Method for measuring particle size of mannitol by laser diffraction particle size method-wet method

Abstract

The invention discloses a method for measuring the particle size of mannitol by a laser diffraction particle size method-wet method, which belongs to the technical field of pharmaceutical analysis, and is characterized in that the particle size of mannitol is measured by a wet method, and the method comprises the following steps: preparation of a test solution: adding mannitol into 15ml of absolute ethyl alcohol and 5 drops of a 5% Tween 80 ethanol solution, and uniformly stirring; stirring with a glass rod to obtain a uniform suspension, performing ultrasonic treatment in a water bath for 30 seconds, stirring while performing ultrasonic treatment, and keeping the sample suspension in a uniformly dispersed state all the time to obtain a test solution; the particle type is non-spherical, the refractive index is 1.597, the absorptivity is 0.01, the density is 1.51 g / cm < 3 >, the dispersing agent is absolute ethyl alcohol, the refractive index of the dispersing agent is 1.36, the threshold value of the sensor is 20, the measurement time is 10s, the measurement frequency is 2 times, the shading degree is 5%-14%, the stirring speed is 1700 revolutions per minute, and the particle size of mannitol is investigated. Operation is simple, sensitivity is high, and results are accurate.

Description

Technical Field

[0001] The invention relates to the technical field of drug detection, in particular to a method for measuring mannitol particle size by a laser diffraction particle size method-wet method. Background Art

[0002] Mannitol is a commonly used drug. It is an odorless, sweet, and crystalline white powder that is readily soluble in water. It is used to treat cerebral edema and reduce intracranial pressure. It is an important first-aid agent for brain diseases such as cerebral hemorrhage and traumatic brain injury. It also reduces intraocular pressure and can be used to treat acute glaucoma attacks or preoperatively. Mannitol significantly outperforms other excipients in terms of physiological inertness, tolerability, and chemical compatibility with raw materials and excipients. Its extremely low water content and hygroscopicity make it a preferred excipient for moisture-sensitive drugs and dosage forms such as orally disintegrating tablets. Regarding tableting performance, due to its plastic properties, mannitol can reduce the sensitivity of the formulation to tableting speed and improve the formability of the formulation. Mannitol's creamy texture, sweetness, and cooling sensation enhance the taste of the formulation, making it ideal for orally disintegrating tablets, chewable tablets, and sublingual tablets.

[0003] The direct powder tableting process places strict demands on the selection of excipients. Excipients of varying particle sizes can directly impact powder properties such as flowability, filling capacity, and compressibility. When used as an excipient, mannitol of varying particle sizes exhibits distinct characteristics during mixing and tableting. Therefore, mannitol particle size testing is crucial.

[0004] Existing analytical methods for mannitol particle size determination include dry methods. However, not every sample is suitable for dry methods in laser particle size testing. For sticky samples like mannitol, dry methods are prone to sample agglomeration during testing, forming large particles that affect the accuracy of the results. Dry methods require a gas circulation system to maintain particle suspension, which can easily adhere to equipment surfaces, causing contamination and making cleaning difficult. Furthermore, dry methods require large sample volumes, increasing testing costs. Furthermore, the dry method's dispersion mechanism is more destructive, preventing reproducible results. Summary of the Invention

[0005] In order to solve the technical problems mentioned in the above background technology, the present invention provides a method for measuring the particle size of mannitol by laser diffraction particle size method-wet method, and the technical solution adopted is as follows, comprising the following steps:

[0006] (1) The laser diffraction particle size analyzer measurement conditions were set as follows: particle type was non-spherical, refractive index was 1.597, absorptivity was 0.01, density was 1.51 g / cm3, dispersant was anhydrous ethanol, dispersant refractive index was 1.36, sensor threshold was 20, measurement time was 10 s, number of measurements was 2 times, shading degree was 5%-14%, and stirring speed was 1700 rpm.

[0007] (2) Rinse the Hydro MV wet sampler with anhydrous ethanol at 3000 rpm for 3 times to drain it completely; then use a lens cleaning cloth dipped in ethanol to gently wipe the lens of the Hydro MV wet sampler accessory to ensure that the lens is clean and free of contamination; finally, use anhydrous ethanol at 1700 rpm at 20-25℃ to circulate and stabilize for 4 minutes before retaining it.

[0008] (3): Add dispersant, measure the background, observe the background test status to confirm whether the test is passed and the light energy is displayed as fluctuating up and down on the coordinate axis, and the fluctuation value is stable. If the background does not pass, it is necessary to re-execute step (2) and measure the background until the background measurement passes.

[0009] (4): Preparation of the test solution: weigh 150 mg of the sample and place it in a 50 mL beaker. Add about 15 mL of anhydrous ethanol and then 5 drops of 5% Tween 80 ethanol solution. Stir with a glass rod to form a uniform suspension. Ultrasonicate in a water bath for 30 seconds while stirring to keep the sample suspension uniformly dispersed.

[0010] (5) Take about 3-6 mL of the sample solution and add it to the wet sampler to make the shading degree between 5% and 14%. After the shading degree stabilizes, start measuring the particle size of mannitol.

[0011] Preferably, in the measurement conditions, the measurement interval time is 0S, the delay before testing is 0S, and the delay before light is 0S.

[0012] Preferably, in the measurement conditions, ultrasound mode: none, ultrasound duration 0 s, ultrasound 0%.

[0013] Preferably, in the determination conditions, the sample pool is cleaned, wherein the cleaning type is fast, the sample tank injection behavior is manual and degassing after cleaning is selected, and no ultrasound is selected during the cleaning process.

[0014] Preferably, in the measurement conditions, the automatic start of measurement when the shading degree is within the range is not enabled, and the screening is not enabled.

[0015] Preferably, in the measurement conditions, the alarm is set to enable checking the background cleanliness, the sample reservoir filling behavior is manual and degas after filling is selected.

[0016] The present invention has the following advantages: in wet method determination, mannitol particles can be uniformly dispersed by a dispersion medium, measurement errors caused by particle agglomeration are reduced, the actual size of the mannitol particles is accurately measured, and the advantage is more obvious when measuring small particles. It is applicable to the measurement of various particle size ranges, has higher sensitivity and more accurate results. Sample processing only requires mixing the mannitol sample with the dispersion medium, and then injecting the dispersed mannitol sample into the instrument for measurement, so that the particle size distribution result can be quickly obtained. The method is simple to operate, reduces equipment pollution, is easy to clean, and requires very little sample amount for detection. A single solution preparation only requires about 150 mg, greatly saving detection costs. The wet method uniformly disperses the mannitol particles by a dispersion medium, is less destructive to the particles, and can obtain better result repeatability. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 This is an example of the detection spectrum of the present invention. DETAILED DESCRIPTION

[0018] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0019] The detection method used in the following examples is laser diffraction particle size method-wet method:

[0020] Example 1

[0021] Measurement conditions

[0022]

[0023]

[0024] Operation process

[0025] (1) Cleaning cycle:

[0026] Before analysis begins:

[0027] 1) Rinse the Hydro MV with anhydrous ethanol at 3000 rpm three times and drain completely;

[0028] 2) Use a lens cleaning cloth dipped in ethanol to gently wipe the lens of the Hydro MV accessory to ensure that the lens is clean and free of contamination;

[0029] 3) Circulate with anhydrous ethanol at a speed of 1700 rpm at a temperature of 20-25°C for 4 minutes and then retain it.

[0030] After completing a sampling and subsequent runs:

[0031] 1) Rinse the Hydro MV with anhydrous ethanol at 3000 rpm three times and drain completely;

[0032] 2) Circulate with anhydrous ethanol at a speed of 1700 rpm at a temperature of 20-25°C for 4 minutes and then retain it.

[0033] End of analysis:

[0034] 1) Rinse the Hydro MV with anhydrous ethanol at 3000 rpm three times and drain completely;

[0035] (2) Sample

[0036] Open the created method, edit the sample name, and follow the instrument prompts to add dispersant and measure the background (observe the background test status to confirm whether the test has passed and the light energy displayed fluctuates up and down on the coordinate axis, and the fluctuation value is controlled to be stable within ±10. If the background fails, re-measure the background and, if necessary, re-clean the system according to the "Before Analysis" cleaning steps).

[0037] After the background measurement is passed, weigh 150mg of sample and place it in a 50mL beaker, add about 15mL of anhydrous ethanol, then add 5 drops of 5% Tween 80 ethanol solution, stir with a glass rod to form a uniform suspension, and ultrasonicate in a water bath for 30S. The ultrasonic machine power is 350W. Stir while ultrasonicating to keep the sample suspension in a uniform dispersed state. According to the prompts, take about 3-6mL of sample suspension and add it to the wet sampler to make the shading degree reach between 5% and 14%. After the shading degree stabilizes, click to start measurement. Measure three needles in parallel and calculate the average value of the three needle samples for each particle size.

[0038] Selection of dispersants and co-dispersants

[0039] Because mannitol is readily soluble in water, water cannot be used as a dispersant. Other solvents were considered, and common isoparaffins can also dissolve mannitol. Therefore, anhydrous ethanol was selected as the organic solvent for dispersant, and a 5% Tween 80 solution in ethanol was used as a co-dispersant. Methodological validation was performed.

[0040] Precision test

[0041] Repeatability: The precision of the results obtained by the same analyst under the same operating conditions and within a short time interval is evaluated by calculating the RSD value using the particle size values of 6 samples.

[0042] Requirements: RSD requirements for particle size results of 6 samples: D4(4,3):RSD≤15%; D50:RSD≤10%;

[0043] D10, D90: RSD≤15%.

[0044] Intermediate precision: The precision of the results obtained by two analysts at different times under the same operating conditions is evaluated by calculating the RSD value using the particle size values of 6 + 6 samples measured by the two analysts.

[0045] Requirements: RSD requirements for particle size results of 6+6 samples from two people: D4(4,3):RSD≤22.5%; D50:RSD≤15%; D10,D90:RSD≤22.5%.

[0046] The experimental results are shown in Tables 1, 2, and 3. Table 3 shows that the method can meet the precision requirements.

[0047] Table 1 Repeatability results

[0048]

[0049]

[0050] Table 2 Intermediate precision repeatability results

[0051]

[0052]

[0053] Table 3 Precision conclusion table

[0054]

[0055] Durability test

[0056] Based on the original instrument conditions, the durability test was conducted by changing one parameter at a time. The changed parameters are as follows:

[0057]

[0058]

[0059] The experimental results are shown in Table 4. As shown in Table 4, the two parameters of ultrasonic time and ultrasonic power in the method have an impact on the stability and accuracy of the method. Therefore, the method clearly stipulates the ultrasonic time and ultrasonic power to ensure the stability and accuracy of the method.

[0060] Table 4 Durability conclusion table

[0061]

[0062]

[0063] The above detailed description is a specific description of one feasible embodiment of the present invention. This embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not depart from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A method for measuring mannitol particle size by laser diffraction particle size method-wet method, characterized in that: The steps include: Step (1): Setting the laser diffraction particle size analyzer measurement conditions: particle type is non-spherical, refractive index is 1.597, absorptivity is 0.01, density is 1.51 g / cm3, dispersant is anhydrous ethanol, dispersant refractive index is 1.36, sensor threshold is 20, measurement time is 10 s, number of measurements is 2 times, shading degree is 5%-14%, and stirring speed is 1700 rpm; Step (2): Rinse the Hydro MV wet sampler with anhydrous ethanol at 3000 rpm for 3 times to drain; then use a lens cleaning cloth dipped in ethanol to gently wipe the lens of the Hydro MV wet sampler accessory to ensure that the lens is clean and free of contamination; finally, circulate with anhydrous ethanol at 1700 rpm at 20-25°C for 4 minutes and then retain; Step (3): Add dispersant, measure the background, observe the background test status to confirm whether the test is passed and the light energy is displayed as fluctuating up and down on the coordinate axis, and the fluctuation value is stable. If the background does not pass, repeat step (2) and measure the background again until the background measurement passes; Step (4): Preparation of the test solution: weigh 150 mg of the sample and place it in a 50 mL beaker. Add about 15 mL of anhydrous ethanol and then add 5 drops of 5% Tween 80 ethanol solution. Stir with a glass rod to form a uniform suspension. Ultrasonicate in a water bath for 30 s while stirring to keep the sample suspension uniformly dispersed. Step (5): Take 3-6 mL of the test solution and add it to the wet sample injector to make the shading degree reach between 5% and 14%. After the shading degree stabilizes, start measuring the particle size of mannitol.

2. The method of laser diffraction particle size method-wet method for measuring mannitol particle size according to claim 1, wherein The measurement conditions of step (2) also include: measurement interval time 0s, delay before test 0s, and delay before light 0s.

3. The method for laser diffraction particle size method-wet method for measuring mannitol particle size according to claim 1, characterized in that, The measurement conditions of step (2) also include: ultrasound mode: none, ultrasound duration 0s, ultrasound 0%.

4. The method of laser diffraction particle size method-wet method for measuring mannitol particle size according to claim 1, wherein The determination conditions of step (2) also include: cleaning the sample pool, wherein the cleaning type is fast, the sample tank injection behavior is manual and degassing after cleaning is selected, and no ultrasound is selected during the cleaning process.

5. The method of laser diffraction particle size method-wet method for measuring mannitol particle size according to claim 1, wherein The measurement conditions of step (2) also include: not enabling automatic start of measurement when the shading degree is within the range, and not enabling screening (CE).

6. The method for measuring mannitol particle size by laser diffraction particle size method-wet method according to claim 1, wherein The determination conditions of step (2) also include: the alarm is set to enable checking the background cleanliness, the sample tank injection behavior is manual and degassing after filling is selected.

7. The method for measuring mannitol particle size by laser diffraction particle size method-wet method according to any one of claims 1 to 6, characterized in that: This method was used to determine the particle size of mannitol.

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