Method for recovering effective components from ampicillin sodium crystallization mother liquor

Abstract

The invention belongs to the technical field of pharmacy, and relates to a method for recovering effective components from ampicillin sodium crystallization mother liquor, which comprises the steps of diisopropylamine recovery, ampicillin trihydrate acid recovery and sodium isooctanoate recovery. According to the method, the diisopropylamine, the ampicillin trihydrate and the sodium isooctanoate are effectively recovered from the solvent-method ampicillin sodium crystallization mother liquor, the recovery rates of the diisopropylamine, the ampicillin trihydrate and the sodium isooctanoate recovered by the method are all higher than 80%, and the quality of the recovered product is good. According to the method, various effective components of the ampicillin sodium crystallization mother liquor are effectively recovered, the production cost can be greatly reduced, meanwhile, the discharge amount of sewage is reduced, and the economic benefits and social benefits of enterprises are improved.

Description

Technical Field

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

[0002] Ampicillin sodium is a broad-spectrum semi-synthetic penicillin antibiotic drug compound that exerts its bactericidal effect by inhibiting bacterial cell wall synthesis. It has a strong antibacterial effect against hemolytic streptococci, streptococci pneumoniae and non-penicillinase-producing Staphylococci. It has the characteristics of low toxicity, broad spectrum, high efficiency and low cost, and is widely used in clinical practice.

[0003] Currently, there are three methods for producing ampicillin sodium: spray drying, freeze drying, and solvent crystallization. Solvent crystallization produces ampicillin sodium of superior quality to the other two methods, making it a widely used method. For example, Chinese patent document CN115448930A discloses a method for preparing ampicillin sodium using solvent crystallization. The method involves dehydrating ampicillin trihydrate with an organic solvent. The dehydrated ampicillin acid reacts with diisopropylamine in a mixed organic solvent (e.g., a mixed solvent of isopropyl alcohol and ethyl acetate) to produce ampicillin diisopropylamine salt. The resulting product is then crystallized with sodium isooctanoate dissolved in the mixed organic solvent (e.g., a mixed solvent of isopropyl alcohol and ethyl acetate). The product is filtered, washed, and dried to obtain the finished ampicillin sodium. At this time, the filtrate collected by filtration is the crystallization mother liquor of ampicillin sodium, which, in addition to the organic solvent (e.g., a mixed solvent of isopropyl alcohol and ethyl acetate), still contains residual ampicillin sodium, diisopropylamine salt of isooctanoate, diisopropylamine, etc. Currently, the industry only recycles the organic solvent, and organic substances such as diisopropylamine salt of isooctanoate in the kettle residue after recovery are discharged into the sewage system, which not only pollutes the environment but also causes a waste of resources. Therefore, recovering diisopropylamine, ampicillin trihydrate, and sodium isooctanoate from the crystallization mother liquor of ampicillin sodium can not only reduce environmental pollution and reuse resources, but also reduce production costs and improve the economic benefits of the enterprise. Summary of the Invention

[0004] Technical issues

[0005] Therefore, the object of the present invention is to provide a method for recovering diisopropylamine, ampicillin trihydrate and sodium isooctanoate from ampicillin sodium crystallization mother liquor, which can simultaneously recover multiple active ingredients, save production costs, reduce pollution, and have good product quality.

[0006] Technical Solution

[0007] According to the present invention, the present invention provides a method for recovering diisopropylamine, ampicillin trihydrate and sodium isooctanoate from ampicillin sodium crystallization mother liquor, the method comprising the following steps:

[0008] (1) Recovery of diisopropylamine

[0009] The mother liquor of ampicillin sodium crystallization is adjusted to a temperature of 0°C to 25°C and its pH is adjusted to 5 to 7 with concentrated sulfuric acid, so that diisopropylamine octanoate and diisopropylamine in the mother liquor are converted into diisopropylamine sulfate and crystallized, filtered and dried to obtain a diisopropylamine sulfate solid, and the filtrate is collected; the diisopropylamine sulfate solid is dissolved in water, the pH is adjusted to pH>13 with an alkali, stirred, heated to 40°C to 45°C, and allowed to stand for separation, whereby the upper layer is the crude diisopropylamine product and the lower layer is the aqueous phase;

[0010] (2) Recovery of Ampicillin Trihydrate

[0011] Add 1 to 3 times the volume of water to the filtrate collected in step (1), and then adjust the pH to 0.5 to 2 with hydrochloric acid or sulfuric acid to convert ampicillin sodium into ampicillin and dissolve it in water. Allow the phases to stand for separation to obtain an organic phase and an aqueous phase. After removing the residual organic solvent from the aqueous phase by vacuum distillation or evaporation using a vacuum thin film evaporator, nanofiltration and concentration are performed. The resulting concentrate is adjusted to a pH of ampicillin's isoelectric point with alkali for crystallization. After growing the crystals, filtering, and drying, ampicillin trihydrate crystals are obtained.

[0012] (3) Recovery of Sodium 2-ethylhexanoate

[0013] The organic phase obtained by layering in step (2) is subjected to reduced pressure distillation to recover the organic solvent, and water is added to the obtained kettle bottom liquid, stirred, and allowed to stand for layering. The upper oil phase is isooctanoic acid, and the upper oil phase is washed with water, and allowed to stand for layering to obtain a purified isooctanoic acid liquid; a methanol solution of sodium methoxide is added dropwise to the obtained isooctanoic acid liquid to carry out a salt-forming reaction to adjust the pH to 7.8-8.2, and then the solvent is evaporated from the reaction liquid to obtain sodium isooctanoate.

[0014] Next, combine Figure 1 , the method of recovering diisopropylamine, ampicillin trihydrate and sodium isooctanoate from ampicillin sodium crystallization mother liquor of the present invention is described in more detail.

[0015] Figure 1 1 is a process flow chart of the method for recovering diisopropylamine, ampicillin trihydrate and sodium isooctanoate from ampicillin sodium crystallization mother liquor of the present invention, as shown in FIG. Figure 1 The method comprises the recovery of diisopropylamine, the recovery of ampicillin trihydrate and the recovery of sodium isooctanoate.

[0016] As described above, in the solvent crystallization process for preparing ampicillin sodium, for example, Chinese patent document CN115448930A discloses a method for preparing ampicillin sodium. First, ampicillin trihydrate is dehydrated with an organic solvent. The dehydrated ampicillin acid reacts with diisopropylamine in a mixed organic solvent (e.g., a mixed solvent of isopropyl alcohol and ethyl acetate) to form ampicillin diisopropylamine salt. This salt is then crystallized with sodium isooctanoate dissolved in the mixed organic solvent (e.g., a mixed solvent of isopropyl alcohol and ethyl acetate). The finished ampicillin sodium product is obtained through filtration, washing, and drying. The filtrate collected by filtration is the mother liquor for the crystallization of ampicillin sodium, which contains, in addition to the organic solvent (e.g., a mixed solvent of isopropyl alcohol and ethyl acetate), residual ampicillin sodium, diisopropylamine isooctanoate, diisopropylamine, and the like. Specifically, in the ampicillin sodium crystallization mother liquor, as measured by liquid chromatography, the ampicillin sodium content (calculated as anhydrous ampicillin) is approximately 4 mg / ml to 8 mg / ml, the diisopropylamine isooctanoate content (calculated as isooctanoic acid) is approximately 30 mg / ml to 45 mg / ml, and the diisopropylamine isooctanoate and diisopropylamine contents (calculated as diisopropylamine) are approximately 70 mg / ml to 90 mg / ml.

[0017] Specifically, in the step (1) of recovering diisopropylamine, the temperature of the ampicillin sodium crystallization mother liquor is adjusted to 0°C to 25°C, and preferably 15°C to 20°C, and then the pH thereof is adjusted to 5 to 7 with concentrated sulfuric acid, preferably 5 to 7 with concentrated sulfuric acid having a concentration of 80wt% to 98wt%, and preferably 6 to 6.5, so that diisopropylamine octanoate and diisopropylamine in the mother liquor are converted into diisopropylamine sulfate and crystallized, filtered and dried to obtain diisopropylamine sulfate solid, and the filtrate is collected; the diisopropylamine sulfate solid is dissolved in water, the pH thereof is adjusted to pH>13 with alkali, stirred, heated to 40°C to 45°C, and allowed to stand for separation, with the upper layer being the crude diisopropylamine and the lower layer being the aqueous phase.

[0018] More specifically, the diisopropylamine sulfate solid is dissolved in water, 1 to 20 ml of water, preferably 2 to 10 ml of water, is added per gram of diisopropylamine sulfate, and the solution is stirred and dissolved. After the solution is dissolved, the pH is adjusted to pH>13 with an alkali, wherein the alkali can be solid sodium hydroxide, potassium hydroxide, or a mixture thereof, or a sodium hydroxide solution, potassium hydroxide solution, or a mixed solution thereof, wherein the concentration of the sodium hydroxide solution or potassium hydroxide solution is preferably 25 wt% to 35 wt%. The solution is then stirred, heated to 40° C. to 45° C., and allowed to stand for separation, with the upper layer being the crude diisopropylamine product and the lower layer being the aqueous phase. The upper layer of the crude diisopropylamine product can be dried with solid sodium hydroxide and decolorized with activated carbon to obtain purified diisopropylamine.

[0019] In the step (2) of recovering ampicillin trihydrate, water in an amount of 1 to 3 times the volume of the filtrate collected in the above step (1) is added to the filtrate collected, and then the pH thereof is adjusted to 0.5 to 2 with hydrochloric acid or sulfuric acid, so that ampicillin sodium is converted into ampicillin and dissolved in water. The phases are allowed to stand for phase separation to obtain an organic phase and an aqueous phase. The aqueous phase is subjected to reduced pressure distillation or evaporation using a vacuum thin film evaporator to remove residual organic solvent, and then nanofiltration concentration is performed. The obtained concentrate is adjusted to a pH of ampicillin isoelectric point with alkali for crystallization, and the crystals are grown, filtered, and dried to obtain ampicillin trihydrate crystals.

[0020] The ampicillin trihydrate, also known as ampicillin or ampicillin trihydrate, contains three crystal waters and has the following structural formula:

[0021]

[0022] Specifically, 1 to 3 times the volume of water, preferably 1 to 1.8 times the volume of water, is added to the filtrate collected in the above step (1), and then the pH is adjusted to 0.5 to 2, preferably 0.8 to 1.5, with hydrochloric acid or sulfuric acid, so that ampicillin sodium is converted into ampicillin and dissolved in water. The phases are allowed to stand and separate to obtain an organic phase and an aqueous phase, wherein the hydrochloric acid may have a concentration of 15 wt% to 20 wt%, and the sulfuric acid may have a concentration of 10 wt% to 20 wt%.

[0023] Then, the aqueous phase is taken and quickly subjected to reduced pressure distillation to remove the residual organic solvent. For example, at a relatively low temperature, preferably a temperature ≤ 30°C and a vacuum degree of -0.08 MPa to -0.09 MPa, the residual organic solvent is removed by reduced pressure distillation. Alternatively, a vacuum thin film evaporator is used for evaporation to quickly remove the residual organic solvent. The aqueous phase after the organic solvent is removed, i.e., the ampicillin solution, is concentrated by nanofiltration using a nanofiltration membrane and concentrated 5 to 20 times, preferably 8 to 15 times. The concentrated solution obtained after concentration is adjusted to a pH of ampicillin isoelectric point crystallization with alkali, for example, ammonia water can be used to adjust the pH to 4.5 to 5.5, and ampicillin trihydrate crystals are crystallized and precipitated. After crystal growth, filtration, and drying, ampicillin trihydrate crystals are obtained.

[0024] In the step (3) of recovering sodium isooctanoate, the organic phase obtained by layering in step (2) is subjected to reduced pressure distillation to recover the organic solvent, and water is added to the obtained kettle bottom liquid, stirred, and allowed to stand for layering. The upper oil phase is isooctanoic acid, and the upper oil phase is washed with water, and allowed to stand for layering to obtain a purified isooctanoic acid liquid; a methanol solution of sodium methoxide is added dropwise to the obtained isooctanoic acid liquid to carry out a salt-forming reaction to adjust the pH to 7.8-8.2, and then the solvent is evaporated from the reaction liquid to obtain sodium isooctanoate.

[0025] Specifically, the organic phase obtained by layering in step (2) is subjected to reduced pressure distillation to recover the organic solvents isopropanol and ethyl acetate, and 0.5 to 5 times the volume of water, preferably 0.8 to 1.5 times the volume of water, is added to the obtained kettle bottom liquid, and then stirred and allowed to stand for layering. The upper oil phase is isooctanoic acid, and the upper oil phase is washed with 0.8 to 1.5 times the volume of water, and allowed to stand for layering to obtain a purified isooctanoic acid liquid; a methanol solution of sodium methoxide, for example, a 25wt% methanol solution of sodium methoxide, is added dropwise to the obtained isooctanoic acid liquid to carry out a salt-forming reaction, wherein the methanol solution of sodium methoxide is added dropwise until the pH is 7.8 to 8.2, and then the solvent is evaporated from the reaction solution to obtain sodium isooctanoate.

[0026] Beneficial effects

[0027] The present invention effectively recovers diisopropylamine, ampicillin trihydrate, and sodium isooctanoate from the mother liquor of ampicillin sodium crystallization by the solvent process. The recovery rates of diisopropylamine, ampicillin trihydrate, and sodium isooctanoate are all greater than 80%, and the recovered products are of high quality. The present invention effectively recovers multiple active ingredients from the mother liquor of ampicillin sodium crystallization, significantly reducing production costs, while also reducing wastewater discharge and improving the economic benefits of the enterprise. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The present invention is a process flow chart of a method for recovering diisopropylamine, ampicillin trihydrate and sodium isooctanoate from ampicillin sodium crystallization mother liquor. DETAILED DESCRIPTION

[0029] Below, the method of recovering diisopropylamine, ampicillin trihydrate and sodium isooctanoate from the ampicillin sodium crystallization mother liquor of the present invention is further described in detail 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.

[0030] Example 1

[0031] (1) Recovery of diisopropylamine

[0032] 13 L of ampicillin sodium crystallization mother liquor (ampicillin sodium content (calculated as ampicillin anhydrate) 5.23 mg / ml, diisopropylamine octanoate (calculated as isooctanoic acid) content 37.61 mg / ml, diisopropylamine octanoate and diisopropylamine (calculated as diisopropylamine) content 83.35 mg / ml, organic solvent is a mixed solvent of isopropyl alcohol and ethyl acetate) was taken, the temperature of the ampicillin sodium crystallization mother liquor was adjusted to 18° C., and then the pH was adjusted with 98 wt % concentrated sulfuric acid. H is 6.3, so that the diisopropylamine isooctanoate and diisopropylamine in the mother liquor are converted into diisopropylamine sulfate and crystallized. After filtration and drying, a diisopropylamine sulfate solid is obtained, and 12.3 L of filtrate is collected; then, the diisopropylamine sulfate solid is dissolved in 6 L of purified water, stirred to dissolve clearly, and the pH is adjusted to 13.5 with 30 wt % sodium hydroxide solution. The mixture is stirred and heated to about 45° C., and allowed to stand for separation, with the upper layer being the crude diisopropylamine and the lower layer being the aqueous phase.

[0033] Solid sodium hydroxide was added to the separated crude diisopropylamine for drying, and the moisture content was detected to be less than 1.0%. The dried diisopropylamine was then decolorized with activated carbon for 30 minutes. After filtration, 1283 ml of purified diisopropylamine was obtained with a recovery rate of 85.49% and a diisopropylamine purity of 98.2%.

[0034] (2) Ampicillin recovery

[0035] 13 L of purified water was added to 12.3 L of the filtrate collected in step (1) above, and then the pH was adjusted to 1.0 with 20 wt % sulfuric acid to convert ampicillin sodium into ampicillin and dissolve it in water. The mixture was allowed to stand for phase separation to obtain 10.1 L of an organic phase and 15.5 L of an aqueous phase. The aqueous phase was rapidly freed of residual organic solvent using a vacuum thin film evaporator, and then concentrated by nanofiltration to an ampicillin content of 50 mg / ml (based on anhydrous ampicillin). The resulting concentrate was adjusted to a pH of 4.8 with 10% aqueous ammonia, cooled to 5° C., grown for 30 min, filtered, washed, and dried to obtain 63.14 g of ampicillin trihydrate with a yield of 80.43%. The ampicillin content was detected to be 97.2%.

[0036] (3) Recovery of Sodium 2-ethylhexanoate

[0037] 10.1 L of the organic phase obtained by layering in step (2) was subjected to reduced pressure distillation to recover the organic solvents isopropanol and ethyl acetate to obtain 550 ml of a bottom liquid (isooctanoic acid). 600 ml of purified water was added to the obtained bottom liquid, stirred for 15 min, and allowed to stand for layering. The upper oil phase was isooctanoic acid, which was washed with 500 ml of purified water and layered again to obtain 540 ml of an isooctanoic acid liquid. 25 wt % sodium methoxide methanol solution was added dropwise to the isooctanoic acid liquid under stirring to adjust its pH to 8.1, and then the solvent was evaporated to obtain 451.57 g of sodium isooctanoate, with a recovery rate of 80.14%. The sodium isooctanoate content was detected to be 96.76%.

[0038] Recovery calculation:

[0039] Diisopropylamine: Recovery rate = (recovered diisopropylamine volume × diisopropylamine density) / (diisopropylamine content in mother liquor × mother liquor volume) × 100%

[0040] Sodium 2-ethylhexanoate:

[0041]

[0042] Wherein: m1 is the weight of recovered sodium 2-ethylhexanoate;

[0043] M1 is the molecular weight of isooctanoic acid, and M2 is the molecular weight of sodium isooctanoate;

[0044] c is the content of isooctanoic acid in the mother liquor; V is the volume of ampicillin sodium mother liquor.

[0045] Ampicillin trihydrate:

[0046]

[0047] Wherein: m1 is the weight of recovered ampicillin trihydrate;

[0048] M1 is the molecular weight of ampicillin anhydrous acid, and M2 is the molecular weight of ampicillin trihydrate;

[0049] c is the content of ampicillin sodium in the mother liquor (calculated as anhydrous ampicillin);

[0050] V is the volume of ampicillin sodium stock solution.

[0051] Example 2

[0052] (1) Recovery of diisopropylamine

[0053] 13 L of ampicillin sodium crystallization mother liquor (wherein the ampicillin sodium content (as ampicillin anhydrate) is 5.35 mg / ml, the diisopropylamine salt of isooctanoate (as isooctanoic acid) content is 38.12 mg / ml, the diisopropylamine salt of isooctanoate and diisopropylamine (as diisopropylamine) content is 82.86 mg / ml, and the organic solvent is a mixed solvent of isopropyl alcohol and ethyl acetate) is taken. The temperature of the ampicillin sodium crystallization mother liquor is adjusted to about 20° C., and then the temperature is adjusted with 98 wt % concentrated sulfuric acid. The pH value is 6.5, so that the diisopropylamine isooctanoate and diisopropylamine in the mother liquor are converted into diisopropylamine sulfate and crystallized. After filtration and drying, a diisopropylamine sulfate solid is obtained, and 12.2 L of filtrate is collected; then, the diisopropylamine sulfate solid is dissolved in 8 L of purified water, stirred to dissolve clearly, and the pH is adjusted to 13.3 with 30 wt % sodium hydroxide solution. The mixture is stirred and heated to about 45° C., and allowed to stand for separation, with the upper layer being the crude diisopropylamine and the lower layer being the aqueous phase.

[0054] Solid sodium hydroxide was added to the separated crude diisopropylamine for drying, and the moisture content was detected to be less than 1.0%. The dried diisopropylamine was then decolorized with activated carbon for 30 minutes. After filtration, 1279 ml of purified diisopropylamine was obtained with a recovery rate of 85.73% and a diisopropylamine purity of 98.5%.

[0055] (2) Ampicillin recovery

[0056] 15 L of purified water was added to 12.2 L of the filtrate collected in step (1) above, and then the pH was adjusted to 1.1 with 20 wt % sulfuric acid to convert ampicillin sodium into ampicillin and dissolve it in water. The mixture was allowed to stand for phase separation to obtain 10.2 L of an organic phase and 17.3 L of an aqueous phase. The aqueous phase was rapidly freed of residual organic solvent using a vacuum thin film evaporator, and then concentrated by nanofiltration to an ampicillin content of 50 mg / ml (based on anhydrous ampicillin). The resulting concentrate was adjusted to a pH of 5.0 with 10% aqueous ammonia, cooled to 5° C., grown for 30 min, filtered, washed, and dried to obtain 65.23 g of ampicillin trihydrate with a yield of 81.22%. The ampicillin content was detected to be 96.9%.

[0057] (3) Recovery of Sodium 2-ethylhexanoate

[0058] 10.2 L of the organic phase obtained by layering in step (2) was subjected to reduced pressure distillation to recover the organic solvents isopropanol and ethyl acetate to obtain 550 ml of a bottom liquid (isooctanoic acid). 700 ml of purified water was added to the obtained bottom liquid, stirred for 15 minutes, and allowed to stand for stratification. The upper oil phase was isooctanoic acid, which was washed with 700 ml of purified water and layered again to obtain 545 ml of an isooctanoic acid liquid. 25 wt % sodium methoxide methanol solution was added dropwise to the isooctanoic acid liquid under stirring to adjust its pH to 7.9, and then the solvent was evaporated to obtain 458.27 g of sodium isooctanoate with a recovery rate of 80.24%. The sodium isooctanoate content was detected to be 97.25%.

[0059] Example 3

[0060] (1) Recovery of diisopropylamine

[0061] 13 L of ampicillin sodium crystallization mother liquor (wherein the ampicillin sodium content (as ampicillin anhydrate) is 5.87 mg / ml, the diisopropylamine salt of isooctanoate (calculated as isooctanoic acid) content is 38.79 mg / ml, the diisopropylamine salt of isooctanoate and diisopropylamine (calculated as diisopropylamine) content is 82.93 mg / ml, and the organic solvent is a mixed solvent of isopropyl alcohol and ethyl acetate) was taken. The temperature of the ampicillin sodium crystallization mother liquor was adjusted to about 15° C., and then the pH was adjusted with 98 wt % concentrated sulfuric acid. H is 6.0, so that the diisopropylamine isooctanoate and diisopropylamine in the mother liquor are converted into diisopropylamine sulfate and crystallized. After filtration and drying, a diisopropylamine sulfate solid is obtained, and 12.4 L of filtrate is collected; then, the diisopropylamine sulfate solid is dissolved in 10 L of purified water, stirred to dissolve clearly, and the pH is adjusted to 13.4 with 30 wt % sodium hydroxide solution. The mixture is stirred and heated to about 45° C., and allowed to stand for separation, with the upper layer being the crude diisopropylamine and the lower layer being the aqueous phase.

[0062] Solid sodium hydroxide was added to the separated crude diisopropylamine for drying, and the moisture content was detected to be less than 1.0%. The dried diisopropylamine was then decolorized with activated carbon for 30 minutes. After filtration, 1277 ml of purified diisopropylamine was obtained with a recovery rate of 85.52% and a diisopropylamine purity of 98.5%.

[0063] (2) Ampicillin recovery

[0064] To 12.4 L of the filtrate collected in step (1) above was added 20 L of purified water, and then the pH thereof was adjusted to 0.9 with 20 wt % sulfuric acid, so that ampicillin sodium was converted into ampicillin and dissolved in water. The mixture was allowed to stand for phase separation to obtain 10.3 L of an organic phase and 22.4 L of an aqueous phase. The aqueous phase was rapidly freed of the residual organic solvent using a vacuum thin film evaporator, and then concentrated by nanofiltration to an ampicillin content of 50 mg / ml (based on anhydrous ampicillin). The resulting concentrate was adjusted to a pH of 5.0 with 10% aqueous ammonia, cooled to 5° C., grown for 30 min, filtered, washed, and dried to obtain 70.78 g of ampicillin trihydrate with a yield of 80.33%. The ampicillin content was detected to be 97.5%.

[0065] (3) Recovery of Sodium 2-ethylhexanoate

[0066] 10.3 L of the organic phase obtained by layering in step (2) was subjected to reduced pressure distillation to recover the organic solvents isopropanol and ethyl acetate to obtain 570 ml of a bottom liquid (isooctanoic acid). 800 ml of purified water was added to the obtained bottom liquid, stirred for 15 min, and allowed to stand for layering. The upper oil phase was isooctanoic acid, which was washed with 700 ml of purified water and layered again to obtain 560 ml of an isooctanoic acid liquid. 25 wt % sodium methoxide methanol solution was added dropwise to the isooctanoic acid liquid under stirring to adjust its pH to 8.1, and then the solvent was evaporated to obtain 469.22 g of sodium isooctanoate with a recovery rate of 80.74%. The sodium isooctanoate content was detected to be 96.63%.

Claims

1. A method for recovering an active ingredient from ampicillin sodium crystal mother liquor, the method comprising the following steps: (1) Recovery of diisopropylamine The mother liquor of ampicillin sodium crystallization is adjusted to a temperature of 0°C to 25°C and its pH is adjusted to 5 to 7 with concentrated sulfuric acid, so that diisopropylamine octanoate and diisopropylamine in the mother liquor are converted into diisopropylamine sulfate and crystallized, filtered and dried to obtain a diisopropylamine sulfate solid, and the filtrate is collected; the diisopropylamine sulfate solid is dissolved in water, the pH is adjusted to pH>13 with an alkali, stirred, heated to 40°C to 45°C, and allowed to stand for separation, whereby the upper layer is the crude diisopropylamine product and the lower layer is the aqueous phase; (2) Recovery of Ampicillin Trihydrate Add 1 to 3 times the volume of water to the filtrate collected in step (1), and then adjust the pH to 0.5 to 2 with hydrochloric acid or sulfuric acid to convert ampicillin sodium into ampicillin and dissolve it in water. Allow the phases to stand for separation to obtain an organic phase and an aqueous phase. After removing the residual organic solvent from the aqueous phase by vacuum distillation or evaporation using a vacuum thin film evaporator, nanofiltration and concentration are performed. The resulting concentrate is adjusted to a pH of ampicillin's isoelectric point with alkali for crystallization. After growing the crystals, filtering, and drying, ampicillin trihydrate crystals are obtained. (3) Recovery of sodium 2-ethylhexanoate The organic phase obtained by layering in step (2) is subjected to reduced pressure distillation to recover the organic solvent, and water is added to the obtained kettle bottom liquid, stirred, and allowed to stand for layering. The upper oil phase is isooctanoic acid, and the upper oil phase is washed with water, and allowed to stand for layering to obtain a purified isooctanoic acid liquid; a methanol solution of sodium methoxide is added dropwise to the obtained isooctanoic acid liquid to carry out a salt-forming reaction to adjust the pH to 7.8-8.2, and then the solvent is evaporated from the reaction liquid to obtain sodium isooctanoate.

2. The method for recovering active ingredients from ampicillin sodium crystal mother liquor according to claim 1, characterized in that In the ampicillin sodium crystallization mother liquor, the ampicillin sodium content, calculated as anhydrous ampicillin, is 4 mg / ml to 8 mg / ml; the diisopropylamine isooctanoate content, calculated as isooctanoic acid, is 30 mg / ml to 45 mg / ml; and the diisopropylamine isooctanoate and diisopropylamine contents, calculated as diisopropylamine, are 70 mg / ml to 90 mg / ml.

3. The method for recovering active ingredients from ampicillin sodium crystal mother liquor according to claim 1 or 2, characterized in that In the step (1) of recovering diisopropylamine, the temperature of the ampicillin sodium crystallization mother liquor is adjusted to 15° C. to 20° C., and then the pH thereof is adjusted to 6 to 6.5 using concentrated sulfuric acid having a concentration of 80 wt % to 98 wt %, so that diisopropylamine isooctanoate and diisopropylamine in the mother liquor are converted into diisopropylamine sulfate and crystallized, and the diisopropylamine sulfate solid is obtained by filtration and drying.

4. The method for recovering active ingredients from ampicillin sodium crystal mother liquor according to claim 1 or 2, characterized in that In the step (1) of recovering diisopropylamine, the diisopropylamine sulfate solid is dissolved in water, 1 to 20 ml of water is added per gram of diisopropylamine sulfate, and after stirring and dissolving, the pH is adjusted to pH>13 with an alkali, wherein the alkali is solid sodium hydroxide, potassium hydroxide, or a mixture thereof, or a sodium hydroxide solution, a potassium hydroxide solution, or a mixed solution thereof, wherein the concentration of the sodium hydroxide solution or the potassium hydroxide solution is preferably 25 wt% to 35 wt%; and then the mixture is stirred, heated to 40° C. to 45° C., and allowed to stand for separation, wherein the upper layer is the crude diisopropylamine product and the lower layer is the aqueous phase. The crude diisopropylamine product in the upper layer is dried with solid sodium hydroxide and decolorized with activated carbon to obtain purified diisopropylamine.

5. The method for recovering active ingredients from ampicillin sodium crystal mother liquor according to claim 1 or 2, characterized in that In the step (2) of recovering ampicillin trihydrate, 1 to 1.8 times the volume of water is added to the filtrate collected in the above step (1), and then the pH is adjusted to 0.8 to 1.5 with hydrochloric acid or sulfuric acid, so that ampicillin sodium is converted into ampicillin and dissolved in water. The phases are allowed to stand and separate to obtain an organic phase and an aqueous phase, wherein the hydrochloric acid has a concentration of 15 wt% to 20 wt%, and the sulfuric acid has a concentration of 10 wt% to 20 wt%.

6. The method for recovering active ingredients from ampicillin sodium crystal mother liquor according to claim 1 or 2, characterized in that In the step (2) of recovering ampicillin trihydrate, the aqueous phase after removing the organic solvent, i.e., the ampicillin solution, is concentrated by nanofiltration using a nanofiltration membrane and concentrated by 5 to 20 times; the concentrated solution obtained after concentration is adjusted to a pH of 4.5 to 5.5 using aqueous ammonia, and ampicillin trihydrate crystals are crystallized and precipitated. After crystal growth, filtration, and drying, ampicillin trihydrate crystals are obtained.

7. The method for recovering active ingredients from ampicillin sodium crystal mother liquor according to claim 1 or 2, characterized in that In the step (2) of recovering ampicillin trihydrate, the aqueous phase after the organic solvent is removed, i.e., the ampicillin solution, is concentrated by nanofiltration using a nanofiltration membrane and concentrated 8 to 15 times; the concentrated solution obtained after concentration is adjusted to a pH of 4.5 to 5.5 using aqueous ammonia, and ampicillin trihydrate crystals are crystallized and precipitated. After crystal growth, filtration, and drying, ampicillin trihydrate crystals are obtained.

8. The method for recovering active ingredients from ampicillin sodium crystal mother liquor according to claim 1 or 2, characterized in that In the step (3) of recovering sodium isooctanoate, the organic phase obtained by layering in step (2) is subjected to reduced pressure distillation to recover the organic solvents isopropyl alcohol and ethyl acetate, 0.5 to 5 times the volume of water is added to the obtained kettle bottom liquid, and then stirred and allowed to stand for layering. The upper oil phase is isooctanoic acid, and the upper oil phase is washed with 0.8 to 1.5 times the volume of water, and allowed to stand for layering to obtain a purified isooctanoic acid liquid.

9. The method for recovering active ingredients from ampicillin sodium crystal mother liquor according to claim 1 or 2, characterized in that In the step (3) of recovering sodium isooctanoate, the organic phase obtained by layering in step (2) is subjected to reduced pressure distillation to recover the organic solvents isopropyl alcohol and ethyl acetate, 0.8 to 1.5 times the volume of water is added to the obtained kettle bottom liquid, and then the mixture is stirred and allowed to stand for layering, the upper oil phase is isooctanoic acid, the upper oil phase is washed with 0.8 to 1.5 times the volume of water, and the mixture is allowed to stand for layering to obtain a purified isooctanoic acid liquid; 25 wt% of a methanol solution of sodium methoxide is added dropwise to the obtained isooctanoic acid liquid to carry out a salt-forming reaction, wherein the methanol solution of sodium methoxide is added dropwise until the pH is 7.9 to 8.1, and then the solvent is evaporated from the reaction liquid to obtain sodium isooctanoate.

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