High-stability lafutidine tablet and production process thereof
By preparing a solid dispersion system and optimizing the granulation process, the stability and solubility issues of lafutidine were resolved, resulting in lafutidine tablets with efficient disintegration and stable storage.
Patent Information
- Application Number
- CN202511670554.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-14
- Publication Date
- 2026-01-30
AI Technical Summary
Lafutidine molecules are easily oxidized, have poor stability and low solubility. When prepared into tablets, they disintegrate slowly and have insufficient dissolution, which affects human absorption.
A solid dispersion system was formed using β-cyclodextrin, polyethylene glycol, pullulan, and other components. Combined with excipients such as hydroxypropyl cellulose and lactose, and prepared by dry rolling and wet granulation, and the addition of croscarmellose sodium, highly stable lafutidine tablets were prepared.
It improves the dissolution rate and bioavailability of lafutidine, enhances the stability and disintegration properties of tablets, and ensures efficient drug absorption and stable storage.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of medicine preparation, and in particular to a high-stability ranitidine tablet and a production process thereof. BACKGROUND
[0002] Ranitidine is an H2 receptor antagonist that can inhibit gastric acid secretion and protect gastric mucosa, and can be used for treating peptic ulcer. However, ranitidine contains furan ring and sulfinyl group in the molecule, is prone to oxidation reaction, has poor stability, and has extremely low solubility, so that the tablet prepared therefrom has slow disintegration and insufficient dissolution, thereby affecting human body absorption.
[0003] In the prior art, the poor stability of ranitidine can be alleviated by adding excipients, but the excipients have strong hygroscopicity, which can easily lead to tablet moisture absorption and caking in a humid environment, accelerate hydrolysis reaction, and insufficient or poor disintegration of disintegrants can lead to delayed tablet disintegration and insufficient dissolution. In addition, insufficient addition of antioxidants (such as vitamin C) or poor compatibility with the drug can lead to ineffective inhibition of oxidative degradation. Therefore, the present application provides a high-stability ranitidine tablet and a production process thereof to solve the above technical problems. SUMMARY
[0004] The present application aims to provide a high-stability ranitidine tablet and a production process thereof to solve the problems in the prior art.
[0005] To achieve the above-mentioned purpose, the present application provides the following technical solutions. A production process of a high-stability ranitidine tablet, comprising the following steps: S1: mixing ranitidine raw material, β-cyclodextrin, polyethylene glycol and pullulan, grinding and dispersing, dry rolling, and sieving to obtain a ranitidine dispersion system; S2: mixing the ranitidine dispersion system, hydroxypropyl cellulose, lactose F100 and lactose G200, stirring uniformly, adding a stabilizer, and continuing to stir to obtain a premix; S3: adding the premix to a soft material to perform wet granulation, fluidized drying, and whole granulation to obtain an intermediate granule; S4: adding cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and magnesium stearate to the intermediate granule for total mixing, tabletting, and coating to obtain a ranitidine tablet.
[0006] Further, the soft material comprises the following mass components: 5-10 parts of povidone K30, 20-30 parts of hydroxypropyl cellulose, 7-8 parts of sodium dodecyl sulfate, and 70-80 parts of deionized water.
[0007] In the above technical effects, first, by preparing the solid dispersion system of larfotidine, the poorly soluble larfotidine is dispersed in the water-soluble carrier in a molecular, amorphous or microcrystalline state, the dissolution rate of larfotidine is improved, the bioavailability is improved, and the solid dispersion system can significantly reduce the agglomeration between particles, improve the powder flowability, and solve the problem of sticking in the subsequent granulation process; β-cyclodextrin is a hollow cylindrical structure connected by α-1, 4 glycosidic bond with 7 glucose units, which is hydrophobic inside and hydrophilic outside, and can form a cage-like inclusion compound, β-cyclodextrin combines with larfotidine molecules through van der Waals force or hydrogen bond to form host-guest molecular complex, thereby improving the solubility and bioavailability of larfotidine; polyethylene glycol can increase the dispersibility; the adhesion and low hygroscopicity of pullulan can enhance the intermolecular force, at the same time, maintain the stability of the solid dispersion system, and pullulan is non-toxic and non-immunogenic, larfotidine is a receptor antagonist, the film-forming property and gas barrier property of pullulan can protect larfotidine from damage by gastric acid, reduce the perception of bitterness, and increase the acceptability of patients.
[0008] Secondly, hydroxypropyl cellulose as a disintegrant can significantly accelerate tablet disintegration, its pore structure and rough surface can promote water penetration, shorten disintegration time, and be better absorbed by the human body; lactose is used as a filler, and type F100 lactose as a diluent can reduce the hygroscopicity of larfotidine, the disintegrant G200 type lactose and hydroxypropyl cellulose produce a synergistic effect, adjust the disintegration degree of larfotidine, and the two different types of lactose can be compounded to adjust the content and appearance integrity of larfotidine tablets; the addition of stabilizers can balance the easy oxidation of sulfuryl and furan groups in larfotidine; through the synergistic effect of dry rolling and stabilizers, dry rolling densifies the solid dispersion system, increases the particle density, reduces the porosity, reduces the penetration of oxygen and moisture, prevents oxidation, and improves the stability of the microstructure. The particle size is controlled within 50-70 meshes, which can ensure the uniformity of the system and significantly improve the stability.
[0009] Finally, the wet granulation process is adopted, compared with the dry granulation process, the particle density is larger, the compressibility is stronger, and the delamination and loose tablet phenomenon during tabletting can be effectively avoided, which meets the demand of high-stability tablets; cross-linked sodium carboxymethyl cellulose is added as an external disintegrant in the total mixture for tabletting, so that the tablet can disintegrate quickly after being taken, which helps the human body absorption; microcrystalline cellulose as an external filler and binder helps to adjust the tablet compressibility and dose uniformity; magnesium stearate as a lubricant reduces the friction between the particles and the punch die of the tablet machine, prevents sticking, and improves the smoothness of the tablet surface.
[0010] Further, the larfotidine dispersion system comprises the following mass components: 10-15 parts of larfotidine raw material, 1-5 parts of β-cyclodextrin, 20-30 parts of polyethylene glycol, and 2-5 parts of pullulan.
[0011] Furthermore, the premix comprises the following components by weight: 10-15 parts of lafutidine dispersion system, 30-50 parts of hydroxypropyl cellulose, 30-40 parts of lactose F100, 30-40 parts of lactose G200, and 1-3 parts of stabilizer.
[0012] Furthermore, the mass ratio of the premix to the soft material is (20~30):1.
[0013] Furthermore, the amount of microcrystalline cellulose added accounts for 10-15% of the mass of the lafutidine tablets.
[0014] Furthermore, the mass ratio of cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, and magnesium stearate is (3~4):(10~15):(0.3~1).
[0015] Furthermore, the stabilizer is prepared by the following process: Step 1: Mix vitamin C, sodium bicarbonate, and 4-(acetyl chloride)catechol, then add dimethyl sulfoxide, and react at 30-40°C for 6-10 hours. After post-treatment and drying, phenolic vitamin C is obtained. Step 2: Mix phenolic vitamin C, tocopherol, and mannitol, grind and disperse them to obtain a stabilizer.
[0016] Furthermore, the post-processing process is as follows: the reaction solution is added to a 25wt% sodium chloride solution at 5~10℃, extracted with ethyl acetate 5~6 times, the organic phase is mixed and dried with anhydrous sodium sulfate, the ethyl acetate is recovered by vacuum concentration at 60~70℃, and then phenolic vitamin C is obtained by column chromatography.
[0017] In the above-mentioned technical effects, vitamin C is a water-soluble antioxidant, but its own properties are unstable. By phenolic modification of vitamin C, it is endowed with the properties of scavenging free radicals and absorbing ultraviolet rays, thereby enhancing the antioxidant activity of vitamin C. The chlorine atom on 4-(acetyl chloride)catechol undergoes a nucleophilic reaction with the β-hydroxyl group on the furan ring of vitamin C to form a -CO- bond, forming a phenolic hydroxyl group with antioxidant activity. While retaining the core skeleton of vitamin C, the conjugated structure of catechol is introduced, which enhances the free radical scavenging ability. The stabilizer obtained by compounding phenolic vitamin C, tocopherol, and mannitol, tocopherol, as a fat-soluble antioxidant, can inhibit the activity of lipoxygenase by chelating metal ions, delaying rancidity, and can also more gently assist lafutidine in reducing the damage of gastric acid secretion to the gastric mucosa. Mannitol is chemically stable and non-hygroscopic, which can prevent the loss of activity of phenolic vitamin C and tocopherol due to moisture absorption, crystallization, or phase separation during storage. The compounding can improve the compatibility and flowability of the stabilizer with lafutidine.
[0018] Furthermore, the mass ratio of vitamin C, sodium bicarbonate, 4-(acetyl chloride)catechol, and dimethyl sulfoxide is (2~2.5):1:(1.8~2):20.
[0019] Furthermore, the mass ratio of phenolic vitamin C, tocopherol, and mannitol is 1:1:(20~30).
[0020] Furthermore, in step S1, the grinding and dispersing process conditions are: dispersing at a speed of 1200~2400 r / min for 30~40 min.
[0021] Furthermore, in step S1, the particle size of the lafutidine dispersion system is 50-70 mesh.
[0022] Furthermore, in step S2, the mixing process parameters are: stirring frequency 35~40Hz, cutting frequency 35~40Hz, and mixing time 5~10min.
[0023] Furthermore, in step S3, the particle size after wet granulation is 12-15 mesh, and the particle size after granulation is 20-25 mesh.
[0024] Furthermore, in step S4, the tableting process parameters are: turntable speed 10~20 r / min, impeller speed 15~20 r / min, filling depth 8~10 mm, and average tablet thickness 4.9~5.2 mm.
[0025] Furthermore, in step S4, the coating process parameters are as follows: coating is performed using a coating solution with a solid content of 10~20wt%, rotation speed is 5~15r / min, hot air temperature is 60~80℃, material temperature is 40~50℃, atomization pressure is 0.3~0.5MPa, hot air speed is 40~60Hz, exhaust speed is 15~35Hz, and peristaltic pump speed is 6~12r / min.
[0026] Furthermore, the coating solution is Opadry® II.
[0027] Furthermore, in step two, the grinding process parameters are as follows: grinding is performed using a ball mill at a pressure of 0.01~0.5MPa and a rotation speed of 1000~1500r / min for 5~15min.
[0028] The lafutidine tablets prepared by the process of this invention meet the quality standards stipulated in the Pharmacopoeia of the People's Republic of China, and the production operation procedures comply with the Good Manufacturing Practices for Pharmaceuticals.
[0029] Compared with the prior art, the beneficial effects of the present invention are: 1. This invention improves the dissolution rate of lafutidine, increases its bioavailability, reduces particle agglomeration, and improves powder flowability by preparing a solid dispersion system for lafutidine, thereby addressing the issue of sticking and tumbling during subsequent granulation.
[0030] 2. This invention uses lactose as a tablet filler, and lactose F100 as a diluent to reduce the hygroscopicity of lafutidine. Lactose G200 and hydroxypropyl cellulose have a synergistic effect, which can adjust the disintegration degree of lafutidine. The combination of two different types of lactose adjusts the content and appearance integrity of lafutidine tablets. The addition of stabilizers balances the oxidizability of thionyl and furanyl groups in lafutidine, enhancing its stability. Through dry rolling and the synergistic effect of stabilizers, the solid dispersion system is densified, increasing particle density, reducing porosity, reducing oxygen and moisture penetration, preventing oxidation, and improving the stability of the microstructure. The particle size is controlled within the range of 50-70 mesh by sieving, which can ensure the uniformity of the system and significantly improve stability.
[0031] 3. This invention uses a wet granulation process, which, compared to dry granulation, results in higher particle density and stronger compressibility, effectively avoiding delamination and loose tablets during compression, thus meeting the requirements for high-stability tablets; the addition of croscarmellose sodium as an excipient disintegrant enables the tablets to disintegrate rapidly after ingestion, aiding in human absorption.
[0032] 4. This invention modifies vitamin C by phenolation, endowing it with the properties of phagocytizing free radicals and absorbing ultraviolet light, thereby enhancing the antioxidant activity of vitamin C. The stabilizer obtained by compounding phenolic vitamin C, tocopherol, and mannitol, with tocopherol as a fat-soluble antioxidant, can inhibit lipoxygenase activity by chelating metal ions, delaying rancidity, and can also more gently assist lafutidine in reducing gastric acid secretion and damage to the gastric mucosa; mannitol is chemically stable and non-hygroscopic, which can prevent the loss of activity of phenolic vitamin C and tocopherol due to moisture absorption, crystallization, or phase separation during storage. The compounding can improve the compatibility and flowability of the stabilizer with lafutidine. Detailed Implementation
[0033] The technical solutions in the embodiments of the present invention will be clearly and completely described below. 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.
[0034] In the following specific embodiments, unless otherwise specified, the number of “parts” refers to parts by mass; Lafutidine raw material, CAS: 118288-08-7, pharmaceutical grade; Polyethylene glycol, model PEG200; Pullulan, CAS: 9057-02-7; β-Cyclodextrin, CAS: 128446-35-5; Hydroxypropyl cellulose, model EXF; Crosslinked carboxymethyl cellulose sodium, model SD711; Microcrystalline cellulose, model PH102; The coating solution is Opadry® II. Example
[0035] A manufacturing process for highly stable lafutidine tablets includes the following steps: S1: Lafutidine raw material, β-cyclodextrin, polyethylene glycol, and pullulan are mixed and ground and dispersed at 1200 r / min for 30 min. Then, the mixture is dry-rolled and sieved to obtain the lafutidine dispersion system. The particle size of the lafutidine dispersion system is 50 mesh. S2: Mix the lafutidine dispersion system, hydroxypropyl cellulose, lactose F100, and lactose G200 at a stirring frequency of 35Hz and a cutting frequency of 35Hz for 5 minutes. After mixing evenly, add the stabilizer and continue stirring to obtain the premix. S3: Add the premix to the soft material for wet granulation, fluidized drying, and granulation to obtain intermediate particles; the particle size after wet granulation is 12 mesh, and the particle size after granulation is 20 mesh; the mass ratio of premix to soft material is 20:1. S4: Add croscarmellose sodium, microcrystalline cellulose, and magnesium stearate to the intermediate particles, mix, compress, and coat to obtain lafutidine tablets; the amount of microcrystalline cellulose added accounts for 10% of the mass of lafutidine tablets; the mass ratio of croscarmellose sodium, microcrystalline cellulose, and magnesium stearate is 3:10:0.3. The stabilizer is prepared by the following process: Step 1: Mix vitamin C, sodium bicarbonate, and 4-(acetyl chloride)catechol, then add dimethyl sulfoxide and react at 30°C for 6 hours. Then add 100 parts of a 25 wt% sodium chloride solution at 5°C, extract five times with ethyl acetate, mix the organic phases and dry with anhydrous sodium sulfate. Concentrate under reduced pressure at 60°C to recover ethyl acetate, then separate by column chromatography and dry to obtain phenolic vitamin C. The mass ratio of vitamin C, sodium bicarbonate, 4-(acetyl chloride)catechol, and dimethyl sulfoxide is 2:1:1.8:20. Step 2: Mix phenolic vitamin C, tocopherol, and mannitol, and grind them using a ball mill at a pressure of 0.01 MPa and a speed of 1000 r / min for 5 minutes to obtain the stabilizer; the mass ratio of phenolic vitamin C, tocopherol, and mannitol is 1:1:20. The tableting process parameters are: turntable speed 10 r / min, impeller speed 15 r / min, filling depth 8 mm, and average tablet thickness 4.9 mm. The coating process parameters are as follows: coating liquid with a solid content of 10wt% is used for coating, rotation speed is 5r / min, hot air temperature is 60℃, material temperature is 40℃, atomization pressure is 0.3MPa, hot air speed is 40Hz, exhaust speed is 15Hz, and peristaltic pump speed is 6r / min. The soft material comprises the following components by weight: 5 parts of povidone K30, 20 parts of hydroxypropyl cellulose, 7 parts of sodium dodecyl sulfate, and 70 parts of deionized water; The lafutidine dispersion system comprises the following components by weight: 10 parts lafutidine raw material, 1 part β-cyclodextrin, 20 parts polyethylene glycol, and 2 parts pullulan. The premix comprises the following components by weight: 10 parts lafutidine dispersion, 30 parts hydroxypropyl cellulose, 30 parts lactose F100, 30 parts lactose G200, and 1 part stabilizer. Example
[0036] A manufacturing process for highly stable lafutidine tablets includes the following steps: S1: Lafutidine raw material, β-cyclodextrin, polyethylene glycol, and pullulan are mixed and ground and dispersed at 1200 r / min for 30 min. Then, the mixture is dry-rolled and sieved to obtain the lafutidine dispersion system. The particle size of the lafutidine dispersion system is 60 mesh. S2: Mix the lafutidine dispersion system, hydroxypropyl cellulose, lactose F100, and lactose G200 at a stirring frequency of 35Hz and a cutting frequency of 35Hz for 5 minutes. After mixing evenly, add the stabilizer and continue stirring to obtain the premix. S3: Add the premix to the soft material for wet granulation, fluidized drying, and granulation to obtain intermediate particles; the particle size after wet granulation is 14 mesh, and the particle size after granulation is 22 mesh; the mass ratio of premix to soft material is 25:1. S4: Add croscarmellose sodium, microcrystalline cellulose, and magnesium stearate to the intermediate particles, mix, compress, and coat to obtain lafutidine tablets; the amount of microcrystalline cellulose added accounts for 12% of the mass of lafutidine tablets; the mass ratio of croscarmellose sodium, microcrystalline cellulose, and magnesium stearate is 3.5:12:0.8. The stabilizer is prepared by the following process: Step 1: Mix vitamin C, sodium bicarbonate, and 4-(acetyl chloride)catechol, then add dimethyl sulfoxide and react at 30°C for 6 hours. Then add 100 parts of a 25 wt% sodium chloride solution at 5°C, extract five times with ethyl acetate, mix the organic phases and dry with anhydrous sodium sulfate. Concentrate under reduced pressure at 60°C to recover ethyl acetate, then separate by column chromatography and dry to obtain phenolic vitamin C. The mass ratio of vitamin C, sodium bicarbonate, 4-(acetyl chloride)catechol, and dimethyl sulfoxide is 2:1:1.8:20. Step 2: Mix phenolic vitamin C, tocopherol, and mannitol, and grind them using a ball mill at a pressure of 0.01 MPa and a speed of 1000 r / min for 5 minutes to obtain the stabilizer; the mass ratio of phenolic vitamin C, tocopherol, and mannitol is 1:1:25. The tableting process parameters are: turntable speed 10 r / min, impeller speed 15 r / min, filling depth 8 mm, and average tablet thickness 5.0 mm. The coating process parameters are as follows: coating liquid with a solid content of 10wt% is used for coating, rotation speed is 5r / min, hot air temperature is 60℃, material temperature is 40℃, atomization pressure is 0.3MPa, hot air speed is 40Hz, exhaust speed is 15Hz, and peristaltic pump speed is 6r / min. The soft material comprises the following components by weight: 8 parts of povidone K30, 25 parts of hydroxypropyl cellulose, 7 parts of sodium dodecyl sulfate, and 75 parts of deionized water; The lafutidine dispersion system comprises the following components by weight: 12 parts lafutidine raw material, 3 parts β-cyclodextrin, 25 parts polyethylene glycol, and 3 parts pullulan. The premix comprises the following components by weight: 12 parts lafutidine dispersion, 40 parts hydroxypropyl cellulose, 35 parts lactose F100, 35 parts lactose G200, and 2 parts stabilizer. Example
[0037] A manufacturing process for highly stable lafutidine tablets includes the following steps: S1: Lafutidine raw material, β-cyclodextrin, polyethylene glycol, and pullulan were mixed and ground and dispersed at 2400 r / min for 40 min. Then, the mixture was dry-rolled and sieved to obtain the lafutidine dispersion system. The particle size of the lafutidine dispersion system was 70 mesh. S2: Mix the lafutidine dispersion system, hydroxypropyl cellulose, lactose F100, and lactose G200 at a stirring frequency of 40Hz and a cutting frequency of 40Hz for 10 minutes. After stirring evenly, add the stabilizer and continue stirring to obtain the premix. S3: Add the premix to the soft material for wet granulation, fluidized drying, and granulation to obtain intermediate particles; the particle size after wet granulation is 15 mesh, and the particle size after granulation is 25 mesh; the mass ratio of premix to soft material is 30:1. S4: Add croscarmellose sodium, microcrystalline cellulose, and magnesium stearate to the intermediate particles, mix them together, compress them into tablets, and coat them to obtain lafutidine tablets; the amount of microcrystalline cellulose added accounts for 15% of the mass of lafutidine tablets; the mass ratio of croscarmellose sodium, microcrystalline cellulose, and magnesium stearate is 4:15:1. The stabilizer is prepared by the following process: Step 1: Mix vitamin C, sodium bicarbonate, and 4-(acetyl chloride)catechol, then add dimethyl sulfoxide and react at 40°C for 10 hours. Then add 100 parts of a 25 wt% sodium chloride solution at 5°C, extract five times with ethyl acetate, mix the organic phases and dry with anhydrous sodium sulfate. Concentrate under reduced pressure at 60°C to recover ethyl acetate, then separate by column chromatography and dry to obtain phenolic vitamin C. The mass ratio of vitamin C, sodium bicarbonate, 4-(acetyl chloride)catechol, and dimethyl sulfoxide is 2.5:1:2:20. Step 2: Mix phenolic vitamin C, tocopherol, and mannitol, and grind them using a ball mill at a pressure of 0.5 MPa and a speed of 1500 r / min for 15 min to obtain a stabilizer; the mass ratio of phenolic vitamin C, tocopherol, and mannitol is 1:1:30. The tableting process parameters are: turntable speed 20 r / min, impeller speed 20 r / min, filling depth 10 mm, and average tablet thickness 5.2 mm. The coating process parameters are as follows: coating liquid with a solid content of 20wt% is used for coating, rotation speed is 15r / min, hot air temperature is 80℃, material temperature is 50℃, atomization pressure is 0.5MPa, hot air speed is 60Hz, exhaust speed is 35Hz, and peristaltic pump speed is 12r / min. The soft material comprises the following components by weight: 10 parts of povidone K30, 30 parts of hydroxypropyl cellulose, 8 parts of sodium lauryl sulfate, and 80 parts of deionized water; The lafutidine dispersion system comprises the following components by weight: 15 parts lafutidine raw material, 5 parts β-cyclodextrin, 30 parts polyethylene glycol, and 5 parts pullulan. The premix comprises the following components by weight: 15 parts lafutidine dispersion, 50 parts hydroxypropyl cellulose, 40 parts lactose F100, 40 parts lactose G200, and 3 parts stabilizer.
[0038] Comparative Example 1: This comparative example provides a manufacturing process for highly stable lafutidine tablets. Step S2 involves mixing lafutidine raw material, hydroxypropyl cellulose, lactose F100, and lactose G200 at a stirring frequency of 35 Hz and a cutting frequency of 35 Hz for 5 minutes. After mixing evenly, a stabilizer is added, and stirring continues to obtain a premix. The premix comprises the following components by mass: 10 parts lafutidine raw material, 30 parts hydroxypropyl cellulose, 30 parts lactose F100, 30 parts lactose G200, and 1 part stabilizer. The remaining methods are the same as in Example 1.
[0039] Comparative Example 2: This comparative example provides a manufacturing process for highly stable lafutidine tablets. The stabilizer is prepared by the following process: vitamin C, tocopherol, and mannitol are mixed and ground using a ball mill at a pressure of 0.01 MPa and a rotation speed of 1000 r / min for 5 min to obtain the stabilizer; the mass ratio of vitamin C, tocopherol, and mannitol is 1:1:20; the remaining methods are the same as in Example 1.
[0040] Comparative Example 3: This comparative example provides a manufacturing process for highly stable lafutidine tablets. The premix comprises the following components by weight: 10 parts lafutidine dispersion, 30 parts hydroxypropyl cellulose, 30 parts lactose F100, and 30 parts lactose G200. The remaining methods are the same as in Example 1.
[0041] Comparative Example 4: This comparative example provides a production process for highly stable lafutidine tablets. The premix includes the following components by mass: 10 parts lafutidine raw material, 30 parts hydroxypropyl cellulose, 30 parts lactose F100, and 30 parts lactose G200. Step S3 involves dry granulation of the premix to obtain intermediate particles. The remaining methods are the same as in Example 1.
[0042] experiment: Lafutidine tablets obtained in Examples 1-3 and Comparative Examples 1-4 were prepared into samples, and their performance was tested and the test results were recorded: Stability testing: Using GB / T 39476-2020 as the reference standard, stability tests were conducted on the samples, and the data were recorded. Influencing Factors Experiment: 1) Strong light irradiation test: Place the sample in a light box and place it under a light intensity of 5000 Lx for 10 days, and determine its loss on drying (tablets) and relative content (lafutidine). 2) High temperature test: Place the sample in a sealed clean container and place it at 60℃ for 10 days, then determine its loss on drying and relative content; 3) High humidity test: Place the sample in a constant humidity sealed container and place it at 25℃ and 90% relative humidity for 10 days, and determine its loss on drying and relative content. (2) Accelerated test: The sample was placed at 40℃ and 65±5% relative humidity for 6 months, and its loss on drying and relative content were tested; (3) Long-term test: The sample was placed at room temperature and relative humidity of 60±10% for 12 months, and its drying loss and relative content were tested.
[0043] Cost-performance ratio comparison table
[0044] Based on the data in the table above, the following conclusions can be clearly drawn: The lafutidine tablets obtained in Examples 1-3 were compared with those in Comparative Examples 1-4. The test results show that: Compared with the comparative examples, the lafutidine tablets obtained in Examples 1-3 showed less loss on drying after stability testing, higher relative content, and better stability.
[0045] Compared with Example 1, the lafutidine tablets obtained in Comparative Example 1 showed greater weight loss and lower relative content after drying in the stability test. This indicates that the premix prepared by mixing lafutidine raw material with excipients is insufficient to maintain its stability when a stabilizer is added, demonstrating the advantage of preparing lafutidine raw material into a stable solid dispersion system.
[0046] Compared with Example 1, the lafutidine tablets obtained in Comparative Example 2 showed greater weight loss and lower relative content after drying in the stability test. This indicates that the stabilizer obtained by directly mixing vitamin C with tocopherol and mannitol without modifying vitamin C is easily oxidized and cannot meet the long-term stability requirements of a stabilizer. This demonstrates the advantages of modifying vitamin C.
[0047] Compared with Example 1, the lafutidine tablets obtained in Comparative Example 3 showed greater weight loss and lower relative content after drying in the stability test. This indicates that simply preparing the lafutidine raw material into a stable solid dispersion system without adding a stabilizer is insufficient to meet the high stability requirements of lafutidine, demonstrating the advantage of adding a stabilizer in this invention.
[0048] Compared with Example 1, the lafutidine tablets obtained in Comparative Example 4 showed greater weight loss and lower relative content after drying in the stability test. This indicates that the stability of lafutidine tablets prepared by dry granulation after blending lafutidine raw material and excipients is significantly reduced. This shows that the dry granulation process results in low particle density, reduced compressibility, easy delamination and loose tablets during compression, and easy penetration of oxygen and moisture, which cannot meet the requirements for high stability. This verifies the advantages of the preparation process of the present invention.
[0049] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.
Claims
1. A process for the production of highly stable ranitidine tablets, characterized by: The production process comprises the following steps: S1: mixing raw material of lafutidine, β-cyclodextrin, polyethylene glycol and pullulan, grinding and dispersing, dry rolling, screening, and obtaining lafutidine dispersion system; S2: mixing lafutidine dispersion system, hydroxypropyl cellulose, lactose F100 and lactose G200, and stirring uniformly to obtain premix; S3: adding the premix into soft material to perform wet granulation, fluidized drying, and whole granulation to obtain intermediate granules; S4: adding crosslinked sodium carboxymethyl cellulose, microcrystalline cellulose and magnesium stearate into the intermediate granules to perform total mixing, tabletting and coating to obtain lafutidine tablets.
2. A process for the production of highly stable ranitidine tablet as claimed in claim 1, wherein: The lafutidine dispersion system comprises the following components by mass: 10-15 parts of raw material of lafutidine, 1-5 parts of β-cyclodextrin, 20-30 parts of polyethylene glycol and 2-5 parts of pullulan.
3. A process for the production of highly stable ranitidine tablet as claimed in claim 1 wherein: In step S2, after stirring uniformly, a stabilizer is added, and after continuous stirring, the premix is obtained; the premix comprises the following components by mass: 10-15 parts of lafutidine dispersion system, 30-50 parts of hydroxypropyl cellulose, 30-40 parts of lactose F100, 30-40 parts of lactose G200 and 1-3 parts of stabilizer.
4. A process for the production of highly stable ranitidine tablet as claimed in claim 3, wherein: The stabilizer is prepared by the following process: Step one: mixing vitamin C, sodium bicarbonate and 4-(acetyl chloride) catechol, then adding dimethyl sulfoxide, reacting at a temperature of 30-40℃ for 6-10 hours, post-treatment and drying to obtain phenolic vitamin C; Step two: mixing phenolic vitamin C, tocopherol and mannitol, grinding and dispersing to obtain the stabilizer.
5. A process for the production of highly stable ranitidine tablet as claimed in claim 4, wherein: The mass ratio of vitamin C, sodium bicarbonate, 4-(acetyl chloride) catechol and dimethyl sulfoxide is (2-2.5) : 1 : (1.8-2) :
20.
6. A process for the production of highly stable ranitidine tablet as claimed in claim 4, wherein: The mass ratio of phenolic vitamin C, tocopherol and mannitol is 1 : 1 : (20-30).
7. A process for the production of highly stable ranitidine tablet as claimed in claim 1 wherein: In step S3, the particle size of the wet granulation is 12-15 mesh, and the particle size of the whole granulation is 20-25 mesh.
8. A process for the production of highly stable ranitidine tablet as claimed in claim 1 wherein: In step S4, the process parameters of tabletting are as follows: the rotation speed of the turntable is 10-20 r / min, the rotation speed of the impeller is 15-20 r / min, the filling depth is 8-10 mm, and the average thickness of the tablets is 4.9-5.2 mm.
9. A process for the production of highly stable ranitidine tablet as claimed in claim 1 wherein: In step S4, the process parameters of coating are as follows: the coating liquid with a solid content of 10-20 wt% is used for coating, the rotation speed is 5-15 r / min, the hot air temperature is 60-80℃, the material temperature is 40-50℃, the atomization pressure is 0.3-0.5 MPa, the hot air speed is 40-60 Hz, the exhaust speed is 15-35 Hz, and the rotation speed of the peristaltic pump is 6-12 r / min.
10. A highly stable tablet of lafutidine, characterized in that: The production process is used to produce the high-stability lafutidine tablets according to any one of claims 1-9.