A method for detecting the particle size and particle size distribution of azithromycin raw material

Abstract

The present invention belongs to the technical field of drug preparation detection, and specifically relates to a method for detecting the particle size and particle size distribution of azithromycin raw materials. The detection method provided by the present invention uses a nonylphenol polyoxyethylene ether-alkaline solution containing an appropriate amount as a dispersion medium, and uses a wet method to detect the particle size of azithromycin raw materials under specific dispersion steps and exclusive laser particle size analyzer parameters. The present invention has the advantages of effectively and accurately detecting the particle size and particle size distribution of azithromycin raw materials, and is of great significance to the research and development, quality control and clinical application of azithromycin and related preparations.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation detection, and particularly relates to a method for detecting the particle size and particle size distribution of azithromycin raw material medicine. Background Art

[0002] Azithromycin is a macrolide antibiotic that is mainly used clinically to treat infections caused by sensitive bacteria. It has a variety of dosage forms, such as tablets, capsules, granules, dry suspensions, etc.

[0003] Azithromycin is a white or off-white crystalline powder, which dissolves under acidic conditions, is easily soluble in methanol, acetone, anhydrous ethanol or dilute hydrochloric acid, dissolves in acetonitrile, and is almost insoluble in water. Since the particle size and particle size distribution of a drug directly affect its physical properties, such as dissolution rate, absorption performance and stability, etc., an inappropriate particle size of the API makes it difficult to ensure drug production efficiency, drug quality and drug safety, so the particle size and particle size distribution of the API are particularly concerned in the development and production of preparations.

[0004] At present, the detection methods involved in the prior art are all difficult to ensure the authenticity, accuracy and repeatability of the particle size or particle size distribution of azithromycin. In the relevant technical field, the commonly used wet detection method directly uses deionized water as a dispersion medium for detection, and there is an obvious trend of particle size decline during the detection process, which makes the data obviously distorted. Patent CN116930013A uses wet detection, and uses surfactant Tween 80 and deionized water to disperse the raw materials in the azithromycin dry suspension for particle size detection. Patent CN117368056A uses wet detection, and uses xanthan gum aqueous solution and water-dispersed azithromycin raw materials and / or azithromycin dry suspension for drug particle size detection, but xanthan gum has viscosity, and azithromycin itself has poor wettability in aqueous solution, and is easy to agglomerate during the dispersion process, which distorts the detection data. Patent CN109115661A uses dry detection, which has uncontrollable dispersion pressure dependence. Excessive dispersion pressure may cause excessive dispersion of the drug and destroy the structure of the measured drug. The smaller the measured particle size, the smaller the dispersion pressure will cause the material to aggregate and the measured data will be larger. Too much or too little pressure will distort the data.

[0005] Therefore, it is of great significance to develop a method to accurately detect the particle size and particle size distribution of azithromycin API. Summary of the invention

[0006] In order to overcome the deficiencies in the prior art, the present invention aims to provide a method for accurately detecting the particle size of azithromycin raw material.

[0007] The present invention discloses a method for detecting the particle size and particle size distribution of azithromycin raw materials. The method adopts a laser particle size analyzer for wet detection. The sample for wet detection is an azithromycin suspension, wherein the azithromycin suspension is prepared from the azithromycin raw materials and a 0.5% nonylphenol polyoxyethylene ether-alkaline solution.

[0008] In some embodiments, a first alkaline solution is further added during the preparation of the azithromycin suspension.

[0009] In some embodiments, the azithromycin suspension is prepared by mixing and dispersing the azithromycin bulk drug with a 0.5% nonylphenol polyoxyethylene ether-alkaline solution, and then adding the first alkaline solution for continuous stirring and dispersion.

[0010] In some embodiments, before the azithromycin suspension is tested, the second alkaline solution is first added to the laser particle size analyzer wet detection sample injector, and then the azithromycin suspension in a stirring state is added to the sample injector.

[0011] In some embodiments, after the azithromycin suspension is added to the laser particle size analyzer wet detection sampler, the cycle speed, detection time, cycle time, and shielding ratio range of the laser particle size analyzer wet detection are set, and the detection is performed three times in parallel.

[0012] In some embodiments, the alkaline solution, the first alkaline solution, and the second alkaline solution are all alkaline solutions, including at least one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, and barium hydroxide aqueous solution. The concentration of the alkaline solution is 0.05 mol / L and above, and preferably the concentration of the alkaline solution is 0.05 mol / L to 1 mol / L.

[0013] In some embodiments, the nonylphenol ethoxylate includes NP-40.

[0014] In some embodiments, in the preparation of the azithromycin suspension, the mass volume ratio of the azithromycin bulk drug to the 0.5% nonylphenol polyoxyethylene ether-alkaline solution is 0.9:15 g / mL to 1.1:15 g / mL, preferably 1:15 g / mL.

[0015] In some embodiments, the 0.5% nonylphenol polyoxyethylene ether-alkali solution is 0.5% NP-40-0.1 mol / L sodium hydroxide aqueous solution.

[0016] In some embodiments, the volume ratio of the 0.5% nonylphenol polyoxyethylene ether-alkaline solution, the first alkaline solution, and the second alkaline solution is 3:10:20.

[0017] In some embodiments, the rotation speed of the continuous stirring and dispersing is 200 rpm to 600 rpm, and the stirring and dispersing time is 1 min or more, preferably 1 min to 5 min, and more preferably 3 min.

[0018] In some embodiments, the cycle speed is 2000 rpm to 3000 rpm, the detection time is 8s to 12s, the cycle time is 30s to 1min30s, and the shading ratio ranges from 8.0% to 20.0%. Preferably, the cycle speed is 2500 rpm, the detection time is 10s, the cycle time is 1min, and the shading ratio ranges from 8.0% to 20.0%.

[0019] As a specific solution, the method for detecting the particle size and particle size distribution of azithromycin raw material drug, the method adopts a laser particle size analyzer for wet detection, and the steps include:

[0020] (1) Preparation of azithromycin suspension: 1±10% of azithromycin API and 15 parts of 0.5% nonylphenol polyoxyethylene ether-alkaline solution are mixed and dispersed, and then 50 parts of 0.1 mol / L sodium hydroxide aqueous solution are added for continuous stirring and dispersion; the 0.5% nonylphenol polyoxyethylene ether-alkaline solution is 0.5% NP-40-0.1 mol / L sodium hydroxide aqueous solution;

[0021] (2) Sample injection test: Add 100 parts of 0.1 mol / L sodium hydroxide aqueous solution into the laser particle size analyzer wet detection sample injector, add the azithromycin suspension under stirring into the sample injector, set the cycle speed, detection time, cycle time, and shading ratio range, and perform parallel detection 3 times.

[0022] As a preferred embodiment, the method for detecting the particle size and particle size distribution of azithromycin raw material drug, the method adopts a laser particle size analyzer for wet detection, and the steps include:

[0023] (1) Preparation of dispersion medium

[0024] 0.1 mol / L sodium hydroxide solution: weigh 4 g of sodium hydroxide, add 1000 mL of purified water, and stir until dissolved;

[0025] Preparation of 0.5% NP-40-0.1mol / L sodium hydroxide solution: weigh 0.5g of NP-40, add it to 100mL of 0.1mol / L sodium hydroxide solution, and stir until completely dissolved;

[0026] (2) Preparation of azithromycin suspension

[0027] Measure 15 mL of 0.5% NP-40-0.1 mol / L sodium hydroxide solution in a beaker, weigh 1±10% g of azithromycin API and add it to the beaker for mixing and dispersion, add 50 mL of 0.1 mol / L sodium hydroxide solution, place on a magnetic stirrer at 200 rpm to 600 rpm for 3 min;

[0028] (3) Sampling test

[0029] Add 100 mL of 0.1 mol / L sodium hydroxide solution into the wet detection injector of the laser particle size analyzer, add the azithromycin suspension under stirring into the injector, set the cycle speed to 2500 rpm, the detection time to 10 s, the cycle time to 1 min, the shading ratio range to 8.0% to 20.0%, and perform parallel detection 3 times.

[0030] Compared with the prior art, the method for detecting the particle size and particle size distribution of azithromycin raw material provided by the present invention has the following advantages:

[0031] 1. Adding an appropriate amount of surfactant nonylphenol polyoxyethylene ether (such as NP-40) can disperse the API and reduce agglomeration during the dispersion process. NP-40 is chemically stable and will not degrade in alkaline solutions, while Tween 80 may hydrolyze.

[0032] 2. Using alkaline solution of appropriate concentration to disperse the API is conducive to ensuring the particle size stability of the API. Using alkaline solution with a concentration of 0.05 mol / L or above (such as sodium hydroxide, potassium hydroxide, barium hydroxide solution) can ensure that the particle size of the raw material will not change for a long time, and can obtain true test results, which can effectively reduce errors and obtain true API particle size test results;

[0033] 3. The use of nonylphenol polyoxyethylene ether-alkaline solution with appropriate concentration and dosage is conducive to the true and accurate detection of the particle size and particle size distribution of azithromycin. The method of using 0.5% NP-40-alkaline solution (especially when the concentration of the alkaline solution is 0.05 mol / L or above) as the dispersion medium to perform wet detection using a laser particle size analyzer, the set cycle speed, detection time, cycle time, and shading ratio range are drug-specific, the method has good repeatability and intermediate precision, and can accurately and efficiently reflect the true situation of the particle size and particle size distribution of azithromycin, which is conducive to the research and development, quality control and clinical application of azithromycin and related preparations. DETAILED DESCRIPTION

[0034] The present invention is further described in detail in conjunction with the following specific examples, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention, and the attached claims are the scope of protection. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art, and the present invention does not particularly limit the content.

[0035] In the present invention, the term "comprising" is an open expression, i.e., including the contents specified in the present invention, but not excluding contents in other aspects. The term "part" means a mass unit (g) or a volume unit (mL). If a solid is measured in grams (g), then "1 part" means 1 gram of the solid. If a liquid is measured in milliliters (mL), then "1 part" means 1 milliliter of the liquid.

[0036] The term "about" means ± 10% of the stated value; "RSD" is relative standard deviation.

[0037] "Nonylphenol polyoxyethylene ether-alkaline solution" refers to the alkaline solution of nonylphenol polyoxyethylene ether; "NP-40" refers to the specific type of nonylphenol polyoxyethylene ether. NP-40 is polymerized by nonylphenol and ethylene oxide. The "40" in its name represents the degree of polymerization of ethylene oxide, that is, the molecule contains 40 ethylene oxides. Nonylphenol polyoxyethylene ether and nonylphenol polyethylene glycol are the same substance.

[0038] D 10 RSD≤5%: Indicates that in the particle size distribution curve, the equivalent diameter (D 10 The relative standard deviation of the three measurements of ) does not exceed 5%. This reflects the measurement repeatability of the small particle fraction.

[0039] D 50 RSD≤3%: Indicates that in the particle size distribution curve, the equivalent diameter (D 50 The relative standard deviation of the three measurements of the median diameter or average particle size does not exceed 3%. 50 It is an important indicator of particle size distribution. A lower RSD value indicates that the overall particle size distribution has good repeatability.

[0040] D 90 RSD≤5%: Indicates the equivalent diameter (D) of the largest particle when the cumulative distribution is 90% in the particle size distribution curve. 90 The relative standard deviation of the three measurements of ) does not exceed 5%. This reflects the measurement repeatability of the large particle fraction.

[0041] In the present invention, "h" means hour; "min" means minute; "s" means second; "g" means gram; "ml" and "mL" both mean milliliter; "rpm" means revolutions per minute; "M" means mole per liter; "solution" means that the basic solvent is water, such as "sodium hydroxide solution" and "sodium hydroxide aqueous solution" both mean an aqueous solution of sodium hydroxide.

[0042] In the present invention, unless otherwise specified, the rotation speed of the stirring and dispersing using a magnetic stirrer in the following examples is 200 rpm to 600 rpm.

[0043] In the present invention, the actual concentration unit of nonylphenol polyoxyethylene ether solution is g / L. Taking 0.1% nonylphenol polyoxyethylene ether solution as an example, the actual mass volume concentration of nonylphenol polyoxyethylene ether solution is 0.1g / 100mL; taking 0.5% NP-40 as an example, the actual mass volume concentration of NP-40 in the dispersion is 0.5g / 100mL.

[0044] Azithromycin API: Three batches of azithromycin API were purchased from commercial channels and named as Batch 1, Batch 2, and Batch 3. The azithromycin API used in the following examples is Azithromycin Batch 1 unless otherwise specified.

[0045] Example 1 Initial Method Confirmation

[0046] Method for detecting the particle size and particle size distribution of azithromycin raw material: weigh about 1g of azithromycin, add 15ml0.5% NP-40-0.1mol / L sodium hydroxide solution, add 50ml 0.1mol / L sodium hydroxide solution after mixing and dispersing, place on a magnetic stirrer and stir and disperse for 3min (prepare azithromycin suspension), draw the azithromycin suspension while stirring and add it into the laser particle size analyzer injector pre-added with 100ml 0.1mol / L sodium hydroxide solution, set the cycle speed to 2500rpm, the detection time to 10s, the shading ratio range to 8.0% to 20.0%, the cycle time to 1min, perform parallel detection 3 times, and calculate the average value and RSD.

[0047] Table 1 Detection results of the initial method

[0048]

[0049] The results are shown in Table 1. The test results of the particle size and particle size distribution of the raw material drug for three consecutive times met the acceptable standards, the particle size distribution difference was not large, and the RSD met the acceptable standards, indicating that the initial method had good repeatability and met the development requirements.

[0050] Example 2 Detection method optimization

[0051] (1) Investigation of stirring and dispersing time: Weigh about 1g of azithromycin, add 15ml of 0.5% NP-40-0.1mol / L sodium hydroxide solution, add 50ml of 0.1mol / L sodium hydroxide solution after mixing and dispersing, and place on a magnetic stirrer for stirring and dispersing for 1min, 3min, and 5min (preparing azithromycin suspension), draw the azithromycin suspension while stirring and add it to the laser particle size analyzer sampler pre-added with 100ml of 0.1mol / L sodium hydroxide solution, set the cycle speed to 2500rpm, the detection time to 10s, the shading ratio range to 8.0% to 20.0%, and the cycle time to 1min, detect the particle size and particle size distribution results 3 times, and calculate the average value and RSD. The results are shown in Table 2. When the stirring time is within the range of 1min to 5min, the difference in the particle size detection results of the raw material drug is not large, indicating that the stirring time within 1min to 5min has little effect on the particle size of the raw material drug, and the preferred stirring time is 3min.

[0052] Table 2 Test results of stirring and dispersing time

[0053]

[0054] (2) Investigation of detection time: Weigh about 1g of azithromycin, add 15ml of 0.5% NP-40-0.1mol / L sodium hydroxide solution, add 50ml of 0.1mol / L sodium hydroxide solution after mixing and dispersing, place on a magnetic stirrer and stir and disperse for 3min (prepare azithromycin suspension), draw azithromycin suspension while stirring and add it to the laser particle size analyzer sampler pre-added with 100ml of 0.1mol / L sodium hydroxide solution, set the cycle speed to 2500rpm, the cycle time to 1min, the shading ratio range to 8.0% to 20.0%, investigate the detection time to 8s, 10s, and 12s, detect the particle size and particle size distribution results 3 times, and calculate the average value and RSD. The results are shown in Table 3. When the detection time is within the range of 8s to 12s, the difference in the detection results of the bulk drug particle size is not large, indicating that the detection time within 8s to 12s has little effect on the bulk drug particle size, and the preferred detection time is 10s.

[0055] Table 3 Test results of the test time

[0056]

[0057] (3) Investigation of the circulation speed: Weigh about 1 g of azithromycin, add 15 ml of 0.5% NP-40-0.1 mol / L sodium hydroxide solution, mix and disperse, then add 50 ml of 0.1 mol / L sodium hydroxide solution, place on a magnetic stirrer and stir and disperse for 3 min (preparation of azithromycin suspension), while stirring, draw the azithromycin suspension into the laser particle size analyzer sampler that has been pre-added with 100 ml of 0.1 mol / L sodium hydroxide solution, set the circulation speed to 2500 rpm, the detection time to 10 s, the cycle time to 1 min, and the shading ratio range to 8.0% to 20.0%, investigate different circulation speeds (2000 rpm, 2500 rpm, 3000 rpm), detect the particle size and particle size distribution results 3 times, and calculate the average value and RSD. The results are shown in Table 4. When the circulation speed is in the range of 2000rpm to 3000rpm, the differences in the particle size test results of the API are not significant, indicating that the circulation speed in the range of 2000rpm to 3000rpm has little effect on the particle size of the API, and the preferred circulation speed is 2500rpm.

[0058] Table 4 Test results of cycle speed

[0059]

[0060]

[0061] (4) Investigation of cycle time: Weigh about 1 g of azithromycin, add 15 ml of 0.5% NP-40-0.1 mol / L sodium hydroxide solution, mix and disperse, then add 50 ml of 0.1 mol / L sodium hydroxide solution, place on a magnetic stirrer and stir and disperse for 3 min (prepare azithromycin suspension), and add the azithromycin suspension into the laser particle size analyzer sampler pre-added with 100 ml of 0.1 mol / L sodium hydroxide solution while stirring. The fixed cycle speed is 2500 rpm, the detection time is 10 s, and the shading ratio range is 8.0% to 20.0%. The cycle time for investigation is 30 s, 1 min, and 1 min 30 s. The particle size and particle size distribution results are detected 3 times, and the average value and RSD are calculated. The results are shown in Table 5. When the cycle time is in the range of 30s to 1min30s, the differences in the particle size test results of the API are not significant, indicating that the cycle time in the range of 30s to 1min30s has little effect on the particle size of the API, and the preferred cycle time is 1min. Note: The experimental data with a cycle time of 1min determines the initial method of Example 1.

[0062] Table 5 Cycle time inspection sample test results

[0063]

[0064]

[0065] Example 3 Intermediate Precision Test

[0066] Two experimenters detected the particle size and particle size distribution of the same batch of azithromycin API according to the method of Example 1. Each experimenter detected 6 times in parallel, and the results of 6 single-person detections and 12 double-person detections were counted. The results are shown in Table 6. There is no significant difference in the particle size results of the API detected by different personnel, indicating that the repeatability and intermediate precision of the method are good.

[0067] Table 6 Intermediate precision test results

[0068]

[0069]

[0070] Example 4 Investigation of alkaline solution types

[0071] Weigh about 1g of azithromycin, add 15ml of 0.5% NP-40-alkaline solution (the alkaline solution is selected from 0.1mol / L potassium hydroxide solution or 0.05mol / L barium hydroxide solution), add 50ml of 0.1mol / L sodium hydroxide solution after mixing and dispersing, place on a magnetic stirrer and stir and disperse for 3min (prepare azithromycin suspension), draw the azithromycin suspension while stirring and add it into the laser particle size analyzer injector pre-added with 100ml of 0.1mol / L sodium hydroxide solution, set the cycle speed to 2500rpm, the detection time to 10s, the shading ratio range to 8.0% to 20.0%, and the cycle time to 1min, detect the particle size and particle size distribution results 3 times, and calculate the average value and RSD.

[0072] Table 7 Test results of alkaline solution types

[0073]

[0074]

[0075] The results are shown in Table 7. When the alkaline solution is a potassium hydroxide solution or a barium hydroxide solution of appropriate concentration, the particle size test results of azithromycin raw materials are not much different, the RSD meets the acceptable standard, and the method has good repeatability.

[0076] Example 5 Investigation of other types of dispersion media

[0077] (1) Dispersion with purified water: Weigh about 1 g of azithromycin, add 15 ml of purified water, mix and disperse, add 50 ml of purified water, place on a magnetic stirrer and stir and disperse for 3 min (to prepare azithromycin suspension), and add the azithromycin suspension into the laser particle size analyzer sampler pre-added with 100 ml of purified water while stirring. Set the cycle speed to 2500 rpm, the detection time to 10 s, the shading ratio range to 8.0% to 20.0%, and the cycle time to 30 s, 1 min, and 1 min 30 s. Detect the particle size and particle size distribution results 3 times, respectively, and calculate the average value and RSD.

[0078] (2) 0.05% to 3% Tween 80 aqueous solution: The method for detecting the particle size and particle size distribution of azithromycin raw material drug using purified water as the dispersion medium is used as above, except that the purified water is replaced with 0.05% to 3% Tween 80 aqueous solution.

[0079] Table 8 Test results of purified water or Tween aqueous solution dispersion

[0080]

[0081]

[0082] The results are shown in Table 8. When the dispersion medium is purified water or 0.05% to 3% Tween 80 aqueous solution, the particle size of the API has a significant decreasing trend with the increase of the circulation time, indicating that the API has dissolved during the detection process. This method is not conducive to accurately detecting the particle size and particle size distribution of azithromycin. In addition, during the dispersion process, due to the poor wettability of the API, the API agglomerates significantly during the dispersion process in purified water, resulting in a significantly larger RSD of the test results and poor repeatability of the method.

[0083] Example 6 0.5% nonylphenol polyoxyethylene ether aqueous solution dispersion

[0084] Weigh about 1g of azithromycin, add 15ml of 0.5% NP-40 aqueous solution, add 50ml of purified water after mixing and dispersion, place on a magnetic stirrer and stir and disperse for 3min (prepare azithromycin suspension), and add the azithromycin suspension into the laser particle size analyzer sampler pre-added with 100ml of purified water while stirring. Fix the cycle speed to 2500rpm, the detection time to 10s, the shading ratio range to 8.0% to 20.0%, set the cycle time to 30s, 1min, and 1min30s, detect the particle size and particle size distribution results 3 times, and calculate the average value and RSD.

[0085] Table 9 Test results

[0086]

[0087]

[0088] The results are shown in Table 9. As the cycle time increases, the particle size of the API has a significant downward trend, indicating that the API has dissolved during the detection process. In addition, the RSD of this method is relatively large, and the repeatability of the method is slightly poor, which is not conducive to the accurate detection of the particle size and particle size distribution of azithromycin.

[0089] Example 7 0.5% nonylphenol polyoxyethylene ether and low concentration alkaline solution dispersion

[0090] The concentration of sodium hydroxide solution is 0.0001mol / L sodium hydroxide to 0.01mol / L sodium hydroxide solution: weigh about 1g of azithromycin, add 15ml of 0.5% NP-40-sodium hydroxide solution, add 50ml of sodium hydroxide solution after mixing and dispersing, place on a magnetic stirrer and stir and disperse for 3min (prepare azithromycin suspension), draw the azithromycin suspension while stirring and add it into the laser particle size analyzer injector that has been pre-added with 100ml of sodium hydroxide solution, fix the cycle speed to 2500rpm, the detection time to 10s, the shading ratio range to 8.0% to 20.0%, set the cycle time to 30s, 1min, 1min30s, detect the particle size and particle size distribution results 3 times, respectively, and calculate the average value and RSD.

[0091] Table 10 Test results

[0092]

[0093] The results are shown in Table 10. As the cycle time increases, the particle size of the API tends to decrease, and the API still dissolves during the test. However, compared with using purified water or Tween aqueous solution to disperse azithromycin, this method is more suitable for measuring the particle size and particle size distribution of azithromycin.

[0094] Example 8 0.5% nonylphenol polyoxyethylene ether and a relatively high concentration of alkaline solution dispersion

[0095] Weigh about 1g of azithromycin, add 15ml of 0.5% NP-40-1mol / L sodium hydroxide solution, add 50ml of 1mol / L sodium hydroxide solution after mixing and dispersion, place on a magnetic stirrer and stir and disperse for 3min (prepare azithromycin suspension), draw the azithromycin suspension while stirring and add it into the laser particle size analyzer injector that has been pre-added with 100ml of 1mol / L sodium hydroxide solution, fix the cycle speed to 2500rpm, the detection time to 10s, the shading ratio range to 8.0% to 20.0%, set the cycle time to 30s, 1min, 1min30s, detect the particle size and particle size distribution results 3 times, and calculate the average value and RSD.

[0096] Table 11 Test results

[0097]

[0098] The results are shown in Table 11. When 1 mol / L sodium hydroxide solution is used as the alkaline solution (including the alkaline solution, the first alkaline solution, and the second alkaline solution), the particle size of the raw material does not change substantially with the cycle time, and the RSD of the particle size results obtained under each condition meets the requirements, indicating that the strong alkaline solution will not affect the particle size detection. Under the condition of meeting the detection conditions and saving the reagent cost, 0.05 mol / L to 1 mol / L sodium hydroxide solution is preferably used as the alkaline solution. The particle size of the azithromycin raw material is relatively stable, and no dissolution occurs. The method has good repeatability and can accurately detect the particle size and particle size distribution of the azithromycin raw material.

[0099] Example 9 Different amounts of nonylphenol polyoxyethylene ether (0.2%, 1%)-alkaline solution dispersion

[0100] The dosage of nonylphenol polyoxyethylene ether (NP-40) is 0.2% or 1%: weigh about 1g of azithromycin, add 15ml NP-40-0.1mol / L sodium hydroxide solution, add 50ml 0.1mol / L sodium hydroxide solution after mixing and dispersing, place on a magnetic stirrer and stir and disperse for 3min (prepare azithromycin suspension), draw the azithromycin suspension while stirring and add it into the laser particle size analyzer injector pre-added with 100ml 0.1mol / L sodium hydroxide solution, set the cycle speed to 2500rpm, the detection time to 10s, the shading ratio range to 8.0% to 20.0%, the cycle time to 1min, detect the particle size and particle size distribution results 3 times, and calculate the average value and RSD.

[0101] Table 12 Test results

[0102]

[0103] Table 13 Phenomenon records

[0104]

[0105] The results are shown in Tables 12 and 13. When the concentration of NP-40 is too low, the wetting of the raw material is poor. When the concentration of NP-40 is too high, obvious bubbles will appear during the stirring of the azithromycin suspension, causing the particle size test results to fail to meet the acceptable standards and the results have poor reproducibility. The selection of a concentration of 0.5% NP-40 meets the requirements, and the method has good repeatability and the data is not distorted.

[0106] Example 10 Particle size detection of different batches of raw materials

[0107] According to the method for detecting the particle size and particle size distribution of azithromycin API in Example 1, different batches of API were respectively taken for detection. The results are shown in Table 14. The RSD of the particle size results of azithromycin API detected by the method provided by the present invention meets the requirements, the method has good repeatability, and can accurately and efficiently reflect the true situation of the particle size and particle size distribution of azithromycin, which is beneficial to the research and development, quality control and clinical application of azithromycin and related preparations.

[0108] Table 14 Test results

[0109]

[0110] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. It should be pointed out that a person skilled in the art can make several improvements and modifications without departing from the technical principles of the present invention, and these improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for detecting the particle size and particle size distribution of azithromycin raw material, characterized in that: The method adopts a laser particle size analyzer for wet detection, wherein the sample for wet detection is an azithromycin suspension, wherein the azithromycin suspension is prepared from an azithromycin bulk drug and a 0.5% nonylphenol polyoxyethylene ether-alkali solution.

2. The method according to claim 1, characterized in that A first alkaline solution is also added during the preparation of the azithromycin suspension.

3. The method according to any one of claims 1 to 2, characterized in that: The preparation of the azithromycin suspension is to mix and disperse the azithromycin raw material with a 0.5% nonylphenol polyoxyethylene ether-alkali solution, and then add the first alkali solution for continuous stirring and dispersion.

4. The method according to any one of claims 1 to 3, characterized in that: Before the azithromycin suspension is tested, the second alkaline solution is first added into the laser particle size analyzer wet method test sample injector, and then the azithromycin suspension in a stirring state is added into the sample injector.

5. The method according to claim 4, characterized in that After the azithromycin suspension is added to the laser particle size analyzer wet detection sampler, the cycle speed, detection time, cycle time, and shading ratio range of the laser particle size analyzer wet detection are set, and parallel detection is performed 3 times.

6. The method according to any one of claims 1 to 5, characterized in that: The alkaline solution, the first alkaline solution and the second alkaline solution are all alkaline solutions, including at least one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution and barium hydroxide aqueous solution. The concentration of the alkaline solution is 0.05 mol / L or more, preferably the concentration of the alkaline solution is 0.05 mol / L to 1 mol / L; the nonylphenol polyoxyethylene ether includes NP-40.

7. The method according to any one of claims 1 to 6, characterized in that: In the preparation of the azithromycin suspension, the mass volume ratio of the azithromycin bulk drug to the 0.5% nonylphenol polyoxyethylene ether-alkaline solution is 0.9:15 g / mL to 1.1:15 g / mL, preferably 1:15 g / mL.

8. The method according to any one of claims 1 to 7, characterized in that: The 0.5% nonylphenol polyoxyethylene ether-alkali solution is 0.5% NP-40-0.1 mol / L sodium hydroxide aqueous solution.

9. The method according to any one of claims 4 to 8, characterized in that: The volume ratio of the 0.5% nonylphenol polyoxyethylene ether-alkaline solution, the first alkaline solution and the second alkaline solution is 3:10:

20.

10. The method according to any one of claims 3 to 9, characterized in that: The rotation speed of the continuous stirring and dispersing is 200 rpm to 600 rpm, and the stirring and dispersing time is 1 min or more, preferably 1 min to 5 min, more preferably 3 min.

11. The method according to any one of claims 5 to 10, characterized in that: The circulation speed is 2000rpm~3000rpm, the detection time is 8s~12s, the cycle time is 30s~1min30s, and the shading ratio range is 8.0%~20.0%; preferably, the circulation speed is 2500rpm, the detection time is 10s, the cycle time is 1min, and the shading ratio range is 8.0%~20.0%.

12. The method according to any one of claims 1 to 11, characterized in that: The method uses a laser particle size analyzer for wet detection, and the steps include: (1) Preparation of azithromycin suspension: 1±10% of azithromycin API and 15 parts of 0.5% nonylphenol polyoxyethylene ether-alkaline solution are mixed and dispersed, and then 50 parts of 0.1 mol / L sodium hydroxide aqueous solution are added for continuous stirring and dispersion; the 0.5% nonylphenol polyoxyethylene ether-alkaline solution is 0.5% NP-40-0.1 mol / L sodium hydroxide aqueous solution; (2) Sample injection test: Add 100 parts of 0.1 mol / L sodium hydroxide aqueous solution into the laser particle size analyzer wet detection sample injector, add the azithromycin suspension under stirring into the sample injector, set the cycle speed, detection time, cycle time, and shading ratio range, and perform parallel detection 3 times.

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