Industrialized preparation method of carbazochrome calcium for improving stability

Abstract

This invention belongs to the field of pharmaceutical chemical synthesis technology, specifically relating to an industrial-scale preparation method for carbaspirin calcium with improved stability. The method comprises the following steps: First, the mother liquor and ethanol washing solution are added to EDTA-2Na for iron removal, then passed through a mother liquor pretreatment unit, and then transferred to a purification tank. The prepared amounts of water and ethanol are added, along with aspirin and urea. Calcium carbonate is then added to the mixture to react, yielding a carbaspirin calcium suspension. After centrifugation, the wet carbaspirin calcium is washed with ethanol. The mother liquor and ethanol washing solution are then reused in step S1. The wet carbaspirin calcium undergoes a first-stage low-temperature flash evaporation and a second-stage vacuum belt drying to obtain carbaspirin calcium. This invention provides an industrial-scale preparation method for carbaspirin calcium with improved stability, significantly improving the overall yield, reducing raw material consumption, and achieving clean production while ensuring product quality stability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis technology, specifically relating to an industrial preparation method for carbaspirin calcium with improved stability. Background Technology

[0002] Carbaspirin calcium is a calcium salt formed by the complexation of aspirin (acetylsalicylic acid) and urea. As a commonly used antipyretic and analgesic drug in clinical practice, its molecular structure, through the calcium salt form, reduces the gastrointestinal irritation of aspirin while retaining its antipyretic, analgesic, anti-inflammatory, and antiplatelet aggregation pharmacological effects. Based on clinical applications, this drug is divided into two main areas: human and veterinary. Human formulations are used for mild to moderate pain such as fever from colds, headaches, and dysmenorrhea; veterinary formulations are used for high fever caused by swine and avian influenza and Newcastle disease, as well as inflammatory reactions such as kidney swelling and air sacculitis.

[0003] The traditional production process for carbaspirin calcium uses aspirin, urea, and calcium nitrate as raw materials, synthesized in pure ethanol solvent via ethanol-ammonia catalysis. The raw materials react in ethanol to produce carbaspirin calcium, which is then dehydrated using a double-cone dryer, and the mother liquor is recovered by distillation to recover the ethanol. However, this traditional process has the following significant drawbacks: Significant safety hazards exist; residual calcium nitrate during drying is prone to decomposition and explosion; the concentration of liquid ammonia used for neutralization and crystallization must be strictly controlled, as excessive amounts lead to excessive salicylic acid impurities in the product; ethanol recovery requires repeated distillation due to water content, and the concentration of flammable vapors in the workshop remains near the critical explosion limit for extended periods, posing a major safety risk during production. Raw material costs are high; calcium nitrate is expensive to purchase, and liquid ammonia transportation requires specialized equipment, increasing raw material and warehousing costs. Production capacity and yield are limited; the traditional process is constrained by reaction efficiency and equipment, resulting in low yields. Furthermore, the high soluble nature of carbaspirin calcium in water and its slight solubility in ethanol makes it prone to impurity accumulation when the mother liquor is reused, significantly reducing product yield with each reuse. The treatment of mother liquor is crude and wasteful of resources. Traditional processes only recover ethanol from the mother liquor, and unreacted aspirin, urea and by-product ammonium nitrate are not effectively separated and recovered. This not only increases the load on wastewater treatment, but also keeps the raw material consumption ratio high.

[0004] To address the aforementioned issues, improvements have been made to the synthesis process of carbaspirin calcium. For example, Chinese patent CN102382013A discloses a method for preparing carbaspirin calcium, using aspirin, urea, and calcium carbonate as raw materials, and water as a solvent for the reaction. After the reaction is completed, the mixture is filtered, and methanol is added to the filtrate to crystallize and obtain carbaspirin calcium. This technology replaces calcium nitrate and liquid ammonia with calcium carbonate, eliminating the safety hazards associated with the drying explosion of calcium nitrate and the use of liquid ammonia, and also reducing raw material costs. However, this technical solution still has shortcomings: firstly, it uses pure water as a solvent and does not consider the recycling of the mother liquor, resulting in high solvent consumption; secondly, the addition of methanol for crystallization after the reaction introduces new solvent, increasing the burden of solvent recovery; and thirdly, it does not disclose a mother liquor treatment and resource recovery scheme, failing to effectively recover valuable components such as aspirin and urea remaining in the mother liquor.

[0005] For example, Chinese patent CN110483250A discloses a continuous ethanol recovery and salicylic acid removal process for carbaspirin calcium mother liquor. This process obtains high-concentration ethanol through continuous distillation while simultaneously removing salicylic acid. This technology addresses the issues of ethanol recovery and salicylic acid removal from the mother liquor to some extent. However, this technology primarily targets the post-treatment stage of the mother liquor, treating it as "waste liquid" and failing to achieve direct recycling of the mother liquor within the production line. Furthermore, it does not address the graded recovery of components such as aspirin and calcium carbonate from the mother liquor, leaving room for improvement in resource utilization. Summary of the Invention

[0006] The technical problem to be solved by this invention is to overcome the existing technology of how to construct an industrial production method that can stably recycle the mother liquor while adopting the safe route of calcium carbonate, so as to achieve efficient reuse of the mother liquor, effective control of impurities, and graded recovery of multiple components. This invention provides an industrial preparation method for carbaspirin calcium with improved stability, which significantly improves the total yield, reduces raw material consumption, and achieves clean production while ensuring product quality stability.

[0007] The present invention provides an industrial-scale method for improving the stability of carbaspirin calcium, comprising the following steps: S1. First, add EDTA-2Na to the mother liquor and ethanol washing solution to remove iron. EDTA-2Na, as a metal ion chelating agent, can effectively chelate iron ions introduced into the mother liquor due to equipment corrosion, preventing iron ions from catalyzing the hydrolysis of aspirin to produce salicylic acid. Salicylic acid then reacts with Fe... 3+ The solution turns purple, thus ensuring product purity. After passing through the mother liquor pretreatment unit, it is then transferred to the refining tank, where the prescribed amounts of water and ethanol are added, along with aspirin and urea. The mixture is stirred to obtain a final product. S2. Pour the mixture into a calcification tank, add calcium carbonate to react, and after the reaction is complete, cool to 0~5℃ and keep stirring for 20~30 minutes to obtain carbaspirin calcium suspension; S3. Centrifuge the carbaspirin calcium suspension to obtain carbaspirin calcium wet product and mother liquor. The mother liquor is reused in step S1. The carbaspirin calcium wet product is first washed with ethanol, and the ethanol washing liquid is also reused in step S1. The carbaspirin calcium wet product then undergoes a first-stage low-temperature flash evaporation and a second-stage vacuum belt drying to obtain carbaspirin calcium.

[0008] The mass of EDTA-2Na added in step S1 is 100-250g relative to the total mass of 1100-1300kg of mother liquor and ethanol washing solution.

[0009] The mother liquor pretreatment unit in step S1 first treats the mother liquor with a fixed-bed column of a weakly basic anion exchange resin or a salicylic acid molecularly imprinted adsorbent. After the salicylic acid content is qualified (≤0.05%), it is then pumped into the purification tank. A weakly basic anion exchange resin such as type D301 is used.

[0010] In step S1, add the prepared amount of water and ethanol so that the ethanol content in the mixture is 18-22% by mass and the mass ratio of aspirin to ethanol aqueous solution is 1:1-1.3.

[0011] This invention introduces active impurity removal instead of passive dilution or waste mother liquor in the carbaspirin calcium mother liquor reuse process in step S1, and improves aspirin utilization and reduces costs through ethanol washing water in the process. It achieves unlimited reuse, increasing the traditional process from requiring mother liquor replacement after 3-5 reuses to continuous production of over 70 batches, with yield increasing with each reuse and raw material consumption reduced by over 30%. This directly solves the shortcomings of the prior art where product yield significantly decreases with increasing reuse counts and only waste liquid is treated without direct recycling.

[0012] In steps S1 and S2: use 1 / 3 to 1 / 2 of the total mass of the mother liquor, use 1 / 3 to 1 / 2 of the total mass of the ethanol washing solution, add purified water to adjust the ethanol content of the solution to 18-22%, and the mass ratio of aspirin to ethanol aqueous solution is 1:1 to 1.3.

[0013] In step S2, the mass ratio of aspirin to urea in the calcification vessel is 1:0.1~0.4.

[0014] In step S2, the mass ratio of aspirin to calcium carbonate in the calcification vessel is 1:0.2~0.3.

[0015] The rate at which calcium carbonate is added in step S2 is as follows: based on the total amount of calcium carbonate fed, it is continuously added via a screw propeller at a rate of 2% to 5% per minute.

[0016] Step S2: After adding calcium carbonate, control the pH to 5.0~6.5.

[0017] In step S2, the temperature for reacting with calcium carbonate is 10~30℃.

[0018] Step S3: Wash the wet carbaspirin calcium sample with ethanol, using an ethanol solution with a volume concentration of 90%~95%.

[0019] In step S3, during the first stage of low-temperature flash drying, the inlet air temperature of the flash dryer is controlled at 70~80℃ and the outlet air temperature at 45~50℃; during the second stage of vacuum belt drying, the absolute pressure is controlled at 5~10kPa, the temperature at 40~45℃, and the residence time at 60~90min.

[0020] This invention utilizes a first-stage low-temperature flash drying process in step S3, controlling the inlet air temperature of the flash dryer to 70-80℃ (conventionally above 120℃) and the outlet air temperature to 45-50℃. This process removes only surface free ethanol and most of the moisture. At this temperature, carbaspirin calcium hardly decomposes, and the ethanol vapor concentration is below the lower explosive limit (with nitrogen protection). The second stage involves vacuum belt drying, where the pre-dried material enters a vacuum belt dryer at an absolute pressure of 5-10 kPa, a temperature of 40-45℃, and a residence time of 60-90 minutes. Under vacuum conditions, bound water is efficiently removed, and due to the lack of oxygen and low temperature, oxidation and hydrolysis to form salicylic acid are completely prevented. This invention combines flash drying and vacuum drying in series for carbaspirin calcium production, resolving the contradiction between rapid drying and heat-sensitive purity preservation. Low-temperature flash evaporation reduces the risk of combustion and explosion, and the vacuum environment eliminates oxidation and decomposition, completely eradicating the safety hazards and excessive salicylic acid impurities in the background technology. The salicylic acid content is controlled below 0.3% (0.5~1.0% in traditional processes), which is lower than the standard of the Chinese Veterinary Pharmacopoeia. The moisture content is controlled below 0.1% (0.1~0.2% in traditional processes), which meets European standards and meets export conditions.

[0021] Specifically, the industrial preparation method of the carbaspirin calcium with improved stability according to the present invention includes the following steps: S1. First, add the mother liquor and ethanol washing solution to EDTA-2Na to remove iron, then treat it with a fixed bed column of weakly basic anion exchange resin or salicylic acid molecularly imprinted adsorbent. After the salicylic acid is qualified (the salicylic acid content is controlled ≤0.05%), it is then pumped into a purification tank. Add the prepared amount of water and ethanol to make the ethanol mass content in the mixed solution system 18~22%. Add aspirin and urea. The mass ratio of aspirin to ethanol aqueous solution is 1:1~1.3, and the mass ratio of aspirin to urea is 1:0.1~0.4. Stir to obtain a mixed solution. S2. Pour the mixture into the calcification tank and continuously add calcium carbonate at a rate of 2% to 5% per minute through a screw propeller. After adding calcium carbonate, control the pH to 5.0 to 6.5 and react at 10 to 30°C. After the reaction is completed, cool down to 0 to 5°C and keep stirring for 20 to 30 minutes to obtain carbaspirin calcium suspension. S3. Centrifuge the carbaspirin calcium suspension to obtain carbaspirin calcium wet product and mother liquor. The mother liquor is reused in step S1. The carbaspirin calcium wet product is first washed with an ethanol solution with a volume concentration of 90%~95%, and the ethanol washing solution is also reused in step S1. The carbaspirin calcium wet product then undergoes a first-stage low-temperature flash evaporation and a second-stage vacuum belt drying. In the first-stage low-temperature flash evaporation, the inlet air temperature of the flash dryer is controlled at 70~80℃ and the outlet air temperature at 45~50℃. In the second-stage vacuum belt drying, the absolute pressure is controlled at 5~10kPa, the temperature at 40~45℃, and the residence time at 60~90min to obtain carbaspirin calcium.

[0022] Compared with the prior art, the beneficial effects of the present invention are: (1) This invention enables long-term stable reuse of mother liquor, significantly improving the overall yield. An active impurity removal step is introduced into the carbaspirin calcium mother liquor reuse process, effectively controlling the accumulation of impurities such as salicylic acid. This breaks through the limitation of traditional processes where mother liquor can only be reused 3 to 5 times, enabling stable production of more than 70 batches continuously. The product yield is stable at more than 90%, and the overall yield is 7% to 10% higher than that of traditional processes, while reducing raw material consumption by more than 30%.

[0023] (2) The product of this invention has high purity and significantly improved stability. It adopts a two-stage drying process of "low-temperature flash evaporation and vacuum belt drying" to avoid the decomposition of carbaspirin calcium and the formation of salicylic acid caused by high temperature. The salicylic acid content is controlled below 0.3% (0.5~1.0% in traditional processes), which is lower than the standard. The moisture content is controlled below 0.1% (0.1~0.2% in traditional processes), which meets European standards and meets export requirements. After 6 months of accelerated testing, the carbaspirin calcium content still remains above 98%, demonstrating excellent long-term stability.

[0024] (3) This invention is green and environmentally friendly with high resource utilization. The mother liquor is directly reused in the production line after pretreatment, and the ethanol washing liquid is reused at the same time, realizing the efficient recycling of solvent and unreacted raw materials. The mother liquor treatment unit recovers valuable components such as aspirin, calcium carbonate, and ethanol in stages, which greatly reduces wastewater discharge and sewage treatment load, and meets the requirements of clean production. Detailed Implementation

[0025] The present invention will be further described below with reference to specific embodiments.

[0026] Example 1 The present invention provides an industrial-scale method for improving the stability of carbaspirin calcium, comprising the following steps: S1. Add 945 kg of water and 255 kg of industrial ethanol to the refining tank, then add 1000 kg of aspirin and 300 kg of urea, and stir to obtain a mixture; S2. The mixture is pumped into the calcification tank, and 250 kg of calcium carbonate is continuously added through the screw propeller at a rate of 4% per minute for 2 hours. After adding calcium carbonate, the pH is controlled at 6.0. The reaction is carried out at 20℃ for 4 hours. After the reaction is completed, the temperature is lowered to 0~5℃ and stirred for 25 minutes to obtain carbaspirin calcium suspension. S3. Centrifuge the carbaspirin calcium suspension to obtain wet carbaspirin calcium and mother liquor. Wash the wet carbaspirin calcium with a 90% ethanol solution (volume concentration). The ethanol washing solution is also used in step S1. The wet carbaspirin calcium then undergoes a first-stage low-temperature flash evaporation and a second-stage vacuum belt drying. In the first-stage low-temperature flash evaporation, the inlet air temperature of the flash dryer is controlled at 75℃ and the outlet air temperature at 45℃. In the second-stage vacuum belt drying, the absolute pressure is controlled at 7kPa, the temperature at 42℃, and the residence time at 70min. 1093kg of carbaspirin calcium is obtained, with a yield of 85.9% (based on aspirin calculations). This step yields 1330kg of mother liquor and 1200kg of ethanol washing solution.

[0027] The mother liquor from S3 and the ethanol washing solution were then used in step S1 to continue the reaction. Before further use, the ethanol content was tested. Based on the actual test data, the amount of water and ethanol added was controlled during the reuse to ensure that the ethanol content was consistent with the initial state, as follows: The mother liquor and ethanol washing solution are reused for the first time: S11. First, add 100g of EDTA-2Na to 450kg of mother liquor and 480kg of ethanol washing liquid used in step S3 to remove iron. Then, treat the mixture with a fixed bed column of D301 type anion exchange resin. After the salicylic acid is qualified (the salicylic acid content is controlled ≤0.05%), it is then pumped into a refining tank, 230kg of water and 40kg of ethanol are added, along with 1000kg of aspirin and 300kg of urea. Stir to obtain a mixed solution. The process steps and parameters of S22~S33 are carried out exactly according to the steps of S2~S3, and finally the carbaspirin calcium product, mother liquor and ethanol washing solution are obtained; then the process is carried out again with the exact same dosage and steps as S11~S33.

[0028] The process results of the cyclical application process in Example 1 and the control group are shown below: In this embodiment, after 10 cycles of mother liquor and ethanol washing solution reuse following the initial process, the initial carbaspirin calcium yield was 85.9%, the initial salicylic acid content was 0.3%, the product yield per reuse ranged from 92.1% to 93.3%, the product content per reuse ranged from 99.2% to 99.8%, and the salicylic acid content per reuse ranged from 0.1% to 0.3%. The average values ​​for 10 reuses were: salicylic acid content of 0.2%, industrial ethanol consumption of 40 kg, water consumption of 230 kg, and energy consumption of 1.8 yuan.

[0029] Control group: The initial preparation process of Example 1 was repeated 10 times (i.e., no mother liquor was used, and fresh water, ethanol, and raw materials were used in each batch), and the average value was taken. The average value of 10 repetitions: salicylic acid content was 0.5%, the average product yield was 85.8%, the industrial ethanol consumption was 255 kg, the water consumption was 945 kg, and the power consumption was 3.21 yuan.

[0030] As can be seen from the above, the recycling process of the present invention, while maintaining product quality, increases the overall yield by 6.9%, saves 84.3% of ethanol consumption, saves 75.7% of water consumption, and reduces energy consumption by 43.9%, significantly reducing raw material consumption and production costs, and achieving clean production.

[0031] The calcium content of the carbaspirin calcium products prepared in Example 1 and the control group of the present invention is 8.6-8.7%, and the urea content is 13.0-13.2%, both of which comply with the control of the Chinese Veterinary Pharmacopoeia. The range of calcium content in the Chinese Veterinary Pharmacopoeia is 8.1-8.9%, and the range of urea content is 12.9-13.3%.

[0032] Regarding Example 1 of the present invention, the salicylic acid content in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, and 10th cycles of recycling were 0.1%, 0.1%, 0.1%, 0.2%, 0.2%, 0.2%, 0.2%, 0.3%, 0.3%, and 0.3%, respectively, and the product yield per cycle was 92.1%, 92.3%, 92.6%, 92.4%, 92.7%, 92.8%, 93.2%, 93.3%, 93.1%, and 92.8%, respectively. From the above data, it can be seen that as the number of cycles increases, the salicylic acid content first decreases rapidly and then stabilizes between 0.2% and 0.3%, indicating that the mother liquor pretreatment unit (EDTA-2Na for iron removal + anion exchange resin for salicylic acid removal) effectively controls the accumulation of impurities; the product yield per cycle increased from 85.9% in the initial batch to 92.7%, indicating that unreacted raw materials in the mother liquor were effectively recovered and utilized.

[0033] Comparative Example 1 In this comparative example, the mother liquor and ethanol washing solution from Example S11 above are not subjected to iron removal. That is, the recycled solution is directly treated with a fixed-bed column of D301 anion exchange resin. All other processes are exactly the same as the first cycle of the recycled process in Example 1, yielding carbaspirin calcium product. The iron content of the product from the first cycle of Example 1 was 0.8 ppm, while the iron content of this comparative example is 15.6 ppm.

[0034] As can be seen from the above, Comparative Example 1, which did not undergo iron removal treatment, had a significantly increased iron content in its product. The iron ions catalyzed the hydrolysis of aspirin, leading to a salicylic acid content reaching 0.5%, and the product also turned red, failing to meet quality standards. This demonstrates that the EDTA-2Na iron removal step is crucial for ensuring product quality.

[0035] Comparative Example 2 In this comparative example, the mother liquor and ethanol washing solution from Example S11 above are not treated with salicylic acid. That is, the recycled solution is first subjected to EDTA-2Na for iron removal, and then directly fed into the refining tank. Other processes are exactly the same as the first cycle of Example 1, yielding carbaspirin calcium product. The salicylic acid content of the first cycle product in Example 1 was 0.1%, while the salicylic acid content of this comparative example was 0.6%, and the product appearance was also red, failing to meet quality standards.

[0036] As can be seen from the above, Comparative Example 2 did not undergo salicylic acid treatment, and the salicylic acid accumulated in the mother liquor was not effectively removed, resulting in a salicylic acid content as high as 0.6% in the product. Furthermore, the high concentration of salicylic acid interfered with the crystallization process, leading to a decrease in product yield and a reddish appearance. This demonstrates that treatment with a salicylic acid molecularly imprinted adsorbent / anion exchange resin is crucial for the long-term stability of the mother liquor during recycling.

[0037] Comparative Example 3 This comparative example uses the same steps as the first cycle in Example 1, but the drying in step S3 is done using a traditional single-stage flash evaporation process. Specifically, step S3 is as follows: The carbaspirin calcium suspension was centrifuged to obtain wet carbaspirin calcium and mother liquor. The wet carbaspirin calcium was first washed with a 90% (v / v) ethanol solution, and then subjected to a high-temperature flash evaporation. The flash dryer inlet temperature was 125°C and the outlet temperature was 45°C to obtain carbaspirin calcium. The salicylic acid content of the first cycle product in Example 1 was 0.1%, while the salicylic acid content of the comparative example was 0.6%. As can be seen from the above, the conventional high-temperature single flash drying (inlet temperature 125°C) in Comparative Example 3 caused partial decomposition of aspirin to generate salicylic acid, resulting in a salicylic acid content as high as 0.6% in the product, a reddish appearance, and a distinctly pungent acidic odor. Simultaneously, the decomposition led to a decrease in product yield. This indicates that the two-stage drying process of low-temperature flash evaporation and vacuum belt drying used in this invention effectively avoids heat-sensitive decomposition, ensuring product purity and yield.

[0038] The carbaspirin calcium product from the initial process of Example 1 above, as well as the products obtained from the 1st, 5th, and 10th cycle processes, and the control group product and comparative examples 1, 2, and 3 were subjected to stability tests: accelerated tests and long-term tests. The accelerated test conditions were: the samples were placed at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 6 months. Samples were taken at 0, 1, 2, 3, and 6 months to detect the carbaspirin calcium content and free salicylic acid content. The results are shown in Table 1. Long-term experimental conditions: The samples were placed at a temperature of 25℃±2℃ and a relative humidity of 60%±5% for 12 months. Samples were taken and tested at 0, 3, 6, 9 and 12 months. The results are shown in Table 2.

[0039] Table 1. Results of the Accelerated Experiment

[0040] As can be seen from the above, after 6 months of accelerated testing, the free salicylic acid content of the present invention is less than 0.5%, which meets the requirements of the Chinese Veterinary Pharmacopoeia, and the product has good stability.

[0041] Table 2 Results of Long-Term Experiment

[0042] As can be seen from the above, after a long-term test of 12 months, the calcium content of carbaspirin remained above 98%, and the free salicylic acid content was far below the standard of 1.0%, indicating that the carbaspirin calcium prepared by this invention has excellent long-term stability and is suitable for industrial production and long-term storage.

[0043] Example 2 This embodiment utilizes the mother liquor and ethanol washing solution from step S3 of Example 1. The industrial preparation method for improving the stability of carbaspirin calcium of the present invention includes the following steps: S1. First, add 440 kg of mother liquor and 400 kg of ethanol washing liquid from S3 in Example 1 to 150 g of EDTA-2Na to remove iron. Then, treat the mixture with a fixed bed column of salicylic acid molecularly imprinted adsorbent. If the salicylic acid is qualified (the content of salicylic acid is controlled ≤0.05%), the unqualified mixture will be recycled and then pumped into a refining tank. Add 220 kg of water and 40 kg of industrial ethanol, 1000 kg of aspirin and 200 kg of urea, and stir to obtain a mixed solution. S2. The mixture is pumped into the calcification tank, and 200 kg of calcium carbonate is continuously added at a rate of 2% per minute through the screw propeller. After the calcium carbonate is added, the pH is controlled at 5.3. The reaction is carried out at 30℃ for 4 hours. After the reaction is completed, the temperature is lowered to 0~5℃ and stirred for 20 minutes to obtain carbaspirin calcium suspension. S3. Centrifuge the carbaspirin calcium suspension to obtain carbaspirin calcium wet product and mother liquor. The mother liquor is reused in step S1. The carbaspirin calcium wet product is first washed with a 95% ethanol solution, and the ethanol washing solution is also reused in step S1. The carbaspirin calcium wet product then undergoes a first-stage low-temperature flash evaporation and a second-stage vacuum belt drying. In the first-stage low-temperature flash evaporation, the inlet air temperature of the flash dryer is controlled at 70℃ and the outlet air temperature at 45℃. In the second-stage vacuum belt drying, the absolute pressure is controlled at 5kPa, the temperature at 45℃, and the residence time at 90min, yielding 1145kg of carbaspirin calcium.

[0044] The process is repeated in step S1, for a total of 10 cycles. The single-cycle yield of carbaspirin calcium is consistently above 90%, and the salicylic acid content is below 0.4%. After accelerated and long-term testing, the carbaspirin calcium content remains above 98.0%, and the free salicylic acid content is below 0.5%.

[0045] Example 3 This embodiment utilizes the mother liquor and ethanol washing solution from step S3 of Example 1. The industrial preparation method for improving the stability of carbaspirin calcium of the present invention includes the following steps: S1. First, add 200g of EDTA-2Na to 620kg of the mother liquor and 600kg of ethanol washing liquid to remove iron. Then, treat with a weakly basic anion exchange resin. After the salicylic acid is qualified (the salicylic acid content is controlled ≤0.05%), put it into a refining tank, add 40kg of water and 40kg of industrial ethanol, add 1000kg of aspirin and 400kg of urea, and stir to obtain a mixed solution. S2. The mixture is pumped into the calcification tank, and 300 kg of calcium carbonate is continuously added at a rate of 5% per minute through the screw propeller. After the calcium carbonate is added, the pH is controlled at 6.5. The reaction is carried out at 10℃ for 3 hours. After the reaction is completed, the temperature is lowered to 0~5℃ and stirred for 30 minutes to obtain carbaspirin calcium suspension. S3. Centrifuge the carbaspirin calcium suspension to obtain carbaspirin calcium wet product and mother liquor. The mother liquor is reused in step S1. The carbaspirin calcium wet product is first washed with a 95% ethanol solution, and the ethanol washing solution is also reused in step S1. The carbaspirin calcium wet product then undergoes a first-stage low-temperature flash evaporation and a second-stage vacuum belt drying. In the first-stage low-temperature flash evaporation, the inlet air temperature of the flash dryer is controlled at 80℃ and the outlet air temperature at 50℃. In the second-stage vacuum belt drying, the absolute pressure is controlled at 10kPa, the temperature at 40℃, and the residence time at 60min, yielding 1183kg of carbaspirin calcium.

[0046] The process is repeated in step S1 for a total of 10 cycles. The single-cycle yield of carbaspirin calcium is consistently above 92%, and the salicylic acid content is consistently below 0.4%. After accelerated and long-term testing, the carbaspirin calcium content remains above 98.0%, and the free salicylic acid content is below 0.5%.

Claims

1. An industrial preparation method for carbaspirin calcium with improved stability, characterized in that, Includes the following steps: S1. First, add the mother liquor and ethanol washing solution to EDTA-2Na to remove iron, then pass through the mother liquor pretreatment unit, and then pump it into the refining tank. Add the prepared amount of water and ethanol, add aspirin and urea, and stir to obtain a mixed solution. S2. Pour the mixture into a calcification tank, add calcium carbonate to react, and after the reaction is complete, cool to 0~5℃ and keep stirring for 20~30 minutes to obtain carbaspirin calcium suspension; S3. Centrifuge the carbaspirin calcium suspension to obtain carbaspirin calcium wet product and mother liquor. The mother liquor is reused in step S1. The carbaspirin calcium wet product is first washed with ethanol, and the ethanol washing liquid is also reused in step S1. The carbaspirin calcium wet product then undergoes a first-stage low-temperature flash evaporation and a second-stage vacuum belt drying to obtain carbaspirin calcium.

2. The industrial preparation method of carbaspirin calcium with improved stability according to claim 1, characterized in that, The mother liquor pretreatment unit in step S1 first passes the mother liquor through a fixed bed column of weakly basic anion exchange resin or salicylic acid molecularly imprinted adsorbent. After the salicylic acid is qualified, it is then pumped into the purification tank.

3. The method for industrial preparation of carbaspirin calcium with improved stability according to claim 2, characterized in that, In step S1, add the prepared amount of water and ethanol so that the ethanol content in the mixture is 18-22% by mass and the mass ratio of aspirin to ethanol aqueous solution is 1:1-1.

3.

4. The industrial preparation method for carbaspirin calcium with improved stability according to claim 1, characterized in that, In step S2, the mass ratio of aspirin to urea in the calcification vessel is 1:0.1~0.

4.

5. The industrial preparation method for carbaspirin calcium with improved stability according to claim 4, characterized in that, In step S2, the mass ratio of aspirin to calcium carbonate in the calcification vessel is 1:0.2~0.

3.

6. The industrial preparation method of carbaspirin calcium with improved stability according to claim 5, characterized in that, The rate at which calcium carbonate is added in step S2 is as follows: based on the total amount of calcium carbonate fed, it is continuously added via a screw propeller at a rate of 2% to 5% per minute.

7. The industrial preparation method of carbaspirin calcium with improved stability according to claim 6, characterized in that, Step S2: After adding calcium carbonate, control the pH to 5.0~6.

5.

8. The method for industrial preparation of carbaspirin calcium with improved stability according to claim 7, characterized in that, In step S2, the temperature for reacting with calcium carbonate is 10~30℃.

9. The method for industrial preparation of carbaspirin calcium with improved stability according to claim 1, characterized in that, Step S3: Wash the wet carbaspirin calcium sample with ethanol, using an ethanol solution with a volume concentration of 90-95%.

10. The method for industrial preparation of carbaspirin calcium with improved stability according to claim 9, characterized in that, In step S3, during the first stage of low-temperature flash drying, the inlet air temperature of the flash dryer is controlled at 70~80℃ and the outlet air temperature at 45~50℃; during the second stage of vacuum belt drying, the absolute pressure is controlled at 5~10kPa, the temperature at 40~45℃, and the residence time at 60~90min.

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