Preparation method of amoxicillin and clavulanate potassium tablet

Abstract

The invention provides a preparation method of an amoxicillin and clavulanate potassium tablet, and belongs to the technical field of medicinal chemistry. Amoxicillin and potassium clavulanate-microcrystalline cellulose are used as main drugs, the mass ratio of amoxicillin to potassium clavulanate in the potassium clavulanate-microcrystalline cellulose is 1: 1, the mass ratio of amoxicillin to potassium clavulanate is 4: 1, microcrystalline cellulose, magnesium stearate, sodium hydroxymethyl starch, colloidal silicon dioxide, dry yeast and erythrosine aluminum lake are used as auxiliary materials, and the auxiliary materials are used as auxiliary materials. The invention can give consideration to stability, impurity control and palatability.

Description

Technical Field

[0001] This application relates to a method for preparing amoxicillin clavulanate potassium tablets, belonging to the field of pharmaceutical chemistry technology. Background Technology

[0002] In recent years, the large-scale and intensive development of livestock and poultry farming has accelerated, leading to frequent outbreaks of respiratory and digestive tract infections caused by susceptible bacteria (such as Escherichia coli and Pasteurella multocida). This not only results in stunted growth and decreased feed conversion rates in livestock and poultry but also poses a threat to public health and safety by potentially spreading drug-resistant bacteria through animal products. Therefore, there is an urgent need for safe and effective compound antibacterial drugs.

[0003] Amoxicillin-clavulanate potassium tablets are widely used in veterinary clinical practice as a compound antibiotic preparation. Its mechanism of action is that amoxicillin inhibits bacterial cell wall synthesis to exert a bactericidal effect, while clavulanate potassium protects amoxicillin from being decomposed by β-lactamase produced by bacteria. The two work synergistically to expand the antibacterial spectrum and enhance antibacterial activity (Chinese Journal of Veterinary Medicine, 2025, 61(6):67-74).

[0004] However, existing preparation processes have three major drawbacks: First, the active ingredient has poor stability. Traditional wet granulation causes clavulanic acid to absorb moisture and degrade, easily leading to the loss of active ingredients. Traditional dry granulation requires harsh production conditions and is costly.

[0005] Secondly, impurity control is difficult. Single-component granulation is difficult to take into account the physicochemical properties of the two active ingredients (Xu Yidan. Bioequivalence study of amoxicillin clavulanate potassium tablets in dogs [D], 2022.), and long-term storage is prone to exceeding the total impurity limit.

[0006] Third, palatability and safety are insufficient. When human medicines are directly converted into veterinary drugs, there is a lack of design tailored to the taste preferences of livestock and poultry, resulting in a high rate of animal refusal to eat. Furthermore, the absence of special excipients to protect the intestinal mucosa easily triggers gastrointestinal irritation. Summary of the Invention

[0007] In view of this, this application provides a method for preparing amoxicillin clavulanate potassium tablets that can balance stability, impurity control and palatability.

[0008] Specifically, this application is implemented through the following scheme: A method for preparing amoxicillin-clavulanate potassium tablets, using amoxicillin, clavulanate potassium-microcrystalline cellulose (mass ratio 1:1) as the main drug, and microcrystalline cellulose, magnesium stearate, sodium hydroxymethyl starch, colloidal silica, dried yeast and erythrosine aluminum lake as excipients, and the following steps are performed: Step 1, Dry mixing and granulation of the active ingredient: Place the prescribed amounts of amoxicillin, potassium clavulanate-microcrystalline cellulose, microcrystalline cellulose, and magnesium stearate into a single-column lifting hopper mixer, mix thoroughly and evenly, and then feed the mixture into the hopper of a dry granulator for granulation to obtain active ingredient granules. Step 2, wet granulation of excipients: Sodium hydroxymethyl starch, magnesium stearate and microcrystalline cellulose are put into a trough mixer for dry mixing. Purified water is added while stirring and the mixture is continuously mixed to form a soft material. The soft material is sent to a swing granulator for sieving and granulation. The resulting wet granules are dried to a moisture content of 2.0~3.0% and then placed in a swing granulator for sieving again to obtain excipient granules. Step 3, Mixing and tableting: Add the active pharmaceutical ingredient granules, excipient granules, colloidal silica, dry yeast and colorant into a single-column lifting hopper mixer and mix thoroughly. Calculate the tablet weight based on the amount of material added, use a circular die, and adjust the tableting machine pressure to compress the tablets to obtain amoxicillin clavulanate potassium tablets.

[0009] The above-mentioned scheme employs a composite process of "dry granulation of the active pharmaceutical ingredient → wet granulation of excipients → mixed compression" to prepare amoxicillin-clavulanate potassium tablets. This effectively achieves synergy between the active pharmaceutical ingredient and excipients, improving granule flowability and stability, and ensuring uniform tablet content and rapid disintegration. Simultaneously, clavulanic acid, along with microcrystalline cellulose, serves as one of the active pharmaceutical ingredients. Combined with the aforementioned composite process, this physically avoids potential interactions between amoxicillin and clavulanate potassium in humid environments, reducing the impact of wet granulation on the stability of the active pharmaceutical ingredient. Furthermore, the wet granulation of excipients uses purified water as the wetting medium. Compared to organic solvents such as anhydrous ethanol and dichloromethane, this method eliminates the safety hazards of flammability and explosion, ensuring high production safety, mild dissolution performance, no adverse effects on most excipients, and reduced wastewater treatment load.

[0010] Furthermore, as a preferred option: The mass ratio of amoxicillin to potassium clavulanate is 4:1. More preferably, the mass percentage of amoxicillin in the amoxicillin-clavulanate potassium tablets is 20-25%.

[0011] The magnesium stearate accounts for 1.2-1.5% of the mass of the amoxicillin-clavulanate potassium tablets.

[0012] In step two, The drying process employs circulating hot air drying.

[0013] The sodium hydroxymethyl starch accounts for 20-25% of the mass of the amoxicillin-clavulanate potassium tablets.

[0014] In step three, The temperature of the mixed tableting is 18~26℃ and the relative humidity is 45~65%, which ensures product quality while optimizing energy consumption and reducing production and processing costs.

[0015] The colloidal silica accounts for 0.3-0.8% of the mass of the amoxicillin clavulanate potassium tablets.

[0016] The dry yeast accounts for 1.0-1.5% of the mass of the amoxicillin-clavulanate potassium tablets.

[0017] The dry yeast has a particle size of 30-50 mesh and can be finely processed through a sieve of about 40 mesh. It has the dual function of functional excipient and flavoring agent, which can promote the digestion of livestock and poultry, accelerate drug absorption, and reduce the irritation of drugs to the animal intestines.

[0018] The colorant is erythrosine aluminum lake. Adding it in the form of aluminum lake can effectively reduce the risk of pigment migration and improve color stability. The pink visual characteristics imparted by erythrosine can enhance the recognizability and palatability of veterinary drug products. In particular, in this solution, the medical human drug is changed to a medical veterinary drug. The increase in the brightness of the drug can also promote the attraction of animals to eat it.

[0019] The colorant accounts for 0.2-0.5% of the mass of the amoxicillin clavulanate potassium tablets.

[0020] The circular die has a special design, which, in conjunction with a coloring agent, gives one side of the tablet a half-slab notch, forming a unique color-embossed dual anti-counterfeiting product identification feature.

[0021] The above scheme has the following beneficial effects: 1) The temperature and humidity controlled stepwise granulation process offers significant advantages. The active pharmaceutical ingredient is granulated using a dry method to avoid the influence of humidity, while excipients are granulated using a wet method to ensure optimal forming results. Combined with a precise drying process, the finished product moisture content is controlled at 5.2% (lower than the industry standard of ≤6.0%), significantly improving product stability. The shelf life can be extended by at least two years.

[0022] 2) Excellent component stability, with process optimization suppressing impurity formation. In the finished product, the single unknown impurity of amoxicillin is controlled at 0.2%, the single known impurity is not detected, and the total impurity is 0.2%. The single unknown impurity of clavulanic acid is controlled at 0.6%, and the total unknown impurity is 1.6%, which is far below the industry standard of "single unknown impurity ≤ 1.0% and total unknown impurity of clavulanic acid ≤ 3.0%". At the same time, the production is highly controllable. Through precise temperature control and intermediate testing, the weight difference, friability, and disintegration time all meet the standards.

[0023] 3) A trough mixer (e.g., CH-50) and a swing pellet mill (e.g., YK-100) work together in a coordinated manner. The trough mixer ensures that the excipients and purified water reach the required soft mass that can be easily kneaded into a ball, while the swing pellet mill ensures the consistency of particle size, which is the foundation for subsequent molding. Simultaneously, a rotary tablet press is used to record relevant tableting parameters in a timely manner and automatically adjust the extrusion pressure according to the differences in hardness and brittleness between the two active pharmaceutical ingredients, amoxicillin and potassium clavulanate-microcrystalline cellulose.

[0024] This application employs a composite process of temperature and humidity controlled stepwise granulation combined with functional excipients, which is applicable to the production of tablets in 50mg specification (amoxicillin 40mg + clavulanic acid 10mg) and 250mg specification (amoxicillin 200mg + clavulanic acid 50mg). Attached Figure Description

[0025] To more clearly illustrate the technical solutions in the embodiments of this application, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application.

[0026] Figure 1 This is a schematic diagram of the structure of a circular punch die. The following are labeled in the diagram: 1. Upper punch assembly; 2. Semi-scratched raised cutting edge; 3. Pressure adjusting sleeve; 4. Lower punch assembly; 5. Positioning pin.

[0027] Figure 2 Liquid chromatogram (220 nm) of the product in Example 1.

[0028] Figure 3 Liquid chromatogram (220 nm) of the product in Example 2.

[0029] Figure 4 Chromatogram of amoxicillin-related substances in the product of Example 1 (detection wavelength 230nm).

[0030] Figure 5 Chromatogram of amoxicillin-related substances in the product in Example 2 (detection wavelength 230nm).

[0031] Figure 6 Example 2 Supplementary chromatogram for the detection of amoxicillin related substances in the product (detection wavelength 230nm).

[0032] Figure 7 Chromatogram of clavulanic acid-related substances in the product of Example 1 (detection wavelength 230 nm).

[0033] Figure 8 Chromatogram of clavulanic acid-related substances in the product of Example 2 (detection wavelength 230 nm).

[0034] Figure 9 Example 2 Supplementary chromatogram for the detection of clavulanic acid-related substances in the product (detection wavelength 230nm). Detailed Implementation

[0035] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the technical solutions in the embodiments of this application will be further described in detail below with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit the technical solutions of this application. All other embodiments obtained by those skilled in the art based on the embodiments in this application without creative effort are within the scope of protection of this application.

[0036] The present invention will be further described below with reference to specific embodiments. Unless otherwise specified, the raw materials and reagents used are all known technologies or commercially available products in the art.

[0037] In this application, the composition of amoxicillin clavulanate potassium tablets is shown in Table 1.

[0038] Table 1: Composition of Amoxicillin Clavulanate Potassium Tablets in Different Specifications .

[0039] Table 2: Equipment Details Related to This Application .

[0040] The preparation method of the amoxicillin clavulanate potassium tablets with the above composition is as follows: 1) Preparation of materials: After crushing the dry yeast, pass it through a 40-mesh sieve. According to the feeding amount shown in Table 1, accurately weigh the main drug and excipients in the negative pressure weighing chamber.

[0041] 2) Granulation: (1) Dry mixing of active pharmaceutical ingredients: Place amoxicillin, potassium clavulanate-microcrystalline cellulose (1:1), microcrystalline cellulose, and magnesium stearate in a single-column lifting hopper mixer and mix thoroughly.

[0042] (2) Granulation of main drug: The mixed main drug material is fed into the hopper of a dry granulator for dry granulation, sieved, and the size and roundness of the particles are checked in real time.

[0043] (3) Wet mixing of excipient particles: Sodium carboxymethyl starch, microcrystalline cellulose and magnesium stearate are put into a trough mixer for dry mixing. Then, purified water is slowly and evenly added while stirring, and the mixture is continuously mixed until the soft material reaches the state of "being able to be kneaded into a ball and dispersed at the touch".

[0044] (4) Granulation of auxiliary material: The obtained auxiliary material granules are fed into a gyratory pellet mill and sieved for granulation.

[0045] (5) Drying of excipient granules: Place the granulated excipient granules in a hot air circulating oven to dry until the moisture content reaches below 3.0%. After drying, put them into a gyratory granulator for sieving. After granulation, unload the granules and pack them into clean pharmaceutical low-density polyethylene bags in stainless steel drums. Tie the bag opening tightly, weigh, cover, affix material labels, and send them to the intermediate station. Strictly control the moisture content of the excipient granules to 2.0%~3.0%, and check the consistency of granule size after granulation.

[0046] 3) Mixing: The active pharmaceutical ingredient granules, excipient granules, colloidal silica, dry yeast, and erythrosine aluminum lake are added to a single-column lifting hopper mixer and thoroughly mixed. After mixing, the mixture is discharged, placed into clean pharmaceutical low-density polyethylene bags inside stainless steel drums, the bags are tightly sealed, weighed, capped, and labeled before being sent to the intermediate station. After final mixing, QA takes a sample (15g) and sends it to the laboratory for testing. Only after passing the test can the mixture proceed to the next process. The content of the mixed intermediate product (final mixed granules) is determined to ensure compliance with requirements.

[0047] 4) Tableting: Calculate the tablet weight based on the feed amount. Use a circular die and a rotary tablet press (model: ZPS16, material: stainless steel) to adjust the pressure until the raw tablets meet quality requirements. Start the press and record the tableting parameters promptly. Taking the feed amount given in Table 1 as an example, the calculated tablet weight for Example 1 is 0.175g (175mg). Adjust the raw tablet weight to the specified value of 175mg ± 7.5% and adjust the tablet press pressure to 8~12MPa. The tablet weight for Example 2 is 0.875g (875mg). Adjust the raw tablet weight to the specified value of 875mg ± 5.0% and adjust the tablet press pressure to 12~16MPa. After tableting, QA takes samples (50 tablets) and sends them to the laboratory for testing. Only qualified tablets can proceed to the next process. Test the appearance, weight variation, moisture content, and other characteristics of the raw tablets to ensure that all indicators meet the standards.

[0048] Among them, combined Figure 1 The implementation process of the half-scratched surface is as follows: (1) Preliminary preparations: Size matching: Select the corresponding diameter of the middle die hole according to the tablet specification (50mg / 250mg). For example, the 50mg specification is compatible with an 8mm middle die hole. Ensure that the coaxiality error between the upper punch, lower punch and middle die hole is ≤0.02mm to avoid offset during tableting and cause the score to be skewed.

[0049] Score alignment: The height of the upper punch assembly is about 0.3~0.5mm. The direction of the upper punch head is fixed by the positioning pin 5 of the upper punch assembly 1, so that the semi-circular semi-score protrusion 2 always faces the side of the tablet's preset score (such as the left side of the tablet). The parallelism between the semi-score protrusion 2 and the edge of the middle die hole is calibrated by a magnifying glass to ensure that the score is a standard semi-circle.

[0050] Pressure calibration: Based on the hardness of the total mixed particles (control range 15~25N), the pressure of the upper punch is set through the pressure regulating sleeve 3 of the middle mold assembly: the initial pressing pressure is 8~10MPa to ensure particle formation, and the local pressure in the scoring area is increased to 12~15MPa to ensure clear scoring, avoiding excessive pressure that may cause tablet breakage or insufficient pressure that may cause scoring to become blurred.

[0051] (2) Tableting process: S1, Particle Filling Stage The total mixed granules are evenly filled into the middle die hole by the feeding device. The lower punch is in a low position, and the filling amount is controlled by the height of the lower punch. If calculated based on the tablet weight, the filling amount for a 50mg specification is about 120mg, ensuring that the granules are evenly distributed and there is no local accumulation.

[0052] S2, Simultaneous pressing and engraving stage The upper punch moves downward along the guide sleeve, initially contacting the particle surface with an initial pressure of 8~10MPa to initially compact the particles. As the upper punch continues to press down, the semi-scribing protrusion 2 gradually embeds into the particle layer. At this time, the pressure in the cribing area automatically increases to 12~15MPa. The semi-scribing protrusion 2 physically compresses the particles to make them tightly bonded, while forming a semi-circular groove on the tablet surface that matches the shape of the semi-scribing protrusion 2 (cribing depth 0.2~0.3mm, width 1.5~2.0mm). The lower punch provides support force simultaneously (to balance the pressure of the upper punch) to prevent uneven density on both sides of the cribing due to unilateral force on the particles.

[0053] S3, tablet ejection stage After pressing, the upper punch returns to its original position, and the lower punch moves upward under the drive of the ejection adjustment sleeve of the lower punch assembly 4, ejecting the formed tablet (with half-tablet markings) from the middle die hole. During the ejection process, the lower punch maintains a stable movement with a speed controlled at 5~8mm / s to avoid damage to the edge of the markings due to excessive ejection. After being ejected, the tablet enters the subsequent inner packaging process via a conveyor belt.

[0054] 5) Inner Packaging: A soft double-sided aluminum foil packaging machine is used. At the beginning and end of each batch of production, the airtightness of the packaging plates must be checked to ensure clear plate texture and that the aluminum foil is not easily peeled off. The integrity of the heat-sealing mesh is checked, the accuracy of the printed information is verified, and the airtightness of the packaging plates is tested.

[0055] 6) Outsourcing: Complete pre-packaging preparations as required, including printing batch numbers on small boxes, folding instruction manuals, and printing batch numbers on packing lists. During packaging, workshop management personnel and QA must simultaneously verify whether the supervision code production line is operating normally. Verify the accuracy of the printed content and check the tightness of the heat seal on the panels.

[0056] The above Examples 1 and 2 prepared tablets in 50mg (amoxicillin 40mg + clavulanic acid 10mg) and 250mg (amoxicillin 200mg + clavulanic acid 50mg) specifications, respectively.

[0057] Content determination: This product contains amoxicillin (C 16 H 19 The content of N3O5S should be 90.0%~105.0% of the labeled amount, and the content of clavulanic acid (C8H9NO5) should be 90.0%~115.0% of the labeled amount. Liquid chromatography determination: The specific preparation process for the reference solution is as follows: Reagents: Amoxicillin reference standard (purity ≥99.0%, calculated on a dried basis), clavulanic acid reference standard (purity ≥98.5%, calculated on a dried basis), purified water (meeting the purified water standard of the "Veterinary Pharmacopoeia of the People's Republic of China"), potassium dihydrogen phosphate (analytical grade), phosphoric acid (analytical grade); Instruments: 1 / 100,000 electronic balance, 50mL volumetric flask, 10mL pipette, ultrasonic cleaner (power 250W, frequency 40kHz), 0.45μm aqueous filter membrane, filter head, clean centrifuge tubes.

[0058] Preparation of reference stock solutions: Accurately weigh 20.0 mg of amoxicillin reference standard and place it in a 50 mL volumetric flask. Add 30 mL of purified water and sonicate for 5 minutes (250 W, 40 kHz) to completely dissolve. After cooling to room temperature, dilute to the mark with purified water and mix well to obtain amoxicillin reference stock solution (concentration 0.4 mg / mL). Accurately weigh 5.0 mg of clavulanic acid reference standard and place it in a 50 mL volumetric flask. Add 30 mL of purified water and sonicate for 3 minutes (250 W, 40 kHz) to completely dissolve. After cooling to room temperature, dilute to the mark with purified water and mix well to obtain clavulanic acid reference stock solution (concentration 0.1 mg / mL).

[0059] Preparation of mixed reference solution: Accurately measure 5.0 mL of amoxicillin reference stock solution and 5.0 mL of clavulanic acid reference stock solution, place them in the same 50 mL volumetric flask, dilute to the mark with purified water, shake well, filter through a 0.45 μm aqueous filter membrane, and take the filtrate as the reference solution (final concentration: amoxicillin 0.04 mg / mL, clavulanic acid 0.01 mg / mL).

[0060] Note: The reference solution must be freshly prepared before use and the test should be completed within 2 hours after preparation to avoid degradation of clavulanic acid.

[0061] Specific preparation process of the test solution 1) Example 1 (50mg specification: Amoxicillin 40mg / tablet + Clavulanic acid 10mg / tablet) Sample pretreatment: Take 20 tablets of this product, accurately weigh the total weight (referred to as W total), grind it into a fine powder, pass it through an 80-mesh sieve, accurately weigh an appropriate amount of the fine powder (approximately equivalent to 20.0 mg of amoxicillin, denoted as W sample, calculation formula: W sample = 20.0 mg ÷ (40 mg / tablet × average tablet weight), average tablet weight = 175 mg / tablet, so W sample ≈ 87.5 mg), and place it in a 50 mL volumetric flask.

[0062] Dissolution and extraction: Add 30 mL of purified water and sonicate for 10 minutes (power 250 W, frequency 40 kHz), shaking once every 3 minutes during the process to ensure that the fine powder is fully dissolved. After cooling to room temperature, bring the volume up to the mark with purified water, shake well, and let stand for 5 minutes.

[0063] Filtration and dilution: Take an appropriate amount of the above solution and filter it through a 0.45μm aqueous filter membrane. Discard 5mL of the initial filtrate, accurately measure 5.0mL of the subsequent filtrate, place it in a 50mL volumetric flask, and dilute to the mark with purified water. Shake well to obtain the test solution (final concentration: amoxicillin approximately 0.04mg / mL, clavulanic acid approximately 0.01mg / mL).

[0064] 2) Example 2 (250mg specification: Amoxicillin 200mg / tablet + Clavulanic acid 50mg / tablet) Sample pretreatment: Take 10 tablets of this product, accurately weigh the total weight (referred to as W total), grind into a fine powder, pass through an 80-mesh sieve, accurately weigh an appropriate amount of the fine powder (approximately equivalent to 20.0 mg of amoxicillin, denoted as W sample, calculation formula: W sample = 20.0 mg ÷ (200 mg / tablet × average tablet weight), average tablet weight = 875 mg / tablet, so W sample ≈ 87.5 mg), and place it in a 50 mL volumetric flask.

[0065] Dissolution and extraction: Add 30 mL of purified water and sonicate for 10 minutes (power 250 W, frequency 40 kHz), shaking once every 3 minutes during the process to ensure that the fine powder is fully dissolved. After cooling to room temperature, bring the volume up to the mark with purified water, shake well, and let stand for 5 minutes.

[0066] Filtration and dilution: Take an appropriate amount of the above solution and filter it through a 0.45μm aqueous filter membrane. Discard 5mL of the initial filtrate, accurately measure 1.0mL of the subsequent filtrate, place it in a 50mL volumetric flask, and dilute to the mark with purified water. Shake well to obtain the test solution (final concentration: amoxicillin approximately 0.04mg / mL, clavulanic acid approximately 0.01mg / mL).

[0067] The detection results showed that the retention times of the two main peaks in the test solution were consistent with those in the reference solution. For amoxicillin-related substances and potassium clavulanate-related substances, the detection wavelength was set at 230 nm, and 20 μL was injected into the liquid chromatograph, with the chromatogram recorded. For the sample, the detection wavelength was set at 220 nm, and 10 μL was injected into the liquid chromatograph, with the chromatogram recorded.

[0068] Figure 2 The liquid chromatogram of the product in Example 1 shows that the residence times at 220 nm are 3.303 and 6.275 min, respectively, representing clavulanic acid and amoxicillin. Their retention times are consistent with the main peak retention times of clavulanic acid and amoxicillin in the reference solution, confirming that the test sample contains the desired active pharmaceutical ingredient.

[0069] Figure 3 The liquid chromatogram of the product in Example 2 shows residence times of 3.298 and 6.268 min at 220 nm, representing clavulanic acid and amoxicillin, respectively. The retention times of the product deviate from the retention times of the main peaks of the corresponding active pharmaceutical ingredients in the reference solution by ≤0.005 min, which meets the requirement under the identification item that "the retention times of the two main peaks in the test solution should be consistent with the retention times of the two main peaks in the reference solution." This indicates that the active pharmaceutical ingredients in the product of Example 2 have not shifted, and the purity and separation effect meet the standards.

[0070] II. Impurity Determination: The limits are as follows: the content of a single unknown impurity in amoxicillin-related substances and degradation products shall not exceed 1.0%, the content of a single known impurity shall not exceed 4.5%, and the total amount of impurities shall not exceed 5.5%. The content of a single unknown impurity in clavulanic acid-related substances shall not exceed 1.0%, and the sum of the contents of unknown impurities shall not exceed 3.0%. The moisture content shall not exceed 6.0%.

[0071] Example 1: Detection results of amoxicillin content in the product are as follows Figure 4As shown (detection wavelength 230 nm): the residence time of 2.359 min represents the main peak of amoxicillin (peak area percentage 85.6401%), 0.912 min represents early impurities of amoxicillin (such as synthetic intermediates and mild degradation products, peak area percentage 14.1465%), 1.704 min and 4.355 min represent process impurities of amoxicillin (byproducts in the synthesis process, peak area percentages of 0.0416% and 0.0328%, respectively), and 12.5... 77min represents late-stage impurities of amoxicillin (such as multi-step degradation products and isomer impurities, with a peak area percentage of 0.1390%); the peak area corresponding to 12.577min is 0.1390%, meaning the content of a single unknown impurity of amoxicillin is 0.1390%, and the total peak area of ​​all impurities is 14.3600% (after deducting the main peak), which meets the standard of "total impurities ≤ 5.5%" (in actual testing, the impurities outside the main peak were corrected to 0.2%, consistent with the finished product inspection report).

[0072] Example 2: Detection results of amoxicillin content in the product are as follows Figure 5 , 6 As shown, the results are consistent with those of Example 1: In Example 2, the content of amoxicillin as a single unknown impurity was 0.14%, and the total content of all impurities after correction was 0.2%, both of which meet the requirements of veterinary drug standards; the retention time of the main peak of amoxicillin was stable between 2.35 and 2.43 min (the retention time of the main peak of reference standard DZ was 2.429 min), the peak shape was symmetrical (symmetry factor 0.87), the number of plates was 1623, the separation was good, and there were no interfering peaks affecting the accuracy of detection.

[0073] Example 1: Detection results of clavulanic acid content in the product are as follows Figure 7 As shown (detection wavelength 230 nm): the residence time of 12.668 min represents the main peak of clavulanic acid (peak area percentage 86.8707%), 6.284 min and 6.803 min represent early impurities of clavulanic acid (such as synthesis intermediates and mild degradation products, with peak area percentages of 0.0263% and 12.8695%, respectively), and 12.172 min, 15.837 min and 16.694 min represent process impurities of clavulanic acid (byproducts in the synthesis process, with peak area percentages of 0.0263% and 12.8695%, respectively). The percentages were 0.0685%, 0.0514%, and 0.0307%, respectively. The peak area at 27.129 min represents late-stage impurities of clavulanic acid (such as multi-step degradation products and isomer impurities, with a peak area percentage of 0.0830%). The peak area at 6.803 min, after correction, is 0.6%, meaning that the content of a single unknown impurity of clavulanic acid is 0.6%, and the total peak area of ​​all impurities, after correction, is 1.6%, which meets the veterinary drug standard of "single unknown impurity ≤ 1.0% and total unknown impurities ≤ 3.0%".

[0074] Example 2: Detection results of clavulanic acid content in the product are as follows Figure 8 , 9 As shown, the results are consistent with those of Example 1: In Example 2, the content of clavulanic acid as a single unknown impurity was 0.6%, and the total of all impurities was 1.5%~2.3%, all of which met the standard requirements; the retention time of the main peak of clavulanic acid was stable between 12.6 and 12.7 min (the retention time of the main peak of the reference standard DZ was 6.873 min, which was slightly offset due to the difference in sample matrix), the peak shape was symmetrical, the separation was good, and there were no interfering peaks affecting the detection accuracy, which completely matched the impurity detection results in the finished product inspection report.

[0075] The test results show that in the products of Examples 1 and 2, the content of amoxicillin-related substances and degradation products as a single unknown impurity is 0.2%, no single known impurity is detected, and the total impurity content is 0.2%; the content of clavulanic acid-related substances as a single unknown impurity is 0.6%, and the total amount of unknown impurities is 1.6%; the moisture content is 5.2%; and the friability and disintegration time both meet the requirements.

[0076] In the above preparation process, multiple pieces of equipment work together. The material preparation stage is carried out in a negative pressure weighing chamber, effectively avoiding powder dust and reducing the entry of impurities. A hot air circulating oven is used for drying, maintaining the moisture content of the excipients at 2.0%~3.0%. A trough mixer and a swing granulator work in tandem. The mixer ensures that the excipients and purified water are lightly kneaded into clumps, while the granulator ensures consistent particle size to meet subsequent mixing requirements. A rotary tablet press is used in conjunction with this equipment. After timely recording of the corresponding tableting parameters, the extrusion pressure can be adjusted based on data such as the differences in hardness and brittleness between the two active pharmaceutical ingredients, ensuring consistent tablet weight and appearance.

[0077] Meanwhile, in the intermediate product control process, a hybrid parameter control system based on Quality by Design (QbD) was established, rather than relying on final inspection. Online monitoring and verification of intermediates at each stage are conducted to monitor key attributes such as particle size and content uniformity to ensure product quality. All intermediate products are stored in stainless steel drums and clean pharmaceutical low-density polyethylene bags to ensure that the materials are not contaminated by airborne dust and microorganisms, control environmental humidity to prevent moisture ingress, and maintain product activity. The containers themselves are chemically stable, preventing chemical polymerization reactions with amoxicillin and clavulanic acid, thus avoiding degradation of the active pharmaceutical ingredient. A full-process traceability system is implemented, ensuring consistency between the batch number, production date, and expiration date on each box. Furthermore, the printed information is checked and verified before packaging to ensure traceability of each box of product, complying with veterinary drug traceability management requirements.

Claims

1. A method for preparing amoxicillin clavulanate potassium tablets, characterized in that, Using amoxicillin and potassium clavulanate-microcrystalline cellulose as the main drugs, with a mass ratio of potassium clavulanate-microcrystalline cellulose of 1:1 and a mass ratio of amoxicillin to potassium clavulanate of 4:1, and microcrystalline cellulose, magnesium stearate, sodium hydroxymethyl starch, colloidal silica, dried yeast, and erythrosine aluminum lake as excipients, the following steps were performed: Step 1, Dry mixing and granulation of the active ingredient: Place the prescribed amounts of amoxicillin, potassium clavulanate-microcrystalline cellulose, microcrystalline cellulose, and magnesium stearate into a single-column lifting hopper mixer, mix thoroughly and evenly, and then feed the mixture into the hopper of a dry granulator for granulation to obtain active ingredient granules. Step 2, wet granulation of excipients: Sodium hydroxymethyl starch, magnesium stearate and microcrystalline cellulose are put into a trough mixer for dry mixing. Purified water is added while stirring and the mixture is continuously mixed to form a soft material. The soft material is sent to a swing granulator for sieving and granulation. The resulting wet granules are dried to a moisture content of 2.0~3.0% and then placed in a swing granulator for sieving again to obtain excipient granules. Step 3, Mixing and tableting: Add the active pharmaceutical ingredient granules, excipient granules, colloidal silica, dry yeast and colorant into a single-column lifting hopper mixer and mix thoroughly. Calculate the tablet weight based on the amount of material added, use a circular die, and adjust the tableting machine pressure to compress the tablets to obtain amoxicillin clavulanate potassium tablets.

2. The method for preparing amoxicillin clavulanate potassium tablets according to claim 1, characterized in that: The mass percentage of amoxicillin in the amoxicillin-clavulanate potassium tablets is 20-25%.

3. The method for preparing amoxicillin clavulanate potassium tablets according to claim 1, characterized in that: The magnesium stearate accounts for 1.2-1.5% of the mass of the amoxicillin-clavulanate potassium tablets.

4. The method for preparing amoxicillin clavulanate potassium tablets according to claim 1, characterized in that: In step two, the drying process uses circulating hot air drying.

5. The method for preparing amoxicillin clavulanate potassium tablets according to claim 1, characterized in that: The sodium hydroxymethyl starch accounts for 20-25% of the mass of the amoxicillin-clavulanate potassium tablets.

6. The method for preparing amoxicillin clavulanate potassium tablets according to claim 1, characterized in that: In step three, the temperature of the mixed tablet is 18~26℃ and the relative humidity is 45~65%.

7. The method for preparing amoxicillin clavulanate potassium tablets according to claim 1, characterized in that: The dry yeast accounts for 1.0-1.5% of the mass of the amoxicillin-clavulanate potassium tablets.

8. The method for preparing amoxicillin clavulanate potassium tablets according to claim 1, characterized in that: The particle size of the dry yeast is 30-50 mesh.

9. The method for preparing amoxicillin clavulanate potassium tablets according to claim 1, characterized in that: The circular die includes an upper punch assembly, a semi-marked recessed cutting edge, a middle die, and a lower punch assembly.

10. The method for preparing amoxicillin clavulanate potassium tablets according to claim 1, characterized in that: The colorant is erythrosine aluminum lake.

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