A gabapentin crystallization reactor

Abstract

The present invention relates to the technical field of crystallization reactors capable of producing crystallization, and more specifically, to a gabapentin crystallization reactor, comprising a reactor drum having a double-layered wall with a coolant inlet and outlet chamber formed between the double-layered walls; a material inlet disposed above the reactor drum and a material outlet disposed below the reactor drum; a motor disposed above the reactor drum and a stirring shaft disposed within the reactor drum, the motor driving the stirring shaft to rotate; a first stirring assembly and a second stirring assembly disposed sequentially from top to bottom on the stirring shaft, the first stirring assembly comprising two radial flow agitators spaced vertically apart, and the second stirring assembly comprising an anchor agitator; and a third stirring assembly, an axial flow agitator, disposed between the two radial flow agitators. The present invention utilizes three sets of stirring assemblies to achieve uniform mixing within the reactor drum, both top to bottom and inside and outside, thereby facilitating uniform crystallization.

Description

Technical Field

[0001] The present invention relates to the technical field of crystallization reaction kettles capable of generating crystals, and in particular to a gabapentin crystallization reaction kettle. Background Art

[0002] Gabapentin, whose scientific name is 1-(aminomethyl)-cyclohexylacetic acid, is the main ingredient in a new class of antiepileptic and antianxiety drugs. It is used as an adjunct treatment for patients with focal seizures that are uncontrolled or intolerant to conventional antiepileptic drugs, as well as for patients with focal seizures that subsequently become generalized. Gabapentin also has other novel uses, including: effectiveness for chemotherapy-induced nausea, treatment of neuropathic pain syndrome, and treatment for post-herpetic neuralgia. Gabapentin is typically used as a medication in the form of capsules or tablets. The raw material for these capsules or tablets is gabapentin powder. The main steps in producing gabapentin powder include preparing a gabapentin solution from gabapentin hydrochloride, stirring and heating until fully dissolved, evaporating the solution to form a supersaturated solution, and then cooling the gabapentin to crystallize it. The crystallized gabapentin is then dried to obtain a gabapentin solid.

[0003] Prior research on gabapentin preparation has primarily focused on its processing and synthesis methods, with relatively little research on its preparation equipment. Current gabapentin crystallization processes utilize conventional reactors equipped with internal stirring paddles and cooling pipes on the outer walls, which simultaneously cool and stir the solution to ensure uniform crystallization. However, due to the large size of conventional reactors, the coolant on the outer walls cools the surrounding solution more quickly, while cooling the solution in the center more slowly. Furthermore, as crystallization progresses, crystals adhere to the inner walls of the reactor, blocking heat transfer and further hindering crystallization within the reactor.

[0004] Therefore, people add scrapers around the stirring paddle to scrape out the crystals in time. For example, the crystallization reaction kettle disclosed in the prior art CN205965091U includes a kettle barrel, which has a cylindrical barrel and a conical barrel bottom. The cylindrical barrel and the conical barrel bottom have double-layer barrel walls, and a coolant inlet and outlet cavity is formed in the middle of the double-layer barrel walls. The characteristics are: a stirring shaft is provided in the kettle barrel, the upper end of the stirring shaft is exposed outside the kettle barrel and is connected to the output shaft of the reduction motor, and the stirring shaft is sequentially installed with first, second, third, fourth, fifth and sixth blades above and below. The first, second, third and fourth blades respectively have outer blade surfaces corresponding to the inner barrel wall of the cylindrical barrel, and the scraping areas of the first, second, third and fourth blades cover the entire inner barrel wall of the cylindrical barrel. The fifth and sixth blades respectively have outer blade surfaces corresponding to the inner barrel wall of the conical barrel bottom, and the scraping areas of the fifth and sixth blades cover the entire inner barrel wall of the conical barrel bottom. The utility model has a small dead angle for crystal accumulation, which is conducive to improving the crystallization rate.

[0005] However, during the preparation of gabapentin, the materials are usually added all at once, and a large amount of the materials accumulate at the bottom of the reactor. The stirring paddle in the prior art requires a long time to stir the solution to evenly distribute it. Crystallization may even begin at the bottom before it is evenly distributed. At the same time, the crystals that quickly crystallize at the bottom grow rapidly, resulting in a low actual density and high water content of the crystals. Subsequent drying treatment is required, which increases the preparation time and production efficiency, while better meeting the needs of downstream customers who prepare tablets. Summary of the Invention

[0006] In order to solve the above technical problems existing in the prior art, the present invention provides a gabapentin crystallization reactor to achieve uniform distribution of the gabapentin solution and improve the solid density of the gabapentin crystals.

[0007] To achieve the above object, the technical solution of the present invention is as follows:

[0008] A gabapentin crystallization reactor comprises a reactor drum having a double-layered wall with a coolant inlet and outlet cavity formed in the middle of the double-layered wall; a material inlet is provided above the reactor drum, and a material outlet is provided below the reactor drum; a motor is also provided above the reactor drum, and a stirring shaft is provided inside the reactor drum, and the motor drives the stirring shaft to rotate; a first stirring assembly and a second stirring assembly are provided on the stirring shaft in order from top to bottom, the first stirring assembly comprising two radial flow agitators spaced apart in an upper and lower manner, and the second stirring assembly comprising an anchor agitator; a third stirring assembly is provided between the two radial flow agitators, and the third stirring assembly is an axial flow agitator.

[0009] Furthermore, the second stirring assembly is arranged close to the bottom wall of the kettle drum, and the shape of the outer wall of the stirring paddle of the anchor stirrer is adapted to the curvature of the bottom wall of the kettle drum.

[0010] Furthermore, the anchor agitator includes a plurality of U-shaped stirring paddles, and a second scraper is provided on the outer wall of the U-shaped stirring paddle, and the outer wall of the second scraper abuts against the bottom wall or side wall of the kettle drum.

[0011] Furthermore, the first stirring assembly also includes a plurality of first scrapers, which are arranged between the two radial flow agitators, and the two ends of the first scrapers are connected to and support the blade ends of the radial flow agitators, and the outer wall of the first scraper abuts the side wall of the kettle drum.

[0012] Furthermore, the two ends of the first scraper are connected to the radial flow agitator through an adjustment mechanism, and the adjustment mechanism includes a horizontal spring and an adjustment rod; a spring is set at the end of the stirring blade of the radial flow agitator, one end of the adjustment rod is connected to the spring, and the other end of the adjustment rod is connected to the first scraper.

[0013] Furthermore, a first temperature sensor is arranged in the cooling liquid inlet and outlet cavity for measuring the cooling liquid temperature, and a second temperature sensor is arranged inside the reactor near the third stirring component for measuring the solution temperature at the center position inside the reactor; a third temperature sensor is arranged inside the reactor above the first stirring component and close to the side wall of the reactor for measuring the solution temperature at the upper position inside the reactor.

[0014] Furthermore, when the supersaturated gabapentin solution begins to cool down, temperature is collected at set time intervals, and the temperature collected by the first temperature sensor is set to T1, the temperature collected by the second temperature sensor is set to T2, and the temperature collected by the third temperature sensor is set to T3;

[0015] Among them, the cooling rate of T1 goes through three stages according to the timeline:

[0016] In the first stage, the cooling rate is ΔT1 and the stirring rate is ΔV1;

[0017] In the second stage, the temperature is kept constant and the stirring rate is ΔV2;

[0018] In the third stage, the cooling rate is ΔT2 and the stirring rate is ΔV3;

[0019] And, ΔT1<ΔT2, ΔV3>ΔV1>ΔV2.

[0020] Furthermore, ΔT1 is 20-30°C / h, and ΔT2 is 45-55°C / h.

[0021] Furthermore, ΔV1 is 45r / min-52r / min, ΔV2 is 27r / min-35r / min, and ΔV3 is 65r / min-70r / min.

[0022] Furthermore, during the cooling process, T1, T2, and T3 are compared, and judgment values Δt1 and Δt2 are set, and Δt2>Δt1.

[0023] When ≥Δt2, reduce the coolant temperature and increase the stirring rate;

[0024] Δt2> When ≥Δt1, increase the stirring rate;

[0025] <Δt1, compare T2 and T3, set the judgment value Δt3, and Δt1>Δt3,

[0026] <Δt3, no adjustment;

[0027] ≥Δt3, increase the stirring rate.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] The gabapentin crystallization reactor provided by the present invention has three stirring assemblies arranged inside the reactor, namely a radial flow first stirring assembly, an anchor flow second stirring assembly, and an axial flow third stirring assembly. The second stirring assembly causes the bottom material to flow upward, and the first stirring assembly causes part of the upwardly flowing solution to flow radially outward. After part of the solution continues to flow upward through the third stirring assembly, it flows outward, so that the interior of the reactor is uniformly mixed from top to bottom and from inside to outside, thereby facilitating uniform crystallization.

[0030] The gabapentin crystallization reactor provided by the present invention has scrapers arranged outside the first stirring component and the third stirring component, which can promptly scrape out crystals crystallized on the side walls, thereby preventing the crystals from affecting heat transfer and promoting crystallization.

[0031] The gabapentin crystallization reactor provided by the present invention monitors the temperature of the coolant, first slowly cools the temperature, then keeps the temperature for a certain period, and then cools the temperature slightly faster. While cooling, the stirring rate is controlled, thereby prompting the crystals to first form many tiny grains, then grow slowly to increase the density of the crystals, and then grow rapidly after the grains grow to a certain size. The purpose of increasing the crystal density is achieved, the water content of the crystals is reduced, and the subsequent drying time is shortened. At the same time, the crystallization efficiency and productivity are improved.

[0032] In addition, the present invention monitors the temperature of the coolant while also monitoring the internal temperature of the reactor. When the internal and external temperatures are higher than the set threshold, the temperature change is adjusted and controlled in a timely manner to ensure uniform temperature inside and outside the reactor and above and below, thereby improving crystallization uniformity. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 It is a structural schematic diagram of the present invention.

[0034] Figure 2 for Figure 1 A cross-sectional view of the enlarged figure.

[0035] Description of reference numerals:

[0036] 1. Kettle drum, 2. Material inlet, 3. Material outlet, 4. Motor, 5. Stirring shaft, 6. First stirring component, 601. Radial agitator, 602. First scraper, 603. Spring, 604. Adjusting rod, 7. Second stirring component, 701. U-shaped stirring paddle, 702. Second scraper, 8. Third stirring component, 9. First temperature sensor, 10. Second temperature sensor, 11. Third temperature sensor. DETAILED DESCRIPTION

[0037] The technical solution of the present invention will be clearly described below in conjunction with the accompanying drawings. Obviously, the described embodiments are not all embodiments of the present invention. All other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0038] It should be noted that, unless otherwise specifically stated, the relative arrangements of components and steps, numerical expressions, and numerical values described in these embodiments should not be construed as limiting the scope of the present invention. Furthermore, it should be understood that, for ease of description, the dimensions of the various components shown in the drawings are not necessarily drawn in accordance with actual proportional relationships; for example, the thickness, width, length, or distance of certain units may be exaggerated relative to other structures.

[0039] The following description of exemplary embodiments is merely illustrative and is not intended to limit the present invention, its application, or use in any sense. Technologies, methods, and apparatus known to those skilled in the art may not be discussed in detail herein, but to the extent applicable, such technologies, methods, and apparatuses should be considered part of this specification.

[0040] like Figure 1-2 As shown, the present invention provides a gabapentin crystallization reactor, comprising a reactor barrel 1 having a double-layered wall with a coolant inlet and outlet chamber formed in the middle of the double-layered wall. Coolant is circulated through the coolant inlet and outlet chamber to cool the reactor and crystallize the supersaturated solution in the reactor. A material inlet 2 is provided above the reactor barrel 1, and a material outlet 3 is provided below the reactor barrel 1. Materials required for preparing gabapentin crystals are added to the reactor through the material inlet 2. After crystallization, the liquid is discharged from the material outlet 3 at the bottom, and the reactor is opened to remove the crystals. A support is also provided at the bottom of the reactor to stably position the reactor.

[0041] A motor 4 is also provided above the kettle drum 1, and a stirring shaft 5 is provided inside the kettle drum 1. The stirring shaft 5 is vertically provided at the center of the kettle drum 1, and the motor 4 drives the stirring shaft 5 to rotate; a first stirring assembly 6 and a second stirring assembly 7 are sequentially provided on the stirring shaft 5 from top to bottom, and the first stirring assembly 6 includes two radial flow agitators 601 spaced apart from each other. The structures of the two radial flow agitators 601 may be the same or different. In this embodiment, the two radial flow agitators 601 both adopt the radial flow agitators in the prior art, and the specific structure will not be described in detail here. The second stirring assembly 7 includes an anchor agitator; a third stirring assembly 8 is provided between the two radial flow agitators 601, and the third stirring assembly 8 is an axial flow agitator. Similarly, the axial flow agitator used in this embodiment adopts the axial flow agitator in the prior art, and the specific structure will not be described in detail here.

[0042] Regarding the method of adding materials into the reactor at one time, three groups of stirring components are set inside the reactor. The second stirring component 7 promotes the bottom material to flow upward, and the first stirring component 6 promotes part of the upward-flowing solution to flow radially outward. Then, part of the solution continues to flow upward through the third stirring component 8 and then flows outward, thereby promoting and accelerating the flow of materials, so that the interior of the reactor achieves the purpose of uniform mixing from top to bottom and inside and outside, which is conducive to uniform crystallization.

[0043] The second stirring assembly 7 is arranged close to the bottom wall of the kettle drum 1 , and the shape of the outer wall of the stirring paddle of the anchor stirrer is adapted to the curvature of the bottom wall of the kettle drum 1 .

[0044] Furthermore, the anchor agitator includes several U-shaped stirring paddles 701, which are evenly spaced along the circumference of the stirring shaft 5. In this embodiment, two U-shaped stirring paddles 701 are provided, spaced 90° apart on the stirring shaft 5. A second scraper 702 is provided on the outer wall of each U-shaped stirring paddle 701, and the outer wall of the second scraper 702 abuts against the bottom wall or side wall of the kettle drum 1. The second scraper 702 scrapes away crystals on the bottom wall or side wall of the kettle drum 1, facilitating heat transfer and improving crystallization efficiency.

[0045] The first stirring assembly 6 also includes a plurality of first scrapers 602, which are positioned between the two radial flow agitators 601. The ends of the first scrapers 602 connect to and support the blade ends of the radial flow agitators 601, and the outer walls of the first scrapers 602 abut the sidewalls of the kettle drum 1. The number of first scrapers 602 can be the same as the number of radial flow agitators 601, or only two or three can be provided, evenly spaced around the circumference. The first scrapers 602 can scrape crystals off the sidewalls of the kettle drum 1, facilitating heat transfer and improving crystallization efficiency.

[0046] Preferably, reference Figure 2 The ends of the first scraper 602 are connected to the radial flow agitator 601 via an adjustment mechanism comprising a horizontal spring 603 and an adjustment rod 604. A spring 603 is provided at the end of the stirring blade of the radial flow agitator 601. One end of the adjustment rod 604 is connected to the spring 603, and the other end of the adjustment rod 604 is connected to the first scraper 602. The first scraper 602 is retractably mounted on the end of the stirring blade of the radial flow agitator 601 via the spring 603. When the first scraper 602 encounters a certain amount of scraping resistance, the elasticity of the spring 603 enables smooth rotation of the first scraper 602, reducing component damage. Furthermore, the assembly requirements for the stirring shaft 5 are reduced. The elasticity of the spring 603 eliminates the need for the stirring shaft 5 to be located at the center of the reactor, thereby improving assembly quality and efficiency.

[0047] In order to improve the crystal density and crystallization efficiency and control the parameters during crystallization, a first temperature sensor 9 is set in the coolant inlet and outlet chamber to measure the coolant temperature, and a second temperature sensor 10 is set inside the reactor near the third stirring component 8 to measure the solution temperature at the center position inside the reactor; a third temperature sensor 11 is set inside the reactor above the first stirring component 6 and close to the side wall of the reactor to measure the solution temperature at the upper position inside the reactor.

[0048] When the gabapentin supersaturated solution begins to cool down, the temperature is collected at set time intervals, and the temperature collected by the first temperature sensor 9 is set to T1, the temperature collected by the second temperature sensor 10 is set to T2, and the temperature collected by the third temperature sensor 11 is set to T3;

[0049] Among them, the cooling rate of T1 goes through three stages according to the timeline:

[0050] In the first stage, the cooling rate is ΔT1 and the stirring rate is ΔV1;

[0051] In the second stage, the temperature is kept constant and the stirring rate is ΔV2;

[0052] In the third stage, the cooling rate is ΔT2 and the stirring rate is ΔV3;

[0053] And, ΔT1<ΔT2, ΔV3>ΔV1>ΔV2.

[0054] The preferred cooling rate ΔT1 is 20-30°C / h, and ΔT2 is 45-55°C / h.

[0055] Preferably, the stirring rate ΔV1 is 45 r / min-52 r / min, ΔV2 is 27 r / min-35 r / min, and ΔV3 is 65 r / min-70 r / min.

[0056] During the cooling process, T1, T2, and T3 are compared, and judgment values Δt1 and Δt2 are set, and Δt2>Δt1.

[0057] When ≥Δt2, reduce the coolant temperature and increase the stirring rate;

[0058] Δt2> When ≥Δt1, increase the stirring rate;

[0059] <Δt1, compare T2 and T3, set the judgment value Δt3, and Δt1>Δt3,

[0060] <Δt3, no adjustment;

[0061] ≥Δt3, increase the stirring rate.

[0062] In this embodiment, the stirring rate is increased slowly, and the increase ratio can be increased in the range of 2-5 r / min. After that, the temperature is continuously measured and regulated according to the set time interval.

[0063] The gabapentin crystallization reactor provided by the present invention monitors the temperature of the coolant, first slowly cools the temperature, then keeps the temperature for a certain period, and then cools the temperature slightly faster. While cooling, the stirring rate is controlled, thereby prompting the crystals to first form many tiny grains, then grow slowly to increase the density of the crystals, and then grow rapidly after the grains grow to a certain size. The purpose of increasing the crystal density is achieved, the water content of the crystals is reduced, and the subsequent drying time is shortened. At the same time, the crystallization efficiency and productivity are improved.

[0064] In addition, the present invention monitors the temperature of the coolant while also monitoring the internal temperature of the reactor. When the internal and external temperatures are higher than the set threshold, the temperature change is adjusted and controlled in a timely manner to ensure uniform temperature inside and outside the reactor and above and below, thereby improving crystallization uniformity.

[0065] The above specific embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to examples, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the scope of the technical solutions of the present invention, and all of these should be included in the scope of the claims of the present invention.

Claims

1. A method for controlling the temperature of a gabapentin crystallization reactor, comprising a reactor drum having a double-layered wall with a cooling liquid inlet and outlet cavity formed between the double-layered wall; a material inlet disposed above the reactor drum and a material outlet disposed below the reactor drum; a motor disposed above the reactor drum and a stirring shaft disposed within the reactor drum, the motor driving the stirring shaft to rotate; and characterized in that: The stirring shaft is provided with a first stirring assembly and a second stirring assembly in order from top to bottom, the first stirring assembly includes two radial flow stirrers spaced apart from each other, and the second stirring assembly includes an anchor stirrer; A third stirring assembly is provided between the two radial flow stirrers, and the third stirring assembly is an axial flow stirrer; A first temperature sensor is provided in the coolant inlet and outlet chamber for measuring the coolant temperature; a second temperature sensor is provided inside the reactor near the third stirring assembly for measuring the solution temperature at the center of the reactor; a third temperature sensor is provided inside the reactor above the first stirring assembly and near the side wall of the reactor for measuring the solution temperature at the upper position inside the reactor; The temperature control method includes: when the gabapentin supersaturated solution begins to cool down, collecting temperature at set time intervals, setting the first temperature sensor collecting temperature to T1, the second temperature sensor collecting temperature to T2, and the third temperature sensor collecting temperature to T3; Among them, the cooling rate of T1 goes through three stages according to the timeline: In the first stage, the cooling rate is ΔT1 and the stirring rate is ΔV1; In the second stage, the temperature is kept constant and the stirring rate is ΔV2; In the third stage, the cooling rate is ΔT2 and the stirring rate is ΔV3; And, ΔT1<ΔT2, ΔV3>ΔV1>ΔV2; ΔT1 is 20-30℃ / h, ΔT2 is 45-55℃ / h; ΔV1 is 45r / min-52r / min, ΔV2 is 27r / min-35r / min, and ΔV3 is 65r / min-70r / min; During the cooling process, T1, T2, and T3 are compared, and judgment values Δt1 and Δt2 are set, and Δt2>Δt1. When ≥Δt2, reduce the coolant temperature and increase the stirring rate; Δt2> When ≥Δt1, increase the stirring rate; <Δt1, compare T2 and T3, set the judgment value Δt3, and Δt1>Δt3, <Δt3, no adjustment; ≥Δt3, increase the stirring rate.

2. The temperature control method of the gabapentin crystallization reaction kettle according to claim 1, characterized in that: The second stirring assembly is arranged close to the bottom wall of the kettle drum, and the shape of the outer wall of the stirring paddle of the anchor stirrer is adapted to the curvature of the bottom wall of the kettle drum.

3. The temperature control method of the gabapentin crystallization reaction kettle according to claim 2, characterized in that: The anchor agitator includes a plurality of U-shaped agitating blades, and a second scraper is provided on the outer wall of the U-shaped agitating blade. The outer wall of the second scraper abuts against the bottom wall or the side wall of the kettle drum.

4. The temperature control method of the gabapentin crystallization reaction kettle according to claim 1, characterized in that: The first stirring assembly also includes a plurality of first scrapers, which are arranged between the two radial flow agitators, and the two ends of the first scrapers are connected to and support the blade ends of the radial flow agitators, and the outer walls of the first scrapers abut against the side walls of the kettle drum.

5. The temperature control method of the gabapentin crystallization reaction kettle according to claim 4, characterized in that: The two ends of the first scraper are connected to the radial flow agitator through an adjustment mechanism, and the adjustment mechanism includes a horizontal spring and an adjustment rod; a spring is set at the end of the stirring blade of the radial flow agitator, one end of the adjustment rod is connected to the spring, and the other end of the adjustment rod is connected to the first scraper.

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