Rupatadine fumarate raw material particle size distribution detection method
Through wet detection and parameter optimization, the problem of cumbersomeness and large errors of the particle size detection method of Lupatadin fumarate raw material is solved, and the accurate particle size distribution measurement of substances with particle size less than 10μm is achieved, ensuring the scientificity of the detection and repeatability.
Patent Information
- Application Number
- CN202411027044.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-07-30
- Publication Date
- 2024-12-20
AI Technical Summary
The existing particle size detection method of Lupatading fumarate raw materials is complicated to operate and has large errors, which cannot meet the requirements of rapid detection and accuracy.
Wet detection method is adopted to disperse the mixture by ultrasonic and adjust the refractive index, shading and stirring rate. Combined with Mich's theory calculation, appropriate solvents such as n-hexane, cyclohexane, and n-heptane are selected to control the detection parameters to reduce measurements. Error ensures the scientificity and repeatability of the detection.
The detection method is optimized, the measurement error is reduced, the accuracy and repeatability of the detection is improved, and the particle size distribution measurement method requirements of the General Rule 0982 of the Chinese Pharmacopoeia are met, so as to achieve accurate particle size distribution measurement of substances with particle size less than 10μm.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of particle size distribution detection of rupatadine fumarate raw materials, and in particular to a method for detecting particle size distribution of rupatadine fumarate raw materials. Background Art
[0002] In the pharmaceutical industry, the particle size distribution (PSD) of powder and granular materials has become one of the key parameters that need to be considered in drug research and development and quality control. In particular, the PSD of APIs affects the quality of drugs, such as dissolution, bioavailability, content uniformity and stability, by affecting the fluidity, mixing uniformity and compressibility of the intermediate products output in the process, and ultimately affects the safety, effectiveness and quality controllability of drugs. Throughout the entire life cycle of drugs, the impact of material PSD on product quality should be included in the risk assessment system, and the drug PSD should be appropriately reflected in the material quality internal control standards, intermediate control standards or product quality standards, and risk assessment tools should be used to control drug quality and ensure production consistency.
[0003] At present, there are no patents or literature reports on particle size detection methods for rupatadine fumarate raw materials at home and abroad. The General Chapter 0982 of the "Chinese Pharmacopoeia" contains three general detection methods, including microscopy, screening, and light scattering. However, the microscopy method has a small sampling volume and is not representative. At the same time, the magnification is limited and sometimes cannot reflect the level of the entire sample; the screening method is generally divided into manual screening, mechanical screening, and air jet screening. Manual screening and mechanical screening are suitable for measuring most samples with a particle size greater than 75μm. The air jet screening method can be used to measure samples with a particle size less than 75μm, but it is impossible to test the three values of D10, D50, and D90 at the same time. It is necessary to replace the sieve and conduct repeated tests many times. The operation is cumbersome and the sample loss is large.
[0004] The light scattering method can calculate the particle size distribution based on Mie scattering theory and Fraunhofer approximation theory. The measurement range can reach 0.02-3500μm. The instrument used is a laser scattering particle size distribution analyzer, which is divided into dry method and wet method. The detection limit of dry method is usually 200nm, which does not meet the requirements, while the detection limit of wet method is usually 20nm, which meets the requirements. The general detection method in the pharmacopoeia lacks specific experimental parameter guidance.
[0005] In view of the above-mentioned related technologies, the inventors found that the existing method for detecting the particle size of rupatadine fumarate raw materials is complicated to operate and has large errors, and cannot meet the requirements of rapid detection and use. Summary of the invention
[0006] In order to improve the defects of the existing method for detecting the particle size distribution of rupatadine fumarate raw materials, which is complicated to operate and has large errors, the present application provides a method for detecting the particle size distribution of rupatadine fumarate raw materials.
[0007] A method for detecting particle size distribution of rupatadine fumarate raw materials, characterized by comprising the following testing steps: The rupatadine fumarate raw material to be tested is mixed with a solvent, ultrasonically dispersed, and the dispersed mixed liquid is collected; The dispersed mixed liquid is taken and placed in a particle size detection device. The wet detection method is adopted. The detection parameters are set. After adjusting the refractive index, shading degree and stirring rate, the particle size distribution is measured. The RSD% of the numerical results of the particle size D10, D50 and D90 of the rupatadine fumarate raw material is detected, and the analysis and detection of the particle size distribution of the rupatadine fumarate raw material can be completed.
[0008] Through the above technical solution, this application optimizes the detection method. After selecting the particle size detection device, the parameters are adjusted and the appropriate solvent is selected based on the Mie theory calculation, so that the detection requirements meet the requirements of the "Chinese Pharmacopoeia" General Chapter 0982 Particle Size and Particle Size Distribution Determination Method: When measuring the particle size distribution of materials with a particle size of less than 10μm, in order to reduce the measurement error, the Mie theory calculation results should be used. The method established by this application is verified to ensure the scientificity, accuracy and repeatability of this method.
[0009] Furthermore, the solvent includes at least one of n-hexane, cyclohexane and n-heptane.
[0010] By controlling the single variable method (sample sampling amount, ultrasonic time, stirring speed and scanning time remain unchanged), experiments were carried out in solvents such as dichloromethane, cyclohexane, n-hexane, n-heptane and n-octane to minimize the data fitting difference of the small-angle detector and make the weighted residual value less than 1%, thereby selecting a suitable solvent.
[0011] Furthermore, the ultrasonic dispersion time is 2-5 min.
[0012] Furthermore, the adjustment range of the refractive index is 1.385~1.410.
[0013] Furthermore, the shading degree ranges from 10-20%.
[0014] Furthermore, the shading degree ranges from 12 to 14%.
[0015] Furthermore, the stirring rate is 1500r / min~2200r / min.
[0016] Furthermore, the RSD% is less than 10%.
[0017] Through the above technical scheme, the present application adopts the principle of controlling variables to screen appropriate parameters, improves the rate at which the sample enters the detection device by selecting a suitable stirring rate, and then adjusts the shading degree and scanning time to prevent the scanning time from being too short, which may lead to unstable results and excessive differences, and the scanning time from being too long, which may cause bubbles and material agglomeration. The various parameters optimized in this application have been verified by analytical methods, and repeatability, intermediate precision and durability tests have been carried out. This method can meet the repeatability (6 samples D50 results RSD% <10%, D10 results RSD% and D90 results RSD% <15%), intermediate precision and durability test requirements.
[0018] In summary, this application has the following beneficial effects: First, this application optimizes the detection method. After selecting a particle size detection device, the parameters are adjusted and the appropriate solvent is selected based on the Mie theory, so that the detection requirements meet the requirements of the Chinese Pharmacopoeia General Chapter 0982 Particle Size and Particle Size Distribution Determination Method: When measuring the particle size distribution of materials with a particle size of less than 10μm, in order to reduce measurement errors, the Mie theory calculation results should be used. The method established in this application is verified to ensure the scientificity, accuracy and repeatability of this method.
[0019] Second, the present application controls the single variable method (sample sampling amount, ultrasonic time, stirring speed and scanning time remain unchanged) and conducts experiments in solvents such as dichloromethane, cyclohexane, n-hexane, n-heptane and n-octane, so that the data fitting difference of the small angle detector is minimized and the weighted residual value is less than 1%, thereby selecting a suitable solvent.
[0020] Third, this application adopts the principle of controlling variables to screen appropriate parameters. By selecting a suitable stirring rate, the rate at which the sample enters the detection device is improved, and then the shading degree and scanning time are adjusted to prevent the scanning time from being too short, which may lead to unstable results and excessive differences. The scanning time is too long, which may cause bubbles and material agglomeration. The parameters optimized in this application are verified by analytical methods, and repeatability, intermediate precision and durability tests are carried out. This method can meet the repeatability (RSD% of D50 results of 6 samples is less than 10%, RSD% of D10 results and RSD% of D90 results are less than 15%), intermediate precision and durability test requirements. DETAILED DESCRIPTION
[0021] The present application is further described in detail below with reference to the embodiments.
[0022] In the examples of the present application, the raw materials and instruments used are as follows, but not limited thereto: Instrument: Malvern Mastersizer 3000 laser particle size analyzer The present application is further described in detail below in conjunction with embodiments.
[0023] Example 1 Jiangsu Haici Biopharmaceutical Co., Ltd. of Zijiang Pharmaceutical Group, Urquima SA, and J.Uriach & Cia., SA were selected as raw materials for determination, and the determination method of this application was adopted, including the following test steps: 50 mg of the rupatadine fumarate raw material to be tested was mixed with 50 mL of n-heptane, and ultrasonically dispersed for 5 minutes and the dispersed mixed liquid was collected; The dispersed mixed liquid was taken and placed in a particle size detection device. The wet detection method was adopted. The detection parameters were set, and the refractive index was adjusted to 1.397, the number of measurements was 3 times, the lower limit of shading was 12%, the upper limit of shading was 14%, and the stirring rate was 2000r / min. Then, the particle size distribution was measured. The RSD% of the numerical results of the particle size D10, D50, and D90 of the rupatadine fumarate raw material was detected, and the analysis and detection of the particle size distribution of the rupatadine fumarate raw material was completed.
[0024] Example 2 Jiangsu Haici Biopharmaceutical Co., Ltd. of Zijiang Pharmaceutical Group, Urquima SA, and J.Uriach & Cia., SA were selected as raw materials for determination, and the determination method of this application was adopted, including the following test steps: 50 mg of the rupatadine fumarate raw material to be tested was mixed with 50 mL of n-hexane, ultrasonically dispersed for 5 minutes and the dispersed mixed liquid was collected; The dispersed mixed liquid was taken and placed in a particle size detection device. The wet detection method was adopted. The detection parameters were set, and the refractive index was adjusted to 1.385, the number of measurements was 3 times, the lower limit of shading was 10%, the upper limit of shading was 16%, and the stirring rate was 1500r / min. Then, the particle size distribution was measured. The RSD% of the numerical results of the particle size D10, D50, and D90 of the rupatadine fumarate raw material was detected, and the analysis and detection of the particle size distribution of the rupatadine fumarate raw material was completed.
[0025] Example 3 Jiangsu Haici Biopharmaceutical Co., Ltd. of Zijiang Pharmaceutical Group, Urquima SA, and J.Uriach & Cia., SA were selected as raw materials for determination, and the determination method of this application was adopted, including the following test steps: 50 mg of the rupatadine fumarate raw material to be tested was mixed with 50 mL of cyclohexane, and ultrasonically dispersed for 2 minutes and the dispersed mixed liquid was collected; The dispersed mixed liquid was taken and placed in a particle size detection device. The wet detection method was adopted. The detection parameters were set, and the refractive index was adjusted to 1.410, the number of measurements was 3 times, the lower limit of shading was 14%, the upper limit of shading was 20%, and the stirring rate was 2200r / min. Then, the particle size distribution was measured. The RSD% of the numerical results of the particle size D10, D50, and D90 of the rupatadine fumarate raw material was detected, and the analysis and detection of the particle size distribution of the rupatadine fumarate raw material was completed.
[0026] Comparative Example Comparative Example 1 Jiangsu Haici Biopharmaceutical Co., Ltd. of Zijiang Pharmaceutical Group, Urquima SA, and J.Uriach & Cia., SA were selected as raw materials for determination, and the determination method of this application was adopted, including the following test steps: 50 mg of the rupatadine fumarate raw material to be tested was mixed with 50 mL of cyclohexane, and ultrasonically dispersed for 5 minutes and the dispersed mixed liquid was collected; The dispersed mixed liquid was taken and placed in a particle size detection device. The wet detection method was adopted. The detection parameters were set, and the refractive index was adjusted to 1.450, the number of measurements was 3 times, the lower limit of shading was 10%, the upper limit of shading was 20%, and the stirring rate was 2000 / min. Then, the particle size distribution was measured. The RSD% of the numerical results of the particle size D10, D50, and D90 of the rupatadine fumarate raw material was detected, and the analysis and detection of the particle size distribution of the rupatadine fumarate raw material was completed.
[0027] Comparative Example 2 Jiangsu Haici Biopharmaceutical Co., Ltd. of Zijiang Pharmaceutical Group, Urquima SA, and J.Uriach & Cia., SA were selected as raw materials for determination, and the determination method of this application was adopted, including the following test steps: 50 mg of the rupatadine fumarate raw material to be tested was mixed with 50 mL of n-heptane, and ultrasonically dispersed for 5 minutes and the dispersed mixed liquid was collected; The dispersed mixed liquid was taken and placed in a particle size detection device. The wet detection method was adopted. The detection parameters were set, and the refractive index was adjusted to 1.397, the number of measurements was 3 times, the lower limit of shading was 6%, the upper limit of shading was 10%, and the stirring rate was 2000 / min. Then, the particle size distribution was measured. The RSD% of the numerical results of the particle size D10, D50, and D90 of the rupatadine fumarate raw material was detected, and the analysis and detection of the particle size distribution of the rupatadine fumarate raw material was completed.
[0028] Comparative Example 3 Jiangsu Haici Biopharmaceutical Co., Ltd. of Zijiang Pharmaceutical Group, Urquima SA, and J.Uriach & Cia., SA were selected as raw materials for determination, and the determination method of this application was adopted, including the following test steps: 50 mg of the rupatadine fumarate raw material to be tested was mixed with 50 mL of n-heptane, and ultrasonically dispersed for 3 minutes and the dispersed mixed liquid was collected; The dispersed mixed liquid was taken and placed in a particle size detection device. The wet detection method was adopted. The detection parameters were set, and the refractive index was adjusted to 1.397, the number of measurements was 3 times, the lower limit of shading was 10%, the upper limit of shading was 20%, and the stirring rate was 2500 / min. Then, the particle size distribution was measured. The RSD% of the numerical results of the particle size D10, D50, and D90 of the rupatadine fumarate raw material was detected, and the analysis and detection of the particle size distribution of the rupatadine fumarate raw material was completed.
[0029] Performance Testing The test results in Examples 1-3 and Comparative Examples 1-3 were recorded, and the record table is as follows: Table 1 Example 1 Record Table
[0030] Table 2 Example 2 Record Table
[0031] Table 3 Example 3 Record Table
[0032] Table 4 Comparative Example 1 Record Table
[0033] Table 5 Comparative Example 2 Record Table
[0034] Table 6 Comparative Example 3 Record Table
[0035] As can be seen from Tables 1-6 above, the RSD of the test results of Examples 1-3 of the present application is less than 10%, and the method is accurate and effective, while the test results of D10, D50, and D90 used in the test schemes of Comparative Examples 1-3 are not in compliance with the standard, which further illustrates that the present application optimizes the detection method, and after selecting a particle size detection device, the parameters are adjusted and a suitable solvent is selected based on the Mie theory calculation, so that the detection requirements meet the requirements of the "Chinese Pharmacopoeia" General Chapter 0982 Particle Size and Particle Size Distribution Determination Method: When measuring the particle size distribution of a substance with a particle size of less than 10 μm, in order to reduce the measurement error, the Mie theory calculation result should be used. The method established by the present application is verified to ensure the scientificity, accuracy, and repeatability of this method.
[0036] The present invention has been described in detail above in conjunction with specific implementations and exemplary examples, but these descriptions cannot be understood as limiting the present invention. Those skilled in the art understand that, without departing from the spirit and scope of the present invention, a variety of equivalent substitutions, modifications or improvements may be made to the technical solution of the present invention and its implementation methods, all of which fall within the scope of the present invention. The scope of protection of the present invention shall be subject to the attached claims.
[0037] All publications, patent applications, patents and other references mentioned in this specification are incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used in this specification have the meanings conventionally understood by those skilled in the art. In the event of a conflict, the definition in this specification shall prevail.
[0038] When this specification uses the prefix "well-known to those skilled in the art", "prior art" or similar terms to introduce materials, substances, methods, steps, devices or components, etc., the objects introduced by the prefix cover those commonly used in the art when this application is filed, but also include those that are not commonly used at present but will become recognized in the art as being suitable for similar purposes.
[0039] In the context of the present specification, any matters or items not mentioned are directly applicable to those known in the art without any changes except those explicitly stated.
Claims
1. A method for detecting particle size distribution of rupatadine fumarate raw materials, characterized in that: The test steps include: The rupatadine fumarate raw material to be tested is mixed with a solvent, ultrasonically dispersed, and the dispersed mixed liquid is collected; The dispersed mixed liquid is taken and placed in a particle size detection device. The wet detection method is adopted. The detection parameters are set. After adjusting the refractive index, shading degree and stirring rate, the particle size distribution is measured. The RSD% of the numerical results of the particle size D10, D50 and D90 of the rupatadine fumarate raw material is detected, and the analysis and detection of the particle size distribution of the rupatadine fumarate raw material can be completed.
2. The method for detecting particle size distribution of rupatadine fumarate raw material according to claim 1, characterized in that: The solvent includes at least one of n-hexane, cyclohexane and n-heptane.
3. The method for detecting particle size distribution of rupatadine fumarate raw material according to claim 1, characterized in that: The ultrasonic dispersion time is 2-5 min.
4. The method for detecting particle size distribution of rupatadine fumarate raw material according to claim 1, characterized in that: The adjustment range of the refractive index is 1.385~1.
410.
5. The method for detecting particle size distribution of rupatadine fumarate raw material according to claim 1, characterized in that: The range of the shading degree is 10-20%.
6. The method for detecting particle size distribution of rupatadine fumarate raw material according to claim 5, characterized in that: The range of the shading degree is 12~14%.
7. The method for detecting particle size distribution of rupatadine fumarate raw material according to claim 5, characterized in that: The stirring rate is 1500r / min~2200r / min.
8. The method for detecting particle size distribution of rupatadine fumarate raw material according to claim 5, characterized in that: The RSD% was less than 10%.