Method for determining granularity of sorafenib tosylate bulk drug
By optimizing the parameters of dry laser scattering method, the accuracy and repetition of the particle size determination of sorafenib toluenesulfonate raw materials was solved, ensuring the stability and efficiency of the measurement results.
Patent Information
- Application Number
- CN202510356554.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-25
- Publication Date
- 2025-08-01
AI Technical Summary
The prior art is difficult to accurately measure the particle size of sorafenib toluenesulfonate raw materials, and there are problems such as electrostatic adsorption, cutting and light shading failure, resulting in unstable measurement results.
The dry laser scattering method was used, with the optimized dispersion pressure of 2.4 to 2.6 bar, the hopper gap was 1.2 to 1.4 mm, and the injection speed was 50% to 60%. The measurement was carried out in conjunction with the Mastersizer 3000, a Malvin laser particle size meter.
The accuracy and repetition of the particle size determination of sorafenib toluenesulfonate raw materials was achieved, the problems of difficulty in electrostatic adsorption and cutting were solved, and the stability and efficiency of measurement were improved.
Smart Images
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of analysis and detection, and particularly relates to a method for measuring the particle size of sorafenib tosylate raw material medicine. Background Art
[0002] Sorafenib tosylate tablets are an oral targeted therapy commonly used clinically to treat inoperable or metastatic hepatocellular carcinoma and inoperable advanced renal cell carcinoma. Its current dosage form is primarily tablets, and the particle size of the API is crucial to the tablet's preparation process, quality, and efficacy. Sorafenib tosylate API consists of irregular, flaky particles with a particle size range of 0.4-6μm. To ensure the uniformity of sorafenib tosylate API quality, a method for determining its particle size is required.
[0003] Particle size determination methods typically use either wet or dry methods, depending on the properties and solubility of the test sample. However, wet light scattering, a laser scattering method for measuring sorafenib tosylate, is difficult to find a suitable dispersion method. The API cannot be dispersed well, making accurate particle size measurement impossible. Existing dry laser scattering methods use conventional parameters (e.g., dispersion pressure 2.0-3.5 bar, hopper gap 1.0-2.0 mm, and injection rate 30%-60%). However, due to the unique properties of this API, these methods are prone to problems such as severe electrostatic adsorption, difficulty in dispensing, and substandard light shielding, resulting in unstable results.
[0004] Currently, there is no established method in the pharmaceutical industry that can accurately determine the particle size of sorafenib tosylate API. Therefore, it is crucial to develop a method with good repeatability, high accuracy, and ease of use for the particle size determination of sorafenib tosylate API. Summary of the Invention
[0005] In order to overcome the problems existing in the above-mentioned prior art, the purpose of the present invention is to provide a method for measuring the particle size of sorafenib tosylate raw material, which can effectively solve the problem of difficulty in dispersion caused by electrostatic adsorption and high viscosity after ultrafine grinding of the raw material.
[0006] In order to achieve the above object, the technical solution adopted by the present invention is:
[0007] The first aspect of the present invention provides a method for measuring the particle size of sorafenib tosylate raw material, which adopts a dry laser scattering method; the measurement parameters include: the measurement parameters include: the dispersion pressure is 2.4-2.6 bar, the hopper gap is 1.2-1.4 mm, and the injection speed is 50%-60%.
[0008] Preferably, the dispersion pressure is 2.4 to 2.5 bar.
[0009] Preferably, the hopper gap is 1.2-1.3 mm.
[0010] Preferably, the injection speed is 50% to 55%.
[0011] More preferably, the dispersion pressure is 2.4 to 2.5 bar, the hopper gap is 1.2 to 1.3 mm, and the injection speed is 50% to 55%.
[0012] More preferably, the injection speed is 50% to 51%.
[0013] In dry laser scattering, appropriate dispersion pressure provides sufficient energy to fully disperse particles in the airflow and prevent particle agglomeration due to interaction forces. If the dispersion pressure is too low, the particles may not be fully dispersed, resulting in an inflated measurement result because agglomerated particles may be mistaken for larger particles. However, excessive dispersion pressure may subject the particles to excessive impact forces, causing them to break. This is particularly true for fragile samples such as needles, rods, or flakes, as excessive pressure can easily break them up, resulting in an inflated measurement result.
[0014] In dry laser scattering, the hopper gap size determines the initial state of the sample as it enters the disperser. If the gap is too small, the sample will flow out, resulting in poor flow and potential accumulation in the hopper, affecting the continuity and stability of the injection. If the gap is too large, the sample may flow out too quickly, making it difficult to control the injection rate, which will also adversely affect the measurement results. Only by selecting the appropriate hopper gap can the sample enter the disperser at a uniform and stable rate, providing the prerequisite for accurate measurement.
[0015] In dry laser scattering, excessively high sample feed rates can prevent the sample from fully dispersing in the disperser before entering the measurement area. This reduces the dispersion efficiency of the sample feed device, increases particle agglomeration, and makes unloading difficult, impacting the accuracy of the measurement results. Furthermore, the sample feed rate directly affects the amount of sample entering the measurement area, which in turn affects the light shielding. If the sample feed rate is too fast, the light shielding may exceed the instrument's optimal measurement range. Excessive light shielding can exacerbate multiple diffraction phenomena, resulting in smaller measurement results. If the sample feed rate is too slow, the light shielding may be too low, resulting in an unrepresentative sample, which also affects the accuracy of the measurement results. This is because too little sample cannot accurately reflect the overall particle size distribution.
[0016] Moreover, parameters such as dispersion pressure, injection speed, and hopper gap are interrelated and affect each other. Therefore, there is a problem that multi-parameter coupling is complex and difficult to optimize. For example, the dispersion pressure affects the dispersion effect of particles, which in turn affects the injection speed and measurement accuracy; the injection speed is related to the hopper gap and also affects the obscuration rate and representativeness of the measurement results. A change in one parameter may cause a chain reaction in other parameters, making the optimization process complex and it is difficult to determine the optimal value of each parameter individually. In addition, the physical properties of different samples (such as particle size distribution, shape, hardness, degree of agglomeration, etc.) are different, and the requirements for parameters also vary. For some easily agglomerated samples, a higher dispersion pressure and appropriate injection speed may be required to achieve sufficient dispersion; while for fragile samples, excessive air pressure should be avoided to prevent particle breakage.
[0017] The present invention provides measurement parameters for sorafenib tosylate bulk drug, with a dispersion pressure of 2.4 - 2.5 bar, the hopper gap of 1.2 - 1.3 mm, and the injection speed of 50% - 55%. This can reduce electrostatic adsorption caused by agglomeration of bulk drug particles, ensure stable and continuous feeding, and at the same time enable the particles to be better dispersed in the air flow during the measurement process, improving the measurement accuracy, solving the problems of serious electrostatic adsorption and difficult feeding that are prone to occur, and the verification passing rate can be as high as 100%.
[0018] Preferably, the measurement parameters further include: the particle morphology of the bulk drug is irregular flaky, and the particle size is 0.4 - 6 μm.
[0019] Dry scattering laser uses light scattering technology to measure the size and distribution of particles. Its principle is to analyze the particle size based on the scattering pattern of particles in the laser beam. For ellipsoidal, cylindrical or flaky models, appropriate shape parameters can be selected to calculate the particle size distribution when analyzing data, and the calculation is relatively direct because there is a clear relationship between the scattering angle and the particle size for regular structures. In the present invention, the sorafenib tosylate bulk drug is irregular flaky, so using the conventional parameters of the existing dry laser scattering method for measurement will result in unstable measurement results. The present invention further optimizes the dispersion pressure, hopper gap, and injection speed according to the physical properties of the sorafenib tosylate bulk drug, and the obtained measurement method has good repeatability, high accuracy, and is easy to operate.
[0020] More preferably, the refractive index of the particles of the bulk drug is 1.52, and the absorption rate is 0.1.
[0021] Preferably, the measurement parameters further include: the sample amount is 0.5 - 1.0 g.
[0022] Preferably, the measurement parameters further include: the obscuration rate is 0.5% - 6%.
[0023] Preferably, the measurement parameters also include: measurement time of 5 - 15 s.
[0024] If the measurement duration in dry - method scattered laser is too long, the instrument may be interfered by some external factors, such as changes in environmental temperature and humidity, as well as the heat generation of the instrument itself. These factors may affect the stability of the instrument and then the accuracy of the measurement results. In the present invention, the detection time for sorafenib tosylate raw material medicine is only the measurement time of 5 - 15 s, which effectively shortens the measurement time on the premise of ensuring good repeatability and high accuracy of the measurement method.
[0025] Preferably, during the sample testing process, D10, D50, and D90 are used as particle size distribution characteristic values.
[0026] More preferably, the method for determining the dry - method verification standard includes: repeating the determination of 6 samples, continuously measuring each sample multiple times, and calculating the RSD% by taking the average value; the dry - method verification standard meets D10 < 15%, D50 < 10%, and D90 < 15%.
[0027] Preferably, a Malvern laser particle size analyzer Mastersizer 3000 is used as the measuring instrument for sample testing.
[0028] The second aspect of the present invention provides an application of the method for determining the particle size of sorafenib tosylate raw material medicine described in the first aspect in the quality control or production preparation of sorafenib tosylate raw material medicine.
[0029] The beneficial effects of the present invention are as follows:
[0030] The present invention has established a method for determining the particle size of sorafenib tosylate raw material medicine. By setting specially selected measurement parameters of dry - method laser scattering within a fixed range, an efficient particle size determination method development process has been established. There are correlations and influences among parameters such as dispersion air pressure, injection speed, and hopper gap, so there is a problem of complex multi - parameter coupling and difficulty in optimization. In view of the physical properties of sorafenib tosylate raw material medicine, the present invention specifically optimizes the dry - method determination method with multi - parameter coupling. The optimized determination method not only has high accuracy and good repeatability, and the results of repeatability and intermediate precision meet D10 < 15%, D50 < 10%, D90 < 15%, but also is simple to operate. It solves the problems of serious electrostatic adsorption of raw materials, difficult feeding, and non - compliance with light obscuration in the dry - method laser scattering method, can effectively improve the efficiency of preparation research and production, reduce the R & D cost, and ensure the uniformity of the quality of sorafenib tosylate raw material medicine. This method provides a reliable technical means for quality control in the production of sorafenib tosylate raw material medicine and process research in preparation development. Detailed implementation manners
[0031] The content of the present invention will be further described in detail through specific embodiments below. The raw materials used in the following embodiments can be obtained from conventional commercial channels or prepared and separated by simple synthesis, unless otherwise specified; the processes used, unless otherwise specified, are all conventional processes in the art.
[0032] Instruments and Reagents
[0033] The refractive index of the sorafenib tosylate API sample is 1.52, the absorption rate is 0.1, the particle morphology is irregular flakes, and the particle size range is 0.4 - 6 μm.
[0034] The Mastersizer 3000, a Malvern laser particle size analyzer, was used as the measuring instrument for sample testing.
[0035] Orthogonal Experiment Design
[0036] An experimenter used the dry light scattering method to determine the particle size of sorafenib tosylate API. The specific operation steps are as follows:
[0037] Weigh 0.5 g of the sorafenib tosylate API sample, and set parameters such as dry dispersion pressure, hopper gap, and injection speed in the Malvern 3000. The parameter settings are shown in Table 1; the measurement time is 10 s; the obscuration is 0.5% - 6%. The obtained results are shown in Table 1.
[0038] Table 1 Results of Orthogonal Experiment
[0039]
[0040] From the results of the orthogonal experiment in Table 1, it is also impossible to predict the influence of different levels of each factor on the experimental index. Further research was carried out on the experimental conditions with a dispersion pressure of 2.0 - 2.5 bar, a hopper gap of 1.3 - 1.5 mm, and an injection speed of 40% - 50%, as shown in Comparative Examples 1 - 3:
[0041] Comparative Example 1
[0042] An experimenter used the dry light scattering method to determine the particle size of sorafenib tosylate API. The specific operation steps are as follows:
[0043] Weigh 0.5 g of the sorafenib tosylate API sample, and set the dry dispersion pressure to 2.5 bar in the Malvern 3000; the hopper gap is 1.3 mm; the injection speed is 40%; the measurement time is 10 s; the obscuration is 0.5% - 6%. Using the above parameters, it is difficult to feed the material, not all of it can be injected, and the obscuration cannot meet the requirements, so measurement is impossible.
[0044] Therefore, the experimenter did not find the correct parameters for determining the particle size of sorafenib tosylate API.
[0045] Comparative Example 2
[0046] An experimenter used the dry light scattering method to determine the particle size of sorafenib tosylate raw material. The specific operation steps are as follows:
[0047] Weigh 0.5 g of sorafenib tosylate raw material sample. In Malvern 3000, set the dry dispersion pressure to 2.5 bar; the hopper gap to 1.5 mm; the injection speed to 50%; the measurement time to 10 s; and the obscuration to 0.5% - 6%. Using the above parameters, there was difficulty in feeding, not all samples could be injected, the obscuration did not meet the requirements, and measurement was impossible.
[0048] Therefore, the experimenter did not find the correct parameters for determining the particle size of sorafenib tosylate raw material.
[0049] Comparative Example 3
[0050] An experimenter used the dry light scattering method to determine the particle size of sorafenib tosylate raw material. The specific operation steps are as follows:
[0051] Weigh 0.5 g of sorafenib tosylate raw material sample. In Malvern 3000, set the dry dispersion pressure to 2.0 bar; the hopper gap to 1.3 mm; the injection speed to 50%; the measurement time to 10 s; and the obscuration to 0.5% - 6%. Using the above parameters, there was difficulty in feeding, not all samples could be injected, the obscuration did not meet the requirements, and measurement was impossible.
[0052] Therefore, the experimenter did not find the correct parameters for determining the particle size of sorafenib tosylate raw material.
[0053] Example 1
[0054] The same experimenter used the dry light scattering method to determine the particle size of the same batch of sorafenib tosylate raw material. The specific operation steps are as follows:
[0055] Weigh 0.5 g of sorafenib tosylate raw material sample. In Malvern 3000, set the dry dispersion pressure to 2.5 bar; the hopper gap to 1.3 mm; the injection speed to 50%; the measurement time to 10 s; and the obscuration to 0.5% - 6%. Using the above parameters, feeding was easy, all samples could be injected, and the measured data was stable and accurate.
[0056] Combining the orthogonal experimental design, Example 1, and Comparative Examples 1 - 3, Example 1 specifically optimized the experimentally coupled parameters, solving the problems of serious electrostatic adsorption of raw materials, difficult feeding, and non - compliant obscuration in the dry laser scattering method.
[0057] Repeatability and intermediate precision verification
[0058] Methodological verification was carried out on the method of Example 1: Six samples of the same batch were repeatedly measured, and the RSD% was calculated. Another experimenter repeatedly measured the six samples, and the RSD% of the 12 results was calculated together with the results of the six repeat experiments. Table 2 shows the results of the repeatability experiment of Example 1, and Table 3 shows the results of the intermediate precision experiment of Example 1.
[0059] Table 2 Results of the repeatability experiment
[0060] Sample D(10) D(50) D(90) 1 0.527 1.99 5.43 2 0.497 1.94 5.40 3 0.504 1.92 5.31 4 0.491 1.95 5.28 5 0.495 1.93 5.40 6 0.497 1.92 5.18 Average value 0.502 1.94 5.33 RSD / % 2.6 1.4 1.8
[0061] Table 3 Results of the intermediate precision experiment
[0062]
[0063]
[0064] From the experimental results in Table 2 and Table 3, it can be seen that the results of repeatability and intermediate precision meet the requirements of D10 < 15%, D50 < 10%, and D90 < 15%, indicating that the method has good repeatability and precision. If the distribution value is less than 10 μm, the requirement of multiplying the RSD value by 2 is met, and the dry method method verification is passed. Therefore, the method for determining the particle size of the sorafenib tosylate API in Example 1 can accurately determine the particle size of the API.
[0065] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.
Claims
1. A method for determining the particle size of sorafenib tosylate bulk drug, characterized in that, The determination method adopts the dry laser scattering method; The determination parameters include: the dispersion pressure is 2.4 - 2.6 bar, the hopper gap is 1.2 - 1.4 mm, and the sample injection speed is 50% - 60%.
2. The method for determining the particle size of sorafenib tosylate bulk drug according to claim 1, characterized in that, The dispersion pressure is 2.4 - 2.5 bar.
3. The method for determining the particle size of sorafenib tosylate bulk drug according to claim 1, characterized in that, The hopper gap is 1.2 - 1.3 mm.
4. The method for determining the particle size of sorafenib tosylate bulk drug according to claim 1, characterized in that, The sample injection speed is 50% - 55%.
5. The method for determining the particle size of sorafenib tosylate bulk drug according to claim 1, wherein The determination parameters also include: the particle morphology of the active pharmaceutical ingredient is irregular flaky, and the particle size is 0.4 - 6 μm.
6. The method for determining the particle size of sorafenib tosylate bulk drug according to claim 1, characterized in that, The determination parameters also include: the sample amount is 0.5 - 1.0 g.
7. The method for determining the particle size of sorafenib tosylate bulk drug according to claim 1, characterized in that, The determination parameters also include: the obscuration is 0.5% - 6%.
8. The method for determining the particle size of sorafenib tosylate bulk drug according to claim 1, wherein The determination parameters also include: the measurement time is 5 - 15 s.
9. The method for determining the particle size of sorafenib tosylate bulk drug according to claim 1, wherein During the sample test, D10, D50, and D90 are used as the particle size distribution characteristic values.
10. Use of the method for determining the particle size of sorafenib tosylate active pharmaceutical ingredient according to any one of claims 1 - 9 in the quality control or production preparation of sorafenib tosylate active pharmaceutical ingredient.