Preparation method of metoclopramide tablet

Abstract

The invention discloses a preparation method of metoclopramide tablets, which comprises the following steps: uniformly mixing a metoclopramide tablet raw material main drug, a filler and a lubricant to prepare premixed powder; performing dry granulation on the premixed powder in a dry granulator to obtain dry granules of metoclopramide tablets; uniformly mixing the dry metoclopramide tablet particles with an external lubricant to prepare intermediate particles; and tabletting the metoclopramide tablet intermediate particles to prepare the metoclopramide tablet. The composition is simple, only contains the main drug, the filler and the lubricant, is safe to use, and does not increase the burden of a patient. The preparation process is simple and convenient to operate, is a dry granulation process, and is white tablets in drug character.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine preparation, and particularly relates to a preparation method of metoclopramide tablets. BACKGROUND

[0002] Metoclopramide is a dopamine receptor antagonist, which is widely used for treating nausea, vomiting and gastrointestinal motility disorders. Traditional metoclopramide tablets are prepared by using a powder direct compression process, which has the defects of poor flowability and unstable dissolution. The dry granulation process solves the problems of flowability, uniformity and safety through physical modification (granule reconstruction), and has cost-effectiveness. The application breaks through the above technical bottlenecks through innovative formula design and process parameter optimization. The molecular formula of metoclopramide hydrochloride is C 14 H 22 ClN3O2•HCl•H2O, the molecular weight is 354.27, and the structural formula is: Metoclopramide is a dopamine D2 receptor antagonist, which is rapidly absorbed after oral administration, reaches a peak blood drug concentration at 0.5-1 hour, has a bioavailability of about 80%, and has a plasma protein binding rate of about 30%. The half-life is relatively short (4-6 hours), and the effective blood drug concentration needs to be maintained by administering 3-4 times a day, but frequent administration can easily cause extrapyramidal reactions (such as dystonia, tremor) and central nervous system side effects such as drowsiness. In addition, metoclopramide belongs to BCS III drugs (high solubility and low permeability), and its absorption is easily affected by the rate of gastric emptying, and uneven dissolution of ordinary tablets can cause fluctuations in efficacy.

[0003] In order to improve its clinical defects, research focuses on the optimization of the preparation process, especially through the improvement of the granulation process (such as dry granulation) to improve the dissolution uniformity, reduce the amount of excipients and the complexity of production. There is a powder direct compression process at present, but there are still the following problems: ‌Mixing uniformity risk: metoclopramide has a low dose, and a large amount of diluent needs to be added for powder direct compression, so it is difficult to mix uniformly and easy to cause dose deviation; ‌Dust pollution: the raw material powder has high fineness, and dust flies during tabletting, which has the risk of cross-contamination and affects the health of the operators; Dissolution influence: the tablets formed by powder direct compression will disintegrate rapidly when meeting the medium, the disintegration time is accelerated, and the early dissolution is rapid.

[0004] The existing methoclopramide tablet preparation technology generally has problems such as unstable process, uneven dissolution and auxiliary material risk. By optimizing the dry granulation parameters (such as roller pressure, stepwise addition of lubricant), simplifying the auxiliary material combination (mannitol-microcrystalline cellulose system), high-efficiency production and quality control can be realized simultaneously. This technical path is especially suitable for generic drug varieties that need to quickly pass consistency evaluation, and provides a new idea for improving patient tolerance. SUMMARY

[0005] The purpose of the present application is to provide a preparation method of methoclopramide tablets to solve the problems raised in the background art.

[0006] To achieve the above-mentioned purpose, the present application provides the following technical solution: a preparation method of methoclopramide tablets, the specific steps are as follows: S1: The hydrochloric acid methoclopramide is crushed by a 60-mesh hammer; the mannitol is sieved through a 40-mesh sieve, and the stearic acid is sieved through a 60-mesh sieve for use; S2: The hydrochloric acid methoclopramide, mannitol, microcrystalline cellulose, and stearic acid and magnesium stearate are weighed according to the prescription amount; S3: The materials weighed in S2 are put into a hopper mixer and mixed at a speed of 10 rpm for 10 min to obtain a premixed powder; S4: The premixed powder prepared in S3 is placed in a dry granulator, and the vertical speed is set to 10-15 r / min, the roller speed is set to 5-10 r / min, the main pressure is set to 8-10 MPa, and the whole granulation speed is set to 100-150 r / min after granulation, and then the granulation is sieved through a 1.0 mm sieve.

[0007] S5: The stearic acid and the remaining magnesium stearate in the granules prepared in S4 are added, and mixed at a speed of 10 rpm for 5 min.

[0008] S6: The intermediate granules prepared in S5 are pressed into tablets using a 10 mm x 4.5 mm special-shaped punch, and methoclopramide tablets are prepared.

[0009] Preferably, the mass percentage of the methoclopramide tablet raw material in S1 is 1%-10% of hydrochloric acid methoclopramide, 10%-95% of the filler composed of mannitol and microcrystalline cellulose, and 0.5%-2.5% of the lubricant composed of stearic acid and magnesium stearate.

[0010] Preferably, in S4, the vertical speed is 10-15 r / min, the roller speed is 5-10 r / min, the main pressure is 8-10 MPa, and the whole granulation speed is 100-150 r / min after granulation, and then the granulation is sieved through a 1.0 mm sieve.

[0011] Preferably, in S5, the magnesium stearate is 30%-60% of the total magnesium stearate.

[0012] Preferably, the S6 is controlled to 50-100N, and the tablet weight difference is ≤±5%.

[0013] Compared with the prior art, the present application has the following advantages: The prepared metoclopramide tablets adopt a dry granulation process, the prescription design is scientific and reasonable, the composition is simple and efficient, and only contains the main drug metoclopramide, a suitable filler and a necessary lubricant; the prescription fully considers the safety of drug use while ensuring the efficacy of the drug, and the selected excipients are all substances recorded in the pharmacopoeia and widely used in clinical practice, which are safe and will not cause additional physical burden or potential risks to patients.

[0014] The dry granulation process has simple and easy-to-operate operation process and significant operability. The core step is to accurately mix the main drug and excipients according to the prescription ratio, and then compress into tablets through a dry granulator, without adding solvent during the process, which avoids the drug quality problems caused by solvent residues in traditional wet granulation. The process not only greatly shortens the production cycle, but also reduces energy consumption and production cost.

[0015] The metoclopramide tablets prepared by the process have an appearance that meets the requirements of the pharmacopoeia, and are in the form of uniform tablets with smooth surface and consistent color.

[0016] In terms of drug dissolution test, the self-prepared metoclopramide tablets and the reference preparation were placed in the same dissolution medium for comparative test. The results showed that the dissolution curves of the two were highly consistent and the dissolution rates were similar within the specified time, which fully indicated that the drug dissolution behavior of the self-prepared metoclopramide tablets was consistent with that of the reference preparation, which could ensure the effective absorption and utilization of the drug in the body, thereby exerting stable drug efficacy. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 is a comparison diagram of the dissolution curves of Example 1 of the present application and the reference preparation; Figure 2 is a comparison diagram of the dissolution curves of Example 1, Example 2 and the reference preparation. DETAILED DESCRIPTION

[0018] The technical solutions in the embodiments of the present application will be described in detail below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, not all. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0019] Example 1 Prescription information Preparation method (1) Material pretreatment: the raw material was hammer milled to 60 mesh, and used as needed; mannitol was passed through a 40 mesh sieve, and stearic acid was passed through a 60 mesh sieve.

[0020] (2) Weighing: the prescribed amount of methoclopramide hydrochloride, mannitol, microcrystalline cellulose, stearic acid, and magnesium stearate was weighed.

[0021] (3) Mixing: methoclopramide hydrochloride, mannitol, and microcrystalline cellulose were mixed for 10 min, and stearic acid and magnesium stearate were added and mixed for 5 min; (4) Tabletting: 10 mm x 4.5 mm irregular shaped punches were used, and the weight difference was controlled to ±5%, and the hardness was 50-100 N.

[0022] Dissolution determination: The dissolution of the sample was determined according to the determination method of the dissolution of methoclopramide tablets in the Chinese Pharmacopoeia 2025 edition, and the medium was hydrochloric acid solution, and compared with the reference preparation REGLAN® (licensee: ANI PHARMACEUTICALS INC).

[0023] The results of the routine detection of the preparation of Example 1 are shown in Table 1, the dissolution results are shown in Table 2, and the dissolution curve is shown in Figure 1 .

[0024] Table 1. Comparison of routine detection results of Example 1 and reference preparation preparation Table 2. Comparison of dissolution detection of Example 1 and reference preparation After routine detection and dissolution detection, the preparation process of Example 1 was smooth, the tablet weight difference was small, but the disintegration time and dissolution were different from the reference preparation.

[0025] Example 2 Prescription information Preparation method (1) Material pretreatment: the raw material was hammer milled to 60 mesh, and used as needed; mannitol was passed through a 40 mesh sieve, and stearic acid was passed through a 60 mesh sieve.

[0026] (2) Weighing: the prescribed amount of methoclopramide hydrochloride, mannitol, microcrystalline cellulose, and magnesium stearate (added inside) was weighed.

[0027] (3) Mixing: mannitol, methoclopramide hydrochloride, magnesium stearate (added inside), and microcrystalline cellulose were sequentially added to the hopper mixer, the mixing speed was set to 10 rpm, and the mixing time was 10 min.

[0028] (4) Granulation: The premixed powder is granulated using a dry granulator. The vertical rotation speed is set to 10~15 r / min, the pressure roller speed is set to 5~10 r / min, the main pressure is set to 8~10 MPa, and the granulation speed is set to 100~150 r / min. After granulation, the powder is granulated through a 1.0 mm sieve.

[0029] (5) Total mixing: Calculate the amount of stearic acid and magnesium stearate (added) according to the formula, add stearic acid and magnesium stearate (added), set the mixing speed to 10 rpm, mix for 5 min, and then discharge.

[0030] (6) Pressing: Use 10mm×4.5mm irregular stamping sheets, control the weight difference ±5%, and the hardness 50~100N.

[0031] Dissolution test: The dissolution rate of the sample was determined according to the method for determining the dissolution rate of metoclopramide tablets in the 2025 edition of the Chinese Pharmacopoeia, using hydrochloric acid solution as the medium, and compared with the reference preparation REGLAN® (certified by ANI PHARMACEUTICALS INC).

[0032] The routine testing results of the formulation in Example 2 are shown in Table 3, the dissolution results are shown in Table 4, and the dissolution curve is shown in Table 5. Figure 2 As shown.

[0033] Table 3. Comparison of routine test results of Example 1, Example 2 and reference formulation. Table 4. Comparison of dissolution rates of Example 1, Example 2, and the reference formulation. Based on routine formulation testing and dissolution testing, the formulation of Example 2 was deemed to have the same routine testing results and dissolution rate as the reference formulation REGLAN®.

[0034] The test results showed that in hydrochloric acid medium, the dissolution behavior of Example 1 (direct powder compression process) was significantly faster than that of the reference formulation, which was inconsistent with the reference formulation; after dry granulation, the dissolution behavior of Example 2 (dry granulation process) in hydrochloric acid medium was similar to that of the reference formulation, which indicates that after dry granulation, the dissolution behavior of the self-made product was similar to that of the reference formulation.

[0035] Although embodiments of the invention have been shown and described in detail above, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing metoclopramide tablets, characterized in that: The specific steps are as follows: S1: Metoclopramide hydrochloride is pulverized using a 60-mesh hammer mill; mannitol is passed through a 40-mesh sieve, and stearic acid is passed through a 60-mesh sieve for later use. S2: Weigh out the prescribed amounts of metoclopramide hydrochloride, mannitol, microcrystalline cellulose, stearic acid, and magnesium stearate; S3: Put the material weighed in S2 into the hopper mixer and mix at 10 rpm for 10 minutes to obtain premixed powder; S4: Place the premixed powder obtained in S3 into a dry granulator, set the vertical speed to 10-15 r / min, the pressure roller speed to 5-10 r / min, the main pressure to 8-10 MPa, and the granulation speed to 100-150 r / min. After granulation, granulate through a 1.0 mm sieve. S5: Add stearic acid and the remaining magnesium stearate to the granules obtained in S4, and mix at 10 rpm for 5 min; S6: The intermediate particles obtained in S5 are pressed into tablets using a 10mm×4.5mm irregular die to obtain metoclopramide tablets.

2. The method for preparing metoclopramide tablets according to claim 1, characterized in that: The raw materials of the S1 metoclopramide tablets are, by mass percentage, 1% to 10% metoclopramide hydrochloride, 10% to 95% filler composed of mannitol and microcrystalline cellulose, and 0.5% to 2.5% lubricant composed of stearic acid and magnesium stearate.

3. The method for preparing metoclopramide tablets according to claim 1, characterized in that: In S4, the vertical rotation speed is 10-15 r / min, the pressure roller speed is 5-10 r / min, the main pressure is 8-10 MPa, and the granulation speed is 100-150 r / min. After granulation, the pellets are granulated through a 1.0 mm sieve.

4. The method for preparing metoclopramide tablets according to claim 1, characterized in that: In S5, magnesium stearate accounts for 30%-60% of the total magnesium stearate mass.

5. The method for preparing metoclopramide tablets according to claim 1, characterized in that: In S6, the tablet hardness is controlled to be 50~100N, and the tablet weight difference is ≤±5%.

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