A kind of beclomethasone dipropionate suspension for inhalation and its preparation method and particle size detection method

Abstract

The present invention relates to the field of pharmaceutical preparations and analytical technology, and specifically discloses a beclomethasone dipropionate suspension for inhalation, a preparation method thereof, and a particle size detection method. Each 100mL beclomethasone dipropionate suspension for inhalation is composed of 0.5g-3g beclomethasone dipropionate, 0.05wt%-0.3wt% Triton X-100, and water. The prepared beclomethasone dipropionate suspension for inhalation is subjected to particle size detection by using 0.05%-0.3% Triton X-100 beclomethasone dipropionate saturated solution as a dispersion medium. The preparation method of the beclomethasone dipropionate suspension for inhalation provided by the present invention can achieve a narrower particle size distribution and a better suspension effect; at the same time, the particle size detection method of the beclomethasone dipropionate suspension for inhalation provided by the present invention has high detection accuracy and good repeatability, and provides reliable guarantee and basis for improving the quality of the beclomethasone dipropionate suspension for inhalation, and has high practical value.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations and pharmaceutical analysis, and in particular to a beclomethasone dipropionate suspension for inhalation, a preparation method thereof and a particle size detection method thereof. Background Art

[0002] Beclomethasone dipropionate is a potent topical glucocorticoid drug with anti-inflammatory, anti-allergic and antipruritic effects. It can inhibit bronchial exudates, eliminate bronchial mucosal swelling, and relieve bronchospasm. The main preparation of beclomethasone dipropionate is beclomethasone dipropionate suspension for inhalation, which can be used for the treatment of chronic and allergic asthma, allergic rhinitis, etc. For suspensions, the particle size and particle size distribution of beclomethasone dipropionate are the key factors determining its efficacy. The difference in particle size may affect the release effect and clinical efficacy of the drug. During storage, the beclomethasone dipropionate particles in the suspension are also prone to aggregation, resulting in poor particle size uniformity and affecting efficacy. Therefore, it is of great significance to develop a new preparation process for beclomethasone dipropionate suspension with uniform particle size and good stability.

[0003] In addition, in order to achieve strict control of the quality of beclomethasone dipropionate suspension, it is necessary to develop a detection method that can accurately measure the particle size of beclomethasone dipropionate in beclomethasone dipropionate suspension. At present, the particle size of beclomethasone dipropionate in beclomethasone dipropionate suspension for inhalation is measured by water as a dispersion medium. However, the inventors found in practice that the dispersibility of beclomethasone dipropionate particles is poor when water is directly used as a dispersion medium, and the repeatability of the measurement results is also poor, and there is a deviation between batches, resulting in inaccurate test results, and it is impossible to achieve good quality control of beclomethasone dipropionate suspension for inhalation. Therefore, it is of great significance to develop a preparation method and a particle size detection method for beclomethasone dipropionate suspension for inhalation that can effectively control the particle size of beclomethasone dipropionate particles. Summary of the invention

[0004] In view of the above problems existing in the existing beclomethasone dipropionate suspension for inhalation, the present invention provides a beclomethasone dipropionate suspension for inhalation, a preparation method thereof and a particle size detection method thereof.

[0005] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0006] In a first aspect, the present invention provides a beclomethasone dipropionate suspension for inhalation, which consists of beclomethasone dipropionate, Triton X-100 and water, wherein each 100 mL of the suspension contains 0.5 g to 3 g of beclomethasone dipropionate and 0.05 wt % to 0.3 wt % of Triton X-100.

[0007] The particle size distribution of the beclomethasone dipropionate suspension for inhalation determines the lung deposition rate of the finished product, thereby affecting the efficacy. The inventors have found through research that beclomethasone dipropionate has poor dispersibility in aqueous solution, a wide particle size distribution, and that the beclomethasone dipropionate raw material will partially dissolve in water, causing some of the raw material to dissolve during the preparation process, resulting in unstable quality between batches.

[0008] Compared with the prior art, the present invention makes beclomethasone dipropionate dispersed in water uniformly and stably by adding Triton X-100, and the problem of raw materials dissolving in water does not occur, so that the prepared beclomethasone dipropionate suspension for inhalation has a concentrated particle size distribution, high batch-to-batch quality consistency, and no increase in particle size after long-term storage, indicating good stability, and can better exert the efficacy of the beclomethasone dipropionate suspension for inhalation, improve its drug effectiveness, and the drug quality is stable, and has a high application prospect.

[0009] Preferably, the particle size D90 of beclomethasone dipropionate in the beclomethasone dipropionate suspension for inhalation is 4.2 μm-5.0 μm, D50 is 2.0 μm-2.5 μm, and D10 is 0.7 μm-1.2 μm.

[0010] In a second aspect, the present invention also provides a method for preparing a beclomethasone dipropionate suspension for inhalation, comprising the following steps:

[0011] Step a, ultrafine grinding the beclomethasone propionate raw material to a preset particle size distribution to obtain ultrafine beclomethasone propionate powder;

[0012] Step b, weighing each component according to the designed ratio, dissolving the weighed Triton X-100 in water, adding the weighed beclomethasone propionate ultrafine powder, and mixing to obtain a primary emulsion;

[0013] Step c, homogenizing the primary emulsion by microfluidization to obtain the beclomethasone dipropionate suspension for inhalation.

[0014] The invention adopts an aqueous solution of Triton X-100 as a dispersing medium for dispersing beclomethasone dipropionate, and cooperates with ultrafine grinding and microfluidization homogenization processes, so as to significantly improve the stability of the prepared beclomethasone dipropionate suspension for inhalation, so that the particle size of the prepared suspension is concentrated in 4.2 μm-5.0 μm, effectively improves the deposition rate of beclomethasone dipropionate in the lungs, and is beneficial to improving the drug efficacy of the beclomethasone dipropionate suspension, and the preparation process is simple, the reproducibility is good, and the industrial production is easy to realize.

[0015] Preferably, in step a, the particle size D90 of the beclomethasone dipropionate raw material is 30 μm-150 μm.

[0016] Preferably, in step a, the air flow pressure of the ultrafine grinding is 3 bar-6 bar, and the feed speed is 5 rpm-30 rpm.

[0017] Preferably, the preset particle size distribution is D90 of 5 μm-8 μm, D50 of 2.5 μm-4 μm, and D10 of 0.8 μm-1.2 μm.

[0018] Preferably, in step b, the mixing speed is 900 rpm-1100 rpm, and the mixing time is 25 min-35 min.

[0019] Preferably, in step c, the pressure of microfluidization homogenization is 2000psi-30000psi, and the number of microfluidization homogenization is 1-5 times.

[0020] Exemplarily, the micro-jet homogenization may be performed by a straight-line cavity micro-jet homogenizer or a counter-jet micro-jet homogenizer. As long as the homogenization conditions defined in the present invention are adopted, substantially equivalent homogenization effects can be achieved.

[0021] It should be noted that if a straight-type cavity microfluidizer is used, the pressure of microfluidizer homogenization is 20,000 psi-30,000 psi; if a counter-type microfluidizer is used, the pressure of microfluidizer homogenization is 2,000 psi-10,000 psi.

[0022] The preferred process conditions can obtain beclomethasone dipropionate particles with a smaller particle size, and are conducive to improving the dispersion uniformity and stability of the beclomethasone dipropionate particles in the suspension, thereby greatly improving the stability and quality consistency of the drug.

[0023] In a third aspect, the present invention further provides a method for detecting the particle size of a beclomethasone dipropionate suspension for inhalation, comprising the following steps:

[0024] Adding the beclomethasone dipropionate suspension for inhalation to be tested into the dispersion medium, mixing, and testing;

[0025] Wherein, the dispersion medium is a saturated beclomethasone dipropionate solution, and the solvent is a 0.05%-0.3% Triton X-100 aqueous solution.

[0026] Compared with the prior art, the present invention adopts 0.05%-0.3% of Triton X-100 beclomethasone dipropionate saturated solution as a dispersion medium, so that the beclomethasone dipropionate suspension for inhalation can be dispersed better, and at the same time, the solubility of beclomethasone dipropionate will not be increased, thereby avoiding the influence of the dispersion medium on the detection of beclomethasone dipropionate, thereby ensuring the accuracy and repeatability of the detection result, providing a new method for the particle size determination of the beclomethasone dipropionate suspension for inhalation, and providing a reliable guarantee for improving and better controlling the quality of the beclomethasone dipropionate suspension for inhalation.

[0027] Preferably, the particle size detection method of the beclomethasone dipropionate suspension for inhalation comprises the following specific steps:

[0028] Dissolve Triton X-100 in water, and add beclomethasone dipropionate to the water until saturated to obtain a saturated beclomethasone dipropionate solution;

[0029] The beclomethasone dipropionate suspension for inhalation is added to the saturated beclomethasone dipropionate solution, mixed, and added to a particle size tester for testing.

[0030] Preferably, the shading ratio is controlled to be 5%-15% during the detection process.

[0031] Preferably, a laser particle size analyzer is used for detection, and the parameters are set as follows: the particle type is non-spherical, the refractive index is 1.52, the sample absorptivity is 0.1, the refractive index of the dispersant is 1.33, and the speed of the injector is 1600 r / min.

[0032] The preparation method of the beclomethasone dipropionate suspension for inhalation provided by the present invention can achieve a narrower particle size distribution and a better suspension effect, so that the particle size distribution of the prepared beclomethasone dipropionate suspension is uniform and stable, thereby being conducive to giving full play to the efficacy of the beclomethasone dipropionate suspension, and the preparation method is simple to operate, has strong controllability, and is easy to realize industrialized large-scale production; at the same time, the particle size detection method of the beclomethasone dipropionate suspension for inhalation provided by the present invention has high detection accuracy and good repeatability, provides a reliable guarantee and basis for improving the quality of the beclomethasone dipropionate suspension for inhalation, and has high practical value. DETAILED DESCRIPTION

[0033] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0034] In order to better illustrate the present invention, further examples are given below.

[0035] Example 1

[0036] Screening of dispersion medium

[0037] 1. Water

[0038] Water was directly used as the dispersion medium, and the beclomethasone propionate raw material was added into the water. It was found that the dispersion effect of beclomethasone propionate in water was poor, the distribution was uneven, there were obvious agglomerations visible to the naked eye, and some beclomethasone propionate was dissolved. The agglomerated materials could not achieve good dispersion, which affected the accuracy of the beclomethasone propionate particle size distribution measurement.

[0039] 2. Tween 20 aqueous solution

[0040] Using 0.1% Tween 20 aqueous solution as the dispersion medium, the beclomethasone propionate raw material was added to the 0.1% Tween 20 aqueous solution. It was found that although the dispersion effect of beclomethasone propionate in water was improved to a certain extent, the solubility of beclomethasone propionate in water increased, and more beclomethasone propionate was dissolved. The change of the shading ratio of beclomethasone propionate in 0.1% Tween 20 aqueous solution with the extension of the dispersion time is shown in Table 1.

[0041] Table 1

[0042] Spread out time Shading ratio (%) 0min 11.53 1min 10.21 3min 9.65 5min 7.67

[0043] It can be seen from the above table that after Tween 20 is added to water, the shading ratio of beclomethasone propionate in water decreases continuously with time, indicating that the solubility of beclomethasone propionate in water gradually increases, which will inevitably affect the accuracy of the test results.

[0044] 3. SPAN-80 aqueous solution

[0045] SPAN-80 was added to water as a dispersion medium, and SPAN-80 was prepared into aqueous solutions of different concentrations (0.1%-1%) for comparison.

[0046] The results showed that SPAN-80 had poor dispersibility in water and had visible agglomeration, which would affect the determination of beclomethasone dipropionate suspension.

[0047] 4. Triton X-100 Beclomethasone Dipropionate Saturated Solution

[0048] The inventors have tried various surfactants to improve the dispersibility of beclomethasone dipropionate in water and reduce the solubility of beclomethasone dipropionate in water, but none of them achieved good results. The inventors unexpectedly discovered that using 0.05%-0.3% Triton X-100 beclomethasone dipropionate saturated solution as a dispersion medium can achieve the effect of taking both into account.

[0049] Preparation of beclomethasone dipropionate saturated solution: Add beclomethasone dipropionate raw material into 0.1% Triton X-100 aqueous solution until saturated, stir at 1000 rpm for 12 h, filter through 0.22 μm filter membrane to obtain beclomethasone dipropionate saturated solution.

[0050] The beclomethasone dipropionate powder is added to the above-mentioned saturated beclomethasone dipropionate solution, and after stirring, a suspension which is uniformly dispersed and free of aggregation can be obtained.

[0051] The above suspension was tested for particle size using a laser particle size analyzer with the following parameters: shading ratio 5%-15%, non-spherical particle type, refractive index 1.52, sample absorptivity 0.1, dispersant refractive index 1.33, injector speed 1600r / min, and background subtraction.

[0052] The shading ratio data of different dispersion times are shown in Table 3.

[0053] Table 3

[0054] Spread out time Shading ratio 0min 10.67 1min 10.67 3min 10.66 5min 10.66

[0055] As can be seen from the above table, when Triton X-100 is added to water, and under specific concentration conditions of Triton, the solubility of beclomethasone dipropionate in water does not increase substantially, and the dispersion is uniform without aggregation. Therefore, Triton X-100 aqueous solution is selected as the dispersion medium for preparing beclomethasone dipropionate suspension for inhalation, and Triton X-100 beclomethasone dipropionate saturated solution is selected as the dispersion medium for detecting beclomethasone dipropionate suspension for inhalation.

[0056] Example 2

[0057] This embodiment provides a method for preparing a beclomethasone dipropionate suspension for inhalation, comprising the following steps:

[0058] Step a, ultrafine grinding the beclomethasone dipropionate raw material by using a jet mill, the airflow pressure is 4.5 bar, the feed speed is 10 rpm, and ultrafine beclomethasone dipropionate powder (D90 is 5 μm-8 μm, D50 is 2.5 μm-4 μm, and D10 is 0.8 μm-1.2 μm);

[0059] Step b, dissolving the weighed Triton X-100 in water to obtain a Triton X-100 aqueous solution with a mass concentration of 0.1%;

[0060] Add 1 g of beclomethasone propionate ultrafine powder to the above 0.1 wt % Triton X-100 aqueous solution, and mix at 1000 rpm for 30 min to obtain a primary emulsion;

[0061] Step c, adding the primary emulsion into a counter-cavity microfluidizer for homogenization at a pressure of 2500 psi and homogenization for 2 times to obtain the beclomethasone dipropionate suspension for inhalation.

[0062] Example 3

[0063] This embodiment provides a method for preparing a beclomethasone dipropionate suspension for inhalation, comprising the following steps:

[0064] Step a, ultrafine grinding the beclomethasone dipropionate raw material by using an air flow mill, the air flow pressure is 3 bar, the feed speed is 5 rpm, and ultrafine beclomethasone dipropionate powder (D90 is 5 μm-8 μm, D50 is 2.5 μm-4 μm, and D10 is 0.8 μm-1.2 μm);

[0065] Step b, dissolving the weighed Triton X-100 in water to obtain a Triton X-100 aqueous solution with a mass concentration of 0.05 wt %;

[0066] Add 0.5 g of beclomethasone propionate ultrafine powder to the above 0.05 wt % Triton X-100 aqueous solution, and mix at 900 rpm for 35 min to obtain a primary emulsion;

[0067] Step c, adding the primary emulsion into a counter-cavity microfluidizer for homogenization at a pressure of 2000 psi and homogenization times of 5 times to obtain the beclomethasone dipropionate suspension for inhalation.

[0068] Example 4

[0069] This embodiment provides a method for preparing a beclomethasone dipropionate suspension for inhalation, comprising the following steps:

[0070] Step a, ultrafine grinding the beclomethasone dipropionate raw material by using an air flow mill, the air flow pressure is 6 bar, the feed speed is 30 rpm, and ultrafine beclomethasone dipropionate powder (D90 is 5 μm-8 μm, D50 is 2.5 μm-4 μm, and D10 is 0.8 μm-1.2 μm);

[0071] Step b, dissolving the weighed Triton X-100 in water to obtain a Triton X-100 aqueous solution with a mass concentration of 0.3 wt %;

[0072] Add 3 g of beclomethasone propionate ultrafine powder to the above 0.3 wt % Triton X-100 aqueous solution, and mix at 1100 rpm for 25 min to obtain a primary emulsion;

[0073] Step c, adding the primary emulsion into a counter-cavity microfluidizer for homogenization at a pressure of 10,000 psi and a homogenization time of 1 time to obtain the beclomethasone dipropionate suspension for inhalation.

[0074] The particle size D90 of the beclomethasone dipropionate raw material used in the above Examples 2-4 is 30 μm-150 μm.

[0075] After the ultrafine grinding in step a of the above embodiment 2-4 is completed, the ultrafine powder is tested for particle size to meet the particle size requirements of D90, D50 and D10 before step c is performed. The particle size detection method can be carried out according to 5. Testing of the saturated solution of Triton X-100 beclomethasone dipropionate in embodiment 1.

[0076] In the above-mentioned embodiments 2-4, a counter-cavity micro-jet homogenizer can also be used. As long as the micro-jet homogenization pressure is between 20,000psi and 30,000psi and homogenization is performed 1-3 times, substantially equivalent technical effects can be achieved.

[0077] Example 5

[0078] This embodiment provides a method for detecting the particle size of a beclomethasone dipropionate suspension for inhalation, comprising the following steps:

[0079] Dissolving Triton X-100 in water to obtain a 0.1% Triton X-100 aqueous solution; then adding beclomethasone dipropionate to the solution until saturated to obtain a saturated beclomethasone dipropionate solution;

[0080] The beclomethasone dipropionate suspension for inhalation is added to the saturated beclomethasone dipropionate solution, mixed, and added to a particle size tester for testing. During the testing process, the shading ratio is controlled to be 5%-15%. After the shading ratio is stable, it is stirred for 1 minute and tested.

[0081] A laser particle size analyzer was used for detection, and the parameters were set as follows: particle type was non-spherical, refractive index was 1.52, sample absorptivity was 0.1, refractive index of dispersant was 1.33, injector speed was 1600 r / min, and background was subtracted.

[0082] The particle size of the beclomethasone dipropionate suspension for inhalation prepared in Example 1 was tested by the above method. Twelve samples were randomly taken and tested by two people respectively. The results are shown in Table 4.

[0083] Table 4

[0084]

[0085] According to the results in Table 4, the relative standard deviations of the D10, D50, and D90 of the 6 test samples measured by the first person were 0.91%, 1.86%, and 1.31%, respectively, all less than 6.0%; the relative standard deviations of the D10, D50, and D90 of the 6 test samples measured by the second person were 1.19%, 1.03%, and 1.58%, respectively, all less than 6.0%. The relative standard deviations of the D10, D50, and D90 of the 12 test samples were 1.08%, 1.30%, and 1.44%, respectively, all less than 6.0%; the precision of the determination method of the present invention is good.

[0086] Example 6

[0087] This embodiment provides a method for detecting the particle size of a beclomethasone dipropionate suspension for inhalation, comprising the following steps:

[0088] Dissolving Triton X-100 in water to obtain a 0.05% Triton X-100 aqueous solution; then adding beclomethasone dipropionate to the solution until saturated to obtain a saturated beclomethasone dipropionate solution;

[0089] The beclomethasone dipropionate suspension for inhalation is added to the saturated beclomethasone dipropionate solution, mixed, and added to a particle size tester for testing. During the testing process, the shading ratio is controlled to be 5%-15%.

[0090] Example 7

[0091] This embodiment provides a method for detecting the particle size of a beclomethasone dipropionate suspension for inhalation, comprising the following steps:

[0092] Dissolving Triton X-100 in water to obtain a 0.3% Triton X-100 aqueous solution; then adding beclomethasone dipropionate to the solution until saturated to obtain a saturated beclomethasone dipropionate solution;

[0093] The beclomethasone dipropionate suspension for inhalation is added to the saturated beclomethasone dipropionate solution, mixed, and added to a particle size tester for testing. During the testing process, the shading ratio is controlled to be 5%-15%.

[0094] In Examples 6-7, a laser particle size analyzer was used for detection, and the parameters were set as follows: the particle type was non-spherical, the refractive index was 1.52, the sample absorptivity was 0.1, the refractive index of the dispersant was 1.33, and the speed of the injector was 1600 r / min.

[0095] The particle sizes of the beclomethasone dipropionate suspensions for inhalation prepared in Examples 1-3 were tested using the methods of Examples 6-7, and the test results were substantially equivalent to those in Example 5.

[0096] Particle size stability test

[0097] The beclomethasone dipropionate suspension for inhalation prepared in Example 2-4 was placed under the conditions of 30°C±2°C and RH65%±5% and subjected to a long-term stability test. The test results are shown in Table 5.

[0098] Table 5

[0099] Sampling time D10(μm) D50(μm) D90(μm) 0 month 0.794 2.201 4.780 January 0.801 2.214 4.793 March 0.812 2.276 4.835 June 0.821 2.321 4.890 September 0.825 2.371 4.891 Average value (μm) 0.811 2.228 4.837 RSD 1.61％ 3.15％ 1.08％

[0100] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A beclomethasone dipropionate suspension for inhalation, characterized in that: The beclomethasone dipropionate suspension for inhalation consists of beclomethasone dipropionate, Triton X-100 and water, wherein each 100 mL of the suspension contains 0.5 g to 3 g of beclomethasone dipropionate and 0.05 wt % to 0.3 wt % of Triton X-100; the particle size D90 of beclomethasone dipropionate in the beclomethasone dipropionate suspension for inhalation is 4.2 µm to 5.0 µm, D50 is 2.0 µm to 2.5 µm, and D10 is 0.7 µm to 1.2 µm.

2. A method for preparing the beclomethasone dipropionate suspension for inhalation according to claim 1, characterized in that: The steps include: Step a, ultrafine grinding the beclomethasone propionate raw material to a preset particle size distribution to obtain ultrafine beclomethasone propionate powder; Step b, weighing each component according to the designed ratio, dissolving the weighed Triton X-100 in water, adding the weighed beclomethasone propionate ultrafine powder, and mixing to obtain a primary emulsion; Step c, homogenizing the primary emulsion by microfluidization to obtain the beclomethasone dipropionate suspension for inhalation.

3. The method for preparing the beclomethasone dipropionate suspension for inhalation as claimed in claim 2, characterized in that, In step a, the particle size D90 of the beclomethasone dipropionate raw material is 30µm-150µm.

4. The method for preparing the beclomethasone dipropionate suspension for inhalation as claimed in claim 2, characterized in that, In step a, the air flow pressure of the ultrafine grinding is 3 bar-6 bar, and the feed speed is 5 rpm-30 rpm.

5. The method for preparing the beclomethasone dipropionate suspension for inhalation according to claim 2 or 4, characterized in that, The preset particle size distribution is D90 of 5µm-8µm, D50 of 2.5µm-4µm, and D10 of 0.8µm-1.2µm.

6. The method for preparing the beclomethasone dipropionate suspension for inhalation according to claim 2, characterized in that: In step b, the mixing speed is 900 rpm-1100 rpm, and the mixing time is 25 min-35 min; and / or In step c, the pressure of the microfluidic homogenization is 2000psi-30000psi, and the number of microfluidic homogenization is 1-5 times.

7. A method for detecting the particle size of the beclomethasone dipropionate suspension for inhalation according to claim 1, characterized in that: The method comprises the following steps: adding a beclomethasone dipropionate suspension for inhalation to be tested into a dispersion medium, mixing, and testing; Wherein, the dispersion medium is a saturated beclomethasone dipropionate solution, and the solvent is a 0.05%-0.3% Triton X-100 aqueous solution.

8. The particle size detection method of beclomethasone dipropionate suspension for inhalation as claimed in claim 7, characterized in that, The specific steps are as follows: Dissolve Triton X-100 in water, and add beclomethasone dipropionate to the water until saturated to obtain a saturated beclomethasone dipropionate solution; The beclomethasone dipropionate suspension for inhalation is added to the saturated beclomethasone dipropionate solution, mixed, and added to a particle size tester for testing.

9. The particle size detection method of beclomethasone dipropionate suspension for inhalation according to claim 7, characterized in that, During the test, the shading ratio is controlled to be 5%-15%; and / or The laser particle size analyzer was used for detection, and the parameters were set as follows: particle type was non-spherical, refractive index was 1.52, sample absorptivity was 0.1, refractive index of dispersant was 1.33, and injector speed was 1600 r / min.

Images