Preparation method of aluminum magnesium paracetamol tablet (II)

Abstract

The application relates to a preparation method of an aluminum-magnesium aspirin tablet (II), which comprises the following steps: S1, preparing aspirin particles and aluminum-magnesium particles respectively; S2, performing coating treatment on the aspirin particles to obtain aspirin coated particles; S3, mixing the aspirin coated particles and the aluminum-magnesium particles, adding second micro-powder silica gel and calcium hydrogen phosphate dihydrate, and then performing tabletting, so that the aluminum-magnesium aspirin tablet (II) is obtained. Through the design of zoned granulation, isolated coating and double stabilizers, the chemical stability and anti-cracking performance of the aluminum-magnesium aspirin tablet (II) can be remarkably improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a method for preparing aluminum magnesium aspirin tablets (II). Background Technology

[0002] Aspirin, a classic nonsteroidal anti-inflammatory drug, possesses a wide range of pharmacological effects, including antipyretic, analgesic, anti-inflammatory, and platelet aggregation inhibition, and has been used clinically for over a century. Aluminum Magnesium Aspirin Tablets (II) are a compound preparation composed of aspirin, aluminum hydroxyl, and heavy magnesium carbonate, representing an important improved dosage form of aspirin. The chemical structure of aspirin contains an acetyl group, which is readily hydrolyzed by water, producing degradation products such as free salicylic acid. Free salicylic acid not only affects the efficacy of the drug but may also increase the risk of adverse reactions and irritate the gastric mucosa. To reduce the direct irritation of aspirin to the gastric mucosa, aluminum magnesium aspirin tablets (II) contain the alkaline components aluminum hydroxyl and heavy magnesium carbonate, which neutralize gastric acid and protect the gastric mucosa. However, the presence of an alkaline environment can, to some extent, promote the hydrolysis of aspirin, affecting the stability of aluminum magnesium aspirin tablets (II).

[0003] Existing research attempts to improve the stability of aluminum magnesium aspirin tablets (II) through physical isolation (such as coating after double compression), but these processes still generally have the following defects in practical applications: (1) Insufficient stability: It fails to effectively block the contact between alkaline components and aspirin, and the moisture in the preparation can still gradually migrate to the surface of aspirin, thereby accelerating the hydrolysis reaction of aspirin, resulting in excessive content of impurities such as free salicylic acid, affecting the quality and safety of the drug. (2) Poor compressibility: Aspirin differs from aluminum hydroxyl and heavy magnesium carbonate in terms of compressibility and elastic recovery. Stress concentration is easily generated during the tableting process, leading to problems such as tablet cracking and loosening, affecting the appearance and internal quality of the tablets.

[0004] Therefore, it is necessary to further improve the existing preparation process of aluminum magnesium aspirin tablets (II). Summary of the Invention

[0005] To solve the above-mentioned technical problems, the present invention provides a method for preparing aluminum magnesium aspirin tablets (II).

[0006] The technical solution adopted in this invention is as follows: A method for preparing aluminum magnesium aspirin tablets (II) includes the following steps: S1. Prepare aspirin granules and aluminum-magnesium granules respectively; S2. Coating the aspirin granules to obtain coated aspirin granules; S3. Mix the aspirin-coated granules and the aluminum-magnesium granules, then add the second micro-powder silica gel and calcium hydrogen phosphate dihydrate, compress the mixture into tablets, and obtain the final product.

[0007] Preferably, the preparation of aspirin granules in step S1 includes the following steps: mixing aspirin and the first excipient and granulating, then adding the first micronized silica gel and mixing to obtain the final product; The first excipient comprises one or a combination of two or more of fillers, binders, disintegrants and lubricants.

[0008] Preferably, the mass percentage of the first micronized silica powder in the aspirin particles is 0.9-2%.

[0009] Preferably, the preparation of the aluminum-magnesium particles in step S1 includes the following steps: mixing aluminum hydroxyl, heavy magnesium carbonate, and the second excipient and granulating them to obtain the desired particle size; The second excipient comprises fillers and / or adhesives.

[0010] Preferably, the coating solution used in step S2 is an aqueous solution of hydroxypropyl methylcellulose, and the concentration of the aqueous solution of hydroxypropyl methylcellulose is 4~10% w / v.

[0011] Preferably, the aqueous solution of hydroxypropyl methylcellulose contains a plasticizer, and the mass ratio of the plasticizer to the hydroxypropyl methylcellulose is 1:4~6.

[0012] Preferably, in step S3, the mass ratio of the second micro-powdered silica gel to the calcium hydrogen phosphate dihydrate is 1:1~4.

[0013] Preferably, step S3 further includes adding a third auxiliary material before the total mixing, the third auxiliary material comprising a binder and / or a lubricant.

[0014] Preferably, the moisture content of the aspirin granules in step S1 and the aspirin-coated granules in step S2 is ≤0.5% each, and the moisture content of the aluminum-magnesium granules in step S3 is ≤1.0%.

[0015] The beneficial effects of this invention are: (1) This invention introduces second micro-powder silica gel and calcium hydrogen phosphate dihydrate as dual stabilizers during the total mixing stage of aspirin coated particles and aluminum magnesium particles. The second micro-powder silica gel can form a hydrophobic barrier between the two particles to block moisture and improve the flowability of the two particles. The calcium hydrogen phosphate dihydrate has both chemical buffering and physical dilution effects, which can effectively reduce the intensity of alkaline microenvironment and absorb and balance the tableting stress between the two particles. The synergistic effect of the two can significantly improve the chemical stability and anti-cracking performance of aluminum magnesium aspirin tablets (II).

[0016] (2) The present invention achieves effective barrier between aspirin and alkaline materials through partitioned granulation and isolation coating design, thereby reducing the hydrolysis of aspirin.

[0017] (3) The aluminum magnesium aspirin tablets (II) prepared by the method of this invention have high stability and anti-cracking properties. In the 6-month accelerated stability test, the aspirin content decreased by ≤0.3%, and the free salicylic acid content was <0.1%, which is far below the pharmacopoeia limit of ≤0.3%, and the quality and safety of the drug are significantly improved. In the 24-month long-term stability test, the aluminum magnesium aspirin tablets (II) are chemically stable (low hydrolysis), physically stable (low moisture), and mechanically stable (0 cracks). The tablets have a smooth appearance, moderate hardness, and disintegrate within 8 minutes. The method of this invention is simple, highly operable, and easy to industrialize, and has important clinical value and industrialization significance. Detailed Implementation

[0018] The technical solution of the present invention will be further explained and described below through specific embodiments. Unless otherwise specified, the experimental methods in the following embodiments are conventional methods, and the raw materials and excipients used in the following embodiments are commercially available pharmaceutical-grade products unless otherwise specified.

[0019] A method for preparing aluminum magnesium aspirin tablets (II) includes the following steps: S1. Prepare aspirin granules and aluminum-magnesium granules respectively; S2. Coating aspirin granules to obtain coated aspirin granules; S3. Mix aspirin-coated granules and aluminum-magnesium granules, then add the second micro-powder silica gel and calcium hydrogen phosphate dihydrate, compress into tablets, and obtain the final product.

[0020] This invention significantly improves the stability and anti-cracking properties of aluminum magnesium aspirin tablets (II) through a multi-synergistic mechanism of partitioned granulation, isolation coating, and dual stabilizers. Specifically: (1) Partial granulation separates aspirin and alkaline materials (aluminum hydroxyl and heavy magnesium carbonate) into independent particle systems, avoiding direct contact between the two. (2) The coating process constructs an isolation layer on the surface of aspirin particles, which can effectively delay the diffusion of alkaline ions from aluminum magnesium particles to aspirin particles. (3) By introducing second-micronized silica gel and calcium dicalcium phosphate dihydrate as dual stabilizers during the total mixing stage of aspirin-coated particles and aluminum-magnesium particles, in terms of stability: the second-micronized silica gel utilizes its hydrophobic surface properties to form a moisture barrier between the aspirin-coated particles and aluminum-magnesium particles to block moisture; calcium dicalcium phosphate dihydrate plays a role in chemical buffering and physical dilution—its weak alkalinity (pH 7~8) can buffer the alkalinity of aluminum-magnesium particles, and at the same time, it reduces the local alkalinity concentration of alkaline materials in aluminum-magnesium particles by filling, thereby effectively reducing the intensity of the alkaline microenvironment, significantly improving the stability of aspirin in aluminum-magnesium aspirin tablets (II), and inhibiting the formation of degradation products such as free salicylic acid. In terms of compressibility: the second-micronized silica gel can improve the flowability of aspirin-coated particles and aluminum-magnesium particles; calcium dicalcium phosphate dihydrate can absorb and balance the stress generated by the difference in elastic recovery between the two types of particles during the tableting process, balance the stress distribution between the two types of particles, and thus solve the problem of easy tablet cracking during the compression of aluminum-magnesium aspirin tablets (II).

[0021] In some preferred embodiments, the preparation of aspirin granules in step S1 includes the following steps: mixing and granulating aspirin and a first excipient, then adding and mixing the first micronized silica gel to obtain the final product; The first excipient includes one or a combination of two or more of the following: fillers, binders, disintegrants, and lubricants.

[0022] This invention introduces a first micronized silica gel after aspirin granulation. Utilizing its hydrophobic surface properties, it forms a moisture barrier on the particle surface, reducing the contact between aspirin and moisture. Simultaneously, it acts as a flow aid, improving particle flowability and resulting in a denser film formed during subsequent coating, thus enhancing the isolation effect. The aspirin dosage in this invention can be adjusted according to clinical needs. For example, the mass percentage of aspirin in the aspirin particles should not be less than 70% to ensure adequate loading of the active ingredient. Furthermore, this invention does not specifically limit the type of the first excipient. For example, fillers can be lactose, microcrystalline cellulose, pregelatinized starch, mannitol, corn starch, etc.; binders can be low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, povidone K30, starch paste, etc.; disintegrants can be low-substituted hydroxypropyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, etc.; lubricants can be a third micronized silica gel, talc, polyethylene glycol 6000, stearic acid, etc.

[0023] In some preferred embodiments, the first micronized silica gel comprises 0.9% to 2% of the aspirin particles by mass. The present invention selects the above-mentioned amount of first micronized silica gel, which is beneficial for forming an effective moisture barrier on the surface of the aspirin particles and significantly improves particle flowability. For example, the mass percentage of the first micronized silica gel in the aspirin particles can be 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, etc.

[0024] In some preferred embodiments, the preparation of aluminum-magnesium particles in step S1 includes the following steps: mixing aluminum hydroxyl, heavy magnesium carbonate, and a second excipient and granulating them to obtain the desired particle size; The second auxiliary material includes fillers and / or adhesives.

[0025] In the preparation process of the aluminum-magnesium granules of this invention, the mass ratio of aluminum hydroxylase to heavy magnesium carbonate is 1:2, and the total mass percentage of aluminum hydroxylase and heavy magnesium carbonate in the aluminum-magnesium granules is not less than 50%, to ensure effective neutralization of stomach acid. Furthermore, this invention does not specifically limit the type of the second excipient. For example, the filler can be lactose, microcrystalline cellulose, pregelatinized starch, mannitol, corn starch, etc.; the binder can be low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, povidone K30, starch paste, etc.

[0026] In some preferred embodiments, the coating solution used in step S2 is an aqueous solution of hydroxypropyl methylcellulose, with a concentration of 4-10% w / v. This invention uses an aqueous solution of hydroxypropyl methylcellulose as the protective membrane formed by the coating solution, which can effectively delay the diffusion of alkaline ions into the aspirin particles. For example, the concentration of the aqueous solution of hydroxypropyl methylcellulose can be 4% w / v, 5% w / v, 6% w / v, 7% w / v, 8% w / v, 9% w / v, 10% w / v, etc. In this invention, a fluidized bed is used for coating, and the coating weight gain is controlled to be 3.5-5.5% of the aspirin particle mass.

[0027] In some preferred embodiments, the aqueous solution of hydroxypropyl methylcellulose contains a plasticizer, and the mass ratio of the plasticizer to hydroxypropyl methylcellulose is 1:4 to 6. This invention may also add an appropriate amount of plasticizer to the aqueous solution of hydroxypropyl methylcellulose to improve the flexibility of the coating film, reduce its breakage due to particle compression during subsequent tableting, and thus ensure the isolation effect. For example, the plasticizer may be polyethylene glycol 400, glycerol, triethyl citrate, etc.; the mass ratio of the plasticizer to hydroxypropyl methylcellulose may be 1:4, 1:4.5, 1:5, 1:5.5, 1:6, etc.

[0028] In some preferred embodiments, the mass ratio of the second micronized silica gel to dicalcium phosphate dihydrate in step S3 is 1:1 to 4. If the mass ratio of the second micronized silica gel to dicalcium phosphate dihydrate is greater than 1:1, the amount of dicalcium phosphate dihydrate used is too low, resulting in poor effects of chemical buffering, physical dilution, and stress balancing. If the mass ratio of the second micronized silica gel to dicalcium phosphate dihydrate is less than 1:4, the amount of the second micronized silica gel used is too low, resulting in poor effects of hydrophobicity, moisture resistance, and improvement of particle flowability, both of which are detrimental to improving the stability and crack resistance of aluminum magnesium aspirin tablets (II). For example, the mass ratio of the second micronized silica gel to dicalcium phosphate dihydrate can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, etc.

[0029] In some preferred embodiments, step S3, prior to total mixing, further includes the addition of a third adjuvant, which comprises a binder and / or a lubricant. For example, the binder may be low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, povidone K30, starch paste, etc.; the lubricant may be talc, polyethylene glycol 6000, stearic acid, etc.

[0030] In some preferred embodiments, the moisture content of the aspirin granules in step S1 and the aspirin-coated granules in step S2 is independently ≤0.5%, and the moisture content of the aluminum-magnesium granules in step S3 is ≤1.0%. This invention strictly controls the upper limit of granule moisture at each stage, reducing the risk of aspirin hydrolysis caused by moisture from the source.

[0031] Example 1 A method for preparing aluminum magnesium aspirin tablets (II), the formula of which is shown in Table 1, includes the following steps: (1) Raw material preparation: Aspirin, lactose, third micronized silica gel and low-substituted hydroxypropyl cellulose in the aspirin granule raw material are passed through an 80-mesh sieve, the first micronized silica gel is passed through a 200-mesh sieve, and povidone K30 is prepared into a 5% w / v povidone K30 ethanol solution (using 95% ethanol as solvent) for later use; hydroxyaluminum, heavy magnesium carbonate, mannitol and povidone K30 in the aluminum magnesium granule raw material are passed through a 60-mesh sieve for later use.

[0032] (2) Preparation of aspirin granules: The prescribed amount of aspirin, lactose, third micro powder silica gel and low-substituted hydroxypropyl cellulose are placed in a mixer and mixed evenly. Povidone K30 ethanol solution is added and put into a fluidized bed granulator for granulation. The inlet air temperature is controlled at 50℃±2℃ and the outlet air temperature is controlled at 40℃±2℃. The granulation endpoint is when the granules form agglomerates and do not stick to the wall. After granulation, the granules are dried at 50℃ until the moisture content of the granules is ≤0.5%. The granules are sieved through a 20-mesh sieve and 18~60-mesh granules are collected. Then the first micro powder silica gel is added and mixed in a mixer for 5 minutes to obtain the product. Preparation of aspirin-coated granules: A 4% w / v aqueous solution of hydroxypropyl methylcellulose E5 was prepared as the coating solution according to the prescription amount. The aspirin granules were coated using a fluidized bed coating machine. The inlet air temperature was controlled at 50℃±5℃, the outlet air temperature at 40℃±5℃, the spray rate at 5~8mL / min, and the atomization pressure at 0.20~0.25MPa. The weight gain of the aspirin granules was 4%±0.5% after coating. Samples were taken every 30 minutes during the coating process, and the moisture content of the granules was controlled to be ≤0.5%. After coating, the granules were dried for 5 minutes, discharged, and cooled to obtain the final product. Preparation of aluminum-magnesium granules: Mix the prescribed amounts of aluminum hydroxyl, heavy magnesium carbonate, mannitol and povidone K30 evenly, add purified water as a wetting agent (the amount is 20% of the total amount of solid powder) and put it into a fluidized bed granulator for granulation. After granulation, dry at 60℃ until the moisture content of the granules is ≤1.0%, and granulate through a 20-mesh sieve to collect 18~40 mesh granules to obtain the final product.

[0033] (3) Preparation of aluminum magnesium aspirin tablets (II): Aspirin coated granules and aluminum magnesium granules are mixed in a mixer for 5 minutes. Then, according to the prescription, silica gel powder, calcium hydrogen phosphate dihydrate, low-substituted hydroxypropyl cellulose and talc are added and mixed for 13 minutes. The total mixed granules are put into a rotary tablet press, the main pressure is set to 12 kN, the tablet weight is adjusted to 196 ± 3 mg, and the tablets are compressed to obtain the product.

[0034] Table 1

[0035] Example 2 There is a clinical need for high-dose aspirin, but high drug loading presents a more severe stability challenge. In this embodiment, aluminum magnesium aspirin tablets (II) containing 325mg aspirin were prepared by scaling up the formulation ratio (compared to Example 1, the formulation amounts of each raw material, except for the coating material, were increased by 4 times proportionally), strengthening the isolation coating, and strictly controlling the moisture content, thus achieving the stability and formability standards for high drug loading formulations.

[0036] A method for preparing aluminum magnesium aspirin tablets (II), the formula of which is shown in Table 2, includes the following steps: (1) Raw material preparation: Same as in Example 1.

[0037] (2) Preparation of aspirin granules: The difference from Example 1 is that the moisture content of the granules is adjusted from ≤0.5% to ≤0.4%; Preparation of aspirin-coated granules: Prepare a 10% w / v aqueous solution of hydroxypropyl methylcellulose E5 according to the prescription and add polyethylene glycol 400 and mix well as a coating solution. Coat the above aspirin granules using a fluidized bed coating machine. Control the inlet air temperature at 50℃±5℃, the outlet air temperature at 40℃±5℃, the spray rate at 15~20mL / min, and the atomization pressure at 0.20~0.25MPa. Coat until the weight gain of the aspirin granules is 5%±0.5%. Take samples every 30 minutes during the coating period and control the moisture content of the granules to ≤0.5%. After coating, dry for 5 minutes, discharge and cool to obtain the final product. Preparation of aluminum-magnesium particles: Same as in Example 1.

[0038] (3) Preparation of aluminum magnesium aspirin tablets (II): Aspirin coated granules and aluminum magnesium granules are mixed in a mixer for 8 minutes. Then, according to the prescription, silica gel powder, calcium hydrogen phosphate dihydrate, low-substituted hydroxypropyl cellulose and talc are added and mixed for 15 minutes. The total mixed granules are put into a rotary tablet press with a main pressure of 18 kN and the tablet weight is adjusted to 790 ± 10 mg. The tablets are then compressed to obtain the final product.

[0039] Table 2

[0040] Example 3 This embodiment optimizes the granulation process to improve the structural strength of aspirin granules and aluminum-magnesium granules, reducing problems such as cracking, loosening, and high brittleness that are prone to occur in the production of aluminum-magnesium aspirin tablets (II). The formulation in this embodiment is the same as in Embodiment 1.

[0041] A method for preparing aluminum magnesium aspirin tablets (II), the formula of which is shown in Table 1, includes the following steps: (1) Raw material preparation: Same as in Example 1.

[0042] (2) Preparation of aspirin granules (high-intensity granulation): The prescribed amount of aspirin, lactose, third micro-powder silica gel and low-substituted hydroxypropyl cellulose are placed in a high-speed shear granulator and mixed at 200~300 rpm for 5 min. Povidone K30 ethanol solution is added and granulation is intensified by high-speed shear at 1200~1500 rpm for 3 min. After granulation, the granules are placed in a fluidized bed and dried at 40℃ until the moisture content of the granules is ≤0.4%. The granules are sieved twice through 20 mesh and 18 mesh sieves, and 18~40 mesh granules are collected. Then, the first micro-powder silica gel is added and mixed in a mixer for 5 min to obtain the final product. Preparation of aspirin-coated granules: Same as in Example 1; Preparation of aluminum-magnesium granules (high-strength granulation): Mix the prescribed amounts of aluminum hydroxyl, heavy magnesium carbonate, mannitol and povidone K30 evenly, and granulate using an extrusion granulator at an extrusion pressure of 0.5~1MPa. After granulation, place the granules in a fluidized bed at 60℃ and dry until the moisture content of the granules is ≤0.8%. Then, granulate them through an 18-mesh sieve and collect 18~40-mesh granules to obtain the final product.

[0043] (3) Preparation of aluminum magnesium aspirin tablets (II): Aspirin coated granules and aluminum magnesium granules are mixed in a mixer for 8 minutes. Then, according to the prescription, silica gel powder, calcium hydrogen phosphate dihydrate, low-substituted hydroxypropyl cellulose and talc are added and mixed for 12 minutes. The total mixed granules are put into a rotary tablet press, the main pressure is set to 14 kN, the tablet weight is adjusted to 196 ± 3 mg, and the tablets are compressed to obtain the product.

[0044] Example 4 The difference between this embodiment and Example 1 is that the formulation is different. The 15g lactose in the aspirin granules of Example 1 is adjusted to 8g microcrystalline cellulose and 7g lactose, and the 30g mannitol in the aluminum magnesium granules of Example 1 is adjusted to 28g microcrystalline cellulose and 2g low-substituted hydroxypropyl cellulose. The remaining steps remain unchanged.

[0045] Comparative Example 1 The difference between this comparative example and Example 1 is that the formulation is different. Lactose is used to replace the first and third micronized silica gels in the aspirin granules of Example 1 in equal amounts, and low-substituted hydroxypropyl cellulose is used to replace the second micronized silica gel in the excipients of Example 1 in equal amounts. The remaining steps remain unchanged.

[0046] Comparative Example 2 The difference between this comparative example and Example 1 is that the formulation is different; low-substituted hydroxypropyl cellulose is used to replace an equal amount of the dicalcium phosphate dihydrate in the excipients of Example 1. The remaining steps remain unchanged.

[0047] Comparative Example 3 The difference between this comparative example and Example 1 is that the formulation is different. Lactose is used to replace the first and third micronized silica gels in the aspirin granules of Example 1 in equal amounts, and low-substituted hydroxypropyl cellulose is used to replace the second micronized silica gel and calcium hydrogen phosphate dihydrate in the excipients of Example 1 in equal amounts. The remaining steps remain unchanged.

[0048] Comparative Example 4 The difference between this comparative example and Example 1 is that the aspirin granules were not coated; they were directly mixed with aluminum-magnesium granules and compressed into tablets. The remaining steps remained unchanged.

[0049] Comparative Example 5 This comparative example uses a one-step granulation process to prepare aluminum magnesium aspirin tablets (II) (without partitioned granulation or coating). The formula is as follows (based on 1000 tablets): 81g aspirin, 15g lactose, 11g aluminum hydroxyl, 22g heavy magnesium carbonate, 30g mannitol, 6g povidone K30, 1g first micronized silica gel, 1g third micronized silica gel, 5g low-substituted hydroxypropyl cellulose; excipients: 2g second micronized silica gel, 8g dicalcium phosphate dihydrate, 7g talc, 3g low-substituted hydroxypropyl cellulose.

[0050] The specific preparation method is as follows: Mix all raw materials except for the added excipients at one time, pass through an 80-mesh sieve, granulate in one step using purified water as a wetting agent (the amount used is 20% of the total amount of solid powder), dry and granulate, add the added excipients and mix, and compress tablets using the same tableting parameters as in Example 1 to obtain aluminum magnesium aspirin tablets (II).

[0051] The aluminum magnesium aspirin tablets (II) prepared in Examples 1-4 and Comparative Examples 1-5 were subjected to performance tests, and the results are recorded in Tables 3-7.

[0052] 1. Tablet quality assessment The aluminum magnesium aspirin tablets (II) prepared in Examples 1-4 and Comparative Examples 1-5 were evaluated for tablet quality, and the appearance, tablet weight difference, hardness, cracking rate, friability and drug content were examined. The results are shown in Table 3 below.

[0053] Table 3

[0054] 2. Stability test In accordance with the Guidelines for Drug Stability Testing in General Chapter 9001 of the 2025 Edition of the Chinese Pharmacopoeia and ICH Q1A(R2), accelerated stability studies were conducted on the aluminum magnesium aspirin tablets (II) prepared in Examples 1-4 and Comparative Examples 1-5 (40℃±2℃ / 75%±5% RH, time points 0, 3, and 6 months). The contents of aspirin, free salicylic acid, and water at 0, 3, and 6 months were determined by high-performance liquid chromatography (HPLC). The results are shown in Table 4 below.

[0055] Table 4

[0056] As shown in Table 4, Examples 1-4, through the design of partitioned granulation + isolation coating + dual stabilizers, significantly improved the stability of aluminum magnesium aspirin tablets (II). In accelerated tests, the decrease in drug content did not exceed 0.3%, free salicylic acid was controlled below 0.1%, far below the 0.3% limit of the Chinese Pharmacopoeia, and moisture content was controlled below 1.0%, with virtually no hygroscopicity. In Comparative Example 1, the lack of micronized silica gel led to slow accumulation of moisture inside the tablets, resulting in a slight decrease in stability. In Comparative Example 2, the lack of calcium hydrogen phosphate dihydrate, and in Comparative Example 4, the lack of coating treatment, both led to accelerated hydrolysis of aspirin and a significant increase in the content of free salicylic acid. Comparative Example 5, using the conventional one-step granulation method, had the worst stability.

[0057] After being placed under accelerated testing conditions for 6 months, samples from each example and comparative example were taken, and the contents of salicylic acid and its derivatives and other related substances were determined by high performance liquid chromatography. The results are shown in Table 5 below.

[0058] Table 5

[0059] As shown in Table 5, in Examples 1-4 of the present invention, aspirin and alkaline materials were effectively isolated, the hydrolysis rate was extremely slow, the free salicylic acid was <0.1% after 6 months, and all secondary degradation products were far below the legal limit, with no safety risk.

[0060] In accordance with the Guidelines for Drug Stability Testing in General Chapter 9001 of the 2025 Edition of the Chinese Pharmacopoeia and ICH Q1A(R2), the long-term stability of aluminum magnesium aspirin tablets (II) prepared in Examples 1-4 and Comparative Examples 1-5 was investigated (25℃±2℃ / 60%±5% RH, time points 0, 12, and 24 months). The results of the long-term test are shown in Table 6 below.

[0061] Table 6

[0062] As shown in Table 6, the aluminum magnesium aspirin tablets (II) prepared in Examples 1-4 exhibited chemical stability, physical stability, and mechanical stability during long-term testing. The free salicylic acid content was consistently controlled below 0.1%, and the friability met the requirements during the testing period, achieving a zero cracking rate. This solved the three major problems of hydrolysis degradation, gastrointestinal irritation, and cracking that existed in aluminum magnesium aspirin tablets (II). The formulation process meets the requirements for industrial production and long-term circulation and storage.

[0063] 3. Disintegration time and dissolution rate determination According to General Chapters 0921 and 0931 of Part IV of the 2025 edition of the Chinese Pharmacopoeia, the disintegration time and dissolution rate of aluminum magnesium aspirin tablets (II) prepared in each example and comparative example were determined, and the results are shown in Table 7 below.

[0064] Table 7

[0065] As shown in Table 7, Examples 1-4 of this invention employ partitioned granulation to effectively isolate aspirin from the aluminum-magnesium components, achieving steady disintegration of the aluminum-magnesium aspirin tablets (II) and more complete dissolution of the active ingredients. Among them, Example 3, due to its optimized granulation process, has a more uniform particle porosity and a slightly faster disintegration time than Example 1. Comparative Example 1, lacking micronized silica gel, exhibits a slower disintegration rate. Comparative Examples 2 and 3, lacking calcium hydrogen phosphate dihydrate, experience rapid neutralization of the alkaline aluminum-magnesium components with gastric acid, accelerating tablet disintegration. Comparative Example 4, lacking an isolating coating, results in accelerated disintegration. Comparative Example 5, without partitioned granulation and isolating coating, exhibits the most rapid disintegration.

[0066] 4. Studies on gastrointestinal irritation Experimental animals: SPF-grade male Kunming mice, 6-8 weeks old, weighing 18-22g, acclimatized for 7 days.

[0067] Experimental grouping: Mice were randomly divided into 7 groups, with 6 mice in each group.

[0068] Sample preparation: The aluminum magnesium aspirin tablets (II) prepared in Example 1 and Comparative Examples 1-5 were finely ground and prepared into suspensions with PBS solution. The blank group was fed an equal amount of PBS solution.

[0069] Dosage regimen: Administer the medication by gavage once daily at a fixed time. Mice should be fasted for 4 hours before administration and resumed feeding 1 hour after administration. Continue administration for 14 consecutive days, recording mouse weight and fecal characteristics daily. Fasting should continue for 18 hours before the last administration.

[0070] Sample collection: Mice were euthanized, and the entire stomach and duodenum were removed and fixed in 4% paraformaldehyde. The fixed gastric tissue was cut along the greater curvature of the stomach, gently rinsed with physiological saline, and spread flat on filter paper. Gastric mucosal damage was observed using a stereomicroscope. The Guth scoring system was used for semi-quantitative scoring to calculate the gastric mucosal damage index.

[0071] The experimental results are shown in Table 8 below.

[0072] Table 8

[0073] As shown in Table 8, the aluminum magnesium aspirin tablets (II) prepared in Example 1 of this invention, through a process route of "partitioned granulation, isolation coating, and dual stabilization," achieved physical isolation between aspirin and the alkaline aluminum magnesium components, significantly reducing the generation of irritating impurities such as free salicylic acid, and exhibiting minimal gastrointestinal irritation. Animal experiments showed that the weight gain of mice was not significantly different from the control group, and there were no abnormal manifestations such as melena or diarrhea. The gastric mucosa showed only slight congestion and edema, with no ulceration. In contrast, Comparative Example 5, using a traditional one-step granulation process, resulted in direct contact between aspirin and the alkaline aluminum magnesium components, generating a large amount of irritating impurities such as free salicylic acid during production and storage. At the same time, the alkaline components rapidly neutralized gastric acid in the stomach, damaging the gastric mucosal barrier, posing a serious safety risk.

[0074] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing aluminum magnesium aspirin tablets (II), characterized in that, Includes the following steps: S1. Prepare aspirin granules and aluminum-magnesium granules respectively; S2. Coating the aspirin granules to obtain coated aspirin granules; S3. Mix the aspirin-coated granules and the aluminum-magnesium granules, then add the second micro-powder silica gel and calcium hydrogen phosphate dihydrate, compress the mixture into tablets, and obtain the final product.

2. The method for preparing aluminum magnesium aspirin tablets (II) as described in claim 1, characterized in that, The preparation of aspirin granules in step S1 includes the following steps: mixing aspirin and the first excipient and granulating, then adding the first micro-powdered silica gel and mixing to obtain the final product; The first excipient comprises one or a combination of two or more of fillers, binders, disintegrants and lubricants.

3. The method for preparing aluminum magnesium aspirin tablets (II) as described in claim 2, characterized in that, The first micro-powdered silica gel accounts for 0.9-2% of the mass of the aspirin particles.

4. The method for preparing aluminum magnesium aspirin tablets (II) as described in claim 1, characterized in that, The preparation of aluminum-magnesium granules in step S1 includes the following steps: mixing aluminum hydroxyl, heavy magnesium carbonate, and a second excipient and granulating them to obtain the desired product; The second excipient comprises fillers and / or adhesives.

5. The method for preparing aluminum magnesium aspirin tablets (II) as described in claim 1, characterized in that, The coating solution used in step S2 is an aqueous solution of hydroxypropyl methylcellulose, and the concentration of the aqueous solution of hydroxypropyl methylcellulose is 4~10% w / v.

6. The method for preparing aluminum magnesium aspirin tablets (II) as described in claim 5, characterized in that, The aqueous solution of hydroxypropyl methylcellulose contains a plasticizer, and the mass ratio of the plasticizer to the hydroxypropyl methylcellulose is 1:4~6.

7. The method for preparing aluminum magnesium aspirin tablets (II) as described in claim 1, characterized in that, In step S3, the mass ratio of the second micro-powdered silica gel to the calcium hydrogen phosphate dihydrate is 1:1~4.

8. The method for preparing aluminum magnesium aspirin tablets (II) as described in claim 1, characterized in that, Step S3, prior to the total mixing, also includes the addition of a third auxiliary material, which comprises a binder and / or a lubricant.

9. The method for preparing aluminum magnesium aspirin tablets (II) as described in claim 1, characterized in that, The moisture content of the aspirin granules in step S1 and the aspirin-coated granules in step S2 is ≤0.5% each, and the moisture content of the aluminum-magnesium granules in step S3 is ≤1.0%.

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