Crystallization method of pregabalin

Abstract

The invention discloses a crystallization method of pregabalin, which is characterized in that high-speed shearing equipment is combined with a pregabalin crystallization kettle for use, and pregabalin with different particle size ranges can be obtained by controlling different shearing rotating speeds and time. According to the method, crushing and sieving are not needed, the yield is high, crystal seeds do not need to be added in the crystallization process, the treatment operation on the crystal seeds is omitted, and the danger of opening a tank in the midway can also be avoided; the preparation method is convenient to operate, high in safety and capable of meeting the requirements of industrial production, and the prepared pregabalin is regular in morphology, smooth in surface, good in fluidity and capable of meeting the requirements of preparations.

Description

[0001] This invention is a divisional application of a Chinese invention patent (application date is September 29, 2021, application number is 2021111525978, and the name of the invention is “A crystallization method of pregabalin”). Technical Field

[0002] The invention belongs to the field of chemical pharmacy, and particularly relates to a crystallization method of pregabalin. Background Art

[0003] Chemical processes are complex and cumbersome, accompanied by the transfer and occurrence of mass, heat and momentum. As the output scale changes, the material of production equipment, production process conditions, production methods, product yields, etc. will change, especially the product particle size and product yield are quite different from laboratory results, which is attributed to the "amplification effect". In the chemical production process, the "amplification effect" is inevitable, and the elimination or reduction of the amplification effect is a crucial step in chemical production. The "amplification effect" is particularly significant in the refining process of pregabalin. The particle size of the obtained API product is much larger than the laboratory results, and D (90) can reach more than 1000μm, which cannot be directly used for preparations. In particular, the heat transfer of glass-lined reactors is slow, and the "amplification effect" is more significant.

[0004] If you want to meet the requirements of the preparation, you need to grind and sieve the raw pregabalin powder to reach the particle size range required for the preparation. However, the raw pregabalin powder is relatively brittle and easy to break. Using a conventional mechanical grinder such as FZB-450, it is very easy to turn into fine powder. The particle size is too small and the shape is irregular, resulting in extremely poor fluidity and it is difficult to meet the requirements of the preparation. Summary of the invention

[0005] In order to solve the problems existing in the prior art, the present invention provides a crystallization method of pregabalin, which can stably obtain pregabalin raw materials with different particle size ranges according to demand, and the crystallization method does not need to add crystal seeds, crush and sieve, is simple to operate, safe and controllable, and is suitable for all crystallization kettles and large-scale industrial production.

[0006] The invention provides a crystallization method of pregabalin, which comprises cooling of a clear solution and a heat preservation crystallization process. During the whole heat preservation crystallization process, a high-speed shearing device is used to perform cyclic shearing on a suspension of heat preservation crystallization, and different shearing effects are achieved by controlling the rotation speed and time of the high-speed shearing device, so as to obtain pregabalin with different particle size ranges.

[0007] Furthermore, in a method for crystallizing pregabalin, the cooling of the clear solution includes a primary cooling process and a secondary stirring cooling process.

[0008] Furthermore, a method for crystallizing pregabalin further comprises a process for preparing a clear solution.

[0009] As a preferred technical solution, the process for preparing a clear solution comprises dissolving a crude pregabalin product in a mixed solution of an organic solvent and water, heating the solution to obtain a clear solution.

[0010] As a further preferred technical solution, the organic solvent in the process of preparing the clear solution is isopropanol, methanol or ethanol, the volume ratio of the organic solvent to water is 1:1-1:2, and the weight / volume (Kg / L) ratio of pregabalin to the mixed solution is 1:8-1:13.

[0011] As a preferred technical solution, the temperature of the supernatant during the preparation of the supernatant is 70-85°C.

[0012] As a preferred technical solution, the one-time cooling process is to cool the clear solution from 70-85°C to 60-65°C within 100±10min.

[0013] As a preferred technical solution, the secondary stirring and cooling process is to cool the clear liquid from 60-65°C to 0-10°C within 200±20min, while stirring is started at the same time, and the stirring speed is 50-70rpm.

[0014] As a preferred technical solution, the heat preservation and crystallization time in the heat preservation and crystallization process is 120 minutes.

[0015] As a preferred technical solution, during the heat preservation crystallization process, the high-speed shearing device is connected to the lower liquid outlet of the pregabalin crystallization kettle through an infusion pipeline, and the liquid outlet is provided with a liquid outlet control valve.

[0016] As a preferred technical solution, the type of the crystallization kettle in the heat preservation crystallization process includes but is not limited to a stainless steel reactor and a glass-lined reactor, and is more preferably a glass-lined reactor.

[0017] As a preferred technical solution, the high-speed shearing equipment in the heat preservation crystallization process includes but is not limited to a high-speed shearing pump, a high-shear emulsifier, a high-shear disperser, a high-speed shearing wet mixing granulator, and a high-shear stirring equipment, and more preferably a high-speed shearing pump.

[0018] As a preferred technical solution, the rotation speed of the high-speed shearing device during the heat preservation crystallization process is 500-2900 rpm, preferably 1500-2700 rpm.

[0019] As a preferred technical solution, the particle size range of pregabalin obtained in the heat preservation crystallization process is D90=150-700 μm, preferably D90=190-460 μm, D50=70-280 μm.

[0020] The invention controls the cooling time and the stirring time, and connects the crystallization kettle with the high-speed shearing device to control different shearing speeds and times, and can obtain pregabalin with different particle size ranges without crushing and screening. The invention has high yield, and does not need to add crystal seeds during the crystallization process, which not only saves the processing operation of the crystal seeds, but also avoids the danger of opening the can in the middle of the process. The invention is easy to operate, has high safety, meets the requirements of industrial production, and the obtained pregabalin has a regular morphology, a smooth surface, and good fluidity, which can meet the requirements of preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Schematic diagram of the connection between the crystallization kettle and the high-speed shearing device in Example 1.

[0022] Among them, 1 is a stirrer, 2 is a glass-lined reactor, 3 is a liquid outlet control valve, 4 is a liquid infusion pipeline, and 5 is a high-speed shear pump.

[0023] Figure 2 This is a particle size diagram of the pregabalin finished product obtained in Example 2.

[0024] Figure 3 The particle size diagram of the pregabalin finished product obtained in Example 3.

[0025] Figure 4 The particle size diagram of the pregabalin finished product obtained in Example 4.

[0026] Figure 5 This is a particle size diagram of the pregabalin finished product obtained in Example 5. DETAILED DESCRIPTION

[0027] The following examples are specific descriptions of the present invention and are not intended to limit the scope of the present invention.

[0028] The particle size detection instrument of the present invention is an OMEC LS-POP (9) laser particle size analyzer, and the analysis method is as follows:

[0029]

[0030] Example 1

[0031] like Figure 1It is a schematic diagram of the connection between the crystallization kettle and the high-speed shearing equipment, wherein 1 is an agitator, 2 is a glass-lined reactor, 3 is a liquid outlet control valve, 4 is a liquid infusion pipeline, and 5 is a high-speed shearing pump. The lower liquid outlet of the glass-lined reactor 2 is provided with a liquid outlet control valve 3, and the liquid outlet is connected to the high-speed shearing pump 5 through a liquid infusion pipeline 4. The secondary stirring is cooled to 0-10°C, and the heat preservation crystallization is carried out. The liquid outlet control valve 3 is opened, and the feed enters the high-speed shearing pump 5 from the liquid outlet through the liquid infusion pipeline 4. The high-speed shearing pump 5 is turned on. The rotor of the high-speed shearing pump generates high shear speed and kinetic energy through rotation, so that the material is subjected to comprehensive effects such as impact, shearing, and friction in the rotor and its gap, thereby achieving the effect of refining particles. The sheared material circulates into the glass-lined reactor 2 and circulates continuously during the entire heat preservation crystallization process.

[0032] Example 2

[0033] 200 kg of pregabalin, 800 L of isopropanol and 800 L of water were added to a glass-lined crystallization kettle, heated to 85°C to dissolve, and kept warm for 30 minutes. The reaction system was cooled from 85°C to 61°C within 100±10 minutes, and stirring was started at a speed of 50 rpm. The temperature was continued to drop to 0-10°C within 200±20 minutes. The high-speed shearing device was turned on at a speed of 500 rpm, and the temperature was kept for crystallization for 120 minutes. The white crystals were filtered and dried in vacuum at 65°C. The yield was 80%, and D(90) was 627 μm. The relevant particle size data are shown in Table 1 and Figure 2 .

[0034] Example 3

[0035] 200 kg of pregabalin, 800 L of ethanol and 800 L of water were added to a glass-lined crystallization kettle, heated to 83 ° C to dissolve, and kept warm for 30 minutes. The reaction system was cooled from 83 ° C to 60 ° C within 100 ± 10 minutes, and stirring was started at a stirring speed of 60 rpm. The temperature was continued to drop to 0-10 ° C within 200 ± 20 minutes. The high-speed shearing device was turned on at a speed of 1500 rpm, and the crystallization was kept warm for 120 minutes. Filter to obtain white crystals, which were vacuum dried at 65 ° C. The yield was 84%, D (90) was 451 μm, and the relevant particle size data are shown in Table 1 and Figure 3 .

[0036] Example 4

[0037] 200 kg of pregabalin, 640 L of isopropanol and 960 L of water were added to a glass-lined crystallization kettle, and the temperature was raised to 83°C to dissolve. After keeping the temperature for 30 minutes, the reaction system was cooled from 83°C to 62°C within 100±10 minutes, and stirring was started at a speed of 60 rpm. The temperature was continued to drop to 0-10°C within 200±20 minutes, and the high-speed shearing device was turned on at a speed of 2000 rpm. The temperature was kept for crystallization for 120 minutes, and filtered to obtain white crystals. The crystals were vacuum dried at 65°C with a yield of 82% and a D(90) of 342 μm. The relevant particle size data are shown in Table 1 and Figure 4 .

[0038] Example 5

[0039] 200 kg of pregabalin, 800 L of isopropanol and 800 L of water were added to a glass-lined crystallization kettle, heated to 84°C to dissolve, and kept warm for 30 minutes. The reaction system was cooled from 84°C to 60°C within 100±10 minutes, and stirring was started at a stirring speed of 70 rpm. The temperature was continued to drop to 0-10°C within 200±20 minutes, and the high-speed shearing device was turned on at a speed of 2700 rpm. The crystallization was kept warm for 120 minutes, and filtered to obtain white crystals. The yield was 79% and D(90) was 199 μm at 65°C. The relevant particle size data are shown in Table 1 and Figure 5 .

[0040] Table 1

[0041] batch D(10) D(50) D(90) Example 2 136μm 330μm 627μm Example 3 72μm 209μm 451μm Example 4 80μm 200μm 342μm Example 5 28μm 87μm 199μm

Claims

1. A method for crystallizing pregabalin, comprising cooling a clear solution and maintaining the solution for crystallization, characterized in that During the entire heat preservation and crystallization process, the heat preservation and crystallization suspension is cyclically sheared by using a high-speed shearing device, and different shearing effects are achieved by controlling the rotation speed and time of the high-speed shearing device to obtain pregabalin in different particle size ranges.

2. The crystallization method of pregabalin according to claim 1, characterized in that The cooling of the clear solution includes a primary cooling process and a secondary stirring cooling process.

3. The crystallization method of pregabalin according to claim 1, characterized in that The crystallization method also includes a process for preparing a clear solution, which includes dissolving the crude pregabalin in a mixed solution of an organic solvent and water, heating the solution to obtain a clear solution, and the temperature of the heating solution is 70-85°C.

4. The crystallization method of pregabalin according to claim 3, characterized in that The organic solvent is isopropanol, methanol or ethanol, the volume ratio of the organic solvent to water is 1:1-1:2, and the weight / volume (Kg / L) ratio of pregabalin to the mixed solution is 1:8-1:

13.

5. The crystallization method of pregabalin according to claim 2, characterized in that The primary cooling process is to cool the clear solution from 70-85°C to 60-65°C within 100±10min.

6. The method for crystallizing pregabalin according to claim 2, characterized in that The secondary stirring and cooling process is to cool the clear solution from 60-65°C to 0-10°C within 200±20min, while stirring is started at the same time, and the stirring speed is 50-70rpm.

7. A method for crystallizing pregabalin according to any one of claims 1 to 6, characterized in that The heat preservation and crystallization time in the heat preservation and crystallization process is 120 minutes.

8. The method for crystallizing pregabalin according to claims 1-6, characterized in that The high-speed shearing equipment includes, but is not limited to, a high-speed shearing pump, a high-shearing emulsifier, a high-shearing disperser, a high-speed shearing wet mixing granulator, and a high-shearing stirring equipment, and more preferably a high-speed shearing pump.

9. The method for crystallizing pregabalin according to claim 8, characterized in that The rotation speed of the high-speed shearing device is 500-2900 rpm, preferably 1500-2700 rpm.

10. The method for crystallizing pregabalin according to any one of claims 1 to 6, characterized in that The particle size range of pregabalin obtained in the heat preservation crystallization process is D90=150-700 μm, preferably D90=190-460 μm, and D50=70-280 μm.

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