Comprehensive recovery method of ampicillin sodium crystallization mother liquor

Abstract

The invention discloses a comprehensive recovery method of ampicillin sodium crystallization mother liquor, which comprises the following steps: enabling the ampicillin sodium crystallization mother liquor to pass through oxyhydrogen anion exchange resin, adsorbing ampicillin acid radical ions and isooctanoic acid radical ions on the resin through ion exchange, the ampicillin hydrochloride and the isocaprylic acid desorption solution obtained through desorption are separated through macroporous adsorption resin, and then the ampicillin and the isocaprylic acid salt are obtained through the processes of desorption, crystallization and drying. According to the method, the oxyhydrogen anion exchange resin and the macroporous adsorption resin are combined to separate and recover the active ingredients ampicillin and isocaprylic acid in the mother liquor, and the ion exchange and adsorption process is mild in condition, can be carried out at normal temperature, and has high recovery purity and recovery rate; and the cost and difficulty of the subsequent refining process are reduced.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and relates to a comprehensive recovery method of ampicillin sodium crystal mother liquor, in particular to a method for comprehensively recovering active ingredients from ampicillin sodium crystal mother liquor. Background Art

[0002] Ampicillin sodium is a key first-generation semisynthetic penicillin. As a broad-spectrum semisynthetic antibiotic, its mechanism of action is to inhibit bacterial cell wall synthesis. It exhibits excellent antibacterial activity against both Gram-positive and Gram-negative bacteria, boasting a broad antibacterial spectrum and high efficacy. At normal dosages, it exhibits relatively minimal toxic side effects. In clinical practice, ampicillin sodium is used to treat a variety of bacterial infections, including respiratory, urinary, and gastrointestinal infections, and holds a significant position in the field of antibiotic therapy.

[0003] In today's advanced pharmaceutical process, the preparation of ampicillin sodium primarily relies on solvent crystallization. The specific process involves a directed chemical reaction between ampicillin and diisopropylamine in a precisely proportioned mixed solvent of n-butanol and butyl acetate to produce ampicillin diisopropylamine salt. This salt then undergoes a double decomposition reaction with sodium isooctanoate to produce ampicillin sodium. However, after efficient separation of ampicillin sodium crystals, complex components with recycling value remain in the crystallization mother liquor. Liquid chromatography revealed that the mother liquor contained 8.0 mg / mL to 12.0 mg / mL of ampicillin sodium (measured as anhydrous ampicillin), 60.0 mg / mL to 95.0 mg / mL of diisopropylamine isooctanoate salt (measured as isooctanoic acid), and a large amount of unreacted diisopropylamine, alcohol, and ester organic solvents. Under the traditional industrial production model, organic solvents are routinely recovered only through distillation, but there has always been a lack of a scientific, efficient, and innovative recovery method for the extremely valuable ampicillin and isooctanoic acid in the crystallization mother liquor. This results in these valuable ingredients flowing directly into the sewage treatment system without effective treatment, which not only greatly increases the technical difficulty and operating costs of sewage treatment, but also causes a considerable waste of resources. In view of this, the development of an innovative comprehensive recovery technology to efficiently recover ampicillin and isooctanoic acid from the crystallization mother liquor of ampicillin sodium is of extremely important practical significance. This technology can not only reduce pollution at the source and promote the development of the pharmaceutical industry in a green and sustainable direction, but also open up new economic growth points for enterprises through the secondary utilization of resources, thereby enhancing the comprehensive competitiveness and industry influence of enterprises. Summary of the Invention

[0004] Technical issues

[0005] The present invention is designed to solve the above-mentioned problems of the prior art. The purpose of the present invention is to provide a comprehensive recovery method for ampicillin sodium crystallization mother liquor, so as to comprehensively recover the active ingredients from the ampicillin sodium crystallization mother liquor. The recovery method can complete the separation of the active ingredients in the mother liquor through only two resin steps. The process design is innovative, the operation is simple, the energy consumption is low, and the obtained ampicillin and sodium isooctanoate products are high-quality and stable.

[0006] Technical Solution

[0007] In order to achieve the above-mentioned object of the present invention, the technical solution adopted by the present invention is as follows: the mother liquor of ampicillin sodium crystallization is passed through a hydroxide-type anion exchange resin, and the ampicillin acid anion and the isooctanoic acid anion are adsorbed on the resin through ion exchange. The ampicillin hydrochloride and isooctanoic acid solution obtained by analysis are then passed through a macroporous adsorption resin to complete the separation of the two. Then, through the steps of analysis, crystallization and drying, ampicillin and isooctanoic acid salt are obtained.

[0008] According to the present invention, the comprehensive recovery method of ampicillin sodium crystal mother liquor provided by the present invention comprises the following steps:

[0009] (1) Primary separation of ampicillin sodium crystal mother liquor

[0010] The mother liquor of ampicillin sodium crystallization is passed through a hydroxide-type anion exchange resin, and ampicillin acid ions and isooctanoic acid ions are adsorbed on the resin through ion exchange, and diisopropylamine and an organic solvent flow through the resin to collect the flow-through liquid; the resin is decomposed with hydrochloric acid to obtain a decomposition liquid containing ampicillin hydrochloride and isooctanoic acid;

[0011] Wherein, the hydroxide type anion exchange resin is an anion exchange resin transformed into a hydroxide type anion exchange resin through acid activation and alkali activation treatment;

[0012] (2) Secondary separation of ampicillin sodium crystallization mother liquor

[0013] The desorption solution obtained in the above step (1) is passed through a macroporous adsorption resin, and isooctanoic acid is adsorbed on the resin, while ampicillin hydrochloride is not adsorbed by the resin and flows through the resin with the solution to obtain an ampicillin hydrochloride solution. The ampicillin hydrochloride solution is concentrated by a high-pressure reverse osmosis membrane, and the obtained concentrated solution is crystallized at the isoelectric point to obtain ampicillin; the isooctanoic acid adsorbed on the resin is desorbed using an alcohol salt solution to obtain an isooctanoic acid salt desorption solution, and the isooctanoic acid salt desorption solution is distilled to remove the solvent to obtain isooctanoic acid salt.

[0014] Beneficial effects

[0015] In this invention, the innovative combination of a hydroxide anion exchange resin and a macroporous adsorption resin successfully achieves comprehensive recovery of the active ingredients in the ampicillin sodium crystallization mother liquor. The hydroxide anion exchange resin, based on the ion exchange principle, specifically adsorbs the ampicillin acid ion and isooctanoic acid ion in the crystallization mother liquor, utilizing its ion exchange properties to separate the ampicillin acid ion and isooctanoic acid ion from the mother liquor. The macroporous adsorption resin, based on its unique porous structure and surface properties, physically adsorbs isooctanoic acid in the analyte solution. By selecting appropriate desorption conditions, isooctanoic acid can be desorbed from the resin, thereby achieving the separation and recovery of ampicillin and isooctanoic acid. Compared with traditional processes, this method has significant advantages: on the one hand, the ion exchange and adsorption process conditions are mild and can be carried out at room temperature, without the need for harsh conditions such as high temperature and strong acid and alkali. This not only reduces equipment requirements and energy consumption, but also avoids the decomposition of components or the generation of impurities that may be caused by high temperature, strong acid and alkali; on the other hand, the two resins have high adsorption selectivity for the target components and can accurately separate ampicillin sodium and isooctanoic acid from the complex crystallization mother liquor, greatly improving the recovery purity and recovery rate, and reducing the cost and difficulty of the subsequent refining process. Taking into account the above outstanding advantages, the present invention has higher feasibility and practicality in industrial production, is more suitable for large-scale promotion and application, and is expected to bring significant economic and environmental benefits to ampicillin sodium production companies. DETAILED DESCRIPTION

[0016] The following describes the comprehensive recovery method for the ampicillin sodium crystallization mother liquor of the present invention in detail to facilitate understanding of the present invention. However, the embodiments of the present invention may be modified in various ways, and the scope of the present invention is not limited to the embodiments described below. The embodiments of the present invention are provided to make this disclosure clear and complete, so as to fully illustrate the present invention to those skilled in the art.

[0017] According to one embodiment of the present invention, in the comprehensive recovery method of the ampicillin sodium crystallization mother liquor of the present invention, in the primary separation of the ampicillin sodium crystallization mother liquor in the step (1), the ampicillin sodium crystallization mother liquor is passed through a hydroxide-type anion exchange resin, and the ampicillin acid ions and isooctanoic acid ions are adsorbed on the resin through ion exchange, and diisopropylamine and an organic solvent flow through the resin to collect the overflow liquid; the resin is decomposed using hydrochloric acid to obtain a decomposed liquid containing ampicillin hydrochloride and isooctanoic acid.

[0018] After the crystallization and separation of ampicillin sodium, the ampicillin sodium crystallization mother liquor still contains 8.0 mg / mL to 12.0 mg / mL of ampicillin sodium (measured as anhydrous ampicillin), 60.0 mg / mL to 95.0 mg / mL of diisopropylamine isooctanoate (measured as isooctanoic acid), and diisopropylamine, n-butanol and butyl acetate that do not participate in the reaction. The pH of the mother liquor system is 9.0 to 10.0.

[0019] Among them, the anion exchange resin is preferably a weakly basic anion exchange resin, and an anion exchange resin with brown or brown spherical particles, a particle size of 0.4mm to 1.25mm, and a mass full exchange capacity of ≥5.5mmol / g can be selected. Any anion exchange resin that meets this condition can be used as the preferred anion exchange resin in the method of the present invention. For example, the LXT-267 anion exchange resin produced by Gaoling Lanxiao Technology New Materials Co., Ltd. and the FPA-53 anion exchange resin produced by Shanghai Anlande Biotechnology Co., Ltd. can be selected. The hydroxide anion exchange resin used in step (1) is an anion exchange resin that has been transformed into a hydroxide anion exchange resin through acid activation and alkali activation treatment. Specifically, the hydroxide-type anion exchange resin is transformed by treating the anion exchange resin according to the following method: after the anion exchange resin is loaded into a column, a 4wt% to 5wt% hydrochloric acid solution is used to activate the anion exchange resin (i.e., flow through it), and then the resin is rinsed with purified water until the eluate is neutral and the conductivity is less than 50μs / cm; then a 4wt% to 5wt% sodium hydroxide solution is used to activate the resin (i.e., flow through it) to transform it into the hydroxide-type, and then the resin is rinsed with purified water until it is neutral and the conductivity is less than 50μs / cm.

[0020] The hydroxide anion exchange resin is applied in the form of a circular resin column bed by wet column packing. The ratio of the height to the diameter (ie, the aspect ratio) of the circular resin column bed is preferably greater than or equal to 4, more preferably greater than or equal to 8. The ampicillin sodium crystallization mother liquor is passed through the resin column bed at a certain flow rate, preferably at a flow rate of 1.0 to 3.0 times the total volume of the resin per hour, and preferably at a flow rate of 1.0 to 2.0 times the total volume of the resin per hour. During the passage of the crystallization mother liquor through the resin, the ampicillin acid ions and isooctanoic acid ions in the crystallization mother liquor are exchanged with the hydroxide ions bound to the resin, and the ampicillin acid ions and isooctanoic acid ions are adsorbed on the resin. The hydroxide ions released by the resin combine with diisopropylammonium ions to form diisopropylamine and water. Diisopropylamine, n-butanol, and butyl acetate are not adsorbed by the resin and flow through the resin, and are collected as a flow-through. The resin column bed is then rinsed with purified water at the same flow rate, at a volume of 1.0 to 3.0 times the total volume of the resin, to remove residual solvent components in the column and combine with the flow-through. Finally, the flow-through is separated and recovered by conventional distillation, utilizing the difference in boiling points of diisopropylamine, n-butanol, and butyl acetate. It should be noted that n-butanol and butyl acetate have an azeotropic phenomenon. For the collected n-butanol and butyl acetate that form an azeotropic phase, when they are reused, the ratio of the two is detected, and then n-butanol or butyl acetate is added to adjust the two to the process concentration before reuse.

[0021] The ampicillin acid anion and isooctanoic acid anion adsorbed on the anion exchange resin in step (1) are resolved using hydrochloric acid to obtain a resolution solution containing ampicillin hydrochloride and isooctanoic acid. The molar concentration of the hydrochloric acid in the resolution agent is preferably between 2.0 and 4.0 mol / L, more preferably between 2.0 and 3.0 mol / L; the flow rate of the resolution agent is 0.5 to 1.0 times the total volume of the resin per hour, and the amount of the resolution agent is 1.0 to 2.0 times the total volume of the resin. After the resolution is completed, the resin column is rinsed with purified water at a volume of 0.5 to 1.0 times the total volume of the resin, and the collected liquid is added to the resolution solution. The resolution solution collected in this process has a pH of 0.5 to 1.0 and contains 20 mg / mL to 30 mg / mL of ampicillin hydrochloride (measured as anhydrous ampicillin) and 160 mg / mL to 220 mg / mL of isooctanoic acid (measured as isooctanoic acid).

[0022] According to one embodiment of the present invention, in the comprehensive recovery method of the ampicillin sodium crystallization mother liquor of the present invention, in the secondary separation of the ampicillin sodium crystallization mother liquor in the step (2), the decomposition solution obtained in the above step (1) is passed through a macroporous adsorption resin, and isooctanoic acid is adsorbed on the resin, while ampicillin hydrochloride is not adsorbed by the resin and flows through the resin with the solution to obtain an ampicillin hydrochloride solution. The ampicillin hydrochloride solution is concentrated by a high-pressure reverse osmosis membrane, and the obtained concentrated solution is crystallized at the isoelectric point to obtain ampicillin; the isooctanoic acid adsorbed on the resin is decomposed using an alcohol salt solution to obtain an isooctanoic acid salt decomposition solution, and the isooctanoic acid salt decomposition solution is distilled to remove the solvent to obtain isooctanoic acid salt.

[0023] The macroporous adsorption resin can be selected from any one of the LX-033 model produced by Gaoling Lanxiao Technology New Materials Co., Ltd. and the DM-700 model produced by Aimicogen (China) Biopharmaceutical Co., Ltd. The macroporous adsorption resin needs to be rinsed with methanol before use. Specifically, 2.0 to 3.0 times the total volume of the macroporous adsorption resin is used to rinse the resin, and then purified water is used to rinse the resin outlet until there is no methanol smell before use. The macroporous adsorption resin is applied in the form of a circular resin column bed by wet column packing. The height to diameter ratio (i.e., height-to-diameter ratio) of the circular resin column bed is preferably greater than or equal to 4, more preferably greater than or equal to 8. The analytical solution obtained in the above step (1) is passed through the macroporous adsorption resin at a flow rate of 0.5 to 1.0 times the total volume of the resin per hour. The isooctanoic acid in the analytical solution is adsorbed on the resin, while ampicillin hydrochloride is not adsorbed by the resin and flows through the resin with the solution and is collected as the overflow liquid. After adsorption is complete, the resin column is then flushed with purified water at the same flow rate, 2.0 to 3.0 times the total volume of the resin, to remove any residual ampicillin hydrochloride. This water is then added to the flowthrough. This flowthrough contains ampicillin hydrochloride and is the ampicillin hydrochloride solution, which can be used to prepare ampicillin.

[0024] Isooctanoic acid adsorbed on the resin can be desorbed using an alkoxide solution. Alkoxide is an organic base that reacts with the isooctanoic acid on the resin to produce isooctanoic acid salt and the corresponding alcohol. The alkoxide can be a methoxide or an ethanolate. For example, a methanol solution of sodium methoxide or an ethanol solution of sodium ethoxide can be used to desorb the isooctanoic acid adsorbed on the resin, yielding a desorption solution of sodium isooctanoate. The alkoxide must be dissolved in the corresponding alcohol. The amount of alkoxide added is calculated based on the amount of isooctanoic acid adsorbed, using a 1:1 molar ratio. The alkoxide is dissolved in 1.0-2.0 times the total volume of the resin in alcohol. The isooctanoic acid adsorbed on the resin is then desorbed at a flow rate of 0.5-1.0 times the total volume of the resin per hour. Avoid using an excessive amount of alkoxide, as this will reduce product purity. After desorption with the alkoxide, rinse the resin with 0.5-1.0 times the total volume of the resin in alcohol to remove any remaining sodium isooctanoate. The collected liquid is then added to the desorption solution. The concentration of sodium isooctanoate in the analytical solution collected in this process is 150 mg / mL to 300 mg / mL (measured in isooctanoic acid). The isooctanoate analytical solution is then collected and the corresponding alcohol is removed by atmospheric distillation or reduced pressure distillation to obtain isooctanoate.

[0025] The collected ampicillin hydrochloride solution is concentrated. Specifically, the ampicillin hydrochloride solution is concentrated at 10°C to 30°C using a high-pressure reverse osmosis membrane. The membrane is a composite membrane composed of a polyester non-woven fabric layer, a polysulfone porous intermediate support layer, and a polyamide separation layer. For example, a high-pressure reverse osmosis membrane core produced by Shanghai Kaixin Separation Technology Co., Ltd. can be selected. The ampicillin hydrochloride concentrate obtained after concentration using the high-pressure reverse osmosis membrane at 10°C to 30°C can have a concentration of 60-100 mg / mL, calculated as anhydrous ampicillin acid. The solution is then cooled to 0-10°C, and 10%-15% (v / v) ammonia water is slowly added to the concentrate. Once crystals precipitate in the solution, the addition of ammonia water is stopped, and the crystals are allowed to grow for 20-30 minutes. The ammonia water is then added dropwise until the pH reaches 4.5-5.5, and the crystals are allowed to grow for 120-240 minutes. After the crystals are grown, the ampicillin can be isolated by filtering, washing, and drying.

[0026] Hereinafter, the comprehensive recovery method of the ampicillin sodium crystal mother liquor of the present invention will be described in more detail by way of examples, but the protection scope of the present invention is not limited to these examples.

[0027] Treatment of resin before use

[0028] The hydroxide type anion exchange resin was transformed by treating the anion exchange resin according to the following method: the anion exchange resin was packed into a column (model FPA-53, from Shanghai Anlande Biotechnology Co., Ltd.) with a column volume of 2000 ml and a column height-to-diameter ratio of 10, and then the anion exchange resin was activated (i.e., flowed through) with 4 L of 5 wt% hydrochloric acid solution, and then rinsed with purified water until the eluate was neutral and the conductivity was less than 50 μs / cm; then the resin was activated (i.e., flowed through) with 4 L of 5 wt% sodium hydroxide solution to transform it into the hydroxide type, and then rinsed with purified water until it was neutral and the conductivity was less than 50 μs / cm.

[0029] Pre-treatment of macroporous adsorption resin: The macroporous adsorption resin was packed into a column (model DM-700, from Amicogen (China) Biopharmaceutical Co., Ltd.) with a loading volume of 2000 ml and a height-to-diameter ratio of 5. The resin was then rinsed with 4 L of methanol and then with purified water until there was no methanol smell at the outlet of the resin column.

[0030] Example 1

[0031] 10 L of the crystallization mother liquor from the crystallization separation of ampicillin sodium was collected. It was found to contain 10.5 mg / mL of ampicillin sodium (measured as anhydrous ampicillin) and 82 mg / mL of diisopropylamine octanoate (measured as isooctanoic acid), with a pH of 9.8. This crystallization mother liquor was passed through the above-described hydroxyl-type anion exchange resin column at a flow rate of 2.0 L / h. After adsorption was complete, the resin column was rinsed with 2 L of purified water, and the flowthrough was collected for recovery of diisopropylamine, n-butanol, and butyl acetate. Then, 3 L of 2.0 mol / L hydrochloric acid was used to decompose the ampicillin acid ion and isooctanoic acid ion adsorbed on the resin at a flow rate of 1.0 L / h. After decomposition, the resin column was rinsed with 1.0 L of purified water to obtain 3.8 L of decomposition solution. After testing, the decomposition solution contained 26.9 mg / mL of ampicillin hydrochloride (measured as anhydrous ampicillin) and 213.6 mg / mL of isooctanoic acid (measured as isooctanoic acid), and the pH was 0.95.

[0032] The above-mentioned solution was passed through a macroporous adsorption resin column bed at a flow rate of 1.0 L / h. After adsorption was complete, the resin column was rinsed with 4 L of purified water, and the flow-through was collected to obtain an ampicillin hydrochloride solution. The isooctanoic acid adsorbed on the resin was then desorbed using 2 L of a methanol solution containing 304.0 g of sodium methoxide at a flow rate of 1.0 L / h. After desorption, the resin column was rinsed with 1.0 L of methanol to obtain 2.8 L of solution. The sodium isooctanoate concentration in the solution was determined to be 286.1 mg / mL (measured as isooctanoic acid). The methanol was then recovered by vacuum distillation to obtain 923.2 g of sodium isooctanoate, with a content of 85.8% based on isooctanoic acid, for a molar yield of 96.6%.

[0033] The ampicillin hydrochloride solution obtained above was concentrated to 1.2 L using a high-pressure reverse osmosis membrane. The concentrate was found to contain 83.9 mg / mL of ampicillin hydrochloride (measured as anhydrous ampicillin). This concentrate was then used for ampicillin recovery. 15% (v / v) aqueous ammonia was then slowly added to the ampicillin hydrochloride concentrate, which had been cooled to 5°C. Addition of aqueous ammonia was stopped after crystals precipitated, and the crystals were grown for 20 minutes. Ammonia was then added dropwise until the pH reached 5.0, and the crystals were grown at 5°C for 120 minutes. After the crystals were grown, the solution was filtered, washed, and dried to yield 109.5 g of ampicillin, with a molar yield of 90.6% and a content of 86.9% as anhydrous ampicillin.

[0034] Example 2

[0035] 10 L of the crystallization mother liquor from the crystallization separation of ampicillin sodium was collected. Testing revealed that the mother liquor contained 9.6 mg / mL of ampicillin sodium (measured as anhydrous ampicillin) and 78 mg / mL of diisopropylamine octanoate (measured as isooctanoic acid), with a pH of 9.7. This crystallization mother liquor was passed through the aforementioned hydroxyl-type anion exchange resin column at a flow rate of 2.0 L / h. After adsorption was complete, the resin column was rinsed with 2 L of purified water, and the flowthrough was collected for recovery of diisopropylamine, n-butanol, and butyl acetate. Then, 4 L of 2.0 mol / L hydrochloric acid was used to decompose the ampicillin acid ion and isooctanoic acid ion adsorbed on the resin at a flow rate of 1.0 L / h. After decomposition, the resin column was rinsed with 1.0 L of purified water to obtain 4.7 L of decomposition solution. After testing, the decomposition solution contained 20.1 mg / mL of ampicillin hydrochloride (measured as anhydrous ampicillin) and 162.6 mg / mL of isooctanoic acid (measured as isooctanoic acid), and the pH was 0.86.

[0036] The above-mentioned solution was passed through a macroporous adsorption resin column bed at a flow rate of 1.0 L / h. After adsorption was complete, the resin column was rinsed with 4 L of purified water, and the flow-through was collected to obtain an ampicillin hydrochloride solution. Next, 360.6 g of sodium ethoxide dissolved in 4 L of ethanol was dissolved at a flow rate of 1.0 L / h to desorb the isooctanoic acid adsorbed on the resin. After desorption, the resin column was rinsed with 1.0 L of ethanol to obtain 4.7 L of solution. This solution was tested to contain 160.2 mg / mL of isooctanoic acid (measured as isooctanoic acid). Ethanol was then recovered by vacuum distillation to obtain 867.5 g of sodium isooctanoate, with a content of 85.6% as isooctanoic acid, for a molar yield of 95.2%.

[0037] The ampicillin hydrochloride solution obtained above was concentrated to 1.0 L using a high-pressure reverse osmosis membrane. The concentrate was found to contain 92.6 mg / mL of ampicillin hydrochloride (measured as anhydrous ampicillin). This concentrate was then used for ampicillin recovery. 15% (v / v) aqueous ammonia was then slowly added to the ampicillin hydrochloride concentrate, which had been cooled to 5°C. Addition of aqueous ammonia was stopped after crystals precipitated, and the crystals were grown for 30 minutes. Ammonia was then added dropwise until the pH reached 5.0, and the crystals were grown at 5°C for 120 minutes. After the crystals were grown, the solution was filtered, washed, and dried to yield 101.2 g of ampicillin, with a molar yield of 91.4% and a content of 86.7% based on anhydrous ampicillin.

[0038] Example 3

[0039] 10 L of the crystallization mother liquor from the crystallization separation of ampicillin sodium was collected. Testing revealed that it contained 9.9 mg / mL of ampicillin sodium (measured as anhydrous ampicillin) and 86 mg / mL of diisopropylamine octanoate (measured as isooctanoic acid), with a pH of 9.7. This crystallization mother liquor was passed through the aforementioned hydroxyl-type anion exchange resin column at a flow rate of 3.0 L / h. After adsorption was complete, the resin column was rinsed with 2 L of purified water, and the flowthrough was collected for recovery of diisopropylamine, n-butanol, and butyl acetate. Then, 4 L of 2.0 mol / L hydrochloric acid was used to decompose the ampicillin acid ion and isooctanoic acid ion adsorbed on the resin at a flow rate of 1.0 L / h. After decomposition, the resin column was rinsed with 1.0 L of purified water to obtain 4.8 L of decomposition solution. After testing, the decomposition solution contained 20.3 mg / mL of ampicillin hydrochloride (measured as anhydrous ampicillin) and 175.6 mg / mL of isooctanoic acid (measured as isooctanoic acid), and the pH was 0.83.

[0040] The desorption solution was passed through the macroporous adsorption resin column at a flow rate of 2.0 L / h. After adsorption was complete, the resin column was rinsed with 4 L of purified water, and the flowthrough was collected to obtain an ampicillin hydrochloride solution. The isooctanoic acid adsorbed on the resin was then desorbed using 4 L of methanol containing 315.7 g of sodium methoxide at a flow rate of 1.5 L / h. After desorption, the resin column was rinsed with 1.0 L of methanol to obtain 4.6 L of desorption solution, which was tested to contain 180.7 mg / mL of isooctanoic acid (measured as isooctanoic acid). Methanol was then recovered by vacuum distillation to obtain 957.8 g of sodium isooctanoate, with a content of 85.7% based on isooctanoic acid, for a molar yield of 95.4%.

[0041] The ampicillin hydrochloride solution obtained above was concentrated to 1.1 L using a high-pressure reverse osmosis membrane. The concentrate was found to contain 87.1 mg / mL of ampicillin hydrochloride (measured as anhydrous ampicillin). This concentrate was then used for ampicillin recovery. 15% (v / v) aqueous ammonia was then slowly added to the ampicillin hydrochloride concentrate, which had been cooled to 5°C. Addition of aqueous ammonia was stopped after crystals precipitated, and the crystals were grown for 30 minutes. Ammonia was then added dropwise until the pH reached 5.1, and the crystals were grown at 5°C for 120 minutes. After the crystals were grown, the solution was filtered, washed, and dried to yield 104.8 g of ampicillin, with a molar yield of 91.9% and a content of 86.8% as anhydrous ampicillin.

Claims

1. A comprehensive recovery method for ampicillin sodium crystal mother liquor, comprising the following steps: (1) Primary separation of ampicillin sodium crystal mother liquor The mother liquor of ampicillin sodium crystallization is passed through a hydroxide-type anion exchange resin, and ampicillin acid ions and isooctanoic acid ions are adsorbed on the resin through ion exchange, and diisopropylamine and an organic solvent flow through the resin to obtain a flow-through solution; the resin is decomposed with hydrochloric acid to obtain a decomposition solution containing ampicillin hydrochloride and isooctanoic acid; in, The hydroxide anion exchange resin is an anion exchange resin that has been transformed into a hydroxide anion exchange resin through acid activation and alkali activation treatment; (2) Secondary separation of ampicillin sodium crystal mother liquor The analytical solution obtained in the above step (1) is passed through a macroporous adsorption resin, where the isooctanoic acid is adsorbed on the resin, while the ampicillin hydrochloride is not adsorbed by the resin and flows through the resin with the solution, thereby obtaining an ampicillin hydrochloride solution. The ampicillin hydrochloride solution is concentrated by a high-pressure reverse osmosis membrane, and the obtained concentrated solution is crystallized at the isoelectric point to obtain ampicillin; The isooctanoic acid adsorbed on the resin is decomposed using an alkoxide solution to obtain an isooctanoic acid salt decomposition solution, and the isooctanoic acid salt decomposition solution is distilled to remove the solvent to obtain isooctanoic acid salt.

2. The comprehensive recovery method of ampicillin sodium crystal mother liquor according to claim 1, characterized in that: The pH value of the ampicillin sodium crystallization mother liquor is 9.0-10.0; the ampicillin sodium content in the ampicillin sodium crystallization mother liquor is 8.0 mg / mL-12.0 mg / mL, calculated as anhydrous ampicillin; and the content of diisopropylamine isooctanoate is 60.0 mg / mL-95.0 mg / mL, calculated as isooctanoic acid.

3. The comprehensive recovery method of ampicillin sodium crystal mother liquor according to claim 1 or 2, characterized in that In the primary separation of the ampicillin sodium crystal mother liquor in the step (1), the anion exchange resin is a weakly basic anion exchange resin, and is an anion exchange resin having brown or brown spherical particles, particles with a particle size of 0.4 mm to 1.25 mm accounting for ≥95% of the total particles, and a mass full exchange capacity ≥5.5 mmol / g.

4. The comprehensive recovery method of ampicillin sodium crystal mother liquor according to claim 3, characterized in that In the primary separation of the ampicillin sodium crystal mother liquor in the step (1), the hydroxide-type anion exchange resin is transformed into the anion exchange resin by treating the anion exchange resin according to the following method: after the anion exchange resin is loaded into a column, the anion exchange resin is activated with a 4wt% to 5wt% hydrochloric acid solution, and then rinsed with purified water until the eluate is neutral and the conductivity is less than 50μs / cm; then, the resin is activated with a 4wt% to 5wt% sodium hydroxide solution to transform it into the hydroxide type, and then rinsed with purified water until it is neutral and the conductivity is less than 50μs / cm.

5. The comprehensive recovery method of ampicillin sodium crystal mother liquor according to claim 4, characterized in that In the primary separation of the ampicillin sodium crystallization mother liquor in the step (1), the hydroxide-type anion exchange resin is applied in the form of a circular resin column bed by wet column packing, and the height-to-diameter ratio of the circular resin column bed is greater than or equal to 4. The ampicillin sodium crystallization mother liquor passes through the resin column bed at a flow rate of 1.0 to 3.0 times the total volume of the resin per hour, and the ampicillin acid anion and the isooctanoic acid anion are adsorbed on the resin through ion exchange. Diisopropylamine and the organic solvent flow through the resin, and the flow-through is collected. Then, the resin column bed is rinsed with purified water at the same flow rate of 1.0 to 3.0 times the total volume of the resin to remove the residual solvent components in the column and merged into the flow-through.

6. The comprehensive recovery method of ampicillin sodium crystal mother liquor according to claim 1 or 2, characterized in that In the primary separation of the ampicillin sodium crystal mother liquor in step (1), the molar concentration of hydrochloric acid as an analytical agent is between 2.0 and 4.0 mol / L, the flow rate of the analytical agent is 0.5 to 1.0 times the total volume of the resin per hour, and the amount of the analytical agent is 1.0 to 2.0 times the total volume of the resin; after the analysis is completed, the resin column is rinsed with purified water in an amount of 0.5 to 1.0 times the total volume of the resin, and the collected liquid is added to the analytical solution; the analytical solution has a pH of 0.5 to 1.0, contains 20 mg / mL to 30 mg / mL of ampicillin hydrochloride, calculated as anhydrous ampicillin, and contains 160 mg / mL to 220 mg / mL of isooctanoic acid, calculated as isooctanoic acid.

7. The comprehensive recovery method of ampicillin sodium crystal mother liquor according to claim 1 or 2, characterized in that In the secondary separation of the ampicillin sodium crystal mother liquor in the step (2), the macroporous adsorption resin is selected from any one of the macroporous adsorption resins of model LX-033 produced by Gaoling Lanxiao Technology New Materials Co., Ltd. and model DM-700 produced by Aimigene (China) Biopharmaceutical Co., Ltd.; the macroporous adsorption resin is rinsed with methanol in an amount of 2.0 to 3.0 times the total volume of the macroporous adsorption resin before use, and then rinsed with purified water until there is no methanol smell at the resin outlet before use; the macroporous adsorption resin is applied in the form of a circular resin column bed by wet column packing, and the height to diameter ratio of the circular resin column bed is greater than or equal to 4.

8. The comprehensive recovery method of ampicillin sodium crystal mother liquor according to claim 7, characterized in that In the secondary separation of the ampicillin sodium crystal mother liquor in the step (2), the analytical solution obtained in the above step (1) is passed through a macroporous adsorption resin and passed through the resin column bed at a flow rate of 0.5 to 1.0 times the total volume of the resin per hour. The isooctanoic acid in the analytical solution is adsorbed on the resin, while the ampicillin hydrochloride is not adsorbed by the resin and flows through the resin with the solution and is collected as the overflow. After the adsorption is completed, the resin column is then rinsed with purified water at the same flow rate of 2.0 to 3.0 times the total volume of the resin to remove the residual ampicillin hydrochloride in the column and merged into the overflow. This part of the overflow contains ampicillin hydrochloride, that is, the ampicillin hydrochloride solution.

9. The comprehensive recovery method of ampicillin sodium crystal mother liquor according to claim 1 or 2, characterized in that In the secondary separation of the ampicillin sodium crystal mother liquor in step (2), a methanol solution of sodium methoxide or an ethanol solution of sodium ethoxide is used to desorb the isooctanoic acid adsorbed on the resin at a flow rate of 0.5 to 1.0 times the total volume of the resin per hour. After desorption, the sodium isooctanoate remaining in the resin is washed with alcohol in an amount of 0.5 to 1.0 times the total volume of the resin, and the collected liquid is added to the desorption liquid. The sodium isooctanoate concentration of the desorption liquid collected in this process is 150 mg / mL to 300 mg / mL, measured in terms of isooctanoic acid, wherein the amount of sodium methoxide or sodium ethoxide is calculated according to the molar ratio of 1:1 based on the adsorption amount of isooctanoic acid.

10. The comprehensive recovery method of ampicillin sodium crystal mother liquor according to claim 1 or 2, characterized in that In the secondary separation of the ampicillin sodium crystal mother liquor in step (2), the ampicillin hydrochloride solution collected above is concentrated at 10°C to 30°C using a high-pressure reverse osmosis membrane to obtain an ampicillin hydrochloride concentrate having a concentration of 60 to 100 mg / mL based on anhydrous ampicillin acid; the concentrate is then cooled to 0 to 10°C, and aqueous ammonia is added to the concentrate. After crystals precipitate in the solution, the addition of aqueous ammonia is stopped, and the crystals are grown for 20 to 30 minutes. Ammonia is then added dropwise until the pH is 4.5 to 5.5, and the crystals are grown for 120 to 240 minutes. After the crystals are grown, the concentrate is filtered, washed, and dried to obtain ampicillin.