Method for eliminating bubbles in process of detecting dissolution rate of calcium carbonate D3 chewable tablets

Abstract

The invention belongs to the technical field of medicine quality detection, and particularly relates to a method for eliminating bubbles in the process of detecting the dissolution rate of calcium carbonate D3 chewable tablets, the method comprises the following steps: S1, adding a hydrochloric acid solution and a defoaming agent into a container as a dissolution medium, the defoaming agent containing a polyether modified polysiloxane component; s2, adding a to-be-detected sample into the dissolution medium, and uniformly stirring; and S3, taking out the solution from the container, filtering, adding water, a sodium hydroxide solution, a triethanolamine solution and a calcium sodium carboxylate indicator into the filtrate to obtain a detection solution, titrating with a disodium ethylene diamine tetraacetate titrating solution until the detection solution is changed from amaranth to blue, and calculating the dissolution rate of the to-be-detected sample according to the consumption of the disodium ethylene diamine tetraacetate titrating solution. According to the method, the polyether modified polysiloxane component is added into the dissolution medium, so that bubbles generated in the dissolution process can be eliminated in time, wrapping of the bubbles is eliminated, and the accuracy of a detection result is remarkably improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical quality testing technology, specifically relating to a method for eliminating air bubbles during the process of testing the dissolution rate of calcium carbonate D3 chewable tablets. Background Technology

[0002] Dissolution rate is a core indicator for assessing the bioavailability of oral solid dosage forms in vivo, and its test results are directly related to the clinical efficacy and safety of drugs.

[0003] When testing the dissolution rate of calcium carbonate D3 chewable tablets, the slurry method (General Chapter 0931, Method II, Chinese Pharmacopoeia 2015 Edition) is generally used, with hydrochloric acid solution (9→1000ml) as the dissolution medium to simulate the acidic environment in the human stomach.

[0004] However, in actual operation, when calcium carbonate D3 chewable tablets are placed in the hydrochloric acid dissolution medium, the calcium carbonate in the chewable tablets reacts chemically with the hydrochloric acid. During the reaction, a large number of carbon dioxide bubbles are continuously generated. These bubbles not only adhere to the surface of the disintegrated tablet particles but also encapsulate some of the particles, making it difficult for the dissolution medium to penetrate into the disintegrated particles, thus resulting in a lower-than-expected dissolution rate. This is especially noticeable when tested with a closed dissolution apparatus; compared to the results from an open dissolution apparatus, the accuracy of the results from a closed dissolution apparatus is poor. Summary of the Invention

[0005] To address the problems existing in the prior art, this invention provides a method for eliminating air bubbles during the dissolution testing of calcium carbonate D3 chewable tablets. By adding polyether-modified polysiloxane components to the dissolution medium, air bubbles generated during the dissolution process can be eliminated in a timely manner, removing the encapsulation of air bubbles and significantly improving the accuracy of the test results.

[0006] The specific technical solution adopted in this invention is as follows: A method for eliminating air bubbles during the detection of the dissolution rate of calcium carbonate D3 chewable tablets, comprising the following steps: S1. Add hydrochloric acid solution and defoamer to a container as a dissolution medium, wherein the defoamer contains polyether-modified polysiloxane components; The defoamer includes any one of the following: Tegopren 5853 nonionic polyether modified polysiloxane manufactured by Degussa, Corning Q2-5211 defoamer manufactured by Dow, and Silicone Defoamer AK 30 manufactured by Wacker.

[0007] S2. Add the calcium carbonate D3 chewable tablet sample to be tested into the dissolution medium and rotate it at a speed of 50-100 rpm for 20-40 minutes. S3. Remove the solution from the container and filter it. Add water, sodium hydroxide solution, triethanolamine solution and sodium calcium carboxylate indicator to the filtrate to obtain the test solution. Titrate with disodium ethylenediaminetetraacetate titrant until the test solution changes from purple-red to blue. Calculate the dissolution rate of the sample to be tested based on the amount of disodium ethylenediaminetetraacetate titrant consumed.

[0008] Furthermore, the concentration of the hydrochloric acid solution in step S1 is 0.10-0.12 mol / L.

[0009] Preferably, the concentration of the hydrochloric acid solution in step S1 is 0.1 mol / L.

[0010] Furthermore, the amount of defoamer added in step S1 is 0.005%-2% of the volume of the hydrochloric acid solution.

[0011] Furthermore, the concentration of the sodium hydroxide solution in step S3 is 8-12 mol / L, and the volume ratio of solute to solvent in the triethanolamine solution is 1:3-4. The solute is triethanolamine and the solvent is water.

[0012] Furthermore, the detection solution in step S3 comprises, by volume, 8-10 parts filtrate, 45-55 parts water, 8-12 parts sodium hydroxide solution, and 4-6 parts triethanolamine solution. The detection solution also contains sodium calcium carboxylate indicator, with 0.1g of sodium calcium carboxylate indicator added for every 45-55ml of water.

[0013] Furthermore, the concentration of the disodium ethylenediaminetetraacetate titrant in step S3 is 0.05 mol / L, and the amount of calcium consumed per 1 mL of disodium ethylenediaminetetraacetate titrant is equal to 2.004 mg.

[0014] Furthermore, the defoamer mentioned in step S1 needs to be pretreated before being added to the hydrochloric acid solution. The specific pretreatment steps are as follows: Q1. Add the defoamer to the ethanol and stir until homogeneous to obtain the core material; Q2. Add hydroxypropyl methylcellulose to water, stir at 50°C for 20-40 minutes, and cool to room temperature to obtain the shell material; Q3. Drop the core material into the shell material and shear it with a high-speed shearing machine at a speed of 10,000-12,000 rpm for 10-15 minutes to form an emulsion. Q4. Transfer the emulsion to a rotary evaporator and rotary evaporate until the ethanol is completely evaporated to obtain a core-shell suspension; Q5. The core-shell suspension is fed into a spray dryer and dried to obtain powdered core-shell particles, which are the pretreated defoamer.

[0015] Furthermore, the mass ratio of the defoamer to hydroxypropyl methylcellulose is 2:1-2.

[0016] Furthermore, the temperature of the rotary evaporator is 20-35℃, the rotation speed is 75-100rpm, and the rotary evaporation time is 30-40min.

[0017] Furthermore, the spray dryer has an inlet air temperature of 75-80℃, an outlet air temperature of 35-40℃, a feed rate of 8-12mL / min, and an atomization pressure of 0.2MPa.

[0018] The beneficial effects of this invention are: 1. This invention, by adding 0.005%-2% by volume of polyether-modified polysiloxane to the dissolution medium, can promptly eliminate bubbles generated during the dissolution process, remove bubble encapsulation, and not affect the solubility of the raw material calcium carbonate in the system. This ensures that the dissolution results on different models of dissolution apparatus are basically consistent, significantly improving the precision of the dissolution method.

[0019] Among them, polyether-modified polysiloxane components can reduce the surface tension of bubbles and disrupt their stability, thereby enabling rapid bubble rupture. At the same time, polyether-modified polysiloxane components will form a monolayer in the solution, covering the liquid surface, occupying the active sites where bubbles may form, and inhibiting bubble regeneration.

[0020] 2. When polyether-modified polysiloxane is directly added to the dissolution medium, uneven dispersion may lead to excessively high local solubility and the appearance of "oil droplets". The oil droplets will adsorb bubbles to form complexes, causing bubble agglomeration and reducing the defoaming efficiency.

[0021] Therefore, this invention employs a core-shell structured defoamer to address the issues of uneven dispersion and easy aggregation of defoamers in hydrochloric acid dissolution media. The core-shell structure uses easily dispersible, acid-soluble, low-viscosity hydroxypropyl methylcellulose as the shell material, encapsulating the core defoamer into micron-sized core-shell particles. This structure achieves uniform distribution of the defoamer in the dissolution medium through the dispersing and guiding effect of the shell material, and also allows for rapid dissolution of the shell material and release of the defoamer in the hydrochloric acid dissolution environment, thus improving detection accuracy. Attached Figure Description

[0022] Figure 1 A comparison of the pH-solubility curves of calcium carbonate in two media; Figure 2 The dissolution curves of calcium carbonate D3 chewable tablets in Example 5 at different times are shown. Figure 3 The dissolution curves of calcium carbonate D3 chewable tablets in Comparative Example 2 at different times; Figure 4 The dissolution curves of Example 5 and Comparative Example 2 are compared. Detailed Implementation

[0023] The present invention will be further described below with reference to the accompanying drawings and specific embodiments: The defoamer used in this invention is Tegopren® 5853, a nonionic polyether-modified polysiloxane produced by Degussa. The preparation method of the sodium calcium carboxylate indicator is as follows: take 0.1g of sodium calcium carboxylate, add 10g of anhydrous sodium sulfate, and grind evenly. I. Specific Implementation Methods Example 1 S1. Add 0.01% by volume of polyether-modified polysiloxane to the hydrochloric acid solution (9→1000ml) to form 900ml of dissolution medium; S2. Add the calcium carbonate D3 chewable tablets to the dissolution medium and rotate at 75 rpm for 30 minutes. S3. Remove the solution from the container and filter it. Take 10 mL of the filtrate and add 50 mL of water, 10 mL of 10 mol / L sodium hydroxide solution, 5 mL of triethanolamine solution with a solute-to-solvent volume ratio of 1:3, and 0.1 g of sodium calcium carboxylate indicator. Titrate with 0.05 mol / L disodium ethylenediaminetetraacetate titrant until the test solution changes from purple-red to blue. Each 1 mL of disodium ethylenediaminetetraacetate titrant is equivalent to 2.004 mg of calcium.

[0025] Example 2 S1. Add 0.005% by volume of polyether-modified polysiloxane to the hydrochloric acid solution (9→1000ml) to form 900ml of dissolution medium; S2. Add the calcium carbonate D3 chewable tablets to the dissolution medium and rotate at 50 rpm for 40 minutes. S3. Remove the solution from the container and filter it. Take 8 mL of the filtrate and add 45 mL of water, 8 mL of 10 mol / L sodium hydroxide solution, 4 mL of triethanolamine solution with a solute-to-solvent volume ratio of 1:3, and 0.1 g of sodium calcium carboxylate indicator to the filtrate. Titrate with 0.05 mol / L disodium ethylenediaminetetraacetate titrant until the test solution changes from purple-red to blue. Each 1 mL of disodium ethylenediaminetetraacetate titrant is equivalent to 2.004 mg of calcium.

[0026] Example 3 S1. Add 0.005% by volume of polyether-modified polysiloxane to the hydrochloric acid solution (9→1000ml) to form 900ml of dissolution medium; S2. Add the calcium carbonate D3 chewable tablets to the dissolution medium and rotate at 100 rpm for 20 minutes. S3. Remove the solution from the container and filter it. Take 10 mL of the filtrate and add 55 mL of water, 12 mL of 10 mol / L sodium hydroxide solution, 6 mL of triethanolamine solution with a solute-to-solvent volume ratio of 1:3, and 0.1 g of sodium calcium carboxylate indicator. Titrate with 0.05 mol / L disodium ethylenediaminetetraacetate titrant until the test solution changes from purple-red to blue. Each 1 mL of disodium ethylenediaminetetraacetate titrant is equivalent to 2.004 mg of calcium.

[0027] Example 4 S1. First, pre-treat the defoamer. The pre-treatment process is as follows: S101. Add 10g of polyether-modified polysiloxane to 50ml of ethanol and stir until homogeneous to obtain the core material; S102. Add 5g of hydroxypropyl methylcellulose to 200mL of water, stir in a water bath at 50℃ for 30min, and cool to room temperature to obtain the shell material. S103. Slowly drip the core material into the shell material at a drip rate of 5 mL / min, and use a high-speed shearing machine to shear at a speed of 12000 rpm for 10 min to form an emulsion. S104. Transfer the emulsion to a rotary evaporator and rotary evaporate until the ethanol is completely evaporated to obtain a core-shell suspension. The rotary evaporator was set at a temperature of 35℃, a vacuum of -0.08MPa, a rotation speed of 100rpm, and a rotary evaporation time of 30min. S105. The core-shell suspension is fed into a spray dryer and dried to obtain powdered core-shell particles. The powdered core-shell particles are the pretreated defoamer. The spray dryer has an inlet air temperature of 80℃, an outlet air temperature of 40℃, a feed rate of 10mL / min, and an atomization pressure of 0.2MPa. S2. Add 0.135g of granular defoamer (containing the same amount of polyether-modified polysiloxane as the polyether-modified polysiloxane added in Example 1) to 900mL of hydrochloric acid solution (9→1000ml) to form a dissolution medium. S3. Add the calcium carbonate D3 chewable tablets to the dissolution medium and rotate at 75 rpm for 30 minutes. S4. Remove the solution from the container and filter it. Take 10 mL of the filtrate and add 50 mL of water, 10 mL of 10 mol / L sodium hydroxide solution, 5 mL of triethanolamine solution with a solute-to-solvent volume ratio of 1:3, and 0.1 g of sodium calcium carboxylate indicator. Titrate with 0.05 mol / L disodium ethylenediaminetetraacetate titrant until the test solution changes from purple-red to blue. Each 1 mL of disodium ethylenediaminetetraacetate titrant is equivalent to 2.004 mg of calcium.

[0028] Example 5 S1. Add 0.01% by volume of polyether-modified polysiloxane to the hydrochloric acid solution (9→1000ml) to form 900ml of dissolution medium; S2. Add calcium carbonate D3 chewable tablets to the dissolution medium and rotate at 75 rpm for 90 minutes. Take 20 ml of solution at 5, 10, 15, 30, 45, 60 and 90 minutes respectively, filter, and add 20 ml of dissolution medium at the same temperature at the same time. S3. Take 10 mL of filtrate, add 50 mL of water, 10 mL of 10 mol / L sodium hydroxide solution, 5 mL of triethanolamine solution with a solute-to-solvent volume ratio of 1:3, and 0.1 g of sodium calcium carboxylate indicator. Titrate with 0.05 mol / L disodium ethylenediaminetetraacetate titrant until the test solution changes from purple-red to blue. Each 1 mL of disodium ethylenediaminetetraacetate titrant is equivalent to 2.004 mg of calcium.

[0029] Comparative Example 1 S1. Prepare 900 ml of hydrochloric acid solution (9→1000 ml) as the dissolution medium; S2. Add the calcium carbonate D3 chewable tablets to the dissolution medium and rotate at 75 rpm for 30 minutes. S3. Remove the solution from the container and filter it. Take 10 mL of the filtrate and add 50 mL of water, 10 mL of 10 mol / L sodium hydroxide solution, 5 mL of triethanolamine solution with a solute-to-solvent volume ratio of 1:3, and 0.1 g of sodium calcium carboxylate indicator. Titrate with 0.05 mol / L disodium ethylenediaminetetraacetate titrant until the test solution changes from purple-red to blue. Each 1 mL of disodium ethylenediaminetetraacetate titrant is equivalent to 2.004 mg of calcium.

[0030] Comparative Example 2 S1. Prepare 900 ml of hydrochloric acid solution (9→1000 ml) as the dissolution medium; S2. Add calcium carbonate D3 chewable tablets to the dissolution medium and rotate at 75 rpm for 90 minutes. Take 20 ml of solution at 5, 10, 15, 30, 45, 60 and 90 minutes respectively, filter, and add 20 ml of dissolution medium at the same temperature at the same time. S3. Take 10 mL of filtrate, add 50 mL of water, 10 mL of 10 mol / L sodium hydroxide solution, 5 mL of triethanolamine solution with a solute-to-solvent volume ratio of 1:3, and 0.1 g of sodium calcium carboxylate indicator. Titrate with 0.05 mol / L disodium ethylenediaminetetraacetate titrant until the test solution changes from purple-red to blue. Each 1 mL of disodium ethylenediaminetetraacetate titrant is equivalent to 2.004 mg of calcium.

[0031] II. Performance Testing 1. Experiment comparing the solubility of calcium carbonate in two media Two equal amounts of calcium carbonate were prepared and added to the dissolution media of Example 1 and Comparative Example 1, respectively. The solubility of calcium carbonate in the two different dissolution media was tested, and the test results are shown in [Figure 1]. Figure 1 .

[0032] As can be seen from the comparison of pH-solubility curves in different media, the addition of 0.01% polyether-modified polysiloxane has no effect on the solubility of calcium carbonate.

[0033] 2. Comparison of the precision of detection results from different dissolution testing methods Dissolution testing was performed on equal amounts of calcium carbonate D3 chewable tablets using the dissolution testing methods described in Examples 1, 4, and Comparative Example 1. Multiple sets of experiments were conducted for each testing method, and the results are as follows.

[0034] 2.1 Test results of Comparative Example 1 Table 1 shows the repeatability of dissolution results in hydrochloric acid solution (9→1000ml) medium, Table 2 shows the intermediate precision of dissolution results in hydrochloric acid solution (9→1000ml) medium, and Table 3 shows the reproducibility of dissolution results in hydrochloric acid solution (9→1000ml) medium.

[0035] 2.2 Test Results of Example 1 Table 4 shows the repeatability of the dissolution results in the medium of hydrochloric acid solution (9→1000ml) + 0.01% polyether modified polysiloxane (Example 1); Table 5 shows the intermediate precision of the dissolution results in the medium of hydrochloric acid solution (9→1000ml) + 0.01% polyether modified polysiloxane (Example 1); and Table 6 shows the reproducibility of the dissolution results in the medium of hydrochloric acid solution (9→1000ml) + 0.01% polyether modified polysiloxane (Example 1).

[0036] 2.3 Detection Results of Example 4 Table 7 shows the repeatability of the dissolution results in the medium of hydrochloric acid solution (9→1000ml) + 0.01% polyether-modified polysiloxane (Example 4); Table 8 shows the intermediate precision of the dissolution results in the medium of hydrochloric acid solution (9→1000ml) + 0.01% polyether-modified polysiloxane (Example 4); and Table 9 shows the reproducibility of the dissolution results in the medium of hydrochloric acid solution (9→1000ml) + 0.01% polyether-modified polysiloxane (Example 4).

[0037] 2.4 Comparison of Test Results As can be seen from Table 10, when using the existing method to test dissolution in Comparative Example 1, the dissolution result was low at the same rotation speed and time due to the influence of bubbles. Moreover, the results of dissolution testers from different manufacturers or models (all of which meet the requirements of the Chinese Pharmacopoeia) fluctuated greatly, ranging from 75% to 87%. A dissolution rate of 75% is already at the edge of the standard limit, which poses a great risk to daily product quality monitoring.

[0038] By using the method of the present invention, both Examples 1 and 4 eliminated most of the air bubbles, which allowed the product dissolution medium to effectively wet the product during the dissolution process, enabling the product to disintegrate and dissolve smoothly, resulting in a faster dissolution rate and more accurate results.

[0039] Table 10 shows the comparison of dissolution results (75 r / min, 30 min), and Table 11 shows the comparison of method repeatability.

[0040] As can be seen from Table 10, when using the existing method to test dissolution in Comparative Example 1, the dissolution result was low at the same rotation speed and time due to the influence of bubbles. Moreover, the results of dissolution testers from different manufacturers or models (all of which meet the requirements of the Chinese Pharmacopoeia) fluctuated greatly, ranging from 75% to 87%. A dissolution rate of 75% is already at the edge of the standard limit, which poses a great risk to daily product quality monitoring.

[0041] By using the method of the present invention, both Examples 1 and 4 eliminated most of the air bubbles, which allowed the product dissolution medium to effectively wet the product during the dissolution process, enabling the product to disintegrate and dissolve smoothly, resulting in a faster dissolution rate and more accurate results.

[0042] As can be seen from Table 11, when using the existing method to detect dissolution in Comparative Example 1, the repeatability, intermediate precision, and reproducibility of the test results are poor due to the influence of air bubbles, which is insufficient to reflect the true dissolution value of calcium carbonate D3 chewable tablets. In particular, when using a closed dissolution apparatus in Laboratory 2, the detected dissolution is significantly reduced.

[0043] Using the method of this invention, most of the air bubbles in Examples 1 and 4 were eliminated, improving the accuracy of the test results. The RSD values ​​of repeatability, intermediate precision, and reproducibility experiments were all below 1.7%, which can more accurately reflect the true dissolution value of calcium carbonate D3 chewable tablets.

[0044] Furthermore, in Example 4, the pretreatment of the defoamer improved its dispersibility, resulting in repeatability, intermediate precision, and RSD values ​​of the reproducibility test all being below 1.2%, further improving the accuracy of the test results.

[0045] 2.5 Detection results of Example 5 and Comparative Example 2 The detection results of Example 5 are shown in Table 12 and Figure 2 The test results for Comparative Example 2 are shown in Table 13 and Figure 3 The comparison results between Example 5 and Comparative Example 2 are shown in Table 14 and Figure 4 .

[0046] (Note: Some solubility measurements in Table 12 are greater than 100%. This is due to errors. On the one hand, there is a certain error between the actual added content and the standard added content during the preparation of calcium tablets. The actual added amount may be slightly higher than the standard added amount. On the other hand, there are systematic errors in the measurement process. The superposition of the two errors will lead to a certain deviation in the final value, thus exceeding 100%.) A comparison between Example 5 and Comparative Example 2 shows that when using the existing method to detect dissolution in Comparative Example 2, the dissolution results at each time point are lower due to the influence of bubbles at the same rotation speed and time, resulting in a much lower result at 30 min. Furthermore, the RSD values ​​among the 12 tablets are relatively large, with significant differences.

[0047] Using the method of the present invention, Example 5 eliminates most of the air bubbles, allowing each tablet to be well wetted by the dissolution medium during the dissolution process, enabling the tablet to disintegrate and dissolve quickly, and the RSD values ​​among the 12 tablets are small, with minimal differences.

Claims

1. A method for eliminating air bubbles during the process of detecting the dissolution rate of calcium carbonate D3 chewable tablets, characterized in that, Includes the following steps: S1. Add hydrochloric acid solution and defoamer to a container as a dissolution medium, wherein the defoamer contains polyether-modified polysiloxane components; S2. Add the calcium carbonate D3 chewable tablet sample to be tested into the dissolution medium and rotate it at a speed of 50-100 rpm for 20-40 minutes. S3. Remove the solution from the container and filter it. Add water, sodium hydroxide solution, triethanolamine solution and sodium calcium carboxylate indicator to the filtrate to obtain the test solution. Titrate with disodium ethylenediaminetetraacetate titrant until the test solution changes from purple-red to blue. Calculate the dissolution rate of the sample to be tested based on the amount of disodium ethylenediaminetetraacetate titrant consumed.

2. The method for eliminating air bubbles during the detection of the dissolution rate of calcium carbonate D3 chewable tablets according to claim 1, characterized in that, The concentration of the hydrochloric acid solution in step S1 is 0.10-0.12 mol / L.

3. The method for eliminating air bubbles during the detection of the dissolution rate of calcium carbonate D3 chewable tablets according to claim 2, characterized in that, The amount of defoamer added in step S1 is 0.005%-2% of the volume of the hydrochloric acid solution.

4. The method for eliminating air bubbles during the detection of the dissolution rate of calcium carbonate D3 chewable tablets according to claim 1, characterized in that, The concentration of the sodium hydroxide solution in step S3 is 8-12 mol / L, and the volume ratio of solute to solvent in the triethanolamine solution is 1:3-4.

5. The method for eliminating air bubbles during the detection of the dissolution rate of calcium carbonate D3 chewable tablets according to claim 4, characterized in that, The detection solution in step S3 comprises, by volume, 8-10 parts filtrate, 45-55 parts water, 8-12 parts sodium hydroxide solution, and 4-6 parts triethanolamine solution. The detection solution also contains sodium calcium carboxylate indicator, with 0.1g of sodium calcium carboxylate indicator added for every 45-55ml of water.

6. The method for eliminating air bubbles during the detection of the dissolution rate of calcium carbonate D3 chewable tablets according to claim 1, characterized in that, The concentration of the disodium ethylenediaminetetraacetate titrant in step S3 is 0.05 mol / L, and the amount of calcium consumed per 1 mL of disodium ethylenediaminetetraacetate titrant is equal to 2.004 mg.

7. The method for eliminating air bubbles during the detection of the dissolution rate of calcium carbonate D3 chewable tablets according to claim 1, characterized in that, The defoamer mentioned in step S1 needs to be pretreated before being added to the hydrochloric acid solution. The specific pretreatment steps are as follows: Q1. Add the defoamer to the ethanol and stir until homogeneous to obtain the core material; Q2. Add hydroxypropyl methylcellulose to water, stir at 50°C for 20-40 minutes, and cool to room temperature to obtain the shell material; Q3. Drop the core material into the shell material and shear it with a high-speed shearing machine at a speed of 10,000-12,000 rpm for 10-15 minutes to form an emulsion. Q4. Transfer the emulsion to a rotary evaporator and rotary evaporate until the ethanol is completely evaporated to obtain a core-shell suspension; Q5. The core-shell suspension is fed into a spray dryer and dried to obtain powdered core-shell particles, which are the pretreated defoamer.

8. The method for eliminating air bubbles during the detection of the dissolution rate of calcium carbonate D3 chewable tablets according to claim 7, characterized in that, The mass ratio of the defoamer to hydroxypropyl methylcellulose is 2:1-2.

9. The method for eliminating air bubbles during the detection of the dissolution rate of calcium carbonate D3 chewable tablets according to claim 7, characterized in that, The rotary evaporator has a temperature of 20-35℃, a rotation speed of 75-100rpm, and a rotary evaporation time of 30-40min.

10. The method for eliminating air bubbles during the detection of the dissolution rate of calcium carbonate D3 chewable tablets according to claim 7, characterized in that, The spray dryer has an inlet air temperature of 75-80℃, an outlet air temperature of 35-40℃, a feed rate of 8-12mL / min, and an atomization pressure of 0.2MPa.

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