Preparation method of valsartan granules
By dynamically controlling the inlet air temperature and atomization pressure, the problems of uneven particle size and low dissolution in the preparation of valsartan granules were solved, achieving high dissolution and stability and improving product quality.
Patent Information
- Application Number
- CN202511741993.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-25
- Publication Date
- 2026-01-09
AI Technical Summary
In the existing valsartan granule preparation process, parameters such as inlet air temperature and atomization pressure are poorly controlled, resulting in uneven particle size distribution and low dissolution, which affects product quality stability and clinical efficacy.
Dynamic gradient control of inlet air temperature and atomization pressure is adopted to adjust the matching of spray volume and inlet air temperature. Dynamic balance is formed through multi-stage spraying to avoid particles that are too coarse or too fine, thereby improving particle size distribution uniformity and dissolution.
It achieves highly uniform particle size distribution, reduces particle size span, increases dissolution rate to over 95%, and maintains high dissolution rate in accelerated tests, thereby improving product quality stability and batch repeatability.
Smart Images
Figure CN121287632A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical preparations, and more specifically to a method for preparing valsartan granules. Background Technology
[0002] Valsartan, an angiotensin II receptor antagonist, has become a mainstream drug for the treatment of hypertension. One-step granulation (fluidized bed granulation) is widely used in the preparation of valsartan capsules due to its high efficiency and continuous production advantages. However, because the control of parameters such as inlet air temperature and atomization pressure in the preparation process is often rough, uneven particle size distribution can easily occur, ultimately leading to problems such as large differences between capsule particles and low dissolution, which restricts the stability of product quality and clinical efficacy. Summary of the Invention
[0003] This invention provides a method for preparing valsartan granules, which improves the uniformity of particle size distribution and dissolution rate of valsartan granules.
[0004] This invention provides a method for preparing valsartan granules, comprising the following steps: After a partial spraying of the solution containing the binder, the resulting droplets are sprayed onto the surface of the powder containing valsartan to obtain initial valsartan particles. After a second spraying of the remaining solution containing the adhesive, the resulting droplets are sprayed onto the surface of the initial valsartan particles and then dried to obtain the valsartan particles. During the first spraying, the valsartan-containing powder is in a fluidized state; The inlet air temperature during the first spray is 30~80℃, the spray volume is 500~1000g / min, the atomization pressure is 1.8~5.0bar, and the inlet air volume is 500~2500m³. 3 / h; The first spray includes several stages of spray, and the inlet air temperature gradient of the several stages of spray in the first spray increases. During the second spray, the initial valsartan particles are in a fluidized state; The inlet air temperature for the second spray is 40~90℃, the spray volume is 100~750g / min, the atomization pressure is 1~3.0bar, and the inlet air volume is 2000~4000m³. 3 / h; The first spray includes several stages of spraying, and the inlet air temperature gradient of the several stages of spraying in the second spray increases. The inlet air temperature during the second spray is higher than that during the first spray.
[0005] Preferably, based on the mass fraction of the adhesive, the valsartan-containing powder comprises: Valsartan 40-70 parts and microcrystalline cellulose 10-30 parts.
[0006] Preferably, by weight, the solution containing the adhesive comprises 50-100 parts water, 5-10 parts adhesive, and 1-2 parts sodium dodecyl sulfate; The adhesive includes povidone.
[0007] Preferably, the mass ratio of the portion containing the adhesive to the remaining portion containing the adhesive is 1 to 3:1.
[0008] Preferably, the inlet air humidity during the first and second sprays is independently 5~15g / kg.
[0009] Preferably, the first spray includes a first spray, a second spray, a third spray, and a fourth spray; The inlet air temperature during the first spray is 35~45℃, the inlet air temperature during the second spray is 0.5~3℃ higher than the inlet air temperature during the first spray, the inlet air temperature during the third spray is 0.5~3℃ higher than the inlet air temperature during the second spray, and the inlet air temperature during the fourth spray is 0.5~4℃ higher than the inlet air temperature during the third spray. The air volume during the first spray is less than the air volume during the second spray, which is less than the air volume during the third spray, which is less than the air volume during the fourth spray.
[0010] Preferably, the second spray includes a first spray and a second spray; The inlet air temperature during the first spray is 40℃~55℃, and the inlet air temperature during the second spray is 4~10℃ higher than the inlet air temperature during the first spray. The air intake volume during the first spray is less than the air intake volume during the second spray.
[0011] Preferably, the moisture content of the material after the first and second sprays is 8-30%.
[0012] Preferably, the inlet air temperature during drying is 35~100℃, and the inlet air volume is 1500~4000m³. 3 / h, the inlet air humidity is 1~5g / kg, and the moisture content of the dried material is 1~20%.
[0013] Preferably, after drying, the process further includes: mixing the dried particles with crospovidone and magnesium stearate sequentially to obtain the valsartan particles; Based on the mass fraction of the adhesive, the amount of crosslinked polyvinyl ketone used is 10-20 parts; Based on the mass fraction of the adhesive, the amount of magnesium stearate used is 1 to 2 parts.
[0014] This invention achieves significant technical effects by dynamically controlling the inlet air temperature gradient (the inlet air temperature gradient increases in several stages of the first and second sprays) and adjusting the atomization pressure, spray volume, and inlet air temperature to ensure a dynamic balance between the inlet air temperature increase rate, droplet size, and particle growth rate in several stages of the first and second sprays. This avoids over-melting of particle surfaces or wet nucleus aggregation, eliminates the generation of "overly coarse" or "overly fine" particles, ensures the consistency of particle size growth kinetics, and improves product quality stability. ① Highly uniform particle size distribution: The particle size span ((D90-D10) / D50) is reduced to below 2.0; the variation in D90 is reduced to below 20μm. Batch repeatability is better, and the difference in D90 between batches is reduced to below 20μm; ② Significantly improved dissolution (≥95% in 30 min): The dissolution rate in 30 min is increased from 80%-85% to over 95%, and the dissolution rate is still ≥90% after 6 months of accelerated testing (40℃ / 75% RH), which is significantly better than existing technologies (the dissolution rate usually decreases by >15% after 6 months of accelerated testing). Furthermore, this invention controls the particle porosity to 10-50% by precisely controlling the inlet air humidity and atomization pressure during the first and second sprays. The high humidity range (5g-15g / kg) increases the contact area between the liquid and the particles, inducing the liquid bridge to change from a "pendulum shape" to a "capillary shape", thereby increasing the particle growth rate. The low humidity range (1-5g / kg, dry) promotes the rapid evaporation of the solvent to form a porous structure, thereby increasing the porosity and further accelerating the penetration of the dissolution medium and improving dissolution. Attached Figure Description
[0015] Figure 1 Particle size (D90) curves for 3 batches; Figure 2 Dissolution rate curves for three batches of finished products under different storage times (accelerated conditions); Figure 3 For comparison group ①, the particle size (D90) curve is shown. Figure 4 For comparison, the particle size (D90) curves for group ② are shown. Figure 5 For comparison group ③, the particle size (D90) curve is shown. Figure 6 For comparison group ④, the particle size (D90) curve is shown. Detailed Implementation
[0016] This invention provides a method for preparing valsartan granules, comprising the following steps: After a partial spraying of the solution containing the binder, the resulting droplets are sprayed onto the surface of the powder containing valsartan to obtain initial valsartan particles. After a second spraying of the remaining solution containing the adhesive, the resulting droplets are sprayed onto the surface of the initial valsartan particles and then dried to obtain the valsartan particles. During the first spraying, the valsartan-containing powder is in a fluidized state; The inlet air temperature during the first spray is 30~80℃, the spray volume is 500~1000g / min, the atomization pressure is 1.8~5.0bar, and the inlet air volume is 500~2500m³. 3 / h; The first spray includes several stages of spray, and the inlet air temperature gradient of the several stages of spray in the first spray increases. During the second spray, the initial valsartan particles are in a fluidized state; The inlet air temperature for the second spray is 40~90℃, the spray volume is 100~750g / min, the atomization pressure is 1~3.0bar, and the inlet air volume is 2000~4000m³. 3 / h; The second spray comprises several stages of spray, wherein the inlet air temperature gradient of the several stages of spray in the second spray increases; The inlet air temperature during the second spray is higher than that during the first spray.
[0017] In this invention, a solution containing a binder is first sprayed, and the resulting droplets are then sprayed onto the surface of a powder containing valsartan to obtain initial valsartan particles.
[0018] In this invention, the solution containing the adhesive preferably comprises 5 to 10 parts by weight, and in specific embodiments of this invention, it may be 6, 7, 8, or 9 parts; the adhesive preferably comprises povidone. Based on the mass fraction of the adhesive, the solution containing the adhesive preferably includes 50 to 100 parts of water, and in specific embodiments of the present invention, it can be 60, 70, 80 or 90 parts.
[0019] Based on the mass fraction of the adhesive, the solution containing the adhesive preferably includes 1 to 2 parts of sodium dodecyl sulfate, which may be 1.2 parts, 1.5 parts, or 1.8 parts in specific embodiments of the present invention.
[0020] Based on the mass fraction of the adhesive, the valsartan-containing powder preferably includes 40 to 70 parts of valsartan, and in specific embodiments of the present invention, it can be 45, 50, 55, 60, or 65 parts.
[0021] Based on the mass fraction of the adhesive, the valsartan-containing powder preferably includes 10 to 30 parts of microcrystalline cellulose, which in specific embodiments of the present invention can be 12, 15, 18, 20, 22, 25, or 28 parts.
[0022] In this invention, the inlet air temperature during the first spray is 30~80℃, the spray volume is 500~1000g / min, the atomization pressure is 1.8~5.0bar, and the inlet air volume is 500~2500m³. 3 In a specific embodiment of the present invention, the inlet air temperature during the first spray can be 35°C, 40°C, 45°C, 50°C, 55°C, 65°C, 70°C, or 75°C; the spray volume can be 550 g / min, 600 g / min, 650 g / min, 700 g / min, 750 g / min, 800 g / min, 850 g / min, 900 g / min, or 950 g / min; the atomization pressure can be 2 bar, 2.2 bar, 2.5 bar, 3 bar, 3.5 bar, 4 bar, or 4.5 bar; and the inlet air volume can be 600 m³ / h. 3 / h, 700m 3 / h、800m 3 / h、900m 3 / h, 1000m 3 / h、1100m 3 / h, 1200m 3 / h, 1300m 3 / h, 1400m 3 / h, 1500m 3 / h, 1600m 3 / h, 1700m 3 / h, 1800m 3 / h, 1900m 3 / h、2000m 3 / h、2100m 3 / h、2200m 3 / h, 2300m 3 / h or 2400m 3 / h.
[0023] In this invention, the first spray includes several stages of spraying, and the inlet air temperature gradient of the several stages of spraying in the first spray increases.
[0024] In this invention, the first spray preferably includes a first spray, a second spray, a third spray, and a fourth spray; the inlet air temperature during the first spray is preferably 35°C to 45°C, the inlet air temperature during the second spray is preferably 0.5°C to 3°C higher than the inlet air temperature during the first spray, the inlet air temperature during the third spray is preferably 0.5°C to 3°C higher than the inlet air temperature during the second spray, and the inlet air temperature during the fourth spray is preferably 0.5°C to 4°C higher than the inlet air temperature during the third spray; the inlet air volume during the first spray is less than the inlet air volume during the second spray, less than the inlet air volume during the third spray, and less than the inlet air volume during the fourth spray; the duration of the first spray, the second spray, the third spray, and the fourth spray is preferably equal.
[0025] In this invention, the inlet air humidity of the first spray is preferably 5~15 g / kg, and in specific embodiments of this invention it can be 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg, 10 g / kg, 11 g / kg, 12 g / kg, 13 g / kg or 14 g / kg; the moisture content of the material after the first spray is preferably 8~30%, and in specific embodiments of this invention it can be 10%, 15%, 18%, 20%, 22%, 25% or 28%.
[0026] In this invention, during the first spraying, the valsartan-containing powder is in a fluidized state.
[0027] After obtaining the initial valsartan particles, the present invention performs a second spraying of the remaining solution containing the binder, sprays the resulting droplets onto the surface of the initial valsartan particles, and then dries them to obtain the valsartan particles.
[0028] In this invention, the mass ratio of the portion containing the adhesive to the remaining portion containing the adhesive is preferably 1 to 3:1, and in specific embodiments of this invention, it can be 1.5:1, 1.8:1, 2:1, 2.5:1 or 2.8:1.
[0029] In this invention, the inlet air temperature during the second spraying is 40~90℃, the spray volume is 100~7050g / min, the atomization pressure is 1~3.0 bar, and the inlet air volume is 2000~4000m³. 3In a specific embodiment of the present invention, the inlet air temperature during the second spraying can be 45°C, 50°C, 55°C, 65°C, 70°C, 75°C, 80°C, or 85°C; the spraying rate can be 150 g / min, 200 g / min, 250 g / min, 300 g / min, 350 g / min, 400 g / min, 450 g / min, 500 g / min, 550 g / min, 600 g / min, 650 g / min, or 700 g / min; the atomization pressure can be 1.2 bar, 1.5 bar, 1.8 bar, 2 bar, 2.5 bar, or 2.8 bar; and the inlet air volume can be 2100 m³ / h. 3 / h、2200m 3 / h, 2300m 3 / h, 2400m 3 / h, 2500m 3 / h, 2600m 3 / h, 2700m 3 / h, 2800m 3 / h, 2900m 3 / h, 3000m 3 / h、3100m 3 / h, 3200m 3 / h, 3300m 3 / h, 3400m 3 / h, 3500m 3 / h, 3600m 3 / h, 3700m 3 / h, 3800m 3 / h or 3900m 3 / h.
[0030] In this invention, the inlet humidity of the second spray is preferably 5~15 g / kg, and in specific embodiments of this invention it can be 6 g / kg, 7 g / kg, 8 g / kg, 9 g / kg, 10 g / kg, 11 g / kg, 12 g / kg, 13 g / kg or 14 g / kg; the moisture content of the material after the second spray is preferably 8~30%, and in specific embodiments of this invention it can be 10%, 15%, 18%, 20%, 22%, 25% or 28%.
[0031] In this invention, the second spray includes several stages of spray, and the inlet air temperature gradient of the several stages of spray in the second spray increases.
[0032] In this invention, the second spray preferably includes a first spray and a second spray; the inlet air temperature during the first spray is preferably 40~55°C, and the inlet air temperature during the second spray is preferably 5~10°C higher than the inlet air temperature during the first spray; the inlet air volume during the first spray is preferably less than the inlet air volume during the second spray; and the duration of the first spray and the second spray is preferably equal.
[0033] In this invention, during the second spraying, the valsartan-containing powder is in a fluidized state.
[0034] In this invention, the inlet air temperature during drying is preferably 35~100℃, and the inlet air volume is preferably 1500~4000 m³ / h. 3 The inlet air humidity is preferably 1~5 g / kg. In a specific embodiment of the present invention, the inlet air temperature during drying can be 40℃, 50℃, 60℃, 70℃, 80℃ or 90℃, and the inlet air volume can be 1600 m³ / h. 3 / h, 1700m 3 / h, 1800m 3 / h, 1900m 3 / h、2000m 3 / h、2100m 3 / h、2200m 3 / h, 2300m 3 / h, 2400m 3 / h, 2500m 3 / h, 2600m 3 / h, 2700m 3 / h, 2800m 3 / h, 2900m 3 / h, 3000m 3 / h、3100m 3 / h, 3200m 3 / h, 3300m 3 / h, 3400m 3 / h, 3500m 3 / h, 3600m 3 / h, 3700m 3 / h, 3800m 3 / h or 3900m 3 / h, the intake air humidity can be 2g / kg, 3g / kg or 4g / kg.
[0035] In this invention, the moisture content of the dried material is preferably 1-20%, and in specific embodiments of this invention it can be 3%, 5%, 8%, 10%, 12%, 15% or 18%.
[0036] After drying, the present invention preferably further includes: mixing the dried particles with crospovidone and magnesium stearate successively to obtain the valsartan particles.
[0037] Based on the mass fraction of the adhesive, the amount of crosslinked polyvinyl ketone is preferably 10 to 20 parts, and in specific embodiments of the present invention, it can be 11, 12, 13, 14, 15, 16, 17, 18 or 19 parts.
[0038] Based on the mass fraction of the adhesive, the amount of magnesium stearate is preferably 1 to 2 parts, and in specific embodiments of the present invention, it can be 1.2 parts, 1.5 parts or 1.8 parts.
[0039] The following detailed description of the preparation method of valsartan granules provided by the present invention, in conjunction with the embodiments, should not be construed as limiting the scope of protection of the present invention.
[0040] Example 1 Three batches of valsartan capsules were prepared in parallel using the method described in the technical solution, and the particle size and hardness of the intermediate particles were tested. Simultaneously, the dissolution rate and stability of the finished product were investigated. The specific preparation process is as follows: Weigh out 55 parts of valsartan, 20 parts of microcrystalline cellulose PH101, 15 parts of crospovidone, and 1 part of magnesium stearate for later use. Dissolve 9 parts of povidone and 1 part of sodium dodecyl sulfate in 50 parts of water to prepare an adhesive solution.
[0041] 55 parts valsartan and 20 parts microcrystalline cellulose PH101 were added to a fluidized bed using vacuum feeding at a speed of 700 m³ / h. 3 The premixed powder is premixed with an airflow rate of / h, and the first spraying process is carried out after 10 minutes. The first spraying is divided into 4 stages, totaling 40 minutes, with each stage lasting 10 minutes. After the first spraying, the particle moisture content should be 15%~20%. The second spraying is divided into 2 stages, totaling 30 minutes, with each stage lasting 15 minutes. After the second spraying, the particle moisture content should be 20%~30%. The mass ratio of the binder solution used in the first spraying to the second spraying is 1.8:1. The drying process lasts for 50 minutes, and the particle moisture content should be 2%~3% after drying. The dried particles are granulated using a 1.0mm round hole sieve at 400rpm, and then 15 parts of crosslinked polyvinyl chloride are added for primary mixing (mixing parameters: 10rpm, 9min: 3min clockwise, 3min counterclockwise, 3min clockwise), and then 1 part of magnesium stearate is added for final mixing (mixing parameters: 10rpm, 9min: 3min clockwise, 3min counterclockwise, 3min clockwise).
[0042] The inlet air humidity for the first spray was controlled at 10 g / kg, the atomization pressure at 2.2 bar, and the spray volume at 900 g / min. The inlet air volume and temperature for the first spray increased gradually, with the first stage having an inlet air temperature of 39℃ and an inlet air volume of 1000 m³ / min. 3 / h; The second stage is with an inlet air temperature of 40℃ and an inlet air volume of 1300m³ / h. 3 / h; The third stage is with an inlet air temperature of 41℃ and an inlet air volume of 1700m³ / h. 3 / h; the fourth stage is an inlet air temperature of 42℃ and an inlet air volume of 2000m³ / h. 3 / h.
[0043] The inlet air humidity for the second spray is controlled at 12 g / kg, the atomization pressure at 1.8 bar, and the spray volume at 650 g / min. The first stage has an inlet air temperature of 45℃ and an inlet air volume of 2300 m³ / min. 3 / h; the second stage is an inlet air temperature of 50℃ and an inlet air volume of 2500m³ / h. 3 / h.
[0044] The humidity of the incoming air is controlled at 3 g / kg, the temperature at 60℃, and the air volume at 2000 m³ / kg. 3 / h.
[0045] Dissolution was tested in a pH 6.8 medium using the basket method according to the 2020 edition of the Chinese Pharmacopoeia (0931 Determination of Dissolution and Release).
[0046] Table 1. Particle size and hardness data for three batches of particles
[0047] Table 2 Dissolution data of three batches of finished products
[0048] Table 3. Accelerated dissolution data of three batches of finished products in January.
[0049] Table 4. Accelerated dissolution data of three batches of finished products in February.
[0050] Table 5. Accelerated dissolution data of three batches of finished products in March.
[0051] Experimental results show that this preparation method can obtain particles with uniform particle size and good batch-to-batch reproducibility. The dissolution rate of the finished product is above 95%, and it remains above 90% even after accelerated dissolution for 3 months.
[0052] Example 2 Unlike the parameter range in Example 1, three batches of valsartan capsules were prepared in parallel, and the particle size and hardness of the intermediate particles were tested. Simultaneously, the dissolution rate and stability of the finished product were tested to screen for a suitable range of process parameters. The specific preparation process is as follows: Weigh out 55 parts valsartan, 20 parts microcrystalline cellulose PH101, 15 parts crospovidone, and 1 part magnesium stearate for later use. Dissolve 9 parts povidone and 1 part sodium dodecyl sulfate in 50 parts water to prepare an adhesive solution. (The above operation is the same as in Example 1) 55 parts valsartan and 20 parts microcrystalline cellulose PH101 were added to a fluidized bed using vacuum feeding at a speed of 700 m³ / h. 3 The premixed powder is premixed with an airflow rate of / h, and the first spraying process is carried out after 10 minutes. The first spraying is divided into 4 stages, totaling 40 minutes, with each stage lasting 10 minutes. After the first spraying, the particle moisture content should be 22%~25%. The second spraying is divided into 2 stages, totaling 26 minutes, with each stage lasting 13 minutes. After the second spraying, the particle moisture content should be 27%~30%. The mass ratio of the binder solution used in the first spraying to the second spraying is 2:1. The drying process lasts for 80 minutes, and the particle moisture content should be 2%~3% after drying. The dried particles are granulated using a 1.0mm round hole sieve at 400rpm, and then 15 parts of crosslinked polyvinyl acetate are added for primary mixing (mixing parameters: 10rpm, 9min: 3min clockwise, 3min counterclockwise, 3min clockwise), and then 1 part of magnesium stearate is added for final mixing (mixing parameters: 10rpm, 9min: 3min clockwise, 3min counterclockwise, 3min clockwise).
[0053] The inlet air humidity for the first spray was controlled at 13 g / kg, the atomization pressure at 1.8 bar, and the spray volume at 1000 g / min. The inlet air volume and temperature for the first spray increased gradually, with the first stage having an inlet air temperature of 44℃ and an inlet air volume of 1400 m³ / min. 3 / h; The second stage is with an inlet air temperature of 45℃ and an inlet air volume of 1800m³ / h. 3 / h; The third stage is with an inlet air temperature of 46℃ and an inlet air volume of 2000m³ / h. 3 / h; the fourth stage is an inlet air temperature of 47℃ and an inlet air volume of 2500m³ / h. 3 / h.
[0054] The humidity of the inlet air for the second spray is controlled at 15 g / kg, the atomization pressure at 1.5 bar, and the spray volume at 750 g / min. The first stage has an inlet air temperature of 50℃ and an inlet air volume of 2600 m³ / min. 3 / h; The second stage is with an inlet air temperature of 54℃ and an inlet air volume of 2800m³ / h. 3 / h.
[0055] The humidity of the incoming air is controlled at 3 g / kg, the temperature at 65℃, and the air volume at 2200 m³ / kg. 3 / h.
[0056] Compared to Example 1, Example 2 uses lower atomization pressure, higher inlet air humidity, and higher spray volume for the first and second sprays. The mass ratio of the binder solution and the particle moisture content are also higher in Example 1. The inlet air temperature and airflow gradients for the first and second sprays are increased, with values at each stage higher than in Example 1. Particle moisture control after drying is the same as in Example 1, but the drying time is longer. Example 2 uses a higher granulation intensity matched with a gradient increase in inlet air temperature and airflow within the process parameters of the technical solution to examine the applicability and rationality of the technical solution.
[0057] Dissolution was tested in a pH 6.8 medium using the basket method according to the 2020 edition of the Chinese Pharmacopoeia (0931 Determination of Dissolution and Release).
[0058] Table 6. Particle size and hardness data for three batches of particles
[0059] Table 7 Dissolution data of 3 batches of finished products
[0060] Table 8. Accelerated dissolution data of three batches of finished products in January.
[0061] Table 9. Accelerated dissolution data of three batches of finished products in February.
[0062] Table 10 Accelerated Dissolution Data for 3 Batches of Finished Products in March
[0063] Experimental results show that, according to the preparation method in the technical solution, by using different granulation intensities and matching appropriate gradients of inlet air temperature and airflow, uniform particles (D) can be obtained. 90 -D 10 ) / D 50 ≤2.0 (uniformity worse than Example 1), good batch-to-batch reproducibility of particles. The average dissolution rate of the finished product is above 90%, and the dissolution rate remains above 90% even after 3 months of accelerated dissolution.
[0064] Example 3 Unlike the parameter range in Example 1, three batches of valsartan capsules were prepared in parallel, and the particle size and hardness of the intermediate particles were tested. Simultaneously, the dissolution rate and stability of the finished product were tested to screen for a suitable range of process parameters. The specific preparation process is as follows: Weigh out 55 parts valsartan, 20 parts microcrystalline cellulose PH101, 15 parts crospovidone, and 1 part magnesium stearate for later use. Dissolve 9 parts povidone and 1 part sodium dodecyl sulfate in 50 parts water to prepare an adhesive solution. (The above operation is the same as in Example 1) 55 parts valsartan and 20 parts microcrystalline cellulose PH101 were added to a fluidized bed using vacuum feeding at a speed of 700 m³ / h. 3 The premixed powder is premixed with an airflow rate of / h, and the first spraying process is carried out after 10 minutes. The first spraying is divided into 4 stages, totaling 40 minutes, with each stage lasting 10 minutes. After the first spraying, the particle moisture content should be 8%~12%. The second spraying is divided into 2 stages, totaling 40 minutes, with each stage lasting 20 minutes. After the second spraying, the particle moisture content should be 15%~25%. The mass ratio of the binder solution used in the first spraying to the second spraying is 1.5:1. The drying process lasts for 40 minutes, and after drying, the particle moisture content should be 2%~3%. The dried particles are granulated using a 1.0mm round hole sieve at 400rpm, and then 15 parts of crosslinked polyvinyl acetate are added for primary mixing (mixing parameters: 10rpm, 9min: 3min clockwise, 3min counterclockwise, 3min clockwise), and then 1 part of magnesium stearate is added for final mixing (mixing parameters: 10rpm, 9min: 3min clockwise, 3min counterclockwise, 3min clockwise).
[0065] The inlet air humidity for the first spray was controlled at 5 g / kg, the atomization pressure at 2.8 bar, and the spray volume at 850 g / min. The inlet air volume and temperature for the first spray increased gradually, with the first stage having an inlet air temperature of 38℃ and an inlet air volume of 900 m³ / min. 3 / h; The second stage is with an inlet air temperature of 39℃ and an inlet air volume of 1200m³ / h. 3 / h; The third stage is with an inlet air temperature of 40℃ and an inlet air volume of 1600m³ / h. 3 / h; The fourth stage is with an inlet air temperature of 41℃ and an inlet air volume of 1800m³ / h. 3 / h.
[0066] The inlet air humidity for the second spray is controlled at 10 g / kg, the atomization pressure at 2.2 bar, and the spray volume at 550 g / min. The first stage has an inlet air temperature of 44℃ and an inlet air volume of 2200 m³ / min. 3 / h; The second stage is with an inlet air temperature of 50℃ and an inlet air volume of 2400m³ / h. 3 / h.
[0067] The humidity of the incoming air is controlled at 3 g / kg, the temperature at 60℃, and the air volume at 2000 m³ / kg. 3 / h.
[0068] Compared to Example 1, Example 3 uses higher atomization pressure, lower inlet air humidity, and lower spray volume for the first and second sprays. The mass ratio of the binder solution and the particle moisture content are both lower in Example 1. The inlet air temperature and airflow gradients for the first and second sprays are increased, with most stages showing values lower than in Example 1. The particle moisture control after drying is the same as in Example 1, but the drying time is shorter than in Example 1. Example 2 uses a smaller granulation intensity matched with a gradient increase in inlet air temperature and airflow within the process parameters of the technical solution to examine the applicability and rationality of the technical solution.
[0069] Dissolution was tested in a pH 6.8 medium using the basket method according to the 2020 edition of the Chinese Pharmacopoeia (0931 Determination of Dissolution and Release).
[0070] Table 11 Particle size and hardness data for 3 batches
[0071] Table 12 Dissolution data of 3 batches of finished products
[0072] Table 13 Accelerated dissolution data for 3 batches of finished products in January
[0073] Table 14 Accelerated Dissolution Data for 3 Batches of Finished Products in February
[0074] Table 15 Accelerated Dissolution Data for 3 Batches of Finished Products in March
[0075] Experimental results show that, according to the preparation method in the technical solution, by using different granulation intensities and matching appropriate gradients of inlet air temperature and airflow, uniform particles (D) can be obtained. 90 -D 10 ) / D 50 ≤2.0 (uniformity worse than Example 1), good batch-to-batch reproducibility of particles. The average dissolution rate of the finished product is above 90%, and the average dissolution rate remains above 90% even after 3 months of accelerated dissolution.
[0076] The experiment mainly analyzed and screened suitable spray parameters and their combinations by adjusting single and synergistic parameters during the spraying phase. The design groups and the production parameters used in each group are detailed in the table below: Table 16 Experimental Design Table
[0077] Note: The items marked with "—" in the table are parameters not examined in this group, i.e., this variable is the same as in Example 1 (i.e. Figure 6 The same as the control group in the study.
[0078] Table 17 Comparison Group ① Particle size and hardness data
[0079] Table 18 Comparison Group ① Finished Product Dissolution Data
[0080] Table 19 Comparison Group ② Particle size and hardness data
[0081] Table 20 Dissolution data of finished products in comparison group ②
[0082] Table 21 Comparison Group ③ Particle size and hardness data
[0083] Table 22 Dissolution data of finished products in comparison group ③
[0084] Table 23 Comparison Group ④ Particle size and hardness data
[0085] Table 24 Comparison Group ④ Dissolution Data
[0086] Figure 1 The particle size (D90) curves for three batches of particles are shown.
[0087] Figure 2 The dissolution rate curves are shown for three batches of finished products under different storage times (accelerated conditions).
[0088] Figure 3 For comparison group ①, the particle size (D90) curve is shown.
[0089] Figure 4 For comparison of particle size (D90) curves in group ②.
[0090] Figure 5 For comparison group ③, the particle size (D90) curve is shown.
[0091] Figure 6 For comparison group ④, the particle size (D90) curve is shown.
[0092] Depend on Figures 1-6 It can be seen that the particle uniformity and product dissolution obtained by adjusting different parameters such as inlet air temperature, inlet air humidity, atomization pressure and spray volume are not ideal; the preparation method of the control group can significantly improve particle uniformity.
[0093] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A method for preparing valsartan granules, characterized in that, Includes the following steps: After a partial spraying of the solution containing the binder, the resulting droplets are sprayed onto the surface of the powder containing valsartan to obtain initial valsartan particles. After a second spraying of the remaining solution containing the adhesive, the resulting droplets are sprayed onto the surface of the initial valsartan particles and then dried to obtain the valsartan particles. During the first spraying, the valsartan-containing powder is in a fluidized state; The inlet air temperature during the first spray is 30~80℃, the spray volume is 500~1000g / min, the atomization pressure is 1.8~5.0bar, and the inlet air volume is 500~2500m³. 3 / h; The first spray includes several stages of spray, and the inlet air temperature gradient of the several stages of spray in the first spray increases. During the second spray, the initial valsartan particles are in a fluidized state; The inlet air temperature for the second spray is 40~90℃, the spray volume is 100~750g / min, the atomization pressure is 1~3.0bar, and the inlet air volume is 2000~4000m³. 3 / h; The second spray comprises several stages of spray, wherein the inlet air temperature gradient of the several stages of spray in the second spray increases; The inlet air temperature during the second spray is higher than that during the first spray.
2. The preparation method according to claim 1, characterized in that, Based on the mass fraction of the adhesive, the valsartan-containing powder comprises: Valsartan 40-70 parts and microcrystalline cellulose 10-30 parts.
3. The preparation method according to claim 2, characterized in that, The solution containing the adhesive comprises, by weight, 50-100 parts water, 5-10 parts adhesive and 1-2 parts sodium dodecyl sulfate; The adhesive includes povidone.
4. The preparation method according to claim 1 or 2, characterized in that, The mass ratio of the portion containing the adhesive to the remaining portion containing the adhesive is 1 to 3:
1.
5. The preparation method according to claim 1, characterized in that, The inlet air humidity during the first and second sprays is independently 5~15g / kg.
6. The preparation method according to claim 1, characterized in that, The first spray includes a first spray, a second spray, a third spray, and a fourth spray; The inlet air temperature during the first spray is 35~45℃, the inlet air temperature during the second spray is 0.5~3℃ higher than the inlet air temperature during the first spray, the inlet air temperature during the third spray is 0.5~3℃ higher than the inlet air temperature during the second spray, and the inlet air temperature during the fourth spray is 0.5~4℃ higher than the inlet air temperature during the third spray. The air volume during the first spray is less than the air volume during the second spray, which is less than the air volume during the third spray, which is less than the air volume during the fourth spray.
7. The preparation method according to claim 1, characterized in that, The second spray includes spray ① and spray ②; The inlet air temperature during the first spray is 40~55℃, and the inlet air temperature during the second spray is 4~10℃ higher than the inlet air temperature during the first spray. The air intake volume during the first spray is less than the air intake volume during the second spray.
8. The preparation method according to claim 1, characterized in that, The moisture content of the material after the first and second sprays is independently 8-30%.
9. The preparation method according to claim 1, characterized in that, The inlet air temperature during drying is 35~100℃, and the inlet air volume is 1500~4000m³. 3 / h, the inlet air humidity is 1~5g / kg; The moisture content of the dried material is 1-20%.
10. The preparation method according to claim 1, characterized in that, After drying, the process further includes: mixing the dried particles with crospovidone and magnesium stearate sequentially to obtain the valsartan particles; Based on the mass fraction of the adhesive, the amount of crosslinked polyvinyl ketone used is 10-20 parts; Based on the mass fraction of the adhesive, the amount of magnesium stearate used is 1 to 2 parts.