An amoxicillin soluble powder and a method for preparing the same

Abstract

The application discloses amoxicillin soluble powder and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The soluble powder is prepared by taking amoxicillin trihydrate as an active ingredient, compounding carboxymethyl chitosan, glycine and meglumine, and matching a buffer and a filler, so that the water solution of the preparation can maintain a stable pH environment. The preparation adopts a process flow of raw material pretreatment, wet grinding, vacuum drying, whole-grain screening and total mixing and packaging. The application effectively solves the problems of poor water solubility and insufficient stability of traditional amoxicillin preparations, and has excellent preparation solubility, clear and stable water solution, good storage period stability, simple preparation process, and is suitable for veterinary clinical large-scale production and livestock and poultry water medication.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to an amoxicillin soluble powder and its preparation method. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Amoxicillin is a semi-synthetic broad-spectrum β-lactam antibiotic with a broad antibacterial spectrum, strong bactericidal activity, and low toxicity. It is rapidly absorbed orally and is widely used in veterinary clinical practice for the prevention and treatment of bacterial infections in livestock and poultry. It is often formulated as a soluble powder for water-based administration and is one of the core veterinary drug preparations for intensive farming. However, amoxicillin has two major technical defects: firstly, its water solubility is extremely low, and it readily reacts with calcium in water. ²+ Mg ²+ Firstly, the formation of precipitates by metal ion complexation makes it difficult to meet the clinical requirements for concentrated preparation, dilution, and drinking administration. Secondly, the presence of a β-lactam ring in the molecular structure makes it chemically unstable, easily degraded and inactivated in acidic or alkaline environments. Furthermore, water solubility and stability are contradictory; alkaline environments can increase solubility but accelerate drug degradation, affecting the quality of the preparation and the efficacy of the medication.

[0004] Traditional amoxicillin soluble powder is mostly prepared by simple physical mixing of amoxicillin and anhydrous glucose. This type of preparation has poor water solubility and insufficient stability, making it unsuitable for the medication requirements of modern intensive aquaculture. To address these issues, the industry has conducted several improvement studies: Chinese patent CN110522730A discloses an amoxicillin soluble powder. By adding buffers, water softeners, fillers and flavoring agents to optimize the formulation, the pH of the solution after dissolution is stabilized at 6.5~8.0, which significantly improves the water solubility, water stability and gastric acid stability of amoxicillin and solves the problem of poor solubility of traditional formulations.

[0005] Chinese patent CN118267361A discloses a veterinary compound amoxicillin soluble powder, which combines amoxicillin with potassium clavulanate and adds excipients such as poloxamer 188, xylitol, and curcumin. It is prepared by co-precipitation process, which effectively increases the amoxicillin content, reduces the content of single impurities and total impurities during storage, and extends the shelf life. At the same time, curcumin can enhance the efficacy of the drug.

[0006] In summary, existing amoxicillin soluble powders still suffer from problems such as difficulty in synergistically optimizing the stability and solubility of single-component formulations, complex formulations of compound formulations, and insufficient process adaptability. There is an urgent need for an amoxicillin soluble powder that is easy to prepare, has good water solubility, strong stability, and is suitable for large-scale clinical application in veterinary medicine, as well as its preparation method. Summary of the Invention

[0007] The purpose of this invention is to overcome the technical defects of existing amoxicillin soluble powder, such as poor water solubility and difficulty in synergistically optimizing the solubility and stability of single-component preparations, and to provide an amoxicillin soluble powder with excellent water solubility, strong aqueous solution stability, stable storage period, simple preparation process, and suitable for large-scale application in veterinary clinical practice, as well as its preparation method.

[0008] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: This invention provides an amoxicillin soluble powder, composed of the following components in parts by weight: Amoxicillin trihydrate 30-65 parts, carboxymethyl chitosan 2-8 parts, glycine 3-10 parts, meglumine 1-5 parts, buffer 5-15 parts, filler 20-50 parts, and purified water as needed.

[0009] Furthermore, the buffer is selected from one or more of anhydrous citric acid, sodium citrate, and anhydrous potassium dihydrogen phosphate; the buffer can stabilize the pH of the aqueous solution after the preparation is dissolved at 4.5-5.5.

[0010] Furthermore, the filler is selected from one or two of anhydrous glucose and pregelatinized starch.

[0011] The present invention also provides a method for preparing the above-mentioned amoxicillin soluble powder, comprising the following steps: 1) Raw material pretreatment: Amoxicillin trihydrate, carboxymethyl chitosan, glycine, meglumine, buffer, and filler are pulverized separately, passed through an 80-mesh sieve, and sealed for later use; 2) Wet grinding: Weigh amoxicillin trihydrate, carboxymethyl chitosan, glycine, meglumine, and buffer according to the prescription amount, add purified water, and grind in a wet grinder to obtain a uniform slurry; 3) Vacuum drying: The slurry is vacuum dried to obtain dried drug blocks; 4) Granulation and sieving: Crush and sieve the dried medicinal blocks to obtain fine medicinal powder; 5) General mixing and packaging: Mix the powder and filler evenly, and after passing the quality inspection, package and seal to obtain amoxicillin soluble powder.

[0012] Further, in step 2), the amount of purified water added is 30% to 50% of the total mass of the prescription; the wet grinding speed is 1500 to 3000 r / min, and the grinding time is 30 to 60 min; the particle size of the slurry is ≤10 μm.

[0013] Furthermore, in step 3), the vacuum drying temperature is 40–50°C, the vacuum degree is -0.06–-0.08 MPa, the drying time is 4–6 h, and the moisture content of the dried drug block is ≤3.0%.

[0014] Furthermore, the sieve mesh size mentioned in step 4) is 100 mesh; in step 5), a three-dimensional motion mixer is used for total mixing, and the mixing time is 20-40 min.

[0015] Compared with the prior art, the technical advantages of the present invention are as follows: (1) The water solubility is significantly improved, the dissolution speed is fast, and the aqueous solution is clear without precipitation or turbidity, which can meet the clinical needs of livestock and poultry drinking water administration.

[0016] (2) The stability of the aqueous solution is greatly improved, the active ingredient of amoxicillin degrades slowly, and the retention rate of the active ingredient is high within 24 hours, which is suitable for the duration of clinical administration via drinking water.

[0017] (3) The pH of the preparation is stable at 4.5 to 5.5 after dissolution, and there is no significant pH fluctuation after long-term storage, which provides a reliable environmental guarantee for drug stability.

[0018] (4) It has excellent storage stability and high retention rate of active ingredients after 6 months of accelerated testing, which meets the shelf life quality requirements of veterinary drug preparations. Detailed Implementation

[0019] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0020] Example 1: Amoxicillin soluble powder Prescription composition: Amoxicillin trihydrate: 50g Carboxymethyl chitosan: 5g Glycine: 6g Meglumine: 3g Buffer (anhydrous citric acid: sodium citrate = 1:2.5): 10g Filler (anhydrous glucose: pregelatinized starch = 1:1): 35g Purified water: 30g Preparation process: 1) Raw material pretreatment Amoxicillin trihydrate, carboxymethyl chitosan, glycine, meglumine, buffer, and filler were placed in a universal pulverizer and pulverized. After pulverization, all were passed through an 80-mesh standard pharmaceutical sieve, and then sealed and stored separately for later use.

[0021] 2) Wet grinding Accurately weigh amoxicillin trihydrate, carboxymethyl chitosan, glycine, meglumine, and buffer according to the prescription, and put them all into a wet grinder. Add 30g of purified water; turn on the grinder, adjust the speed to 2000r / min, and grind continuously for 40min. Take samples for testing during the grinding process to ensure that the particle size of the slurry is ≤10μm, so as to obtain a uniform and fine slurry.

[0022] 3) Vacuum drying The slurry was evenly spread in a vacuum drying tray and placed in a vacuum drying oven. The drying temperature was set to 45℃ and the vacuum degree to -0.07MPa. The drying was carried out at a constant temperature and pressure for 5 hours. After drying, a sample was taken for testing. The moisture content of the slurry was ≤3.0%, and the dried slurry was obtained.

[0023] 4) Granulation and sieving The dried medicinal blocks are placed in a pulverizer and pulverized. After pulverization, all of them are passed through a 100-mesh standard sieve to remove coarse particles and obtain fine medicinal powder.

[0024] 5) Mixed Packaging The sieved powder and the prescribed amount of filler are added to a three-dimensional motion mixer and mixed for 30 minutes until homogeneous. Samples are taken to test the content, solubility, pH value and other indicators. After passing the test, the powder is packaged and sealed to obtain the finished product.

[0025] Example 2 Amoxicillin soluble powder Prescription composition: Amoxicillin trihydrate: 30g Carboxymethyl chitosan: 2g Glycine: 3g Meglumine: 1g Buffer (anhydrous citric acid: sodium citrate = 1:3): 5g Filler (anhydrous glucose): 20g Purified water: 12g Preparation process: 1) Raw material pretreatment All raw materials are crushed separately, passed through an 80-mesh standard pharmaceutical sieve, and sealed for later use.

[0026] 2) Wet grinding Weigh all raw materials except fillers and put them into a wet grinding mill. Add 12g of purified water. Adjust the speed to 1500r / min and grind for 30min. Control the particle size of the slurry to ≤10μm to obtain a uniform slurry.

[0027] 3) Vacuum drying The slurry was spread evenly in a drying oven, and the temperature was set at 40℃ and the vacuum degree at -0.06MPa for 4 hours. The moisture content of the slurry was ≤3.0%.

[0028] 4) Granulation and sieving The dried medicinal blocks are crushed and passed through a 100-mesh standard sieve to obtain medicinal powder.

[0029] 5) Mixed Packaging The powder and filler are added to a three-dimensional motion mixer and mixed for 20 minutes; after passing the test, they are packaged and sealed to obtain the finished product.

[0030] Example 3 Amoxicillin soluble powder Prescription composition: Amoxicillin trihydrate: 65g Carboxymethyl chitosan: 8g Glycine: 10g Meglumine: 5g Buffer (anhydrous citric acid: sodium citrate = 1:2): 15g Filler (pregelatinized starch): 50g Purified water: 51.5g Preparation process: 1) Raw material pretreatment All raw materials are crushed separately, passed through an 80-mesh standard pharmaceutical sieve, and sealed for later use.

[0031] 2) Wet grinding Weigh all raw materials except fillers and put them into a wet grinding mill. Add 51.5g of purified water. Adjust the speed to 3000r / min and grind for 60min. Control the particle size of the slurry to ≤10μm to obtain a uniform slurry.

[0032] 3) Vacuum drying The slurry was spread evenly in a drying oven, and the temperature was set to 50℃ and the vacuum degree to -0.08MPa. It was dried for 6 hours, and the moisture content of the slurry was ≤3.0%.

[0033] 4) Granulation and sieving The dried medicinal blocks are crushed and passed through a 100-mesh standard sieve to obtain medicinal powder.

[0034] 5) Mixed Packaging The powder and filler are added to a three-dimensional motion mixer and mixed for 40 minutes; after passing the test, they are packaged and sealed to obtain the finished product.

[0035] Comparative Example 1: Amoxicillin Soluble Powder Prescription composition: Amoxicillin trihydrate: 50g, glycine: 6g, meglumine: 3g, buffer (anhydrous citric acid: sodium citrate = 1:2.5): 10g, filler (anhydrous glucose: pregelatinized starch = 1:1): 35g, purified water: 30g.

[0036] Preparation process: 1) Raw material pretreatment: Amoxicillin trihydrate, glycine, meglumine, buffer, and filler are placed in a universal pulverizer and pulverized. After pulverization, all are passed through an 80-mesh standard drug sieve, and after sieving, they are sealed and stored separately for later use.

[0037] 2) Wet grinding: Accurately weigh amoxicillin trihydrate, glycine, meglumine, and buffer according to the prescription, put them all into a wet grinder, add 30g of purified water; turn on the grinder, adjust the speed to 2000r / min, grind continuously for 40min, take samples for testing during the grinding process to ensure that the particle size of the drug slurry is ≤10μm, and obtain a uniform and fine drug slurry.

[0038] 3) Vacuum drying: Spread the slurry evenly in a vacuum drying tray and place it in a vacuum drying oven; set the drying temperature to 45℃ and the vacuum degree to -0.07MPa, and dry at constant temperature and pressure for 5 hours; after drying, take a sample for testing, and the moisture content of the slurry is ≤3.0%, thus obtaining dried slurry.

[0039] 4) Granulation and sieving: Put the dried medicine blocks into a pulverizer and pulverize them. After pulverization, all of them are passed through a 100-mesh standard medicine sieve to remove coarse particles and obtain fine medicine powder.

[0040] 5) Mixed Packaging: Add the sieved powder and the prescribed amount of filler to a three-dimensional motion mixer and mix for 30 minutes until homogeneous; take samples to test the content, solubility, pH value and other indicators. After passing the test, package and seal to obtain the finished product.

[0041] Comparative Example 2: Amoxicillin Soluble Powder Prescription composition: Amoxicillin trihydrate: 50g, carboxymethyl chitosan: 5g, meglumine: 3g, buffer (anhydrous citric acid: sodium citrate = 1:2.5): 10g, filler (anhydrous glucose: pregelatinized starch = 1:1): 35g, purified water: 30g.

[0042] Preparation process: 1) Raw material pretreatment: Amoxicillin trihydrate, carboxymethyl chitosan, meglumine, buffer, and filler are placed in a universal pulverizer and pulverized. After pulverization, all are passed through an 80-mesh standard pharmaceutical sieve, and after sieving, they are sealed and stored separately for later use.

[0043] 2) Wet grinding: Accurately weigh amoxicillin trihydrate, carboxymethyl chitosan, meglumine, and buffer according to the prescription, put them all into a wet grinder, add 30g of purified water; turn on the grinder, adjust the speed to 2000r / min, grind continuously for 40min, take samples for testing during the grinding process to ensure that the particle size of the drug slurry is ≤10μm, and obtain a uniform and fine drug slurry.

[0044] 3) Vacuum drying: Spread the slurry evenly in a vacuum drying tray and place it in a vacuum drying oven; set the drying temperature to 45℃ and the vacuum degree to -0.07MPa, and dry at constant temperature and pressure for 5 hours; after drying, take a sample for testing, and the moisture content of the slurry is ≤3.0%, thus obtaining dried slurry.

[0045] 4) Granulation and sieving: Put the dried medicine blocks into a pulverizer and pulverize them. After pulverization, all of them are passed through a 100-mesh standard medicine sieve to remove coarse particles and obtain fine medicine powder.

[0046] 5) Mixed Packaging: Add the sieved powder and the prescribed amount of filler to a three-dimensional motion mixer and mix for 30 minutes until homogeneous; take samples to test the content, solubility, pH value and other indicators. After passing the test, package and seal to obtain the finished product.

[0047] Comparative Example 3: Amoxicillin Soluble Powder Prescription composition: Amoxicillin trihydrate: 50g, carboxymethyl chitosan: 5g, glycine: 6g, buffer (anhydrous citric acid: sodium citrate = 1:2.5): 10g, filler (anhydrous glucose: pregelatinized starch = 1:1): 35g, purified water: 30g.

[0048] Preparation process: 1) Raw material pretreatment: Amoxicillin trihydrate, carboxymethyl chitosan, glycine, buffer, and filler are placed in a universal pulverizer and pulverized. After pulverization, all are passed through an 80-mesh standard drug sieve, and after sieving, they are sealed and stored separately for later use.

[0049] 2) Wet grinding: Accurately weigh amoxicillin trihydrate, carboxymethyl chitosan, glycine, and buffer according to the prescription, put them all into a wet grinder, add 30g of purified water; turn on the grinder, adjust the speed to 2000r / min, grind continuously for 40min, take samples for testing during the grinding process to ensure that the particle size of the drug slurry is ≤10μm, and obtain a uniform and fine drug slurry.

[0050] 3) Vacuum drying: Spread the slurry evenly in a vacuum drying tray and place it in a vacuum drying oven; set the drying temperature to 45℃ and the vacuum degree to -0.07MPa, and dry at constant temperature and pressure for 5 hours; after drying, take a sample for testing, and the moisture content of the slurry is ≤3.0%, thus obtaining dried slurry.

[0051] 4) Granulation and sieving: Put the dried medicine blocks into a pulverizer and pulverize them. After pulverization, all of them are passed through a 100-mesh standard medicine sieve to remove coarse particles and obtain fine medicine powder.

[0052] 5) Mixed Packaging: Add the sieved powder and the prescribed amount of filler to a three-dimensional motion mixer and mix for 30 minutes until homogeneous; take samples to test the content, solubility, pH value and other indicators. After passing the test, package and seal to obtain the finished product.

[0053] Comparative Example 4: Amoxicillin Soluble Powder Prescription composition: Amoxicillin trihydrate: 50g, sodium alginate: 5g, glycine: 6g, meglumine: 3g, buffer (anhydrous citric acid: sodium citrate = 1:2.5): 10g, filler (anhydrous glucose: pregelatinized starch = 1:1): 35g, purified water: 30g.

[0054] Preparation process: 1) Raw material pretreatment: Amoxicillin trihydrate, sodium alginate, glycine, meglumine, buffer, and filler are placed in a universal pulverizer and pulverized. After pulverization, all are passed through an 80-mesh standard drug sieve, and after sieving, they are sealed and stored separately for later use.

[0055] 2) Wet grinding: Accurately weigh amoxicillin trihydrate, sodium alginate, glycine, meglumine, and buffer according to the prescription, put them all into a wet grinder, add 30g of purified water; turn on the grinder, adjust the speed to 2000r / min, grind continuously for 40min, take samples for testing during the grinding process to ensure that the particle size of the slurry is ≤10μm, and obtain a uniform and fine slurry.

[0056] 3) Vacuum drying: Spread the slurry evenly in a vacuum drying tray and place it in a vacuum drying oven; set the drying temperature to 45℃ and the vacuum degree to -0.07MPa, and dry at constant temperature and pressure for 5 hours; after drying, take a sample for testing, and the moisture content of the slurry is ≤3.0%, thus obtaining dried slurry.

[0057] 4) Granulation and sieving: Put the dried medicine blocks into a pulverizer and pulverize them. After pulverization, all of them are passed through a 100-mesh standard medicine sieve to remove coarse particles and obtain fine medicine powder.

[0058] 5) Mixed Packaging: Add the sieved powder and the prescribed amount of filler to a three-dimensional motion mixer and mix for 30 minutes until homogeneous; take samples to test the content, solubility, pH value and other indicators. After passing the test, package and seal to obtain the finished product.

[0059] Comparative Example 5: Amoxicillin Soluble Powder Prescription composition: Amoxicillin trihydrate: 50g, carboxymethyl chitosan: 5g, L-arginine: 6g, meglumine: 3g, buffer (anhydrous citric acid: sodium citrate = 1:2.5): 10g, filler (anhydrous glucose: pregelatinized starch = 1:1): 35g, purified water: 30g.

[0060] Preparation process: 1) Raw material pretreatment: Amoxicillin trihydrate, carboxymethyl chitosan, L-arginine, meglumine, buffer, and filler are placed in a universal pulverizer and pulverized. After pulverization, all are passed through an 80-mesh standard drug sieve, and after sieving, they are sealed and stored separately for later use.

[0061] 2) Wet grinding: Accurately weigh amoxicillin trihydrate, carboxymethyl chitosan, L-arginine, meglumine, and buffer according to the prescription, and put them all into a wet grinder. Add 30g of purified water. Turn on the grinder, adjust the speed to 2000r / min, and grind continuously for 40min. Take samples for testing during the grinding process to ensure that the particle size of the slurry is ≤10μm, so as to obtain a uniform and fine slurry.

[0062] 3) Vacuum drying: Spread the slurry evenly in a vacuum drying tray and place it in a vacuum drying oven; set the drying temperature to 45℃ and the vacuum degree to -0.07MPa, and dry at constant temperature and pressure for 5 hours; after drying, take a sample for testing, and the moisture content of the slurry is ≤3.0%, thus obtaining dried slurry.

[0063] 4) Granulation and sieving: Put the dried medicine blocks into a pulverizer and pulverize them. After pulverization, all of them are passed through a 100-mesh standard medicine sieve to remove coarse particles and obtain fine medicine powder.

[0064] 5) Mixed Packaging: Add the sieved powder and the prescribed amount of filler to a three-dimensional motion mixer and mix for 30 minutes until homogeneous; take samples to test the content, solubility, pH value and other indicators. After passing the test, package and seal to obtain the finished product.

[0065] Comparative Example 6: Amoxicillin Soluble Powder Prescription composition: Amoxicillin trihydrate: 50g, carboxymethyl chitosan: 5g, glycine: 6g, meglumine: 3g, buffer (anhydrous citric acid: sodium citrate = 1:2.5): 10g, filler (anhydrous glucose: pregelatinized starch = 1:1): 35g, purified water: 30g.

[0066] Preparation process: 1) Raw material pretreatment: Amoxicillin trihydrate, carboxymethyl chitosan, glycine, meglumine, buffer, and filler are placed in a universal pulverizer and pulverized. After pulverization, all are passed through an 80-mesh standard pharmaceutical sieve. After sieving, they are sealed and stored separately for later use.

[0067] 2) Wet grinding: Accurately weigh amoxicillin trihydrate, carboxymethyl chitosan, glycine, meglumine, and buffer according to the prescription, put them all into a wet grinder, add 30g of purified water; turn on the grinder, adjust the speed to 2000r / min, grind continuously for 40min, take samples for testing during the grinding process to ensure that the particle size of the slurry is ≤10μm, and obtain a uniform and fine slurry.

[0068] 3) Vacuum drying: Spread the slurry evenly in a vacuum drying tray and place it in a vacuum drying oven; set the drying temperature to 45℃ and the vacuum degree to -0.07MPa, and dry at constant temperature and pressure for 5 hours; after drying, take a sample for testing, and the moisture content of the slurry is ≤3.0%, thus obtaining dried slurry.

[0069] 4) Granulation and sieving: Put the dried medicine blocks into a pulverizer and pulverize them. After pulverization, all of them are passed through a 100-mesh standard medicine sieve to remove coarse particles and obtain fine medicine powder.

[0070] 5) Mixed Packaging: Add the sieved powder and the prescribed amount of filler to a three-dimensional motion mixer and mix for 30 minutes until homogeneous; take samples to test the content, solubility, pH value and other indicators. After passing the test, package and seal to obtain the finished product.

[0071] Comparative Example 7: Amoxicillin Soluble Powder Prescription composition: Amoxicillin trihydrate: 50g, carboxymethyl chitosan: 5g, glycine: 6g, poloxamer 188: 3g, buffer (anhydrous citric acid: sodium citrate = 1:2.5): 10g, filler (anhydrous glucose: pregelatinized starch = 1:1): 35g, purified water: 30g.

[0072] Preparation process: 1) Raw material pretreatment: Amoxicillin trihydrate, carboxymethyl chitosan, glycine, poloxamer 188, buffer, and filler are placed in a universal pulverizer and pulverized. After pulverization, all are passed through an 80-mesh standard drug sieve, and after sieving, they are sealed and stored separately for later use.

[0073] 2) Wet grinding: Accurately weigh amoxicillin trihydrate, carboxymethyl chitosan, glycine, poloxamer 188, and buffer according to the prescription, and put them all into a wet grinder. Add 30g of purified water; turn on the grinder, adjust the speed to 2000r / min, and grind continuously for 40min. Take samples for testing during the grinding process to ensure that the particle size of the slurry is ≤10μm, so as to obtain a uniform and fine slurry.

[0074] 3) Vacuum drying: Spread the slurry evenly in a vacuum drying tray and place it in a vacuum drying oven; set the drying temperature to 45℃ and the vacuum degree to -0.07MPa, and dry at constant temperature and pressure for 5 hours; after drying, take a sample for testing, and the moisture content of the slurry is ≤3.0%, thus obtaining dried slurry.

[0075] 4) Granulation and sieving: Put the dried medicine blocks into a pulverizer and pulverize them. After pulverization, all of them are passed through a 100-mesh standard medicine sieve to remove coarse particles and obtain fine medicine powder.

[0076] 5) Mixed Packaging: Add the sieved powder and the prescribed amount of filler to a three-dimensional motion mixer and mix for 30 minutes until homogeneous; take samples to test the content, solubility, pH value and other indicators. After passing the test, package and seal to obtain the finished product.

[0077] Comparative Example 8: Amoxicillin Soluble Powder Prescription composition: Amoxicillin trihydrate: 50g, carboxymethyl chitosan: 5g, glycine: 6g, meglumine: 3g, buffer (anhydrous citric acid: sodium citrate = 1:2.5): 10g, filler (anhydrous glucose: pregelatinized starch = 1:1): 35g.

[0078] Preparation process: 1) Raw material pretreatment: Amoxicillin trihydrate, carboxymethyl chitosan, glycine, meglumine, buffer, and filler are placed in a universal pulverizer and pulverized. After pulverization, all are passed through an 80-mesh standard pharmaceutical sieve, and after sieving, they are sealed and stored separately for later use.

[0079] 2) Dry grinding: Accurately weigh amoxicillin trihydrate, carboxymethyl chitosan, glycine, meglumine, and buffer according to the prescription, put them all into the grinder, adjust the speed to 2000 r / min, and grind continuously for 40 min. Take samples for testing during the grinding process to ensure that the particle size of the drug powder is ≤10μm.

[0080] 3) Vacuum drying: Spread the drug powder evenly in a vacuum drying tray and place it in a vacuum drying oven; set the drying temperature to 45℃ and the vacuum degree to -0.07MPa, and dry at constant temperature and pressure for 2 hours; after drying, take a sample for testing, and the moisture content of the drug block is ≤3.0%, thus obtaining dried drug blocks.

[0081] 4) Granulation and sieving: Put the dried medicine blocks into a pulverizer and pulverize them. After pulverization, all of them are passed through a 100-mesh standard medicine sieve to remove coarse particles and obtain fine medicine powder.

[0082] 5) Mixed Packaging: Add the sieved powder and the prescribed amount of filler to a three-dimensional motion mixer and mix for 30 minutes until homogeneous; take samples to test the content, solubility, pH value and other indicators. After passing the test, package and seal to obtain the finished product.

[0083] Amoxicillin soluble powder quality evaluation 1. Solubility test To simulate the drug administration scenario in livestock and poultry drinking water, 1.0 g of each test sample was weighed and added to 100 mL of purified water at 25 °C. The mixture was magnetically stirred at 200 r / min, and the complete dissolution time was recorded. The clarity of the solution was observed, and after standing for 24 h, it was observed whether precipitation or turbidity occurred.

[0084] Table 1 Solubility Test Results In this experiment, the amoxicillin soluble powder prepared in Examples 1-3 could completely dissolve within 1.5-2.0 min, and the solution remained clear and without precipitation after standing for 24 h. In contrast, the comparative samples had a dissolution time of up to 10.5 min, and all showed turbidity and precipitation after standing. This invention uses carboxymethyl chitosan as the core solubilizing and anti-precipitation component, which binds to amoxicillin through electrostatic interaction to form a water-soluble complex. At the same time, it chelates metal ions in water to prevent drug precipitation. Combined with the synergistic solubilizing effect of glycine and meglumine, as well as a buffer pair adapted to the optimal solubility range of the drug, and then achieving uniform mixing of the drug and excipients through wet grinding, this invention improves the industry pain points of poor water solubility of amoxicillin and easy aggregation and precipitation during clinical administration.

[0085] 2. Aqueous solution stability test Each sample was prepared into a 5 mg / mL amoxicillin aqueous solution and placed at 25°C in the dark. Samples were taken at 0 h, 2 h, 4 h, 8 h, and 24 h, and the amoxicillin content was determined by HPLC.

[0086] Table 2 Results of aqueous solution stability test In this experiment, the amoxicillin aqueous solution of Examples 1-3 retained 98.2% of the drug content within 24 hours, while the comparative examples had only 84.5%-93.7% of the drug residue within 24 hours, indicating a significant degree of degradation. The core instability of amoxicillin aqueous solution is the hydrolytic ring-opening of the β-lactam ring. The formulation of this invention precisely stabilizes the solution pH at 4.5-5.5, minimizing drug hydrolysis. Simultaneously, carboxymethyl chitosan forms a hydration film around the drug molecules, reducing the contact between water molecules and the β-lactam ring. Combined with the synergistic stabilizing effect of glycine and meglumine, the hydrolysis reaction is further inhibited, solving the problem that amoxicillin aqueous solution is easily hydrolyzed and inactivated, failing to meet the clinical requirements for drinking water administration time.

[0087] 3. pH value determination of solution Weigh 1.0g of each sample, add 100mL of purified water to dissolve, and use a precision pH meter to measure the pH value of the solution to verify whether it is stable between 4.5 and 5.5.

[0088] Table 3 Results of pH value determination of solution The amoxicillin soluble powders prepared in Examples 1-3 of this invention maintained a precisely stable initial pH of 4.5-5.5 in their aqueous solutions. After 6 months of accelerated testing, the pH showed no significant fluctuation, with a change range ≤0.1, and a stable pH environment was maintained even during long-term storage. In contrast, the pH of the comparative samples continuously shifted towards alkalinity after 6 months of accelerated testing, failing to maintain a stable dissolution environment. This invention achieves precise pH stability of the formulation's aqueous solution through the synergistic regulation of buffer formulation, carboxymethyl chitosan, glycine, and meglumine, combined with a preparation process involving wet grinding and vacuum drying, providing a core environmental guarantee for the solubility and storage stability of amoxicillin.

[0089] 4. Accelerated stability test Following the guidelines for veterinary drug stability, each sample was placed in a constant temperature and humidity chamber at 40℃±2℃ and 75%±5% relative humidity. Samples were taken in 0 months, 1 month, 2 months, 3 months, and 6 months to test the amoxicillin content and solution pH value to assess storage stability.

[0090] Amoxicillin content determination method: Chromatographic conditions and system suitability test: Octadecylsilane-bonded silica gel was used as the stationary phase; 0.05 mol / L potassium dihydrogen phosphate solution (adjusted to pH 5.0 with 2 mol / L potassium hydroxide solution) - acetonitrile (97.5:2.5) was used as the mobile phase; the detection wavelength was 254 nm. Take approximately 25 mg of amoxicillin system suitability reference standard, place it in a 50 ml volumetric flask, dissolve and dilute to the mark with the mobile phase, shake well, and inject 20 μl into the liquid chromatograph. The recorded chromatogram should be consistent with the standard chromatogram. Assay method: Accurately weigh approximately 25 mg of this product, place it in a 50 ml volumetric flask, dissolve and dilute to the mark with the mobile phase, shake well, and accurately inject 20 μl into the liquid chromatograph. Record the chromatogram; separately, take an appropriate amount of amoxicillin reference standard and determine it using the same method. Calculate the result by peak area using the external standard method.

[0091] Table 4. Amoxicillin content in accelerated tests In this experiment, after 6 months of accelerated testing, the amoxicillin content in Examples 1-3 remained above 98.7%, meeting the shelf-life requirements of veterinary drug preparations. In contrast, the drug residue content in the comparative examples after 6 months of accelerated testing was only 87.2%-93.8%. This invention constructs a dual moisture-proof system with carboxymethyl chitosan film-forming moisture protection as its core, isolating the drug from moisture and oxygen in the air. Combined with a low-hygroscopic filler, it reduces the migration of moisture within the preparation. Simultaneously, through a low-moisture process of wet grinding and vacuum drying, the moisture content of the preparation is strictly controlled, inhibiting the hydrolysis of the β-lactam ring. Furthermore, by stabilizing the internal microenvironment of the preparation, a positive cycle of inhibiting degradation is formed, significantly improving the long-term storage stability of the preparation.

Claims

1. An amoxicillin soluble powder, characterized in that, The amoxicillin soluble powder is composed of the following components: Amoxicillin trihydrate 30-65 parts, carboxymethyl chitosan 2-8 parts, glycine 3-10 parts, meglumine 1-5 parts, buffer 5-15 parts, filler 20-50 parts.

2. The amoxicillin soluble powder according to claim 1, characterized in that, The buffer is selected from one or more of anhydrous citric acid, sodium citrate, and anhydrous potassium dihydrogen phosphate.

3. The amoxicillin soluble powder according to claim 1, characterized in that, The buffer stabilizes the pH of the formulation at 4.5–5.5 after dissolution.

4. The amoxicillin soluble powder according to claim 1, characterized in that, The filler is selected from one or two of anhydrous glucose and pregelatinized starch.

5. A method for preparing the amoxicillin soluble powder according to any one of claims 1 to 4, characterized in that, Includes the following steps: 1) Raw material pretreatment: Amoxicillin trihydrate, carboxymethyl chitosan, glycine, meglumine, buffer, and filler are pulverized separately and passed through an 80-mesh sieve for later use; 2) Wet grinding: Weigh amoxicillin trihydrate, carboxymethyl chitosan, glycine, meglumine, and buffer according to the prescription amount, add purified water, and grind in a wet grinder to obtain a uniform slurry; 3) Vacuum drying: The slurry is vacuum dried to obtain dried drug blocks; 4) Granulation and sieving: The dried medicinal blocks are crushed and sieved to obtain medicinal powder; 5) General mixing and packaging: Mix the powder and filler evenly, and after passing the test, package and seal to obtain amoxicillin soluble powder.

6. The preparation method according to claim 5, characterized in that, The amount of purified water added in step 2) is 30% to 50% of the total mass of the prescription.

7. The preparation method according to claim 5, characterized in that, The wet grinding speed described in step 2) is 1500-3000 r / min, and the grinding time is 30-60 min.

8. The preparation method according to claim 5, characterized in that, The particle size of the slurry in step 2) is ≤10μm.

9. The preparation method according to claim 5, characterized in that, The vacuum drying temperature in step 3) is 40-50℃, the vacuum degree is -0.06--0.08MPa, the drying time is 4-6h, and the moisture content after drying is ≤3.0%.

10. The preparation method according to claim 5, characterized in that, The sieve mesh size mentioned in step 4) is 100 mesh; the mixing in step 5) is carried out using a three-dimensional motion mixer, and the mixing time is 20-40 minutes.

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