CN212560058U

CN212560058U - L-aspartic acid amlodipine bulk drug crystallization refining device

Info

Publication number: CN212560058U
Application number: CN202022910299.8U
Authority: CN
Inventors: 许鹏飞; 于学珍; 蒋玉伟; 鲍晓芳
Original assignee: Nanjing Baimai Biotechnology Co ltd
Current assignee: Nanjing Baimai Biotechnology Co ltd
Priority date: 2020-12-08
Filing date: 2020-12-08
Publication date: 2021-02-19
Anticipated expiration: 2030-12-08

Abstract

The utility model discloses a L-aspartic acid amlodipine bulk drug crystallization refining device, which comprises a pressurizing dissolving tank, a filter and a crystallization reaction kettle, wherein the pressurizing dissolving tank adopts a stirring kettle connected with pressurizing equipment, the bottom of the pressurizing dissolving tank is provided with an outlet and is communicated with the inlet of the filter through a pipeline, and the outlet of the pressurizing dissolving tank is also directly communicated with the crystallization reaction kettle through a bypass pipeline with a control valve; the outlet of the filter is connected with the inlet of the crystallization reaction kettle through a pipeline, and the outlet of the crystallization reaction kettle is also connected with a buffer liquid storage tank. The utility model discloses a continuous crystallization of L-aspartic acid amlodipine bulk drug target crystal form to effectively realize the accurate control of gradient cooling through dual cooling and solenoid valve control, be favorable to obtaining the higher target crystal form of purity.

Description

L-aspartic acid amlodipine bulk drug crystallization refining device

Technical Field

The utility model mainly relates to an aspartic acid amlodipine bulk drug crystallization refining plant.

Background

Amlodipine is a new generation calcium ion antagonist, effectively overcomes the defects of unstable blood pressure reduction and large adverse reaction of a second generation calcium ion antagonist diltiazem and nifedipine, is clinically used for treating hypertension and stable angina pectoris, has the characteristics of obvious curative effect, stable effect, long drug effect time, small side effect and the like, is convenient to take, only needs to be taken once every day, has good tolerance of patients, is recognized as a safe and effective drug by the American FDA, is accepted by vast hypertension patients, and becomes a preferred drug for treating hypertension. The amlodipine salt comprises amlodipine besylate, amlodipine maleate, amlodipine mesylate, L-amlodipine aspartate, amlodipine nicotinate, amlodipine camsylate and the like, and the invention patent with the application number of CN201910065643.7 reports the crystal form of the L-amlodipine aspartate, but reports that the crystal form has poor stability and is not beneficial to preparing corresponding pharmaceutical preparations.

In the prior process of preparing a target crystal form of L-amlodipine aspartate, the source of a raw material liquid is unstable, so that the target product is excessive in impurities, meanwhile, the cooling speed of the amlodipine conducted by a target needs to be accurately controlled, the cooling speed of the prior reaction kettle device is difficult to accurately control, the temperature is reduced from 55 ℃ to room temperature or even 0 ℃ during feeding for nearly 8 hours, the control of cooling gradient is difficult to accurately control, so that the target crystal form is difficult to obtain, in addition, the target crystal form is more sticky during crystallization and precipitation, difficult to clean and lower the product yield.

Disclosure of Invention

The purpose of the invention is as follows: to the problem and the defect that above-mentioned exists, the utility model provides a L-aspartic acid amlodipine bulk drug crystallization refining plant has realized the continuous crystallization that L-aspartic acid amlodipine bulk drug target goes on to effectively realize the accurate control of gradient cooling through dual cooling and solenoid valve control, be favorable to obtaining the higher target crystal form of purity.

The technical scheme is as follows: in order to achieve the purpose, the utility model adopts the following technical scheme: an L-aspartic acid amlodipine bulk drug crystallization refining device comprises a pressurization dissolving tank, a filter and a crystallization reaction kettle,

the pressurized dissolving tank adopts a stirring kettle connected with a pressurizing device, an outlet is arranged at the bottom of the pressurized dissolving tank and is communicated with an inlet of the filter through a pipeline, and the outlet of the pressurized dissolving tank is also directly communicated with the crystallization reaction kettle through a bypass pipeline with a control valve; the outlet of the filter is connected with the inlet of the crystallization reaction kettle through a pipeline, and the outlet of the crystallization reaction kettle is also connected with a buffer liquid storage tank.

Preferably, the crystallization reaction kettle comprises a reaction kettle main body and a cover body arranged at the top of the reaction kettle main body, wherein the inner part and the outer wall of the reaction kettle main body are respectively provided with a cooling straight pipe and a cooling jacket, the top and the bottom of the reaction kettle main body are respectively provided with a raw material inlet and a product outlet, and the lower part of the reaction kettle main body is also provided with a reaction liquid outlet and is connected with a buffer liquid storage tank through a pipeline.

Preferably, the reaction kettle main body comprises an upper straight cylinder section and a lower conical section.

Preferably, an arc baffle is arranged below the bottom of the cooling straight pipe in the reaction kettle.

Preferably, a stirring paddle is further arranged in the crystallization reaction kettle.

Preferably, the control valve on the bypass pipeline between the outlet of the pressurized dissolving tank and the crystallization reaction kettle is an electromagnetic flow valve.

Preferably, the inner wall of the crystallization reaction kettle and the outer wall of the cooling straight pipe are both coated with Teflon coatings.

Has the advantages that: compared with the prior art, the utility model realizes the continuous crystallization of the L-amlodipine aspartate bulk drug target, and effectively realizes the precise control of gradient cooling through double cooling and electromagnetic valve control, thereby being beneficial to obtaining a target crystal form with higher purity; in addition, the conical section of the crystallization reaction kettle is more favorable for transferring the target crystal form product.

Drawings

Fig. 1 is a schematic structural diagram of a device for refining the amlodipine besylate bulk drug crystal according to the present invention.

The device comprises a pressurizing and dissolving tank 1, a filter 2, a crystallization reaction kettle 3, a reaction kettle main body 31, a cover body 32, a cooling straight pipe 33, a cooling jacket 34, a straight cylinder section 35, a conical section 36, a stirring paddle 37, an arc baffle 38, a buffering liquid storage tank 4, a bypass pipeline 5, an electromagnetic valve 6 and a sensor 7.

Detailed Description

The present invention will be further clarified by the following description with reference to the attached drawings and specific examples, which should be understood as being merely illustrative of the present invention and not limiting the scope of the present invention, and modifications of various equivalent forms of the present invention by those skilled in the art after reading the present invention, all fall within the scope defined by the appended claims of the present application.

As shown in fig. 1, an L-aspartic acid amlodipine bulk drug crystallization refining device mainly comprises a pressurized dissolving tank 1, a filter 2, a crystallization reaction kettle 3 and a buffer liquid storage tank 4, wherein: the pressurized dissolving tank 1 is used for heating, preserving heat and dissolving the crystal form raw material of the L-amlodipine aspartate, and meanwhile, the dissolved liquid medicine is conveyed in a mode of combining internal pressurization and control of the electromagnetic valve 6, so that the pollution of a liquid pump assembly and engine oil to the crystal form of the medicine is avoided; the filter 2 is used for carrying out primary filtration on the crystal form raw material to remove impurities and improve the purity of the crystal form; the crystallization reaction kettle 3 is the core equipment of the utility model, which mainly precisely controls the cooling speed of the liquid medicine, thereby obtaining the target crystal form of L-aspartic acid amlodipine.

Pressurization dissolving tank 1 adopts the stirred tank who is connected with the pressure equipment, just 1 bottom of pressurization dissolving tank is equipped with the export, and this export is connected through the entry of pipeline with filter 2, sets up bypass pipeline 5 simultaneously and is connected with crystallization reation kettle 3, and the pipeline of 2 entries of filter and bypass pipeline 5 set up solenoid electric valve respectively and carry out PIC control, and the export rethread pipeline of filter 2 is connected with 3 entries of crystallization reation kettle.

The bulk drug is sent into a pressurized dissolving kettle to be pressurized, heated and dissolved to form a uniform solution, the temperature of the bulk drug is 55 +/-3 ℃ when the bulk drug is discharged from the bottom of the pressurized dissolving kettle through a communicated pressurizing device, the bulk drug enters a filter 2 during normal conveying and is sent into a crystallization reaction kettle 3 after being filtered in a primary mode to be subjected to gradient slow cooling crystallization to obtain a target crystal form, the conveying speed is controlled through an electromagnetic valve 6 and pressure and flow stabilizing feeding is achieved during liquid drug conveying, the liquid drug conveying is matched with cooling control of the crystallization reaction kettle 3, when the crystallization reaction kettle 3 is in an emergency situation of too fast cooling, automatic deviation correction of step cooling is achieved through direct partial feeding of the electromagnetic valve 6 on a bypass pipeline 5, the liquid drug is automatically closed after a preset temperature range is achieved, and.

Crystallization reation kettle 3 includes reation kettle main part 31 and establishes the lid 32 at reation kettle main part 31 top, reation kettle main part 31's inside and outer wall are equipped with cooling straight tube 33 and cooling jacket 34 respectively to all coating has special fluorine dragon coating to avoid the clastic pollution of equipment wear at crystallization reation kettle 3's inner wall and cooling straight tube 33's outer wall. The top and the bottom of the reaction kettle main body 31 are respectively provided with a raw material inlet and a product outlet, and the lower part of the reaction kettle main body 31 is also provided with a reaction liquid outlet and is connected with the buffer liquid storage tank 4 through a pipeline.

Preferably, the reaction vessel body 31 comprises an upper straight tube section 35 and a lower tapered section 36, and the double cooling of the cooling straight tube 33 and the cooling jacket 34 improves the cooling efficiency and simultaneously maximizes the uniformity of cooling to avoid local over-temperature, and simultaneously improves the cooling uniformity through the stirring paddle 37. The lower section of the reaction kettle is designed into a conical section 36 for crystallization, sedimentation and standing, an arc baffle 38 is arranged below the bottom of the straight cooling pipe 33 in the reaction kettle to prevent disturbance, and finally, a target crystal form is obtained through extraction and filtration of a product at the bottom of the reaction kettle, and the residual liquid medicine is sent into a buffer liquid storage tank 4 or sent back to the system.

Claims

1. The L-aspartic acid amlodipine bulk drug crystallization refining device is characterized in that: comprises a pressurized dissolving tank (1), a filter (2) and a crystallization reaction kettle (3),

the pressurized dissolving tank (1) adopts a stirring kettle connected with a pressurizing device, an outlet is formed in the bottom of the pressurized dissolving tank (1) and is communicated with an inlet of the filter (2) through a pipeline, and the outlet of the pressurized dissolving tank (1) is directly communicated with the crystallization reaction kettle (3) through a bypass pipeline (5) with a control valve; the outlet of the filter (2) is connected with the inlet of the crystallization reaction kettle (3) through a pipeline, and the outlet of the crystallization reaction kettle (3) is also connected with a buffer liquid storage tank (4).

2. The L-aspartic acid amlodipine bulk drug crystallization refining device as claimed in claim 1, wherein: crystallization reation kettle (3) include reation kettle main part (31) and establish lid (32) at reation kettle main part (31) top, the inside and the outer wall of reation kettle main part (31) are equipped with cooling straight tube (33) and cooling jacket (34) respectively, the top and the bottom of reation kettle main part (31) are equipped with raw materials import and product respectively and adopt the export, the lower part of reation kettle main part (31) still is equipped with the reaction liquid export to be connected with buffering liquid storage pot (4) through the pipeline.

3. The L-aspartic acid amlodipine bulk drug crystallization refining device as claimed in claim 2, wherein: the reaction kettle main body (31) comprises an upper straight cylinder section (35) and a lower conical section (36).

4. The L-aspartic acid amlodipine bulk drug crystallization refining device as claimed in claim 2, wherein: an arc baffle (38) is arranged below the bottom of the straight cooling pipe (33) in the reaction kettle.

5. The L-aspartic acid amlodipine bulk drug crystallization refining device as claimed in claim 2, wherein: and a stirring paddle (37) is also arranged in the crystallization reaction kettle (3).

6. The L-aspartic acid amlodipine bulk drug crystallization refining device as claimed in claim 1, wherein: and a control valve on a bypass pipeline (5) between the outlet of the pressurized dissolving tank (1) and the crystallization reaction kettle (3) is an electromagnetic flow valve.

7. The L-aspartic acid amlodipine bulk drug crystallization refining device as claimed in claim 1, wherein: the inner wall of the crystallization reaction kettle (3) and the outer wall of the cooling straight pipe (33) are coated with Teflon coatings.