A crystallization method and device for preparing 7-ACT

Abstract

The present invention relates to a kind of crystallization method and device prepared by 7 ACT, and the device comprises the following steps: 1) hydrolyzate is cooled to 0 10 DEG C, is divided into solution A and solution B, solution A adds alkali and is adjusted to pH value a, solution B is adjusted to pH value b, controls 0.5≤(a b)≤1, observes that solution A has crystal precipitation, stops adding alkali;2) solution A grows crystal after 30min, mixes with solution B, adds alkali and adjusts pH value to 3.0 4.0, temperature is maintained at below 10 DEG C, carries out stirred crystallization, and washes crystal after suction filtration.The present invention can realize the accurate control of solution nucleation stage supersaturation degree, is conducive to the control of nucleation quality in crystallization process, and then controls crystallization quality.The present invention can realize the improvement of 7 ACT crystallization quality, thereby improving product yield and product quality.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and in particular relates to a crystallization method and device for preparing 7-ACT. Background Art

[0002] 7-ACT is an intermediate used in the preparation of ceftriaxone sodium. The process generally uses 7-ACA and triazinic acid as raw materials, reacting in acetonitrile as a solvent with boron trifluoride as a catalyst to obtain it. Although some new synthesis processes have been disclosed in the prior art, they ultimately involve crystallization of the hydrolyzed solution, separation by filtration, and drying. In acidic systems, 7-ACT has a high solubility in the aqueous phase. At a pH of 3-4, its solubility is less than 5g / L. Therefore, crystallization can be achieved by adjusting the pH to 3-4 by adding alkali.

[0003] Adjusting the pH during crystallization significantly impacts crystal size. Improper control results in excessively fine crystals, making filtration difficult and leading to high product loss and reduced yield. Given the high value of both the raw material and the product, a reduced yield has a significant impact on economic efficiency. Furthermore, excessively fine particles can lead to high moisture content after filtration, resulting in prolonged drying times. This prolonged drying time significantly impacts product quality, potentially causing substandard color. Summary of the Invention

[0004] In view of the above problems, the specific solutions of the present invention are:

[0005] A crystallization method for preparing 7-ACT comprises the following steps:

[0006] 1) Cool the hydrolyzate to 0-10°C and separate it into solution A and solution B. Add alkali to solution A to adjust the pH to a, and adjust the pH of solution B to b, controlling 0.5≤ab≤1. Stop adding alkali when crystals are observed in solution A.

[0007] 2) After solution A has been grown for 30 minutes, it is mixed with solution B and the pH value is adjusted to 3.0-4.0 by adding alkali. The temperature is maintained below 10°C and stirred for crystallization. The crystals are then filtered and washed.

[0008] During crystallization, if the degree of supersaturation is not properly controlled, the supersaturation is too large, and the nucleation rate is too fast, it is easy to cause a large number of nuclei, a small particle size, and overly fine particles after crystallization. During the crystallization of 7-ACT, the pH value is adjusted by adding alkali to reduce the solubility of 7-ACT, thereby reaching a supersaturated state. In actual production, when crystals are observed to precipitate in the solution, it is judged that the solution has just reached a supersaturated state, and at this time, the addition of alkali is stopped to control the degree of supersaturation of the solution. This method is difficult to control. When the pH value of 7-ACT is close to 2, the solubility of 7-ACT in water decreases significantly. When crystal precipitation is observed, the degree of supersaturation may be high. In addition, the pH value change of the solution can be monitored by a pH meter. After the alkali is added, there is a diffusion period. When the volume of the crystallization tank is large, the pH values at different positions vary greatly. The pH meter can only monitor the local pH value, cannot reflect the overall pH value, and cannot accurately control the degree of supersaturation of the solution.

[0009] This scheme divides the hydrolyzate to be crystallized into two parts and controls the pH difference between the two solutions. The part with a higher pH value is used for nucleation, and the part with a lower pH value is used for comparison to control the degree of supersaturation. This method is beneficial to improving the quality of nucleation and crystallization.

[0010] The pH value of Solution A is adjusted directly with alkali solution, which can be aqueous ammonia or sodium hydroxide solution. The pH value of Solution B can also be adjusted directly with alkali solution, or with Solution A, which has been adjusted in pH.

[0011] Preferably, in step 1), (ab) is controlled at 0.5. The smaller the value, the more conducive it is to controlling the supersaturation of solution A. When it is lower than 0.5, the actual operation is difficult and cannot be achieved.

[0012] Preferably, the mass ratio of solution A to solution B is 5-7:3. Solution A is used for nucleation, and this ratio can ensure that there are an appropriate amount of crystal nuclei after mixing.

[0013] Furthermore, in step 1), the hydrolyzate is first cooled to 0-5°C. When crystals precipitate from solution B, the addition of alkali is stopped, and the temperatures of solution A and solution B are simultaneously raised until the crystals in solution B disappear. Considering the difficulty of practical operation, it is possible that when crystals are observed to precipitate from solution A, crystals have also precipitated from solution B, indicating that the supersaturation of solution A is already relatively high. In this case, the supersaturation can be reduced by appropriately raising the solution temperature.

[0014] In order to implement the method of the present invention, the present invention discloses a crystallization device for preparing 7-ACT, comprising a main tank body and a sub-tank body connected in series, the main tank body being provided with an alkali liquid feed pipe, and the sub-tank body being connected to the main tank body through an underflow pipe; stirring paddles, a pH meter and a thermometer are provided inside the main tank body and the sub-tank body; and water cooling jackets are provided outside the main tank body and the sub-tank body.

[0015] During crystallization, a portion of the hydrolyzate enters the main tank as Solution A, while the remaining portion enters the auxiliary tank as Solution B. A pH meter and thermometer are used to monitor the pH and temperature of the solutions. Alkali solution is first added to Solution A. As the pH of Solution A increases, a portion of Solution A flows through the underflow pipe into Solution B, causing the pH of Solution B to also increase. Since the pH of Solution A is significantly lower than that of the alkali solution, the pH of Solution B will also be lower than that of Solution A. The main tank is used for nucleation, while the auxiliary tank is used for comparative control of supersaturation.

[0016] Another crystallization device for preparing 7-ACT includes an outer tank body and an inner tank body. The inner tank body is arranged inside the outer tank body, the inner tank body is provided with an alkali liquid feed pipe, and the lower part of the inner tank body is provided with an openable and closable opening; a pH meter and a thermometer are provided inside and outside the inner tank body, and a stirring paddle is provided inside the inner tank body; and a water cooling jacket is provided on the outside of the outer tank body.

[0017] This solution is similar to the first crystallization device in that solution A enters the inner tank and solution B enters the area between the inner and outer tanks. This solution facilitates synchronous temperature control of solution A and solution B.

[0018] Furthermore, the inner tank body includes a cylinder and a base, the base is fixedly connected to the outer tank body, and the cylinder body is provided with a lifting mechanism. When the cylinder body descends and contacts the base, the inner tank body and the outer tank body are separated from each other, and when the cylinder body rises and separates from the base, the inner tank body and the outer tank body are connected.

[0019] The present invention is beneficial in that it can precisely control the degree of supersaturation during the solution nucleation stage, facilitating control of nucleation quality during the crystallization process, and thus controlling crystallization quality. The present invention can improve the quality of 7-ACT crystals, thereby increasing product yield and quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The present invention will be further described below with reference to the accompanying drawings and examples.

[0021] Figure 1 It is a structural schematic diagram of the crystallization device in Example 5.

[0022] Figure 2 It is a structural schematic diagram of the crystallization device in Example 6. DETAILED DESCRIPTION

[0023] Example 1

[0024] 7-ACA and triazinic acid were added proportionally to a mixed solution of acetonitrile and boron trifluoride acetonitrile complex. The reaction was stirred until complete, then cooled to 0-10°C. Purified water was added for hydrolysis, and extraction was performed to obtain a hydrolyzate. The hydrolyzate was divided into Solution A and Solution B in a mass ratio of 5:3. Ammonia was added to Solution A, and the pH of Solution B was adjusted using Solution A. When crystals were observed in Solution A, the addition of ammonia was stopped. At this point, the pH of Solution A was 2.2, the pH of Solution B was 1.7, and no crystals were precipitated in Solution B. After growing Solution A for 30 minutes, it was mixed with Solution B and stirred for 1 hour. The crystals were filtered, washed, and vacuum dried to a moisture content of ≤1%. The crystals were weighed, the mass yield was calculated, and the particle size and color grade were measured.

[0025] Example 2

[0026] 7-ACA and triazinic acid were added proportionally to a mixed solution of acetonitrile and boron trifluoride acetonitrile complex. The reaction was stirred until complete, then cooled to 0-10°C. Purified water was added for hydrolysis, and the hydrolyzate was extracted to obtain a hydrolyzate. The hydrolyzate was divided into Solution A and Solution B in a mass ratio of 7:3. Ammonia was added to Solution A, and the pH of Solution B was adjusted using Solution A. When crystals were observed in Solution A, the addition of ammonia was stopped. At this point, the pH of Solution A was 2.5, the pH of Solution B was 1.3, and no crystals were precipitated in Solution B. After growing Solution A for 30 minutes, it was mixed with Solution B and stirred for 1 hour. The crystals were filtered, washed, and vacuum dried to a moisture content of ≤1%. The crystals were weighed, the mass yield was calculated, and the particle size and color grade were measured.

[0027] Example 3

[0028] 7-ACA and triazinic acid were added proportionally to a mixed solution of acetonitrile and boron trifluoride acetonitrile complex. The reaction was stirred until complete, then cooled to 0-10°C. Purified water was added for hydrolysis, and the hydrolyzate was extracted to obtain a hydrolyzate. The hydrolyzate was divided into Solution A and Solution B in a mass ratio of 6:3. Ammonia was added to Solution A, and the pH of Solution B was adjusted using Solution A. When crystals were observed in Solution A, the addition of ammonia was stopped. At this point, the pH of Solution A was 2.6, the pH of Solution B was 2.1, and crystals also precipitated in Solution B. After growing Solution A for 30 minutes, it was mixed with Solution B and stirred for 1 hour. The crystals were filtered, washed, and vacuum-dried to a moisture content of ≤1%. The crystals were weighed, the mass yield was calculated, and the particle size and color grade were measured.

[0029] Example 4

[0030] 7-ACA and triazinic acid were added proportionally to a mixed solution of acetonitrile and boron trifluoride acetonitrile complex. The reaction was stirred until complete, then cooled to 0-10°C. Purified water was added for hydrolysis, and extraction was performed to obtain a hydrolyzate. The hydrolyzate was first cooled to 0-5°C and then divided into Solution A and Solution B in a 6:3 mass ratio. Ammonia was added to Solution A, and the pH of Solution B was adjusted using Solution A. When crystals formed in Solution A, the addition of ammonia was stopped. At this point, the pH of Solution A was 2.3, and the pH of Solution B was 1.7. Crystals also formed in Solution B. The temperatures of both Solution A and Solution B were raised by 3°C. The crystals in Solution B redissolved and disappeared, but crystals still formed in Solution A. After crystallization in Solution A for 30 minutes, Solution A was mixed with Solution B and stirred for 1 hour. The crystals were filtered, washed, and vacuum-dried to a moisture content of ≤1%. The crystals were weighed, the mass yield was calculated, and the particle size and color grade were measured.

[0031] Comparative Example 1

[0032] Add 7-ACA and triazinic acid in a proportional mixture to a solution of acetonitrile and boron trifluoride acetonitrile complex. Stir until the reaction is complete, cool to 0-10°C, add purified water for hydrolysis, and extract to obtain a hydrolyzate. Add ammonia water to the hydrolyzate until the pH reaches 2.6. When crystal precipitation is observed, stop adding ammonia water. After growing the crystals for 30 minutes, stir the crystals for 1 hour, filter, wash, and vacuum dry to a moisture content of ≤1%. Weigh the crystals, calculate the mass yield, and inspect the appearance quality.

[0033] The results of Examples 1-4 and Comparative Example 1 are compared in the following table:

[0034] Yield Appearance Example 1 125.3％ White Example 2 122.5％ White Example 3 122.0％ yellowish Example 4 126.5％ White Comparative Example 1 121.7％ yellowish

[0035] From the comparison, it can be seen that the yields of Examples 1-3 fluctuate greatly. In Example 3, the yield is significantly reduced due to the failure to effectively control the supersaturation of the solution during nucleation. The crystal drying takes a long time and the appearance after drying is yellowish. In Example 4, the control method is improved, the supersaturation of the solution is effectively controlled during nucleation, the yield is improved, and the product appearance is normal. The comparative example is carried out according to the conventional process. Similarly, due to the inability to effectively control the supersaturation, the crystal quality is poor, the yield is low, the drying time is long, and the appearance is yellowish.

[0036] Example 5

[0037] This example is used to illustrate a crystallization device for preparing 7-ACT. Figure 1The system comprises a main tank 1 and a secondary tank 2 connected in series. The main tank is equipped with an alkali solution feed pipe 3, and the secondary tank is connected to the main tank via an underflow pipe 4. A stirring paddle, pH meter 5, and thermometer 6 are installed inside the main and secondary tanks. Water cooling jackets are installed outside the main and secondary tanks. Peristaltic pumps 7 are installed in both the alkali solution feed pipe and the underflow pipe to control the feed rate. Circulating cooling water is passed through the water cooling jacket to control the temperature of the solution inside the tank.

[0038] During crystallization, a portion of the hydrolyzate enters the main tank as Solution A, while the remaining portion enters the auxiliary tank as Solution B. A pH meter and thermometer are used to monitor the pH and temperature of the solutions. Alkali solution is first added to Solution A. As the pH of Solution A increases, a portion of Solution A flows through the underflow pipe into Solution B, causing the pH of Solution B to also increase. Since the pH of Solution A is significantly lower than that of the alkali solution, the pH of Solution B will also be lower than that of Solution A. The main tank is used for nucleation, while the auxiliary tank is used for comparative control of supersaturation.

[0039] Example 6

[0040] This example is used to illustrate another crystallization device for preparing 7-ACT. Figure 2 , including an outer tank body 8 and an inner tank body 9. The inner tank body 9 is arranged inside the outer tank body. The inner tank body 9 is provided with an alkali liquid feeding pipe 3, and a closable opening is provided at the lower part of the inner tank body; a pH meter 5 and a thermometer 6 are provided inside and outside the inner tank body, and a stirring paddle is provided inside the inner tank body; a water cooling jacket is provided outside the outer tank body.

[0041] This solution is similar to the first crystallization device in that solution A enters the inner tank and solution B enters the area between the inner and outer tanks. This solution facilitates synchronous temperature control of solution A and solution B.

[0042] The inner tank 9 comprises a barrel 901 and a base 902, which is fixedly connected to the outer tank. The barrel is equipped with a lifting mechanism driven by a lead screw 10. When the barrel 901 descends and contacts the base 902, the inner tank 9 and outer tank 8 are separated from each other. When the barrel 901 ascends and clears the base 902, the inner tank 9 and outer tank 8 are connected. The size of the lower opening of the inner tank is controlled by the lifting height. During nucleation, the inner tank only needs to be slightly raised; during crystallization, the inner tank rises to the upper limit, fully connecting the inside and outside.

Claims

1. A crystallization method for preparing 7-ACT, characterized in that: The following steps are involved: 1) Cool the hydrolyzate to 0-10°C and separate it into solution A and solution B. Add alkali to adjust solution A to pH a and solution B to pH b, controlling the pH at 0.5≤(ab)≤1. Stop adding alkali when crystals are observed in solution A. 2) After growing solution A for 30 minutes, mix it with solution B and add alkali to adjust the pH to 3.0-4.

0. Keep the temperature below 10℃ and stir to crystallize. Filter and wash the crystals.

2. The crystallization method for preparing 7-ACT according to claim 1, characterized in that: In step 1), (ab) is controlled at 0.

5.

3. The crystallization method for preparing 7-ACT according to claim 1, characterized in that: The mass ratio of solution A to solution B is 5-7:

3.

4. The crystallization method for preparing 7-ACT according to claim 1, characterized in that: In step 1), the hydrolyzate is first cooled to 0-5°C. When crystals are observed to precipitate from solution B, the addition of alkali is stopped and the temperatures of solution A and solution B are simultaneously raised until the crystals in solution B disappear.

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