A jacketed crystallizer based on heat pipe phase change heat transfer and application thereof

Abstract

This invention discloses a jacketed crystallizer based on heat pipe phase change heat transfer and its application, belonging to the field of jacketed reactor technology. The jacketed crystallizer includes a reactor body and a top cover. The reactor body includes a stirred tank and a jacket. Two coils are installed inside the jacket: a cooling coil near the top and a heating coil near the bottom. After the working fluid is filled into the jacket, it can be heated and evaporated by the heating coil and condensed by the cooling coil. A temperature sensor A is installed inside the jacket to monitor the real-time temperature of the working fluid. This invention controls the temperature and flow rate of the medium in the heating and cooling coils, thereby controlling the slow and uniform rise and fall of the working fluid temperature, and can be applied to the field of drug crystallization. Furthermore, this invention can also fill only the heating or cooling coils with the medium to achieve efficient control of the temperature rise or fall inside the reactor, making it suitable for use as a melting pot, reaction vessel, etc.

Description

Technical Field

[0001] This invention relates to the field of jacketed reactor technology, specifically to a jacketed crystallizing reactor based on phase change heat transfer. Background Technology

[0002] Since the 1920s, the study of drug polymorphism has received increasing attention. Polymorphism affects physicochemical properties such as solubility, dissolution rate, and bioavailability; different polymorphs of the same drug may exhibit drastically different drug activities. Therefore, polymorph screening is crucial in the crystallization process of polymorphic drugs. For drugs with high medicinal value in their metastable polymorphs, screening for metastable polymorphs is necessary during the crystallization process. Due to the solubility advantage of the most stable polymorph, obtaining metastable polymorphs is more difficult during drug crystallization. Screening for metastable polymorphs requires designing specific crystallization processes based on their physicochemical properties. This often necessitates specific process parameters such as solvents, cooling rates, and temperature uniformity, which places new demands on crystallization equipment.

[0003] For example, tolmediazole, also known as mebendazole, has the molecular formula C. 16 H 13 N3O3 is a broad-spectrum anthelmintic used to treat pinworm, ascariasis, and whipworm infections. Mebendazole exists in three crystal forms: A, B, and C. Form C is widely used in medicine due to its relatively good water solubility. However, form C is metastable, and conventional crystallization methods struggle to obtain high-purity C-form crystals. Cooling crystallization in 2-propanol is one method for obtaining C-form mebendazole crystals. The crystal morphology can be altered by changing the cooling rate and crystallization temperature. Excessively high cooling rates and uneven temperature fields within the material lead to uneven crystal size distribution. Cooling rates below 3°C / h yield C-form mebendazole crystals with uniform particle size.

[0004] Conventional crystallization equipment cannot meet the cooling rate requirements of the tolueneimidazole crystallization process, and the uniformity of the internal temperature of the material is also insufficient to meet the crystallization requirements of the metastable crystal form. Therefore, this invention, based on the heat pipe phase change heat transfer principle, designs a crystallization device that utilizes the evaporation and condensation process of the working fluid for heat transfer, thereby controlling the temperature of the tolueneimidazole material inside the reactor. This device can ensure the uniformity of the internal temperature of the tolueneimidazole material and the uniform and slow decrease of the crystallization temperature, thus enabling the tolueneimidazole crystals to crystallize into the metastable crystal form C. Summary of the Invention

[0005] For the crystallization process of metastable drug crystal forms, the internal temperature uniformity of the material and the slow and uniform decrease in crystallization temperature are crucial. This invention provides a reactor based on phase change heat transfer, which can obtain drug crystals of specific metastable forms while ensuring the safety of the drug crystallization process.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] A jacketed crystallizer based on heat pipe phase change heat transfer includes a vessel body 1 and a stirring device 2, which is inserted into the vessel body 1 from the top. A jacket 3 surrounds the entire vessel body 1 from the outside and together with the vessel body 1 forms a heat exchange zone 4. A cooling coil 10 is provided at the top of the heat exchange zone 4, and a heating coil 11 is provided at the bottom of the heat exchange zone 4. The heat exchange zone 4 is filled with a working fluid. A temperature sensor A107 is provided inside the heat exchange zone 4 to monitor the real-time temperature of the working fluid.

[0008] Furthermore, the vessel body 1 is equipped with a stirring paddle 9, a temperature sensor B110, and a baffle 7. The stirring paddle 9 is used to stir the materials in the vessel body 5, the temperature sensor B110 is used to monitor the real-time temperature of the reactants, and the baffle 7 is arranged on the inner wall of the vessel body 5 in an axially symmetrical manner to increase the degree of mixing of the materials.

[0009] Furthermore, the vessel body 1 is composed of a cylindrical body 5 and a head 6; the material is stirred and mixed by a speed-regulating motor 8 and a stirring paddle 9 driven by it.

[0010] Furthermore, the two ends of the cooling coil 10 are respectively connected to the refrigerant inlet 101 and the refrigerant outlet 102 provided on the outer wall of the jacket 3, and the two ends of the heating coil 11 are respectively connected to the heat medium inlet 103 and the heat medium outlet 104 provided on the outer wall of the jacket 3.

[0011] Furthermore, a vacuum valve 12 is installed on the outer wall of the jacket 3, which is connected to the heat exchange zone 4 and is used for working fluid filling and vacuuming operations. The heat exchange zone is equipped with a pressure sensor 105 and a rupture disc 106. The pressure sensor 105 is used to measure the temperature inside the heat exchange zone 4. The rupture disc 106 ruptures when the pressure in the heat exchange zone 4 is higher than 0.3 MPa, releasing the pressure inside the jacket and preventing excessive pressure inside the jacket, thus ensuring the safe operation of the equipment.

[0012] Furthermore, the outer wall of the jacket 3 is provided with a blind hole 13, which is inserted obliquely into the heat exchange area 4 for installing a temperature sensor A107.

[0013] Furthermore, a working fluid drain port 14 is provided at the bottom of the jacket 3.

[0014] Furthermore, an observation hole 108 and a temperature measuring hole 109 are provided on the top of the vessel. The temperature measuring hole 109 is used to install a temperature sensor B110. The material drain port 15 is located at the bottom of the end cap 6.

[0015] Furthermore, the refrigerant inlet 101 and refrigerant outlet 102 are located above the outer wall of the jacket 3 and are arranged horizontally side by side, connected to the external refrigerant circulation path; the heat medium inlet 103 and outlet 104 are arranged horizontally side by side below the outer wall of the jacket 3 and are connected to the external heat medium circulation path. The external refrigerant circulation path consists of a water storage tank and a constant temperature water bath, and the external refrigerant circulation path consists of a refrigeration unit and a constant temperature water bath. The constant temperature water bath consists of an electric heating rod and a centrifugal pump, and the refrigeration unit consists of a compressor and a centrifugal pump.

[0016] A jacketed crystallizer based on heat pipe phase change heat transfer is applied in crystallization and other fields.

[0017] Compared with the prior art, the advantages of this invention are:

[0018] (1) This invention incorporates cooling and heating coils in the jacket, enabling the working fluid to evaporate on the heating coil and condense on the cooling coil. Simultaneously, during operation, the working fluid vapor condenses and releases heat on the vessel wall, achieving efficient and precise heat transfer. Furthermore, the phase change process of the working fluid on the vessel wall ensures a highly uniform wall temperature, thereby guaranteeing the uniformity of the temperature within the material, allowing the material to crystallize in a specific crystal form with uniform crystal size.

[0019] (2) This invention simultaneously introduces a medium into both the heating coil and the cooling coil, enabling a slow and uniform decrease in the temperature of the material inside the reactor, which has broad application prospects in the crystallization field. In addition, this invention can also introduce a medium only into the heating coil or the cooling coil, thereby achieving efficient control over the rise or fall of the material temperature inside the reactor. When only the heating coil is circulated with a heating medium, this invention can be used as a melting pot, etc.; when only the cooling coil is circulated with a cooling medium, this invention can be used as a reaction vessel, etc., with broad application prospects.

[0020] (3) This invention controls the working fluid temperature in the heat exchange area by controlling the temperature and flow rate of the medium in the heating and cooling coils, thereby indirectly controlling the temperature of the material inside the reactor. Simultaneously, when the working fluid temperature overshoots during heating or cooling, it can be quickly adjusted using another set of coils without the need for slow control through heat exchange with the material and the outside environment. Therefore, it can achieve high-precision control of the material temperature inside the reactor. This invention can achieve heating and cooling rates as low as 0.3℃ / h.

[0021] (4) This invention can achieve a high degree of temperature uniformity inside the material in the reactor. The working fluid in the heat exchange area transfers heat to the material inside the reactor through condensation and heat release on the reactor wall. The working fluid vapor is evenly distributed in the jacket, so the condensation and heat release process of the working fluid vapor on the outer wall of the reactor is also uniform. At a cooling rate of 0.3℃ / h, the temperature difference between the highest and lowest points of the wall temperature is less than 1℃. Attached Figure Description

[0022] Figure 1This is a front sectional view of the structure of the present invention.

[0023] Figure 2 This is a right-side view of the present invention.

[0024] Figure 3 This is a partial sectional view of the right side of the present invention.

[0025] In the attached diagram: 1. Reactor body; 2. Stirring device; 3. Jacket; 4. Heat exchange zone; 5. Main body of the vessel; 6. End cap; 7. Baffle; 8. Speed ​​regulating motor; 9. Stirring paddle; 10. Cooling coil; 11. Heating coil; 12. Vacuum valve; 13. Blind hole; 14. Working fluid drain port; 15. Material drain port; 101. Refrigerant inlet; 102. Refrigerant outlet; 103. Heat medium inlet; 104. Heat medium outlet; 105. Pressure sensor; 106. Rupture disc; 107. Temperature sensor A; 108. Observation hole; 109. Temperature measuring hole; 110. Temperature sensor B. Detailed Implementation

[0026] To make the advantages and technical solutions of the present invention clearer and easier to understand, the following examples, in conjunction with the accompanying drawings, will provide a clear and complete description of the structure and technical solutions of the present invention.

[0027] See Figure 1 A jacketed crystallizer based on phase change heat transfer consists of a vessel body 1 and a stirring device 2. The stirring device 2 is placed on top of the vessel body 1. A speed-regulating motor 8 on the stirring device 2 has a connecting rod that is directly connected to a stirring paddle 9 inside the vessel body 1. The stirring paddle 9 extends into the material inside the vessel body 1 and is driven by the speed-regulating motor 8 to stir the material. The top of the vessel is provided with an observation hole 108 and a temperature measuring hole 109. A temperature sensor B110 is installed in the through hole.

[0028] The jacket 3 surrounds the entire vessel body 1 from the outside and together they form the heat exchange zone 4, where tolueneimidazole material crystallizes. The main body of the vessel body 1 is a cylindrical shell 5 with an elliptical end cap 6 at the bottom. A baffle 7 is welded inside the shell of the vessel body 1, and the bottom of the end cap is a material drain port 15, which is controlled by a valve.

[0029] See Figure 2The jacket 3 is located outside the vessel body 1, completely enclosing the vessel body 1 and partially covering the vessel body 1 end cap 6, leaving space for the material drain port 15. The working fluid is introduced into the jacket under vacuum conditions through the vacuum valve 12. The upper part of the heat exchange zone 4 is equipped with a cooling coil 10, and the lower part with a heating coil 11, which are respectively connected to and fixed within the heat exchange zone 4 via the refrigerant inlet 101, refrigerant outlet 102, and heat medium inlet 103 and heat medium outlet 104 on the wall of the jacket 3. The heat medium and refrigerant are introduced into the coils through their respective inlets and outlets. The working fluid inside the jacket evaporates on the heating coil 11 and is cooled by the cooling coil 10 and the wall of the vessel body 1. The temperature of the gaseous working medium is detected by temperature sensor A107 inside the blind hole 13 on the outer wall of jacket 3; the gas pressure inside the vessel 1 is detected by gas pressure sensor 105 inside the top branch pipe of jacket 3. After the crystallization process is completed, vacuum valve 12 is opened to balance the gas pressure inside and outside heat exchange zone 4, and the working medium is released through working medium drain port 14.

[0030] Example 1

[0031] The material selected is a 0.55 mg / ml methylimidazolium isopropanol solution, with methanol as the working fluid and water as the heat and coolant. First, add 8 kg of the methylimidazolium solution to the vessel 1. Place the stirring device 2 on the vessel and turn on the speed-regulating motor 8. Install the temperature sensor B110 in the temperature measuring port 109. Open the vacuum valve 12 on the wall of the jacket 3 and connect the vacuum pump to it. Turn on the vacuum pump to evacuate the heat exchange zone 4. Observe the gas pressure gauge 110. Once the gas pressure in the heat exchange zone 4 meets the requirements, close the vacuum valve 12 and then turn off the vacuum pump. After a short wait, repeat the above evacuation operation to ensure that all non-condensable gases in the heat exchange zone 4 are extracted. Then close the vacuum valve 12 and the vacuum pump. Connect the working fluid container to the vacuum valve 12 and open it. The material is filled into the heat exchange zone 4 under atmospheric pressure. After filling with 25% of the working fluid by mass, close the vacuum valve 12.

[0032] The heat transfer medium inlet 103 and outlet 104 are connected to the heat transfer medium circulation path, and the cold transfer medium inlet 101 and outlet 102 are connected to the cold transfer medium circulation path. The heat transfer medium inlet temperature is set to 70℃, the flow rate to 2.4 kg / min, and the cold transfer medium inlet temperature to 40℃. The flow rate is 0.78 kg / min, the initial working fluid temperature is 55℃, and the cooling rate is 3℃ / h. By controlling the temperature and flow rate of the heat and cold transfer medium, the temperature and cooling rate of the gaseous working fluid in heat exchange zone 4 are controlled, thereby indirectly controlling the temperature of the material in vessel 1, achieving a uniform temperature decrease and uniform crystallization process. After uniform cooling for 5 hours, the material outlet is opened to remove the methylimidazole crystals and solution, separating C-type methylimidazole crystals. A yield of 97.2% and a purity of 99.4% of C-type tolueneimidazole crystals are obtained.

[0033] Example 2

[0034] The material selected is solid chocolate blocks, methanol is used as the working fluid, and water is used as the heat transfer medium; no refrigerant is introduced. 6 kg of solid chocolate blocks are placed in the reactor, and temperature sensor B110 is installed in the temperature measuring port 109. Vacuum valve 12 is opened, and the vacuum pump is connected to vacuum valve 12. The vacuum pump is then turned on to evacuate the heat exchange zone 4. The evacuation operation in heat exchange zone 4 is performed according to Example 1. The gas pressure gauge 110 is observed. Once the gas pressure inside the jacket meets the requirements, vacuum valve 12 is closed, and then the vacuum pump is turned off.

[0035] Connect the heat transfer medium inlet 103 and outlet 104 to the heat transfer medium circulation path, and connect the coolant inlet 101 and outlet 102 to the coolant circulation path. Set the heat transfer medium inlet temperature to 50℃ and the flow rate to 5kg / min. After the working fluid temperature rises to 48℃, maintain it stable and turn on the agitator. After maintaining this temperature for 30 minutes, open the material drain port to discharge the chocolate mixture.

[0036] The above description is only one specific embodiment of the present invention; however, the scope of protection of the present invention is not limited thereto. Improvements and equivalent substitutions made by those skilled in the art within the scope of the technology disclosed in the present invention should also be covered within the scope of protection of the present invention.

Claims

1. A jacketed crystallizer based on heat pipe phase change heat transfer, characterized in that, It includes a vessel body (1) and a stirring device (2), the stirring device (2) being inserted into the vessel body (1) from the top; a jacket (3) wraps around the entire vessel body (1) from the outside and together with the vessel body (1) forms a heat exchange zone (4), a cooling coil (10) is provided at the top of the heat exchange zone (4), a heating coil (11) is provided at the bottom of the heat exchange zone (4), and a working medium is filled in the heat exchange zone (4); a temperature sensor A (107) is provided inside the heat exchange zone (4) to monitor the real-time temperature of the working medium.

2. The jacketed crystallizer based on heat pipe phase change heat transfer according to claim 1, characterized in that, The vessel body (1) is equipped with a stirring paddle (9), a temperature sensor B (110), and a baffle (7). The stirring paddle (9) is used to stir the material in the vessel body (5). The temperature sensor B (110) is used to monitor the real-time temperature of the reactant. The baffle (7) is set on the inner wall of the vessel body (5) and is axially symmetrically distributed to increase the degree of mixing of the material.

3. A jacketed crystallizer based on heat pipe phase change heat transfer as described in claim 1, characterized in that, The vessel body (1) consists of a cylindrical body (5) and a head (6); the material is stirred and mixed by a speed-regulating motor (8) and its driven stirring paddle (9).

4. A jacketed crystallizer based on heat pipe phase change heat transfer as described in claim 1, characterized in that, The cooling coil (10) is connected at both ends to the refrigerant inlet (101) and refrigerant outlet (102) on the outer wall of the jacket (3), and the heating coil (11) is connected at both ends to the heat medium inlet (103) and heat medium outlet (104) on the outer wall of the jacket (3).

5. A jacketed crystallizer based on heat pipe phase change heat transfer according to claim 1, characterized in that, A vacuum valve (12) is installed on the outer wall of the jacket (3) and is connected to the heat exchange zone (4) for filling the working fluid and vacuuming operations. The heat exchange zone is equipped with a pressure sensor (105) and a rupture disc (106). The pressure sensor (105) is used to measure the temperature inside the heat exchange zone (4). The rupture disc (106) bursts when the pressure in the heat exchange zone (4) is higher than 0.3 MPa, releasing the pressure inside the jacket and preventing excessive pressure inside the jacket, thus ensuring the safe operation of the equipment.

6. A jacketed crystallizer based on heat pipe phase change heat transfer as described in claim 1, characterized in that, The jacket (3) has a blind hole (13) on its outer wall, which is inserted obliquely into the heat exchange area (4) for installing temperature sensor A (107).

7. A jacketed crystallizer based on heat pipe phase change heat transfer according to claim 1, characterized in that, The jacket (3) is provided with a working fluid drain port (14) at the bottom.

8. A jacketed crystallizer based on heat pipe phase change heat transfer as described in claim 1, characterized in that, An observation hole (108) and a temperature measuring hole (109) are provided on the top of the vessel. The temperature measuring hole (109) is used to install a temperature sensor B (110). The material discharge port (15) is located at the bottom of the end cap (6).

9. A jacketed crystallizer based on heat pipe phase change heat transfer as described in claim 1, characterized in that, The refrigerant inlet (101) and refrigerant outlet (102) are located above the outer wall of the jacket (3) and are arranged horizontally side by side, connected to the external refrigerant circulation path; the heat medium inlet (103) and outlet (104) are arranged horizontally side by side below the outer wall of the jacket (3) and are connected to the external heat medium circulation path. The external refrigerant circulation path consists of a water storage tank and a constant temperature water bath. The external refrigerant circulation path consists of a refrigeration unit and a constant temperature water bath. The constant temperature water bath consists of an electric heating rod and a centrifugal pump. The refrigeration unit consists of a compressor and a centrifugal pump.

10. The application of a jacketed crystallizer based on heat pipe phase change heat transfer as described in any one of claims 1-9, characterized in that, It is applied in fields such as crystallization.

Images