark experienced improvement in palpitations (i.e., atrial fibrillation). By the mid-20th century, quinidine was the first-line standard drug for treating supraventricular arrhythmias such as atrial fibrillation and atrial flutter. With the development of electrophysiology, its mechanism of action was clarified (sodium channel blocker, class Ia). In 2010, Nuedexta, a combination of quinidine sulfate and dextromethorphan hydrobromide developed by Avanir Pharmaceuticals Inc., received marketing approval from the U.S. Food and Drug Administration (FDA) for the treatment of pseudobulbar affective disorder (PBA).

[0005] Currently, in existing technologies, thin-layer chromatography is commonly used for the determination of quinidine sulfate using column chromatography. Although this method is relatively fast, it cannot provide quantitative results. While high-performance liquid chromatography can provide quantitative results, it is time-consuming and not easy to operate, making it unsuitable as an online detection method.

[0006] Therefore, this invention proposes a method for online detection of quinidine sulfate in a column chromatography process using potentiometric titration to solve the above-mentioned problems. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a method for online detection of quinidine sulfate in column chromatography using potentiometric titration, which is simple to operate.

[0008] To solve the above-mentioned technical problems, the technical solution of the present invention is: a method for online detection of quinidine sulfate using potentiometric titration in a column chromatography process, the innovation of which lies in the following steps: S1. Take 50 ml of the effluent from the column chromatography process of quinidine sulfate at different time points, add 1 ml of inert solvent, and then add 50 ml of diluent to make a test solution. S2. Place the test solution on a potentiometric titrator and titrate with perchloric acid titrant to obtain a titration curve. When the titration curve shows a second-order jump, it is determined that the titration endpoint has been reached and the titration is stopped. S3. Calculate the concentration of quinidine sulfate in the effluent based on the volume of the perchloric acid titrant, plot the quinidine sulfate concentration-time curve, and determine the progress of the quinidine sulfate column chromatography process.

[0009] Furthermore, the inert solvent is toluene.

[0010] Furthermore, the diluent is a mixture of propionic anhydride and propionic acid.

[0011] Furthermore, the ratio of propionic acid to propionic anhydride in the diluent is 1:9, and the purity is analytical grade.

[0012] Furthermore, the concentration of the perchloric acid titrant is 0.05 mol / L.

[0013] Furthermore, the electrodes of the potentiometric titrator are glass composite electrodes and contain a polytetrafluoroethylene protective sleeve.

[0014] The advantages of this invention are: The present invention provides a method for online detection of quinidine sulfate in a column chromatography process using potentiometric titration. By employing a propionic acid-propionic anhydride diluent system and adding the inert solvent toluene, the interference of dichloromethane and methanol contained in the column chromatography effluent on the potentiometric titration method is eliminated. By optimizing the solvent ratio, a second-order potential jump appears in the titration curve, and the titration endpoint is marked by the second-order potential jump, making the detection more convenient, faster, and more accurate. Attached Figure Description

[0015] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.

[0016] Figure 1 The chemical structure of quinidine sulfate of the present invention is shown below.

[0017] Figure 2 The titration curves obtained for embodiments of the present invention.

[0018] Figure 3 The concentration-time curve of quinidine sulfate obtained for an embodiment of the present invention. Detailed Implementation

[0019] To further illustrate the technical means and effects of the present invention in achieving its intended purpose, the following detailed description of the specific implementation methods, structures, features, and effects of the present invention, in conjunction with the accompanying drawings and preferred embodiments, is provided below.

[0020] Comparative Example 1 This comparative example uses perchloric acid titration to determine quinidine sulfate. The procedure is as follows: Take 0.2 g of the effluent from the quinidine sulfate column chromatography process, dissolve it in 5 ml of glacial acetic acid, add 20 ml of acetic anhydride and 1 drop of crystal violet indicator, and titrate with 0.1 mol / L perchloric acid titrant until the solution turns green. Correct the titration result with a blank test. Each 1 ml of perchloric acid titrant (0.1 mol / L) is equivalent to 24.90 mg of (C 20 H24 The results showed that the effluent from the column chromatography process contained dichloromethane and methanol, which interfered with the accuracy of the perchloric acid titration method.

[0021] Comparative Example 2 This comparative example uses potentiometric titration for online detection of quinidine sulfate in a column chromatography process. The potentiometric titrator is equipped with a glass composite electrode and a polytetrafluoroethylene protective sleeve.

[0022] The process of online detection of quinidine sulfate column chromatography using potentiometric titration in this comparative example is as follows: 50 ml of the effluent from the quinidine sulfate column chromatography process at different time points was taken, and 25 ml of propionic acid and 25 ml of propionic anhydride were added to prepare the test solution; the purity of propionic acid and propionic anhydride was analytical grade; the test solution was placed on a potentiometric titrator, and titration was performed with 0.05 mol / L perchloric acid titrant to obtain a titration curve. No second-order jump appeared in the titration curve.

[0023] Comparative Example 3 This comparative example uses potentiometric titration for online detection of quinidine sulfate in a column chromatography process. The potentiometric titrator is equipped with a glass composite electrode and a polytetrafluoroethylene protective sleeve.

[0024] The process of online detection of quinidine sulfate column chromatography using potentiometric titration in this comparative example is as follows: 50 ml of the effluent from the quinidine sulfate column chromatography process at different time points was taken, and 10 ml of propionic acid and 40 ml of propionic anhydride were added as the test solution; the purity of propionic acid and propionic anhydride was analytical grade; the test solution was placed on a potentiometric titrator, and titration was performed with 0.05 mol / L perchloric acid titrant to obtain the titration curve. The second-order jump in the titration curve was not obvious, and the titration curve was disordered.

[0025] Comparative Example 4 This comparative example uses potentiometric titration for online detection of quinidine sulfate in a column chromatography process. The potentiometric titrator is equipped with a glass composite electrode and a polytetrafluoroethylene protective sleeve.

[0026] The process of online detection of quinidine sulfate column chromatography using potentiometric titration in this comparative example is as follows: 50 ml of the effluent from the quinidine sulfate column chromatography process at different time points was taken, 1 ml of toluene was added, and then 50 ml of propionic anhydride was added as the test solution; the purity of the propionic anhydride was analytical grade; the test solution was placed on a potentiometric titrator, and a titration curve was obtained by titration with a concentration of 0.05 mol / L perchloric acid titrant. No second-order jump appeared in the titration curve.

[0027] Example This embodiment provides a method for online detection of quinidine sulfate in a column chromatography process using potentiometric titration. The method employs a potentiometric titrator with glass composite electrodes and a polytetrafluoroethylene protective sleeve.

[0028] The method for online detection of quinidine sulfate using potentiometric titration in column chromatography includes the following steps: S1. Take 50 ml of the effluent from the column chromatography process of quinidine sulfate at different time points, add 1 ml of inert solvent toluene, then add 5 ml of propionic acid and 45 ml of propionic anhydride to prepare the test solution; the purity of propionic acid and propionic anhydride is analytical grade. S2. Place the test solution on a potentiometric titrator, and obtain the titration curve by titrating with a 0.05 mol / L perchloric acid titrant, as shown below. Figure 1 As shown, when the titration curve shows a second-order jump, it is determined that the titration endpoint has been reached, and the titration is stopped. S3. Calculate the concentration of quinidine sulfate in the effluent based on the volume of the perchloric acid titrant, and plot the quinidine sulfate concentration-time curve, as follows: Figure 2 As shown, the degree of progress of the quinidine sulfate column chromatography process is determined.

[0029] The methodological validation of the column chromatography process for online detection of quinidine sulfate using potentiometric titration in this embodiment was performed, and the results are shown in Table 1: Table 1. Methodological Validation Results project CP2020 Acceptable Standards Verification results Exclusivity The blank solvent should be free of interference. Solvent does not interfere with the determination Linearity and Range Prepare standard solutions of quinidine sulfate with concentrations of 0.001, 0.005, 0.01, 0.05, and 0.1 mg / mL, respectively, and perform potentiometric titrations. Plot a standard curve with concentration as the abscissa and titrant consumption as the ordinate, requiring a correlation coefficient R 2 ≥ 0.999.]]> Quinidine sulfate exhibits a good linear relationship between concentration and peak area within the concentration range of 0.01–1.0 mg / ml. Accuracy Take a sample of quinidine sulfate of known concentration (e.g., 0.01 mg / mL), perform three parallel titrations, calculate the recovery rate, and the recovery rate should be between 98% and 102%. Based on the results of three parallel titrations, the recovery rate was calculated, which was between 98% and 102%, indicating a good recovery rate. Precision Perform six parallel titrations on a standard solution of the same concentration (0.01 mg / mL) and calculate the relative standard deviation (RSD). The RSD should be ≤ 1.0%. Experimental results show that the RSD of the standard solution was less than 1.0% in six parallel titrations, indicating that the injection precision of this method is good. Anti-interference Impurities that may be present in the column chromatography process (such as quinine or other alkaloids) are added to the quinidine sulfate standard solution, and the concentration change is measured. When the impurity concentration is ≤5%, the detection error is ≤2%. Experimental results show that when impurities that may be present in the column chromatography process are added to the quinidine sulfate standard solution, and the concentration change is measured, the detection error is ≤2% when the impurity concentration is ≤5%. The validation results show that all indicators of this method meet the requirements of the 2020 edition of the Chinese Pharmacopoeia and are suitable for detection.

[0030] The method of online detection of quinidine sulfate column chromatography using potentiometric titration enables real-time and accurate monitoring of the quinidine sulfate column chromatography process, providing reliable data support for optimizing elution parameters and improving product recovery and purity. It is especially suitable for industrial continuous production scenarios and is of indispensable significance for the detection of quinidine sulfate.

[0031] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A method for online detection of quinidine sulfate via column chromatography using potentiometric titration, characterized in that: Includes the following steps: S1. Take 50 ml of the effluent from the column chromatography process of quinidine sulfate at different time points, add 1 ml of inert solvent, and then add 50 ml of diluent to make a test solution. S2. Place the test solution on a potentiometric titrator and titrate with perchloric acid titrant to obtain a titration curve. When the titration curve shows a second-order jump, it is determined that the titration endpoint has been reached and the titration is stopped. S3. Calculate the concentration of quinidine sulfate in the effluent based on the volume of the perchloric acid titrant, plot the quinidine sulfate concentration-time curve, and determine the progress of the quinidine sulfate column chromatography process.

2. The method for online detection of quinidine sulfate using potentiometric titration in column chromatography according to claim 1, characterized in that: The inert solvent is toluene.

3. The method for online detection of quinidine sulfate using potentiometric titration in column chromatography according to claim 2, characterized in that: The diluent is a mixture of propionic anhydride and propionic acid.

4. The method for online detection of quinidine sulfate using potentiometric titration column chromatography according to claim 3, characterized in that: The ratio of propionic acid to propionic anhydride in the diluent is 1:9, and the purity is analytical grade.

5. The method for online detection of quinidine sulfate using potentiometric titration in column chromatography according to claim 1, characterized in that: The concentration of the perchloric acid titrant is 0.05 mol / L.

6. The method for online detection of quinidine sulfate using potentiometric titration column chromatography according to claim 1, characterized in that: The electrodes of the potentiometric titrator are glass composite electrodes and contain a polytetrafluoroethylene protective sleeve.

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