Febuxostat raw material particle size detection method

Abstract

The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a febuxostat raw material granularity detection method which comprises the following steps: (1) preparing a dispersing agent; (2) preparing a test solution; and (3) verifying the analysis method. The febuxostat saturated aqueous solution added with the Tween 80 beneficial to dispersion is used as the febuxostat dispersing agent, and the problems that the febuxostat floats to form clusters and is non-uniform in dispersion are solved. Febuxostat has a good dispersion effect, is not easy to agglomerate, and does not destroy the particle size, so that an instrument can tolerate a dispersing agent, and does not cause interference on a determination background. The detection method provided by the invention has good repeatability, intermediate precision, accuracy, stability and durability, and also has the advantages of simple detection method, strong operability, no toxicity, environmental protection and low cost.

Description

Technical Field

[0001] The invention belongs to the technical field of drug analysis, and particularly relates to a method for detecting particle size of febuxostat raw materials. Background Art

[0002] The chemical name of febuxostat is 2-[(3-cyano-4-isobutyloxy)phenyl]-4-methyl-5-thiazolecarboxylic acid, and the structural formula is shown in Formula I. The main component is febuxostat. As a xanthine oxidase (XO) inhibitor, febuxostat is mainly used for the long-term treatment of hyperuricemia with gout symptoms.

[0003]

[0004] The particle size of APIs is an important factor in the development and control of solid dosage forms, and will have a significant impact on the quality indicators of the final product, such as bioavailability, solubility, uniformity, and stability. Currently, the commonly used methods for determining particle size and particle size distribution are: microscopy, sieving, and laser scattering. Among them, the microscopy method cannot control the particle size limit of the API and there is no agglomeration phenomenon in the field of view. The microscopy method can be used to assist in observing the dispersion of the API particles. Since Febuxostat has a strong electrostatic adsorption effect and is not suitable for dry determination in sieving and laser scattering methods, the Febuxostat API is mainly determined by wet determination.

[0005] In the wet method, the dispersion method of the sample is the key to the determination. In order to better disperse the sample, a surfactant can be added to the dispersant. Febuxostat is almost insoluble in water. In order to completely eliminate the influence of dissolution, the commonly used surfactant polysorbate 80 (Tween 80) can be used as an option. Patent CN116036056 mentions a particle size detection method for beclomethasone dipropionate suspension for inhalation, by using 0.05% to 0.3% Triton X-100 beclomethasone dipropionate saturated solution as a dispersion medium to detect the particle size of the prepared beclomethasone dipropionate suspension for inhalation. However, this method is only applicable to the beclomethasone dipropionate suspension for inhalation mentioned in this patent using Triton X-100 as a surfactant, and is not applicable to the febuxostat suspension using Tween 80 as a surfactant. Therefore, a method for detecting febuxostat suspension using Tween 80 as a surfactant is developed to accurately determine the particle size of febuxostat raw materials, which helps to break through the bottleneck in the research and development of generic drugs and is of great significance for the quality control of febuxostat suspension. Summary of the invention

[0006] In view of the problems existing in the background technology, the present invention provides a detection method capable of accurately measuring the particle size of Febuxostat API, selecting a saturated Febuxostat aqueous solution and adding Tween 80 as a dispersant, using Tween 80 to fully disperse the sample, and eliminating the effect of dissolution on the particle size distribution. The method is simple to operate and has good reproducibility. It is achieved by the following technical scheme:

[0007] A method for detecting the particle size of febuxostat raw materials comprises the following steps:

[0008] (1) dispersing the raw materials into a sample suspension, i.e., adding a surfactant to purified water, stirring and dissolving, and then adding febuxostat and ultrasonically filtering to obtain a dispersant;

[0009] (2) Preparation of test solution;

[0010] (3) After determining the parameters such as stirring speed, ultrasonic dispersion, upper limit of shading rate, lower limit of shading rate, and dispersion medium, the analytical method is verified and experiments on precision-repeatability, intermediate precision, durability-shading rate, and storage stability of the test sample are carried out.

[0011] Preferably, the surfactant in step (1) is a non-ionic surfactant Tween 80.

[0012] Preferably, the specific preparation steps of the dispersant in step (1) are: adding a certain amount of Tween 80 to purified water, stirring to dissolve, then adding a certain amount of febuxostat, and filtering with a microporous filter membrane after ultrasonication for 30 minutes to obtain the dispersant.

[0013] More preferably, the microporous filter membrane is 0.45 μm.

[0014] Preferably, the specific preparation steps of the test solution in step (2) are: adding the dispersant obtained in step (1) to a beaker, then adding febuxostat, shaking to disperse the febuxostat, and then adding the dispersion medium, shaking to disperse, the febuxostat precipitates when the sample is allowed to stand, and if retesting is required, it should be shaken again before adding the sample.

[0015] Preferably, the test parameters described in step (3) include: stirring speed (circulation speed): 1600 rpm; ultrasonic dispersion: always off; upper limit of shading rate: 20%; lower limit of shading rate: 10%; dispersion medium: purified water.

[0016] Compared with the prior art, the beneficial effects of the present invention are:

[0017] The commonly used surfactant Tween 80 has significant resistance to electrolytes and can help solid powders to be evenly dispersed in liquids. Febuxostat is almost insoluble in water. To increase its solubility, the present invention selects a saturated Febuxostat aqueous solution plus Tween 80 as a dispersant. Tween 80 can completely dissolve the sample and eliminate the effect of solubility on particle size distribution. The present invention uses a saturated Febuxostat aqueous solution plus Tween 80 as a dispersant to solve the problem of sample floating into agglomerates and uneven dispersion, so that the instrument can tolerate it and the measurement background will not be disturbed.

[0018] In addition, the detection method described in the present invention is simple and highly operable. It is non-toxic, environmentally friendly and low-cost. The present invention adopts the wet determination method in the laser scattering method to improve the problem of interference determination in the dry determination; at the same time, through the precision-repeatability, intermediate precision, durability-shading rate, and sample placement stability tests, it is found that the Febuxostat raw material particle size detection method described in the present invention shows good reproducibility and precision. DETAILED DESCRIPTION

[0019] The following embodiments of the technical solution of the present invention are described in detail in conjunction with the embodiments. The following embodiments are only used to more clearly illustrate the technical solution of the present invention, and are therefore only used as examples, and cannot be used to limit the protection scope of the present invention.

[0020] It should be noted that the experimental methods used in the implementation examples are all conventional methods unless otherwise specified; the materials, reagents, etc. used, unless otherwise specified, can be obtained from commercial channels.

[0021] In the present invention, unless otherwise specified, the numerical range "a-b" represents an abbreviation of any real number combination between a-b, where a and b are real numbers. For example, the numerical range "0-5" means that all real numbers between "0-5" are listed in this document, and "0-5" is just an abbreviation of these numerical combinations.

[0022] In the present invention, unless otherwise specified, all embodiments and preferred embodiments mentioned herein can be combined with each other to form a new technical solution.

[0023] In the present invention, unless otherwise specified, all the steps mentioned herein may be performed sequentially or randomly, but are preferably performed sequentially; for example, the method includes steps (a) and (b), which means that the method may include steps (a) and (b) performed sequentially, or may include steps (b) and (a) performed sequentially; for example, the method may further include step (c), which means that step (c) may be added to the method in any order, for example, the method may include steps (a), (b) and (c), or may include steps (a), (c) and (b), or may include steps (c), (a) and (b), etc.

[0024] The particle size test method of the febuxostat raw material in the embodiment of the present invention is as follows:

[0025] 1. Preparation of solvent (0.5% polysorbate 80 febuxostat saturated solution):

[0026] Take 5.0g polysorbate 80, add purified water to 1000ml, stir to dissolve, then add 0.2g febuxostat, ultrasonicate for 30min, filter with 0.45μm microporous membrane, and obtain 0.5% polysorbate 80 febuxostat saturated solution. The solvent is stored at room temperature. If it is not used on the same day, it should be filtered with 0.45μm microporous membrane before use every day. From the first filtration, the use time shall not exceed 3 days.

[0027] 2. Preparation of test solution:

[0028] Add 10-14g of solvent (0.5% polysorbate 80 febuxostat saturated solution) to a 100ml beaker, then add 0.6g of febuxostat, shake to disperse the febuxostat, and use the dropper head to break up large clumps that are difficult to disperse if necessary, add dispersion medium to 20g, and shake to disperse (a small amount of incompletely dispersed particle clumps with a diameter of less than 1mm that are precipitated at the bottom is allowed to exist, but there should be no floating objects). The febuxostat will precipitate while the sample is standing. If re-testing is required, shake again to disperse it before adding the sample.

[0029] 3. Instrument parameter settings:

[0030] Stirring speed (circulation speed): 1600 rpm;

[0031] Ultrasonic dispersion: always off;

[0032] Upper limit of shading rate: 20%;

[0033] Lower limit of shading rate: 10%;

[0034] Dispersion medium: purified water.

[0035] 4. Sample measurement.

[0036] Example 1

[0037] Determination of precision-repeatability

[0038] The experimenter prepares 6 test solutions from a batch of samples and performs the measurement according to the instrument parameters.

[0039] After injection according to the injection sequence, calculate D 10 , D 50 , D 90 The relative standard deviation (RSD) of

[0040] The acceptance criteria for the six replicates of the test sample in Example 1 are shown in Table 1:

[0041] Table 1

[0042]

[0043] The results are shown in Table 2:

[0044] Table 2

[0045]

[0046] It can be seen from Table 2 that the RSD of the results detected by the particle size detection method of the present invention meets the limit requirements and has good repeatability.

[0047] Example 2

[0048] The intermediate precision is determined by the experimenter preparing 6 test sample solutions from a batch of samples and performing the measurements according to the instrument parameters.

[0049] After injection according to the injection sequence, calculate the results of 12 measurements under the repeatability item D 10 , D 50 , D 90 The relative standard deviation (RSD) of

[0050] The acceptance criteria for the 12 samples of precision in Example 2 are shown in Table 3:

[0051] Table 3

[0052]

[0053]

[0054] The results are shown in Table 4:

[0055] Table 4

[0056]

[0057] As can be seen from Table 4, the D values ​​of 12 samples determined by two analysts were 10 , D50 , D 90 The RSDs were 7.2%, 2.4% and 1.9% respectively, indicating that the test method of the present invention meets the intermediate precision requirements.

[0058] Example 3

[0059] Durability-Determination of light blocking rate

[0060] Three test samples were prepared, and each test sample was tested in three different shading rate ranges (6%-12%, 13%-18%, 19%-25%) by adjusting the injection volume, and the relative standard deviation (RSD) of the data obtained under different shading rates was calculated.

[0061] The durability acceptance criteria in Example 3 are shown in Table 5:

[0062] Table 5

[0063]

[0064] The results are shown in Table 6:

[0065] Table 6

[0066]

[0067] The above results show that the D 10 , D 50 , D 90 The RSDs of the results were 13.4%, 3.8% and 2.8%, respectively, indicating that the test method of the present invention meets the durability acceptance standard.

[0068] Example 4

[0069] Determination of the storage stability of the test product

[0070] Measurement and calculation

[0071] Three samples were prepared and measured according to the instrument parameters as the 0h data of the sample stability. They were placed at room temperature and tested again after 1h and 2h. The relative standard deviation (RSD) between the test results after different placement times and those under standard conditions was calculated.

[0072] The stability acceptance criteria in Example 4 are shown in Table 7:

[0073] Table 7

[0074]

[0075] The experimental results are shown in Table 8:

[0076] Table 8

[0077]

[0078] The results showed that D 10 , D 50 , D 90 The RSDs were 7.6%, 2.7% and 3.1%, respectively, indicating that the test method of the present invention meets the stability acceptance criteria.

[0079] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein by equivalents. These modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be included in the scope of the claims and specification of the present invention.

Claims

1. A method for detecting the particle size of febuxostat raw materials, characterized in that: The steps include: (1) dispersing the raw materials into a sample suspension, i.e., adding a surfactant to purified water, stirring and dissolving, and then adding febuxostat and ultrasonically filtering to obtain a dispersant; (2) Preparation of test solution; (3) After determining the parameters such as stirring speed, ultrasonic dispersion, upper limit of shading rate, lower limit of shading rate, and dispersion medium, the analytical method is verified and experiments on precision-repeatability, intermediate precision, durability-shading rate, and storage stability of the test sample are carried out.

2. The method for detecting particle size of febuxostat raw materials according to claim 1, characterized in that: The surfactant in step (1) is a non-ionic surfactant Tween 80.

3. A method for detecting particle size of febuxostat raw materials according to claim 1, characterized in that: The specific preparation steps of the dispersant in step (1) are: adding a certain amount of Tween 80 to purified water, stirring to dissolve, then adding a certain amount of febuxostat, ultrasonicating for 30 minutes and filtering with a microporous filter membrane to obtain the dispersant.

4. The preparation of a dispersant in a method for detecting particle size of a febuxostat raw material according to claim 3, characterized in that: The microporous membrane used is 0.45μm.

5. A method for detecting particle size of febuxostat raw materials according to claim 1, characterized in that: The specific preparation steps for preparing the test solution in step (2) are: add the dispersant prepared in step (1) to a beaker, then add febuxostat, shake to disperse the febuxostat, then add the dispersion medium, and shake to disperse. The febuxostat precipitates when the sample is allowed to stand. If retesting is required, the sample should be shaken again for dispersion before adding the sample.

6. A method for detecting particle size of febuxostat raw materials according to claim 1, characterized in that: The test parameters described in step (3) include: stirring speed (circulation speed): 1600 rpm; ultrasonic dispersion: always off; upper limit of shading rate: 20%; lower limit of shading rate: 10%; dispersion medium: purified water.

7. A method for detecting particle size of febuxostat raw materials, characterized in that: The method comprises the method described in claims 1 to 6.

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