A method for preparing diazepam tablets

Abstract

This invention discloses a method for preparing diazepam tablets, comprising the following steps: S1. Diazepam is mixed with corn starch, and 5% corn starch slurry is sprayed in under stirring to obtain wet granules. After being air-dried at room temperature until surface dry, the granules are sized to 0.5-1 mm; S2. The sized wet granules are added to a pelletizing machine, along with dicalcium phosphate and corn starch. The pellets are then sprayed with 5% corn starch slurry and sized to a particle size of 1.6-2 mm; S3. The agglomerated material from step S2 is dried and sized to obtain 1.5 mm granules. After total mixing, the granules are compressed into tablets to obtain diazepam tablets. The preparation method uses corn starch slurry to pre-coat small-diameter granules using a wet method, and then pelletizes them to obtain coarser granules. This method can reasonably control the granulation quality of diazepam and effectively avoid the problems of over-granulation or insufficient granulation.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine tablet preparation, more particularly, the present application relates to a preparation method of diazepam tablet. BACKGROUND

[0002] Diazepam, chemical formula is C 16 H 13 ClN2O, is listed as the second type of psychotropic drug control, clinically used for treating: ① anxiety and various functional neurosis; ② insomnia, especially for the treatment of anxiety insomnia; ③ epilepsy: can be combined with other antiepileptic drugs, treatment of grand mal or petit mal, control of status epilepticus should be intravenous injection. ④ Convulsions caused by various reasons, such as eclampsia, tetanus, high fever convulsions in children, etc.; ⑤ Cerebrovascular accident or spinal cord injury central muscle rigidity or lumbar muscle strain, endoscopic examination and other causes of muscle spasm; ⑥ other: migraine, muscle tension headache, hiccups, inflammation caused by reflex muscle spasm, panic disorder, alcohol withdrawal syndrome, can also be used for the treatment of familial, senile and idiopathic tremor, can be used for preoperative administration.

[0003] Diazepam is a long-acting drug, and the commonly used dosage forms include injection and tablet. The tablet usually adopts wet granulation, which is a mature granulation technology. Because the equipment is simple, the granules have strong wear resistance and good compression molding, and have been used until now. The ordinary wet granulation is to mix the active ingredients and the optional pharmaceutically acceptable adjuvant in a metering ratio, and then add the solution of the binder, so as to form wet granules with a certain particle size by stirring or shearing under certain external force. Then, wet granulation, drying and finally dry granulation are carried out to obtain dry granules suitable for tabletting.

[0004] The factors affecting wet granulation usually include the particle size and crystal form of diazepam, the binder used and the properties of the adjuvant. Generally, the greater the viscosity of diazepam and the adjuvant or the greater the amount and the higher the concentration of the binder, the stronger the adhesion between diazepam and the adjuvant, the more sufficient the granulation, and the greater the particle size and hardness. For the process parameters, the stirring paddle speed, the granulating knife speed and the granulating time of the wet granulator have great influence on the granulation. The greater the stirring speed and the longer the granulating time, the more sufficient the granulation. In the process of wet granulation, there are also excessive granulation phenomena due to excessive amount of binder, too fast stirring paddle speed or too long granulating time, and insufficient granulation phenomena due to insufficient amount of binder, too slow stirring paddle speed or too short granulating time. Excessive granulation leads to the generation of lumps and poor flowability, and insufficient granulation leads to a large amount of fine powder, which has an influence on the granulation or tabletting process of diazepam, and is not conducive to the high-quality production of diazepam tablets. SUMMARY

[0005] In view of this, the present invention provides a method for preparing diazepam tablets, which solves the defects in the existing wet granulation process, such as over-granulation or insufficient granulation, which affects the granulation or tableting process of diazepam, thereby affecting production efficiency and quality.

[0006] Based on this, the technical solution of the present invention is as follows:

[0007] A method for preparing diazepam tablets, characterized by comprising the following steps:

[0008] S1. Diazepam and corn starch are mixed in equal amounts, and 5% corn starch slurry is sprayed in while stirring to obtain wet granules. After being air-dried at room temperature until surface dry, the granules are sized to 0.5-1 mm.

[0009] S2. Add the sized granules to the pelletizer, along with dicalcium phosphate and corn starch. Spray with 5% corn starch slurry to pelletize until the particle size reaches 1.6-2mm.

[0010] S3. The agglomerated material from step S2 is dried and granulated to obtain 1.5mm particles, which are then mixed and compressed into tablets to obtain diazepam tablets.

[0011] Further, the raw material components, by weight, are: 1 part diazepam, 10-20 parts corn starch, 5-12 parts 5% corn starch slurry, and 10-20 parts dicalcium phosphate; wherein the ratio of the amount of 5% corn starch slurry used in steps S1 and S2 is 1:(2-5).

[0012] Further, the raw material components, by mass, are: 1 part diazepam, 17 parts corn starch, 8 parts total of 5% corn starch slurry, and 12 parts dicalcium phosphate; wherein the ratio of the amount of 5% corn starch slurry used in steps S1 and S2 is 1:3.

[0013] Furthermore, the air volume during the drying process in step S1 is 500-800 m³ / h. 3 / h, air drying time is 10-25min.

[0014] Furthermore, in step S2, the rotation speed of the baller is 1-5 revolutions per second, 5-15 seconds per spray, and the spray frequency is 1-2 times per minute.

[0015] Further, in step S3, magnesium stearate, silicon dioxide, and sodium dodecyl sulfate are added and mixed with the granules before tableting. The amounts are calculated as follows: 1 part diazepam, 0.5-1 part magnesium stearate, 2-4 parts silicon dioxide, and 0.05-0.1 parts sodium dodecyl sulfate.

[0016] Furthermore, the drying process described in step S3 uses a boiling dryer, with the temperature controlled at 50-60℃.

[0017] Preferably, the moisture content of the dried material is less than 3.0 wt%.

[0018] Furthermore, the tableting process described in step S3 employs a rotary tablet press. Shallow concave stamping sheet.

[0019] The beneficial effects of this invention are as follows:

[0020] 1. The preparation method of the present invention obtains small-diameter granules by pre-coating with corn starch slurry using a wet method, and then obtains coarser granules by pelleting. This method can reasonably control the granulation quality of diazepam and effectively avoid the problems of over-granulation or insufficient granulation.

[0021] 2. The preparation method described in this invention produces diazepam tablets with stable quality and low dust content, providing a new direction for the industrial production of diazepam preparations. Attached Figure Description

[0022] Figure 1 This is a flowchart of the preparation method of diazepam tablets according to the present invention. Detailed Implementation

[0023] 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.

[0024] In one embodiment, such as Figure 1 The present invention provides a method for preparing diazepam tablets, comprising the following steps:

[0025] S1. Diazepam and corn starch are mixed in equal amounts, and 5% corn starch slurry is sprayed in while stirring to obtain wet granules. After being air-dried at room temperature until surface dry, the granules are sized to 0.5-1 mm.

[0026] S2. Add the sized wet granules to the pelletizer, along with dicalcium phosphate and corn starch. Spray with 5% corn starch slurry to pelletize until the particle size reaches 1.6-2mm.

[0027] S3. The agglomerated material from step S2 is dried and granulated to obtain 1.5mm particles, which are then mixed and compressed into tablets to obtain diazepam tablets.

[0028] The above preparation method involves premixing and dispersing diazepam in corn starch slurry, followed by air-drying to surface dryness to form a water-containing core that is not easily sheared. This results in high uniformity during the first granulation. During pelleting, the disintegrant calcium phosphate is coated onto the surface of the microspheres, and then a corn starch slurry is used to coat them, forming a uniform coating structure and further increasing the particle size. This ensures uniform particle growth and reduces dust generation after drying and tableting. The corn starch slurry is chosen to coat the active ingredients, and the external corn starch provides better adhesion for other excipients. Spraying is used to avoid dust generation during granulation.

[0029] In a preferred embodiment, the raw materials used in the preparation of the above diazepam tablets are configured according to the prescription requirements. Optionally, the raw material components, by weight, are: 1 part diazepam, 10-20 parts corn starch, 5-12 parts 5% corn starch slurry, and 10-20 parts dicalcium phosphate; wherein the ratio of the amount of 5% corn starch slurry used in step S1 to S2 is 1:(2-5). Preferably, the raw materials are: 1 part diazepam, 17 parts corn starch, 8 parts 5% corn starch slurry, and 12 parts dicalcium phosphate; wherein the ratio of the amount of 5% corn starch slurry used in step S1 to S2 is 1:3.

[0030] In a preferred embodiment, the air volume during the drying process in step S1 is 500-800 m³ / h. 3 / h, air drying time is 10-25min; room temperature refers to a temperature of 15-25℃. Air drying at room temperature allows for reasonable control of surface dryness and internal moisture, which facilitates better granulation.

[0031] In a preferred embodiment, step S1, which involves granulation, specifically involves setting a screen of a specified size in a granulator and passing the wet granules, which have been air-dried at room temperature, through the screen at a specified rotation speed to achieve the target particle size.

[0032] In a preferred embodiment, the granulator speed in step S2 is 1-5 revolutions per second, 5-15 seconds per spray, and the spray frequency is 1-2 times per minute.

[0033] In a preferred embodiment, in step S3, magnesium stearate, silicon dioxide, and sodium dodecyl sulfate are added before tableting and mixed with the granules. The amount of magnesium stearate is 0.5-1 part, silicon dioxide is 2-4 parts, and sodium dodecyl sulfate is 0.05-0.1 parts, based on 1 part diazepam. The excipients added before tableting can improve the lubricity of the granules, ensure the quality of tableting, and prevent disintegration.

[0034] In a preferred embodiment, the drying process in step S3 uses a fluidized bed dryer, with the temperature controlled at 50-60°C; preferably, the moisture content of the dried material is less than 3.0 wt%.

[0035] In a preferred embodiment, the tableting process in step S3 employs a rotary tablet press. Shallow concave stamping sheet.

[0036] In this solution, the pelletizing machine used is a common pelletizing machine or a round pot granulator. The spray enters from the round pot opening to further suppress the escape of dust.

[0037] In this method, the final diazepam tablets refer to standard tablets containing 2.5 mg of diazepam. The yield can be determined based on the amount of diazepam used; for example, if 2.5 kg of diazepam is used, 1 million tablets can be produced. The above preparation method effectively controls the granulation quality of diazepam, avoiding over-granulation or insufficient granulation. The resulting diazepam tablets have a low breakage rate and high compression efficiency, providing a new direction for the industrial production of diazepam tablet formulations.

[0038] In this scheme, the particle size is controlled by sampling with a sieve analyzer. The specific required particle size distribution is controlled by adjusting the granulation process according to the range into which the sample falls. As common sense or experience of those skilled in the art, based on the pattern of particle size change, sampling and testing can be carried out in the early, middle or late stages of granulation.

[0039] Example 1

[0040] The composition of diazepam tablets is as follows: 2.5 kg of diazepam, 42.5 kg of corn starch, 20 kg of corn starch paste with a content of 5 wt%, 30 kg of dicalcium phosphate, 1.5 kg of magnesium stearate, 6 kg of silicon dioxide, and 0.2 kg of sodium dodecyl sulfate.

[0041] 1) Mix diazepam and corn starch in a 1:1 ratio, and while stirring, spray in 5 kg of 5% corn starch slurry to obtain wet granules. Cure at room temperature for 800 minutes. 3 Ventilate for 10 minutes at an air volume of / h, then granulate to 0.5-1mm using a granulator;

[0042] 2) Add the sized granules to the pelletizing machine, add dicalcium phosphate, the remaining corn starch and 5% corn starch slurry, and spray to pelletize until the particle size reaches 1.6-2mm; the pelletizing machine speed is 3 revolutions / second, the spraying frequency is 1 time / minute, 6 seconds / time;

[0043] 3) The agglomerated material in step 2) is placed in a fluidized bed dryer and dried at 55°C until the moisture content is less than 3%. The granules are sized to obtain 1.5 mm particles, which are then mixed with magnesium stearate, silicon dioxide, and sodium dodecyl sulfate and compressed into tablets to obtain diazepam tablets.

[0044] Example 2

[0045] The composition of diazepam tablets is as follows: 2.5 kg of diazepam, 47.5 kg of corn starch, 24 kg of corn starch paste with a content of 5 wt%, 25 kg of dicalcium phosphate, 1.3 parts of magnesium stearate, 6 kg of silicon dioxide, and 0.2 kg of sodium dodecyl sulfate.

[0046] 1) Mix diazepam and corn starch in a 1:1 ratio, and while stirring, spray in 6 kg of 5% corn starch slurry to obtain wet granules. Cure at room temperature for 600 minutes. 3 Ventilate for 20 minutes at an air volume of / h, then granulate to 0.5-1mm using a granulator;

[0047] 2) Add the sized granules to the pelletizing machine, add dicalcium phosphate, the remaining corn starch and 5% corn starch slurry, and spray to pelletize until the particle size reaches 1.6-2mm; the pelletizing machine speed is 2 rpm, the spraying frequency is 2 times / minute, and 7 seconds / time;

[0048] 3) The agglomerated material in step 2) is placed in a fluidized bed dryer and dried at 55°C until the moisture content is less than 3%. The granules are sized to obtain 1.5 mm particles, which are then mixed with magnesium stearate, silicon dioxide, and sodium dodecyl sulfate and compressed into tablets to obtain diazepam tablets.

[0049] Example 3

[0050] The composition of diazepam tablets is as follows: 2.5 kg of diazepam, 30 kg of corn starch, 30 kg of corn starch paste with a content of 5 wt%, 40 kg of dicalcium phosphate, 2.5 parts of magnesium stearate, 7 kg of silicon dioxide, and 0.2 kg of sodium dodecyl sulfate.

[0051] 1) Mix diazepam and corn starch in a 1:1 ratio, and while stirring, spray in 6 kg of 5% corn starch slurry to obtain wet granules. Cure at room temperature for 500 minutes. 3 Ventilate for 25 minutes at an air volume of / h, then granulate to 0.5-1mm using a granulator;

[0052] 2) Add the sized granules to the pelletizing machine, add dicalcium phosphate, the remaining corn starch and 5% corn starch slurry, and spray to pelletize until the particle size reaches 1.6-2mm; the pelletizing machine speed is 5 rpm, the spraying frequency is 1 time / minute, 5 seconds / time;

[0053] 3) The agglomerated material in step 2) is placed in a fluidized bed dryer and dried at 55°C until the moisture content is less than 3%. The granules are sized to obtain 1.5 mm particles, which are then mixed with magnesium stearate, silicon dioxide, and sodium dodecyl sulfate and compressed into tablets to obtain diazepam tablets.

[0054] Comparative Example 1

[0055] The overall composition of diazepam is the same as in Example 1. Using the traditional method, 2.5 kg of diazepam is mixed with 17.5 kg of corn starch, then pulverized and sieved to 100 mesh. Then, 25 kg of starch, 30 kg of dicalcium phosphate, and 20 kg of 5 wt% corn starch slurry are added and wet granulated in a granulator. The granules are then dried at 55°C in a fluidized bed dryer until the moisture content is below 3%. Finally, the granules are granulated to 1.5 mm particles using a granulator. Subsequent steps are the same as in Example 1.

[0056] Comparative Example 2

[0057] Replace the room temperature ventilation method in step 1) of Example 1 with 55°C hot air drying, 500m 3 Ventilate for 3 minutes at an airflow rate of / h. The composition and other preparation process are the same as in Example 1.

[0058] Experimental Example

[0059] 1. The yield of particles granulated to 1.5 mm in Examples 1-3 and Comparative Examples 1-2 was statistically analyzed. The granulation yield represents the ratio of particles reaching the target particle size to the total feed amount (dry weight), serving as a basis for judging whether there was excessive or insufficient granulation. The results are shown in Table 1.

[0060] Table 1:

[0061] Group Whole grain yield % Example 1 96.3 Example 2 95.2 Example 3 95.6 Comparative Example 1 86.2 Comparative Example 2 90.8

[0062] It is easy to see from Table 1 that the yield of the final granulation using the schemes of Examples 1-3 is significantly higher than that of Comparative Examples 1 and 2. Comparative Example 1 uses a traditional granulator for wet granulation, which leads to over-granulation or insufficient granulation. In Comparative Example 2, the use of hot air drying in step 1) inevitably reduces the moisture content inside the particles, affecting the growth of particle size.

[0063] Finally, it should be noted that although the present invention has been described in detail above with general descriptions and specific embodiments, the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A process for the preparation of diazepam tablets, characterized in that, It comprises the following steps: S1. After blending diazepam with an equal amount of corn starch, spray 5% corn starch slurry under stirring and prepare wet granules, and then dry to tack dry at room temperature, and then size to 0.5-1mm; S2. Add the sized wet granules to the balling machine, add calcium hydrogen phosphate, and the rest of the corn starch, and ball under the spraying of the rest of the 5% corn starch slurry to a particle size of 1.6-2mm; S3. Dry and size the material formed in step S2 to obtain 1.5mm granules, and then tablet after general mixing to obtain diazepam tablets; The raw material components are diazepam 1 part, total corn starch 10-20 parts, total 5% corn starch slurry 5-12 parts, and calcium hydrogen phosphate 10-20 parts; wherein the amount of 5% corn starch slurry in steps S1 and S2 is 1:(2-5). The drying process in step S3 uses a fluidized bed dryer, and the temperature is controlled at 50-60℃, and the moisture content of the dried material is less than 3.0wt%.

2. The production method according to claim 1, characterized by, The raw material components are diazepam 1 part, corn starch 17 parts, total 5% corn starch slurry 8 parts, and calcium hydrogen phosphate 12 parts; The amount of 5% corn starch slurry in steps S1 and S2 is 1:

3.

3. The preparation method according to claim 1, characterized in that, The air flow in the air drying process in step S1 is 500-800 m 3 / h, and the air drying time is 10-25 min.

4. The production method according to claim 1, characterized by, The speed of the balling machine in step S2 is 1-5 revolutions / second, 5-15 seconds / turn, and the spraying frequency is 1-2 times / minute.

5. The method of claim 1, wherein, In step S3, magnesium stearate, silicon dioxide, and sodium lauryl sulfate are added before tabletting and mixed with the granules. Based on 1 part of diazepam, 0.5-1 parts of magnesium stearate, 2-4 parts of silicon dioxide, and 0.05-0.1 parts of sodium lauryl sulfate are added.

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