Method for measuring particle size and particle size distribution of gel preparation

Abstract

The invention discloses a method for determining the granularity and granularity distribution of a gel preparation, which comprises the following steps: adding the gel preparation into a dispersion medium, stirring or ultrasonically dispersing, and then determining the granularity, the dispersion medium is a solution containing acid or salt, and the mass concentration of the acid or salt is 0.5-10%. According to the present invention, the acid-containing or salt-containing solution is adopted, and the mass ratio of the acid or the salt in the solution is reasonably designed, such that the gel can be uniformly dispersed, the influence of the medium bubble on the detection result is avoided, and the method is stable, easy to operate and low in cost.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical analysis, and particularly relates to a method for determining the particle size and particle size distribution of a gel preparation. Background Art

[0002] There are the following problems when determining the particle size of a gel preparation:

[0003] 1. The particle size and particle size distribution are important detection items for gel preparations. In the "Technical Guidelines for the Research of Topical Dermatological Chemical Generic Drugs (Trial)" issued by the CDE, it is required to detect the particle size and particle size distribution of gels. In the "Chinese Pharmacopoeia" 2020 edition, the recommended methods for determining the particle size and particle size distribution are microscopy, sieving method, and light scattering method; for gel preparations, the sieving method cannot be used, and the commonly used method is microscopy. However, in microscopy, particle accumulation easily occurs, resulting in inaccurate results, and it is not applicable to samples with a wide particle size distribution range. Moreover, due to different processing methods, the result reproducibility is poor, the subjectivity is strong, the particle size of solid particles in the gel cannot be objectively evaluated, and the particle size distribution cannot be evaluated. In addition, the microscope has requirements for the particle size, and generally, particles smaller than 1 μm cannot be evaluated. Therefore, there is still a need for a more objective and accurate method for measuring the particle size and particle size distribution.

[0004] 2. There are existing reported mature methods for determining the gel particle size by light scattering method. If the light scattering method is used to determine the particle size and particle size distribution of a gel, the particles need to be uniformly dispersed in an aqueous medium; however, gel preparations generally contain matrix excipients with relatively high viscosity, such as carbomer, xanthan gum, cellulose, etc. If the particle size and particle size distribution of the solids therein are to be determined, it is necessary to ensure that the matrix does not affect the particle size measurement, and the solid particles therein need to be separated out without damage. However, due to the easy aggregation of the matrix in the gel preparation, it cannot be uniformly dispersed, and the solid particles are not easily separated from the matrix, which cannot meet the high requirements for sample preparation in the light scattering method determination, resulting in great difficulty in developing a mature and robust method based on the light scattering method for determination.

[0005] 3. In addition, when using the light scattering method to determine the solid particle size in a gel, since the dispersed gel increases the viscosity of the dispersion liquid, bubbles are extremely likely to be generated during the measurement process, which affects the measurement result, resulting in errors in the result, and it is necessary to develop a suitable method to avoid the interference of the generated bubbles on the result.

[0006] In view of this, the present patent application is proposed. Summary of the Invention

[0007] To solve the above problems, the present invention provides a method for determining the particle size and particle size distribution of a gel preparation. By using an acid-containing solution or a salt-containing solution and reasonably designing the mass ratio of the acid or salt in the solution, the gel can be evenly dispersed without adding a surfactant, and the influence of medium bubbles on the results can be avoided. This method is robust, easy to operate, and low in cost.

[0008] The present invention adopts the following technical solutions:

[0009] The object of the present invention is to provide a method for determining the particle size and particle size distribution of a gel preparation, including: adding the gel preparation into a dispersion medium, then performing stirring or ultrasonic dispersion (pretreatment stage), and then performing particle size determination;

[0010] The dispersion medium is an acid-containing solution or a salt-containing solution, and the mass concentration of the acid or salt is 0.5% - 10%.

[0011] Currently, when using the microscopy method to determine the particle size and particle size distribution of a gel preparation, there are disadvantages such as inaccurate results, inapplicability to samples with a wide distribution range, and inability to analyze samples below 1 μm. When using the light scattering method for determination, there is a disadvantage of high requirements for the sample preparation method. To solve the problem of difficult dispersion of gel preparation in the light scattering method, someone has tried to add a surfactant to the dispersion medium. Although this method can disperse the gel matrix, it will simultaneously cause more bubbles, interfere with the detection, and the results are inaccurate.

[0012] In the present invention, by using an acid-containing solution or a salt-containing solution and reasonably designing the mass ratio of the acid or salt in the solution, the gel can be evenly dispersed without adding a surfactant, and the influence of medium bubbles on the results can be avoided. This method is robust, easy to operate, and low in cost.

[0013] Further, the concentration of the gel preparation in the dispersion medium is 0.02% - 0.5% (the mass concentration of the gel preparation in the system after the gel is added to the dispersion medium); preferably, the volume ratio of the gel preparation to the dispersion medium is less than or equal to 50. The purpose of such design is to avoid excessive concentration of the gel preparation, which may increase the liquid viscosity and make it difficult to disperse the particles.

[0014] Further, the gel preparation is adapalene gel, progesterone gel, or selenium disulfide gel.

[0015] Further, the acid is any one of inorganic acids and organic acids; preferably, the acid is any one of phosphoric acid, acetic acid, citric acid, and the acids derived therefrom; preferably, the acid content in the dispersion medium is 0.5% - 10.0%. More preferably, any one of phosphoric acid, acetic acid, and citric acid is used.

[0016] Further, the salt is any one of inorganic salts, and preferably any one of inorganic sodium salts and inorganic potassium salts.

[0017] Further, the salt is any one of sodium chloride, potassium chloride, dipotassium hydrogen phosphate, and sodium pyrophosphate; preferably, the dispersion medium contains 1.0% to 9.0% of the salt.

[0018] Further, in the pretreatment process, the stirring time is 0 min to 30 min, the ultrasonic time is 0 min to 30 min, and the stirring speeds during stirring and ultrasonic treatment are both lower than 2000 rpm. It is advisable that the gel is completely and evenly dispersed. The stirring method can be manual stirring with a glass rod or magnetic stirring with a magnetic stirrer. No bubbles are generated during the stirring and ultrasonic processes, improving the accuracy of the detection results.

[0019] Further, heating is also included during the stirring or ultrasonic treatment in the pretreatment, and the heating temperature is 10°C to 30°C, which is beneficial to the full dispersion of the sample.

[0020] Further, a laser particle size analyzer is used for particle size determination, and the manual measurement mode is adopted, which is beneficial to the uniform dispersion of the gel and does not generate bubbles. For example, a MASTERSIZER 3000 laser particle size analyzer is used. And during the determination, the entire dispersed sample can be directly replaced with the liquid in the sample cell for detection, or a small amount of the well-dispersed sample can be slowly added to the sample cell for detection for further dilution. The laser particle size analyzer adopted in the present invention has the characteristics of fast measurement speed, wide measurement dynamic range, high precision, good repeatability, and simple operation.

[0021] Further, the stirring speed during particle size determination is 800 rpm to 2000 rpm, and the sample is measured 3 times, and no bubbles are easily generated during the determination.

[0022] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0023] 1. In the present invention, a solution containing an acid or a salt is adopted, and the mass ratio of the acid or the salt in the solution is reasonably designed, so that the gel can be evenly dispersed without adding a surfactant, and the influence of medium bubbles on the detection results is avoided. This method is robust, easy to operate, and has low cost.

[0024] 2. By selecting a suitable dispersion medium and optimizing the detection method, and choosing a stirring speed of less than 2000 rpm during ultrasonic treatment, manual stirring, or measurement of the gel preparation, the generation of bubbles can be effectively avoided. The manual measurement mode is adopted. Through the mutual cooperation of the above means, both the uniform dispersion of the gel preparation in the dispersion medium and the avoidance of bubble generation can be achieved. The measurement results are accurate, the method has good reproducibility, it is applicable to the detection of samples with a relatively wide particle size distribution range, and it also solves the problem that the gel is not easily dispersed during preparation, thus solving the technical difficulties in the determination by the light scattering method. Description of the Drawings

[0025] To more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention, and thus should not be regarded as limiting the scope. For those of ordinary skill in the art, without creative efforts, other related drawings can also be obtained based on these drawings. In the drawings:

[0026] Figure 1 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 1.

[0027] Figure 2 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 2.

[0028] Figure 3 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 3.

[0029] Figure 4 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 4.

[0030] Figure 5 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 5.

[0031] Figure 6 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 6.

[0032] Figure 7 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 7.

[0033] Figure 8 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 8.

[0034] Figure 9 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 9.

[0035] Figure 10 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 10.

[0036] Figure 11 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 1.

[0037] Figure 12 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 12.

[0038] Figure 13 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 13.

[0039] Figure 14 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 14.

[0040] Figure 15 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 15.

[0041] Figure 16 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Comparative Example 1.

[0042] Figure 17 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 16.

[0043] Figure 18 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Comparative Example 2.

[0044] Figure 19 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 17.

[0045] Figure 20 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Example 18.

[0046] Figure 21 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Comparative Example 3.

[0047] Figure 22 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Comparative Example 4.

[0048] Figure 23 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Comparative Example 5.

[0049] Figure 24 The particle size distribution diagram and measurement data obtained by measuring the gel preparation by the method of Comparative Example 6. Detailed Implementation Modes

[0050] To make the objectives, technical solutions, and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below with reference to embodiments. The illustrative implementation modes of the present invention and their descriptions are only used to explain the present invention and do not limit the present invention.

[0051] I. Influence of Dispersing Medium on Particle Size and Distribution Detection of Gel Preparation

[0052] Example 1 (1% Sodium Chloride Solution):

[0053] Take 1 g of the preparation (adapalene gel) and place it in a beaker containing 200 ml of a 1% sodium chloride solution by mass concentration (1:200). Add a magnetic stir bar and slowly stir at room temperature (below 600 rpm) on a magnetic stirrer for 30 min.

[0054] Measure the particle size of the dispersed sample using a MASTERSIZER 3000 laser particle size analyzer. Use the manual measurement mode, with a stirring speed of 1200 rpm. The background measurement medium is purified water. When measuring the sample, replace the entire purified water with the stirred and dispersed sample, and measure the sample 3 times. The results are as Figure 1 shown.

[0055] As can be seen from Figure 1 when the dispersing solvent is a 1% sodium chloride solution, the gel mass has been significantly dispersed, the peak height above 100 μm has decreased significantly, the particles have been separated and particle size data has been obtained. However, at the same time, it is observed that the viscosity of the solution increases due to the dispersion of the gel matrix, a peak is generated near 1000 μm, and a certain amount of bubbles are generated.

[0056] Example 2 (3% Sodium Chloride Solution):

[0057] Take 1 g of the preparation (adapalene gel) and place it in a beaker containing 200 ml of a 3% sodium chloride solution by mass concentration (1:200). Add a magnetic stir bar and slowly stir at room temperature (below 600 rpm) on a magnetic stirrer for 30 min.

[0058] Measure the particle size of the dispersed sample using a MASTERSIZER 3000 laser particle size analyzer. Use the manual measurement mode, with a stirring speed of 1200 rpm. The background measurement medium is purified water. When measuring the sample, replace the entire purified water with the stirred and dispersed sample, and measure the sample 3 times. The results are as Figure 2 shown.

[0059] As can be seen from Figure 2It can be seen that in this embodiment, the gel mass has been significantly dispersed, the peak height above 100 μm has significantly decreased, the particles have been separated and particle size data has been obtained, and the peak above 1000 μm has significantly become smaller, and the air bubbles have significantly decreased.

[0060] Example 3 (6% sodium chloride solution):

[0061] The difference between this embodiment and Example 1 is that the dispersion medium is a sodium chloride solution with a mass concentration of 6%, and the rest are the same as in Example 1. The results are as Figure 3 shown.

[0062] From Figure 3 it can be seen that when measuring the particle size, the peak shape in the obtained particle size distribution diagram is improved, a single narrow peak appears, and the dispersion effect is good. The air bubbles have significantly decreased, the relative standard deviation RSD has significantly decreased, the measurement reproducibility is good, and the measurement results are relatively accurate.

[0063] Example 4 (9% sodium chloride solution):

[0064] The difference between this embodiment and Example 1 is that the dispersion medium is a sodium chloride solution with a mass concentration of 9%, and the rest are the same as in Example 1. The results are shown in Figure 4 .

[0065] From Figure 4 it can be seen that when measuring the particle size, the peak shape is still very good, a single narrow peak with a very high overlap appears between 1 and 10 microns, and there is no air bubble interference, the measurement reproducibility is good, and the measurement results are accurate.

[0066] It can be seen that when using a sodium chloride solution with a mass concentration of 1-9% as the dispersion medium, the gel preparation can be well dispersed, the air bubble interference is reduced or even eliminated, the reproducibility of the measurement results is good, the test results are accurate, and the particle size measurement results are greatly improved.

[0067] Example 5 (6% potassium chloride solution):

[0068] The difference between this embodiment and Example 1 is that: the dispersion medium is a potassium chloride solution with a mass concentration of 6%, and the rest are the same as in Example 1. The results are as Figure 5 shown.

[0069] From Figure 5 it can be seen that when sodium chloride is replaced with potassium chloride, no peak is generated above 100 μm in the obtained particle size distribution diagram, no air bubbles are generated, the relative standard deviation RSD is low, the measurement reproducibility using this method is good, and the measurement results are relatively accurate.

[0070] Example 6 (6% dipotassium hydrogen phosphate solution):

[0071] The difference between this example and Example 1 is that the dispersion medium is a potassium hydrogen phosphate solution with a mass concentration of 6%, and the rest are the same as in Example 1. The results are as Figure 6 shown below.

[0072] It can be Figure 6 seen that when sodium chloride is replaced with a potassium hydrogen phosphate solution, there is no peak above 100 μm in the obtained particle size distribution graph, no bubbles are generated, and the relative standard deviation RSD is relatively low. The measurement reproducibility of this method is good and the measurement results are relatively accurate.

[0073] Example 7 (6% sodium pyrophosphate solution):

[0074] The difference between this example and Example 1 is that the dispersion medium is a sodium pyrophosphate solution with a mass concentration of 6%, and the rest are the same as in Example 1. The results are as Figure 7 shown below.

[0075] It can be Figure 7 seen that when sodium chloride is replaced with a sodium pyrophosphate solution, the peak shape in the obtained particle size distribution graph is still good, no bubbles are generated, the test reproducibility is good, and the measurement results are relatively accurate.

[0076] It can be seen from Examples 5 to 7 that by replacing with other different types of salts, such as potassium chloride, potassium hydrogen phosphate, sodium pyrophosphate, etc., the same effect can be achieved. This may be because after adding salts, the gel matrix will be combined with sodium, potassium and other ions, the structure is broken up, and the API powder dispersed in it is released.

[0077] Example 8 (0.5% phosphoric acid solution):

[0078] Take 1.25 g of the preparation (adapalene gel) and place it in a beaker containing 250 ml of a phosphoric acid solution with a mass concentration of 0.5% (1:200). Add a magnetic stir bar and stir slowly at room temperature (below 600 rpm) on a magnetic stirrer for 30 min.

[0079] Measure the particle size of the dispersed sample with a MASTERSIZER 3000 laser particle size analyzer. Use the manual measurement mode, the stirring speed is 1200 rpm, the background measurement medium is purified water, and when measuring the sample, the purified water is completely replaced with the stirred and dispersed sample. The sample is measured 3 times. The results are shown in Figure 8 .

[0080] It can be Figure 8 seen that when measuring the particle size, when using a 0.5% phosphoric acid solution as the dispersion medium, the gel mass has been significantly dispersed, the peak height above 100 μm is relatively low, the particles have been separated and particle size data have been obtained, and only a small amount of bubbles are generated during the measurement process, indicating that adding a certain amount of phosphoric acid can successfully disperse the gel matrix.

[0081] Example 9 (1% phosphoric acid solution):

[0082] The difference between this example and Example 8 is that the dispersion medium is a phosphoric acid solution with a mass concentration of 1%, and the rest are the same as in Example 8. The results are shown in Figure 9 .

[0083] Example 10 (5% phosphoric acid solution):

[0084] The difference between this example and Example 8 is that the dispersion medium is a phosphoric acid solution with a mass concentration of 5%, and the rest are the same as in Example 8. The results are shown in Figure 10 .

[0085] According to the results of Example 9 and Example 10, it can be seen that when measuring particle size, when using phosphoric acid solutions with mass concentrations of 1% and 5% as the dispersion medium, the dispersion effects are both good, there are basically no bubbles generated during the measurement process, there are no peaks above 100 μm, and the relative standard deviation RSD is relatively low. It can be seen that the reproducibility of the measurement method is good and the measurement results are relatively accurate.

[0086] Example 11 (10% phosphoric acid solution):

[0087] The difference between this example and Example 8 is that the dispersion medium is a phosphoric acid solution with a mass concentration of 10%, and the rest are the same as in Example 8. The results are shown in Figure 11 , and there are also no bubbles generated, there are no peaks above 100 μm, and the gel preparation is well dispersed.

[0088] According to Examples 8 to 11, it can be seen that adding acid to the dispersion medium can significantly improve the measurement results, and the higher the concentration, the better the effect. The mass concentration of acid in the dispersion medium can be as high as 10%.

[0089] Example 12 (1% acetic acid solution):

[0090] The difference between this example and Example 8 is that the dispersion medium is an acetic acid solution with a mass concentration of 1%, and the rest are the same as in Example 8. The results are as Figure 12 . It can be seen that the dispersion effect is good, there are no bubbles generated, and the method has good reproducibility.

[0091] Example 13 (1% citric acid solution):

[0092] The difference between this example and Example 8 is that the dispersion medium is a citric acid solution with a mass concentration of 1%, and the rest are the same as in Example 8. The results are shown in Figure 13 as shown.

[0093] As can be seen from Examples 12 to 13, adding an acid to the dispersion medium can significantly improve the measurement results. Moreover, not only phosphoric acid, but also other inorganic acids or organic acids such as acetic acid and citric acid have an effect. This may be achieved by adding an acid to adjust the pH of the matrix, making it easier for the gel to disperse.

[0094] Example 14 (10% phosphoric acid solution):

[0095] Take 1.25 g of the preparation (progesterone gel) and place it in a beaker containing 250 ml of a 10% phosphoric acid solution (1:200). Add a stir bar and slowly stir at room temperature (below 600 rpm) on a magnetic stirrer for 30 min. The rest is the same as in Example 8. The results are as Figure 14 . From Figure 14 it can be seen that when measuring progesterone gel using the method of the present invention, the progesterone gel can also be well dispersed, without the generation of bubbles, the measurement results are accurate, and the method has good reproducibility.

[0096] Example 15 (9% sodium chloride solution):

[0097] Take 1.25 g of the preparation (selenium disulfide gel) and place it in a beaker containing 250 ml of a 9% sodium chloride solution (1:200). Add a stir bar and slowly stir at room temperature (below 600 rpm) on a magnetic stirrer for 30 min. The rest is the same as in Example 8. The results are shown in Figure 15 .

[0098] From the results of Example 14 and Example 15, it can be seen that for different gel preparations, the dispersion effect is better when using a phosphoric acid solution or a sodium chloride solution as the dispersion medium, and there are fewer bubbles during the measurement process. Therefore, salts or acids can be selected and added to the medium, and good effects can be obtained when the salt concentration is 1 - 9% and the acid concentration is 0.5 - 10%.

[0099] Comparative Example 1 (water medium):

[0100] In this comparative example, water is used as the dispersion medium. Specifically, take 1 g of the preparation (adapalene gel) and place it in a beaker containing 200 ml of purified water (1:200). Add a stir bar and slowly stir at room temperature (below 600 rpm) on a magnetic stirrer for 30 min. The rest is the same as in Example 1. The results are as Figure 16 .

[0101] From Figure 16 the results, it can be seen that when simply using water as the dispersion medium and measuring the particle size of the gel using the common method of a laser particle size analyzer, the sample cannot be evenly dispersed, and there is still gel agglomeration, resulting in inaccurate measurement results.

[0102] II. Influence of sample pretreatment on the detection of gel preparation particle size and particle size distribution

[0103] To further reduce the interference of bubbles on the results, the methods of stirring or ultrasonic treatment during sample pretreatment were investigated.

[0104] Example 16 (ultrasonic):

[0105] Take 1.25 g of the preparation (adapalene gel) and place it in a beaker containing 250 ml of a 1% phosphoric acid solution by mass concentration (1:200). Ultrasonic it in an ultrasonic cleaner for 5 min with an ultrasonic frequency of 40 kHz. The rest is the same as in Example 9. The results are as Figure 17 shown, the dispersion effect is good and no bubbles are generated.

[0106] Comparative Example 2 (high-speed stirring):

[0107] Take 1.25 g of the preparation (adapalene gel) and place it in a beaker containing 250 ml of a 1% phosphoric acid solution by mass concentration (1:200). Add a magnetic stir bar and stir at high speed (above 600 rpm) at room temperature on a magnetic stirrer for 30 min. The rest is the same as in Example 9. The results are shown in Figure 18 , it can be seen that high-speed stirring during the pretreatment process will cause more bubbles to be generated, and the dispersion effect on the gel is not ideal.

[0108] Since the common sample pretreatment method is high-speed stirring to help disperse the sample, but according to Example 16 and Comparative Example 2, a gentle and slow treatment method can successfully separate the particles while reducing the generation of bubbles, while the commonly used violent pretreatment methods (such as high rotation speed) may generate bubbles that cannot dissipate and affect the measurement results instead.

[0109] III. Influence of the measurement method using a laser particle size analyzer on the particle size and particle size distribution detection of gel preparations

[0110] Example 17 (stirring at 1200 rpm):

[0111] Take 1 g of the preparation (adapalene gel) and place it in a beaker containing 50 ml of a 1% phosphoric acid solution by mass concentration (1:50). Add a magnetic stir bar and stir slowly (below 600 rpm) at room temperature on a magnetic stirrer for 30 min.

[0112] Measure the particle size of the dispersed sample with a MASTERSIZER 3000 laser particle size analyzer. Use the manual measurement mode, the stirring speed is 1200 rpm, the background measurement medium is 250 ml of purified water, and when measuring the sample, take 2.5 ml of the dispersed sample into the sample cell (1:5000), and measure the sample 3 times. The results are as Figure 19 shown. From Figure 19 it can be seen that this method can effectively disperse the gel, and no bubbles are generated. The method has good accuracy and reproducibility.

[0113] Example 18 (stirring at 2000 rpm):

[0114] Take 1 g of the preparation (adapalene gel) and place it in a beaker containing 50 ml of 1% phosphoric acid solution (1:50). Add a magnetic stir bar and stir slowly at room temperature (below 600 rpm) on a magnetic stirrer for 15 min.

[0115] Measure the particle size of the dispersed sample using a MASTERSIZER 3000 laser particle size analyzer. In the manual measurement mode, the stirring speed is 2000 rpm, the background measurement medium is 250 ml of purified water. When measuring the sample, take 2.5 ml of the dispersed sample into the sample cell (1:5000), and measure the sample 3 times. The results are as Figure 20 shown. The measurement effect of this method is still good.

[0116] Comparative Example 3 (stirring at 3000 rpm):

[0117] The difference between this comparative example and Example 18 is that the stirring speed in the manual measurement mode is 3000 rpm, and the rest are the same as in Example 20. The results are shown in Figure 21 . The dispersion effect of this method is poor and more bubbles are generated.

[0118] From the results of the above Examples 17 - 18 and Comparative Example 3, it can be seen that when measuring the particle size, when the stirring speed is 3000 rpm, bubbles are easily generated, which in turn affects the measurement results. After reducing the speed to 2000 rpm and below, the bubbles significantly decrease, and the peaks above 1000 μm disappear.

[0119] Moreover, the sample concentrations in Examples 17 - 18 were all increased to 1:50. The increase in sample concentration will further increase the difficulty of particle size measurement, and it is more difficult to disperse the particles. However, from the measurement results, it can be seen that using the method of this patent invention to measure high - concentration gel preparations still gives ideal results.

[0120] The inventor further compared the measurement effects when using surfactants as the dispersion medium. The specific comparative examples are as follows.

[0121] Comparative Example 4:

[0122] Take 1.25 g of the preparation (adapalene gel) and place it in a beaker containing 250 ml of cetostearyl alcohol polyoxyethylene ether solution with a mass concentration of 1% (1:200). Add a magnetic stir bar and stir slowly at room temperature (below 600 rpm) on a magnetic stirrer for 30 min. The rest are the same as in Example 10. The results are shown in Figure 22 shown. It can be seen that more bubbles are generated, and there are multiple wide peaks between 1 and 100 microns, with more peak interferences. It can be seen that using surfactants will not only cause bubbles to be generated, but also affect the dispersion effect of the gel, and the method reproducibility is poor and the measurement accuracy is low.

[0123] Comparative Example 5:

[0124] The difference from Comparative Example 4 is that the preparation is changed to progesterone gel, and the rest is the same as Comparative Example 4. The results are shown in Figure 23 the figure. Similarly, when the gel preparation is changed, more bubbles are still generated, there are some peak interferences in the particle size distribution diagram, and the dispersion effect is not as good as that of the examples of the present invention.

[0125] It can be seen that when both Comparative Example 4 and Comparative Example 5 use a surfactant as the dispersion medium to disperse the gel and the wet method is used to measure the particle size, more bubbles are observed during the experiment. From the measurement results of the two comparative examples, there are large peaks led by more than 1000μm bubbles and the medium fails to uniformly disperse the gel and disperse the solid particles.

[0126] Comparative Example 6:

[0127] Take 1.25 g of the preparation (progesterone gel) and place it in a beaker containing a mixed solution of 250 ml of a 1% cetostearyl polyoxyethylene ether solution and a 1% sodium chloride solution (1:200). Add a magnetic stir bar and stir slowly at room temperature (below 600 rpm) on a magnetic stirrer for 30 min.

[0128] Measure the particle size of the dispersed sample with a MASTERSIZER 3000 laser particle size analyzer. Use the manual measurement mode, the stirring speed is 1200 rpm, the background measurement medium is purified water, and when measuring the sample, the purified water is completely replaced with the stirred and dispersed sample. The results are as Figure 24 shown in the figure.

[0129] According to the results, it can be known that compared with Comparative Example 5, in Comparative Example 6, when the surfactant and 1% sodium chloride solution are mixed simultaneously, the large bubble peak above 100μm can be reduced to a certain extent, and the wide peak between 1 and 100 microns is also significantly reduced. The overlap of the peaks generated by multiple sets of measurement data is improved. It can be seen that when the salt solution is added, not only can the bubbles be reduced, but also the dispersion effect of the gel is significantly improved, and the accuracy and reproducibility of the method are also improved, indicating that adding the salt solution can indeed improve the particle size measurement results. However, due to the presence of the surfactant, the bubble peak still cannot be completely eliminated, interfering with the accuracy of the results.

[0130] At the same time, from the results of Comparative Examples 4, 5, and 6, it can be seen that the presence of the surfactant has a great influence on the accuracy of the measurement results. It will not only generate bubbles but also affect the dispersion effect of the gel. And although adding the salt solution can improve the particle size measurement results, the presence of the surfactant still affects the measurement results.

[0131] In summary, by selecting a suitable dispersion medium and designing a reasonable mass concentration, the gel of the present invention is well dispersed without generating bubbles, and the method has good reproducibility, solving the technical problems that the current measurement method cannot effectively disperse the gel and the solid particles cannot be well separated from the matrix. At the same time, it also solves the technical problems of bubble generation, poor dispersion effect and influence on measurement accuracy caused by adding surfactants.

[0132] The above specific embodiments further elaborate on the object, technical solution and beneficial effects of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not used to limit the protection scope of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for determining the particle size and particle size distribution of a gel preparation, characterized in that, Comprising: Adding a gel preparation into a dispersion medium, then stirring or ultrasonically dispersing, and then performing particle size determination; The dispersion medium is a solution containing an acid or a salt, and the mass concentration of the acid or the salt is 0.5-10%.

2. The method for determining the particle size and particle size distribution of a gel preparation according to claim 1, wherein The concentration of the gel preparation in the dispersion medium is 0.02%-0.5%.

3. The determination method for the particle size and particle size distribution of a gel preparation according to claim 1, characterized in that, The gel preparation is adapalene gel, progesterone gel or selenium disulfide gel.

4. A method for determining the particle size and particle size distribution of a gel preparation according to claim 1, wherein The acid is any one of inorganic acids and organic acids; Preferably, the acid is any one of phosphoric acid, acetic acid, citric acid and the acids derived therefrom.

5. A method for determining the particle size and particle size distribution of a gel preparation according to claim 1, characterized in that, The salt is any one of inorganic salts; Preferably, the salt is any one of inorganic sodium salts, inorganic potassium salts, inorganic magnesium salts and inorganic aluminum salts.

6. The method for determining the particle size and particle size distribution of a gel preparation according to claim 1, characterized in that, The salt is any one of sodium chloride, potassium chloride, dipotassium hydrogen phosphate and sodium pyrophosphate.

7. A method for determining the particle size and particle size distribution of a gel preparation according to claim 1, characterized in that, The stirring time is 0 min to 30 min, the ultrasonic time is 0 min to 30 min, and the stirring speed during stirring and ultrasonic treatment is lower than 2000 rpm.

8. A method for determining the particle size and particle size distribution of a gel preparation according to claim 1, characterized in that, Heating is also included during stirring or ultrasonic treatment, and the heating temperature is 10°C to 30°C.

9. A method for determining the particle size and particle size distribution of a gel preparation according to claim 1, characterized in that, Particle size determination is performed using a laser particle size analyzer in the manual measurement mode.

10. The method for determining the particle size and particle size distribution of a gel preparation according to claim 9, wherein The stirring speed during particle size determination is 800 rpm to 2000 rpm, and the sample is measured 3 times.

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