A method for determining the content of vardenafil fumarate tablets

Abstract

This invention belongs to the field of pharmaceutical content detection, specifically relating to a method for determining the content of vonoprazan fumarate tablets. The vonoprazan fumarate tablets of this invention are prepared using mannitol, fumaric acid, croscarmellose sodium, hydroxypropyl cellulose, microcrystalline cellulose, and magnesium stearate as excipients. The preparation method described in this invention simplifies the preparation process and reduces production costs. This invention also provides the above-mentioned method for determining the content of vonoprazan fumarate tablets. High-performance liquid chromatography (HPLC) is used to accurately determine the content of the active ingredient vonoprazan in the prepared vonoprazan fumarate tablets. This method effectively eliminates the influence of added excipients and impurities on the determination of the active ingredient vonoprazan content, providing important assurance for clinical medication safety and offering a new method for the quality control of vonoprazan fumarate tablets.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical content detection, specifically relating to a method for determining the content of vonoprazan fumarate tablets. Background Technology

[0002] Vonoprazan fumarate tablets are an acid-suppressing drug used to treat reflux esophagitis. Because vonoprazan fumarate tablets may cause adverse reactions such as gastrointestinal reactions, allergic reactions, liver damage, edema, and eosinophilia, high dosage requirements are necessary during clinical use. During tablet manufacturing, various excipients such as mannitol and croscarmellose sodium are often added to maintain the stability of the active ingredient vonoprazan and meet dosage form requirements. The addition of these components significantly affects the detection of vonoprazan fumarate content in the tablets. Therefore, accurate determination of the vonoprazan fumarate content in vonoprazan fumarate tablets is crucial to ensure the safety of clinical use. Summary of the Invention

[0003] This invention provides a method for detecting the content of vonoprazan fumarate tablets, which can accurately determine the content of vonoprazan fumarate in the tablets, providing an important guarantee for the clinical use of vonoprazan fumarate tablets.

[0004] The technical solution of this invention is implemented as follows:

[0005] A vonoprazan fumarate tablet, each tablet containing the following components in parts by weight: 10-30 parts vonoprazan fumarate, 130-170 parts mannitol, 0.1-0.5 parts fumaric acid, 2-6 parts croscarmellose sodium, 5.5-7.5 parts hydroxypropyl cellulose, 25-35 parts microcrystalline cellulose, 1-3 parts magnesium stearate, and 5-7 parts film coating premix (gastric-soluble).

[0006] Furthermore, each of the vonoprazan fumarate tablets contains the following components by weight: 26.72 parts vonoprazan fumarate; 148.93 parts mannitol; 0.33 parts fumaric acid; 4.38 parts croscarmellose sodium; 6.57 parts hydroxypropyl cellulose; 29.90 parts microcrystalline cellulose; 2.19 parts magnesium stearate; and 6.57 parts film-coating premix (gastric-soluble type).

[0007] The preparation method of the aforementioned vonoprazan fumarate tablets includes the following steps:

[0008] a. Pretreatment: Mannitol and hydroxypropyl cellulose are passed through a 40-mesh sieve;

[0009] b. Ingredients:

[0010] ① Solution preparation: Weigh purified water, heat it to 50℃, add fumaric acid until it is completely dissolved, control the fumaric acid aqueous solution at 55±5℃, weigh the discharged material, and add the evaporated purified water.

[0011] ②Preparation: Add half of the mannitol, vonoprazan fumarate, microcrystalline cellulose, hydroxypropyl cellulose, and the other half of the mannitol into a high-efficiency mixing granulator in that order, premix to obtain a powder; then process into a soft mass and discharge.

[0012] c. Granulation: Granulate using a 2.5mm round-hole stainless steel sieve with oscillation.

[0013] d. Drying: Dry the wet granules until the moisture content is ≤1.0% before discharging;

[0014] e. Granulation and blending:

[0015] ① Granulation: The dried granules are sieved and granulated to obtain dry granules with a mesh size of 24.

[0016] ② Final Mixing: Weigh out the prescribed amount of croscarmellose sodium based on the dry granule yield. If the granule yield is not less than 98.0%, weigh out the prescribed amount of croscarmellose sodium directly. First, add half of the dry granules to the hopper mixer, then add the croscarmellose sodium, and finally add the remaining dry granules to the hopper mixer. Adjust the hopper mixer speed to 8 rpm and mix for 20 minutes. Next, weigh out the prescribed amount of magnesium stearate based on the dry granule yield and add it to the mixer. If the granule yield is not less than 98.0%, weigh out the prescribed amount of magnesium stearate directly. Adjust the mixer speed to 8 rpm and mix for 5 minutes. Then stop the machine and discharge the material.

[0017] f. Tableting: Calculate the tablet weight based on the intermediate product content determination results; add the granules to the hopper for tableting to obtain white tablets;

[0018] g. Film coating: Prepare a coating solution by adding water to the film coating premix (gastric-soluble type), put the uncoated tablets into the coating pan for coating, and discharge the material after cooling.

[0019] Furthermore, in step b, “① Solution preparation”, the amount of purified water added is 10-15% of the total amount of fumaric acid, mannitol, vonoprazan fumarate, microcrystalline cellulose, and hydroxypropyl cellulose.

[0020] Furthermore, in step b, “② preparation”, the premixing process is set as follows: paddle speed 100 rpm, blade speed 1200 rpm, and timing 600 s; the soft material preparation process is as follows: keep the blade speed at 1200 rpm constant, set the paddle speed to 90 rpm, and add the prepared fumaric acid aqueous solution to the high-efficiency mixing granulator within 40-60 s, timing 180 s, including the 40-60 s time for adding the fumaric acid aqueous solution.

[0021] Furthermore, in step d, the wet granules are fed into the fluidized bed granulator, the inlet air temperature is set to 60-75℃, the fan frequency is 20-50Hz, the drying is paused when the material temperature is ≥45℃, the moisture content is sampled and tested, and the material is discharged after the moisture content is ≤1.0%.

[0022] Furthermore, in step e "① Granulation", the dried granules are added to a 24-mesh sieve. The granules below 24 mesh are qualified granules, and the coarse granules above 24 mesh are granulated using a 1.5mm sieve pulverizer. In step e "② Mixing", half of the dry granules are first added to the hopper mixer, then cross-linked sodium carboxymethyl cellulose is added, and finally the remaining dry granules are added to the hopper mixer. The hopper mixer speed is adjusted to 8 rpm, and the mixing time is 20 minutes.

[0023] Furthermore, in step f, during the tableting process, the tablet weight, disintegration time, friability, and hardness are monitored to ensure they meet the requirements.

[0024] Further, in step g, a 15% coating solution is prepared with a 3% weight gain. During the coating process, the inlet air temperature of the coating pan is set to 60-65℃, and the main machine speed is controlled between 3-15 rpm to begin preheating. After preheating to a material temperature ≥40℃, the coating solution is sprayed in, with the main machine speed (3-15 rpm) and the peristaltic pump speed (5-50 rpm) maintained during the spraying process. After the coating solution is consumed, the main machine speed is adjusted to 5-8 rpm, and drying continues until the moisture content is ≤1.5%. Heating is then stopped, and the material is cooled to below 40℃ before being discharged.

[0025] The above-mentioned method for detecting the content of vonoprazan fumarate tablets includes the following steps:

[0026] (1) Test solution: Take vonoprazan fumarate tablets to prepare a solution containing about 0.1 mg of vonoprazan per 1 ml, shake well, filter, and take the filtrate as the test solution; Reference solution: Accurately weigh an appropriate amount of vonoprazan fumarate reference standard, add the mobile phase to dissolve and quantitatively prepare a solution containing 0.1 mg of vonoprazan per 1 ml;

[0027] (2) Octadecylsilane-bonded silica gel was used as the packing material, and elution was performed using a phosphate buffer-acetonitrile-methanol mobile phase with a volume ratio of 65:5:30; the column temperature was 35℃; the detection wavelength was 230nm; and the flow rate was 1ml per minute.

[0028] (3) Accurately measure 10µl of the reference solution and the test solution, inject them into the liquid chromatograph, record the chromatogram, and calculate the content of vonoprazan fumarate in the test solution.

[0029] Furthermore, in step (1), the preparation method of the test solution is as follows: take vonoprazan fumarate tablets and place them in the corresponding volumetric flask, add an appropriate amount of mobile phase, shake for 30 minutes to allow the tablets to completely disintegrate, then sonicate for 5 minutes, shaking twice during the process, and dilute to the mark with the mobile phase.

[0030] Furthermore, in step (2), the chromatographic column is a CAPCELL PAK C18 MGII with a specification of 4.6mm*150mm and a packed particle size of 3µm; or a chromatographic column with equivalent performance.

[0031] Furthermore, in step (3), the content of vonoprazan fumarate is calculated by peak area using the external standard method, and the result is multiplied by 0.7485 to obtain the content of vonoprazan.

[0032] Furthermore, the detection method described herein is operated under light-protected conditions.

[0033] The above-mentioned method for detecting the content of vonoprazan fumarate tablets is applied to the determination of vonoprazan content in vonoprazan fumarate tablets, the separation and detection of impurities in vonoprazan fumarate tablets, and / or the detection of impurities in vonoprazan fumarate tablets, wherein the impurities are impurity A, impurity B, impurity C, impurity D, and / or impurity E.

[0034] The above-mentioned method for detecting the content of vonoprazan fumarate tablets is applied in the preparation of vonoprazan fumarate tablets, the quality control of vonoprazan fumarate tablets, and / or the determination of the vonoprazan content in vonoprazan fumarate tablets.

[0035] Beneficial effects:

[0036] The vonoprazan fumarate tablets of this invention are made with mannitol, fumaric acid, croscarmellose sodium, hydroxypropyl cellulose, microcrystalline cellulose, and magnesium stearate as excipients. Because vonoprazan is highly susceptible to hydrolysis in alkaline environments, the added fumaric acid acts as a stabilizer. The fumaric acid excipient, dissolved in the granulation solution, provides an acidic environment after entering the formulation, preventing the decomposition of vonoprazan. The preparation method of this invention simplifies the preparation process and reduces production costs. This invention also provides a method for detecting the content of the above-mentioned vonoprazan fumarate tablets. High-performance liquid chromatography (HPLC) is used to accurately determine the content of the active ingredient vonoprazan in the prepared vonoprazan fumarate tablets. This method effectively eliminates the influence of added excipients and impurities on the determination of the active ingredient vonoprazan content, providing important assurance for clinical medication safety and offering a new method for the quality control of vonoprazan fumarate tablets. Attached Figure Description

[0037] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0038] Figure 1 For content determination analytical method validation - specificity - localization - diluent.

[0039] Figure 2 For content determination analytical method validation - specificity - localization - blank excipient solution.

[0040] Figure 3 For the content determination analytical method validation - specificity - localization - fumaric acid solution.

[0041] Figure 4 For content determination analytical method validation - specificity - localization - impurity mixed solution.

[0042] Figure 5 The chromatogram of the reference solution in the assay for the determination of content analytical method - specificity - localization test.

[0043] Figure 6 The chromatogram of the test solution in the assay for the determination of content analytical method - specificity - localization test.

[0044] Figure 7 Spectrum of undegraded test sample solution in forced degradation test for content determination analytical method validation - specificity.

[0045] Figure 8 A spectrum of acid degradation of the test sample solution in the forced degradation test for content determination analytical method validation - specificity.

[0046] Figure 9 The chromatogram of the test sample solution under alkaline degradation in the forced degradation test for the content determination analytical method validation - specificity.

[0047] Figure 10 The chromatogram of the oxidative degradation of the test sample solution in the forced degradation test for the content determination analytical method validation - specificity.

[0048] Figure 11 For the content determination analytical method validation - specificity - forced degradation test, the high temperature degradation spectrum of the test sample solution is shown.

[0049] Figure 12 The spectrum of the test sample solution under light degradation in the forced degradation test for the content determination analytical method validation - specificity. Detailed Implementation

[0050] The present invention will be further described below with reference to the accompanying drawings and specific embodiments to better understand the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0051] Example 1

[0052] A vonoprazan fumarate tablet, each tablet containing the following components by weight: vonoprazan fumarate 26.72 mg, mannitol 148.93 mg, fumaric acid 0.33 mg, croscarmellose sodium 4.38 mg, hydroxypropyl cellulose 6.57 mg, microcrystalline cellulose 29.90 mg, magnesium stearate 2.19 mg, and film-coating premix (gastric-soluble) 6.57 mg.

[0053] Based on a production batch of 200,000 pieces, the calculated input quantities of each material are as follows:

[0054] Vonoprazan fumarate 5.344 kg; mannitol 29.79 kg; fumaric acid 0.066 kg; croscarmellose sodium 0.876 kg; hydroxypropyl cellulose 1.314 kg; microcrystalline cellulose 5.979 kg; magnesium stearate 0.438 kg; film coating premix (gastric-soluble type) 1.314 kg.

[0055] The preparation method of the aforementioned vonoprazan fumarate tablets includes the following steps:

[0056] a. Pretreatment: Mannitol and hydroxypropyl cellulose are passed through a 40-mesh sieve;

[0057] b. Ingredients:

[0058] ① Solution preparation: Weigh 5.26 kg of purified water (approximately 12.67% of the total amount of fumaric acid, mannitol, vonoprazan fumarate, microcrystalline cellulose, and hydroxypropyl cellulose) and place it in a heat-insulated stirring tank. When the material water temperature reaches 50℃, add 66 g of fumaric acid until it is completely dissolved. The fumaric acid aqueous solution is controlled at 55±5℃. Weigh the material after discharge and add the evaporated purified water.

[0059] ② Preparation: Add half of the mannitol, vonoprazan fumarate, microcrystalline cellulose (SH-101), hydroxypropyl cellulose, and the other half of the mannitol into a high-efficiency mixing granulator in the following order for premixing (setting: paddle speed 100 rpm, blade speed 1200 rpm). After 600 seconds, the powder is obtained. Then, the soft material is prepared by keeping the blade speed at 1200 rpm and setting the paddle speed at 90 rpm. The prepared fumarate aqueous solution is added to the high-efficiency mixing granulator within 40-60 seconds. After 180 seconds (including the 40-60 seconds for adding the fumarate aqueous solution), the material is discharged.

[0060] c. Granulation: Granulate using a 2.5mm round-hole stainless steel sieve with oscillation.

[0061] d. Drying: Put the wet granules into the fluidized bed granulator, set the inlet air temperature to 60-75℃ and the fan frequency to 20-50Hz. When the material temperature is ≥45℃, stop drying, take a sample to test the moisture content, and discharge the material when the moisture content is ≤1.0% (using a rapid moisture analyzer).

[0062] e. Granulation and blending:

[0063] ① Granulation: Add the dried granules to a 24-mesh manual sieve. The granules below 24 mesh are qualified granules. The coarse granules above 24 mesh are granulated using a pulverizer and granulator (1.5mm sieve). The granulated granules and the granules below 24 mesh are dry granules.

[0064] ② Final Mixing: Weigh out the prescribed amount of croscarmellose sodium based on the yield of the dry granules (if the yield of some granules is not less than 98.0%, weigh out the prescribed amount of croscarmellose sodium directly). First, add half of the dry granules to the hopper mixer, then add the croscarmellose sodium, and finally add the remaining dry granules to the hopper mixer. Adjust the speed of the hopper mixer to 8 rpm and mix for 20 minutes. Then, weigh out the prescribed amount of magnesium stearate based on the yield of the dry granules and add it to the mixer (if the yield of some granules is not less than 98.0%, weigh out the prescribed amount of magnesium stearate directly). Adjust the speed of the mixer to 8 rpm and mix for 5 minutes. Then, stop the machine and discharge the material.

[0065] f. Tableting: Calculate the tablet weight based on the intermediate product content determination results; add the granules into the hopper, jog to confirm normal equipment operation, start the machine, monitor the tablet weight, disintegration time, friability, and hardness, and then operate normally to obtain white raw tablets;

[0066] g. Film Coating: Prepare a 15% coating solution using a 3% weight gain premix of film coating premix (gastric-soluble type). Place the uncoated flakes into the coating pan, set the inlet air temperature to 60-65℃, and control the main machine speed between 3-15 rpm to begin preheating. After preheating to a material temperature ≥40℃, begin spraying the coating solution, maintaining the main machine speed (3-15 rpm) and peristaltic pump speed (5-50 rpm) during spraying. Once the coating solution is consumed, adjust the main machine speed to 5-8 rpm and continue drying until the moisture content is ≤1.5%. Stop heating and cool to below 40℃ before discharging.

[0067] h. Aluminum-plastic packaging: The qualified coated sheets are packaged in batches of 7 sheets per blister pack on a fully automatic high-speed blister packaging machine. The forming heating plate temperature is 115-143℃, and the heat sealing temperature is 200-240℃.

[0068] Example 2

[0069] A vonoprazan fumarate tablet, each tablet containing the following components by weight: vonoprazan fumarate 10 mg, mannitol 130 mg, fumaric acid 0.1 mg, croscarmellose sodium 2 mg, hydroxypropyl cellulose 5.5 mg, microcrystalline cellulose 25 mg, magnesium stearate 1 mg, and film-coating premix (gastric-soluble) 5 mg.

[0070] The preparation method is the same as in Example 1.

[0071] Example 3

[0072] A vonoprazan fumarate tablet, each tablet containing the following components by weight: vonoprazan fumarate 30 mg, mannitol 170 mg, fumaric acid 0.5 mg, croscarmellose sodium 6 mg, hydroxypropyl cellulose 7.5 mg, microcrystalline cellulose 35 mg, magnesium stearate 3 mg, and film-coating premix (gastric-soluble) 7 mg.

[0073] The preparation method is the same as in Example 1.

[0074] Example 4

[0075] The method for detecting the content of the vonoprazan fumarate tablets prepared above includes the following steps:

[0076] (1) Test solution: Take 10 tablets of vonoprazan fumarate and place them in a 100ml (10mg specification) or 200ml (20mg specification) volumetric flask. Add an appropriate amount of mobile phase (phosphate buffer-acetonitrile-methanol with a volume ratio of 65:5:30). Shake for 30 minutes to allow the tablets to completely disintegrate. Sonicate for 5 minutes, shaking twice during the process. Dilute to the mark with the mobile phase to prepare a solution containing approximately 0.1mg of vonoprazan per ml. Shake well, filter the supernatant, and accurately transfer 5ml of the filtrate into two 50ml bottles. Dilute to the mark with the mobile phase to prepare the test solution. Reference solution: Accurately weigh an appropriate amount of vonoprazan fumarate reference standard, dissolve it in the mobile phase, and quantitatively prepare a solution containing 0.1mg of vonoprazan per ml.

[0077] (2) Use octadecylsilane-bonded silica gel as the packing material (the chromatographic column is CAPCELL PAK C18 MGII, 4.6mm*150mm, 3µm; or a column with equivalent performance), and use a phosphate buffer-acetonitrile-methanol mobile phase with a volume ratio of 65:5:30 for elution; the column temperature is 35℃; the detection wavelength is 230nm; the flow rate is 1ml per minute; the phosphate buffer is prepared by taking 3.40g of potassium dihydrogen phosphate and 8.94g of disodium hydrogen phosphate, dissolving them in water and diluting them to 1000ml, and adjusting the pH value to 6.8 with phosphoric acid or sodium hydroxide test solution.

[0078] (3) Accurately measure 10 µl of the reference solution and the test solution, inject them into the liquid chromatograph, record the chromatogram, calculate the vonoprazan fumarate content by peak area using the external standard method, and multiply the result by 0.7485 to obtain the vonoprazan content in the test solution. The calculation formula is as follows (taking 10 mg and 20 mg specifications as examples):

[0079]

[0080] For the 30mg sample prepared in Example 3, the same method can be used for determination.

[0081] System suitability requirements: The theoretical plate number of the von Rasen peak in the reference solution shall not be less than 3000, and the tailing factor shall not be greater than 2.0.

[0082] I. Validation of the content detection method described in this invention

[0083] The vonoprazan fumarate tablets prepared in the examples were subjected to content detection method verification using the method described in Example 4 of this invention. The blank excipient for vonoprazan fumarate tablets (batch number: KB240530) was produced by Zhejiang Jinshiya Pharmaceutical Technology Co., Ltd.

[0084] Table 1. Reference Standard Information

[0085]

[0086] The relevant information for each impurity is as follows:

[0087] Impurity A (CAS No.: 2170020-79-6), English name: 2-[[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]methyl-methylamino]butanedioic acid. Impurity B (CAS No.: 928325-82-0), English name: N-methyl-1-(5-phenyl-1-pyridin-3-ylsulfonylpyrrol-3-yl)methanamine monofumarate. Impurity C (CAS No.: 1885094-62-1), English name: 1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-N,N-dimethylmethanamine (CAS No.: 1885094-62-1). Impurity D (CAS No.: 636-73-7), English name: Pyridine-3-sulfonic acid.

[0088] Impurity E (CAS No.: 1610043-62-3) English name: 1-[5-(2-fluorophenyl)-1H-pyrrol-3-yl]-N-methylmethanamine.

[0089] The structural formulas of each impurity are as follows:

[0090]

[0091] Table 2 Solution Preparation

[0092]

[0093] 1. System adaptability test

[0094] Take the system suitability solution and reference solution for determination, and record the chromatogram. Examine the theoretical plate number of the main peak and the tailing factor, and calculate the RSD of the main peak area and the RSD of the retention time.

[0095] Table 1. Content Validation - System Suitability Test Results

[0096]

[0097] Results analysis: The reference solution was measured 5 times consecutively. The RSD of the main peak retention time was 0.1%, the RSD of the peak area was 0.1%, the theoretical plate number was ≥9097, and the tailing factor was 1.5, all of which met the requirements.

[0098] 2. Specificity test

[0099] 2.1 Specificity - Positioning

[0100] Take diluent, blank excipient, reference solution, and test solution for analysis, and record the chromatograms. Investigate the retention times of the main peaks for each solution. Results are shown in Table 2 and... Figure 1-7 .

[0101] Table 2 Results of Specificity-Location Test

[0102]

[0103] Results Analysis: The retention times of the chromatographic peaks in the diluent and blank excipient were all within 0.871 minutes, showing no interference with the Vonolasen peaks in the reference solution and test solution. The resolution between each impurity peak and the Vonolasen peak in the impurity mixture was not less than 5.7. The retention times of the Vonolasen peaks in the test solution and reference solution differed by 0.068 minutes, which was essentially consistent. All of the above items met the requirements.

[0104] 2.2 Specificity-Forced Degradation Test

[0105] Test samples under each forced degradation condition were injected and analyzed, and chromatograms were recorded. The preparation methods for each test sample are shown in Table 3 below. Results are shown in Table 4 and... Figure 8-12 .

[0106] Table 3 Content Validation - Specificity (Forced Degradation) Formulation Method

[0107]

[0108] Table 4. Content Verification - Specificity (Forced Degradation) Test Results

[0109]

[0110] Results analysis: Under all degradation conditions, the resolution between the main peak and adjacent chromatographic peaks in the sample solution was ≥1.7, and the peak purity of the main component in the sample solution was ≥996 under all degradation conditions, which all met the requirements.

[0111] 3. Linear

[0112] Using the concentration of the reference solution as a 100% baseline, linear concentration series of 50%, 80%, 100%, 150%, and 200% of the reference solution concentration were prepared as linear assay solutions. One aliquot was prepared for each concentration, and each aliquot was injected once, with chromatograms recorded. Linear regression was performed with the principal component concentration on the x-axis and the peak area on the y-axis to obtain the regression equation and correlation coefficient. The specific preparation of the linear solutions is as follows:

[0113] Table 5 Content Validation - Linear Formulation Method

[0114]

[0115] Table 6. Content Verification - Linearity Test Results

[0116]

[0117] Results Analysis: The correlation coefficient R of the regression line 2 =0.9999, Y-intercept is 1.0% of 100% response value, regression residuals, the data points in the residual distribution plot are randomly distributed, all in accordance with the regulations.

[0118] 4. Membrane adsorption

[0119] a) Validity: Prepare one test solution according to the requirements under the Assay section, and then filter the solution using a nylon filter membrane with a pore size of 0.45 μm. Take two aliquots of the filtrate; inject one directly for analysis, and inject the other after sonication for 10 minutes. Record the chromatogram.

[0120] b) Leachate: Use one dose of content diluent, and then filter the solution through a nylon filter membrane with a pore size of 0.45 μm. Inject the solution directly for analysis without discarding it. Record the chromatogram.

[0121] c) Discarded Volume: Prepare one volume of test solution according to the requirements of the content determination section in Example 4. Filter the test solution using a nylon filter membrane with a pore size of 0.45 μm. Discard 1 ml, 2 ml, 3 ml, and 4 ml of the initial filtrate, and inject them as filtrate 1, filtrate 2, filtrate 3, and filtrate 4, respectively, for analysis. Record the chromatogram.

[0122] Table 7 Content Verification - Filter Membrane Adsorption Test Results

[0123]

[0124] Results analysis: When filtering the test solution using a nylon filter membrane with a pore size of 0.45 μm, discarding at least 1 ml of the initial filtrate allows it to meet the requirements.

[0125] 5. Accuracy

[0126] Using the concentration of the reference solution as a 100% baseline, prepare accuracy solutions at 60%, 130%, and 200% of the reference solution concentration, respectively. Prepare three replicates for each concentration and record the chromatograms. Calculate the recovery rate and RSD. The specific accuracy solution preparation is as follows: Background solution preparation: Weigh approximately 192 mg of vonoprazan fumarate blank excipient into a 200 ml volumetric flask, add an appropriate amount of diluent to dissolve and dilute to the mark, and shake well.

[0127] Table 8. Preparation Method for Content Validation - Accuracy (Recovery Rate)

[0128]

[0129] Table 9. Results of Content Validation - Accuracy (Recovery) Tests

[0130]

[0131] Results analysis: The recovery rate RSD (n=3) within each concentration level was between 0.6% and 1.1%. The recovery rate of the accuracy solution at all concentration levels was between 98.0% and 102.0%, with an average recovery rate of 100.0%. The recovery rate RSD (n=9) for all concentration levels was 1.4%, all of which met the requirements.

[0132] 6. Precision

[0133] 6.1 Repeatability

[0134] Prepare two reference solutions and six test solutions according to the "Solution Preparation" in Table 2. Inject the samples and record the chromatograms. Calculate the content and RSD values ​​of the six test solutions.

[0135] Table 10 Content Validation - Repeatability Test Results

[0136]

[0137] Results analysis: The content of vonoprazan in the six test solutions was all within the range of 100.6% to 101.1%, and the RSD of the content in the six solutions was 0.2%, all of which met the requirements.

[0138] 6.2 Intermediate Precision

[0139] Different analysts, on different dates, and using different instruments prepared the relevant solutions under "6.1 Repeatability," injected them for testing, and recorded the chromatograms. The content and RSD values ​​of the six test solutions were calculated, and these results were combined with the six content results under "6.1 Repeatability" to calculate the RSD values ​​of the 12 test solutions.

[0140] Table 11 Content Validation - Intermediate Precision Test Results

[0141]

[0142] Results analysis: The content of vonoprazan in the six test solutions of the other experimenter was all within the range of 98.8% to 100.5%, and the RSD of the six contents was 0.6%; the combined RSD of the contents of the two experiments, totaling 12 samples, was 0.7%, which all met the requirements.

[0143] 7. Solution stability

[0144] Prepare the reference solution and test solution according to Table 2. Place the reference solution and test solution under the following conditions for 3 days, and inject samples for detection on days 0, 1, 2, and 3, respectively. Record the peak area of ​​the main peak and calculate the ratio of the peak area on day 0 to that on day 0. (The specific time points for the investigation can be adjusted according to the actual situation during the investigation period, and the sequence can be flexibly adjusted).

[0145] Table 12 Content Verification - Solution Stability Test Results

[0146]

[0147] Results analysis: The ratio of the main peak area to the Oh peak area in both the test solution and the reference solution after being placed at room temperature for 48 hours was between 98.0% and 102.0%, which met the requirements.

[0148] 8. Durability

[0149] Take the system suitability solution, diluent, reference solution, and test solution, and inject them into the liquid chromatograph under different robustness test conditions. Record the chromatograms, examine system suitability, and calculate the content and the absolute value Δ of the difference between the content under normal conditions and the content under normal conditions. The specific robustness test conditions are as follows:

[0150] Table 13 Content Verification - Durability Test Conditions

[0151]

[0152] Table 14 Content Verification - Durability Test Results

[0153]

[0154] Results analysis: The theoretical plate number of the Vonolasen peak in the system suitability solution was ≥4618, the tailing factor was ≤1.5, and the absolute value Δ of the difference between the content of the test sample solution under each test condition and the content under the original condition was ≤0.6%.

[0155] The specific results are summarized in Table 15.

[0156] Table 15 Validation results of the content detection method described in this invention

[0157]

[0158] As can be seen from Table 15, after verification, the analytical method for determining the content of vonoprazan fumarate tablets showed that all indicators met the requirements.

[0159] III. Quality Testing of Vonoprazan Fumarate Tablets as Described in this Invention

[0160] Vonoprazan fumarate tablets prepared in the three examples were taken as example groups, and comparative examples were set up according to the component ratios and preparation methods in Table 1.

[0161] Table 16 Comparative Example: Partition Ratio and Preparation Method of Vonoprazan Fumarate Tablets

[0162]

[0163] The appearance of the tablets in the three examples and five comparative examples was observed. All eight samples were pink film-coated tablets, which turned white after the coating was removed. The content of the eight samples (vonoprazan) was determined according to the detection method in Example 4. Content uniformity, hardness, disintegration time, and friability were measured according to the methods in the Pharmacopoeia (2020 edition). The test results are shown in Table 17.

[0164] Table 17 Detection results of tablets prepared by each treatment

[0165]

[0166] As shown in Table 17, the tablets prepared using the three example groups had a hardness of 5-8 kg, a disintegration time of about 60 s, and a friability of less than 0.03%. In contrast, the tablets prepared using the five comparative examples had a hardness of only 5 in comparative example 3. The hardness of the other comparative examples was either higher or lower than that of the three examples. The disintegration time of the five comparative examples also increased or decreased to varying degrees, while the friability was significantly higher than that of the three comparative examples, and the tablet quality decreased to varying degrees.

[0167] The content of different tablets was determined using the method of Example 4. The content of the three examples ranged from 98.3% to 101.7%, which met the requirements. However, when the content of the tablets prepared in the five comparative examples was determined using the method of Example 4, the highest content reached 83.6%, which was significantly lower than that of the five examples. This indicates that the content determination method described in Example 4 can detect the content of the tablets prepared in the three examples, but the content detection effect is significantly reduced for the tablets prepared in the five comparative examples, and it is impossible to accurately detect the content of the active ingredient vonoprazan in the tablets.

[0168] The specific embodiments of the present invention have been described in detail above, but they are merely examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions to the present invention are also within the scope of the present invention. Therefore, all equivalent transformations and modifications made without departing from the spirit and scope of the present invention should be covered within the scope of the present invention.

Claims

1. A vonoprazan fumarate tablet, characterized in that, Each tablet contains the following components in parts by weight: 10-30 parts vonoprazan fumarate, 130-170 parts mannitol, 0.1-0.5 parts fumarate, 2-6 parts croscarmellose sodium, 5.5-7.5 parts hydroxypropyl cellulose, 25-35 parts microcrystalline cellulose, 1-3 parts magnesium stearate, and 5-7 parts film coating premix (gastric-soluble).

2. A vonoprazan fumarate tablet, characterized in that, Each of the aforementioned vonoprazan fumarate tablets contains the following components by weight: 26.72 parts vonoprazan fumarate; 148.93 parts mannitol; 0.33 parts fumaric acid; 4.38 parts croscarmellose sodium; 6.57 parts hydroxypropyl cellulose; 29.90 parts microcrystalline cellulose; 2.19 parts magnesium stearate; and 6.57 parts film-coating premix (gastric-soluble).

3. The preparation method of vonoprazan fumarate tablets as described in claim 1, comprising the following steps: a. Pretreatment: Mannitol and hydroxypropyl cellulose are passed through a 40-mesh sieve; b. Ingredients: ① Solution preparation: Weigh purified water, heat it to 50℃, add fumaric acid until it is completely dissolved, control the fumaric acid aqueous solution at 55±5℃, weigh the discharged material, and add the evaporated purified water. ②Preparation: Add half of the mannitol, vonoprazan fumarate, microcrystalline cellulose, hydroxypropyl cellulose, and the other half of the mannitol into a high-efficiency mixing granulator in that order, premix to obtain a powder; then process into a soft mass and discharge. c. Granulation: Granulate using a 2.5mm round-hole stainless steel sieve with oscillation. d. Drying: Dry the wet granules until the moisture content is ≤1.0% before discharging; e. Granulation and blending: ① Granulation: The dried granules are sieved and granulated to obtain dry granules with a mesh size of 24. ② Final Mixing: Weigh out the prescribed amount of croscarmellose sodium based on the dry granule yield. If the granule yield is not less than 98.0%, weigh out the prescribed amount of croscarmellose sodium directly. First, add half of the dry granules to the hopper mixer, then add the croscarmellose sodium, and finally add the remaining dry granules to the hopper mixer. Adjust the hopper mixer speed to 8 rpm and mix for 20 minutes. Next, weigh out the prescribed amount of magnesium stearate based on the dry granule yield and add it to the mixer. If the granule yield is not less than 98.0%, weigh out the prescribed amount of magnesium stearate directly. Adjust the mixer speed to 8 rpm and mix for 5 minutes. Then stop the machine and discharge the material. f. Tableting: Calculate the tablet weight based on the intermediate product content determination results; add the granules to the hopper for tableting to obtain white tablets; g. Film coating: Prepare a coating solution by adding water to the film coating premix (gastric-soluble type), put the uncoated tablets into the coating pan for coating, and discharge the material after cooling.

4. The method as described in claim 3, characterized in that, In step b, "① Solution preparation", the amount of purified water added is 10-15% of the total amount of fumaric acid, mannitol, vonoprazan fumarate, microcrystalline cellulose, and hydroxypropyl cellulose. In step b, "② Preparation", the premixing settings are: paddle speed 100 rpm, blade speed 1200 rpm, and timing 600 s; the soft material preparation process is as follows: keep the blade speed constant at 1200 rpm, set the paddle speed to 90 rpm, add the prepared fumaric acid aqueous solution to the high-efficiency mixing granulator within 40-60 s, and timing 180 s, including the 40-60 s time for adding the fumaric acid aqueous solution; In step d, the wet granules are fed into the fluidized bed granulator, the inlet air temperature is set to 60-75℃, the fan frequency is 20-50Hz, the drying is paused when the material temperature is ≥45℃, the moisture content is sampled and tested, and the material is discharged after the moisture content is ≤1.0%.

5. The method as described in claim 3, characterized in that, In step e"① "granulation", the dried granules are added to a 24-mesh sieve. The granules below 24 mesh are qualified granules, and the coarse granules above 24 mesh are granulated using a 1.5mm sieve pulverizer. In step e"② "total mixing", half of the dry granules are first added to the hopper mixer, then cross-linked sodium carboxymethyl cellulose is added, and finally the remaining dry granules are added to the hopper mixer. The speed of the hopper mixer is adjusted to 8 rpm, and the mixing time is 20 minutes. In step f, during the tableting process, the tablet weight, disintegration time, friability, and hardness are monitored to ensure they meet the requirements. In step g, a 15% coating solution is prepared with a 3% weight gain. During the coating process, the inlet air temperature of the coating pan is set to 60-65℃, and the main machine speed is controlled between 3-15 rpm to begin preheating. After preheating to a material temperature ≥40℃, the coating solution is sprayed in. During the spraying process, the main machine speed is maintained at 3-15 rpm and the peristaltic pump speed is maintained at 5-50 rpm. After the coating solution is consumed, the main machine speed is adjusted to 5-8 rpm, and drying continues until the moisture content is ≤1.5%. Heating is then stopped, and the material is cooled to below 40℃ before being discharged.

6. The method for detecting the content of vonoprazan fumarate tablets as described in claim 1 or 2, characterized in that, Includes the following steps: (1) Test solution: Take vonoprazan fumarate tablets to prepare a solution containing about 0.1 mg of vonoprazan per 1 ml, shake well, filter, and take the filtrate as the test solution; Reference solution: Accurately weigh an appropriate amount of vonoprazan fumarate reference standard, add the mobile phase to dissolve and quantitatively prepare a solution containing 0.1 mg of vonoprazan per 1 ml; (2) Octadecylsilane-bonded silica gel was used as the packing material, and elution was performed using a phosphate buffer-acetonitrile-methanol mobile phase with a volume ratio of 65:5:30; the column temperature was 35℃; the detection wavelength was 230nm; and the flow rate was 1ml per minute. (3) Accurately measure 10µl of the reference solution and the test solution, inject them into the liquid chromatograph, record the chromatogram, and calculate the content of vonoprazan fumarate in the test solution.

7. The detection method as described in claim 6, characterized in that, In step (1), the test solution is prepared by placing vonoprazan fumarate tablets in a volumetric flask, adding an appropriate amount of mobile phase, shaking for 30 minutes to completely disintegrate the tablets, then sonicating for 5 minutes, shaking twice during the process, and diluting to the mark with the mobile phase; in step (2), the chromatographic column is a CAPCELL PAKC18 MGII with a specification of 4.6mm*150mm and a packed particle size of 3µm; or a chromatographic column with equivalent performance; in step (3), the content of vonoprazan fumarate is calculated by peak area using the external standard method, and the result is multiplied by 0.7485 to obtain the content of vonoprazan.

8. The detection method as described in claim 6, characterized in that, The detection method described herein shall be operated under light-protected conditions.

9. The method for detecting the content of vonoprazan fumarate tablets as described in claims 6-8 is applied to the determination of vonoprazan content in vonoprazan fumarate tablets, the separation and detection of impurities in vonoprazan fumarate tablets, and / or the detection of impurities in vonoprazan fumarate tablets, wherein the impurities are impurity A, impurity B, impurity C, impurity D, and / or impurity E.

10. The method for detecting the content of vonoprazan fumarate tablets as described in claims 6-8 is used in the preparation of vonoprazan fumarate tablets, the quality control of vonoprazan fumarate tablets, and / or the determination of the vonoprazan content in vonoprazan fumarate tablets.

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