System and method for continuously preparing medicinal lactose with porous flower type structure

Abstract

The invention provides a system and a method for continuously preparing medicinal lactose with a porous flower type structure. The system comprises a spray drying unit, a spray drying unit, a drying unit and a control unit, wherein the spray drying unit is used for atomizing and drying a lactose solution into amorphous lactose powder; the powder transferring and sealing unit is connected to a discharge hole of the spray drying unit and is used for receiving the amorphous lactose powder and quantitatively and hermetically conveying the amorphous lactose powder to the downstream and isolating a gas environment between the upstream and the downstream; and the gas phase crystallization unit is connected to a discharge hole of the powder transferring and sealing unit and is used for receiving the amorphous lactose powder and crystallizing the amorphous lactose powder into porous flower type structure lactose in a controllable solvent steam environment. Compared with traditional batch-type reaction kettle production, continuous feeding and discharging of materials are achieved, preparation, cleaning and waiting time among batches is eliminated, continuous production is achieved, efficiency is greatly improved, and the method is very suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of lactose production technology, specifically, it demonstrates a system and method for the continuous preparation of porous flower-shaped pharmaceutical lactose. Background Technology

[0002] Pharmaceutical lactose is an important pharmaceutical excipient. Lactose with a porous, flower-like structure is highly favored due to its large specific surface area and good adsorption properties, which effectively improves drug uniformity and dissolution.

[0003] Currently, the preparation of this type of flower-shaped lactose mostly employs a batch solvent crystallization method. Specifically, lactose is first dissolved, then mixed with an antisolvent (such as ethanol) in a reaction vessel, and the target crystal form is obtained by controlling crystallization conditions (such as temperature and stirring speed). This traditional method has the following inherent drawbacks: 1. Low production efficiency and inability to operate continuously: The steps of material feeding, reaction, discharge, and cleaning must be carried out in batches, resulting in a large amount of idle time, low equipment utilization, and difficulty in meeting the needs of large-scale production.

[0004] 2. Large batch-to-batch variations in product quality: Because it is difficult to ensure that the crystallization conditions (such as cooling rate and mixing uniformity) of each batch are completely consistent, the key quality attributes such as crystal form, particle size and porosity of different batches of products fluctuate greatly, affecting the stability of the final drug quality.

[0005] Therefore, there is an urgent need in the field for a system that can continuously and stably produce pharmaceutical lactose with a porous flower-shaped structure to overcome the disadvantages of the aforementioned intermittent production. Summary of the Invention

[0006] The purpose of this invention is to provide a system and method for the continuous preparation of porous flower-shaped pharmaceutical lactose, which has a reasonable structural design and can produce efficiently.

[0007] The technical solution is as follows: On the one hand, this application proposes a system for the continuous preparation of porous flower-shaped pharmaceutical lactose, comprising the following components sequentially connected along the material flow direction: A spray drying unit is used to atomize and dry lactose solution into amorphous lactose powder; A powder transfer and sealing unit is connected to the outlet of the spray drying unit to receive the amorphous lactose powder and quantitatively and sealedly transport it downstream, while isolating the gas environment between the upstream and downstream. A vapor-phase crystallization unit is connected to the outlet of the powder transfer and sealing unit to receive the amorphous lactose powder and crystallize it into porous flower-shaped lactose in a controlled solvent vapor environment.

[0008] In addition, the above embodiments of the present invention may also have the following additional technical features: According to one embodiment of the present invention, the powder transfer and sealing unit includes a star-shaped feeder; the star-shaped feeder includes a housing and a rotor rotatably disposed within the housing, the rotor having an array of multiple blades, the ends of the blades having gaps between them and the inner wall of the housing. When the rotor rotates, the cavities between the blades carry a fixed volume of powder, and the powder conveying rate can be precisely controlled by controlling the rotation speed, thus achieving quantitative feeding.

[0009] In one embodiment, the rotor of the star feeder is driven by a servo motor, which is electrically connected to a controller to control the rotor speed within the range of 5 to 30 revolutions per minute. The servo motor offers fast response and precise control; combined with the closed-loop control of the controller, it ensures highly stable and precisely adjustable powder conveying speed, further guaranteeing the stability of system production and product consistency.

[0010] According to one embodiment of the present invention, the vapor-phase crystallization unit comprises: A crystallization chamber, the outer wall of which is provided with a jacket for the flow of heat-conducting medium to control the crystallization temperature; A solvent vapor distributor is located at the bottom of the crystallization chamber. It has an annular tube structure and multiple distribution holes are provided on the tube wall. A stirring mechanism is provided inside the crystallization chamber for gently stirring the powder.

[0011] The temperature control jacket ensures that the entire crystallization process takes place at a constant optimal temperature; the distributor allows solvent vapor to pass evenly through the powder layer from bottom to top, avoiding local concentrations that are too high or too low; the stirring mechanism prevents powder from clumping and ensures that each particle can fully contact the vapor; the three work together to help form a complete flower structure.

[0012] In one embodiment, the stirring mechanism includes a drive motor and an anchor-type stirring paddle. The drive motor drives the anchor-type stirring paddle to rotate via a magnetic coupler. The anchor-type stirring paddle is shaped to fit the inner wall of the crystallization chamber, generating strong radial flow, effectively eliminating powder retention and dead zones on the wall surface, and resulting in more uniform stirring.

[0013] According to one embodiment of the present invention, a condensation recovery unit is further included. The condensation recovery unit is connected to the exhaust port of the gas-phase crystallization unit via a pipeline, and is used to condense and recover solvent vapors that did not participate in crystallization. This allows for the recovery and recycling of organic solvents (such as ethanol), reducing raw material consumption costs.

[0014] According to one embodiment of the present invention, the connecting pipes between the spray drying unit, the powder transfer and sealing unit, and the vapor phase crystallization unit are all connected using quick-connect clamps. Quick-connect clamps are standardized, tool-free fast connectors that greatly facilitate equipment installation, routine maintenance and cleaning, and component replacement.

[0015] On the other hand, this application also proposes a method for the continuous preparation of porous flower-shaped pharmaceutical lactose, using the system described above, which includes the following steps: S1. Spray drying: The lactose solution is passed into the spray drying unit and dried to obtain amorphous lactose powder; S2. Powder transfer: The amorphous lactose powder is continuously, quantitatively, and in a closed manner transported to the vapor phase crystallization unit through the powder transfer and sealing unit; S3. Vapor phase crystallization: In the vapor phase crystallization unit, solvent vapor is introduced into the amorphous lactose powder, and crystallization is carried out at a temperature of 20-60°C for 1-5 hours to obtain the porous flower-shaped pharmaceutical lactose.

[0016] In step S2, the powder conveying rate is adjusted by controlling the rotation speed of the star feeder to precisely control the powder conveying rate.

[0017] In step S3, the solvent vapor is ethanol vapor with a concentration of 70%–95% v / v. If the concentration is too low, the crystallization driving force is insufficient, resulting in low efficiency; if the concentration is too high, crystallization may be too rapid, leading to irregular morphology or agglomeration.

[0018] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. Compared with traditional batch reactor production, the system of this application realizes continuous feeding and discharging of materials, eliminates preparation, cleaning and waiting time between batches, realizes continuous production, greatly improves efficiency, and is very suitable for large-scale industrial production; 2. Because the entire process is carried out continuously and automatically in a closed system, process parameters (such as temperature, pressure, and flow rate) can be precisely controlled and kept stable, greatly reducing the impact of human operation and environmental fluctuations. This ensures that key quality attributes such as crystal form, particle size, and porosity of different batches of products are highly consistent, thereby guaranteeing stable and reliable product quality. Attached Figure Description

[0019] Figure 1 This is a simplified block diagram of a system for the continuous preparation of porous flower-shaped pharmaceutical lactose according to Embodiment 1 of the present invention; Figure 2 This is a simplified system diagram of the spray drying unit according to an embodiment of the present invention; Figure 3This is a simplified system diagram of the powder transfer and sealing unit according to an embodiment of the present invention; Figure 4 This is a simplified system diagram of the vapor phase crystallization unit according to an embodiment of the present invention; Figure 5 This is a simplified system diagram of the condensation recovery unit according to an embodiment of the present invention; The relevant markings in the attached diagram are as follows: 100-Spray drying unit, 200-Powder transfer and sealing unit, 300-Vacuum crystallization unit, 400-Condensation and recovery unit; 101-Spray drying tower, 102-Atomizer, 103-Hot air system, 104-Discharge valve; 210-Star feeder, 211-Shell, 212-Rotor, 213-Blade, 220-Servo motor; 310-Crystallization chamber, 311-Temperature control jacket, 320-Solvent vapor distributor, 330-Stirring mechanism; 410-Shell-and-tube condenser, 411-Return pipeline, 412-Solvent collection tank. Detailed Implementation

[0020] 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.

[0021] Example 1: This invention provides a system for the continuous preparation of porous flower-shaped pharmaceutical lactose. (See attached document.) Figure 1 As shown, it mainly consists of a spray drying unit 100, a powder transfer and sealing unit 200, a vapor phase crystallization unit 300, and an optional condensation recovery unit 400 connected in sequence to form a continuous closed loop.

[0022] The system adopts a vertical layout to fully utilize gravity-assisted material transport. Specifically, it includes a top-mounted spray drying unit 100, fixed by a support frame, whose bottom outlet is connected via a pipe to a middle powder transfer and sealing unit 200. The lower outlet of the powder transfer and sealing unit 200 is connected to the top inlet of the bottom-mounted vapor-phase crystallization unit 300. All connecting pipes between units are sealed using quick-connect clamps 700 to ensure system airtightness and facilitate disassembly and cleaning. The system has a processing capacity of 50–100 kg lactose solution / hour. The expected specifications for the final product, fancy lactose, include a specific surface area ≥25 m² / g, porosity 40–80%, and a particle size distribution span (Span value) ≤1.0. These specifications can be achieved by adjusting process parameters.

[0023] The material flow of the system is as follows: the lactose solution first enters the spray drying unit 100, where it is atomized and dried into amorphous lactose microspheres; the microspheres are then quantitatively and tightly conveyed to the vapor-phase crystallization unit 300 via the powder transfer and sealing unit 200; in the vapor-phase crystallization unit 300, the microspheres undergo recrystallization in a solvent vapor environment, forming a flower-like structure; the final product is discharged from the bottom of the vapor-phase crystallization unit 300. Throughout the process, the solvent vapor can be recycled through the condensation and recovery unit 400 to improve economic efficiency and environmental friendliness. The system is automatically controlled by a central control system (such as a PLC), integrating sensors for temperature, pressure, and flow rate, enabling precise monitoring and regulation.

[0024] See Figure 2 As shown, regarding the spray drying unit 100: the spray drying unit 100 is responsible for converting lactose solution into amorphous lactose microspheres. Its core components include the spray drying tower body 101, the atomizer 102, the hot air system 103, and the discharge valve 104.

[0025] The spray drying tower 101 is made of 316L stainless steel, with a height of about 2.5 meters and a diameter of about 0.8 meters. The cone angle of the conical bottom is about 60°, and the inner wall is mirror polished to Ra≤0.4μm to reduce powder adhesion and improve cleanliness.

[0026] The atomizer 102 is a high-pressure two-fluid nozzle type with a nozzle orifice diameter of 0.5 mm, an adjustable atomization pressure range of 0.3 to 0.6 MPa, and an atomized particle size controlled between 50 and 100 μm. Alternatively, the atomizer 102 can be a centrifugal atomizing disc with a disc diameter of 100 mm and a rotation speed range of 10,000 to 15,000 rpm, driven by a variable frequency motor to ensure uniform atomization.

[0027] The hot air system 103 includes an electric heater (power 30 kW) and a hot air distributor. The hot air inlet temperature is adjustable from 100 to 200°C with a control accuracy of ±2°C. The hot air flow rate is monitored by a vortex flow meter and ranges from 100 to 500 m³ / h. The opening of the damper is adjusted by a PID controller to ensure uniform distribution of hot air.

[0028] The discharge valve 104 is a pneumatic butterfly valve with a valve body made of 316L stainless steel and a sealing ring made of food-grade silicone. The response time is less than 1 second, ensuring a tight discharge.

[0029] Operating parameters of spray drying unit 100: lactose solution mass concentration of 10-40%, feed flow rate of 10-50 L / h, and powder moisture content of dried powder <5%.

[0030] The powder transfer and sealing unit 200 is used to achieve continuous production of the system, as shown in the reference. Figure 3As shown, its core component is a star feeder 210, which includes a housing 211 and a rotor 212. The housing 211 is made of hard alumina ceramic, and its internal cavity is cylindrical with a diameter of approximately 150 mm. The rotor 212 is also made of wear-resistant ceramic, and eight blades 213 are uniformly welded along its circumference. The height of each blade 213 is approximately 50 mm. The gap between the end of the blade 213 and the inner wall of the housing 211 is designed to be approximately 0.1 mm. This small gap helps to form a certain degree of sealing, which can effectively isolate the upstream and downstream gas environments (such as the hot air from the spray drying unit and the solvent vapor from the gas phase crystallization unit) while ensuring the smooth passage of powder.

[0031] The rotor 212 is driven by a servo motor 220, which is directly connected via a coupling. The servo motor 220 is electrically connected to the PLC controller, which precisely controls the rotation speed of the rotor 212 within the range of 5 to 30 rpm, thereby realizing the quantitative conveying of powder.

[0032] The powder transfer and sealing unit 200 is connected to the upstream and downstream via flanges. The flange gaskets are made of graphite composite material to ensure sealing. The entire unit's housing is made of 316L stainless steel and can be equipped with a vibrator to prevent powder bridging.

[0033] The vapor-phase crystallization unit 300 is used to induce the recrystallization of amorphous lactose microspheres into a flower-like structure in a solvent vapor environment. (See also...) Figure 4 As shown, its core components include a crystallization chamber 310, a solvent vapor distributor 320, a stirring mechanism 330, and a temperature control jacket 311. The crystallization chamber 310 is a vertical cylindrical structure with a volume of approximately 100 L. It is made of 316L stainless steel, and the inner wall is polished to Ra≤0.4μm. The upper part of the chamber has a feed inlet connected to the powder transfer and sealing unit 200, and the lower part has a second discharge valve (such as a pneumatic butterfly valve). The temperature control jacket 311 is wrapped around the outer wall of the chamber. The jacket has a semi-pipe structure and is filled with heat transfer oil. It is circulated and heated by an external temperature control unit, with a temperature range of 20~80°C.

[0034] A solvent vapor distributor 320 is located at the bottom of the crystallization chamber 310. It is an annular stainless steel tube with a diameter slightly smaller than the inner diameter of the crystallization chamber. Micro-holes (approximately 0.5 mm in diameter) are drilled in the tube wall at 15 mm intervals. The distributor is fixed by support legs and positioned at a distance from the inner surface of the bottom cover of the crystallization chamber, ensuring uniform diffusion of solvent vapor from bottom to top. The stirring mechanism 330 includes a drive motor 331 and an anchor-type stirring paddle 332. The drive motor 331 is an explosion-proof variable frequency motor. The stirring paddle is anchor-type, matching the contour of the inner wall of the crystallization chamber with a gap between them. The drive motor 331 is driven by a magnetic coupler, which includes an outer magnetic rotor (fixed to the motor shaft) and an inner magnetic rotor (fixed to the stirring paddle), sealed in the middle by a 316L stainless steel isolation cover to completely prevent dynamic seal leakage. The stirring speed is adjustable from 10 to 50 rpm and controlled by a frequency converter to achieve gentle stirring and prevent powder agglomeration. This gas phase crystallization unit is also equipped with pressure and temperature sensors for real-time monitoring of environmental conditions.

[0035] See Figure 5 As shown, the condensation recovery unit 400 is connected to the exhaust port of the vapor phase crystallization unit 300 and is used to recover and recycle solvent vapor, improving environmental friendliness and economy. The condensation recovery unit 400 includes a shell-and-tube condenser 410, a return pipeline 411, and a solvent collection tank 412. The condensing medium is cold water; the solvent vapor is condensed into liquid. The return pipeline is equipped with a U-shaped bend liquid seal to prevent backflow of gas. The solvent collection tank is made of glass and equipped with a liquid level sensor. The collected solvent can be pumped back to the solvent storage tank for recycling. The entire unit is connected to the system via quick-release clamps for easy maintenance.

[0036] This embodiment of the system primarily achieves continuous operation and stable product quality through its integrated and precise control features. Firstly, the star-shaped feeder 210 enables dynamic sealing and quantitative conveying, resolving the issues of cross-contamination and unstable conveying in traditional processes. Secondly, the application of the magnetic coupler 333 eliminates the risk of dynamic seal leakage, improving safety. Finally, the uniform gas distribution and gentle stirring of the vapor-phase crystallization unit 300 ensure the uniformity of the flower-shaped structure.

[0037] Example 2 Flower-shaped lactose was prepared based on the system of Example 1.

[0038] Preparation stage: Prepare a 25% lactose aqueous solution (using pharmaceutical grade lactose and deionized water), check the status of valves in each unit of the system, turn on the temperature control system, and preheat the gas phase crystallization unit 300 to 45°C.

[0039] Start-up phase: Turn on the spray drying unit 100, set the hot air inlet temperature to 160℃, start the feed pump, and send the lactose solution into the atomizer 101 at a flow rate of 30L / h, with the atomization pressure set to 0.4 MPa; at this time, uniform amorphous lactose microspheres (particle size of about 80μm) are rapidly formed in the tower and discharged from the first discharge valve; the powder transfer and sealing unit 200 operates synchronously: the rotation speed of the star feeder 210 is set to 20 rpm by the PLC, and the powder is stably conveyed to the gas phase crystallization unit 300 at a conveying rate of about 75 kg / h.

[0040] Gas-phase crystallization process: The gas-phase crystallization unit system is turned on, and pharmaceutical grade ethanol is pumped into the solvent evaporator at a flow rate of 2 L / h. The heating power is set to 4 kW to generate ethanol vapor with a concentration of 85% (v / v). The vapor enters the chamber evenly through the micropores of the solvent vapor distributor 320. At the same time, the stirring mechanism 330 is started to gently stir the powder bed at a speed of 25 rpm. The crystallization reaction continues for 3 hours, during which the temperature is maintained at 45°C and the pressure is maintained at 0.2 bar.

[0041] Product Collection: After the reaction is complete, turn off the steam and purge with nitrogen for 30 minutes; then open the second discharge valve to collect the product. Testing showed that the obtained flower-shaped lactose product had a specific surface area of ​​35 m² / g, a porosity of 65%, a particle size distribution span of 0.8, and a moisture content of 0.5%, meeting pharmaceutical standards and shortening the production cycle.

[0042] Example 3 This embodiment explores the effect of crystallization temperature on product performance. Except for the crystallization temperature, the other parameters are the same as in Example 2.

[0043] The lactose solution concentration was 25%, the atomization pressure was 0.4 MPa, the feeder speed was 20 rpm, the ethanol vapor concentration was 85%, and the crystallization time was 3 hours.

[0044] Comparative experiments were conducted by setting the crystallization temperature to 30°C, 45°C, and 60°C, respectively.

[0045] Results: At 30°C, the crystallization rate was slow, the product porosity was 55%, the specific surface area was 30 m² / g, and some microspheres were not fully crystallized; at 45°C, the crystallization was sufficient, the product porosity was 65%, the specific surface area was 35 m² / g, and the flower-like structure was complete; at 60°C, the crystallization rate accelerated, but the product porosity decreased to 50%, the specific surface area was 28 m² / g, and some crystals sintered.

[0046] This indicates that the system in this embodiment can optimize product quality through precise temperature control (range of 20 to 80°C), with the optimal temperature being 45°C.

[0047] 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 system for the continuous preparation of porous flower-shaped pharmaceutical lactose, characterized in that, Including those connected sequentially along the material flow direction: A spray drying unit (100) is used to atomize and dry a lactose solution into amorphous lactose powder; A powder transfer and sealing unit (200) is connected to the outlet of the spray drying unit (100) for receiving the amorphous lactose powder and quantitatively and tightly conveying it downstream, while isolating the gas environment between the upstream and downstream. A vapor-phase crystallization unit (300) is connected to the outlet of the powder transfer and sealing unit (200) for receiving the amorphous lactose powder and crystallizing it into porous flower-shaped lactose in a controlled solvent vapor environment.

2. The system for continuous preparation of porous flower-shaped pharmaceutical lactose according to claim 1, characterized in that, The powder transfer and sealing unit (200) includes a star feeder (210); the star feeder (210) includes a housing (211) and a rotor (212) rotatably disposed in the housing (211), the rotor (212) having an array of multiple blades (213), the ends of the blades (213) having a gap between them and the inner wall of the housing (211).

3. The system for continuous preparation of porous flower-shaped pharmaceutical lactose according to claim 2, characterized in that, The rotor (212) of the star feeder (210) is driven by a servo motor (220), which is electrically connected to a controller to control the rotational speed of the rotor (212) within the range of 5 to 30 revolutions per minute.

4. The system for continuous preparation of porous flower-shaped pharmaceutical lactose according to claim 1, characterized in that, The vapor phase crystallization unit (300) includes: A crystallization chamber (310) has a jacket (311) on its outer wall for the flow of heat-conducting medium to control the crystallization temperature; A solvent vapor distributor (320) is disposed at the bottom of the crystallization chamber (310), and has an annular tube structure with multiple distribution holes on the tube wall; A stirring mechanism (330) is disposed inside the crystallization chamber (310) for gently stirring the powder.

5. The system for continuous preparation of porous flower-shaped pharmaceutical lactose according to claim 4, characterized in that, The stirring mechanism (330) includes a drive motor (331) and an anchor-type stirring paddle (332). The drive motor (331) drives the anchor-type stirring paddle (332) to rotate through a magnetic coupler (333).

6. The system for continuous preparation of porous flower-shaped pharmaceutical lactose according to claim 1, characterized in that, It also includes a condensation recovery unit (400), which is connected to the exhaust port of the gas phase crystallization unit (300) via a pipeline, for condensing and recovering solvent vapors that have not participated in crystallization.

7. The system for continuous preparation of porous flower-shaped pharmaceutical lactose according to claim 1, characterized in that, The connecting pipes between the spray drying unit (100), the powder transfer and sealing unit (200), and the vapor phase crystallization unit (300) are all connected by quick-release clamps.

8. A method for continuously preparing porous flower-shaped pharmaceutical lactose using the system described in any one of claims 1 to 7, characterized in that, The method includes the following steps: S1. Spray drying: The lactose solution is passed into the spray drying unit (100) and dried to obtain amorphous lactose powder; S2. Powder transfer: The amorphous lactose powder is continuously, quantitatively, and in a closed manner transported to the vapor phase crystallization unit (300) through the powder transfer and sealing unit (200). S3. Gas phase crystallization: In the gas phase crystallization unit (300), solvent vapor is introduced into the amorphous lactose powder, and crystallization is carried out at a temperature of 20-60°C for 1-5 hours to obtain the porous flower-shaped pharmaceutical lactose.

9. A method for continuous preparation of porous flower-shaped pharmaceutical lactose according to claim 8, characterized in that, In step S2, the powder conveying rate is adjusted by controlling the rotation speed of the star feeder (210).

10. A method for continuous preparation of porous flower-shaped pharmaceutical lactose according to claim 8, characterized in that, In step S3, the solvent vapor is ethanol vapor with a concentration of 70% to 95% v / v.

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