Method for detecting dissolution rate of ilaprazole

Abstract

The invention discloses a method for detecting the dissolution rate of ilaprazole. The invention provides a method for detecting the dissolution rate of ilaprazole. The dissolution rate of ilaprazole is detected by adopting an ultraviolet-visible spectrophotometric method. The detection method disclosed by the invention has the advantages of simplicity and convenience in operation, good repeatability, more stable dissolution rate data, better dissolution amount, convenience and rapidness, easiness in automation, more accurate and stable detection result and more suitability for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for detecting the dissolution rate of ilaprazole. BACKGROUND

[0002] Ilaprazole, chemical name 5-(1 hydrogen-pyrrole-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]-sulfinyl-1 hydrogen-benzimidazole, as a new generation of proton pump inhibitor (PPI), is widely used in various acid-related digestive diseases, such as duodenal ulcer, gastric ulcer, reflux esophagitis, etc. Compared with other PPIs, ilaprazole has the advantages of the strongest anti-acid activity, no individual difference in treatment, stronger ability to control acid at night, etc., and is expected to become a core product in the PPI market.

[0003] Ilaprazole is easily destroyed in gastric acid, so the ilaprazole enteric-coated tablets used in domestic and international clinical practice at present are all enteric-coated tablets, and the dissolution rate of the enteric-coated tablets in the body is crucial to the efficacy of the drug. The current standard for ilaprazole enteric-coated tablets is to add 30% isopropyl alcohol to the medium, and the existing technology requires removal of organic solvents. CN10846939B reports a dissolution rate detection method for ilaprazole composition, which uses high performance liquid chromatography for detection, but ilaprazole is unstable and can easily degrade, the impurities and main components peak at different times using the liquid phase method, the concentration of the dissolution solution is low, and many impurities cannot be detected, resulting in insufficient accuracy of the dissolution data.

[0004] Therefore, it is an urgent technical problem to be solved to find a dissolution rate determination method which is simple to operate, has good repeatability, high stability, convenient and fast, easy to automate, and high accuracy. SUMMARY

[0005] The present application provides a method for detecting the dissolution rate of ilaprazole, which is completely different from the prior art. The detection method of the present application is simple to operate, simple to calculate, has high repeatability, good stability, and high accuracy, and is more suitable for industrial production.

[0006] The present application provides a method for detecting the dissolution rate of ilaprazole, which is completely different from the prior art. The detection method of the present application is simple to operate, simple to calculate, has high repeatability, good stability, and high accuracy, and is more suitable for industrial production.

[0007] In the present application, the detection wavelength of the ultraviolet-visible spectrophotometry is preferably 231nm-238nm, for example, 237nm.

[0008] In the present application, the ultraviolet-visible spectrophotometry preferably uses an ultraviolet spectrophotometer; the model of the ultraviolet spectrophotometer can be Evolution 201 of Thermo.

[0009] In the present application, the blank solution for the UV-visible spectrophotometry detection can be pH 6.8+0.1% SDS medium-pH 6.8+1.0% SDS medium, for example, pH 6.8+0.5% SDS medium.

[0010] In the present application, the ilaprazole includes ilaprazole raw material and pharmaceutical preparation with ilaprazole as active ingredient, for example, ilaprazole capsule, ilaprazole injection and ilaprazole tablet (for example, ilaprazole enteric-coated tablet) and the like.

[0011] In the present application, the detection method of ilaprazole dissolution degree includes the following steps: taking the control solution and the sample solution to be detected at 231 nm-238 nm wavelength, taking pH 6.8+0.1% SDS-pH 6.8+1.0% SDS medium as blank solution, respectively measuring the absorbance of the control solution and the sample solution to be detected, obtaining the absorbance value, and then calculating the dissolution degree of ilaprazole by external standard method.

[0012] In the present application, the detection method of ilaprazole dissolution degree specifically includes the following steps: blank solution (medium solution) preparation, sample solution preparation, control solution preparation, blank excipient solution preparation, absorbance curve determination and ilaprazole dissolution degree calculation; the above solution preparation steps are not in sequence.

[0013] The blank solution (medium solution or diluent) solution is preferably prepared by the following steps: taking 0.1%-1% sodium dodecyl sulfate (the percentage refers to the mass of sodium dodecyl sulfate accounting for the total mass of the dissolution medium) medium and pH 5.5-pH 6.8 sodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution as blank solution.

[0014] The sample solution preparation preferably adopts the following steps: taking ilaprazole sample, dissolving in the dissolution medium, adding buffer solution and shaking, taking appropriate amount of dissolution solution, filtering, immediately adding appropriate amount of sodium hydroxide solution to adjust pH 10.5-11.5, shaking, filtering, and obtaining the sample solution.

[0015] In the sample solution preparation step, the dissolution medium is preferably sodium chloride hydrochloric acid solution. The buffer solution is preferably phosphate buffer solution; the phosphate buffer solution is preferably sodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution. The pH of the buffer solution is preferably 5.5-6.8.

[0016] The control solution preparation preferably adopts the following steps: weighing ilaprazole control, adding organic solvent to constant volume, diluting with dissolution medium, shaking, filtering, diluting the filtrate in alkaline solution, shaking, and obtaining the control solution.

[0017] In the preparation of the control solution, the organic solvent is preferably a nitrile solvent, and the nitrile solvent is preferably acetonitrile. The dissolution medium can be a solution of pH 6.8+0.1% SDS to pH 6.8+1.0% SDS.

[0018] Preferably, the blank excipient solution is prepared by the following steps: weighing the blank excipient, adding the dissolution medium for dilution, shaking, filtering, diluting the filtrate in an alkaline solution, and shaking to obtain the blank excipient solution.

[0019] In the preparation of the blank excipient solution, the dissolution medium can be a solution of pH 6.8+0.1% SDS to pH 6.8+1.0% SDS. The alkaline solution is preferably a sodium hydroxide solution. The concentration of the sodium hydroxide solution is preferably 0.1 mol / L to 1.0 mol / L, for example, 0.5 mol / L.

[0020] Preferably, the absorbance curve is determined by the following steps: taking the test sample solution and the control solution, respectively, and determining the absorbance value according to the ultraviolet-visible spectrophotometry.

[0021] Preferably, the dissolution of ilaprazole is calculated by the following steps: calculating the dissolution of the test sample using the external standard method based on the above-mentioned absorbance value.

[0022] Without deviating from the common knowledge in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain various preferred examples of the present application.

[0023] The reagents and raw materials used in the present application are commercially available.

[0024] The positive progress effect of the present application is that the detection method of the present application has the advantages of simple operation, good repeatability, convenience, easy automation, more stable dissolution data, higher accuracy, and better suitability for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 : Liquid phase cumulative dissolution curve of ilaprazole enteric-coated tablets;

[0026] Figure 2 : UV cumulative dissolution curve of ilaprazole enteric-coated tablets. DETAILED DESCRIPTION

[0027] The present application will be further described by way of examples, but the present application is not limited to the examples. In the following examples, the experimental methods not specified in the examples are selected according to conventional methods and conditions, or according to the instructions of the goods.

[0028] Example 1:

[0029] 1. Instruments and apparatus: UV spectrophotometer Thermo Fisher Evolution 201;

[0030] 2. Reference substance: Esomeprazole reference substance, China Institute for Drug Control, batch number 00908-202002, content 99.5%.

[0031] 3. UV test conditions: detection wavelength 237 nm, blank solution pH 6.8 + 0.5% SDS medium.

[0032] Experimental operation

[0033] Step 1: Preparation of blank solution (medium solution or diluent):

[0034] Preparation of pH 6.8 + 0.5% SDS medium solution: take sodium dihydrogen phosphate 6 g, add sodium hydroxide 0.9 g, add water to 1000 ml, and then add sodium dodecyl sulfate 5.0 g, and you get it.

[0035] 0.5 mol / L sodium hydroxide solution: weigh sodium hydroxide 2.0 g, add water 100 ml, and you get it.

[0036] Step 2: Preparation of test sample solution:

[0037] Take 1 piece of esomeprazole test product (175 mg) and sodium chloride hydrochloric acid solution (take sodium chloride 2 g, add hydrochloric acid 7 ml, and add water to 1000 ml) 900 ml as the dissolution medium, the rotation speed is 100 revolutions per minute, and the operation is carried out according to the law. After 120 minutes, discard the hydrochloric acid solution, take out the test product, wash the surface hydrochloric acid solution with water, immediately add the preheated phosphate buffer solution (sodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution, adjust the pH to 5.5-6.8 with sodium hydroxide solution) 900 ml to the dissolution cup, continue to operate according to the law, take sample after 45 minutes, filter the dissolution liquid, accurately take 5 ml of the filtrate, immediately accurately add 1 ml of 0.05 mol / L sodium hydroxide solution, shake well, filter, and take the filtrate.

[0038] Step 3: Preparation of reference solution:

[0039] Accurately weigh 5.5 mg of esomeprazole reference substance into a 20 ml volumetric flask, ultrasonically dissolve with an appropriate amount of acetonitrile, dilute to the mark with acetonitrile, shake well, and use as a reference stock solution. Prepare two copies in parallel.

[0040] Accurately transfer 1 ml of the reference stock solution to a 50 ml volumetric flask containing 9.5 mg of blank auxiliary material, dilute to the mark with pH 6.8 + 0.5% SDS medium, shake well, filter, accurately transfer 5.0 ml to a 10 ml centrifuge tube, and then accurately transfer 1.0 ml of 0.5 mol / L sodium hydroxide solution to the centrifuge tube, shake well, and you get it.

[0041] Step 4, blank excipient solution preparation:

[0042] Accurately weigh 9.5 mg of blank excipient into a 50 ml volumetric flask, dilute to the mark with pH 6.8 + 0.5% SDS medium, shake well, filter, accurately transfer 5.0 ml into a 10 ml centrifuge tube, and then accurately transfer 1.0 ml of 0.5 mol / L sodium hydroxide solution into the centrifuge tube, shake well, and obtain.

[0043] Step 5: absorbance curve determination

[0044] Accurately transfer the control solution of step 3 into the corresponding volumetric flask according to the table below, dilute to the mark with pH 6.8 + 0.5% SDS medium, shake well, accurately transfer 5.0 ml into a 10 ml centrifuge tube, and then accurately transfer 1.0 ml of 0.5 mol / L sodium hydroxide solution into the centrifuge tube, shake well, and obtain;

[0045] Linear horizontal 25％ 50％ 100％ 125％ 150％ Aliquot volume / ml 1 1 1 5 3 Vial volume / ml 200 100 50 200 100

[0046] Step 6: elprazole dissolution test

[0047] Time (min) Mean dissolution (%) RSD % 0 0 0 5 0 0 10 1 / 20 94 1.9 30 96 0.7 45 98 0.7 60 98 0.7 75 97 0.8

[0048] Example 2: recovery experiment of detection method

[0049] 100% accuracy solution preparation:

[0050] Accurately transfer 1 ml of the control stock solution of step 3 into a 50 ml volumetric flask containing 9.5 mg of blank excipient, dilute to the mark with pH 6.8 + 0.5% SDS medium, shake well, filter, accurately transfer 5.0 ml into a 10 ml centrifuge tube, and then accurately transfer 1.0 ml of 0.5 mol / L sodium hydroxide solution into the centrifuge tube, shake well, and obtain three parallel preparations. The recovery test results are shown in Table 1; the linear test results are shown in Table 2; the liquid chromatography dissolution spectrum is shown in Figure 1 ; and the ultraviolet dissolution spectrum is shown in Figure 2 .

[0051] Table 1: recovery test results

[0052]

[0053] Table 2: linear test results

[0054]

[0055] Conclusion: the ultraviolet method has been verified, the 100% concentration accuracy values are all between 98% and 105%, and the linearity also meets the requirements, indicating that the method can accurately detect the dissolution data of elprazole.

[0056] Comparative Example Dissolution Method of Esomeprazole Enteric-coated Tablets Liquid Phase Method (Method reported in CN108469398B) and UV Detection Method of the Invention

[0057] The specific operation is as follows:

[0058] Dissolution was determined according to Dissolution and Release Determination Method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Second Enteric-coated Preparation Method 2). 900 ml of sodium chloride hydrochloric acid solution (take 2 g of sodium chloride, add 7 ml of hydrochloric acid, and add water to 1000 ml) was used as the dissolution medium, the rotation speed was 100 revolutions per minute, and the operation was performed according to the law. After 120 minutes, the hydrochloric acid solution was discarded, the test sample was taken out, the surface hydrochloric acid solution was washed with water, and immediately 900 ml of preheated to 37°C phosphate buffer (6.8 g of sodium hydrogen phosphate-sodium dihydrogen phosphate, 1.65 g of sodium hydroxide, 5.0 g of sodium dodecyl sulfate, add water to 1000 ml, use 2 mol / L phosphoric acid solution or 2 mol / L sodium hydroxide solution, and adjust the pH to 8.0 with sodium hydroxide solution) was added to the dissolution cup, and the operation was continued according to the law. Sample was taken after 45 minutes.

[0059] The test solution was taken out of the solution, filtered, and 5 ml of the filtrate was accurately taken. Immediately, 1 ml of 0.05 mol / L sodium hydroxide solution was accurately added, shaken, filtered, and the filtrate was taken.

[0060] The reference solution was taken about 11 mg of esomeprazole reference substance, accurately weighed, placed in a 20 ml volumetric flask, dissolved and diluted to the mark with acetonitrile, shaken, accurately taken 1 ml, placed in a 100 ml volumetric flask, diluted to the mark with phosphate buffer solution (pH 8.0), if necessary, a small amount of acetonitrile was added to remove foam, shaken, and accurately taken 5 ml. Immediately, 1 ml of 0.05 mol / L sodium hydroxide solution was accurately added, shaken, and accurately taken 5 ml.

[0061] The system suitability solution, chromatographic conditions, and system suitability requirements are as follows: see the content determination item. The sample plate is not temperature controlled.

[0062] The determination method is as follows: see the content determination item. The dissolution amount of each tablet was calculated.

[0063] Two batches of esomeprazole were detected by this method, and the detection results were as follows:

[0064]

[0065] According to the above data, the dissolution is unstable and the sample has a degradation trend when determined according to the method reported in CN108469398B.

[0066] According to the description of CN108469398B, the residual content of esomeprazole under different pH dissolution conditions is as follows:

[0067]

[0068] From the above table, it can be seen that ilaprazole degrades significantly in a pH 6.8 medium.

[0069] The results of the saturation solubility and solution stability test of the inventors in a pH 6.8 + 0.5% SDS medium show that ilaprazole degrades severely in a pH 6.8 + 0.5% SDS medium, and it is more difficult to detect by liquid phase method, so the ultraviolet method is used to test the dissolution curve in a pH 6.8 + 0.5% SDS medium.

[0070] 2. Test the dissolution curve of two batches of ilaprazole in a pH 6.8 + 0.5% SDS medium by ultraviolet method

[0071] The results are as follows:

[0072]

[0073] Conclusion: Compared with the liquid phase detection method, the dissolution data of ilaprazole by ultraviolet method is more stable, the ultraviolet method can detect the dissolution data in a pH 6.8 + 0.5% SDS medium which is difficult to detect by liquid phase method, the dissolution amount by ultraviolet detection method is better, more accurate and stable, and more suitable for industrial production.

Claims

1. A method for detecting the dissolution of ilaprazole, characterized by: The dissolution of esomeprazole is detected by UV-visible spectrophotometry.

2. The method for detecting the dissolution rate of ilaprazole according to claim 1, wherein: The detection wavelength of the UV-visible spectrophotometry is 231nm-238nm.

3. The method for detecting the dissolution rate of ilaprazole according to claim 2, wherein: The detection wavelength of the UV-visible spectrophotometry is 237nm.

4. The method for detecting the dissolution rate of ilaprazole according to claim 1, wherein: The UV-visible spectrophotometry adopts an ultraviolet spectrophotometer.

5. The method for detecting the dissolution rate of ilaprazole according to claim 4, wherein: The model of the ultraviolet spectrophotometer is Evolution 201 of Thermo Fisher.

6. The method of claim 1, wherein the method is for detecting the dissolution of ilaprazole. The esomeprazole includes esomeprazole raw materials and pharmaceutical preparations with esomeprazole as an active ingredient.

7. The method of claim 6, wherein the method is for detecting the dissolution of ilaprazole. The pharmaceutical preparations with esomeprazole as an active ingredient are esomeprazole capsules, esomeprazole injection and esomeprazole tablets; the esomeprazole tablets can be esomeprazole enteric-coated tablets.

8. The method of claim 1, wherein the method is for detecting the dissolution of ilaprazole. The blank solvent for the UV-visible spectrophotometry is pH6.8+0.1%SDS medium-pH6.8+1.0%SDS medium; for example, pH6.8+0.5%SDS medium. The detection method of the dissolution of esomeprazole includes the following steps: the control solution and the sample solution to be detected are measured at 231nm-238nm wavelength, with pH6.8+0.1%SDS-pH6.8+1.0%SDS medium as the blank, the absorbance of the control solution and the sample solution to be detected is determined respectively, the absorbance value is obtained, and then the dissolution of esomeprazole is calculated by the external standard method.

9. The method of claim 1, wherein the method is for detecting the dissolution of ilaprazole. The detection method of the dissolution of esomeprazole specifically includes the following steps: blank solution preparation, sample solution preparation, control solution preparation, blank auxiliary solution preparation, absorbance curve determination and esomeprazole dissolution calculation; the above solution preparation steps are not sequential.

10. The method for detecting the dissolution rate of ilaprazole according to claim 9, wherein: ​

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