A novel process for the preparation of sorbitol granules for direct compression process

Abstract

This invention provides a novel preparation process for pharmaceutical sorbitol granules using direct compression, belonging to the field of sorbitol crystallization technology. The preparation process includes seed crystal pretreatment, fluidized bed granulation, post-treatment, and drying. The seed crystal pretreatment method involves selecting sorbitol γ-type seed crystals, performing ultrafine pulverization using a low-temperature pulverizing device, controlling the pulverization temperature at 20–40°C, and then passing the pulverized crystals through an 80–120 mesh standard sieve to obtain fine sorbitol γ-type seed crystal powder. This powder is then preheated to 100–103°C, kept at this temperature for 10–20 minutes to induce sweating, and then cooled to 80–90°C to obtain pretreated γ-type seed crystals, which are then kept at this temperature for later use. The sorbitol granules of this invention have a γ-crystal form ratio of 97.9–98.6%, a granule moisture content of 0.2–0.4%, an angle of repose of 25°–27°, and a fine powder content of 1.2–1.6%.

Description

Technical Field

[0001] This invention belongs to the field of sorbitol crystallization technology, specifically relating to a novel preparation process for pharmaceutical sorbitol granules using a direct compression process. Background Technology

[0002] Sorbitol (D-sorbitol, C6H) 14 O6, as a polyol pharmaceutical excipient, has advantages such as high sweetness (about 0.6 times that of sucrose), low calories, stable chemical properties, good biocompatibility, and non-irritating properties. It is widely used in preparations such as tablets, capsules, granules, and lyophilized powder injections. It can be used as a filler, flavoring agent, binder, humectant, and lyophilization protectant. It is especially suitable for sugar-free preparations, pediatric preparations, elderly preparations, and medications for diabetic patients. Market demand continues to grow.

[0003] Sorbitol tableting refers to the direct compression of sorbitol granules into tablets after sieving and mixing with suitable excipients without granulation. The process is relatively simple, improves production efficiency, and saves energy. It is a novel and practical tableting technology, and therefore it is increasingly being adopted by pharmaceutical companies around the world. In sorbitol tableting, the crystal form of sorbitol has a significant impact on the variation in tablet weight, tablet hardness, and uniformity of content.

[0004] γ-type sorbitol has dense crystals with a melting point of 98–101°C. It has high hardness after compression and relatively low hygroscopicity. It does not transform into crystals or soften during storage, making it the first choice for direct tableting. However, in the crystallization process, γ-type sorbitol is not preferentially formed in terms of crystallization kinetics. Instead, it preferentially forms α-type sorbitol. α-type sorbitol is a fine needle-like crystal with poor fluidity. During compression, it is prone to solid-state phase transformation → recrystallization → volume expansion, leading to top cracking and a decrease in hardness.

[0005] Solution recrystallization is a common crystallization method for sorbitol. The main steps are to prepare a high-concentration sorbitol aqueous solution, filter to remove impurities, add γ-seed crystals, cool, crystallize, filter, and dry. This method has high crystal purity, low hygroscopicity, good storage stability, mild process, simple equipment, and low investment threshold. However, the production efficiency is extremely low and the cycle is long, with a single batch crystallization cycle of 24 to 72 hours. In addition, the aqueous solution system is very prone to forming hydrates, the crystal form control window is narrow, the seed crystal particles have irregular morphology and poor flowability, and cannot be directly used in high-speed direct pressure process. Granulation treatment must be performed, which adds a process. Summary of the Invention

[0006] To address the problems existing in the prior art, this invention provides a novel preparation process for pharmaceutical sorbitol granules using a direct compression process, achieving the following objectives: increasing the content of sorbitol γ-type seed crystals, thereby improving the flowability of sorbitol granules, reducing the water content, and thus achieving direct compression.

[0007] To solve the above technical problems, the technical solution adopted by the present invention is as follows: A novel preparation process for pharmaceutical sorbitol granules using direct compression includes the following steps: 1. Seed crystal pretreatment Sorbitol γ-type seed crystals were selected and ultra-finely pulverized using a low-temperature pulverizing device. The pulverizing temperature was controlled at 20–40°C. After pulverization, the crystals were passed through an 80–120 mesh standard sieve to obtain fine powder of sorbitol γ-type seed crystals. The powder was then preheated to 100–103°C and kept at this temperature for 10–20 minutes to induce sweating. After cooling to 80–90°C, pretreated γ-type seed crystals were obtained and kept at this temperature for later use. The sorbitol γ-type seed crystals have a purity of 95-98%.

[0008] 2. Fluidized bed granulation The sorbitol solution was concentrated to 96-98% by vacuum evaporation to obtain a concentrated sorbitol solution for later use. Pretreated γ-type seed crystals were fed into a fluidized bed, and then the fluidized bed induced draft fan was started. The three-stage air inlet was heated simultaneously. The upper air inlet temperature was set to 110-120℃, the middle air inlet temperature to 95-100℃, and the lower air inlet temperature to 85-90℃. When the bed temperature stabilized at 85-90℃, the atomized compressed air was turned on and the pressure was adjusted to 0.4-0.6MPa. The feed pump was started to spray the concentrated sorbitol solution into the fluidized bed. When the particle size reached 150-450μm, continuous discharge was started. The feed rate of the concentrated sorbitol solution is 25-30 kg / h; The hourly feed rate of the concentrated sorbitol solution to the mass ratio of the pretreated γ-type seed crystals is 0.9–1.1:3.5–4.5.

[0009] 3. Post-processing The material is discharged into a three-stage vibrating screen for grading. Qualified particles (150-450μm) are sent to a high-speed rounding machine. The stirring is started, and the speed is set to 200-300r / min. Hot air at 80-90℃ is introduced. After 3-5 minutes, the material is output. Coarse particles larger than the specified size are collected, pulverized at low temperature, and returned as seed crystals. Fine powder smaller than the specified size is conveyed back to the fluidized bed to continue growing.

[0010] 4. Drying The material is evenly spread on the microwave conveyor belt, with a layer thickness of 2-3 cm, and passes through the microwave heating device at a uniform speed. The microwave frequency is controlled at 2000-2500 MHz, and the power density is 5-7 kW / m³. 2 The material temperature is 82-85℃, the residence time is 40-60s, and then it is slowly dried at a low temperature of 30-45℃ in a vacuum drying oven until constant weight is obtained to obtain sorbitol granules.

[0011] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. This invention utilizes a synergistic effect of three crystal form control methods: low-temperature crystal pulverization-sweating pretreatment, three-stage gradient airflow fluidized bed granulation, and microwave curing. The product's γ-crystal form ratio can reach 97.9% to 98.6%, while effectively inhibiting the formation of α-type impurities and hydrates. This fundamentally avoids problems such as top cracking, hardness reduction, and tablet weight drift caused by crystal form transformation during tableting. The product has stable crystal form during storage and a longer shelf life.

[0012] 2. This invention uses fluidized bed spray agglomeration to prepare near-spherical particles, and combines steam rounding post-treatment to optimize the particle surface morphology. The product has a low angle of repose of 25° to 27°, high particle sphericity, low inter-particle friction, and high flowability.

[0013] 3. This invention employs a three-stage screening closed-loop circulation process, where fine powder is recycled for further growth and coarse particles are pulverized at low temperature and reused as seed crystals. Combined with the rounding process to create a dense particle surface structure, the fine powder rate of the product is only 1.2% to 1.6%, and the particle's resistance to breakage is significantly improved.

[0014] 4. This invention employs microwave selective drying (water molecules and amorphous regions preferentially absorb heat, and internal moisture rapidly migrates out) combined with low-temperature vacuum drying to finish, which can deeply remove free water trapped inside the particles, resulting in a product moisture content as low as 0.2% to 0.4%, which is lower than the level of traditional crystallization and spraying processes. At the same time, the amorphous regions are recrystallized at 85°C to perfect the γ-type. Detailed Implementation

[0015] Example 1 1. Seed crystal pretreatment Sorbitol γ-type seed crystals were selected and ultra-finely pulverized using a low-temperature pulverizing device. The pulverizing temperature was controlled at 30℃. After pulverization, the seeds were passed through a 100-mesh standard sieve to obtain fine powder of sorbitol γ-type seed crystals. The powder was then preheated to 102℃ and kept at this temperature for 15 minutes to induce sweating. After cooling to 85℃, pretreated γ-type seed crystals were obtained and kept at this temperature for later use. The sorbitol γ-type seed crystals have a purity of 97%.

[0016] 2. Fluidized bed granulation The sorbitol solution was concentrated to 97% by vacuum evaporation to obtain a concentrated sorbitol solution for later use. The pretreated γ-type seed crystals were fed into a fluidized bed, and then the fluidized bed induced draft fan was started. The three-stage air inlet was heated simultaneously. The upper air inlet temperature was set to 115℃, the middle air inlet temperature to 97℃, and the lower air inlet temperature to 86℃. When the bed temperature stabilized at 88℃, the atomized compressed air was turned on and the pressure was adjusted to 0.5MPa. The feed pump was started to spray the concentrated sorbitol solution into the fluidized bed. When the particle size reached 300μm, continuous discharge was started. The feed rate of the concentrated sorbitol solution is 27 kg / h; The hourly feed rate of the concentrated sorbitol solution is 1:4 with the mass ratio of the pretreated γ-type seed crystals.

[0017] 3. Post-processing The material is discharged into a three-stage vibrating screen for grading. Qualified particles (300μm) are sent to a high-speed rounding machine. Stirring is started, and the speed is set to 240r / min. Hot air at 85℃ is introduced. After 4 minutes, the material is output. Coarse particles larger than this size are collected, pulverized at low temperature, and returned as seed crystals. Fine powder smaller than this size is conveyed back to the fluidized bed to continue growing.

[0018] 4. Drying The material is evenly spread on the microwave conveyor belt to a thickness of 2.5 cm, and passes through the microwave heating device at a constant speed. The microwave frequency is controlled at 2300 MHz, and the power density is 6 kW / m³. 2 The material temperature was 84℃, the residence time was 50s, and then it was slowly dried at a low temperature of 38℃ in a vacuum drying oven until constant weight was obtained to obtain sorbitol granules.

[0019] Example 2 1. Seed crystal pretreatment Sorbitol γ-type seed crystals were selected and ultra-finely pulverized using a low-temperature pulverizing device. The pulverizing temperature was controlled at 20℃. After pulverization, the crystals were passed through an 80-mesh standard sieve to obtain fine powder of sorbitol γ-type seed crystals. The powder was then preheated to 100℃ and kept at this temperature for 10 minutes to induce sweating. After cooling to 80℃, pretreated γ-type seed crystals were obtained and kept at this temperature for later use. The sorbitol γ-type seed crystals have a purity of 95%.

[0020] 2. Fluidized bed granulation The sorbitol solution was concentrated to 96% by vacuum evaporation to obtain a concentrated sorbitol solution for later use. Pretreated γ-type seed crystals were fed into a fluidized bed, and then the fluidized bed induced draft fan was started. The three-stage air inlet was heated simultaneously. The upper air inlet temperature was set to 110℃, the middle air inlet temperature to 95℃, and the lower air inlet temperature to 85℃. When the bed temperature stabilized at 85℃, the atomized compressed air was turned on and the pressure was adjusted to 0.4MPa. The feed pump was started to spray the concentrated sorbitol solution into the fluidized bed. When the particle size reached 150μm, continuous discharge was started. The feed rate of the concentrated sorbitol solution is 25 kg / h; The hourly feed rate of the concentrated sorbitol solution to the mass ratio of the pretreated γ-type seed crystals is 0.9:3.5.

[0021] 3. Post-processing The material is discharged into a three-stage vibrating screen for grading. Qualified particles (150μm) are sent to a high-speed rounding machine. Stirring is started, and the speed is set to 200r / min. Hot air at 80℃ is introduced. After 3 minutes, the material is output. Coarse particles larger than this size are collected, pulverized at low temperature, and returned as seed crystals. Fine powder smaller than this size is conveyed back to the fluidized bed to continue growing.

[0022] 4. Drying The material is evenly spread on the microwave conveyor belt to a thickness of 2 cm, and passes through the microwave heating device at a constant speed. The microwave frequency is controlled at 2000 MHz, and the power density is 5 kW / m³. 2 The material temperature was 82℃, the residence time was 40s, and then it was slowly dried at a low temperature of 30℃ in a vacuum drying oven until constant weight was obtained to obtain sorbitol granules.

[0023] Example 3 1. Seed crystal pretreatment Sorbitol γ-type seed crystals were selected and ultra-finely pulverized using a low-temperature pulverizing device. The pulverizing temperature was controlled at 40℃. After pulverization, the crystals were passed through a 120-mesh standard sieve to obtain fine powder of sorbitol γ-type seed crystals. The powder was then preheated to 103℃ and kept at this temperature for 20 minutes to induce sweating. After cooling to 90℃, pretreated γ-type seed crystals were obtained and kept at this temperature for later use. The sorbitol γ-type seed crystals have a purity of 98%.

[0024] 2. Fluidized bed granulation The sorbitol solution was concentrated to 98% by vacuum evaporation to obtain a concentrated sorbitol solution for later use. Pretreated γ-type seed crystals were fed into a fluidized bed, and then the fluidized bed induced draft fan was started. The three-stage air inlet was heated simultaneously. The upper air inlet temperature was set to 120℃, the middle air inlet temperature to 100℃, and the lower air inlet temperature to 90℃. When the bed temperature stabilized at 90℃, the atomized compressed air was turned on and the pressure was adjusted to 0.6MPa. The feed pump was started to spray the concentrated sorbitol solution into the fluidized bed. When the particle size reached 450μm, continuous discharge was started. The feed rate of the concentrated sorbitol solution is 30 kg / h; The hourly feed rate of the concentrated sorbitol solution to the mass ratio of the pretreated γ-type seed crystals is 1.1:4.5.

[0025] 3. Post-processing The material is discharged into a three-stage vibrating screen for grading. Qualified particles (450μm) are sent to a high-speed rounding machine. Stirring is started, and the speed is set to 300r / min. Hot air at 90℃ is introduced. After 5 minutes, the material is output. Coarse particles larger than this size are collected, pulverized at low temperature, and returned as seed crystals. Fine powder smaller than this size is transported back to the fluidized bed to continue growing.

[0026] 4. Drying The material is evenly spread on the microwave conveyor belt to a thickness of 3 cm, and passes through the microwave heating device at a constant speed. The microwave frequency is controlled at 2500 MHz, and the power density is 7 kW / m³. 2 The material temperature was 85℃, the residence time was 60s, and then it was slowly dried at a low temperature of 45℃ in a vacuum drying oven until constant weight was obtained to obtain sorbitol granules.

[0027] Comparative Example 1 Based on Example 1, steps 3 and 4 are cancelled, and step 2 is changed to: The sorbitol solution was concentrated to 80% by vacuum evaporation. The solution temperature was then reduced from 80°C to 71°C at a rate of 2°C / h. Pretreated γ-type seed crystals, equivalent to 2.5% of the solute mass, were weighed and evenly sprinkled onto the solution surface in one go. After stirring at low speed (30 rpm) for 4–6 h, the temperature was reduced to 30°C at a rate of 0.8°C / h. The solution was then vacuum filtered and transferred to a vacuum drying oven at 55°C for 10 h. After naturally cooling to room temperature, sorbitol particles were obtained.

[0028] Experimental Example 1 The following indicators of the sorbitol particles prepared in Examples 1-3 and Comparative Example 1 were tested, and the test results are shown in Table 1. Table 1:

Claims

1. A novel preparation process for pharmaceutical sorbitol granules using direct compression, characterized in that: The preparation process includes seed crystal pretreatment, fluidized bed granulation, post-treatment, and drying; The method for pretreatment of the seed crystals is as follows: select sorbitol γ-type seed crystals, perform ultrafine pulverization using a low-temperature pulverizing device, control the pulverization temperature at 20-40℃, pass the pulverized crystals through an 80-120 mesh standard sieve to obtain fine powder of sorbitol γ-type seed crystals, then preheat it to 100-103℃, keep it at this temperature for 10-20 minutes to induce sweating, and then cool it to 80-90℃ to obtain pretreated γ-type seed crystals, which are then kept warm for later use.

2. The novel preparation process of pharmaceutical sorbitol granules using direct compression according to claim 1, characterized in that: In the seed pretreatment method, the sorbitol γ-type seed crystals have a purity of 95-98%.

3. The novel preparation process of pharmaceutical sorbitol granules using direct compression according to claim 1, characterized in that: The fluidized bed granulation method is as follows: sorbitol solution is vacuum evaporated and concentrated to 96-98% to obtain concentrated sorbitol solution for later use. Pretreated γ-type seed crystals are fed into the fluidized bed, and then the fluidized bed induced draft fan is started. The three-stage air inlet is heated simultaneously. The upper stage air inlet temperature is set to 110-120℃, the middle stage air inlet temperature to 95-100℃, and the lower stage air inlet temperature to 85-90℃. When the bed temperature stabilizes at 85-90℃, atomized compressed air is turned on, and the pressure is adjusted to 0.4-0.6MPa. The feed pump is started to spray the concentrated sorbitol solution into the fluidized bed. When the particle size reaches 150-450μm, continuous discharge is started.

4. The novel preparation process of pharmaceutical sorbitol granules using direct compression according to claim 3, characterized in that: In the fluidized bed granulation method, the feed rate of concentrated sorbitol solution is 25-30 kg / h; The hourly feed rate of concentrated sorbitol solution to the mass ratio of pretreated γ-type seed crystals is 0.9–1.1:3.5–4.

5.

5. The novel preparation process of pharmaceutical sorbitol granules using direct compression according to claim 1, characterized in that: The post-processing method is as follows: the discharged material enters a three-stage vibrating screen for classification, and qualified particles (150-450μm) are sent to a high-speed rounding machine. The stirring is started, the speed is set to 200-300r / min, and hot air at 80-90℃ is introduced. After 3-5 minutes, the material is output. Coarse particles larger than the particle size are collected, pulverized at low temperature, and returned as seed crystals. Fine powder smaller than the particle size is conveyed back to the fluidized bed to continue growing.

6. The novel preparation process of pharmaceutical sorbitol granules using direct compression according to claim 1, characterized in that: The drying method involves evenly spreading the material on a microwave conveyor belt, with a layer thickness of 2-3 cm, and passing it at a constant speed through a microwave heating device. The microwave frequency is controlled at 2000-2500 MHz, and the power density is 5-7 kW / m³. 2 The material temperature is 82-85℃, the residence time is 40-60s, and then it is slowly dried at a low temperature of 30-45℃ in a vacuum drying oven until constant weight is obtained to obtain sorbitol granules.

Images