Parallel crystal form screening and process optimizing system integrating online ultraviolet and imaging

Abstract

The invention provides a parallel crystal form screening and process optimization system integrating online ultraviolet and imaging, and belongs to the technical field of crystal preparation and optimization. The temperature control device consists of a temperature control device, a process monitoring device, a stirring device, a feeding device and an upper computer and is used for performing closed-loop control on the temperature in the crystallizer; the process monitoring device comprises a multi-probe online ultraviolet spectrometer, an online imaging probe, a probe type turbidity meter, a Raman spectrometer and the like and is used for measuring the solution concentration and the solution supersaturation degree in the crystallizer in real time, observing the growth condition of crystals and other information and providing support for particle size measurement; the stirring device adopts two stirring modes of mechanical stirring and magnetic stirring and is used for stirring solutions with different viscosities; the feeding device comprises a feeding pump, a feeding pipe and a material taking pipe; the problems of long experiment period and low experiment efficiency in the medicine crystallization production process can be solved.

Description

Technical Field

[0001] The present invention belongs to the technical field of crystal preparation and optimization, and more specifically, relates to a parallel crystal form screening and process optimization system integrating on-line ultraviolet and imaging. Background Art

[0002] In the pharmaceutical field, drugs are usually produced, transported, and sold in crystal form. Solubility measurement and metastable zone width measurement are very critical steps in the process of crystal preparation, and play an important role in improving crystal quality and optimizing crystal preparation processes. For the same drug, there may be multiple crystal forms. Different crystal forms have significant differences in solubility, stability, and bioavailability, and these differences directly affect the efficacy of the drug. Therefore, screening out the optimal crystal form is crucial for ensuring the quality and efficacy of the drug. Therefore, during the development of new products, it is usually necessary to conduct solubility determination, metastable zone width determination, and crystal form (including crystal form, salt form, and eutectic) screening. At present, pharmaceutical enterprises in China mainly rely on a single stirring tank to complete the above tasks. This method has problems such as long experimental cycles and low experimental efficiency, and there is an urgent market need for equipment that can significantly improve experimental efficiency.

[0003] High-throughput screening technology originated in the 1980s and was initially developed to find lead compounds. Its characteristic is that it can process multiple groups of samples simultaneously, improving experimental efficiency. High-throughput technology can be used for crystal screening to shorten the time for processing a large number of samples and can well complete tasks such as crystal form screening.

[0004] Currently, there are already some high-throughput crystal screening devices abroad, such as: Easymax of METTLER, CrystalSCAN of HEL, and Crystal16, Crystalline developed by Technobis. Easymax is configured with two channels, which can conduct two groups of independent parallel experiments simultaneously, shortening the screening experiment time by half; it is equipped with a temperature probe to obtain the temperature value inside the reactor in real time. Its disadvantage is that it can only conduct two groups of experiments simultaneously, and the improvement of experimental efficiency is not obvious enough; moreover, it does not have a turbidity measurement function, which makes it impossible for experimenters to know the real-time reaction situation inside the reactor. The reactor volume of Crystal16 is 1 milliliter, and it has heating, cooling, temperature control, and stirring modules, which can meet the needs of various experimental conditions. Its disadvantage is that the reactor volume is single, so it is impossible to explore process scale-up. CrystalSCAN has four channels and can conduct 4 groups of independent parallel tests simultaneously. It is equipped with an ultra-small turbidity probe with a probe diameter of up to 3.5 millimeters, which can obtain the turbidity value inside the reactor in real time. Crystalline is configured with eight channels, the reactor volume is 8 milliliters, the temperature control accuracy can reach 0.5 °C, and it integrates two methods of mechanical stirring and magnetic stirring. They generally have disadvantages such as high price, low temperature control accuracy, slow maximum rotation speed, and small rotation speed range, and none of them integrate online supersaturation measurement technology, so they cannot measure the supersaturation during the crystallization process and cannot measure the position of the operating point during the crystallization process in real time. Summary of the Invention

[0005] In view of this, the present invention provides a parallel polymorph screening and process optimization system integrating online ultraviolet and imaging, which integrates online concentration / supersaturation measurement technology and high-throughput technology, and can solve the problems of long experimental period and low experimental efficiency existing in the pharmaceutical crystallization production process.

[0006] The present invention is implemented as follows:

[0007] The present invention provides a parallel polymorph screening and process optimization system integrating online ultraviolet and imaging, which includes a number of crystallization unit slots for placing crystallization units. Each crystallization unit includes a temperature control device, a process monitoring device, a stirring device, a feeding device, and a host computer. The temperature control module is used to adjust the temperature of the crystallization unit; the process monitoring device is used to monitor the temperature of the crystallization unit, the stirring device is used to stir the crystals inside the crystallization unit, and the host computer is electrically connected to the temperature control device, the process monitoring device, the stirring device, and the feeding device.

[0008] Based on the above technical solution, the parallel polymorph screening and process optimization system integrating online ultraviolet and imaging of the present invention can also be improved as follows:

[0009] The crystallization unit has six channels, and each crystallization unit can hold no more than 12 crystallizers. The volume of the crystallizer in each slot can be changed (2.5 ml to 500 ml). The small crystallizer is suitable for crystal form screening when there are fewer materials in the early stage of product development, and the larger crystallizer is used for crystallization design and optimization of crystallization conditions. Each unit can independently perform temperature rise and fall, stirring rate adjustment, feeding operation, and real-time tracking of the optimal supersaturation curve and temperature curve to achieve closed-loop automatic control.

[0010] Furthermore, each of the crystallizers is matched with a sealing cover made of polytetrafluoroethylene, which is corrosion-resistant and has a plurality of sealable holes thereon; the sealable holes are used to respectively place process monitoring probes, temperature sensor probes, mechanical stirring paddles, feed pipelines and other equipment; the sealing cover is also provided with threaded holes to ensure the stability and reliability of the connection.

[0011] Further, the temperature control device includes an electric refrigeration unit, an electric heating unit, a PID temperature control unit, and a metal heat conductive kit. The electric refrigeration unit is located on the side of the metal heat conductive kit, and the electric refrigeration unit uses electric energy for refrigeration. The PID temperature control unit is electrically connected to the electric refrigeration unit to control the refrigeration temperature of the electric refrigeration unit. The metal heat conductive kit is sleeved on the surface around the crystallizer and is in close contact with the crystallizer to control the process of temperature change inside the crystallizer. The electric heating unit is located at the bottom of the crystallizer, and the PID temperature control unit is electrically connected to the electric heating unit to control the heating temperature of the electric heating unit. The realization of the temperature measurement control function requires a precise and sensitive temperature measuring unit. The temperature measuring unit enters the interior of the crystallizer through the hole on the crystallizer sealing cover, accurately measures the sample temperature inside the crystallizer, and transmits the temperature to the PID temperature control unit. The temperature measuring unit adopts a PT100 thermal resistance probe with a diameter of 3mm, which can also be conveniently used in small crystallizers.

[0012] Furthermore, the electric refrigeration unit includes a semiconductor refrigeration plate, one on each of the two sides of each channel. During cooling, the two semiconductor refrigeration plates of each crystallization unit work simultaneously for cooling. During the cooling process, the PID temperature control unit outputs a signal to adjust the cooling power of the electric refrigeration unit, thereby controlling the temperature of the electric refrigeration unit. The electric refrigeration unit indirectly transfers the temperature to the inside of the crystallizer through the metal heat conduction kit, thereby ensuring the cooling efficiency and cooling rate of the electric refrigeration unit.

[0013] Furthermore, a circulating coolant is provided outside the semiconductor refrigeration chip. The coolant is in indirect contact with the semiconductor refrigeration chip and is used to take away the heat of the semiconductor refrigeration chip. During the circulation process, the coolant passes through the U-shaped tube built into the fan, and the fan transfers the heat to the outside of the platform.

[0014] The beneficial effects of adopting the above improvement scheme are as follows: efficient cooling is achieved through the electric refrigeration unit and the coolant.

[0015] Furthermore, the electric heating unit is a copper block located at the bottom of each crystallizer; the copper block is electrically connected to the PID temperature control unit, and the PID temperature control unit adjusts the heating power of the electric heating unit by outputting signals, thereby controlling the temperature of the electric heating unit, and the electric heating unit is in direct contact with the bottom of the crystallizer.

[0016] Furthermore, the metal heat conduction kit is divided into a structure that can hold one or two of the above-mentioned crystallizers. The outer diameter of the crystallizer is enlarged by a metal diameter-expanding ring, and the crystallizer, the metal heat conduction kit, the semiconductor refrigeration sheet, and the water storage tank are in close contact with each other in sequence from the inside to the outside. The metal heat conduction kit is a heat-conducting aluminum block, which is in a cylindrical structure and is provided with at least one hole. There are various specifications for the heat-conducting aluminum block. One is for a single crystallizer of different sizes, and its structure is a hollow cylinder. The inner diameter of the aluminum block is slightly larger than the outer diameter of the crystallizer to ensure that the crystallizer can be smoothly placed and in contact. The other is for multiple crystallizers placed in the same crystal screening unit, and its structure is a cylinder with multiple holes, and each hole can hold a crystallizer.

[0017] The beneficial effects of adopting the above improvement scheme are as follows: This structural design not only ensures the high efficiency of temperature conduction but also provides a high degree of flexibility and scalability to meet the configuration requirements of crystallizers with different specifications and quantities.

[0018] Furthermore, the process monitoring device is an online ultraviolet spectrometer, a probe-type turbidimeter, a Raman spectrometer, an on-line imaging system for the process, an infrared concentration meter, and an ultrasonic particle size distribution meter. The online ultraviolet spectrometer, the probe-type turbidimeter, the Raman spectrometer, the on-line imaging system for the process, the infrared concentration meter, and the ultrasonic particle size distribution meter respectively pass through the sealing holes on the sealing cover of the crystallizer to detect the inside of the crystallizer.

[0019] Furthermore, the probes of the online ultraviolet spectrometer, the probe-type turbidimeter, the Raman spectrometer, the on-line imaging system for the process, the infrared concentration meter, and the ultrasonic particle size distribution meter are inserted into the inside of the crystallizer through the sealing holes. The probe of the online ultraviolet spectrometer is connected to the online ultraviolet spectrometer host through a connecting wire, and the probe of the probe-type turbidimeter is connected to the turbidimeter host through a connecting wire.

[0020] Further, the stirring device includes a magnetic stirring device and a mechanical stirring device. The magnetic stirring device and the mechanical stirring device are used to stir samples in crystallizers of different capacities, and the rotational speed ranges of the magnetic stirring device and the mechanical stirring device are different. The mechanical stirring device includes a top motor and a bottom stirring paddle. The stirring paddle enters the crystallizer through a hole in the crystallizer sealing cover and is fixedly connected to the sealing cover. The top motor is fixedly connected to the crystallization unit through a clamp on the crystallization unit channel to prevent the crystallizer from being driven when the stirrer rotates at high speed and affecting the crystallization process of the samples in the crystallizer. The mechanical stirring device communicates with the host computer through RS485. The stirring rate of each channel of the mechanical stirring device is set by software, and at the same time, the actual stirring rate is returned to the host computer for display.

[0021] The stirring device can make the temperature in the crystallizer stably approach the target temperature. At the same time, it can make the samples evenly distributed in the crystallizer, which is beneficial to the accuracy of process monitoring.

[0022] Further, the feeding device includes a feed pump, a feed pipe, and a sampling pipe. The host computer is communicatively connected to the feed pump and can accurately control the feeding amount and feeding rate of the samples. Both ends of the feed pump are fixedly connected to the sampling pipe and the feed pipe respectively. The sampling pipe sucks samples from an external sample pool, and the feed pipe injects samples into the crystallizer through a hole in the crystallizer sealing cover, realizing the synchronous progress of multiple crystallization screening reactions.

[0023] Further, there is a communication connection between the PID temperature control unit and the host computer. The host computer sets the target temperature and sends it to the PID temperature control unit. The PID temperature control unit returns the current temperature to the host computer. The computer displays the current temperature value, and at the same time, the temperature value is displayed in the form of a curve in a graph. The computer synchronously saves the temperature data and can export the data for offline analysis.

[0024] Further, when the parallel crystal form screening and process optimization system runs, it includes the following steps:

[0025] Weigh the medicine and prepare the solution;

[0026] Feeding of samples. The sampling pipe of the feed pump sucks samples from an external sample pool and injects the samples into the crystallizer through the feed pipe passing through the hole in the crystallizer sealing cover. There is a communication connection between the feed pump and the host computer. By setting the feeding amount and feeding rate in the host computer, the feed pump is controlled to complete the work, realizing the synchronous progress of multiple crystallization screening reactions;

[0027] Setting of stirring rate. The type of stirring can be selected in the host computer, and the stirring rate of magnetic stirring or mechanical stirring can be set;

[0028] Temperature task setting. Set a multi-segment temperature control program with limited slope for heating and cooling on the host computer, including the heating process, cooling process, and constant temperature process. Match the above three temperature control process tasks according to the process required for crystal screening, add them to the task bar, and then send them to the PID temperature control unit. The PID temperature control unit completes the temperature control during the crystal screening process according to the output signal of the set program;

[0029] Observe the experimental situation through various online monitoring instruments such as a multi-probe online ultraviolet spectrometer, Raman spectrometer, online imaging system, probe type turbidimeter, infrared concentration measuring instrument, ultrasonic particle size distribution measuring instrument, etc.; after the experiment, take samples and analyze.

[0030] Compared with the prior art, the beneficial effects of an integrated online ultraviolet and imaging parallel crystal form screening and process optimization system provided by the present invention are:

[0031] 1. This system integrates a multi-probe online ultraviolet spectrometer on a high-throughput system for the first time, that is, integrates high-throughput technology with online solution concentration / supersaturation measurement technology for the first time. The ultraviolet probe is used to monitor the solution concentration and the supersaturation of the crystallization process in real time, so as to measure the position of the operating point during the crystallization process and the movement trajectory of the operating point within the metastable zone in real time. Of course, the online concentration / supersaturation measurement method involved in this system is not the latest, but no one has integrated it into a high-throughput system before.

[0032] 2. This system integrates an ultraviolet probe, which can record the supersaturation curve in real time, and can find the change of supersaturation during the formation of different crystal forms, which has guiding significance for process scale-up. At the same time, the specific operating conditions for synthesizing different crystal forms can also be found, providing a reference for production.

[0033] 3. The stirring rate range of this system is 56 rpm to 4030 rpm, which has the advantages of a large maximum rotational speed and a large rotational speed range. And the temperature control accuracy can reach 0.1 °C, which is better than other similar products on the market. Brief Description of the Drawings

[0034] Figure 1 It is a software screenshot of an integrated online ultraviolet and imaging parallel crystal form screening and process optimization system;

[0035] Figure 2 It is a schematic diagram of an integrated online ultraviolet and imaging parallel crystal form screening and process optimization system;

[0036] Figure 3 It is a schematic structural diagram of a metal heat conduction kit of an integrated online ultraviolet and imaging parallel crystal form screening and process optimization system;

[0037] Figure 4Communication flowchart of a parallel polymorph screening and process optimization system integrating on-line ultraviolet and imaging;

[0038] Figure 5 Working method flowchart of a parallel polymorph screening and process optimization system integrating on-line ultraviolet and imaging;

[0039] Figure 6 X-ray powder diffraction pattern of a sample obtained from a polymorph screening experiment using this system;

[0040] Figure 7 Metastable zone of carbamazepine cooling crystallization at different cooling rates;

[0041] Figure 8 Structure diagram of a multi-probe ultraviolet spectrometer configured with a parallel polymorph screening and process optimization system integrating on-line ultraviolet and imaging;

[0042] Figure 9 Schematic diagram for measuring the movement trajectory and real-time position of an operating point using this system. Detailed implementation manners

[0043] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention.

[0044] The following are the detailed implementation manners of a parallel polymorph screening and process optimization system integrating on-line ultraviolet and imaging provided by the present invention. As Figures 1-5 shown in this embodiment, it includes several crystallization unit slots for placing crystallization units. Each crystallization unit includes a temperature control device, a process monitoring device, a stirring device, a feeding device, and a host computer. The temperature control module is used to adjust the temperature of the crystallization unit; the process monitoring device is used to monitor the temperature of the crystallization unit, the stirring device is used to stir the crystals inside the crystallization unit, and the host computer is electrically connected to the temperature control device, the process monitoring device, the stirring device, and the feeding device.

[0045] Among them, in the above technical solution, the crystallization unit has a six-channel structure and contains multiple crystallizers inside. The crystallizers have various volume specifications. The outer diameter of the crystallizer is enlarged by a metal diameter-expanding ring. Each crystallizer is provided with a sealing cover. The sealing cover is provided with several sealable holes, and there are multiple sealable holes with different sizes. The sealing block is used to insert the process monitoring probe, the temperature sensor probe, the mechanical stirring paddle, and the feeding pipeline; the sealing cover is made of polytetrafluoroethylene, and the sealing cover is also provided with threaded holes for connecting the crystallizer.

[0046] Furthermore, in the above technical solution, the temperature control device includes an electric refrigeration unit, an electric heating unit, a PID temperature control unit, and a metal heat conduction kit; the metal heat conduction kit is arranged on the surface around the mold and is in close contact with the mold, and is used to control the process of the temperature change of the sample inside the mold; the PID temperature control unit is electrically connected to the electric heating unit and is used to control the heating temperature of the electric heating unit; the PID temperature control unit is electrically connected to the electric refrigeration unit and is used to control the cooling temperature of the electric refrigeration unit.

[0047] Furthermore, in the above technical solution, the electric refrigeration unit includes a semiconductor refrigeration chip, one on each of the two sides of each channel, and they work simultaneously. The PID temperature control unit adjusts the refrigeration power of the electric refrigeration unit by outputting signals, thereby controlling the temperature of the electric refrigeration unit. The electric refrigeration unit indirectly transfers the temperature to the inside of the mold through the metal heat conduction kit; there is also a coolant outside the semiconductor refrigeration chip, and the coolant is used to take away the heat of the refrigeration chip.

[0048] During heating, the copper block generates heat when electrified, and the heat is directly transferred to the mold. During the heating process, the PID temperature control unit adjusts the heating power of the electric heating unit by outputting signals, thereby controlling the temperature of the electric heating unit. The electric heating unit is in direct contact with the bottom of the mold, and can transfer heat to the inside of the mold directly through the bottom or indirectly through the metal heat conduction kit, ensuring the heating efficiency of the electric heating unit.

[0049] Furthermore, in the above technical solution, the metal heat conduction kit has a cylindrical structure, and the material is an aluminum block. One or two holes are opened on the side wall for placing one or two molds respectively. The mold, the metal heat conduction kit and the semiconductor refrigeration chip are in close contact with each other in sequence from the inside to the outside.

[0050] Furthermore, in the above technical solution, the process monitoring device is an online ultraviolet spectrometer, a probe type turbidimeter, a Raman spectrometer, an online imaging system for the process, an infrared concentration measuring instrument, and an ultrasonic particle size distribution measuring instrument. The online ultraviolet spectrometer, the probe type turbidimeter, the Raman spectrometer, the online imaging system for the process, the infrared concentration measuring instrument, and the ultrasonic particle size distribution measuring instrument respectively pass through the sealing holes on the mold cover and enter the mold to detect the inside of the mold.

[0051] Further, in the above technical solution, the stirring device includes a magnetic stirring device and a mechanical stirring device. The magnetic stirring device and the mechanical stirring device are used to stir the samples in crystallizers of different capacities, and the rotational speed ranges of the magnetic stirring device and the mechanical stirring device are different. The mechanical stirring device includes a top motor and a bottom stirring paddle. The stirring paddle enters the crystallizer through a hole in the crystallizer sealing cover and is fixedly connected to the sealing cover. The top motor is fixedly connected to the crystallization unit through an iron clamp on the crystallization unit channel to prevent the stirrer from driving the crystallizer at high speed and affecting the crystallization process of the samples in the crystallizer. The mechanical stirring device communicates with the host computer through RS485.

[0052] Further, in the above technical solution, the feeding device includes a feed pump, a feed pipe, and a sampling pipe. The feed pump is communicatively connected to the host computer and communicates with the host computer to control the feeding amount and feeding rate of the samples. One end of the sampling port of the sampling pipe is located in the external sampling pool, the other end is fixedly connected to the sampling pump, the other end of the sampling pump is fixedly connected to the feed pipe, and the other end of the feed pipe passes through a hole in the crystallizer sealing cover and is located inside the crystallizer.

[0053] Further, in the above technical solution, the PID temperature control unit is communicatively connected to the host computer. The PID temperature control unit receives the target temperature received by the host computer and returns the current temperature to the host computer.

[0054] Further, in the above technical solution, the operation includes the following steps:

[0055] Weigh the medicine and prepare the solution.

[0056] Inhale the sample from the external sample pool and inject the sample into the crystallizer through the feed pipe passing through the hole in the crystallizer sealing cover. Set the feeding amount and feeding rate in the host computer.

[0057] Select the stirring type and set the stirring rate of magnetic stirring or mechanical stirring through the host computer.

[0058] Set a multi-segment limited slope heating and cooling program in the host computer, including a heating process, a cooling process, and a constant temperature process. Match the three temperature control process tasks according to the required process of crystal screening, add them to the task bar, and then send them to the PID temperature control unit. The PID temperature control unit completes the temperature control during the crystal screening process according to the output signal of the set program.

[0059] Use online monitoring instruments such as a multi-probe online ultraviolet spectrometer, a probe-type turbidimeter, a Raman spectrometer, a process online imaging system, an infrared concentration meter, and an ultrasonic particle size distribution meter to complete real-time observation of the experimental situation. After the experiment, take samples and complete the analysis work.

[0060] The following is the first embodiment of a parallel polymorph screening and process optimization system integrating online ultraviolet and imaging provided by the present invention, mainly explaining the steps of polymorph screening: drugs such as carbamazepine, absolute ethanol, methanol, ethyl acetate, etc. are all of analytical grade; X-ray powder diffractometer, electronic balance, vacuum drying oven; conduct carbamazepine polymorph screening experiment.

[0061] The experiment includes the following steps:

[0062] Step 1: Weigh the drugs and prepare the solution.

[0063] Step 2: Feed the sample. The feed pump suction pipe sucks the sample from the external sample pool and injects the sample into the crystallizer through the hole on the crystallizer seal cover through the feed pipe. The feed pump is communicatively connected to the host computer. By setting the feed volume and feed rate in the host computer, the feed pump is controlled to complete the work, realizing the synchronous progress of multiple crystallization screening reactions.

[0064] Step 3: Set the stirring rate. The stirring type can be selected in the host computer, and the magnetic stirring rate or mechanical stirring rate can be set.

[0065] Step 4: Set the temperature task. Set a multi-stage limited slope heating and cooling program in the host computer, including the heating process, cooling process, and constant temperature process. Match the above three temperature control process tasks according to the required process of crystallization screening, add them to the task bar, and then send them to the PID controller. The PID controller completes the temperature control during the crystallization screening process according to the output signal of the set program.

[0066] Step 5: Observe the experimental situation through various online monitoring instruments such as a multi-probe online ultraviolet spectrometer, Raman spectrometer, online imaging probe, probe type turbidimeter, infrared concentration measuring instrument, ultrasonic particle size distribution measuring instrument, etc. After the experiment, take samples and analyze.

[0067] As Figure 6 shown, the carbamazepine crystals obtained from the experiment are characterized by X-ray powder diffraction. The experimental results are shown in Table 1. Four polymorphs of carbamazepine are found: polymorph I, polymorph II, polymorph III, and dihydrate, that is, four different polymorphs of carbamazepine are prepared in total.

[0068] Table 1 Experimental conditions and results of polymorph screening

[0069]

[0070] The following is the second embodiment of a parallel polymorph screening and process optimization system integrating online ultraviolet and imaging provided by the present invention, mainly explaining the measurement of the width of the metastable zone:

[0071] Drugs such as carbamazepine, absolute ethanol, methanol, and ethyl acetate are all of analytical grade; X-ray powder diffractometer, electronic balance, vacuum drying oven; an experiment on measuring the width of the metastable zone of carbamazepine was carried out.

[0072] The experiment includes the following steps:

[0073] Step 1: Weigh the drugs and prepare the solution.

[0074] Step 2: Feeding of the sample. The feeding pump suction tube sucks the sample from the external sample pool and injects the sample into the crystallizer through the hole on the sealing cover of the feeding tube and the crystallizer. The feeding pump is communicatively connected to the host computer. By setting the feeding volume and feeding rate in the host computer, the feeding pump is controlled to complete the work, realizing the synchronous progress of multiple groups of experiments.

[0075] Step 3: Setting the stirring rate. The stirring type can be selected in the host computer to set the stirring rate.

[0076] Step 4: Setting the temperature task. Heat the reactor to the target temperature, stir at a constant temperature for 1 h to ensure that the carbamazepine in the beaker is completely dissolved. After the solution is stable, start cooling at different cooling rates (0.5 K / min, 1.0 K / min).

[0077] Step 5: Observe the experimental situation through various on-line monitoring instruments such as a multi-probe on-line ultraviolet spectrometer, Raman spectrometer, on-line imaging probe, probe type turbidimeter, infrared concentration measuring instrument, ultrasonic particle size distribution measuring instrument, etc.

[0078] After the experiment, data are obtained. The experimental results are shown in Table 2. According to the experimental data, the diagram of the width of the metastable zone drawn is as Figure 7 shown.

[0079] Table 2 Measured values of the width of the metastable zone

[0080] b (K / min) Nr (rpm) T (K) 0.5 300 293.15 298.15 303.15 305.15 308.15 313.15 5.6 5.1 4.8 4.6 4.5 4.5 315.15 318.15 320.15 323.15 328.15 333.15 4.5 4.5 4.4 4.2 3.9 3.6 1.0 300 293.15 298.15 303.15 305.15 308.15 313.15 13.2 10.9 9.1 8.4 7.7 7.7 315.15 318.15 320.15 323.15 328.15 333.15 7.6 7.5 7.1 6.5 6 5.6

[0081] The following is the second embodiment of an integrated on-line ultraviolet and imaging parallel crystal form screening and process optimization system provided by the present invention, mainly explaining the measurement of the current position and movement trajectory of the operating point: Drugs such as carbamazepine, absolute ethanol, methanol, and ethyl acetate are all of analytical grade; X-ray powder diffractometer, electronic balance, vacuum drying oven; measure the current position of the operating point and the movement trajectory of the operating point in the metastable zone.

[0082] The experiment includes the following steps:

[0083] Step 1: Weigh the drugs and prepare the solution.

[0084] Step 2: Feeding of the sample. The sampling tube of the feeding pump sucks the sample from the external sample pool and injects the sample into the crystallizer through the hole on the sealing cover of the feeding tube and the crystallizer. The feeding pump is communicatively connected to the host computer. By setting the feeding volume and feeding rate in the host computer, the feeding pump is controlled to complete the work, and the synchronous progress of multiple groups of experiments is realized.

[0085] Step 3: Setting of the stirring rate. The stirring type can be selected in the host computer, and the stirring rate can be set.

[0086] Step 4: Setting of the temperature task. The reactor is heated to the target temperature and stirred at a constant temperature for 1 h to ensure that the carbamazepine in the beaker is completely dissolved. After the solution is stable, cooling is started at different cooling rates (0.5 K / min, 1.0 K / min).

[0087] Step 5: Observe the experimental situation through various on-line monitoring instruments such as a multi-probe on-line ultraviolet spectrometer, a Raman spectrometer, an on-line imaging probe, a probe type turbidimeter, an infrared concentration measuring instrument, an ultrasonic particle size distribution measuring instrument, etc. The movement trajectory and real-time position of the operating points obtained during the experiment are as Figure 9 shown.

[0088] Specifically, the principle of the present invention is as follows: The present invention integrates the on-line concentration / supersaturation measurement technology with the high-throughput technology; six channels of this system are all integrated with ultra-fine ultraviolet probes, and the solution concentration / supersaturation measurement technology based on the multi-probe on-line ultraviolet spectroscopy technology is integrated on the high-throughput system, which can real-time monitor the solution concentration and the supersaturation during the crystallization process. And because this system is equipped with ultra-fine ultraviolet probes, the change of supersaturation during the formation of different crystal forms can be found, which has guiding significance for process amplification. This system also integrates the particle shape and particle size measurement technology based on on-line imaging / image processing, and can obtain the image in the crystallizer in real time through the on-line imaging probe to realize the measurement of the particle shape and particle size. This system contains six channels, and can integrate process monitoring devices to realize temperature measurement, temperature control, solution concentration measurement, supersaturation measurement, measurement of operating points during the crystallization process, particle shape and particle size measurement, process monitoring, stirring control and feeding control during the crystallization process. Each channel is independent of each other and is equipped with a host computer. The above functions realize automatic control, can complete the tasks of solubility determination and crystallization metastable zone determination, and can greatly accelerate the speed of crystal form screening and preparation of target crystals at the same time.

[0089] The above is only the specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, and all should be covered within the protection scope of the present invention.

Claims

1. A parallel crystal screening and process optimization system integrating online UV and imaging, characterized in that: The invention comprises a plurality of crystallization unit slots for placing the crystallization units, each of the crystallization units comprises a temperature control device, a process monitoring device, a stirring device, a feeding device and a host computer, the temperature control module is used to adjust the temperature of the crystallization unit; the process monitoring device is used to monitor the temperature of the crystallization unit, the stirring device is used to stir the crystal inside the crystallization unit, and the host computer is electrically connected with the temperature control device, the process monitoring device, the stirring device and the feeding device.

2. The parallel crystal screening and process optimization system integrating online UV and imaging according to claim 1, characterized in that: The crystallization unit is a six-channel structure with multiple crystallizers placed inside. The crystallizers have various sizes. The outer diameter of the crystallizer is enlarged by a metal expansion ring. Each crystallizer is provided with a sealing cover. The sealing cover is provided with a plurality of sealable holes and a plurality of sealing holes of different sizes. The sealing block is used to insert a process monitoring probe, a temperature sensor probe, a mechanical stirring paddle, and a feed pipeline. The sealing cover is made of polytetrafluoroethylene and is also provided with a threaded hole for connecting the crystallizer.

3. The parallel crystal screening and process optimization system integrating online UV and imaging according to claim 2, characterized in that: The temperature control device includes an electric refrigeration unit, an electric heating unit, a PID temperature control unit, and a metal thermal conductive kit; the metal thermal conductive kit is arranged on the surface around the crystallizer and is in close contact with the crystallizer, and is used to control the process of temperature change of the sample inside the crystallizer; the PID temperature control unit is electrically connected to the electric heating unit, and is used to control the heating temperature of the electric heating unit; the PID temperature control unit is electrically connected to the electric refrigeration unit, and is used to control the cooling temperature of the electric refrigeration unit.

4. The parallel crystal screening and process optimization system integrating online UV and imaging according to claim 3, characterized in that: The electric refrigeration unit includes a semiconductor refrigeration plate, one on each side of each channel, and working simultaneously. The PID temperature control unit adjusts the refrigeration power of the electric refrigeration unit by outputting a signal, thereby controlling the temperature of the electric refrigeration unit. The electric refrigeration unit indirectly transfers the temperature to the inside of the crystallizer through a metal heat conduction kit; a coolant is also provided on the outside of the semiconductor refrigeration plate, and the coolant is used to take away the heat of the refrigeration plate.

5. The parallel crystal screening and process optimization system integrating online UV and imaging according to claim 4, characterized in that: The metal heat-conducting kit is in a cylindrical structure and is made of an aluminum block. One or two holes are opened on the side wall for placing one or two crystallizers respectively. The crystallizer, the metal heat-conducting kit and the semiconductor refrigeration plate are in close contact from the inside to the outside.

6. The parallel crystal screening and process optimization system integrating online UV and imaging according to claim 5, characterized in that: The process monitoring device includes an online ultraviolet spectrometer, a probe turbidity meter, a Raman spectrometer, an online imaging system for the process, an infrared concentration meter, and an ultrasonic particle size distribution meter. The online ultraviolet spectrometer, the probe turbidity meter, the Raman spectrometer, the online imaging system for the process, the infrared concentration meter, and the ultrasonic particle size distribution meter respectively pass through the sealing hole on the crystallizer sealing cover to enter the crystallizer to detect the inside of the crystallizer.

7. The parallel crystal screening and process optimization system integrating online UV and imaging according to claim 6, characterized in that: The stirring device includes a magnetic stirring device and a mechanical stirring device. The magnetic stirring device and the mechanical stirring device are used to stir samples in crystallizers of different capacities, and the magnetic stirring device and the mechanical stirring device have different rotation speed ranges; the mechanical stirring device includes a top motor and a bottom stirring paddle, the stirring paddle enters the crystallizer through a hole on a sealing cover of the crystallizer and is fixedly connected to the sealing cover, and the top motor is fixedly connected to the crystallization unit through an iron clamp on a channel of the crystallization unit, so as to prevent the crystallizer from being driven when the stirrer rotates at a high speed and affecting the crystallization process of the sample in the crystallizer; the mechanical stirring device communicates with a host computer via RS485.

8. The parallel crystal screening and process optimization system integrating online UV and imaging according to claim 7, characterized in that: The feeding device includes a feeding pump, a feeding pipe and a feeding pipe. The feeding pump is communicatively connected to a host computer and is used to control the feeding amount and feeding rate of the sample. One end of the feeding port of the feeding pipe is located in an external sampling pool, and the other end is fixedly connected to the feeding pump. The other end of the feeding pump is fixedly connected to the feeding pipe, and the other end of the feeding pipe passes through a hole on a sealing cover of the crystallizer and is located inside the crystallizer.

9. The parallel crystal screening and process optimization system integrating online UV and imaging according to claim 8, characterized in that: The PID temperature control unit is connected to the host computer for communication. The PID temperature control unit receives the target temperature received by the host computer and returns the current temperature to the host computer.

10. The parallel crystal screening and process optimization system integrating online UV and imaging according to claim 9, characterized in that: The parallel crystal screening and process optimization system comprises the following steps when running: Weighing of drugs and preparation of solutions; The sample is sucked from the external sample pool and injected into the crystallizer through the feed pipe through the hole on the crystallizer sealing cover; the feed amount and feed rate are set in the upper computer; Select the stirring type and set the stirring rate of magnetic stirring or mechanical stirring through the host computer; By setting up a multi-stage limited slope temperature rise and fall program in the host computer, including a temperature rise process, a temperature drop process and a constant temperature process, the three temperature control process tasks are matched according to the process required for crystallization screening, added to the task bar and sent to the PID temperature control unit. The PID temperature control unit completes the temperature control in the crystallization screening process according to the output signal of the set program; The experimental conditions are observed in real time using online monitoring instruments such as a multi-probe online UV spectrometer, a probe turbidity meter, a Raman spectrometer, an online process imaging system, an infrared concentration meter, and an ultrasonic particle size distribution meter. After the experiment, sampling is carried out and analysis is completed.

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