Centrifugal granulation process for producing slow-release indapamide

Abstract

The invention discloses a centrifugal granulation process for producing slow-release indapamide, which comprises the following steps: S1, stirring and mixing indapamide, a slow-release framework material, a lubricant and a filler; s2, putting the mixed powder into a disc of a granulation device, and performing low-speed centrifugal granulation in a vacuum state to form a mother nucleus; s3, transferring the mother nucleus to a high-pressure state for centrifugal granulation; s4, performing low-temperature drying on the granules; and S5, after drying, tabletting by using a tablet press, and finally coating and packaging by using double aluminum to obtain the indapamide sustained-release tablet. According to the invention, high and low pressure conversion is carried out in the centrifugal granulation process, so that gas in the sustained-release tablet is reduced, the density is increased synchronously, and the sustained-release capability and the efficacy durability of the tablet are improved.

Description

Technical Field

[0001] This invention relates to the field of centrifugal granulation technology, and in particular to a centrifugal granulation process for the production of sustained-release indapamide. Background Technology

[0002] Indapamide belongs to the sulfonamide diuretic class. At lower doses, it primarily lowers blood pressure by dilating peripheral blood vessels and reducing vascular resistance, with a relatively weak diuretic effect, making it commonly used to treat hypertension. Hypertension requires stable 24-hour control to avoid large fluctuations in blood pressure. Indapamide only provides a stable blood pressure-lowering effect by releasing the drug slowly and maintaining a stable blood concentration throughout the day; the sustained-release capability of indapamide determines the duration of its efficacy.

[0003] Currently, there are two main methods for the sustained-release of indapamide tablets. One method involves directly compressing a gel-type sustained-release matrix material using a tablet press, where the drug reacts with water to form a gel and slowly releases the drug from within, as in patent 202010123017. The other method involves coating the tablet with a thin film material after granulation, using lasers or similar methods to create micropores on the coating, through which the drug is slowly released, as in patent 200810239717. Both of these methods neglect the gas during granulation. Dry tableting directly compresses the gas into the sustained-release material, and rapid compression can also cause internal fine lines or even cracking. Wet granulation directly encapsulates the gas, which, during its escape from the intestines, can also propel the drug release from within. Both methods accelerate the drug release rate, which has adverse effects on the sustained-release tablets and severely reduces the duration of efficacy. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings of the prior art and provide a centrifugal granulation process for the production of sustained-release indapamide, so as to solve the problem that the presence of trace amounts of gas in existing sustained-release tablets reduces the sustained-release effect.

[0005] The objective of this invention is achieved through the following technical solution: a centrifugal granulation process for the production of sustained-release indapamide, comprising the following steps, S1. Stir and mix indapamide, sustained-release skeleton material, lubricant, and filler; S2. The mixed powder is fed into the disc of the granulation device for low-speed centrifugal granulation under vacuum to form the mother nucleus; S3. The parent nucleus is transferred to centrifugation granulation under high pressure; S4. Dry the granular material at a low temperature; S5. After drying, tablets are compressed using a tablet press, and finally coated and packaged in aluminum foil to obtain indapamide sustained-release tablets.

[0006] Preferably, in step S2, the vacuum state is -0.08 to -0.095 MPa.

[0007] Preferably, in step S3, the high pressure is 0.2 to 0.5 MPa.

[0008] Preferably, in step S4, the drying temperature is 40-60°C.

[0009] Preferably, the sustained-release skeleton material is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, and methylcellulose; the lubricant is one or more of magnesium stearate and talc; and the filler is one or more of lactose, microcrystalline cellulose, or starch.

[0010] Preferably, the granulation device includes a pressure tank, a first centrifugal disc, a second centrifugal disc, and a rotary feeding mechanism. The rotary feeding mechanism divides the internal space of the pressure tank into an upper low-pressure zone and a lower high-pressure zone. The first centrifugal disc is disposed in the low-pressure zone, and the second centrifugal disc is disposed in the high-pressure zone. A first liquid inlet pipe and a first feed pipe passing through the pressure tank are provided above the first centrifugal disc, and a second liquid inlet pipe and a second feed pipe passing through the pressure tank are provided above the second centrifugal disc. A vacuum extraction pipe is provided at the upper part of the low-pressure zone, and a pressurization pipe is provided at the upper part of the high-pressure zone. A discharge pipe is provided at the bottom of the pressure tank.

[0011] Preferably, the rotary feeding mechanism includes a sealing plate, a feeding plate, and a first rotating shaft. The sealing plate is connected inside the pressure tank and has a cylindrical hollow cavity inside. The first rotating shaft passes through the sealing plate and is rotatably connected to it. The feeding plate is located inside the hollow cavity, and one end of the feeding plate is fixedly connected to the first rotating shaft. Multiple feeding plates are arranged radially around the first rotating shaft. Two adjacent feeding plates and the inner surface of the hollow cavity together form a sealed space. The upper surface of the sealing plate has a feed inlet, and the lower surface of the sealing plate has a discharge outlet. The feed inlet and the discharge outlet are offset from each other around the first rotating shaft.

[0012] Preferably, the upper surface of the sealing plate is provided with an exhaust hole, which is located between the feed inlet and the discharge outlet. Above the exhaust hole, a piston cylinder, a piston plate, a piston rod, and a spring are arranged. The opening of the piston cylinder is sealed to the exhaust hole. One end of the piston rod is fixedly connected to the piston plate, and the other end of the piston rod passes through the piston cylinder and is slidably connected to it in a sealed manner. The spring is fitted outside the piston rod and is located between the piston cylinder and the piston plate. A stop bar is fixedly provided inside the exhaust hole to block the movement of the piston plate. A Venturi mixer is provided above the first centrifugal disc. The low-pressure liquid inlet port of the Venturi mixer is connected to the first liquid addition pipe. The air inlet of the Venturi mixer is provided with an air guide pipe, which is connected to the middle of the piston cylinder.

[0013] Preferably, the edge of the first centrifugal disc is provided with a re-rolling plate, the re-rolling plate is an annular structure with a circular arc cross-section, the lower edge of the re-rolling plate abuts against the edge of the first centrifugal disc, the top of the piston rod is fixedly connected to the re-rolling plate, and the edge of the re-rolling plate is slidably connected to the first centrifugal disc.

[0014] Preferably, the first rotating shaft is a tubular structure, a material collection funnel is provided between the second centrifugal disc and the sealing plate, a second rotating shaft is fixedly provided at the center of the second centrifugal disc, the second rotating shaft passes through the discharge port of the material collection funnel and is located inside the first rotating shaft, and the first rotating shaft and the second rotating shaft are rotatably connected relative to each other.

[0015] The present invention has the following advantages: 1. A centrifugal granulation process for the production of sustained-release indapamide is provided. This process first involves low-pressure granulation, then high-pressure granulation, and finally compression into tablets. Through these three processes, the gas inside the sustained-release tablets is gradually released, avoiding the internal fine lines caused by direct compression, increasing the overall density of the sustained-release tablets, thereby improving the sustained-release capacity of indapamide and enhancing the duration of efficacy. 2. A centrifugal granulation device adapted to this process is provided. This device can simultaneously provide low-pressure and high-pressure environments without frequent on / off air exchange to achieve the high-low pressure state transition of the granules, saving energy, reducing costs, and realizing continuous production of centrifugal granulation. 3. By designing vent holes between the inlet and outlet of the sealing plate, the gas entering the high-pressure zone can be discharged in advance, avoiding the problem of poor feeding caused by gas backflow at the inlet; 4. Through the unique design of the rotary feeding mechanism, not only is stable feeding from the low-pressure zone to the high-pressure zone achieved, but also the high-pressure gas generated between the high-pressure zone and the low-pressure zone, in conjunction with the spring, enables the piston plate to move up and down reciprocally, thereby realizing the pulse atomization function of the Venturi mixer and the intermittent discharge function of the re-rolling plate to the first centrifugal disc. Attached Figure Description

[0016] Figure 1 This is a process flow diagram of the present invention; Figure 2 This is a three-dimensional structural schematic diagram of the present invention; Figure 3 This is a schematic diagram of the internal structure of the present invention; Figure 4 This is a partial cross-sectional structural diagram of the present invention; Figure 5 yes Figure 4 Enlarged diagram of point A in the middle.

[0017] In the diagram, 1. Pressure tank; 2. Discharge pipe; 3. Rotary feeding mechanism; 4. First centrifugal disc; 5. Second centrifugal disc; 6. First feeding pipe; 7. First liquid feeding pipe; 8. Second feeding pipe; 9. Second liquid feeding pipe; 10. First rotating shaft; 11. Second rotating shaft; 12. Sealing plate; 13. Feeding disc; 14. Feed inlet; 15. Discharge outlet; 16. Collection funnel; 17. Venturi vent; 18. Piston cylinder; 19. Spring; 20. Piston plate; 21. Piston rod; 22. Stop bar; 23. Air guide pipe; 24. Venturi mixer; 25. Re-rolling plate; 26. Pressurization pipe; 27. Vacuum extraction pipe. Detailed Implementation

[0018] 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.

[0019] A centrifugal granulation process for the production of sustained-release indapamide, such as Figure 1 As shown, the method for producing indapamide sustained-release tablets includes the following steps: S1. Raw material mixing: Indapamide, hydroxypropyl methylcellulose, magnesium stearate and starch are put into a multi-dimensional mixer and mixed evenly to make a premix; S2. Vacuum degassing: The mixed powder is put into a proprietary granulation device and centrifuged at a low speed of 100 rpm under a vacuum of -0.08 to -0.095 MPa to form a core. The vacuum state can remove a large amount of gas and reduce the gas content in the core. S3. High-pressure compaction density: After the core granulation is completed, the pressure is changed to 0.2-0.5 MPa for "isostatic pressure" granulation, with a rotation speed of 400-500 rpm, to uniformly squeeze the wet particles from all directions, causing them to deform and tightly arrange, thus further compacting the density; S4. Low-temperature drying: Dry the granules at a low temperature of 40-60℃; S5. After drying, use a tablet press to compress the tablets to achieve a tight density. Finally, coat and package them in double aluminum foil to obtain indapamide sustained-release tablets.

[0020] Existing granulation equipment uses wet granulation under normal pressure, which cannot meet the requirements of granulation that proceeds from low pressure to high pressure. Therefore, a granulation device suitable for this method is designed, such as... Figure 2 , Figure 3 As shown, the granulation device includes a pressure tank 1, a first centrifugal disc 4, a second centrifugal disc 5, a rotary feeding mechanism 3, and a drive mechanism. The rotary feeding mechanism 3 includes a sealing plate 12, multiple feeding discs 13, and a first rotating shaft 10. The sealing plate 12 is sealed in the middle of the pressure tank 1. The rotary feeding mechanism 3 divides the internal space of the pressure tank 1 into an upper low-pressure zone and a lower high-pressure zone. Low-pressure granulation is achieved in the low-pressure zone, and high-pressure granulation is achieved in the high-pressure zone. The interior of the sealing plate 12 is hollow, forming a cylindrical hollow chamber used for transferring materials. The first rotating shaft 10 passes through the pressure tank 1 and the sealing plate 12 in sequence and is rotatably and sealingly connected to them. The feeding discs 13 are located in the hollow chamber, with one end of the feeding disc 13 fixedly connected to the first rotating shaft 10. The multiple feeding discs 13 are arranged radially around the first rotating shaft 10. Adjacent feeding discs 13 are arranged in a radial pattern. 3 and the inner surface of the hollow chamber together form a sealed space. The first centrifugal disc 4 is installed in the low-pressure area, and the second centrifugal disc 5 is installed in the high-pressure area. Both the first centrifugal disc 4 and the second centrifugal disc 5 are disc structures with a flat center and raised edges. A material collection funnel 16 is provided between the second centrifugal disc 5 and the rotating feeding mechanism 3. The material collection funnel 16 is connected to the bottom of the sealing plate 12. The material collection funnel 16 is used to collect the material from the top and discharge it to the center of the second centrifugal disc 5. The first rotating shaft 10 is a tubular structure. The second rotating shaft 11 is fixedly installed at the center of the second centrifugal disc 5. The second rotating shaft 11 passes through the discharge port of the material collection funnel 16 and is located inside the first rotating shaft 10. The drive mechanism can be a servo motor. The first rotating shaft 10 and the second rotating shaft 11 are respectively connected to the drive mechanism through bevel gears to realize the relative rotation of the first rotating shaft 10 and the second rotating shaft 11.

[0021] Above the first centrifugal disc 4, there is a first liquid inlet pipe 7 and a first feed pipe 6 passing through the pressure tank 1. Above the second centrifugal disc 5, there is a second liquid inlet pipe 9 and a second feed pipe 8 passing through the pressure tank 1. The upper part of the low-pressure zone is equipped with a vacuum extraction pipe 27, and the upper part of the high-pressure zone is equipped with a pressurizing pipe 26. The pressurizing pipe 26 is connected to the exhaust port of an external air compressor, and the vacuum extraction pipe 27 is connected to the intake port of an air compressor to continuously maintain the high and low pressure states inside. The lower part of the high-pressure zone is used to store the granulated granules. The bottom of the pressure tank 1 is equipped with a discharge pipe 2, through which the granules are discharged uniformly.

[0022] like Figure 5As shown, the upper surface of the sealing plate 12 is provided with a fan-shaped feed inlet 14 and a circular exhaust hole 17. The lower surface of the sealing plate 12 is provided with an outlet 15, which has the same shape as the feed inlet 14. The feed inlet 14 and the outlet 15 are offset about the first rotating shaft 10. The exhaust hole 17 is located between the feed inlet 14 and the outlet 15. The exhaust hole 17 can discharge high-pressure gas in advance, avoiding the material blowing during the feed inlet 14, which would cause feeding difficulties. Above the exhaust hole 17, there is a piston cylinder 18, a piston plate 20, a piston rod 21, and a spring 19. The opening of the piston cylinder 18 is sealed and connected to the exhaust hole 17. One end of the piston rod 21 is fixedly connected to the piston plate 20, and the other end of the piston rod 21 passes through the piston cylinder 18 and is sealed and slidably connected to it. The spring 19 is sleeved outside the piston rod 21 and is located between the piston cylinder 18 and the piston plate 20. A stop rod 22 is fixedly provided inside the exhaust hole 17 to block the movement of the piston plate 20.

[0023] like Figure 4 As shown, a Venturi mixer 24 is installed above the first centrifugal disc 4. The low-pressure liquid inlet port of the Venturi mixer 24 is connected to the first liquid inlet pipe 7. Water or adhesive is introduced into the first liquid inlet pipe 7. The air inlet of the Venturi mixer 24 is provided with an air guide pipe 23, which is connected to the middle of the piston cylinder 18. The gas in the high-pressure zone moves upward through the push piston plate 20 to enter the Venturi mixer 24 and form a high-pressure airflow, thereby realizing pulse spraying of the Venturi mixer 24.

[0024] like Figure 3 , Figure 4 As shown, a re-rolling plate 25 is installed on the edge of the first centrifugal disc 4. The re-rolling plate 25 is a ring structure with a circular arc cross-section. The centrifugally moving particles are guided to move upward and then backward under the action of the re-rolling plate 25, forming a circular multi-wheel rolling motion, which greatly extends the rolling distance and time. The lower edge of the re-rolling plate 25 abuts against the edge of the first centrifugal disc 4. The top of the piston rod 21 is fixedly connected to the re-rolling plate 25. The edge of the re-rolling plate 25 is slidably connected to the first centrifugal disc 4. The piston rod 21 pushes the re-rolling plate 25 up and down to achieve the intermittent discharge function of the masterbatch from the first centrifugal disc 4.

[0025] Working principle: The drive mechanism drives the first rotating shaft 10 and the second rotating shaft 11 to rotate through bevel gear meshing. The first rotating shaft 10 drives the feeding plate 13 and the first centrifugal disc 4 to rotate, and the second rotating shaft 11 drives the second centrifugal disc 5 to rotate. When the air compressor starts, gas is introduced into the high-pressure zone through the pressurization pipe 26. The air compressor vents the gas in the low-pressure zone through the vacuum extraction pipe 27. Powder and other materials are added into the first centrifugal disc 4 through the first feeding pipe 8. The feeding plate 13 rotates around the first rotating shaft 11, and the gas in the high-pressure zone exits through the discharge port. 15 enters the sealing plate 12, and as it rotates, it enters the exhaust port 17 and pushes the piston plate 20 and piston rod 21 upward, while simultaneously compressing the spring 19. When the piston plate 20 exceeds the interface of the air guide pipe 23, the gas is quickly passed through the air guide pipe 23 into the Venturi mixer 24, spraying the liquid in the first liquid addition pipe 7 onto the first centrifugal disc 4 to form a nucleus. The nucleus forms on the surface of the powder and falls into the interior, contacting the first centrifugal disc 4 and moving outward under the action of centrifugal force. It is then lifted by the action of the re-rolling plate 25 and thrown to the rear. The centrifugal disc 4 is centrifugally rolled again. As the piston rod 21 pushes the re-rolling plate 25 upwards, it separates from the first centrifugal disc 4, forming a discharge channel. The nucleus, having been rolled multiple times, falls through this channel onto the sealing plate 12 and into the interior through the inlet 14. Under the action of the feeding plate 13, it is pushed above the outlet 15 and falls from there. Subsequently, under the action of the collecting funnel 16, it falls into the center of the second centrifugal disc 5. It then grows again under the action of the powder spraying through the second feeding pipe 8 and the liquid adding pipe 9, and finally... The material slides down at high speed from the second moving disc 5 and falls to the bottom of the pressure tank 1 for storage. After the gas in the sealing plate 12 is discharged, the spring 19 rebounds and pushes the piston plate 20, piston rod 21 and re-rolling plate 25 downward and is blocked by the stop rod 22. The re-rolling plate 25 comes into contact with the first centrifugal disc 4 again to achieve rolling. The material-pushing plate 13 rotates continuously and pushes the piston plate 20 downward, so that the Venturi mixer 24 forms pulse spray granulation, and the particle size is more uniform. At the same time, the re-rolling plate 25 moves up and down to realize the discharge function of the first centrifugal disc 4.

[0026] Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A centrifugal granulation process for the production of sustained-release indapamide, characterized in that, Includes the following steps, S1. Stir and mix indapamide, sustained-release skeleton material, lubricant, and filler; S2. The mixed powder is fed into the disc of the granulation device for low-speed centrifugal granulation under vacuum to form the mother nucleus; S3. The parent nucleus is transferred to centrifugation granulation under high pressure; S4. Dry the granular material at a low temperature; S5. After drying, tablets are compressed using a tablet press, and finally coated and packaged in aluminum foil to obtain indapamide sustained-release tablets.

2. The centrifugal granulation process for producing sustained-release indapamide according to claim 1, characterized in that, In step S2, the vacuum state is -0.08 to -0.095 MPa.

3. The centrifugal granulation process for producing sustained-release indapamide according to claim 1, characterized in that: In step S3, the high pressure is 0.2 to 0.5 MPa.

4. The centrifugal granulation process for producing sustained-release indapamide according to claim 1, characterized in that: In step S4, the drying temperature is 40-60℃.

5. The centrifugal granulation process for producing sustained-release indapamide according to claim 1, characterized in that: The sustained-release skeleton material is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, and methylcellulose; the lubricant is one or more of magnesium stearate and talc; and the filler is one or more of lactose, microcrystalline cellulose, or starch.

6. The centrifugal granulation process for producing sustained-release indapamide according to claim 1, characterized in that, The granulation device includes a pressure tank (1), a first centrifugal disc (4), a second centrifugal disc (5), and a rotary feeding mechanism (3). The rotary feeding mechanism (3) divides the internal space of the pressure tank (1) into an upper low-pressure zone and a lower high-pressure zone. The first centrifugal disc (4) is located in the low-pressure zone, and the second centrifugal disc (5) is located in the high-pressure zone. Above the first centrifugal disc (4) are a first liquid filling pipe (7) and a first feeding pipe (6) passing through the pressure tank (1). Above the second centrifugal disc (5) are a second liquid filling pipe (9) and a second feeding pipe (8) passing through the pressure tank (1). A vacuum extraction pipe (27) is located at the top of the low-pressure zone, and a pressurizing pipe (26) is located at the top of the high-pressure zone. A discharge pipe (2) is located at the bottom of the pressure tank (1).

7. The centrifugal granulation process for producing sustained-release indapamide according to claim 6, characterized in that: The rotating feeding mechanism (3) includes a sealing plate (12), a feeding plate (13), and a first rotating shaft (10). The sealing plate (12) is connected inside the pressure tank (1). The interior of the sealing plate (12) is provided with a cylindrical hollow cavity. The first rotating shaft (10) passes through the sealing plate (12) and is rotatably connected to it. The feeding plate (13) is located in the hollow cavity. One end of the feeding plate (13) is fixedly connected to the first rotating shaft (10). Multiple feeding plates (13) are arranged radially with the first rotating shaft (10) as the center. Two adjacent feeding plates (13) together with the inner surface of the hollow cavity form a sealed space. The upper surface of the sealing plate (12) is provided with a feed inlet (14), and the lower surface of the sealing plate (12) is provided with a discharge outlet (15). The feed inlet (14) and the discharge outlet (15) are offset from the first rotating shaft (10) as the center.

8. The centrifugal granulation process for producing sustained-release indapamide according to claim 7, characterized in that: The upper surface of the sealing plate (12) is provided with an exhaust hole (17), which is located between the feed inlet (14) and the discharge outlet (15). Above the exhaust hole (17) are arranged a piston cylinder (18), a piston plate (20), a piston rod (21), and a spring (19). The opening of the piston cylinder (18) is sealed to the exhaust hole (17). One end of the piston rod (21) is fixedly connected to the piston plate (20), and the other end of the piston rod (21) passes through the piston cylinder (18) and is slidably sealed to it. A spring (19) is fitted outside the piston rod (21) and located between the piston cylinder (18) and the piston plate (20). A stop bar (22) is fixedly provided inside the exhaust hole (17) to block the movement of the piston plate (20). A Venturi mixer (24) is provided above the first centrifugal disc (4). The low-pressure liquid inlet port of the Venturi mixer (24) is connected to the first liquid filling pipe (7). The air inlet of the Venturi mixer (24) is provided with a guide pipe (23). The guide pipe (23) is connected to the middle part of the piston cylinder (18).

9. The centrifugal granulation process for producing sustained-release indapamide according to claim 8, characterized in that: The first centrifugal disc (4) has a rerolling plate (25) on its edge. The rerolling plate (25) is an annular structure with a circular arc cross-section. The lower edge of the rerolling plate (25) abuts against the edge of the first centrifugal disc (4). The top of the piston rod (21) is fixedly connected to the rerolling plate (25). The edge of the rerolling plate (25) is slidably connected to the first centrifugal disc (4).

10. The centrifugal granulation process for producing sustained-release indapamide according to claim 9, characterized in that: The first rotating shaft (10) is a tubular structure. A material collection funnel (16) is provided between the second centrifugal disc (5) and the sealing plate (12). A second rotating shaft (11) is fixedly provided at the center of the second centrifugal disc (5). The second rotating shaft (11) passes through the discharge port of the material collection funnel (16) and is located inside the first rotating shaft (10). The first rotating shaft (10) and the second rotating shaft (11) are rotatably connected relative to each other.

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