Granularity determination method of mirabegron raw material

Abstract

The invention discloses a method for determining the granularity of a mirabegron raw material, and belongs to the technical field of medicine preparation. According to the measuring method, a dry laser scattering method is adopted, and measuring parameters comprise dispersion air pressure, sample feeding speed, hopper gaps and measuring duration. According to the method, the particle size and the particle size distribution of the mirabegron bulk drug are measured by using the dry laser scattering method, the accuracy is high, the repeatability is good, the operation is simple, convenient, rapid, effective and reliable, and the product quality can be effectively controlled.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and particularly relates to a method for measuring the particle size of a mirabegron raw material. Background Art

[0002] Mirabegron extended-release tablets are a urinary system drug used for the symptomatic treatment of urinary urgency, frequent urination and / or urge urinary incontinence in adult patients with overactive bladder (OAB). Its main ingredient is mirabegron, a selective β3 adrenergic receptor agonist that relaxes bladder smooth muscle by acting on bladder tissue. Mirabegron is 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide, molecular formula: C 21 H 24 N4O2S, molecular weight is 251.76, structural formula is as follows:

[0003]

[0004] Mirabegron sustained-release tablets are a generic product that our company is currently developing. During the research and development stage, we studied the particle size of its main ingredients and performed particle size measurements on multiple batches of raw materials to ensure the parallelism of product quality.

[0005] At present, there are few reports on the research of mirabegron particle size determination at home and abroad. Conventional dry particle size determination parameter adjustment cannot effectively detect it and has poor parallelism. In view of the shortcomings in the prior art, the present invention aims to provide a particle size determination method for mirabegron raw materials to provide more reliable guarantee for product quality and drug safety. Summary of the invention

[0006] The technical problem solved by the invention is to provide a method for measuring the particle size of mirabegron raw materials. The method is rapid, simple, effective, reliable and has good repeatability, so that the product quality can be effectively controlled.

[0007] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0008] A method for measuring the particle size of a mirabegron raw material, the method adopts a dry laser scattering method, and comprises the following steps:

[0009] 1) Set instrument parameter conditions;

[0010] 2) Prepare the test sample and keep it ready for use;

[0011] 3) Add the sample to the sample tray, start the method for determination, and after the background determination is completed, measure the sample and collect data.

[0012] The particle type is non-spherical.

[0013] The dispersion pressure is 3.0 bar-4.0 bar.

[0014] The shading degree is 0.5%-6%.

[0015] The injection speed is 60%-80%.

[0016] The feed gap is 0.9mm-1.1mm.

[0017] The sample measurement duration is 9s-11s.

[0018] The refractive index is 1.42 and the absorptivity is 0.1.

[0019] During the sample testing process, D10, D50 and D90 were used as characteristic values ​​of particle size distribution.

[0020] Preparation of the test sample: Take no less than 10 g of the product and pass it through a 40-mesh sieve to disperse the sample without agglomeration, and use it as the test sample.

[0021] Compared with the prior art, the present invention has the following advantages:

[0022] The particle size determination method of mirabegron raw material provided by the present invention establishes a dry laser scattering method by setting determination parameters. The particle size and particle size distribution of mirabegron raw material are determined by the dry laser scattering method, which is not only highly accurate and repeatable, but also simple, fast, effective and reliable in operation, so that the product quality can be effectively controlled. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is a comparison diagram of particle size distribution under different dispersion pressures of the present invention;

[0024] Figure 2 This is a comparison diagram of particle size distribution at different injection speeds of the present invention;

[0025] Figure 3 This is a comparison diagram of particle size distribution under different hopper gaps of the present invention;

[0026] Figure 4 This is a comparison diagram of particle size distribution under different measurement durations of the present invention. DETAILED DESCRIPTION

[0027] The present invention is further illustrated below in conjunction with specific examples. The examples are implemented based on the technical solutions of the present invention. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0028] Example 1

[0029] A method for measuring the particle size of mirabegron raw materials, using a dry laser scattering method, comprises the following steps:

[0030] 1) Instrument and sample selection: Malvern 3000 laser particle size detector, instrument number CA062101, mirabegron raw material comes from Jiangxi Tonghe Pharmaceutical Co., Ltd., batch number 102-20220801V;

[0031] 2) Instrument parameter settings: non-spherical particle mode, sample refractive index is 1.42, absorptivity is 0.1, density is 1.3 g / cm 3 , sample measurement duration is 10s, number of measurements is 1, lower limit of shading is 0.5%, upper limit of shading is 6%, stabilization time is 0.1s, gas pressure is 3.5barg, injection speed is 70%, venturi is high energy venturi, universal sample tray (with funnel), hopper gap is 1mm;

[0032] 3) Preparation of test sample: Take an appropriate amount of this product, not less than 10g, add the raw material into a 40-mesh sieve, tap the sieve wall gently to make the raw material fall freely and sieve out from the sieve hole. Do not press the raw material manually to artificially change the particle size. According to the particle size data in the COA provided by the raw material manufacturer, obtain preliminary particle size data, D (90) It is about 20μm, while the mesh size of 40 mesh sieve is 425μm, which is much larger than the particle size range of the raw material itself. It will not change the particle size of the raw material itself and does not belong to the artificial screening particle size range. This operation only disperses the sample without agglomeration. After sieving, the particle size determination of the test sample is completed within 10 minutes to prevent the raw material from agglomerating again due to backlog;

[0033] 4) Test method: Use Malvern 3000 particle size analyzer, set the instrument parameters according to 2) above, add appropriate amount of sample into the sample tray, fill about 1 / 2 volume of the sample tray with newly sieved raw materials, start the method for measurement, and measure the sample after the background measurement is completed.

[0034] Example 2

[0035] The determination method of Example 1 was verified from the aspects of repeatability, intermediate precision and durability, which are described in detail below.

[0036] 1. Repeatability test

[0037] Take an appropriate amount of this product and measure the sample 6 times in parallel according to the above particle size determination method. Record the chromatogram and the results are shown in Table 1.

[0038] Table 1 Repeatability test results

[0039] Sample name <![CDATA[D (10) (μm)]]> <![CDATA[D (50) (μm)]]> <![CDATA[D (90) (μm)]]> Repeatability 1 1.45 6.02 17.2 Repeatability 2 1.80 6.60 19.2 Repeatability 3 1.68 6.39 18.6 Repeatability 4 1.48 6.04 17.1 Repeatability 5 1.78 6.51 18.3 Repeatability 6 1.79 6.57 19.2 average value 1.66 6.36 18.3 RSD(%) 9.61 4.12 5.11

[0040] Conclusion: From the results in Table 1, we can see that after 6 parallel determinations of the test sample, D (10) RSD < 15%, D (50) RSD < 10%, D (90) RSD<10%, which meets the requirements, indicating that the method has good repeatability.

[0041] 2. Intermediate precision test

[0042] Replace the test personnel, take an appropriate amount of this product, and measure the sample 6 times in parallel according to the above particle size determination method. Record the chromatogram, and the results are shown in Table 2.

[0043] Table 2 Intermediate precision test results

[0044]

[0045] Conclusion: From the results in Table 2, we can see that after 12 tests, D (10) RSD < 15%, D (50) RSD < 10%, D (90) RSD<10%, which meets the requirements and the intermediate precision is good.

[0046] 3. Durability test

[0047] Normal conditions: Use normal condition parameters;

[0048] Adjust sample measurement duration: 9s and 11s;

[0049] Adjustable air pressure: 3.0 barg and 4.0 barg;

[0050] Adjust the injection speed: 60% and 80%;

[0051] Adjust the hopper gap (mm): 0.9mm and 1.1mm;

[0052] The samples were measured three times under different conditions. The results are shown in Table 3. Figure 1 , Figure 2 , Figure 3 and Figure 4 .

[0053] Table 3 Durability test results

[0054]

[0055]

[0056] Conclusion: From Table 3, Figure 1 , Figure 2 , Figure 3 and Figure 4The results show that the normal air pressure is 3.5 bar. When the air pressure is slightly adjusted, such as 3.5 bar ± 0.5 bar, it is found that there is no significant difference in the particle size determination spectrum of 3 bar, 3.5 bar, and 4 bar, and D (10) The RSD value is less than 15%, D (50) and D (90) The RSD value is less than 10%, and the durability is good;

[0057] Under normal conditions, the injection speed is 70%. When the injection speed is slightly adjusted, such as 70% ± 10%, it is found that there is no significant difference in the particle size determination spectrum of 60%, 70%, and 80%, and D (10) The RSD value is less than 15%, D (50) and D (90) The RSD value is less than 10%, and the durability is good;

[0058] Under normal conditions, the hopper gap is 1.0mm. When the hopper gap is slightly adjusted, such as 1.0mm±0.1mm, it is found that there is no obvious difference in the particle size determination spectrum of 0.9mm, 1.0mm, and 1.1mm, and D (10) The RSD value is less than 15%, D (50) and D (90) The RSD value is less than 10%, and the durability is good;

[0059] Under normal conditions, the sample measurement duration is 10s. When the sample measurement duration is slightly adjusted, such as the sample measurement duration is 10s±1s, it is found that there is no obvious difference in the particle size determination spectrum of 9s, 10s, and 11s, and D (10) The RSD value is less than 15%, D (50) and D (90) The RSD value is less than 10%, and the durability is good.

[0060] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for measuring the particle size of mirabegron raw materials, characterized in that: The method adopts a dry laser scattering method and comprises the following steps: 1) Set instrument parameter conditions; 2) Prepare the test sample and keep it ready for use; 3) Add the sample to the sample tray, start the method for determination, and after the background determination is completed, measure the sample and collect data.

2. The method for measuring the particle size of the mirabegron raw material according to claim 1, characterized in that: The particle type is non-spherical.

3. The particle size determination method of mirabegron raw material according to claim 1, characterized in that: The dispersion pressure is 3.0 bar-4.0 bar.

4. The method for measuring the particle size of mirabegron raw material according to claim 1, characterized in that: The shading degree is 0.5%-6%.

5. The method for measuring the particle size of mirabegron raw material according to claim 1, characterized in that: The injection speed is 60%-80%.

6. The method for measuring the particle size of mirabegron raw material according to claim 1, characterized in that: The feed gap is 0.9mm-1.1mm.

7. The method for measuring the particle size of mirabegron raw material according to claim 1, characterized in that: The sample measurement duration is 9s-11s.

8. The method for measuring the particle size of mirabegron raw material according to claim 1, characterized in that: The refractive index is 1.42 and the absorptivity is 0.

1.

9. The method for measuring the particle size of mirabegron raw material according to claim 1, characterized in that: During the sample testing process, D10, D50 and D90 were used as characteristic values ​​of particle size distribution.

10. The method for measuring the particle size of mirabegron raw material according to claim 1, characterized in that: Preparation of the test sample: Take no less than 10 g of the product and pass it through a 40-mesh sieve to disperse the sample without agglomeration, and use it as the test sample.

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