Anti-solvent fluid mechanics control device and control method of flower-shaped porous lactose recrystallization equipment

Abstract

The invention provides an anti-solvent fluid mechanics control device and method for flower-shaped porous lactose recrystallization equipment, and the device comprises a reaction kettle, a first stirrer, a second stirrer, a flow guide member, a nozzle unit, a multi-zone sensor and a dynamic controller, the flow guide member divides the interior of the reaction kettle into a low-shear growth zone and a high-shear mixing zone; the nozzle unit comprises at least one first nozzle, a second nozzle and a third nozzle; the multi-zone sensor comprises a PVM probe, an FBRM probe and a turbidimeter; when the reaction kettle runs, injecting a lactose saturated solution into the low-shear growth area, starting the first nozzle to add an anti-solvent in a dispersion mode, starting a pulse mode of the second nozzle when the PVM probe detects that the petal profile ratio reaches a preset value, and increasing the flow of the third nozzle when the FBRM probe detects that the growth rate is lower than the preset value. According to the invention, the problem of unstable form of flower type lactose crystal is solved mainly through fluid mechanics partitioning, multi-nozzle cooperation and dynamic control.

Description

Technical Field

[0001] This invention relates to the field of enhanced crystallization technology, specifically, it demonstrates an antisolvent hydrodynamic control device and control method for a flower-shaped porous lactose recrystallization apparatus. Background Technology

[0002] Flower-shaped porous lactose, as a highly efficient drug carrier, is widely used in the pharmaceutical industry for its antisolvent recrystallization process. Traditional crystallization equipment uses a mechanically stirred tank structure, with the antisolvent injected into the central region of the reactor through a single pipeline. This structure results in a turbulent and disordered flow field within the reactor, making it impossible to form stable hydrodynamic zones.

[0003] During the crystallization process, the antisolvent and lactose solution mix violently to generate local supersaturated hot spots (supersaturation S > 2.0). These hot spots trigger explosive nucleation, generating a large number of submicron-sized fine crystals (<5μm accounting for more than 30%). These fine crystals further aggregate into irregular blocky structures, rather than the target flower-shaped porous morphology.

[0004] More seriously, the existing technology lacks a real-time morphological feedback mechanism. Operators need to take samples every 30 minutes for offline electron microscopy. When petal fusion or pore collapse is found, crystal growth has already entered an irreversible stage. This directly leads to significant batch-to-batch quality fluctuations, with a flower shape integrity rate of only 60-70% (industry report data, International Journal of Pharmaceutics 2023) and a porosity deviation as high as ±15%.

[0005] Existing technologies have attempted to improve the design of the impeller blades in mixers, but have failed to solve the fundamental problem: 1. Fluid control problem: The high-shear zone and the low-shear zone are mixed and overlapping, which cannot provide a stable growth environment for the flower-shaped main stem; 2. Concentration control issue: Single-point injection of antisolvent causes abrupt changes in the concentration gradient, resulting in random crystal growth direction; 3. Control strategy issues: The stirring rate depends on empirical settings and cannot be quantitatively maintained at the optimal shear rate. Summary of the Invention

[0006] To address the shortcomings of existing technologies, the purpose of this invention is to provide an antisolvent hydrodynamic control device and control method for a flower-shaped porous lactose recrystallization apparatus.

[0007] According to the present invention, an antisolvent hydrodynamic control device for a flower-shaped porous lactose recrystallization apparatus includes a matching reaction vessel and a stirrer, wherein the stirrer is located inside the reaction vessel, and the reaction vessel is further provided with: Flow guiding component: Fixed inside the reactor and maintaining a gap with the inner wall and bottom of the reactor. The internal space of the flow guiding component serves as a low-shear growth zone, and the space between the outer wall of the flow guiding component and the inner wall of the reactor serves as a high-shear mixing zone. The flow guiding component also has growth slots. Nozzle unit: includes at least one first nozzle extending into the low-shear growth zone and the first nozzle having a microporous diffuser head, at least one second nozzle pointing towards the growth gap and the second nozzle having a pulse valve, and at least one third nozzle located in the high-shear mixing zone and the third nozzle having a Y-shaped laminar flow outlet; Multi-zone sensors include a PVM probe installed in the low-shear growth zone, an FBRM probe embedded in the growth gap, and a turbidimeter located in the high-shear mixing zone. Each nozzle unit group and multi-zone sensor are connected to an external dynamic controller via signal lines, which is used to dynamically switch the working mode of each nozzle according to the real-time flower crystallization state.

[0008] The flow guiding structure divides the reactor into a low-shear growth zone (stable growth of the main stem) and a high-shear mixing zone (rapid dispersion of the antisolvent), fundamentally eliminating the problem of flow field chaos. The three nozzles operate independently: the first nozzle (micropore diffusion) achieves smooth nucleation in the low-shear zone; the second nozzle (pulse jet) achieves directional expansion of petals in the growth gap zone; and the third nozzle (laminar flow guidance) achieves uniform mixing in the high-shear zone, avoiding explosive nucleation problems caused by local oversaturation.

[0009] Preferably, the flow guiding member is a vertically arranged cylindrical body, and the upper part of its side wall is provided with flow guiding plates evenly distributed in the circumferential direction. The flow guiding plates extend obliquely downward from the side wall of the flow guiding member with the radial direction as the reference, and the growth gap is formed between adjacent flow guiding plates.

[0010] The downward-sloping guide vanes will guide the fluid to radiate at a certain angle, increasing the residence time of the crystal at the gap. By using the physical guidance of the growth gap structure to expand the petals, the symmetry of the crystal is improved.

[0011] Furthermore, the flow guiding member has 6 to 12 radially extending flow guiding vanes evenly distributed along its circumference. The angle between each vane and the horizontal plane is 15° to 30°, and its length is 15% to 25% of the diameter of the flow guiding member. The width of the growth gap is 1 to 10 mm. mm .

[0012] The inclined baffles guide the fluid flow to the growth gaps, promoting petal extension.

[0013] Preferably, the orifice diameter of the microporous diffuser head of the first nozzle is 10 to 100 mm. μm The pulse quantity of the second nozzle is 0.05 to 5. ml / time, the Y-shaped laminar flow outlet split angle of the third nozzle is 60°~90°.

[0014] The 10–100 μm pore size can generate micron-sized antisolvent droplets, increasing the nucleation particle size D50 from submicron (<5 μm) to 20–50 μm; the Y-shaped outlet with a 60–90° split angle achieves laminar flow coverage, reducing the crystal collision breakage rate.

[0015] Preferably, the gap between the bottom end of the flow guiding member and the bottom of the reactor is 5 to 10 cm, and the top end of the flow guiding member needs to be 10 to 20 cm lower than the steady liquid level of the reactor during operation.

[0016] A high-shear inlet is formed at the bottom gap of the flow guiding component, and the top liquid positioning guides the fluid circulation, thereby improving the mixing efficiency.

[0017] Preferably, the laser window of the FBRM probe is flush with the inner wall of the growth crevice, and the detection depth is ≤0.5m from the crevice surface. mm This allows the FBRM probe to capture the crystal growth dynamics in real time, reducing errors.

[0018] The present invention also provides an antisolvent hydrodynamic control method, employing the control device described above, comprising the following steps: (a) Inject a lactose-saturated solution into the low-shear growth zone and start the first nozzle to add the antisolvent in diffusion mode; (b) When the PVM probe detects a petal profile ratio ≥ 1.0, the second nozzle pulse mode is activated at a frequency of... f satisfy: in k For growth rate, It is the circumferential arc length between the center lines of adjacent growth slots on the flow guiding component; (c) If the FBRM probe detects a growth rate < 0.5 μm / min Increase the flow rate of the third nozzle by 10-30%.

[0019] When the profile ratio is ≥1.0, it indicates that the petal buds have formed. The pulse mode of the second nozzle is automatically activated. The pulse jet precisely stimulates the radial expansion of the petals, avoiding the deformity problem of "overly thick trunk and short petals" caused by traditional continuous injection.

[0020] Preferably, in step (b), the pulse frequency f The range is 5 to 20. Hz Furthermore, the pulse timing is synchronized with the stirrer speed, with a phase difference of ≤10%. This synchronization mechanism prevents the pulse jet from colliding with the stirrer blades.

[0021] Preferably, when the turbidimeter detects a supersaturation S > 1.3, the dynamic controller executes: Close the second nozzle pulse; Switch the first nozzle to ultrasonic atomization mode; The cooling rate was increased to 0.8℃ / min.

[0022] The turbidimeter monitors the S value in real time, shortening the time required to eliminate supersaturated hot spots.

[0023] Preferably, to maintain the shear rate at the growth gap, the rotation speed of the second stirrer is... N satisfy: in: A It is a constant, taking the value 950±50; m Set the shear rate value; r The density of the solution; D The length of the blades on the mixer; i The angle between the guide vane and the horizontal plane; W The width of the growth gap.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. By dividing the reactor into zones using flow guiding components, a stable low-shear growth zone and a high-shear mixing zone are established, making the fluid inside the reactor more orderly and enabling the flower-shaped structure to grow stably. 2. By setting up three independent nozzle units, multi-point corresponding injection is achieved, which works in conjunction with the guide plate to achieve physically guided growth of crystal morphology; 3. Establish a dynamic feedback control model, dynamically adjust parameters based on multi-zone sensor data, flexibly control the stirring rate of the agitator, accurately control the shear rate, and solve the problem of lag in manual experience control. Attached Figure Description

[0025] Figure 1 This is a simplified flowchart of the antisolvent hydrodynamic control method according to an embodiment of the present invention; Figure 2 This is a simplified schematic diagram of the antisolvent hydrodynamic control device for a flower-shaped porous lactose recrystallization apparatus according to an embodiment of the present invention; Figure 3 This is a schematic diagram of the flow guiding component according to an embodiment of the present invention; The relevant markings in the attached diagram are: 1-Reaction vessel, 2-Stirrer No. 1, 3-Stirrer No. 2, 4-Flow guiding component, 5-First nozzle, 6-Second nozzle, 7-Third nozzle, 8-PVM probe, 9-FBRM probe, 10-Turbidimeter, 11-Dynamic controller, 41-Flow guiding plate, 42-Growth gap. Detailed Implementation

[0026] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0027] Example 1 like Figure 2 As shown in the figure, this invention proposes an antisolvent hydrodynamic control device for a flower-shaped porous lactose recrystallization apparatus, including a reaction vessel 1, a first stirrer 2, and a second stirrer 3, both of which are located inside the reaction vessel, which has a volume of 50. L The material is 316 L Made of stainless steel, the reactor 1 is also equipped with a flow guiding component 4, a nozzle unit, and a multi-zone sensor.

[0028] See Figure 3 As shown, the flow guiding component 4 is a vertical cylindrical body; in this embodiment, its diameter is 0.6 mm. m The height is 0.8. m There is a certain gap between the flow guiding component 4 and the inner wall and bottom of the reactor 1. In this way, during subsequent crystallization, the internal space of the flow guiding component 4 can form a low-shear growth zone, and the space between the outer wall of the flow guiding component 4 and the inner wall of the reactor 1 serves as a high-shear mixing zone. The low-shear growth zone and the high-shear mixing zone are interconnected through the upper and lower openings of the flow guiding component. The first stirrer 2 rotates in the low-shear growth zone inside the flow guiding component 4 to provide a gentle circulating flow direction for stable crystal growth. The second stirrer 3 rotates in the high-shear mixing zone between the flow guiding component 4 and the reactor 1 to generate turbulence to quickly disperse the antisolvent. The speed of the second stirrer 3 is greater than that of the first stirrer 2.

[0029] The flow guiding component 4 divides the reactor 1 into a low-shear growth zone (stable growth of the main stem) and a high-shear mixing zone (rapid dispersion of antisolvent), fundamentally eliminating the problem of flow field chaos.

[0030] The gap between the bottom end of the flow guiding component 4 and the bottom of the reactor is 8. cm The top of the flow guide component 4 must be 15 cm below the steady-state liquid level of the reactor during operation. cm This forms a fluid circulation channel.

[0031] Furthermore, eight guide vanes 41 are evenly distributed along the axial direction in the upper part of the side wall of the flow guiding member 4. The cross-sectional shape of each guide vane 41 is similar to that of the flow guiding member 4, and its length is 15-25% of the diameter of the flow guiding member 4. The guide vanes 41 are arranged geometrically to solve the problem of disordered growth. The guide vanes 41 extend obliquely downward from the side wall of the flow guiding member 4 with the radial direction as the reference, and the angle between them and the horizontal plane is 20°. The inclined arrangement can guide the fluid flow and direct it to the growth gap, promoting the extension of the petals. Growth gaps are formed between adjacent guide vanes, and the width of the growth gap between adjacent guide vanes is 3. mm .

[0032] In this embodiment, the "growth gap" specifically refers to the narrow slit structure formed between adjacent guide vanes 41. When the reactor is running, the solution inside the guide vane flows outward from the open space between the guide vane and the bottom of the reactor. The solution rises and wets upward along the surface of the guide vane, mixing with the fluid in the high-shear mixing zone at the growth gap.

[0033] See Figure 2 As shown, the nozzle unit includes at least one first nozzle 5 extending into the low-shear growth zone and the first nozzle 5 includes a microporous diffuser head, at least one second nozzle 6 pointing towards the growth gap 42 and the second nozzle 6 includes a pulse valve, and at least one third nozzle 7 located in the high-shear mixing zone and the third nozzle 7 includes a Y-shaped laminar flow outlet. The first nozzle 5 can be fixed on the inner wall of the flow guiding member 4 and spray antisolvent towards the center of the flow guiding member 4. The second nozzle 6 and the third nozzle 7 can be fixed on the outer wall of the flow guiding member 4.

[0034] The orifice diameter of the microporous diffuser of the first nozzle 5 is 50. μm The pulse quantity of the second nozzle 6 is 1. ml / time, the Y-shaped laminar flow outlet of the third nozzle 7 has a flow split angle of 75°. The first nozzle generates micron-sized antisolvent droplets, which are injected in a diffuse mode during the initial nucleation period to avoid local concentration abrupt changes in the low-shear growth zone and suppress fine crystal bursts; the pulse jet generated by the second nozzle acts precisely on the growth gap, driving the crystal to radiate and expand along the guide vane tilt angle; the Y-shaped flow split generated by the third nozzle suppresses local crystal accumulation in the high-shear mixing zone, and, in conjunction with high-shear turbulence, makes the crystal uniformly dispersed; all three nozzles spray antisolvent, but operate in different modes.

[0035] See Figure 2As shown, the multi-zone sensor includes a PVM probe 8 installed in the low-shear growth zone, an FBRM probe 9 embedded in the growth slit, and a turbidimeter 10 located in the high-shear mixing zone. The PVM probe (particle video microscope) is fixed on the inner wall of the flow guide component and uses an image recognition algorithm to detect "flower shape" and capture the crystal morphology evolution in real time, i.e., the petal outline ratio (petal length / trunk diameter), and monitor the particle chord length distribution, counting, and preliminary morphology (whether a flower-like rudiment has appeared). The laser window of the FBRM probe (focused beam reflectance meter) needs to be flush with the inner wall of the growth slit to monitor the crystal chord length distribution (CLD) and particle number in real time to monitor the crystal growth rate. The turbidimeter is located between the flow guide component and the reactor, i.e., fixed on the inner wall of the reactor, to detect the supersaturated state of the solution in real time and avoid antisolvent agglomeration.

[0036] It should be noted that each nozzle unit and multi-zone sensor is connected to an external dynamic controller 11 via signal lines. This controller dynamically switches the operating mode of each nozzle based on the real-time flower crystallization state (nucleation stage, growth stage, and setting stage). The dynamic controller is an industrial-grade PLC or a real-time industrial control computer. Specifically, during the nucleation stage (supersaturation S = 1.2–1.5), the low-shear mode is activated at the injection point in the low-shear growth zone; during the petal growth stage (supersaturation S = 1.05–1.2), the pulse control mode is activated at the injection point in the growth slit, with a frequency of 5–20. Hz During the pore settling period (supersaturation S=1.0~1.05), the directional laminar flow mode at the injection point of the high-shear mixing zone is initiated.

[0037] Example 2: This invention proposes an antisolvent hydrodynamic control method based on the antisolvent hydrodynamic control device described in Example 1, such as... Figure 1 As shown, the main steps include: ① Initial injection: Inject 40g into the low-shear growth region L Lactose-saturated solution (concentration 30%) w / v ), start the first nozzle to add ethanol antisolvent in dispersion mode (flow rate 10). ml / min The microporous diffuser of the first nozzle generates uniform droplets, promoting initial nucleation (D50=35). μm ).

[0038] ② Petal Expansion: When the PVM probe detects a petal profile ratio ≥ 1.0 (indicating the formation of a preliminary crystal shape), the second nozzle pulse mode is activated, with a frequency of... f satisfy: in k For growth rate, It is the circumferential arc length between the center lines of adjacent growth slots on the flow guiding component; Set growth rate k =1.2 μm / min , =0.15 m (Based on calculations using eight guide vanes), substituting into the above formula, the calculated pulse frequency of the second nozzle is 80. Hz To ensure that the pulse timing is synchronized as much as possible with the rotation speed of the second stirrer (200 rpm) (phase difference of 5%), and to avoid jet interference.

[0039] ③ Growth regulation: If the FBRM probe detects a growth rate decrease to 0.5... μm / min At that time, increase the flow rate of the third nozzle by 20% (from 5). ml / min Up to 6 ml / min ), enhance mixing to accelerate growth.

[0040] ④ Oversaturation control: When the turbidimeter detects S=1.4 (>1.3), the dynamic controller immediately executes: Close the second nozzle pulse; Switch the first nozzle to ultrasonic atomization mode (frequency 40kHz). Meanwhile, the system cooling rate is increased to 0.8°C / min (from 25°C to 20°C), and the system temperature inside the reactor is regulated and controlled by an external temperature control system for heating or cooling.

[0041] ⑤ Shear rate maintenance: Rotation speed of stirrer No. 2 N satisfy: in: A It is a constant, taking the value 950±50; m Set the shear rate value; r The density of the solution; D The length of the blades on the mixer; i The angle between the guide vane and the horizontal plane; W The width of the growth slit; Set shear rate m =50s -1 , solution density r =1200 kg / m 3 , i =20°, W =3mm, A=950, substituting into the formula, we get... N =180 rpm Adjust the speed of mixer number two to 180. rpm To maintain the optimal shearing environment.

[0042] The flower-shaped lactose crystals produced in this embodiment were analyzed by scanning electron microscopy (SEM). The results showed that the flower shape integrity rate reached 93%, the porosity deviation was ±4%, and the proportion of fine crystals was <8%, which is superior to the traditional process.

[0043] This method mainly solves the problem of unstable morphology of flower-shaped lactose crystals through hydrodynamic partitioning, multi-nozzle coordination and dynamic control.

[0044] The above descriptions are merely some embodiments of the present invention. Those skilled in the art can make various modifications and improvements without departing from the inventive concept of the present invention, and these all fall within the scope of protection of the present invention.

Claims

1. A solvent hydrodynamic control device for a flower-shaped porous lactose recrystallization apparatus, comprising a reaction vessel (1), a first stirrer (2), and a second stirrer (3) configured in conjunction, characterized in that, The reactor (1) is also equipped with: The flow guiding component (4) is fixed inside the reactor (1) and maintains a gap with the inner wall and bottom of the reactor (1). The internal space of the flow guiding component (4) serves as a low-shear growth zone, and the space between the outer wall of the flow guiding component (4) and the inner wall of the reactor (1) serves as a high-shear mixing zone. The flow guiding component (4) also has growth gaps (42). The first stirrer (2) and the second stirrer (3) are located inside and outside the flow guiding component (4), respectively. Nozzle unit: includes at least one first nozzle (5) extending into the low-shear growth zone and the first nozzle (5) having a microporous diffuser head, at least one second nozzle (6) pointing towards the growth gap (42) and the second nozzle (6) having a pulse valve, and at least one third nozzle (7) located in the high-shear mixing zone and the third nozzle (7) having a Y-shaped laminar flow outlet; Multi-zone sensor: including a PVM probe (8) installed in the low shear growth zone, an FBRM probe (9) embedded in the growth gap (42), and a turbidimeter (10) located in the high shear mixing zone. Each nozzle unit group and multi-zone sensor are connected to an external dynamic controller (11) via a signal line, which is used to dynamically switch the working mode of each nozzle according to the real-time flower crystallization state.

2. The antisolvent hydrodynamic control device for a flower-shaped porous lactose recrystallization apparatus according to claim 1, characterized in that, The flow guiding member (4) is a vertically arranged cylindrical body. The upper part of its side wall is provided with flow guiding plates (41) evenly distributed in the circumferential direction. The flow guiding plates (41) extend obliquely downward from the side wall of the flow guiding member (4) with the radial direction as the reference, and the growth gap (42) is formed between adjacent flow guiding plates (41).

3. The antisolvent hydrodynamic control device for a flower-shaped porous lactose recrystallization apparatus according to claim 2, characterized in that, The flow guiding member (4) has 6 to 12 radially extending flow guiding plates (41) evenly distributed circumferentially. The angle between the flow guiding plate (41) and the horizontal plane is 15° to 30°, and its length is 15% to 25% of the diameter of the flow guiding member (4). The width of the growth gap (42) is 1 to 10 mm. mm .

4. The antisolvent hydrodynamic control device for a flower-shaped porous lactose recrystallization apparatus according to claim 1, characterized in that, The orifice diameter of the microporous diffuser head of the first nozzle (5) is 10 to 100 mm. μm The pulse quantity of the second nozzle (6) is 0.05 ~ 5. ml / time, the Y-shaped laminar flow outlet split angle of the third nozzle (7) is 60° ~ 90°.

5. The antisolvent hydrodynamic control device for a flower-shaped porous lactose recrystallization apparatus according to claim 1, characterized in that, The gap between the bottom end of the flow guiding component (4) and the bottom of the reactor (1) is 5 to 10 cm, and the top end of the flow guiding component (4) must be 10 to 20 cm lower than the steady liquid level of the reactor (1) during operation.

6. The antisolvent hydrodynamic control device for a flower-shaped porous lactose recrystallization apparatus according to claim 1, characterized in that, The laser window of the FBRM probe (9) is flush with the inner wall of the growth slit (42), and the detection depth is ≤0.5m from the slit surface. mm .

7. A method for controlling antisolvent hydrodynamics, employing the control device as described in any one of claims 1 to 6, characterized in that, Includes the following steps: (a) Inject a lactose-saturated solution into the low-shear growth zone and start the first nozzle to add the antisolvent in diffusion mode; (b) When the PVM probe detects a petal profile ratio ≥ 1.0, the second nozzle pulse mode is activated at a frequency of... f satisfy: in k For growth rate, It is the circumferential arc length between the center lines of adjacent growth slots on the flow guiding component; (c) If the FBRM probe detects a growth rate < 0.5 μm / min Increase the flow rate of the third nozzle by 10-30%.

8. The antisolvent hydrodynamic control method according to claim 7, characterized in that, In step (b), the pulse frequency f The range is 5 to 20. Hz Furthermore, the pulse timing is synchronized with the stirrer speed, with a phase difference of ≤10%.

9. The antisolvent hydrodynamic control method according to claim 7, characterized in that, When the turbidimeter detects a supersaturation S > 1.3, the dynamic controller executes: Close the second nozzle pulse; Switch the first nozzle to ultrasonic atomization mode; The cooling rate was increased to 0.8℃ / min.

10. The antisolvent hydrodynamic control method according to claim 7, characterized in that, To maintain the shear rate at the growth gap, the rotation speed of stirrer number two is... N satisfy: in: A It is a constant, taking the value 950±50; μ Set the shear rate value; ρ The density of the solution; D The length of the blades on mixer number two; θ The angle between the guide vane and the horizontal plane; W The width of the growth gap.

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