In-depth Understanding Of The Optimal Preparation Process Of Aceclofenac Dispersible Tablets Based On Orthogonal Experiments

Aceclofenac is a new type of powerful antipyretic, analgesic and anti-arthritic drug—in order to make aceclofenac into dispersible tablets more efficiently, the preparation process of aceclofenac dispersible tablets was carried out in this paper. Research. Based on the orthogonal test L9(3)4, the dosage of its main functional excipients was selected, and the preparation process of aceclofenac dispersible tablets was carried out with the properties, identification, related substances, and dissolution rate of the dispersible tablets as the investigation indicators. Optimized. The final prepared aceclofenac dispersible tablets all meet the standard requirements in various inspections. The optimized preparation process of aceclofenac dispersible tablets has good reproducibility, uniform dispersion, and rapid dissolution of active ingredients. It is aceclofenac dispersible tablets The production provides a reference basis.

Compared with solid preparations such as ordinary tablets and capsules, dispersible tablets are convenient to take (can be directly swallowed, chewed or taken after dispersing in water), rapid disintegration, uniform dispersion, fast dissolution of active ingredients, fast absorption and biological It has the advantages of high utilization and is convenient for the elderly, young children and patients with dysphagia. It is a popular dosage form and is easy to carry, transport and store.

Aceclofenac is a new type of powerful antipyretic, analgesic and anti-arthritic drug. It is clinically applicable to the treatment of pain and inflammation caused by osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Soluble in water, the common dosage forms are ordinary tablets and hard capsules [5]. In order to take advantage of the advantages of dispersible tablets, aceclofenac with poor solubility is made into dispersible tablets. The dosage and preparation of aceclofenac dispersible tablets The process is optimized to provide the necessary reference for the production of aceclofenac dispersible tablets.

1 Experimental Materials

1.1 Equipment And Instruments

WF-30B universal pulverizer, CH-200 trough mixer, YK-160 swing granulator, FL-200 boiling granulation dryer, SBH-800 three-dimensional swing mixer, ZP37 rotary press Chip machine, JC-TP type analytical balance, BJ-2 type disintegration tester, LC-20AT type high performance liquid chromatograph and SDR1911 type UV-visible spectrophotometer.

1.2 Reagents And Test Solutions

Ethanol, 0.6% potassium ferricyanide solution, 0.9% ferric chloride solution, 1% hydrochloric acid, phosphoric acid, sodium acetate, acetic acid, diclofenac sodium, potassium dihydrogen phosphate, sodium hydroxide, and acetonitrile.

2 Experimental Process

2.1 Preparation Of Aceclofenac Dispersible Tablets

(1) Factor Level Determination

The specification of aceclofenac dispersible tablet is 0.1 g, and the preparation prescription consists of raw materials aceclofenac, filler and disintegrant carboxymethyl starch sodium (CMS-Na), microcrystalline cellulose (MCC), low-substituted hydroxypropyl cellulose Composition of excipients such as L-HPC, crospovidone (PVPP) [6-9], sweetener and flavoring agent aspartame [10], lubricant magnesium stearate [11-12] .

Adjust the amount of sodium carboxymethyl starch, choose the amount of MCC, L-HPC, PVPP as the influencing factors, and set 3 levels for each factor. See Table 1 for the factor levels of the orthogonal test on the amount of excipients in aceclofenac dispersible tablets.

Table 1 Orthogonal Test Factor Levels Of Functional Excipients In Aceclofenac Dispersible Tablets

(2) Experimental Methods And Results

The L9(3)4 orthogonal table was used to arrange the test, and the dispersion time of the dispersible tablets was used as the investigation index. See Table 2 for the arrangement and results of the orthogonal test, and Table 3 for the results of variance analysis of dispersion uniformity.

Table 2 Orthogonal Test Arrangement And Results Of The Preparation Process Of Functional Excipients Of Aceclofenac Dispersible Tablets

Table 3 Analysis of Variance On Dispersion Uniformity of Aceclofenac Dispersible Tablets

(3) Analysis Of Variance

From the results of the orthogonal test and analysis of variance, it can be known that there is no significant difference between the various factors and levels, and the most influential factor is A, namely MCC, followed by L-HPC, and PVPP again; the order of primary and secondary influencing factors is A ＞B＞C; the optimal amount of excipients is A3B2C3, that is, the amount of MCC is  15%, the amount of L-HPC  is 10%, and the amount of PVPP is  10%.

(4) Result Analysis

According to the variance analysis of the dispersion uniformity of aceclofenac dispersible tablets, the amount of raw materials for aceclofenac dispersible tablets was determined, and the amount of functional excipients was comprehensively considered to conduct a pilot test for the preparation of aceclofenac dispersible tablets.

2.2 Pilot Test Of The Preparation Process Of Aceclofenac Dispersible Tablets

2.2.1 Pilot Test Verification Method

Take about 40% of the raw material aceclofenac, and take the excipients: 20% of CMS-Na, 15% of MCC,  10% of L-HPC and 10% of PVPP .

The preparation process is as follows: the raw material aceclofenac is crushed to 100 meshes, the fine powder is mixed with auxiliary materials CMS-Na (15% of the auxiliary materials are added), MCC, L-HPC, PVPP, etc. in a mixer for 10 min → adding a wetting agent ( Appropriate amount of purified water)→mixing for 3 min→shaking granulation (16 mesh)→drying (temperature is 70±5℃, time about 2.5 h)→shaking granulation (16 mesh)→total mixing for 20 min (adding 5% CMS-Na , 2% magnesium stearate)→tabletting (the punch is Φ9 mm shallow concave, the speed is controlled at 25-30  r/min). 10,000 tablets per experiment, 3 experiments. According to the inspection method stipulated in the “Pharmacopoeia of the People’s Republic of China (2020 Edition)”, the properties and content of the granules and the properties, identification, related substances, dissolution rate, dispersion uniformity, and content of the dispersible tablets are used as comprehensive inspection indicators. The pilot test process verification of aceclofenac dispersible tablets was carried out.

2.2.2 Particle Inspection

(1) Eligibility Criteria

Granule traits: It should be white or off-white granules.

Particle moisture: ≤2.5%.

Particle content: The aceclofenac (C16H13Cl2NO4) contained in this product should be 39.5% to 42.5% of the labeled amount.

(2) Inspection Results

See Table 4 for the results of particle inspection of aceclofenac dispersible tablets.

Table 4 Inspection Results Of Granules Of Aceclofenac Dispersible Tablets

(3) Conclusion

According to the proposed preparation process of aceclofenac dispersible tablets, the granulation pilot test was carried out. The process steps and process parameters such as material mixing, granulation, granulation, drying, and total blending all met the process requirements. The properties, moisture, and content of the granules, etc. All inspections met the requirements of the quality standards, the inspection data had good reproducibility, and the inspection results met the requirements.

2.2.3 Inspection Of Dispersible Tablets

(1) Eligibility Criteria

Properties: It should be white or off-white tablets.

Related substances: in the chromatogram of the test solution, if there is a chromatographic peak consistent with the retention time of diclofenac, it shall not exceed 0.4% of the labeled amount of aceclofenac according to the peak area calculation by the external standard method; other single impurities (except aceclofenac The peak area of Spartan excipients peak) shall not be greater than the peak area of aceclofenac in the reference solution (0.2%), and the sum of the peak areas of other impurities shall not be greater than 5 times (1.0%) of the peak area of aceclofenac in the reference solution %).

Dissolution: The limit is not less than 80% of the labeled amount.

Uniformity of dispersion: It should disintegrate completely within 3 min and pass through a 710 µm sieve.

Content determination: The aceclofenac (C16H13Cl2NO4) contained in this product should be 95.0% to 105.0% of the labeled amount.

(2) Inspection Results

The inspection results of aceclofenac dispersible tablets are shown in Table 5.

Table 5 Inspection Results Of Aceclofenac Dispersible Tablets

(3) Conclusion

According to the proposed preparation process of aceclofenac dispersible tablets, the tablet compression pilot test was carried out. The tablet compression process steps and process parameters all met the process requirements. The properties of the dispersible tablets, related substances, dissolution rate, dispersion uniformity, content determination, etc. The inspections all meet the quality standard requirements, the inspection data has good reproducibility, and the inspection results meet the regulations.

3 Epilogue

In this paper, the preparation process of aceclofenac dispersible tablets was optimized based on the orthogonal test L9(3)4, and its usability was verified through pilot experiments, which provided a certain reference for pharmaceutical companies to produce aceclofenac dispersible tablets.

However, it should also be noted that dispersible tablets also have their limitations as a solid dosage form: in the production process, it is generally required to micronize the raw materials (especially insoluble drugs), which increases the production process; disintegrating agent, the cost is high; the quality requirements are relatively high, and the quality standard control is difficult; the storage conditions of dispersible tablets are higher than that of general tablets, because the disintegrating dose used in dispersible tablets is large, and the hygroscopicity is strong , the moisture-proof effect of packaging materials is higher, which may increase packaging and storage costs. Therefore, in order to give full play to the effectiveness of dispersible tablets, it is still to be fully explored in its production and storage.