Crystallization system, crystallization method and application thereof

Abstract

The invention discloses a crystallization system, a crystallization method and application thereof. The crystallization system comprises a crystallizer, a wet grinder and a liquid level control module, the crystallizer is externally connected with a circulation loop, and the wet grinder is arranged on the circulation loop; a liquid discharge pipeline is arranged on the crystallizer, and a liquid discharge pump is arranged on the liquid discharge pipeline; the liquid level control module comprises an ultrasonic liquid level measurement signal transmission and conversion unit and a PID (Proportion Integration Differentiation) control unit; the PID control unit comprises a signal processing element and a feedback element, and the feedback element is connected with the liquid discharge pump. The crystallization system and the crystallization method have the advantages of high yield and high yield, and crystal grains with excellent uniformity can be obtained.

Description

Technical Field

[0001] The invention relates to a crystallization system, a crystallization method and applications thereof. Background Art

[0002] In the production of pharmaceutical and chemical industries, the crystallization process is divided into continuous crystallization and intermittent crystallization according to the operation mode. The intermittent crystallization process is a crystallization process in which raw materials are added once, and then different crystallization methods are used to obtain crystals, and finally the crystals are separated from the mother liquor at one time. It is suitable for products with a small annual output. In order to control the particle size of the product, the intermittent crystallization process can adjust and change the process parameters such as the evaporation rate, cooling rate, feeding rate, and seeding of the material over time, so as to control the appropriate supersaturation and optimize the quality indicators such as the particle size and bulk density of the final product. Due to the characteristics of its operation mode, the process operation control parameters of intermittent crystallization change over time, there are many influencing factors, the control variables are highly coupled, and it is very dependent on the experience and control accuracy of the operator. The product quality and process yield are unstable, and the batch-to-batch differences are large, resulting in poor product consistency and uneven crystal particle size. Problems such as these cannot meet customer needs. Since the intermittent crystallization operation is discontinuous, its production and preparation efficiency is often not high, and the number of equipment or the area occupied is large.

[0003] Continuous crystallization is a process of continuously adding materials to a crystallizer and continuously obtaining a product. It is suitable for large-scale industrial crystallization processes and can be achieved with one or several crystallization devices in series. Each crystallization device is called a stage. The process parameters of each stage of the crystallization device are constant and do not change over time. The crystallization process is more stable and easy to control, thereby ensuring the stability and consistency of the quality of the crystal product and greatly reducing the impact of human factors on the crystallization process. Due to the high production efficiency of the continuous crystallization process, the volume or number of equipment in the crystallization process can be greatly reduced, so that the crystallization process that originally required multiple intermittent crystallizers can be reduced to only one continuous crystallization system. And due to continuous production, the impact of human operation on the crystal can be reduced, and the difference between different batches of products can be reduced, so as to achieve the purpose of stable control of the production process and product quality.

[0004] A major challenge in continuous crystallization applications is meeting the requirements for the quality properties of the crystalline product. Particle size distribution is a common critical quality attribute that affects downstream processability and drug release characteristics. Achieving the desired particle size distribution is often challenging due to the interaction between various process parameters. Many drug molecule crystals require size reduction to increase bioavailability, and for this reason, additional grinding operations are required after crystallization in batch methods. Although continuous processes operating under certain steady-state conditions can alleviate these problems, in some cases, the conditions for obtaining maximum or minimum particle size may not be easy to achieve, such as residence time is too short for heat transfer to proceed well, or the conditions for achieving particle size will cause other problems such as excessive saturation leading to crusting and plugging. Continuous crystallization must be carefully designed and controlled to ensure that the desired product quality is achieved and the feasibility of the process is achieved. One of the main challenges in converting from batch to continuous crystallization is to simultaneously obtain particle size control and the required yield, while also considering a productivity that is at least equivalent to that of batch processing. The lower yields in continuous mode are related to incomplete desaturation at the time of discharge. Higher yields can be obtained by extending the residence time or using multi-stage reactors, but this increases process complexity and reduces productivity; lowering the temperature to reduce solubility can increase the yield, but this may lead to slow growth, resulting in long residence times. Blockage and encrustation are difficult problems in actual operation, which are related to additional unsaturation and slurry transfer problems. Once blockage occurs, the process will not be sustainable. In addition, the limited solvent selection driven by upstream requirements (such as compatibility with reagents) often makes it difficult to control the interaction of various crystallization mechanisms (agglomeration, attrition, breakage, encrustation, etc.). To address these problems, alternative particle engineering strategies have been studied, usually using external fields, such as high shear rotor stator wet grinding (hereinafter referred to as wet grinding) technology. Although integrating wet grinding as a process intensification method with the crystallization process can achieve better particle size distribution control, it still faces problems such as heat and mass transfer.

[0005] One of the key issues of continuous crystallization is steady-state control. A common practice is to use a probe that extends below the liquid surface as a liquid level measurement device. This method occupies space in the reactor and increases the difficulty of arranging the device in the reactor. The level measurement probe is easily scaled when immersed in the slurry sink, which has an adverse effect on the function and sensitivity of the sensor, making the process unable to proceed continuously and posing a serious risk. Scaling will also have an adverse effect on heat and mass transfer, affecting product quality and yield. Insufficient control of particle size distribution can achieve a narrow area; on the other hand, uneven particle size, achieving a smaller particle size condition may cause excessive supersaturation, etc., leading to structural, blockage and other problems. It seriously restricts the application and promotion of continuous crystallization. The material transfer process is one of the key factors for whether the system can operate continuously and stably. The flow behavior of particles in the tube depends on factors such as tube diameter and flow rate. Considering the crystallization dynamics, the flow rate affects many aspects. Summary of the invention

[0006] In order to solve the problems of low yield and production rate of the crystallization process and poor uniformity of crystal grains obtained in the prior art, the present invention provides a crystallization system, a crystallization method and applications thereof. The crystallization system and the crystallization method of the present invention have high yield and high output, and can also obtain crystal grains with excellent uniformity.

[0007] The present invention discloses a crystallization system, which comprises a crystallizer, a wet grinder and a liquid level control module;

[0008] The crystallizer is connected to a circulation loop, and the wet grinder is arranged on the circulation loop; the crystallizer is provided with a drainage pipeline, and the drainage pipeline is provided with a drainage pump;

[0009] The liquid level control module includes an ultrasonic liquid level measurement unit, a signal conversion processing unit and a PID control unit connected in sequence;

[0010] The ultrasonic liquid level measuring unit is arranged on the crystallizer, and is used to measure the liquid level of the crystallizer to obtain a liquid level value;

[0011] The signal conversion processing unit is used to convert the liquid level value into a volume value, and convert the volume value into a volume deviation value according to the comparison between the volume value and the preset volume, so as to obtain a liquid level control signal; wherein the liquid level control signal expression is:

[0012] Formula 1: Rev = u(t) × m + Rev0;

[0013] Formula 2:

[0014] Formula 3: K p +K i +K d =1;

[0015] Formula 4: K d =0.5K i ;

[0016] u(t) is the PID gain of liquid level deviation, mL;

[0017] Rev is the displacement pump speed, rpm;

[0018] Rev0 is the initial speed of the displacement pump, rpm;

[0019] m is the proportionality coefficient, rpm / mL; the range of m is: 10≤m<80;

[0020] K p is the proportional gain; K p The range is 0.55-0.95;

[0021] K i is the integral gain;

[0022] K d is the differential gain;

[0023] e is the volume deviation value, mL;

[0024] t is time, min;

[0025] τ is the integral variable, with values ​​ranging from 0 to t;

[0026] The PID control unit is used to receive the liquid level control signal and control the liquid displacement pump.

[0027] In the present invention, the deviation is preferably set to not exceed 1%.

[0028] In the present invention, preferably, when the inner diameter of the drainage pipeline is 0.2-0.5 cm, the range of m is 20-60.

[0029] In the present invention, preferably, K p The range is 0.75-0.95.

[0030] In the present invention, preferably, K i The range is 0.05-0.25.

[0031] In the present invention, preferably, K d The range is 0.02-0.12.

[0032] In a specific embodiment of the present invention, the expression of the volume deviation value is: volume deviation value = (preset volume - volume value converted from liquid level value) / preset volume × 100%.

[0033] In the present invention, preferably, the range of Rev0 is 40-180 rpm.

[0034] In certain specific embodiments of the present invention, K p The range is 0.75-0.95, K i The range is 0.05-0.25, K d The range of is 0.02-0.12, and the range of m is 20-60.

[0035] Wherein, the crystallization system preferably also includes a feed tank, and the feed tank is connected to the crystallizer through a feed pipeline.

[0036] The inner diameter ratio of the feed pipeline and the discharge pipeline is preferably (0.2-3):1, for example, 1:1.

[0037] Among them, the volume ratio of the feed tank and the crystallizer is preferably (3-5):1, for example, 4:1.

[0038] Wherein, the length of the feed pipeline is preferably 25-100 cm.

[0039] Wherein, the inner diameter of the feed pipeline is preferably 0.2-0.5 cm, for example, 0.32 cm.

[0040] The inner diameter of the drainage pipeline is preferably 0.2-0.5 cm, for example 0.32 cm.

[0041] Preferably, the outside of the feed pipeline is wrapped with an electric heating tape layer and a heat insulation material layer; the material of the feed pipeline is, for example, polytetrafluoroethylene; the volume of the feed tank is, for example, 2 L. The provision of the electric heating tape layer and the heat insulation material layer can effectively control the temperature of the material in the feed pipeline.

[0042] Wherein, the feed pipeline is preferably provided with a feed pump.

[0043] In certain specific embodiments of the present invention, K p is 0.85, K i is 0.1, K d is 0.05, and m is 50.

[0044] In certain specific embodiments of the present invention, the capacity of the wet grinder is 20-30 mL, for example, 26 mL.

[0045] In certain specific embodiments of the present invention, the volume of the crystallizer is 0.5L.

[0046] In certain specific embodiments of the present invention, the material of the liquid discharge pipeline is polytetrafluoroethylene.

[0047] In the present invention, preferably, the crystallization system further comprises an anti-solvent tank, and the anti-solvent tank is connected to the crystallizer via an anti-solvent pipeline.

[0048] Preferably, the inner diameter ratio of the anti-solvent pipeline and the drainage pipeline is (0.2-3):1, for example, 1:1.

[0049] Preferably, the inner diameter of the anti-solvent pipeline is 0.2-0.5 cm, for example, 0.32 cm.

[0050] In certain specific embodiments of the present invention, the anti-solvent pipeline is made of polytetrafluoroethylene.

[0051] In the present invention, preferably, the ultrasonic liquid level measurement unit comprises an ultrasonic sensor, and the ultrasonic sensor is arranged in a vertical direction. The ultrasonic sensor is arranged in a vertical direction so as to more accurately control the liquid level of the crystallizer.

[0052] In the present invention, preferably, the crystallization system further comprises a slurry collecting tank, and the slurry collecting tank is connected to the drainage pipeline and is used to receive the slurry discharged from the drainage pipeline.

[0053] In the present invention, preferably, the kettle body of the crystallizer is a jacketed container, and the jacketed container is also provided with an agitator and a temperature probe.

[0054] The stirrer is, for example, an overhead stirrer.

[0055] The stirrer is, for example, also provided with a pitch-blade turbine.

[0056] Preferably, the temperature probe is disposed inside the jacketed container, and the temperature probe is externally connected to a cooler for controlling the temperature inside the crystallizer.

[0057] Those skilled in the art generally understand that a peristaltic pump is provided on the circulation loop to achieve the flow of materials.

[0058] In certain specific embodiments of the present invention, the peristaltic pump is equipped with a pump head and a silicone tube.

[0059] The model of the pump head is, for example, 77200-62 or BT100FJ.

[0060] The inner diameter of the silicone tube is, for example, 4.8 mm.

[0061] The present invention also discloses a crystallization method, which adopts the above crystallization system and comprises the following steps:

[0062] Adding a solution containing a component to be crystallized and a solvent and an anti-solvent to the crystallizer containing the seed crystals to form a suspension; the suspension is wet-grinded in the wet grinder and then circulated back to the crystallizer;

[0063] The liquid level of the crystallizer is monitored and controlled by the liquid level control module, so that the liquid level of the crystallizer is maintained stable and the product is discharged from the discharge pipeline.

[0064] In the present invention, the liquid level is maintained stable, which means that the deviation of the liquid volume in the crystallizer from the set value does not exceed 1%.

[0065] Those skilled in the art generally understand that the seed crystal of the present invention is a conventional concept in the art and is used to provide a site for crystal growth.

[0066] In certain specific embodiments of the present invention, Kp The range is 0.75-0.95, K i The range is 0.05-0.25, K d The range of is 0.02-0.12, the range of m is 20-60, and the rotation speed of the wet grinding rotor is 3000-10000 rpm.

[0067] In certain specific embodiments of the present invention, K p The range is 0.75-0.95, K i The range is 0.05-0.25, K d The range of is 0.02-0.12, the range of m is 20-60, and the preparation method of the solution comprises the following steps: mixing the component to be crystallized and the solvent to completely dissolve the component to be crystallized; wherein the mixing is carried out in a stirring manner, and the stirring speed is 300-500rpm.

[0068] The mixing temperature is preferably 40-80°C, for example 65°C.

[0069] In certain specific embodiments of the present invention, K p The range is 0.75-0.95, K i The range is 0.05-0.25, K d The range of is 0.02-0.12, the range of m is 20-60, and the flow rate ratio of the anti-solvent and the solution into the crystallizer is preferably (1-2):1, for example, 1.1:1.

[0070] In the present invention, preferably, the volume of the suspension accounts for 60%-100% of the volume of the crystallizer, for example, 90%.

[0071] In the present invention, preferably, the percentage of the preset volume to the volume of the crystallizer is 60%-100%, for example, 90%.

[0072] In the present invention, preferably, the weight of the seed crystals accounts for 100-140 mg / L of the suspension, for example, 120 mg / L.

[0073] In the present invention, preferably, the liquid level control module is turned on before adding the solution containing the component to be crystallized and the solvent and the anti-solvent.

[0074] In the present invention, the wet grinding time is preferably 12-18 seconds, for example 16 seconds. The wet grinding time means the residence time of the suspension in the wet grinder after the reaction is stable, and the wet grinding time is determined by the volume of the wet grinder and the flow rate of the wet grinding. The wet grinding time = the volume of the wet grinder / the flow rate of the wet grinding.

[0075] In the present invention, the flow rate of the wet grinding is preferably 90-200 mL / min, for example 100 mL / min.

[0076] In the present invention, the crystallization temperature is preferably 5-25°C, for example 20°C.

[0077] In the present invention, the crystallization time is preferably 20-45 minutes, for example, 30 minutes. The crystallization time means the residence time of the solution containing the component to be crystallized and the solvent in the crystallizer after the reaction is stabilized, and the crystallization time is determined by the preset volume, the solution containing the component to be crystallized and the solvent, and the flow rate of the anti-solvent. Crystallization time = preset volume / (flow rate of the solution containing the component to be crystallized and the solvent + flow rate of the anti-solvent).

[0078] In the present invention, the flow rate of the solution into the crystallizer is preferably 5-25 mL / min, for example, 10 mL / min, 15 mL / min or 20 mL / min.

[0079] In the present invention, the flow rate of the anti-solvent into the crystallizer is preferably 10-35 mL / min, for example, 11 mL / min, 16.5 mL / min or 22 mL / min.

[0080] In the present invention, the anti-solvent is, for example, heptane.

[0081] In the present invention, the component to be crystallized is preferably a pharmaceutical active ingredient, wherein the pharmaceutical active ingredient is, for example, acetaminophen, ibuprofen or aspirin.

[0082] In the present invention, the solvent is, for example, isopropyl alcohol (IPA) and / or acetone.

[0083] In the present invention, in the solution, the mass ratio of the component to be crystallized to the solvent is, for example, 0.112:1.

[0084] In the present invention, preferably, the method for preparing the seed crystal adopts a cooling method or a combined anti-solvent method. For example, it includes the following steps: cooling a saturated solution containing the component to be crystallized, and adding an anti-solvent to mix at the cooling end point. The cooling end point means that the temperature of the saturated solution is cooled to the target temperature.

[0085] The cooling time is preferably 2-6 hours, for example 4 hours.

[0086] The cooling temperature difference is preferably 40-50°C, for example 45°C.

[0087] The initial cooling temperature is, for example, 65°C, and the final cooling temperature is, for example, 20°C.

[0088] The volume of the anti-solvent preferably accounts for 50% of the volume of the saturated solution.

[0089] Preferably, the mixing is carried out by stirring, wherein the stirring rate is, for example, 400 rpm, and the stirring time is, for example, 12 h.

[0090] The crystallization method of the present invention can be adapted to cooling crystallization, anti-solvent crystallization, reaction crystallization or cooling-anti-solvent combined crystallization.

[0091] The invention also discloses an application of the crystallization method in the field of drug preparation.

[0092] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0093] The reagents and raw materials used in the present invention are commercially available.

[0094] The positive and progressive effects of the present invention are:

[0095] The crystallization system and method of the present invention can accurately, quickly and sustainably measure and control the liquid level, maintain the steady state of the system, are simple and efficient, and do not require contact with the slurry, or the purchase of other equipment and manual operation for liquid level control. The process is easy to control and easy to operate, and the system can be intelligently automated and continuously operated.

[0096] The crystallization system and the crystallization method of the present invention can effectively control the growth of crystals, so that the crystal size is controllable, the particle size distribution is narrow, and the obtained crystal size is uniform. It can effectively improve the problems of large product particle size, uneven distribution, pipeline blockage, serious equipment scaling, short operation cycle, etc. in the continuous crystallization process, thereby improving the system stability and efficiency and ensuring product quality. And the crystallization method of the present invention can achieve high yield and high productivity.

[0097] The crystallization system and the crystallization method of the present invention have a wide range of applications, and the operating conditions are easy to change, thus expanding the application scope of cooling crystallization and dissolution crystallization technology. BRIEF DESCRIPTION OF THE DRAWINGS

[0098] Figure 1 Schematic diagram of the crystallization system of Example 1.

[0099] Figure 2 This is the PSD diagram of Example 1.

[0100] Figure 3 This is the PSD diagram of Example 2.

[0101] Figure 4This is the PSD diagram of Example 3.

[0102] Figure 5 This is the PSD diagram of Example 4.

[0103] Figure 6 This is the PSD diagram of Example 5.

[0104] Figure 7 This is the PSD diagram of Comparative Example 1.

[0105] Figure 8 This is the PSD diagram of Comparative Example 3.

[0106] Fig. 9 This is a microscope image of Example 1.

[0107] Fig.10 This is a microscope image of Example 4.

[0108] Fig.11 This is the microscope image of Comparative Example 3.

[0109] Fig.12 This is a microscope image of Example 6.

[0110] Fig.13 This is the microscope image of Comparative Example 4.

[0111] Fig.14 This is the PSD diagram of Comparative Example 4.

[0112] The reference numerals are as follows:

[0113] 1-crystallizer; 2-wet grinder; 3-discharge pump; 4-feed tank; 5-feed pump; 6-anti-solvent tank; 7-slurry collection tank; 8-peristaltic pump; 9-liquid level control module;

[0114] 1001-circulation loop; 1002-discharge pipeline; 1003-feed pipeline; 1004-anti-solvent pipeline. DETAILED DESCRIPTION

[0115] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0116] Example 1

[0117] The crystallization system used in Example 1 is as follows Figure 1As shown, it includes a crystallizer 1, a wet grinder 2 and a liquid level control module 9; the crystallizer 1 is externally connected to a circulation loop 1001, and the wet grinder 2 is arranged on the circulation loop 1001; the crystallizer 1 is provided with a liquid discharge pipeline 1002, and the liquid discharge pipeline 1002 is provided with a liquid discharge pump 3;

[0118] The liquid level control module 9 includes an ultrasonic liquid level measurement unit, a signal conversion processing unit and a PID control unit connected in sequence; the ultrasonic liquid level measurement unit is arranged on the crystallizer, and is used to measure the liquid level of the crystallizer to obtain the liquid level value; the signal conversion processing unit is used to convert the liquid level value into a volume value, and convert it into a volume deviation value according to the comparison between the volume value and the preset volume, and obtain a liquid level control signal; wherein the liquid level control signal expression is:

[0119] Formula 1: Rev = u(t) × m + Rev0;

[0120] Formula 2:

[0121] Formula 3: K p +K i +K d =1;

[0122] Formula 4: K d =0.5K i ;

[0123] u(t) is the PID gain of liquid level deviation, mL;

[0124] Rev is the displacement pump speed, rpm;

[0125] Rev0 is the initial speed of the displacement pump, rpm;

[0126] m is the proportionality coefficient, rpm / mL;

[0127] K p is the proportional gain;

[0128] K i is the integral gain;

[0129] K d is the differential gain;

[0130] e is the volume deviation value, mL;

[0131] t is time, min;

[0132] τ is the integral variable, with values ​​ranging from 0 to t;

[0133] The PID control unit is used to receive the liquid level control signal and control the liquid displacement pump.

[0134] Wherein, the ultrasonic liquid level measurement signal transmission and conversion unit includes an ultrasonic sensor, and the ultrasonic sensor is arranged along the vertical direction.

[0135] The deviation is set to not exceed 1%.

[0136] Among them, the crystallization system also includes a feed tank 4, which is connected to the crystallizer 1 through a feed pipeline 1003. A feed pump 5 is provided on the feed pipeline 1003. The outside of the feed pipeline 1003 is wrapped with an electric heating belt and a thermal insulation material. The material of the feed pipeline 1003 is polytetrafluoroethylene. The volume of the feed tank 4 is 2L, the volume of the crystallizer 1 is 0.5L, the length of the feed pipeline 1003 is 50cm, the inner diameter of the feed pipeline 1003 is 0.32cm, the inner diameter of the drain pipeline 1002 is 0.32cm, and the material of the drain pipeline 1002 is polytetrafluoroethylene.

[0137] The crystallization system further includes an anti-solvent tank 6 and a slurry collection tank 7. The anti-solvent tank 6 is connected to the crystallizer 1 via an anti-solvent pipeline 1004. The slurry collection tank 7 is connected to a drainage pipeline for receiving the slurry discharged from the drainage pipeline 1002. The inner diameter of the anti-solvent pipeline 1004 is 0.32 cm, and the material of the anti-solvent pipeline 1004 is polytetrafluoroethylene.

[0138] The crystallizer 1 includes a stirrer, a temperature probe and a jacketed container. The stirrer is an overhead stirrer, the stirrer is provided with a pitch blade turbine, the temperature probe is arranged inside the jacketed container, and the temperature probe is externally connected to a cooler for controlling the temperature inside the crystallizer 1.

[0139] Among them, a peristaltic pump 8 is provided on the circulation loop 1001 to realize the flow of materials. The peristaltic pump 8 is equipped with a pump head and a silicone tube. The model of the pump head is BT100FJ, and the inner diameter of the silicone tube is 4.8 mm.

[0140] Example 1 The above crystallization system was used to prepare acetaminophen, and the structural formula of acetaminophen was as follows:

[0141]

[0142] It includes the following steps:

[0143] A solution containing a component to be crystallized and a solvent and an anti-solvent are added to a crystallizer 1 containing seed crystals to form a suspension; the suspension is wet-grinded in a wet grinder and then circulated back to the crystallizer 1;

[0144] The liquid level of the crystallizer 1 is monitored and controlled by the liquid level control module to maintain the liquid level of the crystallizer 1 stable. The liquid level control module is turned on before adding the solution containing the component to be crystallized and the solvent and the anti-solvent. Before turning on the liquid level control module, set: K p is 0.85, Ki is 0.1, K d =0.05, m = 50, Rev0 = 100 rpm, and the preset volume = 500 mL are entered into the liquid level control module. The liquid level is kept stable when the deviation between the liquid volume in the crystallizer 1 and the set value does not exceed 1%.

[0145] The solvent is acetone, and in the solution, the mass ratio of the component to be crystallized to the solvent is 0.112:1.

[0146] The volume of the suspension accounts for 90% of the volume of the crystallizer 1, and the flow rate of the solution into the crystallizer 1 is 10 mL / min.

[0147] The method for preparing the seed crystal comprises the following steps: cooling a saturated solution containing the component to be crystallized, adding an anti-solvent and mixing at the end of cooling. The end of cooling means that the temperature of the saturated solution is cooled to the target temperature.

[0148] The cooling time is 4 hours, the initial cooling temperature is 65°C, the final cooling temperature is 20°C, the anti-solvent is heptane, the volume of the anti-solvent accounts for 50% of the volume of the saturated solution, and the mixing is carried out in a stirring manner, wherein the stirring rate is 400 rpm, the stirring time is 12 hours, the flow rate of the anti-solvent is 11 mL / min, and the amount of seed crystals added is 60 mg.

[0149] The method for preparing the solution comprises the following steps: mixing the component to be crystallized and the solvent to completely dissolve the component to be crystallized, wherein the mixing is performed in a stirring manner, wherein the stirring rate is 400 rpm and the mixing temperature is 40°C.

[0150] The wet grinding time was 16 s, the wet grinding rotor speed was 5000 rpm, the wet grinding flow rate was 100 mL / min, the wet grinder volume was 26 mL, the crystallization temperature was 20° C., and the crystallization time was 24 min.

[0151] Example 2

[0152] The crystallization system used in Example 2 is the same as that in Example 1.

[0153] The rotor speed of wet grinding in Example 2 is 10000 rpm, and other process parameters are the same as those in Example 1.

[0154] Example 3

[0155] The crystallization system used in Example 3 is the same as that in Example 1.

[0156] The flow rate of the solution of Example 3 into the crystallizer 1 is 15 mL / min, the flow rate of the anti-solvent is 16.5 mL / min, the crystallization time is 16 min, and the other process parameters are the same as those of Example 1.

[0157] Example 4

[0158] The crystallization system used in Example 4 is the same as that in Example 1.

[0159] The flow rate of the solution in Example 4 into the crystallizer 1 is 20 mL / min, the flow rate of the anti-solvent is 22 mL / min, the crystallization time is 12 min, and the other process parameters are the same as those in Example 1.

[0160] Example 5

[0161] The crystallization system used in Example 5 is the same as that in Example 1.

[0162] The rotor speed of wet grinding in Example 5 is 2000 rpm, and other process parameters are the same as those in Example 1.

[0163] Comparative Example 1

[0164] The crystallization system used in Comparative Example 1 is Figure 1 The volume of the crystallizer was 500 mL without the wet grinder and anti-solvent tank.

[0165] Comparative Example 1: Paracetamol was prepared by using the above crystallization system, which comprises the following steps:

[0166] A solution containing a component to be crystallized and a solvent is added to a crystallizer containing seed crystals to form a suspension; the suspension is circulated back to the crystallizer without wet grinding;

[0167] The liquid level of the crystallizer is monitored and controlled by the liquid level control module to maintain the liquid level of the crystallizer stable. The liquid level maintenance means that the deviation of the liquid volume in the crystallizer from the set value does not exceed 1%. The parameters of the liquid level control module are the same as those in Example 1.

[0168] The solvent is isopropanol, and in the solution, the mass ratio of the component to be crystallized to the solvent is 0.166:1.

[0169] The volume of the suspension accounts for 90% of the volume of the crystallizer, and the flow rate of the solution into the crystallizer is 24 mL / min.

[0170] The method for preparing the solution comprises the following steps: mixing the component to be crystallized and the solvent to completely dissolve the component to be crystallized, wherein the mixing is performed in a stirring manner, wherein the stirring rate is 400 rpm and the mixing temperature is 65°C.

[0171] The crystallization temperature was 10°C and the crystallization time was 21 min.

[0172] Comparative Example 2

[0173] The crystallization system used in Comparative Example 2 is the same as that in Comparative Example 1.

[0174] The flow rate of the solution in Comparative Example 2 passing into the crystallizer was 18 mL / min, the crystallization time was 28 min, and the other process parameters were the same as those in Comparative Example 1.

[0175] Comparative Example 3

[0176] The crystallization system used in Comparative Example 3 does not include a wet grinder, and the other structures of the crystallization system are the same as those in Example 1.

[0177] In Comparative Example 3, the suspension was directly circulated back into the crystallizer without wet grinding, and other process parameters were the same as those in Example 1.

[0178] Example 6

[0179] The crystallization system used in Example 6 is the same as that in Example 1.

[0180] Example 6 Aspirin was prepared using the above crystallization system. The structural formula of aspirin is as follows:

[0181]

[0182] The rotation speed of the rotor in wet grinding of Example 6 is 10000 rpm, and the other process parameters are the same as those of Example 1.

[0183] Comparative Example 4

[0184] The crystallization system used in Comparative Example 4 does not include a wet grinder, and the other structures of the crystallization system are the same as those in Example 1.

[0185] In Comparative Example 4, aspirin was prepared using the above crystallization system. The suspension was not wet-ground but directly circulated back into the crystallizer. Other process parameters were the same as those in Example 6.

[0186] Comparative Example 5

[0187] The crystallization system of Comparative Example 5 is Figure 1 On the basis of, a conventional liquid level control module is adopted, that is, a liquid level measurement probe is adopted.

[0188] Comparative Example 5 will scale in a short time and cannot be operated for a long time, and the particle size uniformity of the prepared particles is poor.

[0189] Effect Example 1

[0190] Determination of the concentration of the component to be crystallized and the solvent in Examples 1-6 and Comparative Examples 1-4: HPLC was used to determine the concentration of the component to be crystallized and the solvent.

[0191] The yield is calculated as follows: yield = (concentration of the component to be crystallized in the solution before crystallization starts - concentration of the component to be crystallized in the solution after crystallization ends) / concentration of the component to be crystallized in the solution before crystallization starts.

[0192] The yield is calculated as follows: yield = concentration of the component to be crystallized in the solution before crystallization begins × flow rate of the solution into the crystallizer * yield.

[0193] The results of the above measurements are listed in Table 1.

[0194] Table 1

[0195] Yield Yield (mg / g solvent / min) Example 1 79％ 200 Example 2 80％ 200 Example 3 63％ 157.5 Example 4 59％ 147.5 Example 5 73％ 182.5 Comparative Example 1 26％ 65 Comparative Example 2 35％ 87.5 Comparative Example 3 51％ 127.5 Example 6 90％ 335 Comparative Example 4 75％ 279

[0196] As can be seen from the above table, the crystallization system and the crystallization method of the present invention can effectively improve the yield and productivity of the crystal particles. For example, for acetaminophen, the yield can be increased to more than 59%, and the productivity can be increased to more than 147.5 mg / g solvent / min, and for aspirin, the yield can be increased to more than 90%, and the productivity can be increased to more than 335 mg / g solvent / min.

[0197] Effect Example 2

[0198] The particle size distribution (PSD) of the crystal particles of Examples 1-6 and Comparative Examples 1-4 was measured: the suspension discharged from the discharge pipe was centrifuged to obtain a crystal particle product, and the crystal particles were Mastersizer 2000 was used for measurement. BX51 takes pictures and obtains microscope images.

[0199] The measurement results show that the crystal particles of Examples 1-6 have uniform particle size distribution, small particle size, narrow particle size distribution and high product quality, indicating that the crystallization system of the present invention has high stability and efficiency.

[0200] The PSD diagram of Example 1 is as follows: Figure 2 As shown, the PSD diagram of Example 2 is as follows Figure 3 As shown, the PSD diagram of Example 3 is as follows Figure 4 As shown, the PSD diagram of Example 4 is as shown Figure 5 As shown, the PSD diagram of Example 5 is as follows Figure 6 As shown, the PSD diagram of Comparative Example 1 is as follows Figure 7 As shown, the PSD diagram of Comparative Example 3 is as follows Figure 8 As shown, the PSD diagram of Comparative Example 4 is as follows Fig.14 shown.

[0201] from Figure 2-Figure 8 , Fig.14 It can be seen that compared with the comparative example, the crystal particles of Examples 1-5 have uniform particle size distribution, small particle size, narrow particle size distribution and high product quality.

[0202] The microscope image of Example 1 is as follows Fig. 9 As shown, the microscope image of Example 4 is as follows Fig.10 As shown, the microscope image of Comparative Example 3 is as follows Fig.11 As shown, the microscope image of Example 6 is as follows Fig.12 As shown, the microscope image of Comparative Example 4 is as follows Fig.13 As shown. Among them, Figure 9-13 The scale bars in the figures are all 200 μm.

[0203] from Figure 9-13 It can be seen that the crystal particles of Example 1, Example 4 and Example 6 have uniform particle size distribution, small particle size, narrow particle size distribution and high product quality, while the crystal particles of Comparative Example 3 and Comparative Example 4 have uneven particle size distribution and poor product quality.

[0204] According to Table 1 and Figure 2-13 The results show that Examples 1-6 can simultaneously achieve high yield, high productivity and high uniformity of crystal particle size distribution.

[0205] Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that this is only for illustration and the protection scope of the present invention is defined by the appended claims. Those skilled in the art may make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but these changes and modifications all fall within the protection scope of the present invention.

Claims

1. A crystallization system, characterized in that: It includes a crystallizer, a wet grinder and a liquid level control module; The crystallizer is connected to a circulation loop, and the wet grinder is arranged on the circulation loop; the crystallizer is provided with a drainage pipeline, and the drainage pipeline is provided with a drainage pump; The liquid level control module includes an ultrasonic liquid level measurement unit, a signal conversion processing unit and a PID control unit connected in sequence; The ultrasonic liquid level measuring unit is arranged on the crystallizer, and is used to measure the liquid level of the crystallizer to obtain a liquid level value; The signal conversion processing unit is used to convert the liquid level value into a volume value, and convert the volume value into a volume deviation value according to the comparison between the volume value and the preset volume, so as to obtain a liquid level control signal; wherein the liquid level control signal expression is: Formula 1: Rev = u(t) × m + Rev0; Formula 2: Formula 3: K p +K i +K d =1; Formula 4: K d =0.5K i ; u(t) is the PID gain of liquid level deviation, mL; Rev is the displacement pump speed, rpm; Rev0 is the initial speed of the displacement pump, rpm; m is the proportionality coefficient, rpm / mL; the range of m is: 10≤m<80; K p is the proportional gain; K p The range is 0.55-0.95; K i is the integral gain; K d is the differential gain; e is the volume deviation value, mL; t is time, min; τ is the integral variable, with values ​​ranging from 0 to t; The PID control unit is used to receive the liquid level control signal and control the liquid displacement pump.

2. The crystallization system according to claim 1, characterized in that The setting condition of the volume deviation value is no more than 1%; and / or, when the inner diameter of the drainage pipeline is 0.2-0.5 cm, the range of m is 20-60; and / or, K p The range is 0.75-0.95; and / or, K i The range is 0.05-0.25; and / or, K d The range is 0.02-0.12; And / or, the expression of the volume deviation value is: volume deviation value=(preset volume-volume value converted from liquid level value) / preset volume×100%; And / or, the range of Rev0 is 40-180 rpm.

3. The crystallization system according to claim 1, characterized in that K p The range is 0.75-0.95, K i The range is 0.05-0.25, K d The range of is 0.02-0.12, and the range of m is 20-60; Wherein, the crystallization system preferably further comprises a feed tank, and the feed tank is connected to the crystallizer through a feed pipeline; Wherein, the inner diameter ratio of the feed pipeline and the discharge pipeline is preferably (0.2-3): 1; Wherein, the volume ratio of the feed tank and the crystallizer is preferably (3-5): 1; Wherein, the length of the feed pipeline is preferably 25-100 cm; Wherein, the inner diameter of the feed pipeline is preferably 0.2-0.5 cm; Wherein, the inner diameter of the drainage pipeline is preferably 0.2-0.5 cm.

4. The crystallization system according to claim 3, characterized in that K p is 0.85, K i is 0.1, K d is 0.05, m is 50; and / or, the inner diameter ratio of the feed pipeline and the discharge pipeline is 1:1; And / or, the volume ratio of the feed tank to the crystallizer is 4:1; and / or, the inner diameter of the feed pipeline is 0.32 cm; and / or, the inner diameter of the drainage pipeline is 0.32 cm; And / or, the outside of the feed pipeline is wrapped with an electric heating tape layer and a heat insulation material layer; wherein the material of the feed pipeline is, for example, polytetrafluoroethylene; wherein the volume of the feed tank is, for example, 2L; And / or, a feed pump is provided on the feed pipeline.

5. The crystallization system according to claim 1, characterized in that The volume of the wet grinder is 20-30 mL, for example 26 mL; And / or, the volume of the crystallizer is 0.5L; And / or, the material of the liquid discharge pipeline is polytetrafluoroethylene; And / or, the crystallization system further comprises an anti-solvent tank, and the anti-solvent tank is connected to the crystallizer via an anti-solvent pipeline; wherein, preferably, the inner diameter ratio of the anti-solvent pipeline and the drainage pipeline is (0.2-3):1, for example, 1:1; wherein, preferably, the inner diameter of the anti-solvent pipeline is 0.2-0.5 cm, for example, 0.32 cm; wherein the material of the anti-solvent pipeline is, for example, polytetrafluoroethylene; And / or, the ultrasonic liquid level measurement unit comprises an ultrasonic sensor, and the ultrasonic sensor is arranged in a vertical direction; And / or, the kettle body of the crystallizer is a jacketed container, and the jacketed container is also provided with an agitator and a temperature probe; wherein the agitator is, for example, an overhead agitator; wherein the agitator is, for example, also provided with a pitch-blade turbine; wherein, preferably, the temperature probe is arranged inside the jacketed container, and the temperature probe is externally connected to a cooler for controlling the temperature inside the crystallizer.

6. A crystallization method, characterized in that: It adopts the crystallization system as described in any one of claims 1 to 5, which comprises the following steps: Adding a solution containing a component to be crystallized and a solvent and an anti-solvent to the crystallizer containing the seed crystals to form a suspension; the suspension is wet-grinded in the wet grinder and then circulated back to the crystallizer; The liquid level of the crystallizer is monitored and controlled by the liquid level control module, so that the liquid level of the crystallizer is maintained stable and the product is discharged from the discharge pipeline.

7. The crystallization method according to claim 6, characterized in that K p The range is 0.75-0.95, K i The range is 0.05-0.25, K d The range of is 0.02-0.12, the range of m is 20-60, and the rotation speed of the wet grinding rotor is 3000-10000rpm; and / or, K p The range is 0.75-0.95, K i The range is 0.05-0.25, K d The range of is 0.02-0.12, the range of m is 20-60, and the preparation method of the solution comprises the following steps: mixing the component to be crystallized and the solvent to completely dissolve the component to be crystallized; wherein the mixing is carried out in a stirring manner, and the stirring speed is 300-500rpm; wherein the mixing temperature is preferably 40-80°C, for example, 65°C; and / or, K p The range is 0.75-0.95, K i The range is 0.05-0.25, K d The range of is 0.02-0.12, the range of m is 20-60, and the flow rate ratio of the anti-solvent and the solution into the crystallizer is preferably (1-2):1, for example, 1.1:1; And / or, the volume of the suspension accounts for 60%-100% of the volume of the crystallizer, for example, 90%; And / or, the percentage of the preset volume to the volume of the crystallizer is 60%-100%, for example, 90%.

8. The crystallization method according to claim 6, characterized in that The weight of the seed crystals accounts for 100-140 mg / L of the suspension, for example, 120 mg / L; and / or, turning on the liquid level control module before adding the solution containing the component to be crystallized and the solvent and the anti-solvent; And / or, the wet grinding time is 12-18 s, for example 16 s; And / or, the flow rate of the wet grinding is 90-200 mL / min, for example 100 mL / min; And / or, the crystallization temperature is 5-25°C, for example, 20°C; And / or, the crystallization time is 20-45 min, for example, 30 min; and / or, the flow rate of the solution into the crystallizer is 5-25 mL / min, for example, 10 mL / min, 15 mL / min or 20 mL / min; and / or, the anti-solvent is introduced into the crystallizer at a flow rate of 10-35 mL / min, for example, 11 mL / min, 16.5 mL / min or 22 mL / min; And / or, the anti-solvent is heptane.

9. The crystallization method according to claim 6, characterized in that The component to be crystallized is a pharmaceutical active ingredient, wherein the pharmaceutical active ingredient is, for example, acetaminophen, ibuprofen or aspirin; And / or, the solvent is isopropanol and / or acetone; and / or, in the solution, the mass ratio of the component to be crystallized to the solvent is, for example, 0.112:1; And / or, the preparation method of the seed crystal adopts a cooling method or a combined anti-solvent method; for example, it includes the following steps: cooling a saturated solution containing the component to be crystallized, adding an anti-solvent and mixing at the end of cooling; wherein the cooling time is preferably 2-6h, for example 4h; wherein the cooling temperature difference is preferably 40-50°C, for example 45°C; wherein the initial cooling temperature is, for example, 65°C, and the final cooling temperature is, for example, 20°C; wherein the volume of the anti-solvent preferably accounts for 50% of the volume of the saturated solution; wherein, preferably, the mixing is carried out in a stirring manner, wherein the stirring rate is, for example, 400rpm, and the stirring time is, for example, 12h.

10. Use of the crystallization method according to any one of claims 6 to 9 in the field of drug preparation.

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