Preparation method of ampicillin sodium

Abstract

The invention belongs to the technical field of pharmacy, and relates to a preparation method of ampicillin sodium. The preparation method comprises the following steps: mixing ampicillin acid and sodium type cation exchange resin in water according to a certain proportion, stirring and dissolving, filtering to obtain an ampicillin sodium solution, and concentrating and freeze-drying to obtain the ampicillin sodium with the quality meeting the standard. According to the preparation method, the raw material ampicillin acid does not need to be dehydrated, any organic solvent does not need to be used, the ampicillin acid can be directly converted into the ampicillin sodium only through the cation exchange resin, the process design is innovative, the operation is simple and convenient, the energy consumption is low, and the obtained ampicillin sodium product is high in quality and stable.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and relates to a method for preparing ampicillin sodium. More specifically, it relates to a salt-forming method in which ampicillin acid is directly converted into ampicillin sodium through a cation exchange resin. Background Art

[0002] Ampicillin sodium is obtained by converting ampicillin acid into its salt form through a specific chemical reaction. This conversion process not only endows ampicillin sodium with unique chemical properties but also significantly improves its stability and solubility, making it a drug with important medical applications. As a salt derivative of ampicillin acid, ampicillin sodium retains the antibacterial activity of the original drug while being more easily absorbed and utilized by the human body. It is widely used clinically to treat a variety of infections caused by sensitive bacteria, such as respiratory and urinary tract infections, providing strong support for patient recovery. Therefore, the conversion products of ampicillin sodium are not only unique but also hold irreplaceable importance in the medical field.

[0003] Currently, there are two main methods for preparing ampicillin sodium: freeze-drying and solvent crystallization. The freeze-drying method requires the use of a strong base, sodium hydroxide. During the conversion of ampicillin acid to ampicillin sodium, the β-lactam ring is easily destroyed and degraded. The resulting product's quality indicators, including content, impurities, and stability, are inferior to those of the solvent crystallization method. The solvent crystallization method involves dissolving ampicillin acid in an organic solvent using an organic base, then adding an organic salt-forming agent containing sodium ions to cause a double decomposition reaction to produce ampicillin sodium. This method offers superior product quality to the freeze-drying method, but it also suffers from low yields and high costs. Furthermore, the dissolution and salt-forming process uses large amounts of various organic solvents, significantly impacting product quality, particularly its crystal morphology, particle size distribution, stability, and bioavailability. Furthermore, the use of organic solvents poses significant challenges to production safety, personnel health, and the environment. The existing preparation process of ampicillin sodium has certain defects. How to achieve the conversion of ampicillin acid to ampicillin sodium in a high-yield, high-quality, environmentally friendly and low-cost manner is of great practical significance, and it is necessary to continue research and improvement. 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 method for preparing ampicillin sodium. This method does not require dehydration of the raw material ampicillin acid and does not require the use of any organic solvent. Ampicillin acid can be directly converted into ampicillin sodium using only a cation exchange resin. The process design is innovative, the operation is simple, the energy consumption is low, and the obtained ampicillin sodium product is high-quality and stable.

[0006] Technical Solution

[0007] In order to achieve the above-mentioned purpose of the present invention, the technical solution adopted by the present invention is: ampicillin acid and sodium type cation exchange resin are mixed in water in a certain proportion, stirred to dissolve and filtered to obtain ampicillin sodium solution, and then concentrated and freeze-dried to obtain ampicillin sodium that meets the product quality standards.

[0008] According to the present invention, the preparation method of ampicillin sodium provided by the present invention comprises:

[0009] Ampicillin acid and sodium cation exchange resin are added to water and stirred to convert the ampicillin acid into ampicillin sodium and dissolve it; then the resin is removed by filtration to obtain an ampicillin sodium solution, and the ampicillin sodium solution is concentrated and freeze-dried to obtain ampicillin sodium.

[0010] Beneficial effects

[0011] In this invention, sodium cation exchange resin is creatively used to successfully convert ampicillin acid into ampicillin sodium. High-pressure reverse osmosis membrane concentration and freeze-drying are then used to prepare ampicillin sodium. This method eliminates the need for dehydration of the ampicillin acid raw material, significantly improving production efficiency. It also eliminates the large amounts of organic solvents and inorganic bases used in traditional salt-forming processes, significantly enhancing process safety and product quality.

[0012] Taking the above advantages into consideration, compared with the existing conventional technology, the present invention is more suitable for promotion and application in industrial production. DETAILED DESCRIPTION

[0013] The following describes the method for preparing ampicillin sodium according to 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, and to fully illustrate the present invention to those skilled in the art.

[0014] According to an embodiment of the present invention, the present invention provides a method for preparing ampicillin sodium, comprising: adding ampicillin acid and a sodium-type cation exchange resin to water, stirring to convert the ampicillin acid into ampicillin sodium and dissolve it; then filtering to remove the resin to obtain an ampicillin sodium solution, and concentrating and freeze-drying the ampicillin sodium solution to obtain ampicillin sodium.

[0015] Among them, ampicillin acid, also known as ampicillin and ampicillin trihydrate, contains 3 crystal waters.

[0016] The sodium-type cation exchange resin used may be a sodium-type strongly acidic cation exchange resin. For example, the sodium-type cation exchange resins LXT-101 and LXT-105 produced by Gaoling Lanxiao Technology New Materials Co., Ltd. may be selected.

[0017] Newly purchased sodium cation exchange resins generally require activation and regeneration before use to remove residual substances from the resin preparation process. Specifically, the sodium cation exchange resin is acid-activated to hydrogen cation exchange resin, and then treated with a sodium chloride aqueous solution to convert it back to sodium cation exchange resin. Specifically, the sodium cation exchange resin is treated before use as follows: after loading the sodium cation exchange resin into a column, it is activated with a 0.5-1.0 mol / L hydrochloric acid solution, then rinsed with purified water until the eluate is neutral and has a conductivity of less than 50 μs / cm. Next, the resin is treated with a 1.0-2.0 mol / L sodium chloride aqueous solution to convert it to the sodium ion form, and then rinsed with purified water until the eluate is free of sodium chloride and has a conductivity of less than 50 μs / cm. This ensures that the hydrogen ions on the cation exchange resin are completely replaced by sodium ions and that excess sodium chloride is removed by washing to prevent it from being introduced into the reaction system. After the resin has been treated as described above, it is removed from the column and filtered to remove moisture before use.

[0018] During the conversion of ampicillin acid, the conversion temperature is maintained at 20°C to 45°C, preferably 30°C to 35°C. Purified water can be used. Specifically, purified water is added to a reaction vessel and preheated to the aforementioned temperature range. Ampicillin acid is then added thereto; the ampicillin acid does not dissolve and becomes turbid under stirring. A sodium cation exchange resin is then added, and stirring is continued while maintaining the reaction system within the aforementioned temperature range. The amounts of ampicillin acid, sodium cation exchange resin, and purified water are such that the mass ratio of ampicillin acid, sodium cation exchange resin, and purified water can be 1:2 to 4:5 to 8, preferably 1:2 to 3:5 to 6. After the conversion reaction begins, the free hydrogen ions in ampicillin acid exchange with the sodium ions on the sodium cation exchange resin, transforming the sodium cation exchange resin into a hydrogen cation exchange resin. The ampicillin acid is converted into ampicillin sodium, and the reaction system gradually dissolves from its initial turbidity. When the reaction system becomes clear and transparent, the reaction is complete, and the ampicillin acid has been completely converted into ampicillin sodium. The resin is then removed by conventional filtration to obtain an ampicillin sodium solution. This solution typically has a pH of 8.0 to 9.5, and an ampicillin sodium concentration of 100 to 160 mg / ml (based on anhydrous ampicillin acid).

[0019] The ampicillin sodium solution obtained above is concentrated and freeze-dried to obtain ampicillin sodium. Specifically, the ampicillin sodium 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 sodium concentrate obtained after concentration using the high-pressure reverse osmosis membrane at 10°C to 30°C can have a concentration of 300-350 mg / mL, calculated as anhydrous ampicillin acid, and a liquid phase purity greater than 98% (HPLC peak area percentage).

[0020] The ampicillin sodium concentrate is then dried using a freeze-drying process to obtain ampicillin sodium that meets product quality standards. The freeze-drying process is divided into three stages:

[0021] Stage 1: Refrigeration Control Stage; This stage's primary purpose is to fully freeze the ampicillin sodium aqueous solution. Cool the freezer's shelves (the movable plates in contact with the material) to -40.0±5.0°C over 30-60 minutes. Maintain this temperature for 120-180 minutes to ensure the ampicillin sodium aqueous solution is fully frozen. Finally, vacuum the solution to ≤0.2 mbar.

[0022] The second stage is the primary drying stage; this stage's primary purpose is to sublimely remove most of the water from the ampicillin sodium that was fully frozen in the first stage. This stage utilizes a programmed temperature ramp, divided into three stages. Each stage includes a ramp time, temperature duration, and vacuum level. Upon completion of the program, the next stage automatically begins. The first heating stage: the shelf in the freezer is heated to -15.0±5.0°C within 30 minutes, and then maintained at this temperature for 120-180 minutes, while the vacuum degree is maintained at ≤0.3 mbar; the second heating stage: the shelf in the freezer is heated to 0±5.0°C within 10 minutes, and then maintained at this temperature for 90-150 minutes, while the vacuum degree is maintained at ≤0.4 mbar; the third heating stage: the shelf in the freezer is heated to 25.0±5.0°C within 30 minutes, and then maintained at this temperature for 180-240 minutes, while the vacuum degree is maintained at ≤0.5 mbar; after the second stage of programmed heating, most of the water in ampicillin sodium is sublimated and removed.

[0023] The third stage, the desorption and drying stage, further removes residual moisture from ampicillin sodium. The freezer shelf is heated to 45.0±5.0°C over 15 minutes and then maintained at this temperature for 180-240 minutes, with a vacuum level maintained at ≤0.6 mbar. After this stage, the residual moisture in the ampicillin sodium product meets quality standards.

[0024] The preparation method of ampicillin sodium of the present invention is further described in detail below through examples. The protection scope of the present invention is not limited to the following examples. These examples are listed only for illustrative purposes and do not limit the present invention in any way.

[0025] Treatment of resin before use

[0026] Sodium cation exchange resin (LXT-101 model, from Gaoling Lanxiao Technology New Materials Co., Ltd.) was activated and regenerated according to the following method: after the sodium cation exchange resin was loaded into a column, it was activated with a 0.5-1.0 mol / L 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 transformed into a sodium ion type by treating it with a 1.0-2.0 mol / L sodium chloride aqueous solution, and then rinsed with purified water until the eluate did not contain sodium chloride and the conductivity was less than 50 μs / cm; after the resin was treated as described above, the resin was removed from the column, filtered to remove water, and set aside.

[0027] Example 1

[0028] Add 5 kg of purified water to a 10 L reactor, preheat to 35 ° C, add 1 kg of ampicillin acid (containing three crystal waters), and then add the treated sodium cation exchange resin (dry weight before treatment 2 kg) and continue stirring while maintaining the reaction system at 35 ° C. When the reaction system is clear, the reaction is completed and filtered to obtain 5.42 L of ampicillin sodium solution with a pH of 8.65 and an ampicillin sodium concentration of 157 mg / ml (calculated as anhydrous ampicillin acid); then, at 20°C, the ampicillin sodium solution is concentrated using a high-pressure reverse osmosis membrane (RO100 membrane provided by Shanghai Kaixin Separation Technology Co., Ltd.) to obtain 2.60 L of concentrate, in which the concentration of ampicillin sodium is 323 mg / ml (calculated as anhydrous ampicillin acid), and its liquid phase purity reaches 98.7%; then, the aforementioned freeze-drying process is used to freeze-dry the ampicillin sodium concentrate to obtain 898 g of ampicillin sodium, and the product molar yield is 95.6%. The product quality meets the standards according to the 2020 edition of the Chinese Pharmacopoeia. For specific test results, please see Table 1 below.

[0029] Example 2

[0030] Add 5 kg of purified water to a 10 L reactor, preheat to 30 ° C, add 1 kg of ampicillin acid (containing three crystal waters), and then add the treated sodium cation exchange resin (dry weight before treatment 3 kg) and continue stirring while maintaining the reaction system at 30 ° C. When the reaction system is clear, the reaction is completed and filtered to obtain 5.45 L of ampicillin sodium solution with a pH of 8.85 and an ampicillin sodium concentration of 154 mg / ml (calculated as anhydrous ampicillin acid); then, at 30°C, the ampicillin sodium solution is concentrated using a high-pressure reverse osmosis membrane (RO100 membrane provided by Shanghai Kaixin Separation Technology Co., Ltd.) to obtain 2.45 L of concentrate, in which the ampicillin sodium concentration is 336 mg / ml (calculated as anhydrous ampicillin acid), and its liquid phase purity reaches 98.4%; then, the aforementioned freeze-drying process is used to freeze-dry the ampicillin sodium concentrate to obtain 881 grams of ampicillin sodium, and the product molar yield is 93.5%. The product quality meets the standards according to the 2020 edition of the Chinese Pharmacopoeia. For specific test results, please see Table 1 below.

[0031] Example 3

[0032] Add 6 kg of purified water to a 10 L reactor, preheat to 30 ° C, add 1 kg of ampicillin acid (containing three crystal waters), and then add the treated sodium cation exchange resin (dry weight before treatment 2 kg) and continue stirring while maintaining the reaction system at 30 ° C. When the reaction system is clear, the reaction is completed and filtered to obtain 6.44 L of ampicillin sodium solution with a pH of 8.49 and an ampicillin sodium concentration of 133 mg / ml (calculated as anhydrous ampicillin acid); then, at 10°C, the ampicillin sodium solution is concentrated using a high-pressure reverse osmosis membrane (RO100 membrane provided by Shanghai Kaixin Separation Technology Co., Ltd.) to obtain 2.54 L of concentrate, in which the ampicillin sodium concentration is 334 mg / ml (calculated as anhydrous ampicillin acid), and its liquid phase purity reaches 98.9%; then, the aforementioned freeze-drying process is used to freeze-dry the ampicillin sodium concentrate to obtain 907 grams of ampicillin sodium, and the product molar yield is 96.8%. The product quality meets the standards according to the 2020 edition of the Chinese Pharmacopoeia. For specific test results, please see Table 1 below.

[0033] Table 1: Summary of test results of ampicillin sodium products in Examples 1-3:

[0034]

Claims

1. A method for preparing ampicillin sodium, comprising: Add ampicillin acid and sodium cation exchange resin into water and stir to convert ampicillin acid into ampicillin sodium and dissolve it; Then, the resin is removed by filtration to obtain an ampicillin sodium solution, which is concentrated and freeze-dried to obtain ampicillin sodium.

2. The method for preparing ampicillin sodium according to claim 1, wherein: The sodium type cation exchange resin is a sodium type strongly acidic cation exchange resin.

3. The method for preparing ampicillin sodium according to claim 1, wherein: The sodium type cation exchange resin is selected from the sodium type cation exchange resins of LXT-101 and LXT-105 produced by Gaoling Lanxiao Technology New Materials Co., Ltd.

4. The method for preparing ampicillin sodium according to claim 1, wherein: The sodium type cation exchange resin is activated and regenerated before use to remove residual substances in the resin preparation process. That is, the sodium type cation exchange resin is activated by acid to become a hydrogen type cation exchange resin, and then treated with a sodium chloride aqueous solution to transform it into a sodium type cation exchange resin.

5. The method for preparing ampicillin sodium according to claim 1, wherein: The sodium-type cation exchange resin is treated according to the following method before use: after the sodium-type cation exchange resin is loaded into a column, the sodium-type cation exchange resin is activated with a 0.5-1.0 mol / L hydrochloric acid solution, and then rinsed with purified water until the eluate is neutral and the conductivity is lower than 50 μs / cm; then, the resin is transformed into a sodium ion type by treating it with a 1.0-2.0 mol / L sodium chloride aqueous solution, and then rinsed with purified water until the eluate does not contain sodium chloride and the conductivity is lower than 50 μs / cm.

6. The method for preparing ampicillin sodium according to claim 1, wherein: Purified water is added to the reaction vessel and preheated to 20°C to 45°C. Ampicillin acid is then added thereto. Ampicillin acid does not dissolve and becomes turbid under stirring. Sodium cation exchange resin is then added, and stirring is continued while maintaining the reaction system within the above temperature range.

7. The method for preparing ampicillin sodium according to claim 6, wherein the ampicillin sodium The amount of ampicillin acid, sodium type cation exchange resin and purified water is such that the mass ratio of ampicillin acid, sodium type cation exchange resin and purified water is 1:2-4:5-8, preferably 1:2-3:5-6.

8. The method for preparing ampicillin sodium according to claim 1, wherein: The ampicillin sodium solution obtained after removing the resin by filtration has a pH of 8.0 to 9.5 and an ampicillin sodium concentration of 100 to 160 mg / ml, calculated as anhydrous ampicillin acid.

9. The method for preparing ampicillin sodium according to claim 1, wherein: Under the condition of 10℃~30℃, the ampicillin sodium solution is concentrated using a high-pressure reverse osmosis membrane, which is a composite membrane composed of a polyester non-woven fabric layer, a polysulfone porous intermediate support layer and a polyamide separation layer.

10. The method for preparing ampicillin sodium according to claim 9, wherein: The concentration of the ampicillin sodium concentrated solution obtained after concentration reaches 300-350 mg / mL based on anhydrous ampicillin acid, and the liquid phase purity thereof is greater than 98%.

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