Method for detecting fluticasone propionate bulk drug particle size

Abstract

The present application provides a kind of detection method of fluticasone propionate bulk drug particle size, the method is first used to high-power ultrasonic dispersion medium break dispersion medium molecule aggregation, then lower power ultrasonic dispersion system is stabilized, avoid dispersing agent itself aggregation to bulk drug particle is wrapped, form measurement error.In addition, by intermittent electric field, so that particle produces relative displacement or oscillation, while applying ultrasonic dissociation agglomerate, realize the complete wetting of bulk drug particle, stable dispersion and accurate detection, the method is lower to instrument requirement, can realize the accurate detection of strong hydrophobicity bulk drug particle size in the case where not increasing detection cost and detection time.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical analysis technology, specifically relating to a method for detecting the particle size of fluticasone propionate raw material. Background Technology

[0002] Fluticasone propionate, a steroidal lipid-soluble compound, has a particle size distribution that significantly impacts its performance and quality. However, to meet the transdermal absorption requirements of cream formulations, the particle size of fluticasone propionate active pharmaceutical ingredient (API) is typically controlled at the micrometer level, making it highly prone to agglomeration. Even with the use of surfactants, complete dispersion of fluticasone propionate API is impossible. CN119086366A discloses an analytical method for the particle size distribution of fluticasone propionate API. This method incorporates near-infrared spectroscopy and multi-scale feature extraction technology, combines bubble state to determine the degree of settling, and utilizes regression models to optimize laser particle size analyzer parameter settings, thereby improving the accuracy and stability of particle size distribution analysis. However, this method optimizes detection parameters through data analysis and does not fundamentally solve the particle dispersion problem. Therefore, developing an accurate method for determining the particle size of fluticasone propionate API can support formulation development, quality control, and production process optimization, thereby effectively improving drug efficacy and quality stability. Summary of the Invention

[0003] One objective of this invention is to provide a method for detecting the particle size of fluticasone propionate raw material. This method addresses the tendency of fluticasone propionate raw material to agglomerate by employing gradient power ultrasound and intermittent electric field synergistic dispersion to dissociate the agglomerates of fluticasone propionate raw material, thereby achieving complete wetting, stable dispersion, and accurate detection of fluticasone propionate raw material.

[0004] A method for detecting the particle size of fluticasone propionate active pharmaceutical ingredient, comprising the following steps:

[0005] (1) Measure a nonylphenyl polyethylene glycol solution, add an appropriate amount of water, and perform gradient sonication to obtain a dispersion medium;

[0006] (2) Take an appropriate amount of fluticasone propionate raw material, add a dispersion medium, stir and soak, then add an appropriate amount of dispersion medium and sonicate to initially disperse the fluticasone propionate raw material and form a preliminary dispersion solution.

[0007] (3) The initially dispersed sample was transferred to the sample injector of the nanoparticle size and Zeta potential analyzer and subjected to gradient sonication. During sonication, an intermittent alternating electric field was applied to the sample to further disperse it.

[0008] (4) After setting the measurement time and background time, the measurement is performed to obtain particle size distribution data.

[0009] The volume fraction of the nonylphenyl polyethylene glycol solution in step (1) is 1-2%.

[0010] In step (1), the gradient ultrasound is performed at 200W for 1 minute, followed by ultrasound at 100W for 1 minute.

[0011] In step (2), the ultrasonic power is 300W and the ultrasonic time is 30s.

[0012] In step (3), the gradient ultrasound is 300w~350w for 30s, 200w~250w for 2min, and 100w~150w for 30s.

[0013] In step (3), the electric field strength of the intermittent electric field is 3~4kV / m, and the intermittent mode is to turn on the power for 30s and then turn off the power for 30s, and so on.

[0014] In step (4), the measurement time is 12s and the background time is 12s.

[0015] Compared with the prior art, this application has the following advantages:

[0016] (1) Gradient ultrasound is applied to the dispersion medium. First, high-power ultrasound is used to break up the aggregation of dispersant molecules, and then lower-power ultrasound is used to stabilize the dispersion system, thereby avoiding the aggregation of the dispersant itself to encapsulate the raw material particles and form measurement errors.

[0017] (2) Ultrasonic waves are used to further disperse the initial dispersion solution of the active pharmaceutical ingredient. At the same time, an electric field is applied intermittently to cause relative displacement or oscillation of the particles, which can achieve complete wetting, stable dispersion and accurate detection of the active pharmaceutical ingredient particles.

[0018] (3) This method has low requirements for instruments and can achieve accurate detection of particle size of strongly hydrophobic raw materials without increasing detection costs and detection time. Detailed Implementation

[0019] To enable those skilled in the art to more clearly understand the technical solutions described in this invention, the following embodiments are provided for illustration. It should be noted that the following embodiments do not constitute a limitation on the scope of protection claimed by this invention.

[0020] Unless otherwise specified, the raw materials, reagents or devices used in the following examples are available from conventional commercial sources or can be obtained by existing known methods.

[0021] Example 1

[0022] (1) Measure 3 ml of a 1% nonylphenyl polyethylene glycol solution, add it to 300 ml of water and mix. Then, sonicate at 200 W for 1 minute and then at 100 W for 1 minute to obtain the dispersion medium.

[0023] (2) Take 30 mg of fluticasone propionate raw material, add 4-6 drops of dispersion medium, stir and soak, then add 30 mL of dispersion medium, and sonicate at 300 W for 30 s to obtain a preliminary dispersion solution.

[0024] (3) The preliminary dispersion solution was transferred to the sampler of the nanoparticle size and Zeta potential analyzer and sonicated for 30 seconds with 300W, 2 min with 200W, and 30 seconds with 100W. During sonication, an intermittent AC electric field with an electric field strength of 3kV / m was applied. The intermittent mode was to energize for 30 seconds and de-energize for 30 seconds, and so on.

[0025] (4) After the ultrasound and electric field were applied, the measurement time was set to 12 seconds and the background time to 12 seconds. The measurement was then performed to obtain the particle size distribution data of fluticasone propionate raw material. The measurement results are shown in Table 1.

[0026] Table 1. Particle size distribution measurement data from Example 1

[0027]

[0028] As can be seen from Table 1, the RSD values ​​of D90, D50, and D10 of this detection method are all within 3%, indicating good repeatability.

[0029] Example 2

[0030] (1) Measure 3 ml of a 2% nonylphenyl polyethylene glycol solution, add it to 300 ml of water and mix. Then, sonicate at 200 W for 1 minute and then at 100 W for 1 minute to obtain the dispersion medium.

[0031] (2) Take 30 mg of fluticasone propionate raw material, add 4-6 drops of dispersion medium, stir and soak, then add 30 mL of dispersion medium, and sonicate at 300 W for 30 s to obtain a preliminary dispersion solution.

[0032] (3) The preliminary dispersion solution was transferred to the sampler of the nanoparticle size and Zeta potential analyzer and sonicated for 30 seconds with 300W, 2 min with 200W, and 30 seconds with 100W. An intermittent AC electric field with an electric field strength of 4kV / m was applied during sonication. The intermittent mode was 30 seconds of power-on and 30 seconds of power-off, and this cycle was repeated.

[0033] (4) After the ultrasound and electric field were applied, the measurement time was set to 12 seconds and the background time to 12 seconds. The measurement was then performed to obtain the particle size distribution data of fluticasone propionate raw material. The measurement results are shown in Table 2.

[0034] Table 2. Particle size distribution measurement data from Example 2

[0035]

[0036] As can be seen from Table 2, the repeatability of D50 and D90 data is better when the electric field strength increases, indicating that applying an electric field is beneficial to improving the repeatability of measurement data.

[0037] Example 3

[0038] (1) Measure 3 ml of a 2% nonylphenyl polyethylene glycol solution, add it to 300 ml of water and mix. Then, sonicate at 200 W for 1 minute and then at 100 W for 1 minute to obtain the dispersion medium.

[0039] (2) Take 30 mg of fluticasone propionate raw material, add 4-6 drops of dispersion medium, stir and soak, then add 30 mL of dispersion medium, and sonicate at 300 W for 30 s to obtain a preliminary dispersion solution.

[0040] (3) The preliminary dispersion solution was transferred to the sampler of the nanoparticle size and Zeta potential analyzer and sonicated for 30s with 350W, 2min with 250W, and 30s with 150W. During sonication, an intermittent AC electric field with an electric field strength of 4kV / m was applied. The intermittent mode was to energize for 30s and de-energize for 30s, and so on.

[0041] (4) After the ultrasound and electric field were applied, the measurement time was set to 12 seconds and the background time to 12 seconds. The measurement was then performed to obtain the particle size distribution data of fluticasone propionate raw material. The measurement results are shown in Table 3.

[0042] Table 3. Particle size distribution measurement data from Example 3

[0043]

[0044] As can be seen from Table 3, the repeatability of D10 and D50 data is better when the ultrasonic power is increased, indicating that good repeatability of detection data can still be maintained after increasing the ultrasonic power.

[0045] Comparative Example 1

[0046] (1) Take 3 ml of 2% nonylphenyl polyethylene glycol solution, place it in 300 ml of water, and then sonicate it at 200 W for 1 minute and then at 100 W for 1 minute to obtain the dispersion medium. Take 30 mg of fluticasone propionate raw material, add 4-6 drops of dispersion medium, stir and soak, then add 30 mL of dispersion medium and stir to obtain a preliminary dispersion solution.

[0047] (2) The preliminary dispersion solution was transferred to the sampler of the nanoparticle size and Zeta potential analyzer for measurement to obtain the particle size distribution data of fluticasone propionate raw material.

[0048] Table 4. Particle size distribution data for Comparative Example 1

[0049]

[0050] As can be seen from Table 4, in Comparative Example 1, due to the lack of preliminary dispersion by ultrasound, intermittent electric field-assisted synergy, and graded ultrasound, the particles were not sufficiently dispersed and there was obvious agglomeration. This resulted in significantly larger D50 and D90 values, and the RSD values ​​of the three test results were all greater than 8% (D50 > 15%), indicating poor repeatability and inability to accurately reflect the true particle size distribution of the active pharmaceutical ingredient.

[0051] Comparative Example 2

[0052] (1) Take 3 ml of 2% nonylphenyl polyethylene glycol solution, place it in 300 ml of water, and then sonicate it at 200 W for 1 minute and then at 100 W for 1 minute to obtain the dispersion medium. Take 30 mg of fluticasone propionate raw material, add 4-6 drops of dispersion medium, stir and soak, then add 30 mL of dispersion medium and stir to obtain a preliminary dispersion solution.

[0053] (2) The preliminary dispersion solution was transferred to the sampler of the nanoparticle size and Zeta potential analyzer. An intermittent AC electric field was applied with an electric field strength of 3kV / m. The intermittent mode was 30s on and 30s off, and this cycle was repeated for 3min. Then, the measurement time was set to 12 seconds and the background time to 12 seconds. The measurement was performed to obtain the particle size distribution data of fluticasone propionate raw material.

[0054] Table 5. Particle size distribution data for Comparative Example 2

[0055]

[0056] As can be seen from Table 5, due to the application of only an electric field without the application of ultrasound, the particles were not sufficiently dispersed and there was obvious agglomeration, resulting in poor repeatability of the detected D90 value and failing to accurately reflect the true particle size distribution of the active pharmaceutical ingredient.

[0057] Comparative Example 3

[0058] (1) Take 3 ml of 2% nonylphenyl polyethylene glycol solution and place it in 300 ml of water to form a dispersion medium. Take 30 mg of fluticasone propionate raw material, add 4-6 drops of dispersion medium, stir and soak, then add 30 mL of dispersion medium and stir to obtain a preliminary dispersion solution.

[0059] (2) The preliminary dispersion solution was transferred to the sampler of the instrument and subjected to 300W ultrasound for 30s, 200W ultrasound for 2min, and 100W ultrasound for 30s. After the ultrasound was applied, the measurement time was set to 12 seconds and the background time to 12 seconds. The particle size distribution data of fluticasone propionate raw material was obtained.

[0060] Table 6. Particle size distribution data for Comparative Example 3

[0061]

[0062] As can be seen from Table 6, since only ultrasound was applied without an electric field, the particles were not sufficiently dispersed and there was obvious agglomeration, resulting in poor repeatability of the detected D90 value and failing to accurately reflect the true particle size distribution of the active pharmaceutical ingredient.

[0063] Comparative Example 4

[0064] (1) Take 3 ml of a 2% nonylphenyl polyethylene glycol solution, place it in 300 ml of water, and mix and stir to obtain a dispersion medium.

[0065] (2) Take 30 mg of fluticasone propionate raw material, add 4-6 drops of dispersion medium, stir and soak, then add 30 mL of dispersion medium, and sonicate at 300 W / 30 s to obtain a preliminary dispersion solution.

[0066] (3) The preliminary dispersion solution was transferred to the sampler of the nanoparticle size and Zeta potential analyzer and sonicated for 30 seconds with 300W, 2 min with 200W, and 30 seconds with 100W. An intermittent AC electric field with an electric field strength of 4kV / m was applied during sonication. The intermittent mode was 30 seconds of power-on and 30 seconds of power-off, and this cycle was repeated.

[0067] (4) After the ultrasound is applied, set the measurement time to 12 seconds and the background time to 12 seconds, and perform the measurement to obtain the particle size distribution data of fluticasone propionate raw material.

[0068] Table 7 Particle size distribution data for Comparative Example 4

[0069]

[0070] As can be seen from Table 7, because the dispersion medium was not pretreated by gradient ultrasound, the dispersant aggregated itself to encapsulate the active pharmaceutical ingredient particles, resulting in uneven particle dispersion and obvious agglomeration. Consequently, the detected D90 values ​​had poor repeatability and could not accurately reflect the true particle size distribution of the active pharmaceutical ingredient.

[0071] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for detecting the particle size of fluticasone propionate raw material, characterized in that, Includes the following steps: (1) Measure a nonylphenyl polyethylene glycol solution, add an appropriate amount of water, and perform gradient sonication to obtain a dispersion medium; (2) Take an appropriate amount of fluticasone propionate raw material, add a dispersion medium, stir and soak, then add an appropriate amount of dispersion medium and sonicate to initially disperse the fluticasone propionate raw material and form a preliminary dispersion solution. (3) The initially dispersed sample was transferred to the sample injector of the nanoparticle size and Zeta potential analyzer and subjected to gradient sonication. During sonication, an intermittent alternating electric field was applied to the sample to further disperse it. (4) After setting the measurement time and background time, the measurement is performed to obtain particle size distribution data; In step (3), the electric field strength of the intermittent alternating electric field is 3~4kV / m, and the intermittent mode is to turn on the power for 30s and then turn off the power for 30s, and so on.

2. The method for detecting the particle size of fluticasone propionate raw material as described in claim 1, characterized in that, The volume fraction of the nonylphenyl polyethylene glycol solution in step (1) is 1-2%.

3. The method for detecting the particle size of fluticasone propionate raw material as described in claim 1, characterized in that, In step (1), the gradient ultrasound is performed at 200W for 1 minute, followed by ultrasound at 100W for 1 minute.

4. The method for detecting the particle size of fluticasone propionate raw material as described in claim 1, characterized in that, In step (2), the ultrasonic power is 300W and the ultrasonic time is 30s.

5. The method for detecting the particle size of fluticasone propionate raw material as described in claim 1, characterized in that, In step (3), the gradient ultrasound is 300~350w ultrasound for 30s, 200~250w ultrasound for 2min, and 100~150w ultrasound for 30s.

6. The method for detecting the particle size of fluticasone propionate raw material as described in claim 1, characterized in that, In step (4), the measurement time is 12s and the background time is 12s.

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