A method for detecting the dissolution curve of ezetimibe rosuvastatin calcium tablets with distinguishing features

Abstract

The application discloses a method for detecting the dissolution curve of ezetimibe and rosuvastatin calcium tablets, and belongs to the technical field of drug detection. The method uses an aqueous solution containing 0.1-0.3 wt% polysorbate 80 as a dissolution medium, and performs dissolution according to a dissolution instrument basket method, wherein the rotating speed of the rotating basket is 50-100 revolutions per minute, and the mesh number of the rotating basket is 10 meshes. The method provided by the application has good dissolution for both ezetimibe and rosuvastatin calcium, and has the characteristics of strong specificity, high sensitivity, high accuracy, good durability and the like, can effectively distinguish the difference between self-prepared preparations and reference preparations, and is more universal and practical, and is more simple and efficient in operation.

Description

Technical Field

[0001] This invention relates to the field of drug detection technology, and in particular to a method for detecting the dissolution curve of ezetimibe / suvastatin calcium tablets with discriminative power. Background Technology

[0002] The information disclosed in the background section of this invention is intended only to enhance the understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Ezetimibe and rosuvastatin calcium tablets are a combination tablet of ezetimibe and rosuvastatin calcium. It is a dual-action lipid-lowering drug used to treat chronic conditions caused by excessive blood lipids, such as fat, cholesterol, and triglycerides. On November 26, 2013, Merck's application for the combination of ezetimibe tablets and rosuvastatin calcium tablets was approved for marketing in Australia under the brand name EZALO, with strengths (based on ezetimibe / rosuvastatin): 10mg / 5mg, 10mg / 10mg, 10mg / 20mg, and 10mg / 40mg. On March 26, 2019, Merck's application for the ezetimibe and rosuvastatin calcium tablets was approved for marketing in Japan under the brand name ROSUZET, with strengths: 10mg / 2.5mg and 10mg / 5mg. It was approved for marketing in the EU in July 2014 under the trade name Zenon, with strengths of 10mg / 10mg, 10mg / 20mg, and 10mg / 40mg. The licensee is Sanofi-Aventis.

[0004] The quality standard for ezetimibe / rosuvastatin calcium tablets is not included in the pharmacopoeias of China, the UK, the US, Japan, and Korea, but is only listed in the Indian Pharmacopoeia. Its dissolution method is the paddle method, using 900 mL of buffer solution (10 g of sodium dodecyl sulfate dissolved in water to make 1000 mL) as the dissolution medium, at a rotation speed of 50 rpm, and sampling is performed after 45 minutes. However, in practical applications, it has been found that because ezetimibe / rosuvastatin calcium tablets are bilayer tablets with differences in hardness between the upper and lower layers, the disintegration rates of ezetimibe and rosuvastatin are inconsistent at lower paddle rotation speeds (50 rpm), leading to significant measurement deviations between different tablets. Within 10 minutes, the relative standard deviation of the cumulative dissolution of ezetimibe is greater than 10%.

[0005] The FDA review report (213072Orig1s000) uses 900 mL of citrate solution (pH 6.6) as the dissolution medium and a paddle method at 50 rpm to determine rosuvastatin calcium. It also uses 900 mL of acetate-sodium acetate buffer (pH 4.5) containing 0.45% sodium dodecyl sulfate as the dissolution medium and a basket method at 75 rpm to determine ezetimibe. This detection method requires separate sample processing using two different methods, making the process cumbersome and prone to errors in practical use.

[0006] The dissolution medium of patent CN110418637A (publication date: 2019.11.05) is 900 mL of phosphate buffer with pH 7.0±0.05, containing 0.5% sodium lauryl sulfate (i.e., sodium dodecyl sulfate), and a paddle method of 75 rpm. The higher rotation speed can improve the stability of the measurement results to a certain extent. However, if the same system is used to simultaneously measure the dissolution of ezetimibe and rosuvastatin calcium, the presence of sodium dodecyl sulfate will react with the calcium in rosuvastatin calcium, resulting in a decrease in the dissolution of rosuvastatin calcium.

[0007] Therefore, it is an urgent problem to solve the dissolution determination method for ezetimibe and rosuvastatin calcium tablets that has good test stability, high dissolution rates for both ezetimibe and rosuvastatin, and good distinguishing ability. Summary of the Invention

[0008] In view of this, the present invention provides a method for detecting the dissolution curve of ezetimibe / suvastatin calcium tablets with discriminative power. The method provided by the present invention has the characteristics of high specificity, high sensitivity, high accuracy and good robustness. It can effectively distinguish the differences between self-made formulations and reference formulations, and is more universal and practical. It is also simpler and more efficient to operate.

[0009] This invention provides a method for detecting the dissolution curve of ezetimibe / suvastatin calcium tablets with discriminative power, comprising the following steps:

[0010] Preparation of test solution: Take ezetimibe / suvastatin calcium tablets and use 800-1000 mL of an aqueous solution containing 0.1-0.3 wt% polysorbate 80 as the dissolution medium. Dissolve the tablets using the basket method in a dissolution apparatus. The rotation speed of the basket is 50-100 rpm and the mesh size of the basket is 10-40 mesh. At different sampling time points, take an appropriate amount of the dissolution solution, filter it, accurately measure the filtrate, dilute it to the mark with the mobile phase, and shake well to obtain the test solution.

[0011] Preparation of reference solution: Accurately weigh ezetimibe reference standard and rosuvastatin calcium reference standard, add an appropriate amount of mobile phase to dissolve them, dilute with mobile phase to prepare a mixed solution containing 2-3 μg each of ezetimibe and rosuvastatin per 1 ml, shake well, and use as the reference solution.

[0012] Determination: Inject the test solution and the reference solution into the high performance liquid chromatograph, record the chromatograms, and calculate the dissolution amount.

[0013] Preferably, the pH of the leaching medium is 2 to 7.

[0014] Furthermore, the pH of the dissolution medium is adjusted using hydrochloric acid, glacial acetic acid-sodium acetate, or citric acid-sodium citrate.

[0015] Preferably, hydrochloric acid is used to adjust the pH of the dissolution medium to 2.0; or, glacial acetic acid-sodium acetate is used to adjust the pH of the dissolution medium to 4.5; or, citric acid-sodium citrate is used to adjust the pH of the dissolution medium to 6.6.

[0016] Preferably, the polysorbate 80 has a mass concentration of 0.2 wt%.

[0017] Preferably, the rotating basket rotates at a speed of 75 revolutions per minute and has a mesh size of 10.

[0018] Preferably, the volume of the dissolution medium is 900 mL.

[0019] Preferably, the sampling time points include 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min.

[0020] Furthermore, when the sampling time is 10 minutes or more, the relative standard deviation (RSD) of the method for detecting the dissolution curve of ezetimibe and rosuvastatin calcium tablets with discriminative power is less than 10%; when the sampling time is 15 minutes, the dissolution amount of ezetimibe is less than 85%; and when the sampling time is 60 minutes, the cumulative dissolution amounts of both ezetimibe and rosuvastatin calcium are greater than 95%.

[0021] Preferably, the chromatographic conditions for the high-performance liquid chromatography are as follows:

[0022] Chromatographic column: XB-C18, 4.6mm×150mm, 5μm or equivalent column, using octadecylsilane-bonded silica gel as packing material;

[0023] Detector: VWD detector, detection wavelength is 232nm;

[0024] Mobile phase: 0.05 mol / L citrate buffer-acetonitrile (50:50) was used as the mobile phase;

[0025] Column temperature: 30℃;

[0026] Flow rate: 1.5 mL / min;

[0027] Run time: 6 minutes, isocratic elution;

[0028] Injection volume: 50 μL.

[0029] Furthermore, the citrate buffer solution is prepared as follows: take 14.7g of sodium citrate and 0.36g of citric acid, add an appropriate amount of water and sonicate to dissolve, dilute with water to 1000mL, and adjust the pH value to 4.0 with phosphoric acid.

[0030] Compared with the prior art, the present invention has achieved the following beneficial effects:

[0031] (1) The dissolution curve detection method for ezetimibe and rosuvastatin calcium tablets provided by this invention uses an aqueous solution containing polysorbate 80 as the dissolution medium and dissolves the tablets using a dissolution apparatus basket method. Compared with the existing dissolution medium containing sodium dodecyl sulfate (SDS) and dissolution using a dissolution apparatus slurry method, this method has good detection stability within the pH range of 2 to 7. The RSD of sampling times of more than 10 minutes is less than 10%. Moreover, the dissolution rate of ezetimibe is moderate, which will not cause sample accumulation or lead to an excessively fast dissolution rate without discrimination. At the same time, there is no reaction between sodium dodecyl sulfate (SDS) and rosuvastatin calcium, which will reduce the amount of rosuvastatin calcium dissolved. Therefore, the dissolution curve detection method provided by this invention has good stability and discrimination. In addition, when measured simultaneously in the same system, both ezetimibe and rosuvastatin have good dissolution properties, and the cumulative dissolution amount is higher than 95% at 60 minutes.

[0032] (2) The method for detecting the dissolution curve of ezetimibe and rosuvastatin calcium tablets provided by the present invention has the characteristics of high specificity, high sensitivity, high accuracy and good durability. It can effectively compare the differences or similarities between the self-made preparation and the reference preparation, and is more universal and practical. At the same time, since the present invention only requires one injection to complete the simultaneous determination of ezetimibe and rosuvastatin, there is no need to use different dissolution methods to inject separately, so the operation is simpler and more efficient. Attached Figure Description

[0033] The accompanying drawings, which form part of this specification, are used to provide a further understanding of the invention. The illustrative embodiments and descriptions of the invention are used to explain the invention and do not constitute an undue limitation thereof. Obviously, those skilled in the art can obtain other drawings based on these drawings without any inventive effort.

[0034] Figure 1 This is the dissolution detection diagram of Example 1 of the present invention. Detailed Implementation

[0035] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0036] The technical solution of the present invention will be further described below with reference to specific embodiments.

[0037] Example 1

[0038] High performance liquid chromatography conditions:

[0039] Chromatographic column: Octadecylsilane-bonded silica gel as packing material (Yuexu Materials Technology Co., Ltd. XB-C18, 4.6mm×150mm, 5μm or equivalent column);

[0040] Detector: VWD detector (detection wavelength: 232nm);

[0041] Mobile phase: 0.05 mol / L citrate buffer (14.7 g sodium citrate and 0.36 g citric acid were dissolved in water by sonication, diluted with water to 1000 mL, and the pH was adjusted to 4.0 with phosphoric acid) - acetonitrile (50:50) was used as the mobile phase.

[0042] Dissolution medium A: Take 2.99g of sodium acetate, 1.6mL of glacial acetic acid, and about 2g of polysorbate 80. Add an appropriate amount of water and sonicate to dissolve. If necessary, adjust the pH value to 4.5 with 1mol / L sodium hydroxide solution or acetic acid. Dilute with water to 1000mL to obtain an acetate-sodium acetate buffer solution (pH 4.5) containing 0.2% polysorbate 80.

[0043] Preparation of test solution: Take the self-made ezetimiberapresuvastatin calcium tablets and the reference ezetimiberapresuvastatin (trade name: Zenon) Certified manufacturer: Sanofi-Aventis, SRO; Specification: 10mg / 10mg; EU Mutual Recognition and Marketed Formulation (origin: Czech Republic); Dissolution medium: 900mL (A); Dissolution was performed using the basket method in a dissolution apparatus at a rotation speed of 75 rpm and a basket mesh size of 10 mesh. Samples were taken at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min. A suitable amount of the dissolution solution was collected, filtered, and 2mL of the filtrate was accurately measured and placed in a 10mL volumetric flask. The solution was diluted to the mark with the mobile phase, shaken well, and used as the test solution.

[0044] Preparation of reference solution: Weigh 11 mg of ezetimibe reference standard and 11.5 mg of rosuvastatin calcium (calculated as 10 mg of rosuvastatin) reference standard accurately, place them in a 100 mL volumetric flask, add an appropriate amount of mobile phase to dissolve them, dilute to the mark with mobile phase, accurately measure 1 mL, place it in a 50 mL volumetric flask, dilute to the mark with mobile phase to prepare a mixed solution containing 2.2 μg each of ezetimibe and rosuvastatin per mL, shake well, and use as the reference solution;

[0045] Accurately measure 50 μL of each of the above solutions and inject them into a high-performance liquid chromatography system (column temperature: 30℃; flow rate: 1.5 mL / min; run time: 6 minutes; injection volume: 50 μL). Record the chromatograms, as shown below. Figure 1 As shown, calculate the cumulative dissolution amount.

[0046] The calculation formula is as follows:

[0047]

[0048] In the formula: As is the peak area of ​​ezetimibe in the test solution; Ar is the peak area of ​​ezetimibe in the reference solution; Wr is the sample weight of ezetimibe reference standard, mg; labeled amount: each tablet contains 10 mg of ezetimibe; f: conversion factor of ezetimibe 1.0000.

[0049]

[0050] Where: As is the peak area of ​​rosuvastatin in the test solution; Ar is the peak area of ​​rosuvastatin in the reference solution; Wr is the weight of the rosuvastatin calcium reference standard, mg; labeled amount: each tablet contains rosuvastatin (in C... 22 H 28 (FN3O6S) 10mg (both raw material and reference standard are rosuvastatin calcium, and the specification is calculated as 10mg based on rosuvastatin); f: conversion factor of rosuvastatin 1.0395 (the molecular weight of rosuvastatin calcium is 1001.14, and the molecular weight of rosuvastatin is 481.54).

[0051]

[0052]

[0053] If this formula is expressed using the release amount measured at various time points, it can be transformed into:

[0054]

[0055] In the formula: A 样 A represents the peak area of ​​the dissolution solution taken at each time point; 对 The peak area of ​​the reference solution; m 对The sample weight of the reference standard is in mg; P 对 The content of the reference standard; C n V represents the sample concentration at each time point after extraction (i.e., before dilution); 对 V1 is the dilution volume of the reference standard; V2 is the fixed sampling volume at each time point; L is the volume of the dissolution medium; (L / V2 unit needs to be consistent with C) n Consistent).

[0056] The formula for calculating the dissolution similarity factor f2 is:

[0057] f2=50·log{[1+(1 / n)Σ t＝1 n (R t -T t ) 2 ] -0.5 ·100}, when f2≥50, it indicates that the dissolution is similar, or when the dissolution of the test formulation and the reference formulation is ≥85% within 15 minutes, it can be considered that the dissolution behavior of the two is similar, and there is no need to compare f2.

[0058] Table 1 shows the cumulative dissolution and relative standard deviation (RSD) of ezetimibe and rosuvastatin at different times measured in this embodiment. As can be seen from the table, when the sampling time is more than 10 minutes, the RSD of the dissolution curve detection method in this embodiment is less than 10%; when the sampling time is 15 minutes, the dissolution of ezetimibe is less than 85%; when the sampling time is 60 minutes, the cumulative dissolution of both ezetimibe and rosuvastatin calcium is greater than 95%.

[0059] Table 1. Cumulative dissolution and RSD of ezetimibe and rosuvastatin at different times in Example 1 (n=12)

[0060]

[0061] Example 2

[0062] This embodiment provides dissolution media with different pH values; the rest is the same as in Example 1.

[0063] Dissolution medium B: pH=2.0, hydrochloric acid solution containing 0.2% polysorbate 80; the specific preparation method is as follows: take 0.9 mL (mass fraction of about 37%) hydrochloric acid, 2 g polysorbate 80, then add water to dilute to 1000 mL, mix well, and the solution is ready.

[0064] Dissolution medium C: pH = 6.6, citrate buffer containing 0.2% polysorbate 80. The specific preparation method is as follows: Dissolve 147g of sodium citrate (C6H5Na3O7·2H2O, 294.10g / mol) in 2000mL of water, add 3.61g of citric acid (C6H8O7·H2O, 210.14g / mol) and 20g of polysorbate 80, dilute with water to 10000mL, shake well, and adjust the pH to 6.6 with citric acid or sodium citrate.

[0065] Dissolution medium D: An aqueous solution containing 0.2% polysorbate 80. The specific preparation method is as follows: Take 2g of polysorbate 80 and add water to 1000mL.

[0066] The preparation method for the test solution of the reference formulation, ezetimibebrevis suvastatin calcium tablets, was the same as that for the self-made formulation ezetimibebrevis suvastatin calcium tablets in Example 1. The reference formulation was purchased from the Czech Republic (trade name: Zenon). Certified manufacturer: Sanofi-Aventis, SRO; Specification: 10mg / 10mg.

[0067] Table 2 shows the cumulative dissolution amounts of ezetimibe and rosuvastatin at different times in different dissolution media. As can be seen from Table 2, the cumulative dissolution of rosuvastatin calcium in both the self-made sample and the reference formulation was greater than 85% in the three media mentioned above, indicating similarity between the two. Ezetimibe showed an f2 greater than 50 in all three media, confirming the similarity between the self-made sample and the reference formulation.

[0068] Table 2. Cumulative dissolution amounts of ezetimibe and rosuvastatin in different dissolution media (n=12)

[0069]

[0070] Example 3 Specificity Test

[0071] Blank solvent: Take 2 mL of dissolution medium A, place it in a 10 mL volumetric flask, dilute to the mark with the mobile phase, and shake well.

[0072] Blank excipient solution: Take about 50 mg of blank excipient and place it in a 250 mL volumetric flask. Dilute to the mark with the dissolution medium, shake well, filter, and take the filtrate as blank excipient stock solution. Accurately measure 2 mL of each blank excipient stock solution and place it in a 10 mL volumetric flask. Dilute to the mark with the mobile phase and shake well.

[0073] Test solution: Take about 33 mg of the fine powder of this product and place it in a 100 mL volumetric flask. Add an appropriate amount of dissolution medium to dissolve ezetimibe and rosuvastatin calcium. Dilute to the mark with the dissolution medium, shake well, filter, accurately measure 2 mL of the filtrate, place it in a 10 mL volumetric flask, dilute to the mark with the mobile phase, and shake well.

[0074] Preparation of reference solution: Weigh 11 mg of ezetimibe reference standard and 11.5 mg of rosuvastatin calcium (calculated as 10 mg of rosuvastatin) reference standard accurately, place them in a 100 mL volumetric flask, add an appropriate amount of mobile phase to dissolve, dilute to the mark with mobile phase, accurately measure 1 mL, place it in a 50 mL volumetric flask, dilute to the mark with mobile phase, and shake well to obtain the reference solution;

[0075] Accurately measure 50 μL of each of the above solutions and inject them into the liquid chromatography system, then record the chromatograms. The results are shown in Table 3.

[0076] Table 3 Results of specificity tests for dissolution methodology validation

[0077] Ingredient name Retention time (min) Peak area Theoretical number of plates Resolution Tail Factor rosuvastatin 2.455 20170319 4090 0.000 1.354 Izhemabu 4.643 24073325 5320 10.722 1.315

[0078] The experimental results show that the blank solvent does not interfere with the determination of impurities.

[0079] Example 4: Linearity and Range Test

[0080] Accurately weigh appropriate amounts of ezetimibe reference standard and rosuvastatin calcium reference standard, place them in a 100 mL volumetric flask, add mobile phase to dissolve and dilute to prepare a solution containing 0.1 mg of ezetimibe and rosuvastatin per mL. Accurately measure appropriate amounts and dilute with different dissolution media (numbered the same as in Examples 1 and 2) to prepare solutions containing 5 μg, 20 μg, 40 μg, 50 μg and 75 μg of ezetimibe and rosuvastatin per mL, respectively.

[0081] Accurately measure 50 μL of each of the above solutions and inject them into the liquid chromatograph, recording the chromatograms. Perform linear regression on the peak area against concentration. The results are shown in Table 4.

[0082] Table 4. Linear equations for rosuvastatin and ezetimibe in different dissolution media.

[0083]

[0084] The experimental results showed that ezetimibe and rosuvastatin had a good linear relationship within the concentration range of 5 μg / mL to 75 μg / mL.

[0085] Example 5 Accuracy Test

[0086] Reference solution: Weigh appropriate amounts of ezetimibe reference standard and rosuvastatin calcium reference standard accurately, add an appropriate amount of mobile phase to dissolve them, and dilute quantitatively with mobile phase to prepare a mixed solution containing 2.2 μg each of ezetimibe and rosuvastatin per 1 mL.

[0087] Reference stock solution: Weigh appropriate amounts of ezetimibe reference standard and rosuvastatin calcium reference standard accurately, dissolve and dilute with mobile phase to prepare a mixed solution containing 0.22 mg of ezetimibe and rosuvastatin per 1 mL. Accurately measure 10 mL and place it in a 200 mL volumetric flask. Dilute to the mark with each dissolution medium (numbered the same as in Examples 1 and 2) and shake well.

[0088] 20% Recovery Solution: Take approximately 15 mg of blank excipient and place it in a 50 mL volumetric flask. Add an appropriate amount of mobile phase to dissolve the excipient. Accurately measure 2 mL, 8 mL, 10 mL, and 12 mL of the reference standard stock solution and place them in the same volumetric flask. Dilute to the mark with the mobile phase and mix well. These are the 20%, 80%, 100%, and 120% recovery solutions. (Prepare three aliquots using the same method.)

[0089] Accurately measure 50 μL of the above solution and inject it into the liquid chromatograph. Record the chromatogram. Calculate the recovery rate by peak area using the external standard method. The results are shown in Tables 5-12.

[0090]

[0091] Table 5. Results of recovery tests for dissolution method validation of dissolution medium A (rosuvastatin calcium)

[0092]

[0093] Table 6. Results of recovery tests for leaching method validation of leaching medium A (ezetimibe)

[0094]

[0095]

[0096] Table 7. Results of recovery tests for dissolution method validation of dissolution medium B (rosuvastatin calcium)

[0097]

[0098] Table 8 Results of recovery tests for leaching method validation of leaching medium B (ezetimibe)

[0099]

[0100] Table 9. Results of recovery tests for dissolution method validation of dissolution medium C (rosuvastatin calcium)

[0101]

[0102]

[0103] Table 10 Results of recovery tests for leaching method validation of leaching medium C (ezetimibe)

[0104]

[0105] Table 11 Results of recovery tests for dissolution method validation of dissolution medium D (rosuvastatin calcium)

[0106]

[0107] Table 12 Results of recovery tests for leaching method validation of leaching medium D (ezetimibe)

[0108]

[0109] Recovery was performed at concentration levels of 20%, 80%, 100%, and 120%. As shown in Tables 5-12, the recovery rates of ezetimibe and rosuvastatin calcium were both between 98% and 102% (n=12), and the RSDs were all less than 2.0%, which met the validation requirements and indicated that the method was accurate.

[0110] Example 6 Solution Stability

[0111] Reference solution: Weigh appropriate amounts of ezetimibe reference standard and rosuvastatin calcium reference standard accurately, add an appropriate amount of mobile phase to dissolve, and quantitatively dilute with mobile phase to prepare a mixed solution containing 0.11 mg of ezetimibe and rosuvastatin per 1 mL. Accurately measure 1 mL, place it in a 50 mL volumetric flask, and dilute to the mark with mobile phase and each dissolution medium respectively, and shake well.

[0112] Test solution: Weigh 20 tablets of ezetimibe and rosuvastatin calcium, grind them thoroughly in a mortar, take about 33 mg of the fine powder, put it in a 100 mL volumetric flask, add an appropriate amount of dissolution medium to dissolve ezetimibe and rosuvastatin calcium, dilute to the mark with dissolution medium, shake well, filter, accurately measure 2 mL of each filtrate, put it in a 10 mL volumetric flask, dilute to the mark with mobile phase, and shake well.

[0113] Both the reference solution and the test solution were placed at room temperature, and samples were collected at 0, 24, 36, 48, and 72 hours to examine the stability of the reference solution and the test solution in the dissolution medium over 72 hours. The results are shown in the table below.

[0114] Table 13. Stability of rosuvastatin calcium reference solution in dissolution media at different pH values ​​(room temperature)

[0115] time mobile phase Dissolution medium A Dissolution medium B Dissolution medium C Dissolution medium D room temperature 0h 2669850 2740535 2626288 2563276 2607970 Room temperature 24h 2693929 2781999 2666768 2591622 2623285 48h at room temperature 2693290 2794446 2669620 2606924 2641117 72h at room temperature 2713832 2819982 2714221 2623936 2659696 average value 2692725 2784241 2669224 2596440 2633017 RSD% 0.67 1.19 1.35 0.99 0.85

[0116] Table 14. Stability of ezetimibe reference solution in dissolution media at different pH values ​​(room temperature)

[0117] time mobile phase Dissolution medium A Dissolution medium B Dissolution medium C Dissolution medium D room temperature 0h 3081062 3280588 3134055 2976860 3001587 Room temperature 24h 3110302 3316785 3165440 3013029 3032292 48h at room temperature 3126200 3341890 3185057 3038351 3048862 72h at room temperature 3151294 3365805 3213450 3057493 3071465 average value 3117215 3326267 3174501 3021433 3038552 RSD% 0.94 1.10 1.05 1.15 0.97

[0118] Table 15. Stability of rosuvastatin calcium test solution in dissolution media at different pH values ​​(room temperature)

[0119] time mobile phase Dissolution medium A Dissolution medium B Dissolution medium C Dissolution medium D room temperature 0h 2793552 2867957 2509371 2713168 2798231 Room temperature 24h 2816741 2906529 2544689 2730146 2824062 48h at room temperature 2829072 2910795 2555796 2760059 2823771 72h at room temperature 2848362 2946790 2577525 2786414 2873320 average value 2821932 2908018 2546845 2747447 2829846 RSD% 0.81 1.11 1.12 1.18 1.11

[0120] Table 16. Stability of ezetimibe test solution in dissolution media at different pH values ​​(room temperature)

[0121] time mobile phase Dissolution medium A Dissolution medium B Dissolution medium C Dissolution medium D room temperature 0h 2727285 2750531 2897143 2747438 2849844 Room temperature 24h 2761391 2777650 2918501 2778504 2880993 48h at room temperature 2770601 2788805 2933139 2789446 2903375 72h at room temperature 2796887 2826662 2960272 2810581 2943147 average value 2764041 2785912 2927264 2781492 2894340 RSD% 1.04 1.13 0.91 0.95 1.36

[0122] The above experimental results show that the RSD% of the peak area of ​​the reference solution and the test solution diluted with dissolution media of different pH values ​​is less than 2.0 after standing at room temperature for 72 hours. This confirms that the reference solution and the test solution diluted with dissolution media of corresponding different pH values ​​are stable after standing at room temperature for 72 hours.

[0123] It can be seen that the dissolution curve detection method provided by the present invention has the characteristics of strong specificity, high sensitivity, high accuracy, and good durability, and has the advantages of being more universal and practical, and is simpler and more efficient to operate.

[0124] Comparative Example

[0125] This comparative example provides the cumulative dissolution amounts and RSDs of ezetimibe and rosuvastatin at different time points using the following schemes, as shown in Table 17. The preparation process for pH 4.5 acetate buffer + 0.2% SDS is essentially the same as that of dissolution medium A in Example 1, except that sodium dodecyl sulfate SDS is used instead of polysorbate 80. No polysorbate 80 or SDS is added to the pH 4.5 acetate buffer. The methods for determining the cumulative dissolution amount and RSD are the same as in Example 1. The results of the above comparative schemes are shown in Tables 18-21.

[0126] Table 17 Comparison of Scheme Designs

[0127]

[0128]

[0129] Table 18 compares the cumulative dissolution and RSD of ezetimibe and rosuvastatin at different time points in schemes 1 and 2 (n=12).

[0130]

[0131] Table 19 Comparison of cumulative dissolution and RSD of ezetimibe and rosuvastatin at different time points in schemes 3 and 4

[0132]

[0133] Table 20 Comparison of Cumulative Dissolution and RSD of Ezetimibe and Rosuvastatin at Different Time Points in Schemes 5 and 6

[0134]

[0135]

[0136] Table 21 Comparison of Cumulative Dissolution and RSD of Ezetimibe and Rosuvastatin at Different Time Points in Scheme 7

[0137]

[0138] The data in the table above shows that without the addition of surfactants (comparison schemes 1, 2, and 5), the dissolution rate of ezetimibe is very low, regardless of whether the basket or paddle method is used; the cumulative dissolution rate of ezetimibe is less than 20% after 60 minutes. Adding SDS to the dissolution medium (comparison schemes 3, 4, and 6) significantly increases the dissolution rate of ezetimibe compared to not adding surfactants, but it reduces the cumulative dissolution rate of rosuvastatin, which is less than 85% after 60 minutes. Furthermore, the comparison of schemes 3 and 4 shows that increasing the paddle rotation speed increases the dissolution rate of ezetimibe; however, the cumulative dissolution rate exceeds 85% after 15 minutes, indicating excessively rapid dissolution and lack of distinguishability, making it difficult to assess differences between different processes and products. Comparison scheme 7 shows that when the basket mesh is set to 40 mesh, the small pore size and the generation of bubbles from the surfactant dissolving in water cause blockage, resulting in low dissolution rates for both ezetimibe and rosuvastatin.

[0139] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for detecting the dissolution curve of ezetimibe / brevisuvastatin calcium tablets with discriminative power, characterized in that, Includes the following steps: Preparation of test solution: Take ezetimibe / buresuvastatin calcium tablets and use 800-1000 mL of an aqueous solution containing 0.1-0.3 wt% polysorbate 80 as the dissolution medium, wherein the pH of the dissolution medium is 2-7; dissolve the tablets using the basket method in a dissolution apparatus, with the basket rotating at 50-100 rpm and the basket mesh size being 10-40 mesh; at different sampling time points, take an appropriate amount of the dissolution solution, filter it, accurately measure the filtrate, dilute it to the mark with the mobile phase, and shake well to obtain the test solution; Preparation of reference solution: Accurately weigh ezetimibe reference standard and rosuvastatin calcium reference standard, add an appropriate amount of mobile phase to dissolve them, dilute with mobile phase to prepare a mixed solution containing 2~3 μg each of ezetimibe and rosuvastatin per 1 mL, shake well, and use as the reference solution. Determination: Inject the test solution and the reference solution into the high performance liquid chromatograph, record the chromatograms, and calculate the dissolution amount; The chromatographic conditions for the high-performance liquid chromatography are as follows: Chromatographic column: XB-C18, 4.6mm×150mm, 5μm or equivalent column, using octadecylsilane-bonded silica gel as packing material; Detector: VWD detector, detection wavelength is 232nm; Mobile phase: 0.05 mol / L citrate buffer-acetonitrile was used as the mobile phase; wherein the volume ratio of 0.05 mol / L citrate buffer to acetonitrile was 50:

50. Column temperature: 30℃; Flow rate: 1.5 mL / min; Run time: 6 minutes, isocratic elution; Injection volume: 50µL.

2. The method for detecting the dissolution curve of ezetimibe / brevisuvastatin calcium tablets with discriminative power as described in claim 1, characterized in that, The pH of the dissolution medium is adjusted using hydrochloric acid, glacial acetic acid-sodium acetate, or citric acid-sodium citrate.

3. The method for detecting the dissolution curve of ezetimibe / brevisuvastatin calcium tablets with discriminative power as described in claim 1, characterized in that, The pH of the dissolution medium is adjusted to 2 using hydrochloric acid; or, the pH of the dissolution medium is adjusted to 4.5 using glacial acetic acid-sodium acetate; or, the pH of the dissolution medium is adjusted to 6.6 using citric acid-sodium citrate.

4. The method for detecting the dissolution curve of ezetimibe / brevisuvastatin calcium tablets with discriminative power as described in claim 1, characterized in that, The mass concentration of the polysorbate 80 is 0.2 wt%.

5. The method for detecting the dissolution curve of ezetimibe / brevisuvastatin calcium tablets with discriminative power as described in claim 1, characterized in that, The rotating basket rotates at 75 rpm and has a mesh size of 10; the volume of the dissolution medium is 900 mL.

6. The method for detecting the dissolution curve of ezetimibe / brevisuvastatin calcium tablets with discriminative power as described in claim 1, characterized in that, The sampling time points include 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min.

7. The method for detecting the dissolution curve of ezetimibe / brevisuvastatin calcium tablets with discriminative power as described in claim 6, characterized in that, When the sampling time is more than 10 minutes, the relative standard deviation (RSD) of the method for detecting the dissolution curve of ezetimibe and rosuvastatin calcium tablets with discriminative power is less than 10%; when the sampling time is 15 minutes, the dissolution amount of ezetimibe is less than 85%; when the sampling time is 60 minutes, the cumulative dissolution amount of both ezetimibe and rosuvastatin calcium is greater than 95%.

8. The method for detecting the dissolution curve of ezetimibe / brevisuvastatin calcium tablets with discriminative power as described in claim 1, characterized in that, The citrate buffer solution is prepared as follows: Take 14.7g of sodium citrate and 0.36g of citric acid, add an appropriate amount of water and sonicate to dissolve, dilute with water to 1000mL, and adjust the pH value to 4.0 with phosphoric acid.

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