Bismuth potassium citrate particles and dry granulation process thereof

Abstract

The invention discloses bismuth potassium citrate particles and a dry granulation process thereof. On one hand, the invention provides a preparation process of bismuth potassium citrate. On the second aspect, the invention provides a dry granulation process of the bismuth potassium citrate granules, which comprises the following steps: S1, accurately weighing raw materials and auxiliary materials according to the formula ratio in parts by weight of the granules by using the bismuth potassium citrate prepared by the invention; s2, crushing the raw and auxiliary materials weighed in the step S1, adding the crushed raw and auxiliary materials into a boiling granulator, and then weighing purified water as a wetting agent; and S3, granulating the raw and auxiliary materials by using a boiling granulator, screening and collecting particles with the particle size of 10-50 meshes, thereby obtaining the bismuth potassium citrate particles. In the third aspect, the invention provides the bismuth potassium citrate particles prepared by the process. The preparation process is relatively simple, the prepared bismuth potassium citrate is high in purity and bismuth content, ammonia water is not used, raw materials and auxiliary materials in the granulation process are uniformly dispersed, and the prepared bismuth potassium citrate particles are relatively high in quality.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical engineering, and particularly relates to a bismuth potassium citrate granule and a dry granulation process thereof. BACKGROUND

[0002] The main component of bismuth potassium citrate is bismuth tricitrate, which is a drug for treating gastric ulcer and gastritis. Bismuth potassium citrate can form a protective layer on the ulcer surface in a gastric acid environment, preventing the invasion of gastric acid, enzymes and food on the ulcer. It can also reduce the activity of pepsin, increase the secretion of mucin, and promote the release of prostaglandin from the mucosa, thereby protecting the gastric mucosa. In addition, the drug has a killing effect on Helicobacter pylori, thereby promoting the healing of gastritis. The existing bismuth potassium citrate preparations mainly include tablets, capsules and granules, and the main component is bismuth potassium citrate.

[0003] Bismuth potassium citrate is a relatively complex bismuth compound. According to the provisions of the Chinese Pharmacopoeia, the bismuth content of the drug bismuth potassium citrate should reach 35.0% to 38.5%. There are mainly two methods for synthesizing bismuth potassium citrate. The first method is to prepare an intermediate, basic bismuth nitrate, and then react it with citric acid and a potassium source under alkaline conditions to obtain bismuth potassium citrate. The second method is to react bismuth citrate, potassium citrate and a base to obtain bismuth potassium citrate. These processes generally use ammonia water, which has a suitable pH, and there is pollution of irritating odor gas during the preparation process, and a small amount of ammonia impurities also exists in the prepared product.

[0004] Through continuous improvement and adjustment of the process, the process for preparing bismuth potassium citrate is becoming increasingly mature, and the quality of the prepared product is also relatively high. For example, the Chinese invention patent with the publication number CN106278870A and the invention name of a preparation method of bismuth potassium citrate discloses a preparation process of bismuth potassium citrate, and the prepared product does not contain ammonia residues and has high purity. In addition, other methods for preparing bismuth potassium citrate are also disclosed in the prior art, which can not use reagents with irritating odor such as ammonia water, but the purity and bismuth content of the prepared bismuth potassium citrate are difficult to meet the requirements of the Pharmacopoeia. Moreover, these new processes have not yet reached the requirements of industrial production. SUMMARY

[0005] In order to solve at least one of the above technical problems, a preparation process of bismuth potassium citrate suitable for industrial production, relatively simple process, high purity and high bismuth content of the prepared bismuth potassium citrate, no use of ammonia water, and uniform dispersion of raw and auxiliary materials in the granulation process, and high quality of the prepared bismuth potassium citrate granule are developed, and the present application provides a bismuth potassium citrate granule and a dry granulation process thereof.

[0006] In one aspect, the present application provides a preparation process of bismuth potassium citrate, comprising the following steps: Sa, select bismuth oxide with a purity of not less than 99.99%, grind the bismuth oxide, grind to a particle size of not more than 200 mesh, obtain bismuth oxide powder, and then accurately weigh the bismuth oxide powder and anhydrous citric acid according to a mass ratio of 1:1.2~1.4; Sb, prepare the anhydrous citric acid weighed in step Sa into a 0.7~0.75g / mL citric acid solution with purified water, add the bismuth oxide powder into the citric acid solution, stir at a temperature of 85~90℃ and a speed of 500~600rpm for more than 8h, filter out the solid product, wash with anhydrous ethanol for more than 3 times, and vacuum dry to obtain bismuth citrate, grind to a particle size of not more than 200 mesh to obtain bismuth citrate powder; Sc, accurately weigh the bismuth citrate powder obtained in step Sb and potassium citrate according to a molar ratio of 1:3~3.05, prepare the potassium citrate into a 0.4~0.5mol / L potassium citrate solution with purified water, adjust the pH of the solution to more than 9 by adding potassium hydroxide, and then add the bismuth citrate powder into the solution to obtain a reaction solution; Sd, react the reaction solution obtained in step Sc at a temperature of 65~70℃ for 5~10min, and then continue to react under ultrasonic conditions for more than 20min, evaporate and concentrate the reaction solution at a temperature of 70~75℃, and then cool to room temperature to obtain a concentrated solution; Se, add anhydrous ethanol to the concentrated solution obtained in step Sd to crystallize, then filter out the crystalline product, wash with anhydrous ethanol for more than 3 times, and vacuum dry to obtain potassium bismuth citrate.

[0007] Optionally, in step Sb, the particle size is ground to not more than 400 mesh.

[0008] Optionally, in step Sc, the pH of the solution is adjusted to 9.5~10.

[0009] Optionally, in step Sd, the concentration ratio is controlled at 2.4~2.6.

[0010] Optionally, in step Se, the amount of anhydrous ethanol added accounts for 45~50% of the volume of the concentrated solution.

[0011] In a second aspect, the application provides a dry granulation process for preparing potassium bismuth citrate granules using potassium bismuth citrate prepared by the above process as raw material, comprising the following steps: S1, accurately weigh the raw and auxiliary materials according to the granule weight fraction formula, wherein the granule weight fraction formula includes: 25~28 parts of potassium bismuth citrate, 50~55 parts of filler, 18~20 parts of excipient, and 6~8 parts of flavoring agent; S2, crushing the raw and auxiliary materials weighed in step S1, adding into a fluidized granulator, then weighing purified water as a wetting agent according to the mass ratio of the total mass of the raw and auxiliary materials to the mass of the purified water being 1:0.8, and adding into the fluidized granulator, completing the on-site loading of the equipment; S3, using the fluidized granulator to granulate the raw and auxiliary materials, and collecting the particles with a particle size of 10-50 meshes by sieving to prepare the potassium bismuth citrate particles.

[0012] Optionally, in the step S1, the filler is mannitol, the excipient is starch, dextrin or cyclodextrin, and the flavoring agent is sucrose or xylitol.

[0013] Optionally, in the step S2, the raw and auxiliary materials are crushed to a particle size of 80 meshes or less.

[0014] Optionally, in the step S3, the granulation parameters are as follows: air inlet flow rate 2000-4000 m³ / h, air inlet temperature 70-90℃, material temperature 55-65℃, liquid supply peristaltic pump speed 60-100 rpm, and atomization pressure 0.1-0.3 MPa.

[0015] In a third aspect, the present application provides a potassium bismuth citrate particle prepared by the dry granulation process of the above-mentioned potassium bismuth citrate particle.

[0016] In summary, the present application has at least one of the following beneficial technical effects: 1. The present application uses high-purity bismuth oxide as a raw material to prepare high-quality bismuth citrate, and then reacts with potassium citrate under alkaline conditions to prepare high-purity high-quality potassium bismuth citrate with a bismuth content meeting the pharmaceutical requirements by accurately controlling the dosage ratio and adjusting the initial pH value of the reaction solution and designing specific reaction parameter conditions. The process of the present application does not use ammonia water, and the reaction conditions are relatively mild, which is suitable for large-scale industrial production.

[0017] 2. The dry granulation process of the potassium bismuth citrate particle of the present application has relatively simple process steps, is suitable for large-scale industrial production, and has a high utilization rate of raw and auxiliary materials.

[0018] 3. The potassium bismuth citrate particle prepared by the present application has uniform dispersion of raw and auxiliary materials, relatively uniform particles, high bismuth content, and very excellent quality. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 It is a liquid chromatogram detection diagram of the potassium bismuth citrate prepared in Preparation Example 1 of the present application; Figure 2 It is a liquid chromatogram detection diagram of the potassium bismuth citrate of Comparative Example 2 of the present application. DETAILED DESCRIPTION

[0020] The present application will be further described in detail below in combination with examples.

[0021] The application provides a preparation process of bismuth potassium citrate, including the following steps: Sa, bismuth oxide with a purity of not less than 99.99% is selected, the bismuth oxide is ground and treated, and the grinding is performed to a particle size of not more than 200 meshes to obtain bismuth oxide powder, and then the bismuth oxide powder and anhydrous citric acid are accurately weighed according to a mass ratio of 1:1.2-1.4; Sb, the anhydrous citric acid weighed in step Sa is prepared into a citric acid solution with a concentration of 0.7-0.75 g / mL by using purified water, the bismuth oxide powder is added into the citric acid solution, stirring is performed at a temperature of 85-90 ℃ and a rotating speed of 500-600 rpm for more than 8 h, the solid product is filtered out by suction filtration, the solid product is washed with anhydrous ethanol for more than three times, and bismuth citrate is prepared after vacuum drying, and the bismuth citrate is ground to a particle size of not more than 200 meshes to obtain bismuth citrate powder; Sc, the bismuth citrate powder obtained in step Sb and potassium citrate are accurately weighed according to a molar ratio of 1:3-3.05, the potassium citrate is prepared into a potassium citrate solution with a concentration of 0.4-0.5 mol / L by using purified water, the pH of the solution is adjusted to more than 9 by adding potassium hydroxide, and then the bismuth citrate powder is added into the solution to obtain a reaction solution; Sd, the reaction solution obtained in step Sc is reacted at a temperature of 65-70 ℃ for 5-10 min, and then the reaction is continuously performed under ultrasonic condition for more than 20 min, the reaction solution is evaporated and concentrated at a temperature of 70-75 ℃, and then the concentrated solution is cooled to room temperature; Se, anhydrous ethanol is added to the concentrated solution obtained in step Sd to crystallize, and then the crystalline product is filtered out, the crystalline product is washed with anhydrous ethanol for more than three times, and bismuth potassium citrate is prepared after vacuum drying.

[0022] Based on the high-quality bismuth potassium citrate prepared by the process, a dry granulation process of bismuth potassium citrate granules is designed, including the following steps: S1, the raw and auxiliary materials are accurately weighed according to the granule weight fraction formula, and the granule weight fraction formula includes 25-28 parts of bismuth potassium citrate, 50-55 parts of a filler, 18-20 parts of an excipient and 6-8 parts of a flavoring agent; S2, the raw and auxiliary materials weighed in step S1 are crushed and added into a fluidized bed granulator, and then purified water is weighed as a wetting agent according to a mass ratio of 1:0.8 between the total mass of the raw and auxiliary materials and the purified water, and the purified water is added into the fluidized bed granulator to complete the loading of the equipment; S3, the raw and auxiliary materials are granulated by using the fluidized bed granulator, and the granules with a particle size of 10-50 meshes are collected to prepare bismuth potassium citrate granules.

[0023] Before the present application, there has been a preparation process for preparing potassium bicarbonate in the art, which uses bismuth citrate and potassium citrate as raw materials, and potassium hydroxide as a strong base. However, this preparation process is limited by the problems that bismuth citrate is difficult to completely dissolve in the reaction due to its colloidal state, and the bismuth content of the product is difficult to control, so that the bismuth content of the prepared potassium bicarbonate is difficult to exceed 30%, which does not meet the requirements of pharmaceutical use.

[0024] The present application precisely controls the ratio of reaction raw materials by redesigning the process, and grinds and crushes bismuth citrate, and cooperates with the control measures under ultrasonic conditions, which greatly improves the completion of the reaction, and can prepare potassium bicarbonate with high purity and bismuth content meeting the requirements of pharmaceutical use.

[0025] The following are the preparation examples and examples of the present application.

[0026] The main raw materials selected in the preparation examples and examples of the present application are all from the market.

[0027] Among them, bismuth oxide, bismuth trioxide, purity 99.999%, purchased from Shanghai Xiaohuan Nanometer Technology Co., Ltd.; citric acid, anhydrous crystal, purity more than 99%, purchased from Hubei Baishi Electronic Material Co., Ltd.; potassium citrate, purity more than 99%, purchased from Wuhan Dongkangyuan Technology Co., Ltd.

[0028] The following are the preparation examples of the present application.

[0029] Preparation Example 1 The potassium bicarbonate of the present preparation example is prepared by the following preparation process, which includes the following steps: Sa, grind the bismuth oxide to a particle size of not more than 200 mesh, and then accurately weigh 10 kg of bismuth oxide powder and 12 kg of anhydrous citric acid; Sb, prepare a 0.7 g / mL citric acid solution with the anhydrous citric acid weighed in step Sa, and add the bismuth oxide powder into the citric acid solution, stir at a temperature of 85~90℃ and a rotation speed of 550 rpm for 8h, filter out the solid product, wash it with anhydrous ethanol for more than 3 times, and then vacuum dry to obtain bismuth citrate, which is ground to a particle size of not more than 200 mesh to obtain bismuth citrate powder; Sc, according to the molar ratio of bismuth citrate to potassium citrate being 1:3, accurately weigh the bismuth citrate powder obtained in step Sb and potassium citrate, prepare a 0.4 mol / L potassium citrate solution with the potassium citrate and potassium hydroxide, adjust the pH of the solution to 9, and then add the bismuth citrate powder into the solution to obtain a reaction solution; Sd, the reaction solution obtained in step Sc is reacted at a temperature of 65-70°C for 5 min, and then the reaction is continued under ultrasonic condition for 25 min. The reaction solution is evaporated and concentrated at a temperature of 70-75°C, a concentration ratio of 1.5, and then cooled to room temperature to obtain a concentrated solution; Se, anhydrous ethanol is added to the concentrated solution obtained in step Sd at a volume of 0.8 times that of the concentrated solution, and crystallization is carried out under stirring at a speed of 1200 rpm, and then the crystalline product is filtered out, washed with anhydrous ethanol for more than 3 times, and dried under vacuum to obtain potassium bismuth citrate; In step Sd, the power of ultrasonic is 750 W.

[0030] Preparation Example 2 The difference between the present preparation example and Preparation Example 1 is that in step Sa, 14 kg of anhydrous citric acid is weighed; in step Sb, a citric acid solution of 0.75 g / mL is prepared with purified water; and in step Sc, a potassium citrate solution of 0.5 mol / L is prepared.

[0031] Preparation Example 3 The difference between the present preparation example and Preparation Example 2 is that in step Sd, the concentration ratio is 2.5; and in step Sc, anhydrous ethanol is added at a volume of 0.5 times that of the concentrated solution.

[0032] Preparation Example 4 The difference between the present preparation example and Preparation Example 3 is that in step Sc, the pH is adjusted to 9.5.

[0033] Preparation Example 5 The difference between the present preparation example and Preparation Example 3 is that in step Sc, the pH is adjusted to 10.

[0034] Preparation Example 6 The difference between the present preparation example and Preparation Example 5 is that in step Sb, the grinding is performed to a particle size of not more than 400 mesh.

[0035] Preparation Example 7 The difference between the present preparation example and Preparation Example 6 is that in step Sc, the molar ratio of bismuth citrate to potassium citrate is 1:3.05.

[0036] Preparation Example 8 The difference between the present preparation example and Preparation Example 6 is that in step Sc, the molar ratio of bismuth citrate to potassium citrate is 1:3.02.

[0037] Preparation Example 9 The difference between the present preparation example and Preparation Example 8 is that in step Sd, the parameter of ultrasonic is 1500 W.

[0038] Preparation Example 10 The difference between the present preparation example and Preparation Example 8 is that in step Sd, the parameter of ultrasonic is 2000 W.

[0039] Comparative Example 1 The difference between the present comparative example and Preparation Example 10 is that in step Sc, the molar ratio of bismuth citrate to potassium citrate is 1:3.075, and potassium hydroxide is added to adjust the pH of the solution to 12.

[0040] Comparative Example 2 The difference between the present comparative example and Comparative Example 1 is that in step Sb, the bismuth citrate is not ground; and in step Sd, the reaction is not carried out under ultrasonic conditions.

[0041] Comparative Example 3 The difference between the present comparative example and Preparation Example 10 is that in step Sd, the reaction is not carried out under ultrasonic conditions.

[0042] Comparative Example 4 The difference between the present comparative example and Preparation Example 10 is that in step Sb, the bismuth citrate is not ground.

[0043] Comparative Example 5 The present application takes Example 3 of Chinese Invention Patent with the patent number CN106278870A and the invention name A preparation method of bismuth potassium citrate as Comparative Example 5.

[0044] The bismuth potassium citrate prepared by Preparation Examples 1-10 of the present application and the bismuth potassium citrate prepared by Comparative Examples 1-3 are detected to detect the purity, the yield calculated by bismuth oxide, and the content of bismuth.

[0045] Among them, the purity detection is detected by liquid chromatography; The yield calculated by bismuth oxide is calculated by the weight of the obtained bismuth potassium citrate and the content of bismuth to calculate the loss of bismuth in the reaction; The content of bismuth is detected by inductively coupled plasma mass spectrometry.

[0046] The obtained detection results are shown in Table 1, and Figures 1-2 Table 1 shows the detection results of Preparation Examples 1-10 and Comparative Examples 1-5.

[0047] Table 1 shows the detection results of Preparation Examples 1-10 and Comparative Examples 1-5. Purity (%) Product yield (%) Bismuth content (%) Preparation Example 1 99.29 82.8 36.82 Preparation Example 2 99.32 83.0 36.88 Preparation Example 3 99.33 83.7 36.91 Preparation Example 4 99.42 84.1 37.02 Preparation Example 5 99.49 84.4 36.99 Preparation Example 6 99.52 86.6 37.54 Preparation Example 7 99.50 86.3 37.58 Preparation Example 8 99.52 86.8 37.55 Preparation Example 9 99.76 88.4 37.71 Preparation Example 10 99.84 88.8 37.74 Comparative Example 1 94.74 80.3 28.52 Comparative Example 2 86.62 82.9 29.74 Comparative Example 3 89.68 81.2 29.52 Comparative Example 4 93.48 81.9 29.66 Comparative Example 5 99.98 90.0 35.92 From the data in Table 1, it can be seen that the preparation process of the bismuth potassium citrate prepared by Preparation Examples 1-10 of the present application can achieve a purity of more than 99%, a yield of more than 80%, and a bismuth content of not less than 36.8%, fully meeting the requirements of the pharmacopoeia for the bismuth content of bismuth potassium citrate. It can be seen that the preparation process designed by the present application is a kilogram-level preparation process suitable for large-scale production, and does not use any ammonia or other odor reagents, and the alkali dosage is also low, and the quality of the prepared product is high, which is comparable to the prior art Comparative Example 3; in addition, the bismuth content of the bismuth potassium citrate prepared by Preparation Examples 1-10 of the present application is relatively high, which is slightly higher than that of the product of Comparative Example 3.

[0048] From the data in Table 1, the data of Preparation Examples 1-10 can be seen that after optimizing the process parameters and raw material ratio, the yield and purity of the product can be further improved, and the bismuth content can also be further improved. From the data in Table 1, the data of Preparation Example 10 and Comparative Example 1 can be seen that after increasing the amount of potassium hydroxide and increasing the amount of alkali, the content of bismuth in the product will be significantly reduced, and the purity of the product will also be reduced. After analysis, the impurities contain a small amount of unreacted bismuth citrate and potassium citrate. From the data in Table 1, the data of Preparation Example 10 and Comparative Example 2 can be seen that after not using ultrasonic treatment and not grinding bismuth citrate, the reaction is extremely incomplete, the product purity is low, and contains a large amount of unreacted impurities. From the comparison of Figure 1 and Figure 2 , it can also be seen that after refining the particle size of bismuth citrate and ultrasonic treatment during the reaction, the purity of the product is high and the reaction is complete. Without the above treatment, the reaction is extremely incomplete and there are obvious potassium citrate and bismuth citrate impurity peaks. The applicant speculates that refining the particle size of bismuth citrate and high-power ultrasonic treatment during the reaction can effectively prevent the agglomeration of bismuth citrate colloid, greatly promote the dissolution of bismuth citrate, and thus improve the reaction completion rate.

[0049] From the data in Table 1, the data of Preparation Example 10 and Comparative Examples 3 and 4 can be seen that after not using ultrasonic reaction and only grinding the material, the product purity is greatly reduced and there is part of unreacted bismuth citrate impurities. After not grinding the material and only using ultrasonic reaction, the purity of the product is also greatly reduced and there is part of unreacted bismuth citrate impurities. It can be inferred that grinding the material and using ultrasonic reaction can synergistically prevent the agglomeration of the reaction material and make bismuth citrate completely dissolved as much as possible. The use of a single means cannot achieve the above effect.

[0050] The following are examples of preparing bismuth potassium citrate granules according to the present application, all of which use bismuth potassium citrate prepared in Preparation Example 10. Example 1

[0051] The bismuth potassium citrate granules of this example use the dry granulation process of the present application, which includes the following steps: S1, accurately weigh the raw and auxiliary materials according to the granule weight fraction formula, which includes: 25 kg of bismuth potassium citrate, 50 kg of mannitol, 18.75 kg of dextrin, 6.25 kg of sucrose, and 0.008 kg of lemon yellow coloring agent; S2, the raw and auxiliary materials except lemon yellow weighed in step S1 are crushed to a particle size of 80 mesh or less, and then added into the fluidized bed granulator. Then, 80 kg of purified water is weighed and added into the fluidized bed granulator after the lemon yellow is fully dissolved, as a wetting agent, to complete the on-site loading of the equipment. S3, the raw and auxiliary materials are granulated using the fluidized bed granulator, and the particles with a particle size of 10-50 mesh are collected by sieving. The granulation parameters are as follows: air inlet flow rate 3000 m³ / h, air inlet temperature 85°C, material temperature 60°C, liquid supply peristaltic pump speed 80 rpm, and atomization pressure 0.25 MPa. The particles not within the range of 10-50 mesh are granulated using a vacuum granulator, and the granulated particles are sieved again to collect the particles within the range of 10-50 mesh, to obtain the potassium bismuth citrate granules. Example 2

[0052] The difference between this example and Example 1 is that in step S1, the granule weight fraction formula includes: 26 kg of potassium bismuth citrate, 52 kg of mannitol, 18 kg of dextrin, and 8 kg of sucrose; and further includes 0.01 kg of lemon yellow colorant. Example 3

[0053] The difference between this example and Example 1 is that in step S1, the granule weight fraction formula includes: 28 kg of potassium bismuth citrate, 55 kg of mannitol, 20 kg of dextrin, and 6 kg of sucrose; and further includes 0.005 kg of lemon yellow colorant. Example 4

[0054] The difference between this example and Example 1 is that in step S1, the granule weight fraction formula includes: 26.5 kg of potassium bismuth citrate, 53 kg of mannitol, 19 kg of dextrin, and 7 kg of sucrose; and further includes 0.006 kg of lemon yellow colorant.

[0055] It is detected that the granules prepared in Examples 1-4 have a relatively good particle size, the material utilization rate is more than 97%, the water content of the prepared granules is within 2%, and the quality is relatively excellent.

[0056] The bismuth content of the granules of Examples 1-4 is detected by using the ethylenediamine tetraacetic acid disodium titration method recorded in the Chinese Pharmacopoeia, and it is detected that the bismuth content of the potassium bismuth citrate granules of Examples 1-4 is more than 90 mg / g, which meets the bismuth content requirement of the potassium bismuth citrate granules preparation specified in the Pharmacopoeia.

[0057] The above are preferred embodiments of the present application, and do not limit the protection scope of the present application. Therefore, any equivalent changes made on the basis of the structure, shape, and principle of the present application should be covered within the protection scope of the present application.

Claims

1. A preparation process for bismuth potassium citrate, characterized in that, Includes the following steps: Sa, select bismuth oxide with a purity of not less than 99.99%, grind the bismuth oxide to a particle size of not more than 200 mesh to obtain bismuth oxide micro powder, and then accurately weigh the bismuth oxide micro powder and anhydrous citric acid according to a mass ratio of 1:1.2~1.

4. Sb. The anhydrous citric acid weighed in step Sa is prepared into a citric acid solution of 0.7~0.75 g / mL with purified water. Bismuth oxide micro powder is added to the citric acid solution. The mixture is stirred at 85~90℃ and 500~600 rpm for more than 8 hours. The solid product is filtered out by vacuum filtration, washed with anhydrous ethanol more than 3 times, and dried under vacuum to obtain bismuth citrate. The bismuth citrate micro powder is then ground to a particle size of no more than 200 mesh. Sc. Accurately weigh the bismuth citrate micro powder and potassium citrate obtained in step Sb according to the molar ratio of bismuth citrate to potassium citrate of 1:3~3.

05. Prepare a potassium citrate solution of 0.4~0.5 mol / L with purified water. Add potassium hydroxide to adjust the pH of the solution to above 9. Then add the bismuth citrate micro powder to the solution to obtain the reaction solution. Sd. The reaction solution obtained in step Sc is reacted at 65~70℃ for 5~10 minutes, and then the reaction is continued under ultrasonic conditions for more than 20 minutes. The reaction solution is then evaporated and concentrated at 70~75℃, and then cooled to room temperature to obtain a concentrated solution. Se, add anhydrous ethanol to the concentrate obtained in step Sd to crystallize, then filter out the crystallized product, wash it with anhydrous ethanol more than 3 times, and dry it under vacuum to obtain potassium bismuth citrate.

2. The preparation process of bismuth potassium citrate according to claim 1, characterized in that, In step Sb, the particles are ground to a size not exceeding 400 mesh.

3. The preparation process of bismuth potassium citrate according to claim 1, characterized in that, In step Sc, the pH of the solution is adjusted to 9.5-10.

4. The preparation process of bismuth potassium citrate according to claim 1, characterized in that, In step Sd, the concentration ratio is controlled at 2.4~2.

6.

5. The preparation process of bismuth potassium citrate according to claim 1, characterized in that, In step Se, the amount of anhydrous ethanol added accounts for 45-50% of the volume of the concentrate.

6. A dry granulation process for bismuth potassium citrate granules, characterized in that, Includes the following steps: S1. Select the bismuth potassium citrate prepared according to any one of claims 1 to 5, and accurately weigh the raw and auxiliary materials according to the formula of the granules by weight. The formula of the granules by weight includes: 25 to 28 parts of bismuth potassium citrate, 50 to 55 parts of filler, 18 to 20 parts of excipient, and 6 to 8 parts of flavoring agent. S2. Crush the raw and auxiliary materials weighed in step S1 and add them to the fluidized bed granulator. Then, according to the mass ratio of the total mass of the raw and auxiliary materials to the mass of purified water of 1:0.8, weigh the purified water and add it to the fluidized bed granulator as a wetting agent to complete the feeding of the equipment. S3. Using a fluidized bed granulator, granulate the raw and auxiliary materials, and sieve and collect particles with a particle size between 10 and 50 mesh to obtain bismuth potassium citrate granules.

7. The dry granulation process for bismuth potassium citrate granules according to claim 1, characterized in that, In step S1, the filler is selected as mannitol, the excipient is selected as starch, dextrin or cyclodextrin, and the flavoring agent is selected as sucrose or xylitol.

8. The dry granulation process for bismuth potassium citrate granules according to claim 1, characterized in that, In step S2, the raw and auxiliary materials are crushed to a particle size of less than 80 mesh.

9. The dry granulation process for bismuth potassium citrate granules according to claim 1, characterized in that, In step S3, the granulation parameters are: air volume 2000~4000m³ / h, air temperature 70~90℃, material temperature 55~65℃, liquid supply peristaltic pump speed 60~100rpm, and atomization pressure 0.1~0.3MPa.

10. Bismuth potassium citrate granules prepared by a dry granulation process according to any one of claims 6 to 9.

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