Method for detecting particle size of aripiprazole raw material

Abstract

The invention discloses an aripiprazole raw material particle size detection method, and belongs to the technical field of drug detection. Technical breakthrough is realized through specific detection instrument type selection, key parameter optimization and system verification process construction: a new ParaThak laser particle analyzer equipped with an R5 measuring lens, an RODOS / M dispersion system and a VIBRI sample injector is selected, a standardized parameter system with dispersion pressure of 3.0 Bar, a sample injection rate of 70% and optical concentration of 5%-10% is determined, and the measurement accuracy of the system is improved. A complete detection process is formed through sample amount exploration, repeatability and precision verification. According to the present invention, with the core idea of determining the optical concentration control standard, optimizing the sample amount matching concentration and verifying the reliability of the method, the problem of poor optical concentration repeatability is solved, the stability and the accuracy of the detection data are significantly improved, and the reliable detection means is provided for the quality control of the aripiprazole raw material.

Description

Technical Field

[0001] This invention relates to the field of drug testing technology, specifically to a method for particle size detection of aripiprazole raw materials. Background Technology

[0002] Aripiprazole is a commonly used active ingredient in clinical psychotropic drugs. The particle size distribution of its raw materials directly determines the dissolution rate, bioavailability, and storage stability of the drug formulation. Therefore, particle size detection is a core component of the aripiprazole production quality control system, and it is directly related to the clinical efficacy and safety of the drug.

[0003] Currently, laser particle size analyzers are widely used in the industry to detect the particle size of aripiprazole raw materials. However, there are intractable technical bottlenecks in practical applications: when the same batch of samples is measured multiple times under the same testing conditions, the optical concentration data fluctuates drastically, and some test results exceed the normal error range allowed by the instrument, making it impossible to guarantee the reliability of the particle size distribution calculation results. Specifically, the instability of optical concentration causes two major problems: first, the risk of quality misjudgment, as particle size distribution data calculated based on fluctuating optical concentration may misjudge qualified samples as unqualified, or allow unqualified samples to evade detection, posing a serious threat to the quality control of drug production; second, low detection efficiency, as researchers need to repeatedly perform multiple tests and take averages to obtain relatively reliable results, which not only increases sample consumption and prolongs the testing cycle, but also reduces the overall efficiency of production quality control.

[0004] To address the aforementioned issues, existing technologies propose solutions such as forcibly setting optical concentration as an instrument parameter and enabling the instrument's optical concentration filtering function. However, this approach only passively corrects the detection data through instrument algorithms, failing to address the core causes of optical concentration fluctuations and thus unable to fundamentally solve the problem. In practical applications, the stability and accuracy of the detection results still cannot meet the stringent requirements of pharmaceutical production quality control.

[0005] Therefore, there is an urgent need to develop a method for detecting the particle size of aripiprazole raw materials to solve the problem of poor repeatability of optical concentration. Summary of the Invention

[0006] The purpose of this application is to overcome the shortcomings of existing technologies in aripiprazole raw material particle size detection, such as poor optical concentration repeatability, low reliability of detection data, and low detection efficiency. This application provides a method for aripiprazole raw material particle size detection, which includes four core parts: selection and calibration of detection instruments, sample pretreatment, optimization of detection parameter system, and construction of verification process. This method enables accurate and controllable particle size detection data and ensures the reliability and efficiency of drug production quality control.

[0007] This application provides a method for particle size detection of aripiprazole raw material, including the following steps:

[0008] S1: Turn on the new Partek laser particle size analyzer and calibrate it, then install the R5 measuring lens, RODOS / M dispersion system and VIBRI injector;

[0009] S2: Set the dispersion pressure to 3.0 Bar, the injection rate to 70%, and the optical concentration to 5%~10%;

[0010] S3: Conduct sample size exploration tests, repeatability verification tests, and precision verification tests in sequence.

[0011] Preferably, the calibration of the new Partek laser particle size analyzer uses standard latex microspheres, with a calibration error ≤ ±2%.

[0012] Preferably, the measurement range of the R5 measuring lens is 0.1μm to 875μm.

[0013] Preferably, the RODOS / M dispersion system employs a dry dispersion method, and the dispersion gas is clean compressed air.

[0014] In this configuration, the R5 measuring lens ensures full coverage detection of particles of different sizes; the RODOS / M dispersion system uses a dry dispersion method with clean compressed air as the dispersion gas, which can achieve uniform dispersion of sample particles and avoid particle agglomeration affecting the detection results; the VIBRI injector has an adjustable rate function to ensure the stability of the injection rate. The three components work together to provide a hardware foundation for detection accuracy.

[0015] Based on the principle of dry detection technology and combined with the professional advice of the engineers of Newpatek laser particle size analyzer, the target value of optical concentration for aripiprazole raw material particle size detection is 5%, the reasonable control range is 1%~10%, and the optimal sub-range is 5%~8%.

[0016] In this case, a lower limit of 1% can prevent weak detection signals and insufficient data acquisition due to excessively low optical concentration, while an upper limit of 10% can prevent particle agglomeration caused by excessively high concentration. The optimal sub-range of 5% to 8% can further improve the stability of the detection signal. During the detection process, the optical concentration is maintained within the optimal sub-range by fine-tuning the rate of the VIBRI injector.

[0017] Preferably, the sample quantity exploratory test involves selecting aripiprazole raw materials of 30mg, 100mg, 0.2g, 0.5g, and 1.0g as different gradient sample quantities, performing parallel tests on each gradient sample quantity, recording the optical concentration value and particle size detection results corresponding to each gradient sample quantity, and screening out the sample quantity with a stable optical concentration in the range of 5% to 10%.

[0018] Preferably, the repeatability verification test involves the same experimenter performing six consecutive tests on the same batch of aripiprazole raw material under the same testing conditions.

[0019] Preferably, the precision verification test involves two different researchers testing the same batch of aripiprazole raw materials at different times.

[0020] Preferably, in the repeatability verification test, the relative standard deviation (RSD) of optical concentration for 6 tests is ≤0.8%, and the relative standard deviation (RSD) of particle size characteristic parameters D10, D50, and D90 is ≤2%.

[0021] Preferably, in the precision verification test, the relative standard deviation (RSD) of optical concentration detected by each experimenter is ≤2.5%, and the relative standard deviation (RSD) of particle size characteristic parameters D10, D50, and D90 is ≤2.5%.

[0022] Preferably, the aripiprazole raw material needs to be pretreated before testing, and the moisture content of the pretreated sample is ≤0.5%.

[0023] In this case, a 200-mesh standard sieve is used to remove mechanical impurities and agglomerated particles from the sample. The sample is stirred for 5-10 minutes using a vortex mixer to ensure uniformity and avoid the interference of moisture on the dispersion effect and optical detection signal.

[0024] Beneficial technical effects:

[0025] This application utilizes a NewPatek laser particle size analyzer equipped with an R5 measuring lens, a RODOS / M dry dispersion system, and a VIBRI injector as hardware support. First, standard latex microsphere calibration ensures instrument accuracy. Then, sample pretreatment eliminates interference, thereby clarifying a reasonable control range for optical concentration. Key parameters such as sample weight, dispersion pressure, and injection rate are optimized to maintain stable optical concentration. Particle size characteristic parameters are calculated using laser diffraction and volume distribution models. Based on the determined sample weight and optical concentration range, the repeatability and precision of the detection method are verified, establishing a standardized process. This approach achieves precise and controllable detection data across the entire process—from instrumentation and sample selection to parameters and verification—avoiding concentration fluctuations and ensuring stable, reliable, efficient, and accurate detection data. Attached Figure Description

[0026] Figure 1 This is a flowchart of an aripiprazole raw material particle size detection method according to this application. Detailed Implementation

[0027] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions in the embodiments of this application will be clearly and completely described below. Obviously, the described embodiments are some embodiments of this application, but not all embodiments.

[0028] It should be understood that in the various embodiments of this application, the order of the above processes does not imply the order of execution. Some or all steps may be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of this application.

[0029] Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without inventive effort are within the scope of protection of this application.

[0030] The present invention will be further described below with reference to embodiments, but is not limited thereto.

[0031] Example 1

[0032] This embodiment provides a method for particle size detection of aripiprazole raw materials, including the following steps:

[0033] S1: Turn on the new Partek laser particle size analyzer and calibrate it, then install the R5 measuring lens, RODOS / M dispersion system and VIBRI injector;

[0034] S2: Set the dispersion pressure to 3.0 Bar, the injection rate to 70%, and the optical concentration to 1%~10%;

[0035] S3: Conduct sample size exploration tests, repeatability verification tests, and precision verification tests in sequence.

[0036] After powering on the New Patek laser particle size analyzer, preheat for 30 minutes until the instrument's optical system stabilizes and the temperature remains constant at 25±2℃ before calibration. Take a 0.1g sample of standard latex microspheres and spread them evenly in the sample slot of the VIBRI injector. Set the dispersion pressure to 2.0 Bar and the injection rate to 50%. Start the calibration program according to the instrument calibration operating procedure. Record the particle size detection value of the standard latex microspheres during the calibration process. Repeat the calibration 3 times. The calculated average detection value is 10.12μm, and the relative error is 1.2%, which meets the requirement of calibration error ≤±2%. The calibration is qualified, and the instrument can be used for testing.

[0037] Take 50.0g of aripiprazole raw material sample and slowly add it to a 200-mesh standard sieve. Sieve the sample using a manual vibrating sieve and collect the sample passing through the sieve. Weigh the residual impurities on the sieve; the mass is 0.03g, indicating an impurity removal rate ≥99.9%. Transfer the sieved sample to a 100mL clean glass container and place it in a vortex mixer. Set the speed to 2500rpm and stir for 10min to ensure uniform particle dispersion and no local agglomeration. Use a halogen moisture analyzer to determine the moisture content of the pretreated sample. Take three parallel samples (3.0000g each), set the detection temperature to 105℃, the heating rate to 10℃ / min, and the constant weight time to 5min. The moisture contents of the three samples were measured to be 0.32%, 0.35%, and 0.33%, respectively, with an average moisture content of 0.33%, meeting the pretreatment requirement of ≤0.5% moisture content.

[0038] Install the R5 measuring lens, RODOS / M dispersion system, and VIBRI injector; connect a clean compressed air source; and adjust the instrument to normal operating condition. The dispersion pressure is 3.0 Bar, the injection rate is 70%, the optical concentration detection range is 1%~10% (target value 5%), the particle size parameter calculation model is a volume distribution model, and the detection method is laser diffraction. For each sample, the instrument continuously acquires 10 sets of optical signal data, and the average value is taken as the final detection result to avoid the impact of single signal fluctuations on data accuracy.

[0039] In the sample quantity exploratory experiment, the pretreated aripiprazole raw material sample was accurately weighed using an electronic balance and divided into 5 gradient groups. The sample quantities for each group were: 30 mg (group 1), 100 mg (group 2), 0.2 g (group 3), 0.5 g (group 4), and 1.0 g (group 5). Three samples were prepared in parallel for each group. According to the set detection parameters, each group of samples was tested sequentially, with each sample tested once. The optical concentration value and particle size characteristic parameters (D10, D50, D90) were recorded. The optical concentration range, relative standard deviation (RSD) of optical concentration, and particle size parameter RSD of each group of samples were calculated. The results are shown in Table 1 below.

[0040] Table 1. Statistical analysis of test data for samples with different weights.

[0041]

[0042] As shown in Table 1, the optical concentration of Group 2 (100mg sample) is consistently within the reasonable range of 5% to 10%, and the RSD of the optical concentration is only 0.8%. The RSD of the particle size characteristic parameters (D10, D50, D90) are all ≤1.2%, which is significantly better than other sample weight groups. Therefore, 100mg is determined to be the optimal sample weight.

[0043] Accurately weigh 100 mg of pretreated aripiprazole raw material sample and prepare 6 parallel samples, labeled R1 to R6. The same experimenter will conduct tests on samples R1 to R6 sequentially under the same detection conditions (instrument, parameters, ambient temperature 25±2℃, humidity 45%~60%). Record the optical concentration and particle size characteristics of each sample, and calculate the RSD of each index. The results are shown in Table 2 below.

[0044] Table 2. Repeatability verification test data (n=6)

[0045]

[0046] As shown in Table 2, in the repeatability verification test, the optical concentration RSD was 0.8%, and the RSDs of particle size characteristic parameters D10, D50, and D90 were 1.2%, 1.0%, and 0.8%, respectively. All of these met the requirements of optical concentration RSD ≤ 0.8% and particle size parameter RSD ≤ 2%, indicating that the detection method has excellent repeatability.

[0047] Accurately weigh 100 mg of pretreated aripiprazole raw material sample and prepare 12 parallel samples, labeled as samples P1~P12. Two researchers performed the tests: researcher A tested samples P1~P6 on day 1, and researcher B tested samples P7~P12 on day 2, under the same testing conditions as the repeatability verification. Record the test data for both groups of samples and calculate the RSD of the test results for researchers A and B respectively. The results are shown in Table 3 below.

[0048] Table 3. Precision verification test data (n=6 / person)

[0049]

[0050] As shown in Table 3, the optical concentration RSDs for personnel A and personnel B are 1.1% and 1.3%, respectively, and the RSDs of particle size characteristic parameters D10, D50, and D90 are all ≤1.7%, which meets the requirement of RSD≤2.5%, indicating that the detection method has good precision.

[0051] Example 2

[0052] This embodiment provides a method for particle size detection of aripiprazole raw materials, including the following steps:

[0053] S1: Turn on the new Partek laser particle size analyzer and calibrate it, then install the R5 measuring lens, RODOS / M dispersion system and VIBRI injector;

[0054] S2: Set the dispersion pressure to 3.0 Bar, the injection rate to 70%, and the optical concentration to 1%~10%;

[0055] S3: Conduct sample size exploration tests, repeatability verification tests, and precision verification tests in sequence.

[0056] Three different production batches of aripiprazole raw materials were selected, and the specific information is as follows:

[0057] Batch 1: Purity 99.6%, initial moisture content 0.7%; Batch 2: Purity 99.8%, initial moisture content 0.6%; Batch 3: Purity 99.7%, initial moisture content 0.5%.

[0058] Three batches of samples were treated according to the sample pretreatment method in Example 1 to ensure that the moisture content was ≤0.5%. The optimal parameters were determined as follows: sample weight 100mg, dispersion pressure 3.0Bar, injection rate 70%, and optical concentration 5%~10%. Eight parallel tests were performed on each batch of samples. The optical concentration and particle size characteristic parameters (D10, D50, D90) of each test were recorded, and the RSD of each batch of samples was calculated. The experimental results are shown in Table 4.

[0059] Table 4. Statistical analysis of test results for different batches of samples (n=8)

[0060]

[0061] As shown in Table 4, after testing by the method of this invention, the optical concentration RSD of three different batches of aripiprazole raw materials were all ≤0.9%, and the RSD of particle size characteristic parameters D10, D50, and D90 were all ≤1.0%. The test data were stable and consistent, with no significant batch differences.

[0062] Example 3

[0063] This embodiment provides a method for particle size detection of aripiprazole raw materials, including the following steps:

[0064] S1: Turn on the new Partek laser particle size analyzer and calibrate it, then install the R5 measuring lens, RODOS / M dispersion system and VIBRI injector;

[0065] S2: Set the dispersion pressure to 3.0 Bar, the injection rate to 70%, and the optical concentration to 1%~10%;

[0066] S3: Conduct sample size exploration tests, repeatability verification tests, and precision verification tests in sequence.

[0067] Three different particle sizes of aripiprazole raw materials from the same manufacturer were selected. Specific information is as follows:

[0068] Fine-grained sample (S1), D50 = 20~30μm, purity 99.7%, initial moisture content 0.4%; medium-grained sample (S2), D50 = 35~45μm, purity 99.6%, initial moisture content 0.3%; coarse-grained sample (S3), D50 = 50~60μm, purity 99.8%, initial moisture content 0.5%.

[0069] Three batches of samples were pretreated according to the sample pretreatment method in Example 1 to ensure a moisture content ≤0.5%. The optimal parameters were determined: sample weight 100 mg, dispersion pressure 3.0 Bar, injection rate 70%, and optical concentration 5%–10%. Independent detection was performed, with 15 sets of optical signals collected for each sample and the average value taken. The optical concentration and particle size characteristic parameters (D10, D50, D90) of each particle size sample were recorded, and the RSD was calculated. The results are shown in Table 5 below.

[0070] Table 5. Statistical analysis of test data for samples with different particle sizes (n=6)

[0071]

[0072] As shown in Table 5, the method of the present invention has good compatibility with aripiprazole raw materials of fine particle size (20~30μm), medium particle size (35~45μm), and coarse particle size (50~60μm). The optical concentration of samples of the three particle sizes is stable within a reasonable range of 5%~10%, and the RSD of optical concentration is ≤0.9%. The RSD of particle size characteristic parameters D10, D50, and D90 is ≤1.3%.

[0073] In particular, embodiments 1-3 of this application define a scientifically controlled range for optical concentration (target value 5%, reasonable range 5%~10%, optimal sub-range 5%~8%), optimize the matching relationship between sample weight and detection parameters, and combine this with the rate adjustment of the VIBRI injector to stabilize the optical concentration within the optimal range. Multiple measurements show fluctuations of less than 1%, overcoming the limitations of passive correction in existing technologies. This significantly improves the accuracy and reliability of the detection data, effectively avoiding the quality risks of misjudging qualified samples or missing unqualified samples. The detection process is standardized and highly controllable, adding key steps such as instrument calibration (error ≤ ±2%) and sample pretreatment (moisture content ≤ 0.5%), and clarifying the basis for particle size parameter detection (laser diffraction method). The computational model (volume distribution) refines the personnel interval and number of tests for precision verification, forming a standardized operating procedure for the entire process, reducing human error and facilitating industry-wide application. Testing efficiency and economy are simultaneously improved; reliable results can be obtained without multiple repeated tests and averaging, and a single test can meet quality control requirements. This not only shortens the testing cycle but also reduces sample consumption, lowers testing costs, and improves the overall efficiency of production quality control. The parameter settings of the testing instrument and sample processing methods are optimized for the physical characteristics of aripiprazole raw materials. The test results can directly provide accurate data support for the dissolution, bioavailability, and stability control of drug formulations, ensuring the clinical efficacy and safety of the drug.

[0074] It should be understood that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be covered within the scope of the claims and specification of the present invention.

Claims

1. A method for detecting the particle size of aripiprazole raw material, characterized in that, Includes the following steps: S1: Turn on the new Partek laser particle size analyzer and calibrate it, then install the R5 measuring lens, RODOS / M dispersion system and VIBRI injector; S2: Set the dispersion pressure to 3.0 Bar, the injection rate to 70%, and the optical concentration to 5%~10%; S3: Conduct sample size exploration tests, repeatability verification tests, and precision verification tests in sequence.

2. The method for detecting the particle size of aripiprazole raw material according to claim 1, characterized in that, The new Partek laser particle size analyzer is calibrated using standard latex microspheres, with a calibration error ≤ ±2%.

3. The method for detecting the particle size of aripiprazole raw material according to claim 1, characterized in that, The R5 measuring lens has a measurement range of 0.1μm to 875μm.

4. The method for detecting the particle size of aripiprazole raw material according to claim 1, characterized in that, The RODOS / M dispersion system employs a dry dispersion method, using clean compressed air as the dispersion gas.

5. The method for detecting the particle size of aripiprazole raw material according to claim 1, characterized in that, The sample quantity exploratory test involved selecting aripiprazole raw materials of 30mg, 100mg, 0.2g, 0.5g, and 1.0g as different gradient sample quantities. Parallel tests were performed on each gradient sample quantity, and the optical concentration value and particle size detection results corresponding to each gradient sample quantity were recorded. The sample quantity with a stable optical concentration in the range of 5% to 10% was selected.

6. The method for particle size detection of aripiprazole raw material according to claim 1, characterized in that, The repeatability verification test was conducted by the same experimenter on the same batch of aripiprazole raw material under the same testing conditions, six times consecutively.

7. The method for detecting the particle size of aripiprazole raw material according to claim 1, characterized in that, The precision verification test involved two different researchers testing the same batch of aripiprazole raw materials at different times.

8. The method for detecting the particle size of aripiprazole raw material according to claim 1, characterized in that, In the repeatability verification test, the relative standard deviation (RSD) of optical concentration for 6 tests was ≤0.8%, and the relative standard deviation (RSD) of particle size characteristic parameters D10, D50, and D90 was ≤2%.

9. The method for detecting the particle size of aripiprazole raw material according to claim 1, characterized in that, In the precision verification test, the relative standard deviation (RSD) of optical concentration detected by each experimenter was ≤2.5%, and the relative standard deviation (RSD) of particle size characteristic parameters D10, D50, and D90 was ≤2.5%.

10. The method for detecting the particle size of aripiprazole raw material according to claim 1, characterized in that, The aripiprazole raw material needs to be pretreated before testing, and the moisture content of the pretreated sample is ≤0.5%.

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