Dissolution analysis method of minodronic acid tablets

Abstract

The invention discloses a dissolution rate analysis method of minodronic acid tablets, which is carried out according to a dissolution rate determination method, and an adopted dissolution medium is hydrochloric acid with the pH value of 1.2 or a phosphate buffer solution with the pH value of 4.0; the test solution is a dissolution solution at each sampling time point, and is prepared by diluting and quantifying by using a diluent after filtering; the reference substance solution is a solution containing 1 [mu] g of minodronic acid per 1 ml; wherein the diluent is a 0.09 mol / L or 0.06 mol / L sodium hydroxide solution, and a solvent of the sodium hydroxide solution is a mobile phase. According to the application, the diluent of the test solution is optimized and improved, and the mobile phase solution neutralized by sodium hydroxide with a specific concentration is adopted to dilute the test solution, so that the solvent interference is eliminated, and the dissolution rate detection accuracy of minodronic acid tablets in two dissolution media, namely a hydrochloric acid solution with the pH value of 1.2 and a phosphate buffer solution with the pH value of 4.0, is improved.

Description

Technical Field

[0001] The present application belongs to the technical field of drug analysis, and specifically relates to a dissolution analysis method for minodronic acid tablets. Background Art

[0002] Minodronic acid is a third-generation nitrogen-containing aromatic heterocyclic bisphosphonate. Its scientific name is: 1-hydroxy-2-[imidazo(1,2-a)pyridin-3-yl]ethylidene)bisphosphonic acid monohydrate. Its structural formula is as follows:

[0003]

[0004] Minodronic acid tablets (specification: 1mg) are a drug used to treat osteoporosis. It inhibits the farnesyl pyrophosphate synthase in osteoclasts, inhibits the bone resorption function of osteoclasts, and then reduces the bone metabolism cycle, thereby preventing and treating osteoporosis. Studies have shown that the activity of inhibiting bone resorption is stronger, which is twice that of incadronate disodium, 10 times that of alendronate sodium, and 100 times that of pamidronate disodium.

[0005] According to the "Guidelines for the Determination and Comparison of Dissolution Curves of Ordinary Oral Solid Preparations", it is recommended to select no less than 3 pH values ​​of dissolution media for dissolution curve investigation, provided that the stability of the main components of the drug meets the requirements of the determination method. The results of the solubility investigation of minodronic acid raw materials in different media show that its solubility in water, pH 1.2 hydrochloric acid solution, pH 4.0 acetate buffer solution, and pH 6.8 phosphate buffer solution is basically the same, all about 10 mg / 100 ml, which meets the detection requirements. The dosage of minodronic acid tablets is 1 mg / tablet, which is relatively low. At the same time, minodronic acid has weak ultraviolet absorption. Therefore, the use of high-performance liquid chromatography can improve the detection sensitivity of the sample and obtain more accurate dissolution results. However, when the dissolution solution is directly tested after filtration, the solvent peak interference of pH 1.2 hydrochloric acid solution and pH 4.0 acetate buffer solution is relatively large; in addition, in the currently disclosed dissolution test of minodronic acid tablets, the solvent of the test sample is the dissolution medium, but when the test sample uses the dissolution medium as the solvent, the solvent peak interference is relatively large, and the sample cannot be accurately tested. Summary of the invention

[0006] In view of this, it is necessary for the present application to provide a dissolution analysis method for minodronic acid tablets, optimize and improve the solvent of the test solution, and dilute the test solution with a mobile phase solution neutralized with a specific concentration of sodium hydroxide, thereby eliminating solvent interference and improving the dissolution detection accuracy of minodronic acid tablets in two dissolution media: pH 1.2 hydrochloric acid solution and pH 4.0 phosphate buffer.

[0007] In order to achieve the above objectives, this application adopts the following technical solutions:

[0008] The present application provides a dissolution analysis method for minodronic acid tablets, wherein the dissolution medium used is pH 1.2 hydrochloric acid or pH 4.0 phosphate buffer;

[0009] The test solution and reference solution were prepared as follows:

[0010] Test solution: Take the dissolution at each sampling time point, filter, accurately measure 5 ml of the filtrate, put it in a 10 ml quantitative container, dilute it with a diluent, and shake it well;

[0011] Reference solution: accurately weigh 10 mg of minodronic acid reference substance, place it in a 50 ml quantitative container, add blank solvent to dissolve and dilute quantitatively, shake well; then accurately measure the solution, dilute quantitatively with blank solvent to make a solution containing 1 μg minodronic acid per 1 ml;

[0012] Wherein, the diluent is a sodium hydroxide solution with a concentration of 0.09 mol / L or 0.06 mol / L, and the solvent of the sodium hydroxide solution is the mobile phase;

[0013] The blank solvent is prepared by mixing the dissolution medium and the diluent in a volume ratio of 50:50.

[0014] In a further embodiment, the mobile phase is a mixture of sodium pyrophosphate buffer and methanol in a volume ratio of (94-96): (4-6);

[0015] Preferably, the mobile phase is a mixture of sodium pyrophosphate buffer and methanol in a volume ratio of 95:5.

[0016] In a further embodiment, the sodium pyrophosphate buffer has a concentration of 5.32 mg / ml and a pH of 7.5 to 7.7, and contains 0.5 mmol / L of tetrabutylammonium bromide.

[0017] In a further embodiment, the test solution and the reference solution are both detected by high performance liquid chromatography, and the chromatographic conditions are:

[0018] Chromatographic column: C18;

[0019] Mobile phase: sodium pyrophosphate buffer and methanol in a volume ratio of (94-96): (4-6);

[0020] The flow rate was 0.95-1.05 ml / min, the detection wavelength was UV 224-228 nm, the column temperature was 33-37 °C, and the injection volume was 20 μl.

[0021] In a further embodiment, the chromatographic column has a length of 150 mm, a diameter of 4.6 mm, and a filler particle size of 5 μm.

[0022] In a further embodiment, the volume ratio of the sodium pyrophosphate buffer to methanol is 95:5.

[0023] In a further embodiment, the flow rate is 1.0 ml / min.

[0024] In a further embodiment, the detection wavelength is ultraviolet 226 nm.

[0025] In a further embodiment, the column temperature is 35°C.

[0026] In a further embodiment, the sodium pyrophosphate buffer has a concentration of 5.32 mg / ml and a pH of 7.5 to 7.7, wherein the buffer contains 0.5 mmol / L of tetrabutylammonium bromide;

[0027] Preferably, the pH of the sodium pyrophosphate buffer is 7.6.

[0028] Beneficial effects of this application:

[0029] The dissolution analysis method of the present application has high operation reproducibility and accuracy, and can accurately detect the dissolution of minodronic acid tablets in two dissolution media: pH 1.2 hydrochloric acid solution and pH 4.0 phosphate buffer. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 It is an overlay of the chromatograms of the blank solvent, blank excipient solution, reference solution, and test solution in the specificity experiment of Example 1.

[0031] Figure 2 It is the linear curve of the linear experiment in Example 2.

[0032] Figure 3 This is an overlay of the chromatograms of the blank solvent, blank excipient solution, reference solution, and test solution in the specificity experiment of Example 5.

[0033] Figure 4 It is the linear curve of the linear experiment in Example 6.

[0034] Figure 5 This is an overlay of the chromatograms of the various changed chromatographic conditions in the durability experiment in Example 9.

[0035] Figure 6 The chromatograms of the reference substance solution in different dissolution media in Example 10 are overlaid. DETAILED DESCRIPTION

[0036] The following will clearly and completely describe the implementation methods of the present application. The technical solutions in the implementation methods described below are exemplary and are only possible technical implementations of the present application, not all possible implementations. Those skilled in the art can fully combine the implementation methods of the present application to obtain other implementation methods without creative work, and these implementation methods are also within the scope of protection of the present application.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0038] In addition, unless otherwise specified, methods without specific conditions or steps are conventional methods, and the reagents and materials used are all commercially available.

[0039] The raw material information in the following examples and comparative examples is as follows:

[0040]

[0041]

[0042] Dissolution analysis method of minodronic acid tablets (dissolution medium is pH 1.2 hydrochloric acid)

[0043] Example 1 Specificity Experiment

[0044] 1. Selection of HPLC conditions:

[0045] High performance liquid chromatograph: Shimadzu LC-20AT.

[0046] Column: Ultimate XB–C18, 4.6×150 mm, 5 μm.

[0047] Mobile phase: sodium pyrophosphate buffer and methanol are mixed in a volume ratio of 95:5, wherein, sodium pyrophosphate buffer: take 5.32g sodium pyrophosphate, add 1000ml water to dissolve, then add 0.5mmol tetrabutylammonium bromide, and adjust the pH value to 7.6 with phosphoric acid.

[0048] The detection wavelength was UV 226 nm; the column temperature was 30°C; the flow rate was 1.0 ml / min; and the injection volume was 20 μl.

[0049] 2. The solution is prepared as follows:

[0050] Diluent: Accurately weigh 3.6 g of sodium hydroxide, add 1000 ml of mobile phase to dissolve it, and shake well.

[0051] Blank solvent: pH 1.2 hydrochloric acid and diluent were mixed in a volume ratio of 50:50.

[0052] Blank excipient solution: Take about 100 mg (equivalent to 1 mg of minodronic acid) of blank excipient (mix lactose, pregelatinized starch, magnesium stearate and gastric soluble film coating powder in a mass ratio of 92:5:1:2) and place it in a 500 ml volumetric flask, add dissolution medium (pH 1.2 hydrochloric acid) to dilute to the scale, and shake well; filter the above solution, take 5 ml of the filtrate, place it in a 10 ml volumetric flask, add diluent to dilute to the scale, and shake well.

[0053] Reference solution: accurately weigh 10 mg of minodronic acid reference substance, place it in a 50 ml volumetric flask, add blank solvent to dissolve to the scale, and shake well; accurately measure the above solution again, add blank solvent to dilute and quantify, and make a solution containing 1 μg minodronic acid per 1 ml.

[0054] Test solution: Take minodronic acid tablets (batch number: 2006041), place them in a 500ml volumetric flask, add an appropriate amount of dissolution medium (pH 1.2 hydrochloric acid), dissolve them by ultrasound, then add dissolution medium (pH 1.2 hydrochloric acid) to dilute to the scale, and shake well; take the above solution, filter, take 5ml of the filtrate, place it in a 10ml volumetric flask, add diluent to dilute to the scale, and shake well.

[0055] 3. Sample determination:

[0056] After the system is stable, take 20 μl of blank solvent, blank excipient solution, reference solution, and test solution and inject them into the HPLC to perform a specificity experiment. See the chromatogram for details. Figure 1 , the test and analysis results are shown in Table 1.

[0057] Table 1 Specificity test results

[0058]

[0059]

[0060] pass Figure 1 It can be seen from the results in Table 1 that in the analytical method provided by the present application, the blank solvent and blank excipient have no interference with the detection of the main component; the retention time of the main peak in the reference solution and the test solution is consistent, indicating that the analytical method provided by the present application has good specificity.

[0061] Example 2 Linearity Experiment

[0062] 1. Selection of HPLC conditions:

[0063] Same as Example 1.

[0064] 2. The solution is prepared as follows:

[0065] The preparation of blank solvent and diluent is the same as in Example 1.

[0066] Minodronic acid reference stock solution: accurately weigh 10 mg of minodronic acid reference, place it in a 50 ml volumetric flask, add mobile phase to dissolve and dilute to the scale, shake well; accurately measure 5 ml of the above solution again, place it in a 100 ml volumetric flask, add blank solvent to dilute to the scale, shake well, and obtain.

[0067] Accurately measure 1 ml, 2 ml, 3 ml and 5 ml of minodronic acid reference stock solution, place them in 50 ml volumetric flasks respectively, add blank solvent to dilute to the scale, shake well, and use them as linear solutions 2 to 5 respectively.

[0068] Accurately measure 3 ml of minodronic acid reference stock solution, place it in a 25 ml volumetric flask, add blank solvent to dilute to the scale, shake well, and use it as linear solution No. 6.

[0069] Accurately measure 5 ml of linear solution No. 5, place it in a 100 ml volumetric flask, add blank solvent to dilute to the scale, shake well, and use it as linear solution No. 1.

[0070] 3. Sample determination: After the system is stable, take 20 μl of each of the linear solutions 1 to 6 and inject them into the HPLC to perform a linear experiment. The results are shown in Figure 2 and Table 2.

[0071] Table 2 Linearity test results

[0072]

[0073] It can be seen from the results in Table 2 that the dissolution analysis method provided in the present application has a good linear relationship for minodronic acid in a pH 1.2 hydrochloric acid dissolution medium.

[0074] Example 3 Accuracy Experiment

[0075] 1. Selection of HPLC conditions:

[0076] Same as Example 1.

[0077] 2. The solution is prepared as follows:

[0078] The preparation of blank solvent and diluent is the same as in Example 1.

[0079] Reference solution: accurately weigh 10 mg of minodronic acid reference substance, place it in a 50 ml volumetric flask, add blank solvent to dissolve and dilute to the scale, shake well; then accurately measure an appropriate amount, add blank solvent to quantitatively dilute to make a solution containing 1 μg per 1 ml.

[0080] Take about 11 mg, 17 mg, and 23 mg of minodronic acid reference substance respectively, weigh accurately, put into a 100 ml volumetric flask, add blank solvent to dissolve and dilute to the scale, shake well, and use them as 55%, 85%, and 115% sample addition reference substance stock solutions respectively.

[0081] Sample addition test solution: Take about 100 mg of blank excipients (mix lactose, pregelatinized starch, magnesium stearate and gastric soluble film coating powder in a mass ratio of 92:5:1:2) (equivalent to 1 mg of minodronic acid), accurately weigh, place in a 500 ml volumetric flask, accurately add 5 ml of 55%, 85% and 115% sample addition reference stock solution, respectively, sonicate, add dissolution medium (pH 1.2 hydrochloric acid) to dilute to the scale, shake well, filter, accurately transfer 5 ml of the filtrate, place in a 10 ml volumetric flask, add diluent to dilute to the scale, shake well, as 55%, 85% and 115% sample addition test solutions (prepare 3 samples of each concentration in parallel).

[0082] 3. Sample determination: After the system is stable, take 55%, 85% and 115% of the test solution and inject 20μl each into the HPLC to perform an accuracy experiment. The results are shown in Table 3.

[0083] Table 3 Accuracy experimental results

[0084]

[0085] It can be concluded from the results in Table 3 that the dissolution analysis method provided in the present application has good accuracy for minodronic acid in pH 1.2 hydrochloric acid and can accurately detect the content of minodronic acid in the dissolution solution.

[0086] Example 4 Precision Experiment

[0087] 1. Repeatability Experiment

[0088] 1. Selection of HPLC conditions:

[0089] Same as Example 1.

[0090] 2. The solution is prepared as follows:

[0091] The preparation of blank solvent and diluent is the same as in Example 1.

[0092] Reference solution: Take about 10 mg of minodronic acid reference substance, weigh accurately, place in a 50 ml volumetric flask, add blank solvent to dissolve and dilute to the scale, shake well, then accurately measure an appropriate amount, add blank solvent to quantitatively dilute to make a solution containing about 1 μg per 1 ml.

[0093] Test solution: Take an appropriate amount of fine powder of minodronic acid tablets (batch number: 2006041) (equivalent to about 1 mg of minodronic acid), accurately weigh it, place it in a 500ml volumetric flask, add an appropriate amount of dissolution medium (pH 1.2 hydrochloric acid) and ultrasonically dissolve it, and dilute it to the scale with dissolution medium (pH 1.2 hydrochloric acid), shake well, filter, transfer 5ml of the filtrate, place it in a 10ml volumetric flask, add diluent to dilute to the scale, and shake well (prepare 6 portions).

[0094] 3. Sample determination: After the system is stable, take 20 μl of the above-mentioned reference solution and test solution and inject them into the high performance liquid chromatograph for repeatability experiment. The results are shown in Table 4.

[0095] 2. Intermediate precision experiment

[0096] Minodronic acid tablets were taken and sample analysis was performed on another instrument by a different analyst (laborator B) on a different date according to the method of the above repeatability experiment. The results are shown in Table 4.

[0097] Table 4 Precision test results

[0098]

[0099] From the results in Table 4, it can be seen that the average content of the 6 test samples is 97.97%, and the RSD is 0.55%, indicating that the repeatability of this method is good; the average content of the 12 test samples is 98.27%, and the RSD is 0.69%, indicating that the precision of this method is good.

[0100] Dissolution analysis method of minodronic acid tablets (dissolution medium is pH 4.0 phosphate buffer)

[0101] Example 5 Specificity Experiment

[0102] 1. Selection of HPLC conditions:

[0103] Same as Example 1.

[0104] 2. The solution is prepared as follows:

[0105] pH 4.0 phosphate buffer: Take an appropriate amount of 0.2 mol / L sodium dihydrogen phosphate aqueous solution, adjust the pH to 4.0 with sodium hydroxide test solution, and shake well.

[0106] Diluent: Accurately weigh 2.4 g of sodium hydroxide, add 1000 ml of mobile phase to dissolve it, and shake well.

[0107] Blank solvent: pH 4.0 phosphate buffer and diluent were mixed in a volume ratio of 50:50.

[0108] Blank excipient solution: accurately weigh the blank excipient (refer to Example 1, equivalent to 1 mg of minodronic acid), place it in a 500 ml volumetric flask, add dissolution medium (pH 4.0 phosphate buffer) to dilute to the scale, and shake well; filter the above solution, take 5 ml of the filtrate, place it in a 10 ml volumetric flask, add diluent to dilute to the scale, and shake well.

[0109] Reference solution: accurately weigh 10 mg of minodronic acid reference substance, place it in a 50 ml volumetric flask, add blank solvent to dissolve to the scale, and shake well; accurately measure the above solution again, add blank solvent to dilute and quantify, and make a solution containing 1 μg minodronic acid per 1 ml.

[0110] Test solution: Take minodronic acid tablets (batch number: 2006041), place them in a 500ml volumetric flask, add an appropriate amount of dissolution medium (pH 4.0 phosphate buffer), dissolve them by ultrasound, then add dissolution medium (pH 4.0 phosphate buffer) to dilute to the scale, and shake well; take the above solution, filter, take 5ml of the filtrate, place it in a 10ml volumetric flask, add diluent to dilute to the scale, and shake well.

[0111] 3. Sample determination: After the system is stable, take 20 μl of blank solvent, blank excipient solution, reference solution and test solution and inject them into the HPLC for specificity experiment. The chromatogram is shown in Figure 3 , the test and analysis results are shown in Table 5.

[0112] Table 5 Specificity test results

[0113] sample Retention time min Peak area mAu Blank solvent - - Blank excipient solution - - Test solution 6.510 79863 Reference solution 6.504 81738

[0114] pass Figure 3 From the results in Table 5, it can be concluded that the blank solvent and blank excipients have no interference with the detection of the main component; the retention time of the main peak in the reference solution and the test solution is consistent, indicating that the dissolution analysis method provided in this application has good specificity in pH 4.0 phosphate buffer.

[0115] Example 6 Linearity Experiment

[0116] 1. Selection of HPLC conditions:

[0117] Same as Example 1.

[0118] 2. The solution is prepared as follows:

[0119] The preparation of blank solvent and diluent is the same as that in Example 5.

[0120] The preparation of linear solutions 1 to 6 is as described in Example 2.

[0121] 3. After the system is stable, take 20 μl of each of the linear solutions 1 to 6 and inject them into the HPLC to perform a linear experiment. The results are shown in Figure 4 and Table 6.

[0122] Table 6 Linearity test results

[0123]

[0124] The results in Table 6 show that the dissolution analysis method provided by the present application has a good linear relationship for minodronic acid in a pH 4.0 phosphate buffer dissolution medium.

[0125] Example 7 Accuracy Experiment

[0126] 1. Selection of HPLC conditions:

[0127] Same as Example 1.

[0128] 2. The solution is prepared as follows:

[0129] The preparation of blank solvent and diluent is the same as that in Example 5.

[0130] The preparation of the sample solution is as described in Example 3.

[0131] 3. Sample determination: After the system is stable, take 20 μl of 55%, 85% and 115% test sample solutions and inject them into the HPLC for accuracy test. The results are shown in Table 7.

[0132] Table 7 Accuracy experimental results

[0133]

[0134]

[0135] The results in Table 7 show that the dissolution analysis method provided in the present application has good accuracy for minodronic acid in a pH 4.0 phosphate buffer dissolution medium and can accurately detect the content of minodronic acid in the dissolution solution.

[0136] Example 8 Precision Experiment

[0137] 1. Repeatability Experiment

[0138] 1. Selection of HPLC conditions:

[0139] Same as Example 1.

[0140] 2. The solution is prepared as follows:

[0141] The preparation of blank solvent and diluent is the same as that in Example 5.

[0142] The preparation of reference solution and test solution refers to Example 4.

[0143] 3. Sample determination: After the system is stable, take 20 μl of the reference solution and the test solution and inject them into the HPLC to perform a repeatability experiment. The results are shown in Table 8.

[0144] 2. Intermediate precision experiment

[0145] Refer to Example 4, and see Table 8 for the results.

[0146] Table 8 Precision test results

[0147]

[0148]

[0149] The results in Table 8 show that the average content of the 6 test samples was 98.57% and the RSD was 0.54%, indicating that the repeatability of this method was good; the average content of the 12 test samples was 99.17% and the RSD was 0.91%, indicating that the precision of this method was good.

[0150] Example 9 Durability Test

[0151] The preparation of blank solvent and diluent is the same as in Example 1.

[0152] The preparation of the reference solution and the test solution is the same as in Example 1.

[0153] By slightly changing the chromatographic parameters such as mobile phase pH value (±0.1), column temperature (±2°C), flow rate (±0.05ml / min), wavelength (±2nm), mobile phase ratio (±1%), etc., the degree of influence on the determination results was investigated. The chromatographic solution of the reference substance under each condition is shown in Figure 5 The results are shown in Table 9 (it should be noted that the chromatographic conditions in Table 9 are all single variables, and the other chromatographic conditions are the same as those in Example 1).

[0154] Table 9 Durability test results

[0155]

[0156] pass Figure 5 The results in Table 9 show that by fine-tuning chromatographic condition parameters such as column temperature (±2°C), flow rate (±0.05ml / min), wavelength (±2nm), mobile phase ratio, and pH value (±0.1), the relative average deviation of the results under each chromatographic condition was less than 2.0% compared with the standard conditions, indicating that the analytical method provided in the present application has good durability.

[0157] Example 10 Dissolution test results of different batches

[0158] 1. Selection of HPLC conditions:

[0159] Same as Example 1.

[0160] 2. The solution is prepared as follows:

[0161] The preparation of blank solvent, diluent and reference solution refers to Examples 1 and 5.

[0162] 3. Dissolution conditions:

[0163] pH 1.2 hydrochloric acid and pH 4.0 phosphate buffer were used as dissolution media, respectively. One minodronic acid tablet was added and stirred with a paddle method at a speed of 50 rpm. According to the dissolution determination method, the sampling time points were 5, 10, 15, 30, and 45 minutes.

[0164] Test solution: Take an appropriate amount of dissolution solution, filter, accurately measure 5 ml of the filtrate, place it in a 10 ml volumetric flask, dilute to the scale with the corresponding diluent, and shake well.

[0165] 4. Sample determination: After the system is stable, take 20 μl of the reference solution and the test solution and inject them into the HPLC. The chromatograms of the reference solution in different dissolution media are shown in Figure 6 The dissolution test results are shown in Table 10.

[0166] Table 10 Dissolution test results of different batches

[0167]

[0168] Figure 6 The results in Table 10 indicate that the dissolution analysis method provided in this application is applicable to the detection of different batches of test products.

[0169] It should be noted that the present application is not limited to the above-mentioned embodiments. The above-mentioned embodiments are only examples, and the embodiments having the same structure as the technical idea and exerting the same effect within the scope of the technical solution of the present application are all included in the technical scope of the present application. In addition, without departing from the scope of the main purpose of the present application, various modifications that can be thought of by those skilled in the art to the embodiments and other methods of combining some of the constituent elements in the embodiments are also included in the scope of the present application.

Claims

1. A dissolution analysis method for minodronic acid tablets, performed according to a dissolution assay method, characterized in that: The dissolution medium used was pH 1.2 hydrochloric acid or pH 4.0 phosphate buffer; The test solution and reference solution were prepared as follows: Test solution: Take the dissolution at each sampling time point, filter, accurately measure 5 ml of the filtrate, put it in a 10 ml quantitative container, dilute it with a diluent, and shake it well; Reference solution: accurately weigh 10 mg of minodronic acid reference substance, place it in a 50 ml quantitative container, add blank solvent to dissolve and dilute quantitatively, and shake well; Then accurately measure the solution and dilute it with blank solvent to make a solution containing 1 μg minodronic acid per 1 ml; Wherein, the diluent is 0.09 mol / L or 0.06 mol / L sodium hydroxide solution, and the solvent of the sodium hydroxide solution is the mobile phase; The blank solvent is prepared by mixing the dissolution medium and the diluent in a volume ratio of 50:

50.

2. The dissolution analysis method of minodronic acid tablets according to claim 1, characterized in that: The mobile phase is a mixture of sodium pyrophosphate buffer and methanol in a volume ratio of (94-96): (4-6); Preferably, the mobile phase is a mixture of sodium pyrophosphate buffer and methanol in a volume ratio of 95:

5.

3. The dissolution analysis method of minodronic acid tablets according to claim 2, characterized in that: The sodium pyrophosphate buffer has a concentration of 5.32 mg / ml and a pH of 7.5-7.7, and contains 0.5 mmol / L of tetrabutylammonium bromide.

4. The dissolution analysis method of minodronic acid tablets according to claim 1, characterized in that: The test solution and the reference solution were detected by high performance liquid chromatography, and the chromatographic conditions were: Chromatographic column: C18; Mobile phase: sodium pyrophosphate buffer and methanol in a volume ratio of (94-96): (4-6); The flow rate was 0.95-1.05 ml / min, the detection wavelength was UV 224-228 nm, the column temperature was 33-37 °C, and the injection volume was 20 μl.

5. The dissolution analysis method of minodronic acid tablets according to claim 4, characterized in that: The chromatographic column has a length of 150 mm, a diameter of 4.6 mm, and a filler particle size of 5 μm.

6. The dissolution analysis method of minodronic acid tablets according to claim 4, characterized in that: The volume ratio of the sodium pyrophosphate buffer to methanol is 95:

5.

7. The dissolution analysis method of minodronic acid tablets according to claim 4, characterized in that: The flow rate is 1.0 ml / min.

8. The dissolution analysis method of minodronic acid tablets according to claim 4, characterized in that: The detection wavelength is ultraviolet 226nm.

9. The dissolution analysis method of minodronic acid tablets according to claim 4, characterized in that: The column temperature was 35°C.

10. The dissolution analysis method of minodronic acid tablets according to claim 4, characterized in that: The sodium pyrophosphate buffer has a concentration of 5.32 mg / ml and a pH of 7.5 to 7.7, wherein it contains 0.5 mmol / L of tetrabutylammonium bromide; Preferably, the pH of the sodium pyrophosphate buffer is 7.6.

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