Background
The insoluble medicine has low solubility in water, unstable absorption in human body and low bioavailability, and the particle size needs to be controlled to ensure the absorption of the medicine in human body. The particle size detection method must pass through method verification, and meets the requirements of specificity, precision, accuracy and other method verification, so that the reliability of impurity detection results can be ensured, and the method can be used for guiding the quality control of medicines.
The particle size detection method generally selects wet measurement or dry measurement according to the properties and solubility of the sample; at present, only dry measurement of granularity of azithromycin is reported in related researches, for example, patent CN109115661A discloses a method for measuring granularity and granularity distribution of azithromycin bulk drug, and a laser granularity dry measurement mode is adopted, wherein measurement parameters comprise background measurement time, sample measurement time, shading rate, sample injection rate and dispersion air pressure. The detection method has high precision, strong accuracy and convenient operation, and can effectively detect the particle size and the particle size distribution of the azithromycin bulk drug. However, the original preparation contains a large amount of auxiliary materials, so that the method cannot analyze the original preparation. At present, no report on the granularity of the azithromycin bulk drug and the azithromycin preparation by a wet method exists.
Aiming at the defects of the related preparation particle size and particle size distribution of the azithromycin in the prior art and the problem that the azithromycin original development agent is difficult to detect by a dry method, the method for testing the particle size and the particle size distribution of the azithromycin bulk drug is very necessary, wherein the method is simple, convenient and accurate and can efficiently reflect the particle size condition of the azithromycin.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a method for testing the particle size and the particle size distribution of an azithromycin drug, which can meet the detection of the particle size of the azithromycin in the azithromycin bulk drug and the azithromycin dry suspension preparation, and has important significance for research and development, quality control and even clinical application of the azithromycin and the azithromycin dry suspension preparation.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the invention provides a method for testing the particle size and the particle size distribution of an azithromycin drug, which comprises the following steps:
(1) Sample preparation: adding a pre-dispersion medium into a sample to be measured, and uniformly dispersing by vortex; obtaining a test sample;
(2) Adding a redispersing medium into the sample, stirring and dispersing uniformly, and measuring;
the sample to be tested comprises an azithromycin bulk drug and/or an azithromycin dry suspension; the pre-dispersion medium comprises an aqueous xanthan gum solution; the redispersion medium comprises water; the azithromycin medicine comprises azithromycin bulk drug or azithromycin dry suspension.
Further, the weight-to-volume ratio of the sample to be measured and the pre-dispersion medium is (0.1-0.25): 5 g/mL. Preferably, the weight to volume ratio of the sample to be measured and the pre-dispersion medium is 0.1:5 g/mL.
Further, the mass volume concentration of the xanthan gum aqueous solution is 0.1-0.3 g/100mL. Preferably, the aqueous xanthan gum solution has a mass to volume concentration of 0.1 g/100mL.
Further, the speed of the vortex is 3000 rpm, and the time is more than or equal to 30s.
Further, the shade is 5-9%.
Further, the stirring speed is 2200 rpm, and the stirring time is more than or equal to 30 and s.
Further, the weight ratio of the redispersion medium to the test sample is 3-4:200.
Further, the limits of the measurement are specifically: d (0.1) is less than 40.0 mu m, d (0.5) is less than or equal to 60 mu m and less than or equal to 160 mu m, d (0.9) is less than or equal to 200 mu m and less than or equal to 300 mu m; taking d (0.1) < 40.0 μm as an example, d (0.1) < 40.0 μm represents that the particle size of the sample to be measured is 10% or less below 40 μm.
The invention has the technical effects that:
the invention uses the characteristic that azithromycin is dissolved under acidic condition and insoluble under neutral and alkaline conditions, a wet method is selected, the granularity of the azithromycin is measured by taking water as a pre-dispersion medium in the development process of the method, the pre-dispersion medium is optimized according to the test repeatability result, and 0.1-0.3% of xanthan gum is taken as the pre-dispersion medium, so that the granularity detection method with good repeatability is obtained.
Detailed Description
Other advantages and effects of the present invention will become apparent to those skilled in the art from the following disclosure, which describes the embodiments of the present invention with reference to specific examples. The invention may be practiced or carried out in other embodiments that depart from the specific details, and the details of the present description may be modified or varied from the spirit and scope of the present invention.
Before the embodiments of the invention are explained in further detail, it is to be understood that the invention is not limited in its scope to the particular embodiments described below; it is also to be understood that the terminology used in the examples of the invention is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention.
Where numerical ranges are provided in the examples, it is understood that unless otherwise stated herein, both endpoints of each numerical range and any number between the two endpoints are significant both in the numerical range. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It should be noted that the raw materials used in the present invention are all common commercial products, and therefore the sources thereof are not particularly limited.
The instrument and the reagent used in the invention specifically comprise:
instrument: a particle size analyzer, an electronic balance, and a vortex analyzer;
reagent: xanthan gum; the concentration of the xanthan gum solution is g/mL, and taking a 0.1% xanthan gum solution as an example, the mass volume concentration of the xanthan gum aqueous solution is 0.1 g/100mL.
Sample: azithromycin bulk drug, blank auxiliary material and Azithromycin dry suspension, purchased from the company of the sciences pharmaceutical company (hereinafter referred to as formulation, the specific raw materials comprise azithromycin dihydrate, sucrose, anhydrous trisodium phosphate, xanthan gum, hydroxypropyl cellulose, cherry powder essence, banana powder essence and vanilla powder essence).
Example 1
Table 1 test methods and parameters
The particle size is not significantly different when the shading degree is within the range of 5% -9%.
Table 2 test results
Note that: the light shielding degree of the blank auxiliary materials added into the sample cell after pre-dispersing is about 0.2%, and the light shielding degree is consistent with that of the dispersion medium, and cannot be measured.
Example 2
Table 3 test methods and parameters
Table 4 test results
Example 3
Table 5 test methods and parameters
TABLE 6 test results
Comparative example 1
The only difference from example 1 is that the pre-dispersion medium is replaced by an equal volume of water, corresponding to a 1-fold reduction in the concentration of the raw material sample. The same test sample was tested twice.
TABLE 7 test results
From the above table, water is taken as a pre-dispersion medium, the difference of the two measurement results of the same sample is large, the reproducibility is poor, the suspension of the sample is unstable, and the bulk drug is deposited at the bottom more quickly.
Comparative example 2
The only difference from example 1 is that the pre-dispersion medium is replaced by an equal volume of 0.5% xanthan solution.
Comparative example 3
The only difference from example 1 is that the redispersion medium is replaced by an equal volume of 0.1% xanthan gum solution.
Comparative example 4
The difference from example 1 is that the pre-dispersion medium is replaced with an equal volume of 0.1% tween 20 solution.
1. Repeatability of
Samples of each example (each using azithromycin drug) were taken, 6 samples were prepared in parallel for measurement, and RSD (n=6) was calculated to give the following table.
Table 8 example 1 repeatability test results and discussion
TABLE 9 repeatability test results for examples 2-3 and comparative examples 1-4
2. Intermediate precision
The same batch of samples (azithromycin drug substance is selected) was used, the influence on the test results was examined by different operators and different dates, 6 samples were prepared in parallel for measurement, RSD (n=6) was calculated, and RSD (n=12) was calculated for a total of 12 samples. The following table is obtained:
TABLE 10 intermediate precision results and conclusions for example 1
TABLE 11 intermediate precision results for examples 2-3 and comparative examples 1-4
In conclusion, the method for detecting the granularity has the advantages that the blank auxiliary materials have no interference to the granularity detection, the specificity is good, the reproducibility of granularity results of raw materials and preparations is good, the accuracy is high, and the requirement of the granularity detection of samples is met.
The same solvent water was used for the pre-dispersion medium and the re-dispersion medium in comparative example 1, and the same solvent 0.1% xanthan gum solution was used for the pre-dispersion medium and the re-dispersion medium in comparative example 3, so that the repeatability and intermediate precision effects were significantly lower than those of example 1, indicating that different solvents were necessary for the pre-dispersion medium and the re-dispersion medium to have better repeatability and intermediate precision effects.
In comparative example 2, the concentration of the xanthan gum solution is changed, the effect of repeatability and intermediate precision is obviously reduced, which indicates that the concentration of the xanthan gum solution has a great influence on the detection result, and the effect of repeatability and intermediate precision can be better only within a specific range.
The composition of the pre-dispersion medium is changed in comparative example 4, and as a result, the repeatability and the intermediate precision effects are obviously reduced, which means that not all the pre-dispersion medium can obtain good effects for detecting the granularity of azithromycin and related preparations, and the better repeatability and intermediate precision effects can be achieved only when a xanthan gum solution is used as the pre-dispersion medium.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.