A method for measuring the particle size of a pharmaceutical excipient magnesium stearate

Abstract

This invention relates to the field of pharmaceutical analysis technology, and in particular to a method for determining the particle size of magnesium stearate, a pharmaceutical excipient. The method is a wet light scattering method, comprising the following steps: (1) preparing a magnesium stearate suspension; (2) after setting the measurement parameters of a laser particle size analyzer, adding a dispersion medium containing a surfactant, measuring the background, slowly adding the magnesium stearate suspension until the occlusion reaches a preset range, and starting the measurement; (3) statistically analyzing the measurement results to obtain the particle size and particle size distribution. This method has high accuracy, good repeatability, and wide applicability, solving the problem of effectively determining the particle size and particle size distribution of magnesium stearate, a pharmaceutical excipient, filling the current gap in methods for determining the particle size and particle size distribution of magnesium stearate in the pharmaceutical field, and providing a guarantee for reducing the difficulty of drug quality control and improving drug development efficiency.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical analysis technology, and in particular to a method for determining the particle size of magnesium stearate, a pharmaceutical excipient. Background Technology

[0002] Magnesium stearate is a mixture of magnesium and stearic acid, with magnesium stearate and magnesium palmitate as the main components. Its molecular formula is C2. 36 H 70 MgO4 has a molecular weight of 591.24 and the structural formula [CH3(CH2)]. 16 [COO]2Mg. Magnesium stearate is an excellent pharmaceutical excipient. It is a white, light, and non-gritty fine powder. It is generally used as a lubricant, anti-adhesion agent, and flow aid in pharmaceutical preparations such as tablets and capsules. It is particularly suitable for granulation of oils and extracts. The granules produced have excellent flowability and compressibility. It can also be used as a filter aid, clarifying agent, and foaming agent, as well as a suspending agent and thickener for liquid preparations.

[0003] Particle size and particle size distribution are key material properties of specialty and functional pharmaceutical excipients, as well as poorly soluble drug raw materials, and serve as important control and evaluation indicators in drug development. The particle size and particle size distribution of specialty and functional excipients often affect drug manufacturing processes and formulation properties, such as particle flowability, tablet compressibility, and dissolution and release of solid dosage forms.

[0004] Currently, the Chinese Pharmacopoeia (2020 edition) includes microscopy, sieving, and light scattering methods for determining particle size and particle size distribution. Among these, light scattering offers high accuracy and precision. Its principle involves the scattering of light when a monochromatic beam of light strikes the particle sample. Since the energy distribution of the scattered light is related to the particle size, the particle size distribution can be calculated by measuring the energy distribution (scattering angle) of the scattered light and applying Mie scattering theory and the Fraunhofer approximation. The measurement range of light scattering can reach 0.02–3500 μm. The instrument used is a laser scattering particle size analyzer. The determination method is divided into wet and dry methods. Wet methods are used for determining suspended samples or samples insoluble in a dispersion medium, while dry methods are used for determining water-soluble or solid samples without a suitable dispersion medium. Wet methods provide more accurate results and are material-saving, safe, and environmentally friendly; dry methods are simple to operate but require larger quantities of material and pose risks of noise and environmental pollution.

[0005] Magnesium stearate from different sources and manufacturers exhibits diverse physical properties, such as particle size, specific surface area, crystal structure, moisture content, and fatty acid composition. Magnesium stearate possesses a large specific surface area and strong hydrophobicity, and when used as a pharmaceutical excipient in formulations, it can significantly influence the flowability, compressibility, and dissolution behavior of drugs. The particle size and particle size distribution of magnesium stearate directly determine its specific surface area and hydrophobicity. Magnesium stearate is included in the pharmacopoeias of many countries, and both the Chinese Pharmacopoeia and the European Pharmacopoeia require the specification of its particle size distribution range.

[0006] Currently, the published methods for determining the particle size and particle size distribution of magnesium stearate are the sieving method reported in the food additive quality control standards. This method is simple to operate but inefficient, requiring manual weighing and calculation. Furthermore, it demands large quantities of sample, is highly sensitive to environmental humidity, and the results are relatively inaccurate and have poor reproducibility. To reduce the difficulty of drug quality control and improve drug development efficiency, it is essential to develop a highly accurate, reproducible, and widely applicable method for determining the particle size and particle size distribution of magnesium stearate, a pharmaceutical excipient. Summary of the Invention

[0007] The main objective of this invention is to provide a method for determining the particle size and particle size distribution of magnesium stearate, a pharmaceutical excipient. This method is highly accurate, has good repeatability, and is widely applicable. It aims to solve the problem of effectively determining the particle size and particle size distribution of magnesium stearate, a pharmaceutical excipient, and to provide a guarantee for reducing the difficulty of drug quality control and improving drug development efficiency.

[0008] This invention provides a method for determining the particle size and particle size distribution of magnesium stearate, a pharmaceutical excipient, using a wet light scattering method.

[0009] Furthermore, the detection instrument for the wet light scattering method is a laser particle size analyzer.

[0010] Furthermore, the laser particle size analyzer measures parameters including non-spherical particle type, a dispersion medium refractive index of 1.33, and a particle density of 1.028 g / cm³. 3 .

[0011] Furthermore, the measurement parameters also include a particle refractive index of 1.40 to 1.50 and a particle absorbance of 0.01 to 0.1.

[0012] Preferably, the particle has a refractive index of 1.45 and an absorbance of 0.01.

[0013] Furthermore, the measurement parameters also include a sample injector stirring speed of 1200 rpm to 1800 rpm.

[0014] Preferably, the stirring speed of the injector is 1500 rpm.

[0015] Furthermore, the measurement parameters also include the following: before measurement, the ultrasonic method is 30-90 seconds, and the ultrasonic intensity is 10-20%.

[0016] Preferably, the ultrasound method involves an ultrasound duration of 60 seconds and an ultrasound intensity of 15% before measurement.

[0017] Furthermore, the measurement parameters also include background and sample measurement time of 5–20 seconds.

[0018] Preferably, the background and sample measurement time is 10 seconds.

[0019] Furthermore, the measurement parameters also include a light-blocking range of 5% to 20%.

[0020] Preferably, the light-blocking degree ranges from 8% to 15%.

[0021] Furthermore, the method for determining the particle size and particle size distribution of the pharmaceutical excipient magnesium stearate includes the following steps:

[0022] (1) Prepare magnesium stearate suspension;

[0023] (2) Determination of magnesium stearate particle size and particle size distribution: Operate according to the operating procedure of the laser particle size analyzer, select the automatic measurement mode, set the instrument measurement parameters, add the dispersion medium to the dispersion cell of the sampler, and after the background measurement, slowly add the magnesium stearate suspension until the light shading reaches the preset range, and then automatically perform the measurement.

[0024] (3) Statistical analysis of the measurement results yielded the results of particle size and particle size distribution.

[0025] Furthermore, the magnesium stearate suspension is composed of magnesium stearate and solvent B, and the concentration of magnesium stearate in the suspension is 0.5-1.5% W / V.

[0026] Preferably, the concentration of magnesium stearate in the suspension is 1% W / V.

[0027] Furthermore, the dispersion medium in the wet light scattering method described in step (2) is purified water or ultrapure water.

[0028] Preferably, the dispersion medium in the wet light scattering method is ultrapure water.

[0029] Furthermore, the dispersion medium contains a surfactant.

[0030] Furthermore, the surfactant includes, but is not limited to, Tween 80, sodium dodecyl sulfate, sodium hexametaphosphate, etc.

[0031] Preferably, the surfactant is Tween 80.

[0032] Further, the concentration of the surfactant is 0.001 to 0.01% W / W; more preferably, the concentration of the surfactant is 0.004 to 0.006% W / W; even more preferably, the concentration of the surfactant is 0.005% W / W.

[0033] Furthermore, in step (3), d(0.1), d(0.5), and d(0.9) are used as particle size distribution characteristic values. The values ​​d(0.1), d(0.5), and d(0.9) represent the particle size of 10%, 50%, and 90% of the volume of the particle size distribution curve, respectively, which are smaller than these values.

[0034] Furthermore, the instrument software used for the statistical analysis of the results in step (3) is the instrument-compatible analysis software.

[0035] The present invention also provides an application of the method for determining the particle size and particle size distribution of the magnesium stearate.

[0036] The beneficial effects of this invention are:

[0037] This invention proposes a method for determining the particle size and particle size distribution of magnesium stearate, a pharmaceutical excipient. A dispersion medium containing an appropriate surfactant concentration was selected to ensure effective dispersion of the magnesium stearate without dissolution. A magnesium stearate suspension of suitable concentration was chosen to prevent excessive or insufficient sample addition and to ensure that the solvent does not interfere with the detection. The parameters of the laser particle size analyzer were screened and optimized. All operations and instrument parameters must be within the range determined after screening and optimization to ensure the accuracy and stability of the method. The determination method provided by this invention has good results in determining the particle size of magnesium stearate from different manufacturers and sources. This method has high accuracy, good repeatability, and wide applicability, solving the problem of effectively determining the particle size and particle size distribution of magnesium stearate, a pharmaceutical excipient. It fills the gap in current methods for determining the particle size and particle size distribution of magnesium stearate in the pharmaceutical field, and provides a guarantee for reducing the difficulty of drug quality control and improving drug development efficiency. Attached image description:

[0038] Figure 1 This is a particle size distribution diagram of magnesium stearate with batch number F21a220101 (Huzhou Zhanwang). Detailed Implementation

[0039] To illustrate this invention, the following embodiments and accompanying drawings will be used to provide a detailed description of this application.

[0040] The following examples and experiments are helpful in understanding the present invention, but the specific embodiments described herein are only for explaining the present invention and are not intended to limit the scope of this application.

[0041] Example 1

[0042] In the method for determining the particle size and particle size distribution of magnesium stearate provided by this invention, the magnesium stearate sample is added in the form of a suspension, and the solvent of the suspension is anhydrous ethanol. This embodiment details the particle size determination of a batch of magnesium stearate under different suspension concentrations, as follows:

[0043] Magnesium stearate from batch number F21a220101 (Huzhou Zhanwang) was used to prepare suspensions of different concentrations with anhydrous ethanol. The particle size was determined using the method provided in this invention. The average value and relative standard deviation (RSD) of d(0.1), d(0.5), and d(0.9) for six repeated measurements were statistically analyzed. The procedure is as follows:

[0044] (1) Preparation of magnesium stearate suspension: Weigh four 0.5g portions of magnesium stearate and add 200mL, 100mL, 50mL and 25mL of anhydrous ethanol respectively. Stir with a magnetic stirrer to disperse evenly to obtain magnesium stearate suspension with a concentration of 0.5-2% W / V. Stir continuously until ready for testing.

[0045] (2) Determination of magnesium stearate particle size and particle size distribution: The operation was carried out according to the operating procedures of the Mastersizer 3000 laser particle size analyzer. The automatic measurement mode was selected, and the instrument parameters were set as follows: particle type: non-spherical; refractive index of dispersion medium: 1.33; particle refractive index: 1.45; particle absorbance: 0.01; particle density: 1.028 g / cm³. 3 The syringe stirring speed was 1500 rpm, the ultrasonic method was used before measurement, the ultrasonic time was 60 s, the ultrasonic intensity was 15%, the background measurement time and sample measurement time were 10 s, the occlusion range was 8-15%, and the number of cycle measurements was 6. 500 mL of dispersion medium consisting of ultrapure water and Tween 80 (0.005% W / W) was added to the syringe dispersion cell. After background measurement, the test sample suspension was slowly added until the occlusion status bar turned green, at which point the measurement was performed automatically.

[0046] (3) Statistical analysis of test results: The particle size and particle size distribution of the test sample were obtained by software calculation and analysis, as shown in Table 1. The results show that when the concentration of magnesium stearate suspension is 0.25% W / V, the particle size of magnesium stearate was repeatedly measured 6 times. The RSDs of d(0.5) and d(0.9) were higher than 10% and 15%, respectively, which did not meet the standard requirements (acceptance standard: RSDs of d(0.1) and d(0.9) less than 15%, and RSDs of d(0.5) less than 10%). That is, in order to ensure that the light-blocking degree of the test sample suspension meets the requirements at a low concentration, the amount of anhydrous ethanol solvent added was too large, which had an adverse effect on the particle size determination. When the concentration of magnesium stearate suspension is 0.5-2% W / V, the particle size of magnesium stearate was repeatedly measured 6 times. The RSDs of d(0.1), d(0.5), and d(0.9) were not higher than 4.41%, which met the standard requirements. Among them, the RSD was the smallest when the concentration of magnesium stearate suspension was 1% W / V. However, when the concentration of magnesium stearate suspension is 2% W / V or higher, it will affect the control of the amount added, and the light-blocking degree is very likely to exceed the set range during the dripping process.

[0047] Table 1: Results of particle size distribution determination under different magnesium stearate suspension concentrations

[0048]

[0049] Example 2

[0050] In the method for determining the particle size and particle size distribution of magnesium stearate provided by this invention, the dispersion medium contains the surfactant Tween 80. This embodiment details the particle size determination of a batch of magnesium stearate in dispersion media under different surfactant Tween 80 concentrations, as follows:

[0051] Magnesium stearate with batch number F21a220101 (Huzhou Zhanwang) was used to determine the particle size in dispersion media under different surfactant Tween 80 concentrations using the method provided in this invention. The average value and relative standard deviation (RSD) of d(0.1), d(0.5), d(0.9) and opacity were statistically analyzed for six repeated measurements. The implementation is as follows:

[0052] (1) Preparation of magnesium stearate suspension: Weigh 0.5g of magnesium stearate, add 50mL of anhydrous ethanol, stir with a magnetic stirrer to disperse evenly, and obtain magnesium stearate suspension with a concentration of 1% W / V. Continue stirring until ready for testing.

[0053] (2) Determination of magnesium stearate particle size and particle size distribution: The operation was carried out according to the operating procedures of the Mastersizer 3000 laser particle size analyzer. The automatic measurement mode was selected, and the instrument parameters were set as follows: particle type: non-spherical; refractive index of dispersion medium: 1.33; particle refractive index: 1.45; particle absorbance: 0.01; particle density: 1.028 g / cm³. 3 The syringe stirring speed was 1500 rpm, the ultrasonic method was used before measurement, the ultrasonic time was 60 s, the ultrasonic intensity was 15%, the background measurement time and sample measurement time were 10 s, the occlusion range was 8%–15%, and the number of cycle measurements was 6. 500 mL of dispersion medium consisting of ultrapure water and Tween 80 was added to the syringe dispersion cell. The Tween 80 concentrations were 0.0025, 0.005, 0.01, and 0.05% W / W. After background measurement, the test sample suspension was slowly added until the occlusion status bar turned green, at which point the measurement was performed automatically.

[0054] (3) Statistical analysis of test results: The particle size and particle size distribution of the test sample were obtained by software calculation and analysis, as shown in Table 2. The results show that when the concentration of the surfactant Tween 80 is 0.0025% W / W, the measured particle size of magnesium stearate is too large, and floating and agglomeration phenomena can be observed in the dispersion medium, indicating that the surfactant at lower concentrations cannot stably and effectively disperse magnesium stearate. When the concentration of the surfactant Tween 80 is above 0.01% W / W, the measured particle size of magnesium stearate is too small, and the phenomenon of continuous decrease in opacity can be observed, indicating that the surfactant at higher concentrations can dissolve and shrink the magnesium stearate particles, resulting in distorted particle size measurement results. When the concentration of the surfactant Tween 80 is 0.005% W / W, the particle size of magnesium stearate was measured repeatedly for 6 times, and the RSD of d(0.1), d(0.5), and d(0.9) were all not higher than 0.87%, which meets the standard requirements. Moreover, the magnesium stearate is well dispersed in the dispersion medium and the opacity fluctuation is small.

[0055] Table 2: Particle size distribution determination results under different surfactant Tween 80 concentrations

[0056]

[0057] Example 3

[0058] In this embodiment, the particle size and particle size distribution determination method for magnesium stearate provided by the present invention are used to determine the particle size of a batch of magnesium stearate, as detailed below:

[0059] Magnesium stearate with batch number F21a220101 (Huzhou Zhanwang) was used to determine the particle size using the method provided in this invention. The average value and relative standard deviation (RSD) of d(0.1), d(0.5), and d(0.9) from six repeated determinations were statistically analyzed. The procedure is as follows:

[0060] (1) Preparation of magnesium stearate suspension: Weigh 0.5g of magnesium stearate, add 50mL of anhydrous ethanol, stir with a magnetic stirrer to disperse evenly, and obtain magnesium stearate suspension with a concentration of 1% W / V. Continue stirring until ready for testing.

[0061] (2) Determination of magnesium stearate particle size and particle size distribution: The operation was carried out according to the operating procedures of the Mastersizer 3000 laser particle size analyzer. The automatic measurement mode was selected, and the instrument parameters were set as follows: particle type: non-spherical; refractive index of dispersion medium: 1.33; particle refractive index: 1.45; particle absorbance: 0.01; particle density: 1.028 g / cm³. 3 The syringe stirring speed was 1500 rpm, the ultrasonic method was used before measurement, the ultrasonic time was 60 s, the ultrasonic intensity was 15%, the background measurement time and sample measurement time were 10 s, the occlusion range was 8%–15%, and the number of cycle measurements was 6. 500 mL of dispersion medium consisting of ultrapure water and Tween 80 was added to the syringe dispersion cell. The Tween 80 concentration was 0.005% W / W. After the background measurement, the test sample suspension was slowly added until the occlusion status bar turned green, at which point the measurement was performed automatically.

[0062] (3) Statistical analysis of test results: The particle size and particle size distribution of the test sample were calculated and analyzed by the software, as shown in Table 3. The particle size distribution diagram is shown below. Figure 1 The results show that the method provided by this invention can repeatedly determine the particle size of magnesium stearate 6 times. The RSD of d(0.1), d(0.5), and d(0.9) is not higher than 0.62%, which meets the standard requirements (acceptance standard: RSD of d(0.1) and d(0.9) is less than 15%, and RSD of d(0.5) is less than 10%), indicating that the method has good precision.

[0063] Table 3: Particle size and particle size distribution determination results of the magnesium stearate particle size and particle size distribution method provided by the present invention.

[0064]

[0065] Example 4

[0066] This embodiment involves different researchers at different times using the particle size and particle size distribution determination method for magnesium stearate provided by this invention to determine the particle size of the same batch of magnesium stearate in Example 3. The details are as follows:

[0067] Magnesium stearate with batch number F21a220101 (Huzhou Zhanwang) was tested for particle size at different times using the method provided in this invention by two different researchers. The average value and relative standard deviation (RSD) of d(0.1), d(0.5), and d(0.9) were calculated for 6 repeated measurements, and the average value and relative standard deviation (RSD) of d(0.1), d(0.5), and d(0.9) were calculated for 12 measurements. The procedure is as follows:

[0068] (1) Preparation of the test sample suspension: Same as in Example 3.

[0069] (2) Test sample determination: Same as in Example 3.

[0070] (3) Statistical analysis of the test results: The particle size and particle size distribution of the test sample were obtained by software calculation and analysis, as shown in Table 4. The results show that when two different researchers repeatedly measured the particle size of magnesium stearate six times using the method provided by this invention, the RSDs of d(0.1), d(0.5), and d(0.9) were all below 0.13%. The combined RSDs of d(0.1), d(0.5), and d(0.9) for 12 measurements were all below 0.71%, meeting the standard requirements (acceptance criteria: RSDs of d(0.1) and d(0.9) less than 15%, and RSDs of d(0.5) less than 10%), indicating that the method has good intermediate precision and repeatability. The particle size results of the three samples of magnesium stearate from the same batch in Examples 3 and 4 showed no significant differences, indicating that the method has high accuracy.

[0071] Table 4: Particle size determination results using the method provided by this invention by different experimenters

[0072]

[0073]

[0074] Example 5

[0075] This embodiment uses the particle size and particle size distribution determination method for magnesium stearate provided by the present invention to determine the particle size of magnesium stearate from multiple manufacturers, as detailed below:

[0076] Magnesium stearate from multiple manufacturers was measured using the method provided in this invention. The average value and relative standard deviation (RSD) of d(0.1), d(0.5), and d(0.9) were statistically analyzed as follows:

[0077] (1) Preparation of the test sample suspension: Same as in Example 3.

[0078] (2) Test sample determination: Same as in Example 3.

[0079] (3) Statistical analysis of test results: The particle size and particle size distribution of the test samples were obtained by software calculation and analysis, as shown in Table 5. The results show that the particle size of magnesium stearate from multiple manufacturers was repeatedly measured 6 times using the method provided in this invention. The mean values ​​of d(0.1), d(0.5), and d(0.9) were different, but the RSD was not higher than 3.41%, which meets the standard requirements (acceptance standard: RSD of d(0.1) and d(0.9) is less than 15%, and RSD of d(0.5) is less than 10%). This indicates that the method has strong applicability and wide applicability.

[0080] Table 5: Particle size determination results of magnesium stearate from multiple manufacturers using the method provided in this invention.

[0081]

[0082] Based on the above-described preferred embodiments of the present invention, and through the foregoing description, those skilled in the art can make various changes and modifications without departing from the inventive concept. The technical scope of this invention is not limited to the contents of the specification, but must be determined according to the scope of the claims.

Claims

1. A method for determining the particle size of magnesium stearate, a pharmaceutical excipient, characterized in that, The determination method includes the following steps: After setting the measurement parameters of the laser particle size analyzer, add the dispersion medium, measure the background, slowly add magnesium stearate suspension until the light-blocking degree reaches the preset range, start the measurement, and statistically analyze the results after the measurement to obtain the particle size and particle size distribution. The dispersion medium is composed of a mixture of surfactant and solvent A, and the concentration of surfactant in the dispersion medium is 0.004 to 0.006% W / W.

2. The method for determining the particle size of magnesium stearate, a pharmaceutical excipient according to claim 1, is characterized in that, The measured parameters include: non-spherical particle type, refractive index of the dispersion medium of 1.33, and particle density of 1.028 g / cm³. 3 The particle refractive index is 1.40–1.50, the particle absorbance is 0.01–0.1, the sample injector stirring speed is 1200 rpm–1800 rpm, the ultrasonic method is before the measurement, the ultrasonic time is 30–90 s, the ultrasonic intensity is 10–20%, the background and sample measurement time is 5–20 s, and the shading range is 5–20%.

3. The method for determining the particle size of magnesium stearate, a pharmaceutical excipient according to claim 1, is characterized in that, Solvent A includes one or more of purified water and ultrapure water.

4. The method for determining the particle size of magnesium stearate, a pharmaceutical excipient according to claim 1, is characterized in that, The surfactant includes, but is not limited to, one or more of Tween 80, sodium dodecyl sulfate, and sodium hexametaphosphate.

5. The method for determining the particle size of magnesium stearate, a pharmaceutical excipient according to claim 1, is characterized in that, The surfactant is Tween 80.

6. The method for determining the particle size of magnesium stearate, a pharmaceutical excipient according to claim 1, is characterized in that, The magnesium stearate suspension is composed of magnesium stearate and solvent B, and the concentration of magnesium stearate in the suspension is 0.5-1.5% W / V.

7. The method for determining the particle size of magnesium stearate, a pharmaceutical excipient according to claim 6, is characterized in that, Solvent B is anhydrous ethanol.

8. The method for determining the particle size of magnesium stearate, a pharmaceutical excipient according to claim 1, is characterized in that, The statistical analysis was performed using the instrument's accompanying software.

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