Method for reducing impurity content of amoxicillin

Abstract

The invention relates to the technical field of preparation of amoxicillin, in particular to a method for reducing the impurity content of amoxicillin. The invention provides a method for reducing the impurity content of amoxicillin, which comprises the following steps: continuously adding an amoxicillin reaction solution and an acidic regulator to obtain a dissolved reaction solution; adding the dissolved and clarified reaction liquid and a first alkaline regulator for the first time, and carrying out first-stage crystallization to obtain a first crystallization liquid; adding the first crystalline liquid and a second alkaline regulator for secondary crystallization to obtain a second crystalline liquid; the second crystallization liquid is subjected to crystal growing, and amoxicillin is obtained; the first-stage crystallization and the second-stage crystallization are carried out under a stirring condition, and the stirring rotation speed of the first-stage crystallization is greater than that of the second-stage crystallization. The method reduces the generation of impurities in the post-treatment process.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of amoxicillin, and in particular to a method for reducing the impurity content of amoxicillin. Background Art

[0002] Amoxicillin, also known as ampicillin, is a broad-spectrum semi-synthetic antibiotic with high efficiency and broad-spectrum antibacterial effect and very small toxic side effects. It is one of the most commonly used broad-spectrum β-lactam antibiotics and occupies an important position among oral antibiotics.

[0003] The main preparation methods of amoxicillin are chemical method and enzymatic method. The chemical method is relatively mature, but it has obvious defects: 1) The entire process line is very long, and it takes a long time to complete the production, resulting in low overall efficiency; 2) In the production process, the use of a large amount of organic solvents will produce more toxic and harmful wastes, causing greater pollution to the environment. Compared with the chemical synthesis method, the quality of amoxicillin prepared by the enzymatic method is better than that of the chemical synthesis method due to the mild process conditions and green environmental protection. Therefore, the enzymatic synthesis of amoxicillin has been increasingly studied and applied. At present, most of the processes for synthesizing amoxicillin by enzymes use traditional methods in the dissolution and crystallization steps, that is, the reaction solution after synthesis is all entered into a device, and then acid is added to dissolve, and then alkaline solution is added after dissolving to adjust the pH of the clear solution to the isoelectric point of amoxicillin for crystallization. However, in the dissolution or crystallization process of this method, since the dissolution or crystallization is carried out in the same device, the longer the pH adjustment time, the greater the impact on the generation of impurities, so it also affects the final amoxicillin product quality. Summary of the invention

[0004] The object of the present invention is to provide a method for reducing the impurity content of amoxicillin, wherein the method reduces the generation of impurities in a post-treatment process.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides a method for reducing the impurity content of amoxicillin, comprising the following steps:

[0007] Continuously adding the amoxicillin reaction solution and the acidity regulator to obtain a clear reaction solution;

[0008] The reaction solution after dissolving and the first alkaline regulator are first added to perform primary crystallization to obtain a first crystal solution;

[0009] The first crystal solution and the second alkaline regulator are added to perform secondary crystallization to obtain a second crystal solution;

[0010] The second crystal solution is subjected to crystal cultivation to obtain amoxicillin;

[0011] The primary crystallization and the secondary crystallization are both carried out under stirring conditions, and the stirring speed of the primary crystallization is greater than the stirring speed of the secondary crystallization;

[0012] The temperature of the continuous addition is 23-25° C., and the pH value of the reaction solution after dissolving is 0.9-1.2;

[0013] The concentration of the amoxicillin reaction solution is 80-150 mg / mL, and the flow rate of the amoxicillin reaction solution during the continuous addition is 8-12 m / s. 3 / h.

[0014] Preferably, the addition rate of the acidic regulator during the continuous addition process is 200 to 500 L / h.

[0015] Preferably, the acidic regulator is one or more of hydrochloric acid, nitric acid and sulfuric acid.

[0016] Preferably, the addition rate of the dissolved reaction solution is 8 to 12 m / s. 3 / h, the addition rate of the first alkaline regulator is 100-400L / h;

[0017] The first alkaline regulator is ammonia water or sodium hydroxide.

[0018] Preferably, the pH value of the mixed solution obtained after the first addition is 3.5-4.2; the temperature of the primary crystallization is 20° C., and the pH value during the primary crystallization is 3.5-4.2.

[0019] Preferably, the first addition is carried out under stirring, and the stirring speeds of the first addition and the primary crystallization are independently 80-90 rpm.

[0020] Preferably, the flow rate of the first crystallization liquid is 8 to 12 m / s. 3 / h, the addition rate of the second alkaline regulator is 50 to 300 L / h;

[0021] The second alkaline regulator is ammonia water or sodium hydroxide.

[0022] Preferably, the pH value of the mixed solution obtained after the second addition is 4.0 to 5.5;

[0023] The temperature of the secondary crystallization is 20° C., and the pH of the secondary crystallization is 4.0-5.5.

[0024] Preferably, the second addition is carried out under stirring, and the stirring speeds of the second addition and the secondary crystallization are independently 40-50 rpm.

[0025] Preferably, the crystal growing is carried out under stirring, the stirring speed is 10-20 rpm, the temperature of the crystal growing is 2-5° C., and the time is 50-70 min.

[0026] The invention provides a method for reducing the impurity content of amoxicillin, comprising the following steps: continuously adding an amoxicillin reaction solution and an acidic regulator to obtain a dissolved reaction solution; firstly adding the dissolved reaction solution and a first alkaline regulator to perform primary crystallization to obtain a first crystallization solution; secondly adding the first crystallization solution and a second alkaline regulator to perform secondary crystallization to obtain a second crystallization solution; growing the second crystallization solution to obtain amoxicillin; the primary crystallization and the secondary crystallization are both performed under stirring, and the stirring speed of the primary crystallization is greater than the stirring speed of the secondary crystallization; the temperature of the continuous addition is 23-25°C, and the pH value of the dissolved reaction solution is 0.9-1.2; the concentration of the amoxicillin reaction solution is 80-150 mg / mL, and the flow rate of the amoxicillin reaction solution during the continuous addition is 8-12 m / s. 3 / h.

[0027] Compared with the prior art, the method of the present invention has the following beneficial effects:

[0028] 1) The present invention adopts a continuous addition method to prepare the dissolved reaction solution, which shortens the residence time of amoxicillin under acidic conditions and reduces some impurities generated by degradation under acidic conditions;

[0029] 2) The present invention adopts a graded crystallization method, and the purpose of controlling the stirring speed of the primary crystallization to be greater than the stirring speed of the secondary crystallization is: the primary crystallization has a higher speed, and it is just in the crystallization state at this time. The higher speed can avoid the crystal growth too fast due to the crystallization being too fast, thereby enclosing more impurities; the secondary crystallization has a slower speed because this stage is in the crystal growth stage, and a slightly slower speed is conducive to crystal growth. The entire crystallization process is in a continuous state, and no local pH over-alkalinity will occur. The crystallization liquid stays in each crystallization tank for a shorter time, reducing some impurities caused by degradation;

[0030] 3) The amoxicillin prepared by the method of the present invention has a single impurity content of about 0.04wt% and a total impurity content of about 0.08%. DETAILED DESCRIPTION

[0031] The present invention provides a method for reducing the impurity content of amoxicillin, comprising the following steps:

[0032] Continuously adding the amoxicillin reaction solution and the acidity regulator to obtain a clear reaction solution;

[0033] The reaction solution after dissolving and the first alkaline regulator are first added to perform primary crystallization to obtain a first crystal solution;

[0034] The first crystal solution and the second alkaline regulator are added to perform secondary crystallization to obtain a second crystal solution;

[0035] The second crystal solution is subjected to crystal cultivation to obtain amoxicillin;

[0036] The primary crystallization and the secondary crystallization are both carried out under stirring conditions, and the stirring speed of the primary crystallization is greater than the stirring speed of the secondary crystallization;

[0037] The temperature of the continuous addition is 23-25° C., and the pH value of the reaction solution after dissolving is 0.9-1.2;

[0038] The concentration of the amoxicillin reaction solution is 80-150 mg / mL, and the flow rate of the amoxicillin reaction solution during the continuous addition is 8-12 m / s. 3 / h.

[0039] In the present invention, unless otherwise specified, all preparation raw materials are commercially available products well known to those skilled in the art.

[0040] The invention continuously adds the amoxicillin reaction solution and the acidity regulator to obtain a dissolved reaction solution.

[0041] In the present invention, the amoxicillin reaction solution is preferably an amoxicillin reaction solution prepared by reacting 6-aminopenicillanic acid and D-p-hydroxyphenylglycine methyl ester under the action of a synthase.

[0042] In the present invention, the concentration of the amoxicillin reaction solution is 80-150 mg / mL, preferably 120-130 mg / mL. In an embodiment of the present invention, the concentration of the amoxicillin reaction solution can be 120 mg / mL, 130 mg / mL, or 125 mg / mL.

[0043] In the present invention, the acidic regulator is preferably one or more of hydrochloric acid, nitric acid and sulfuric acid, and the mass concentration of the hydrochloric acid is preferably ≥31%; the mass concentration of the nitric acid is preferably 30%; the mass concentration of the sulfuric acid is preferably 20%; more preferably hydrochloric acid. In an embodiment of the present invention, the acidic regulator can be hydrochloric acid with a mass concentration of 31%.

[0044] In the present invention, the flow rate of the amoxicillin reaction solution is 8 to 12 m 3 / h, preferably 9 to 11 m 3 In an embodiment of the present invention, the flow rate of the amoxicillin reaction solution can be 8m / h. 3 / h、10m 3 / h and 12m 3 / h.

[0045] In the present invention, the addition rate of the acidic regulator is preferably 200 to 500 L / h, more preferably 300 to 400 L / h. In an embodiment of the present invention, the addition rate of the acidic regulator can be 300 L / h or 350 L / h.

[0046] In the present invention, the temperature of the continuous addition is preferably 23-25°C, more preferably 25°C; the pH value of the reaction solution after the solution is 0.9-1.2, preferably 1.0-1.1. In an embodiment of the present invention, the temperature of the continuous addition can be 25°C; the pH value of the reaction solution after the solution is 0.9 or 1.0.

[0047] In the present invention, the flow rate, continuous addition temperature and pH of the amoxicillin reaction solution are controlled within the above ranges to avoid excessive acidity and the generation of more impurities.

[0048] In an embodiment of the present invention, the preparation process of the clear reaction solution is specifically as follows: after the amoxicillin reaction solution is continuously introduced into a pipeline mixer, the acidic regulator is immediately added to achieve a desired pH value instantaneously to obtain a clear reaction solution. The obtained clear reaction solution is then immediately introduced into a primary crystallization tank in the next step.

[0049] After the continuous addition is completed, the present invention also preferably includes three-stage filtration. The present invention does not have any special limitation on the process of the three-stage filtration, and the process well known to those skilled in the art can be used.

[0050] After obtaining the clear reaction solution, the present invention adds the clear reaction solution and the first alkaline regulator to perform primary crystallization to obtain a first crystal solution.

[0051] In the present invention, the addition rate of the dissolved reaction solution is preferably 8 to 12 m / s. 3 / h, more preferably 9 to 11 m 3 / h; the addition rate of the first alkaline regulator is preferably 100-400 L / h, more preferably 200-300 L / h. In an embodiment of the present invention, the addition rate of the dissolved reaction solution can be 8m 3 / h、10m 3 / h and 12m 3 / h; the addition rate of the first alkaline regulator can be 200L / h or 250L / h.

[0052] In the present invention, the first alkaline regulator is preferably ammonia water or sodium hydroxide solution; the mass concentration of the ammonia water is preferably 10%; the mass concentration of the sodium hydroxide solution is preferably 20%.

[0053] In the present invention, the first addition is preferably carried out under stirring, and the stirring speeds of the first addition and the primary crystallization are independently preferably 80 to 90 rpm, more preferably 82 to 88 rpm. In an embodiment of the present invention, the stirring speed of the first addition can be 90 rpm or 80 rpm; the stirring speed of the primary crystallization can be 90 rpm or 80 rpm.

[0054] In the present invention, the pH value of the mixed solution obtained after the first addition is preferably 3.5-4.2; the temperature of the primary crystallization is preferably 20°C, and the pH value during the primary crystallization is preferably 3.5-4.2. In an embodiment of the present invention, the pH value of the mixed solution obtained after the first addition can be 3.7 or 4.0, and the pH value during the primary crystallization can be 3.7 or 4.0.

[0055] In the present invention, the primary crystallization preferably uses purified water as the base liquid.

[0056] In an embodiment of the present invention, the process of the first pair of addition and primary crystallization is as follows: 300 to 500 L of purified water is added in advance to the primary crystallization tank as a base liquid, the dissolved reaction liquid is continuously added to the primary crystallization tank, and the first alkaline regulator is continuously added to quickly control the pH in the primary crystallization tank to remain unchanged within the range of 3.5 to 4.2, and after the feed liquid in the primary crystallization tank obtains 60% of the tank volume, the overflow valve is opened to allow the crystallization liquid to flow into the secondary crystallization tank, and thereafter the primary crystallization tank is kept in a continuous feeding, crystallization and overflow state until the crystallization is completed.

[0057] After obtaining the first crystallization liquid, the present invention adds the first crystallization liquid and the second alkaline regulator to perform secondary crystallization to obtain the second crystallization liquid.

[0058] In the present invention, the flow rate of the first crystallization liquid is preferably 8 to 12 m / s. 3 / h, more preferably 9 to 11 m 3 / h; the addition rate of the second alkaline regulator is preferably 50 to 300 L / h, more preferably 100 to 200 L / h. In an embodiment of the present invention, the flow rate of the first crystallization liquid can be 8 m / h. 3 / h、10m 3 / h and 12m 3 / h; the addition rate of the second alkaline regulator can be 100L / h or 150L / h.

[0059] In the present invention, the second alkaline regulator is preferably ammonia water or sodium hydroxide solution; the mass concentration of the ammonia water is preferably 10%; the mass concentration of the sodium hydroxide solution is preferably 20%.

[0060] In the present invention, the second addition is preferably carried out under stirring, and the stirring speeds of the second addition and the secondary crystallization are independently preferably 40 to 50 rpm, more preferably 43 to 46 rpm. In an embodiment of the present invention, the stirring speed of the second addition can be 50 rpm; the stirring speed of the secondary crystallization can be 50 rpm.

[0061] In the present invention, the pH value of the mixed solution obtained after the second addition is preferably 4.0 to 5.5; the temperature of the secondary crystallization is preferably 20°C, and the pH value during the secondary crystallization is preferably 4.5 to 5.2. In an embodiment of the present invention, the pH value of the mixed solution obtained after the second addition can be 5.0 or 5.2, and the pH value during the secondary crystallization can be 5.0 or 5.2.

[0062] In an embodiment of the present invention, the process of the second pair of addition and secondary crystallization is: after the first crystallization liquid is continuously added to the secondary crystallization tank, the second alkaline regulator is continuously added to quickly control the pH in the primary crystallization tank to remain unchanged within the range of 4.0 to 5.5, and after the feed liquid in the secondary crystallization tank obtains 60% of the tank volume, the overflow valve is opened to allow the crystallization liquid to flow into the crystal growing tank, and thereafter the secondary crystallization tank maintains a continuous feeding, crystallization and overflow state until the crystallization is completed.

[0063] After obtaining the second crystallization liquid, the present invention performs crystal cultivation on the second crystallization liquid to obtain amoxicillin.

[0064] In the present invention, the crystal growing is preferably carried out under stirring conditions, the stirring speed is preferably 10-20 rpm, more preferably 13-16 rpm; the crystal growing temperature is preferably 2-5°C, more preferably 3-4°C, and the time is preferably 50-70 min. In an embodiment of the present invention, the stirring speed can be 20 rpm, the crystal growing temperature can be 5°C, and the time can be 60 min or 70 min.

[0065] In an embodiment of the present invention, the crystal growing is carried out in a crystal growing tank.

[0066] After the crystal growing is completed, the present invention also preferably includes centrifugation, washing and drying performed in sequence; the present invention does not have any special limitation on the process of centrifugation and washing, and the process described by those skilled in the art can be used. In the present invention, the drying temperature is preferably 30°C, and the time is preferably 30 minutes. In an embodiment of the present invention, the drying is performed in a closed-circuit boiling dryer. In the present invention, controlling the above-mentioned drying conditions can reduce impurities generated due to excessively high drying temperatures.

[0067] The method for reducing the impurity content of amoxicillin provided by the present invention is described in detail below in conjunction with the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0068] Example 1

[0069] 16m 3 The amoxicillin reaction solution (the content of amoxicillin in the liquid phase test was 120 mg / mL) was heated to 25°C and then heated to 10 m 3 / h flow rate continuously into the pipeline mixer, and at the same time quickly add 31% hydrochloric acid at a rate of 300L / h and control the pH to 1.0, through the dissolution pipeline, after three-stage filtration at 10m 3 / h addition rate into 3m 3 In the first-stage crystallization tank, the stirring speed was turned on at 90 rpm, and ammonia water with a mass concentration of 10% was added at a rate of 200 L / h. The pH value was adjusted to 3.7, and the dissolved reaction solution and ammonia water were continuously added. The pH was maintained at 3.7. After 10 minutes, the feed liquid reached 60% of the volume of the crystallization tank. The overflow valve was opened, and the feed liquid overflowed at a rate of 10m 3 / h addition rate into 1m 3 In the secondary crystallization tank, the stirring speed was turned on at 50 rpm, and ammonia water with a mass concentration of 10% was added at a rate of 100 L / h. The pH was quickly adjusted to 5.0, and then the clear solution and ammonia water were continuously added. The pH was maintained at 5.0. After about 4 minutes, the feed liquid reached 60% of the volume of the crystallization tank. The lower overflow valve was opened, and the feed liquid overflowed into the crystal growing tank with a stirring speed of 20 rpm. After cooling to 5°C and growing the crystal for 60 minutes, the mixture was centrifuged and washed, and then transported to a closed-circuit boiling dryer and dried at 30°C for 30 minutes to obtain 1882.1 kg of amoxicillin (molar yield was 98.02%).

[0070] Example 2

[0071] 16m 3 The amoxicillin reaction solution (the content of amoxicillin in the liquid phase test was 130 mg / mL) was heated to 23°C and then heated to 8 m 3 / h flow rate continuously into the pipeline mixer, and at the same time quickly add 31% hydrochloric acid at a rate of 300L / h and control the pH to 0.9, through the dissolution pipeline, after three-stage filtration at 8m 3 / h addition rate into 3m 3 In the first-stage crystallization tank, the stirring speed was turned on at 90 rpm, and ammonia water with a mass concentration of 10% was added at a rate of 200 L / h. The pH value was adjusted to 4.0, and the dissolved reaction solution and ammonia water were continuously added. The pH was maintained at 4.0. After 12 minutes, the feed liquid reached 60% of the volume of the crystallization tank. The overflow valve was opened, and the feed liquid overflowed at 8m 3 / h addition rate into 1m 3 In the secondary crystallization tank, the stirring speed was turned on at 50 rpm, and ammonia water with a mass concentration of 10% was added at a rate of 100 L / h. The pH was quickly adjusted to 5.2, and then the clear solution and ammonia water were continuously added. The pH was maintained at 5.2. After about 5 minutes, the feed liquid reached 60% of the volume of the crystallization tank. The lower overflow valve was opened, and the feed liquid overflowed into the crystal growing tank with a stirring speed of 20 rpm. After cooling to 5°C and growing the crystal for 70 minutes, the mixture was centrifuged and washed, and then transported to a closed-circuit boiling dryer and dried at 30°C for 30 minutes to obtain 2040 kg of amoxicillin (molar yield was 98.08%).

[0072] Example 3

[0073] 16m 3 The amoxicillin reaction solution (the content of amoxicillin in the liquid phase test was 125 mg / mL) was heated to 25°C and then heated to 12 m 3 / h flow rate continuously into the pipeline mixer, and at the same time quickly add 31% hydrochloric acid at a rate of 350L / h and control the pH to 1.0, through the dissolution pipeline, after three-stage filtration at 12m 3 / h addition rate into 3m 3 In the first-stage crystallization tank, the stirring speed was turned on at 80 rpm, and ammonia water with a mass concentration of 10% was added at a rate of 250 L / h. The pH value was adjusted to 4.0, and the dissolved reaction solution and ammonia water were continuously added. The pH was maintained at 4.0. After 9 minutes, the feed liquid reached 60% of the volume of the crystallization tank. The overflow valve was opened, and the feed liquid overflowed at 12 m 3 / h addition rate into 1m 3In the secondary crystallization tank, the stirring speed is turned on at 40 rpm, and ammonia water with a mass concentration of 10% is added at a rate of 150 L / h. The pH is quickly adjusted to 5.2, and then the clear solution and ammonia water are continuously added. The pH is maintained at 5.2. After about 3 minutes, the feed liquid reaches 60% of the volume of the crystallization tank. The lower overflow valve is opened, and the feed liquid overflows into the crystal growing tank with a stirring speed of 10 rpm. After cooling to 5°C and growing the crystal for 70 minutes, the mixture is centrifuged and washed, and then transported to a closed-circuit boiling dryer and dried at 30°C for 30 minutes to obtain 1962.9 kg of amoxicillin (molar yield is 98.14%).

[0074] The amoxicillin described in Examples 1 to 3 was tested for related substances, and the test results are shown in Table 1:

[0075] Table 1 Impurity content of amoxicillin described in Examples 1 to 3

[0076]

[0077]

[0078] Comparative Examples 1 to 5

[0079] Referring to Example 1, the difference is that the temperature of the amoxicillin reaction solution after heating and the pH value after adding hydrochloric acid, the specific difference and the molar content and total impurity content of the prepared amoxicillin are shown in Table 2: Table 2 The specific difference between Comparative Examples 1 to 5 and Example 1 and the molar content and total impurity content of the prepared amoxicillin

[0080]

[0081] As shown in Table 2, the temperature of the amoxicillin reaction solution after heating is 23-25° C., the pH value after adding hydrochloric acid is in the range of 0.9-1.2, and the impurity content and molar yield of amoxicillin are better.

[0082] Comparative Examples 6 to 10

[0083] With reference to Example 1, the difference is that the concentration of amoxicillin in the amoxicillin reaction solution and the flow rate of the amoxicillin reaction solution are different. The specific difference and the molar content and total impurity content of the prepared amoxicillin are shown in Table 3:

[0084] Table 3 Specific differences between Comparative Examples 6 to 10 and Example 1 and the molar content and total impurity content of the prepared amoxicillin

[0085]

[0086] As shown in Table 3, the concentration of amoxicillin in the amoxicillin reaction solution is in the range of 120-130 mg / mL and the flow rate of the amoxicillin reaction solution is in the range of 8-12 m / s.3 / h, the impurity content and molar yield of amoxicillin are better.

[0087] Comparative Example 11

[0088] 16m 3 The amoxicillin reaction liquid (the content of amoxicillin in the liquid phase test is 120 mg / mL) enters the dissolution tank and is heated to 25°C. Then, stirring is started (the stirring speed is 60 rpm). Hydrochloric acid with a mass concentration of 31% is added and the pH is controlled to 1.0. After passing through the dissolution pipeline, the liquid is filtered through three stages to obtain a 10m 3 / h addition rate into 3m 3 In the first-stage crystallization tank, the stirring speed was turned on at 90 rpm, and ammonia water with a mass concentration of 10% was added at a rate of 200 L / h. The pH value was adjusted to 3.7, and the dissolved reaction solution and ammonia water were continuously added. The pH was maintained at 3.7. After 10 minutes, the feed liquid reached 60% of the volume of the crystallization tank. The overflow valve was opened, and the feed liquid overflowed at a rate of 10m 3 / h addition rate into 1m 3 In the secondary crystallization tank, the stirring speed is turned on at 50 rpm, and ammonia water with a mass concentration of 10% is added at a rate of 100 L / h. The pH is quickly adjusted to 5.0, and then the clear solution and ammonia water are continuously added. The pH is maintained at 5.0. After about 4 minutes, the feed liquid reaches 60% of the volume of the crystallization tank. The lower overflow valve is opened, and the feed liquid overflows into the crystal growing tank with a stirring speed of 20 rpm. After cooling to 5°C and growing the crystal for 60 minutes, it is centrifuged and washed, and then transported to a closed-circuit boiling dryer and dried at 30°C for 30 minutes to obtain 1882.1 kg of amoxicillin (molar yield is 90.55%, and the total impurity content is 0.49%).

[0089] Comparative Example 12

[0090] 16m 3 The amoxicillin reaction solution (the content of amoxicillin in the liquid phase test was 120 mg / mL) was heated to 25°C and then heated to 10 m 3 / h flow rate continuously into the pipeline mixer, and at the same time quickly add 31% hydrochloric acid at a rate of 300L / h and control the pH to 1.0, through the dissolution pipeline, after three-stage filtration at 10m 3 / h addition rate into 25m 3 In the crystal growing tank, start the stirring speed to 90 rpm, add ammonia water with a mass concentration of 10% at a rate of 100 L / h, control the crystallization pH to 5.2, reduce the stirring speed to 20 rpm again, cool to 5°C, grow crystals, and then centrifuge, wash and dry to obtain amoxicillin (molar yield is 91.32%, total impurity content is 0.44%).

[0091] It can be seen from Comparative Examples 11 to 12 that the impurity content and molar yield of amoxicillin prepared by the method of the present invention are better than those prepared by the traditional one-time dissolution method (Comparative Example 1) and crystallization method (Comparative Example 2).

[0092] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for reducing the impurity content of amoxicillin, characterized in that: The following steps are involved: Continuously adding the amoxicillin reaction solution and the acidity regulator to obtain a clear reaction solution; The reaction solution after dissolving and the first alkaline regulator are first added to perform primary crystallization to obtain a first crystal solution; The first crystal solution and the second alkaline regulator are added to perform secondary crystallization to obtain a second crystal solution; The second crystal solution is subjected to crystal cultivation to obtain amoxicillin; The primary crystallization and the secondary crystallization are both carried out under stirring conditions, and the stirring speed of the primary crystallization is greater than the stirring speed of the secondary crystallization; The temperature of the continuous addition is 23-25° C., and the pH value of the reaction solution after dissolving is 0.9-1.2; The concentration of the amoxicillin reaction solution is 80-150 mg / mL, and the flow rate of the amoxicillin reaction solution during the continuous addition is 8-12 m / s. 3 / h.

2. The method according to claim 1, characterized in that The addition rate of the acidic regulator during the continuous addition process is 200 to 500 L / h.

3. The method according to claim 2, characterized in that The acidic regulator is one or more of hydrochloric acid, nitric acid and sulfuric acid.

4. The method according to claim 1, characterized in that The addition rate of the dissolved reaction solution is 8 to 12 m 3 / h, the addition rate of the first alkaline regulator is 100-400L / h; The first alkaline regulator is ammonia water or sodium hydroxide.

5. The method according to claim 4, characterized in that The pH value of the mixed solution obtained after the first addition is 3.5 to 4.2; The temperature of the primary crystallization is 20° C., and the pH value during the primary crystallization is 3.5-4.

2.

6. The method according to claim 5, characterized in that The first addition is carried out under stirring conditions, and the stirring speeds of the first addition and the primary crystallization are independently 80-90 rpm.

7. The method according to claim 1, characterized in that The flow rate of the first crystallization liquid is 8-12 m 3 / h, the addition rate of the second alkaline regulator is 50 to 300 L / h; The second alkaline regulator is ammonia water or sodium hydroxide.

8. The method according to claim 7, characterized in that The pH value of the mixed solution obtained after the second addition is 4.0 to 5.5; The temperature of the secondary crystallization is 20° C., and the pH of the secondary crystallization is 4.0-5.

5.

9. The method according to claim 8, characterized in that The second addition is carried out under stirring conditions, and the stirring speeds of the second addition and the secondary crystallization are independently 40 to 50 rpm.

10. The method according to claim 1, characterized in that The crystal growing is carried out under stirring conditions, the stirring speed is 10-20 rpm, the temperature of the crystal growing is 2-5° C., and the time is 50-70 min.

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