1. A determination method for dissolution curves of solid ulipristal acetate preparations is characterized in that solvents containing Tween 80 are used as dissolution media, under the stirring state, a paddle method is adopted to detect the accumulated dissolution rates of the solid ulipristal acetate preparations in the dissolution media at different dissolution time points, and then the dissolution curves are drawn; the volume percentage concentration of the Tween 80 in the dissolution medium is 0.1-2%.

2. The method according to claim 1, wherein the solvent in the dissolution medium is water or a phosphate buffer solution having a pH of 4 to 7.

3. The method according to claim 1, wherein the solvent in the dissolution medium is a phosphate buffer solution having a pH of 4.5 to 6.8.

4. The method according to claim 1, wherein the rotation speed of the stirring is 50 to 75 r/min.

5. The determination method according to claim 1, wherein the paddle method for determining the dissolution rates of the ulipristal acetate solid preparation in the dissolution medium at different dissolution time points is specifically as follows: taking the solution at different dissolution time points, filtering, and measuring the accumulative dissolution rate of ulipristal acetate by adopting a high performance liquid chromatography.

6. The method according to claim 1, wherein the different elution time points are 6 to 10 elution time points separated by 5 to 30min within 0 to 120 min.

7. The method of claim 1, wherein the different dissolution time points are 5, 10, 15, 20, 30, 45, 60, 90 min.

8. The method according to claim 5, wherein the concentration of the binding agent in the binding agent is determined by the following methodCharacterized in that the chromatographic conditions of the high performance liquid phase are as follows: the buffer solution-organic phase is a mobile phase, the buffer solution is a phosphate buffer solution with the pH value of 3.0-8.0 and the concentration of 0.3-0.6%, and the organic phase is prepared from the following components in percentage by mass (30-50): (10-20) acetonitrile-tetrahydrofuran, wherein the volume ratio of the buffer solution to the organic phase is (35-55) to (65-45); the flow rate is 0.8-1.0 mL/min; the detection wavelength is 305 nm; the column temperature is 20-30 ℃; the chromatographic column is Waters Symmetry Shield^TMRP18 (4.6X 150mm, 5 μm) column, injection volume 20 μ L.

9. The assay method according to any one of claims 1 to 8, wherein the solid preparation of ulipristal acetate is ulipristal acetate tablet.

10. A method for evaluating the quality of ulipristal acetate solid preparation is characterized in that solvent containing Tween 80 is used as dissolution medium, under the stirring state, a paddle method is adopted to detect the accumulative dissolution rates of a reference solid preparation and a solid preparation to be detected in the dissolution medium at different dissolution time points, and then a dissolution curve is drawn; the volume percentage concentration of the Tween 80 in the dissolution medium is 0.1-2%;

and comparing the difference between the dissolution curve of the reference solid preparation and the dissolution curve of the solid preparation to be tested, and evaluating the quality of the solid preparation to be tested.

Background

Ulipristal acetate Tablets (Ulipristal acetate Tablets) mainly comprise Ulipristal acetate, and the chemical name is as follows: 17 alpha-acetoxy-11 beta- (4-N, N-dimethylaminophenyl) 19-norpregna-4, 9-diene-3, 20-dione with molecular formula C₃₀H₃₇NO₄. Ulipristal acetate belongs to a selective progesterone receptor modulator and plays an emergency contraceptive role mainly through ovulation inhibition. The drug can be taken within 120 hours after unprotected sexual intercourse or contraceptive failure, the emergency contraceptive efficacy cannot be reduced along with the delayed administration time, the safety and the tolerance are good, compared with the most commonly used emergency contraceptive levonorgestrel, the ulipristal acetate has the potential benefit of preventing more accidental pregnancies, and the clinical applicability is wider. Ulipristal acetate tablets (trade name: elaone) were developed by Laboratoire HRA Pharma of France with a specification of 30mg, and were marketed in Europe at 15 days 05 and 2009, and in the United states at 13 days 08 and 2010, and were not marketed in Japan and China.

At present, the quality standard of ulipristal acetate tablets is not collected in pharmacopoeias of various countries. In the research and development process of ulipristal acetate tablets, in order to reach the level consistent with the internal and external quality and curative effect of the original preparation, a scientific and reasonable solid preparation dissolution curve is formulated, which is an important step for improving the success rate of in vivo bioequivalence tests and provides guarantee for the consistency of the quality among drug batches and the consistency of the drug quality before and after process change. In order to make a prejudgment on the in vivo bioequivalence test and improve the success rate of the bioequivalence test, an in vitro dissolution detection method with strong discrimination is established, wherein the selection of a proper dissolution medium becomes a key point and a difficult point in the work.

Ulipristal acetate BCS is classified as class II, with pH-dependent solubility. The FDA website 'Dissolution Methods' describes the Dissolution of the product in 0.1mol/L hydrochloric acid solution, the rotating speed is 50 revolutions per minute, but the Dissolution speed of ulipristal acetate in the medium is higher, the difference of the in vitro Dissolution behavior between the ulipristal acetate and the original preparation cannot be evaluated, and the prediction is made for in vivo bioequivalence tests. Ulipristal acetate tablets are practically insoluble in water, phosphate buffer at pH4.5 and phosphate buffer at pH 6.8.

Chinese patent application publication No. CN104865215A discloses an ulipristal acetate tablet and a dissolution rate determination method, and describes that Sodium Dodecyl Sulfate (SDS) is selected as a surfactant in a dissolution medium of the product. In daily work, the sodium dodecyl sulfate has large difference among different purities, manufacturers and different batch numbers in the use process, has high requirements on the purities and the manufacturers, and is not beneficial to daily test activities. In addition, in the process of dissolution experiment operation, SDS and potassium salt are compatible to form precipitate with the reduction of the solution temperature, thereby influencing the determination of the test solution.

In order to predict the bioequivalence test in vivo and to increase the success rate of the bioequivalence test, a dissolution medium with discriminatory power needs to be established to determine the dissolution curve.

Disclosure of Invention

In view of the above, the invention provides a method for measuring a dissolution curve of a solid ulipristal acetate preparation. The method adds surfactant Tween 80 into dissolution medium for evaluating dissolution curve of ulipristal acetate tablet, scientifically and objectively evaluates quality of ulipristal acetate tablet, can be used for evaluating consistency (similarity) of quality between imitation drugs and original research drugs, and can also provide guarantee for consistency of quality between drug batches.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides a method for measuring a dissolution curve of an ulipristal acetate solid preparation, which comprises the steps of taking a solvent containing Tween 80 as a dissolution medium, detecting the accumulated dissolution rates of the ulipristal acetate solid preparation in the dissolution medium at different dissolution time points by adopting a paddle method under a stirring state, and then drawing the dissolution curve; the volume percentage concentration of the Tween 80 in the dissolution medium is 0.1 to 2 percent.

Preferably, the volume percentage concentration of tween 80 in the dissolution medium is 0.5 to 1 percent.

Preferably, the solvent in the dissolution medium is water or a phosphate buffer solution having a pH of 4 to 7.

Preferably, the solvent in the dissolution medium is a phosphate buffer solution of pH4.5 to pH 6.8.

Preferably, the rotation speed of stirring is 50-75 r/min.

Preferably, the method for detecting the dissolution rates of the ulipristal acetate solid preparation in the dissolution medium at different dissolution time points by adopting a paddle method specifically comprises the following steps: taking the solution at different dissolution time points, filtering, and measuring the accumulative dissolution rate of ulipristal acetate by adopting a high performance liquid chromatography.

Preferably, the different dissolution time points are 6-10 dissolution time points with 5-30 min intervals within 0-120 min.

In the specific examples provided by the present invention, the different dissolution time points were 5, 10, 15, 20, 30, 45, 60, 90 min.

Preferably, the chromatographic conditions of the high performance liquid are as follows: the buffer solution-organic phase is a mobile phase, the buffer solution is a phosphate buffer solution with the pH value of 3.0-8.0 and the concentration of 0.3-0.6%, and the organic phase is prepared from the following components in percentage by mass (30-50): (10-20) acetonitrile-tetrahydrofuran, wherein the volume ratio of the buffer solution to the organic phase is (35-55) to (65-45); the flow rate is 0.8-1.0 mL/min; the detection wavelength is 305 nm; the column temperature is 20-30 ℃; the chromatographic column is Waters Symmetry Shield^TMRP18 (4.6X 150mm, 5 μm) column, injection volume 20 μ L.

In the specific embodiment provided by the invention, the chromatographic conditions of the high performance liquid are as follows: the buffer solution-organic phase is a mobile phase, the buffer solution is a phosphate buffer solution with the pH value of 7.0 and the concentration of 0.47%, and the organic phase is a mixture of the following components in a mass ratio of 40: 15 acetonitrile-tetrahydrofuran, the volume ratio of the buffer solution to the organic phase is 45: 55; the flow rate is 1.0 mL/min; the detection wavelength is 305 nm; the column temperature was 26 ℃.

In the specific embodiment provided by the invention, the ulipristal acetate solid preparation is ulipristal acetate tablets.

The invention also provides an evaluation method of the quality of the ulipristal acetate solid preparation, which comprises the steps of taking a solvent containing Tween 80 as a dissolution medium, detecting the cumulative dissolution rates of a reference solid preparation and a solid preparation to be detected in the dissolution medium at different dissolution time points by adopting a paddle method under a stirring state, and then drawing a dissolution curve; the volume percentage concentration of the Tween 80 in the dissolution medium is 0.1 to 2 percent;

and comparing the difference between the dissolution curve of the reference solid preparation and the dissolution curve of the solid preparation to be tested, and evaluating the quality of the solid preparation to be tested.

The invention provides a method for measuring a dissolution curve of an ulipristal acetate solid preparation. The method comprises the steps of taking a solvent containing Tween 80 as a dissolution medium, detecting the accumulated dissolution rates of ulipristal acetate solid preparations in the dissolution medium at different dissolution time points by adopting a paddle method under a stirring state, and then drawing a dissolution curve; the volume percentage concentration of the Tween 80 in the dissolution medium is 0.1 to 2 percent. The invention has the technical effects that:

the method adds the surfactant Tween 80 into the dissolution medium for evaluating the dissolution curve of the ulipristal acetate tablets, scientifically and objectively evaluates the quality of the ulipristal acetate tablets, can be used for evaluating the consistency (similarity) of the quality of the simulated drugs and the quality of the original drugs, and can also provide guarantee for the consistency of the quality among drug batches.

Drawings

FIG. 1 is a dissolution profile of ulipristal acetate in different media;

FIG. 2 is a dissolution curve of ulipristal acetate in aqueous medium under different Tween concentrations and different rotation speeds;

FIG. 3 is a dissolution curve of ulipristal acetate in acetate buffer solution of pH4.5 at different concentrations of Tween and different rotation speeds;

FIG. 4 is a dissolution curve of ulipristal acetate in phosphate buffer solution of pH6.8 at different concentrations of Tween and different rotation speeds;

FIG. 5 is a dissolution curve of a reference formulation under different media and different rotation speeds;

FIG. 6 is a linear spectrum of ulipristal acetate in 0.1mol/L hydrochloric acid solution;

FIG. 7 is a linear chromatogram of ulipristal acetate in pH4.5 phosphate buffer + 1.0% Tween 80;

FIG. 8 is a linear chromatogram of ulipristal acetate in pH6.8 phosphate buffer + 1.0% Tween 80;

FIG. 9 is a linear spectrum of ulipristal acetate in water + 1.0% Tween 80;

FIG. 10 is a graph showing the dissolution profiles of different formulations in pH6.8 phosphate buffer + 1.0% Tween 80 medium;

FIG. 11 is a graph showing the dissolution profiles of different formulations in water + 0.3% sodium lauryl sulfate medium.

Detailed Description

The invention discloses a method for measuring a dissolution curve of an ulipristal acetate solid preparation, and a person skilled in the art can use the contents for reference and appropriately improve process parameters to realize the dissolution curve. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.

The reagents or apparatus used in the present invention are commercially available.

The invention is further illustrated by the following examples:

example 1

The method for measuring the dissolution curve of ulipristal acetate tablets provided by the embodiment of the invention comprises the following steps:

1. paddle method

Taking a reference preparation or a preparation to be tested, respectively adding 900mL of water, pH4.5 phosphate buffer solution and pH6.8 phosphate buffer solution, adopting a paddle method at 50 rpm, respectively sampling 10mL at 5min, 10 min, 15min, 20min, 30min, 45min, 60min and 90min, filtering, and immediately supplementing dissolution media with the same temperature and the same volume. The cumulative dissolution of the sample was determined.

2. Dissolution testing chromatographic conditions

Reference chromatography conditions under the content determination item of ulipristal acetate tablets: dissolving potassium dihydrogen phosphate (4.7 g) in 1000mL of water, adjusting pH to 7.0 with triethylamine), and using an organic phase (acetonitrile-tetrahydrofuran ═ 40: 15) (45:55) as a mobile phase; the flow rate was 1.0mL per minute; the detection wavelength is 305 nm; columnThe temperature is 26 ℃; selecting Waters Symmetry Shield^TMRP18(4.6 × 150mm, 5 μm) chromatographic column as dissolution rate detection method. Meanwhile, the concentration of the dissolved test sample is considered to be small, and the sample injection volume is selected to be 20 mu L.

Test example 1 comparison of effects of dissolution curves under different conditions

Measuring dissolution curve of ulipristal acetate tablet

Taking a reference preparation, respectively adding the reference preparation into 900mL of water, pH4.5 acetate buffer solution, pH6.8 phosphate buffer solution and 0.1mol/L hydrochloric acid solution, adopting a paddle method, sampling 10mL at 5min, 10 min, 15min, 20min, 30min, 45min, 60min, 90min and 120min, filtering, and immediately supplementing dissolution media with the same temperature and volume. The cumulative dissolution of the samples was measured and the results are shown in table 1 and figure 1.

TABLE 1

The dissolution rate of the reference preparation in 0.1mol/L hydrochloric acid solution for 15min is more than 85 percent; the dissolution rates in water, pH4.5 acetate buffer solution and pH6.8 phosphate buffer solution for 120min are respectively 8.45%, 31.27% and 7.37%.

The method comprises the steps of adding a surfactant into a dissolution medium when the conditions of a leak groove are not met in water, a pH4.5 acetate buffer solution and a pH6.8 phosphate buffer solution, selecting the surfactant, setting the cumulative dissolution rate of a target dissolution curve to be more than 85% within 45-120 min, and screening the dosage of the surfactant.

② the determination of the dissolution curve of Sodium Dodecyl Sulfate (SDS) as a surfactant.

The reference publication No. CN104865215A discloses a method for determining dissolution rate of ulipristal acetate tablet, which comprises adding Sodium Dodecyl Sulfate (SDS) as surfactant into water medium as dissolution medium, preferably adding SDS as surfactant into dissolution medium, and determining dissolution behavior of ulipristal acetate tablet in different dissolution media.

Taking from the slide, respectively in water, pH4.5 acetate buffer, pH6.8 phosphate buffer 900mL, using the paddle method, 50 rpm, respectively in 5, 10, 15, 20, 30, 45, 60min sampling 10mL, filtering, and instantly supplementing the same temperature, the same volume of dissolution medium. Determination of the cumulative dissolution of the samples:

TABLE 2

After sodium dodecyl sulfate is added into different media, the product is dissolved out quickly, the cumulative dissolution rate of a dissolution curve within 15min is more than 85%, and the quality of ulipristal acetate tablets cannot be distinguished and evaluated better.

Meanwhile, Sodium Dodecyl Sulfate (SDS) has large difference among different purities, manufacturers and different batch numbers in the using process, has high requirements on the purities and the manufacturers, and is not beneficial to daily test activities. In addition, in the process of dissolution experiment operation, SDS and potassium salt are compatible to form precipitate in a phosphate buffer solution with pH6.8 along with the reduction of the solution temperature, thereby influencing the determination of the test solution.

In summary, tween 80 is subsequently used as a surfactant in the dissolution medium, and the amount thereof is screened.

③ selection of Tween 80 dosage

Taking from the slide, adopting the oar method, respectively adding different amount of Tween 80 in 900mL water, pH4.5 acetate buffer solution, pH6.8 phosphate buffer solution, adopting different rotational speed to investigate, selecting the above-mentioned chromatographic condition, determining the dissolution curve, the result is shown in table 3-5 and figure 2-4:

TABLE 3 selection of different temperature output and rotation speed of aqueous medium

The results show that when 1.0% of tween 80 is added into the aqueous medium, the cumulative dissolution of the self-made sample reaches the expected set target (the cumulative dissolution is more than 85% within 45-120 min), the time points reaching the expected set target are 90min and 60min respectively under the conditions of 50 rpm and 75 rpm, and the cumulative dissolution is 87.84% and 87.30% respectively.

TABLE 4 selection of different amounts of Tween 80 and rotation rates for acetate buffers pH4.5

The results show that when 1.0% tween 80 is added into the acetate buffer solution with the pH value of 4.5, the cumulative dissolution of the self-made sample reaches the expected set target (the cumulative dissolution is more than 85% within 45-120 min), and the time points reaching the expected set target are both 45min under the conditions of 50 revolutions per minute and 75 revolutions per minute, and the cumulative dissolution is 86.80% and 86.30% respectively.

TABLE 5 selection of different amounts of Tween 80 and rotational speeds in pH6.8 phosphate buffer

According to the results, when 1.0% of Tween 80 is added into the phosphate buffer solution with the pH value of 6.8 under the condition of 50 revolutions per minute or 75 revolutions per minute, the cumulative dissolution rate of the self-prepared sample reaches the expected set target (the set target is that the cumulative dissolution rate is more than 85% within 45 min-120 min), the time points are 90min and 45min respectively, and the cumulative dissolution rates are 87.78% and 86.27% respectively.

In summary, under the conditions of 50 rpm and 75 rpm, 1.0% tween 80 is added to the acetate buffer solution of ph4.5, the phosphate buffer solution of ph6.8 and the aqueous medium, and the cumulative dissolution rate of the product can reach the expected set target.

Selection of rotational speed

Taking a reference preparation, adopting a paddle method, respectively taking 900mL of water + 1.0% of Tween 80, a pH4.5 acetate buffer solution + 1.0% of Tween 80, a pH6.8 phosphate buffer solution + 1.0% of Tween 80 as dissolution media at a rotating speed of 50 revolutions per minute or 75 revolutions per minute for investigation, selecting the chromatographic conditions, and determining a dissolution curve, wherein the results are shown in the following table and figure 5.

TABLE 6 dissolution Curve results for the reference formulation at different rotational speeds

According to the results, 1.0% of Tween 80 is added into a pH4.5 acetate buffer solution, a pH6.8 phosphate buffer solution and an aqueous medium, the cumulative dissolution rate of a reference preparation reaches an expected set target (the set target is that the cumulative dissolution rate is more than 85% within 45-120 min), and compared with the cumulative dissolution rate at each time point under the conditions of 50 revolutions per minute and 75 revolutions per minute, the results have no obvious difference, and the rotation speed is selected to be 50 revolutions per minute.

Screening of different producers of Tween 80

Respectively taking the tablets, adding 900mL of acetate buffer solution with pH4.5, phosphate buffer solution with pH6.8 and water into different manufacturers (Tianjin city Fengshan chemical reagent limited, national drug group chemical reagent limited, Sichuan Jinshan pharmaceutical limited) Tween 80 as dissolution medium at the rotation speed of 50 r/min, performing dissolution test, sampling for 90min, filtering, and taking the subsequent filtrate as test solution (Fengshan; national drug; Jinshan). The results were obtained by injecting the solutions into a liquid chromatograph at different time points, respectively, as shown in the following table.

TABLE 7

From the results, it was found that the RSD value of the main peak area of the sample solution in the pH6.8 phosphate buffer solution + 1.0% Tween 80 solution was 4.93% and more than 2.0%, indicating that the sample solution prepared with Tween 80 from Tianjin Shufeng chemical reagent Ltd was unstable at room temperature for 48 hours.

In conclusion, the Tween 80 of Sichuan Jinshan pharmaceutical Co., Ltd is superior to Tween 80 of Tianjin City Fengshan chemical reagent Co., Ltd and Chinese medicine group chemical reagent Co., Ltd, and the Tween 80 of Sichuan Jinshan pharmaceutical Co., Ltd is selected as the surfactant of the product.

Selection of medium with pH4.5

Taking a sample from a slide, adding 1.0% (Sichuan Jinshan pharmaceutical Co., Ltd.) Tween 80 into 900mL of acetate buffer solution with pH4.5 and phosphate buffer solution with pH4.5 as dissolution media at a rotation speed of 50 rpm, performing dissolution test, sampling for 90 minutes, and filtering to obtain a subsequent filtrate as a sample solution. The results were obtained by injecting the solutions into a liquid chromatograph at different time points, respectively, as shown in the following table.

TABLE 8

Time (h)	peak area of acetate buffer solution at pH4.5	peak area of phosphate buffer solution at pH4.5
			0	31.9748	31.9433
4	31.7071	31.8752
			8	31.6013	31.9302
12	31.4016	31.8958
			16	31.2383	31.8542
20	31.1133	31.9027
			24	31.0091	32.0319
RSD(％)	1.10	0.18

The test result shows that the RSD values of the main peak areas of the reference solution prepared from the acetate buffer solution with pH4.5 and the tween 80 with pH 4.0% and the phosphate buffer solution with pH4.5 and the tween 80 with pH 1.0% are less than 2.0%, which indicates that the stability is good within 24 hours when the reference solution is placed at room temperature. Wherein the stability of the test sample in phosphate buffer solution is superior to that of acetate buffer solution, and pH4.5 phosphate buffer solution and 1.0% Tween 80 are formulated as dissolution medium with pH4.5.

Combining the above test results, phosphate buffer solution with pH4.5 + 1.0% Tween 80, phosphate buffer solution with pH6.8 + 1.0% Tween 80, and water + 1.0% Tween 80 were selected as dissolution medium for Ulipristal acetate tablet.

Seventhly, selecting sampling time points of the dissolution curve

Taking a reference preparation, taking 900mL of phosphate buffer solution with pH4.5 + 1.0% Tween 80, phosphate buffer solution with pH6.8 + 1.0% Tween 80, water + 1.0% Tween 80 as a dissolution medium, performing a paddle method at a rotating speed of 50 revolutions per minute, sampling 10mL (and instantly supplementing the dissolution medium with the same temperature and the same volume) at different time points respectively, filtering, taking a subsequent filtrate, and determining a dissolution curve according to the chromatographic conditions under the item of '2 dissolution detection chromatographic conditions', wherein the results are shown in the following table.

TABLE 9 dissolution Curve test results for reference formulations

From the results, it can be seen that in the medium of ph4.5 phosphate buffer solution + 1.0% tween 80, ph6.8 phosphate buffer solution + 1.0% tween 80, and water + 1.0% tween 80, the cumulative dissolution rate of the reference preparation is greater than 85% within 90min, so the sampling time points for the determination of dissolution curves of the three media are set as 5, 10, 15, 20, 30, 45, 60, and 90 min.

Test example 2 verification of the method for measuring the dissolution Medium selected

a. Specificity test

Test solution: taking 1 ulipristal acetate tablet, respectively placing in 900mL dissolution medium (0.1mol/L hydrochloric acid solution, pH4.5 phosphate buffer solution + 1.0% Tween 80, pH6.8 phosphate buffer solution + 1.0% Tween 80, water + 1.0% Tween 80), stirring at 50 rpm for 30min (0.1mol/L hydrochloric acid solution) or 90min (the rest 3 media), taking solution, filtering, and taking subsequent filtrate.

Control solution: accurately weighing ulipristal acetate reference substance about 16.7mg, placing into a 50mL measuring flask, adding dissolved medium (0.1mol/L hydrochloric acid solution) or methanol (the rest 3 media) to dissolve and dilute to scale, shaking up, and using as reference substance stock solution; precisely measuring 5mL, placing in a 50mL measuring flask, diluting to scale with dissolution medium, and shaking.

Precisely measuring 20 μ L of the above solutions under the medium conditions, and injecting into a liquid chromatograph under the chromatographic conditions of "2, dissolution rate detection chromatographic conditions", the results are shown in the following table:

watch 10

The results show that the blank solvent and the blank auxiliary materials do not interfere the determination of ulipristal acetate, and the method has better specificity for determining the dissolution rates of the four media.

b. Adsorption test with filter membrane

The solution of the test sample and the solution of the reference substance are prepared into the solution under the item of the 'a. specificity test' mentioned above.

Centrifuging the solution: centrifuging the control solution and the sample solution (3000rpm for 20min), and collecting the supernatant.

Filter membrane filtration solution (control and test): filtering the solution with 0.45 μm organic filter membrane, discarding 2, 4, 6, 8mL of filtrate, and collecting the corresponding subsequent filtrate.

Precisely measuring 20 μ L of the above solutions under the medium conditions, and injecting into a liquid chromatograph under the chromatographic conditions of "2, dissolution rate detection chromatographic conditions", the results are shown in the following table:

TABLE 11 results of the adsorption test on the control filters

TABLE 12 adsorption test results of test sample filters

From the results, it can be seen that, in the media of 0.1mol/L hydrochloric acid solution, ph4.5 phosphate buffer solution + 1.0% tween 80, ph6.8 phosphate buffer solution + 1.0% tween 80, and water + 1.0% tween 80, the adsorption rates of the control solution and the test solution by the filter membrane were less than 2.0%, which indicates that the control solution and the test solution can be filtered by the filter membrane and the filter membrane does not interfere with the determination of the dissolution rate.

c. Precision degree

Precisely measuring 20 μ L of reference solutions prepared from the four dissolution media under the item of the 'a' specificity test, respectively injecting into a liquid chromatograph, recording chromatogram, and respectively and continuously measuring for 6 times, wherein the results are shown in the following table.

TABLE 13 results of precision test

And (4) conclusion: in the medium of 0.1mol/L hydrochloric acid solution, pH4.5 phosphate buffer solution + 1.0% Tween 80, pH6.8 phosphate buffer solution + 1.0% Tween 80, and water + 1.0% Tween 80, the RSD value of the control solution for continuously measuring the retention time for 6 times and the peak area is less than 2.0%. Indicating that the precision of the sample injection of the instrument meets the requirement.

d. Linear relationship and range

Accurately weighing ulipristal acetate reference substance about 16.7mg, placing in a 50mL measuring flask, adding methanol to dissolve and dilute to scale, shaking up to obtain linear stock solution; precisely measuring appropriate amount of linear stock solution, and quantitatively diluting with dissolution medium to obtain linear solutions with different concentrations.

Precisely measuring 20 μ L of the above solutions under the medium conditions, and injecting into a liquid chromatograph under the chromatographic conditions of "2, dissolution rate detection chromatographic conditions", the results are shown in the following table:

TABLE 140.1 mol/L hydrochloric acid solution-Linear and Range results

TABLE 15 pH4.5 phosphate buffer + 1.0% Tween 80-Linear assay results

TABLE 16 pH6.8 phosphate buffer + 1.0% Tween 80-Linear assay results

TABLE 17 Water + 1.0% Tween 80-Linear test results

From the results, it is known that ulipristal acetate in 0.1mol/L hydrochloric acid solution has good linear relation in the concentration range of 6.67 μ g/mL to 40.01 μ g/mL, the linear equation is that y is 0.9363x +0.2614, and the correlation coefficient r is 0.9997;

the ulipristal acetate in a medium of pH4.5 phosphate buffer solution and 1.0% Tween 80 is in a concentration range of 3.33 mu g/mL-39.95 mu g/mL, a linear equation is that y is 0.9622x +0.1990, a correlation coefficient r is 0.9998, and the linear relation is good;

the ulipristal acetate in a medium of pH6.8 phosphate buffer solution and 1.0% Tween 80 is in a concentration range of 3.32 mu g/mL-39.78 mu g/mL, a linear equation is that y is 0.9389x +0.1031, a correlation coefficient r is 0.9999, and the linear relation is good;

the ulipristal acetate in a medium of water and 1.0% of Tween 80 is in a concentration range of 3.33 mu g/mL-39.98 mu g/mL, a linear equation is that y is 0.9491x +0.0049, a correlation coefficient r is 1.0000, and the linear relation is good.

e. Stability of solution

Precisely measuring 20 μ L of each of the reference solution and the test solution under the item of 'a. specificity test', respectively injecting into a liquid chromatograph at different time, and recording chromatogram. The results are shown in the following table.

TABLE 18 solution stability test results

And (4) conclusion: the test result shows that, under the condition of normal temperature, the reference solution and the test solution are stable in a medium of 0.1mol/L hydrochloric acid solution, pH4.5 phosphate buffer solution + 1.0% Tween 80, pH6.8 phosphate buffer solution + 1.0% Tween 80, and water + 1.0% Tween 80 for 48 h.

f. Accuracy of

Accurately weighing ulipristal acetate reference substance and appropriate amount of corresponding prescription amount of auxiliary materials to prepare test solution with concentration of 20%, 80% and 120%, and performing test on 3 parts in parallel.

Precisely measuring 20 μ L of the above solutions under the medium conditions, and injecting into a liquid chromatograph under the chromatographic conditions of "2, dissolution rate detection chromatographic conditions", the results are shown in the following table:

TABLE 190.1 mol/L hydrochloric acid solution-recovery test results

TABLE 20 pH4.5 phosphate buffer + 1.0% Tween 80-recovery test results

TABLE 21 pH6.8 phosphate buffer + 1.0% Tween 80-recovery test results

TABLE 22 Water + 1.0% Tween 80-recovery test results

And (4) conclusion: in 0.1mol/L hydrochloric acid solution medium, the recovery rate of the product is 99.58-100.88%, and the RSD value of 9 recovery rate solutions is 0.39%; in a medium of pH4.5 phosphate buffer solution and 1.0% Tween 80, the recovery rate of the product is 98.46-99.85%, and the RSD value of 9 parts of recovery rate solution is 0.40%; in a medium of pH6.8 phosphate buffer solution and 1.0% Tween 80, the recovery rate of the product is 99.66% -100.69%, and the RSD value of 9 parts of recovery rate solution is 0.37%; in water and 1.0% Tween 80 medium, the recovery rate of the product is 100.03% -100.61%, and the RSD value of 9 recovery rate solutions is 0.19%. The method meets the requirements, and the method has good accuracy.

The comprehensive test results show that the method has good specificity, no adsorption on the filter membrane and good stability, can accurately determine the dissolution rate of the ulipristal acetate tablet in each medium at each sampling time point, and effectively performs comparative study on the quality of the medicine.

Comparison of the effects of test example 4 and the methods of the prior patents

In order to verify whether the dissolution conditions are selected to distinguish the quality difference of samples of different process batches, the original developer and samples of different prescriptions (the prescriptions are shown in the following table) are used in the test,

TABLE 23

A representative self-pH 6.8 phosphate buffer solution and 1.0% Tween 80 medium and a Chinese patent publication No. CN104865215A of Ulipristal acetate tablet and a dissolution rate determination method of water and 0.3% Sodium Dodecyl Sulfate (SDS) dissolution medium are respectively selected, the dissolution curves are detected, and the results are compared.

a. Self-conditions (representing medium pH6.8 phosphate buffer + 1.0% Tween 80)

Taking 6 tablets of different prescription samples and original preparation, taking 900mL of phosphate buffer solution with pH value of 6.8 and 1.0% of Tween 80 as dissolution media, performing paddle method at a rotation speed of 50 revolutions per minute, sampling 10mL (and instantly supplementing the dissolution media with the same temperature and the same volume) at different time points, filtering, taking subsequent filtrate, and determining the dissolution curve. The results are shown in the following table and in FIG. 10.

TABLE 24 dissolution curves for pH6.8 phosphate buffer + 1.0% Tween 80 in media

According to the results, under the dissolution condition, the dissolution curves of 3 batches of self-made samples and original research samples with different formulas are measured, the difference of different dissolution behaviors is obvious, and the method has stronger discrimination and is suitable for distinguishing the quality difference of samples of different process batches.

b. Patent conditions (Water + 0.3% sodium dodecyl sulfate dissolution Medium)

Taking 6 tablets of different prescription samples and original preparation, taking 900mL of water and 0.3% of lauryl sodium sulfate as dissolution media, adopting a paddle method, rotating at 50 revolutions per minute, respectively sampling 10mL (and instantly supplementing the dissolution media with the same temperature and the same volume) at different time points, filtering, taking subsequent filtrate, and determining the dissolution curve. The results are shown in the following table and in FIG. 11.

TABLE 25 dissolution curves for water + 0.3% sodium dodecyl sulfate medium

The results show that the product is dissolved out quickly after the sodium dodecyl sulfate is added, the cumulative dissolution rate of the dissolution curve within 15min is more than 85 percent, and the quality of the ulipristal acetate tablet cannot be distinguished and evaluated by using the f2 value better.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.