Influencing factors of drug release in vitro from diclofenac potassium hydroxypropyl methylcellulose matrix tablets

Abstract: Objective: To investigate various factors affecting the in vitro release of diclofenac potassium from hydroxypropylmethylcellulose (HPMC) matrix tablets. Methods Using HPMC as the skeleton material, diclofenac potassium sustained-release tablets were prepared by wet granulation method, and the effects of drug/HPMC ratio, HPMC viscosity, HPMC particle size, release medium pH, tablet pressure and paddle speed on drug release behavior in vitro were investigated. Results: The drug/HPMC ratio, HPMC viscosity and release medium pH significantly affected the release rate of diclofenac potassium, while HPMC particle size, compression pressure and paddle speed had little effect on the release rate of diclofenac potassium. Conclusion Diclofenac potassium HPMC sustained-release tablets with ideal drug release behavior can be obtained by using HPMC with appropriate viscosity and adjusting the drug/HPMC ratio.

Key words: diclofenac potassium; hydroxypropyl methylcellulose; sustained-release preparations; influencing factors; drug release in vitro

Diclofenac potassium (diclofenac potassium) is a new generation of non-steroidal analgesic and anti-inflammatory drugs with strong analgesic and anti-inflammatory effects. It is used for short-term treatment of acute pain caused by post-traumatic, postoperative, gynecological and spinal syndromes. The drug has the characteristics of rapid absorption, rapid onset of action, good tolerance, and small individual differences. However, its t1/2 is relatively short, about 2 hours, and the common dosage form needs to be administered three times a day, and the blood drug concentration in the body shows obvious peak and valley phenomena, and has certain irritation to the gastrointestinal tract. In order to reduce the number of times of taking medicine, reduce adverse reactions, and improve the therapeutic effect, it can be made into sustained-release preparations. Hydroxypropylmethylcellulose (HPMC) is a white or near-white fiber, granule and powder. As one of the hydrophilic pharmaceutical excipients, it has been widely used in the research of oral sustained-release preparations. The drug release from the HPMC hydrophilic gel matrix is related to the content of the drug in the matrix, the viscosity, particle size and preparation process of HPMC. We used HPMC as the hydrophilic gel matrix material, and studied the effects of its dosage, viscosity, particle size, tablet pressure, paddle speed and release medium pH on the in vitro release behavior of diclofenac potassium sustained-release tablets.

1. Materials and Methods

1.1 Instruments and medicines

Diclofenac potassium (Yancheng Pharmaceutical Factory, batch number 030105, content >99.5%); HPMC (K4M, K15M, KIMA CHEMICAL CO., LTD). TDP single-punch tablet press (Shanghai No. 1 Pharmaceutical Machinery Factory); ZRS 4 intelligent dissolution tester (Tianjin University Radio Factory); U-3000 UV-visible spectrophotometer (Hitachi, Japan); tablet hardness tester (Shanghai Huanghai Drug Testing Instrument Factory).

1.2 Method

1.2.1 Preparation of Matrix Tablets

Pass diclofenac potassium and auxiliary materials through a 80-mesh sieve, blend evenly with each auxiliary material (HPMC, lactose, etc.) according to the prescription amount, use 80% ethanol as a wetting agent to make a soft material, granulate with a 20-mesh sieve, and dry at 60% , whole grain, add 0.8% magnesium stearate, mix well and compress into tablets, each tablet contains 50 mg of the main drug.

1.2.2 Determination method of release rate

1.2.2.1 Selection of measurement wavelength

Take an appropriate amount of diclofenac potassium reference substance, add pH 6.8 phosphate buffer solution to dissolve, and make a solution containing 15 μg in 1 mL, scan in the wavelength range of 200-400 nm according to ultraviolet spectrophotometry, diclofenac potassium is at 276 nm There is a maximum absorption at this wavelength, and the excipients have no absorption at this wavelength. Therefore, 276 nm was selected as the measurement wavelength.

1.2.2.2 Standard curve

Accurately weigh 25 mg of diclofenac potassium reference substance dried at 105°C to constant weight, put it in a 50 mL measuring bottle, add pH 6.8 phosphate buffer to dissolve, and constant volume to obtain a stock solution. Precisely draw 1, 2, 3, 4, 5, and 6 mL of the stock solution respectively, put them in a 100 mL volumetric flask, add pH 6.8 phosphate buffer to constant volume, measure the absorbance at 276 nm, and calculate the absorbance (A) Perform linear regression on the mass concentration (p), and the regression equation is: ρ=38.01A+0.06, r=0.9999. The results showed that diclofenac potassium had a good linear relationship between ρ and A in the mass concentration range of 5-30 mg·L-1.

1.2.2.3 Recovery rate

Precisely weigh the diclofenac potassium reference substance and the corresponding prescription amount of excipients dried to constant weight, add pH 6.8 phosphate buffer solution to dissolve, and constant volume. Filtrate, take the filtrate, make solutions of 80%, 100%, and 120% of the marked amount, measure A, and calculate the recovery rate as (99.8±0.6)% (n=5).

1.2.3 Determination of release rate

The matrix tablet was taken, and the experiment was carried out according to the paddle method of the release measurement method in Appendix XC of the second part of the "Chinese Pharmacopoeia" in 2000 edition. The experimental conditions were: release medium 900 mL, rotation speed 100 r·min-1, temperature 37 °C, respectively at 0.0. Take samples at 5, 2, 4, 6, 8, 10, and 12 hours, add an equal amount of medium, filter through a microporous membrane, take the subsequent filtrate to measure A, and calculate the cumulative release percentage.

2. Results

2.1 Effect of drug/HPMC ratio

When the diclofenac potassium/HPMC (K15M) ratio was 1:0.3, 1:0.5 and 1:0.8, tablets were prepared and the cumulative release percentage was determined. Visible drug / HPMC ratio can significantly affect the drug release rate.

2.2 Effect of HPMC particle size

When the diclofenac potassium/HPMC (K15M ratio is 1:0.8, and the particle diameters of HPMC are 60-80, 80-100 and 100-120 meshes respectively, tablets are prepared and the cumulative release percentage is determined. It can be seen that when the particle diameters of HPMC are different , the drug release rate changed little.

2.3 The influence of HPMC viscosity

When the ratio of diclofenac potassium / HPMC is 1:0.8, the viscosity of HPMC is K4M and K15M respectively. The cumulative drug release percentage was determined. Visible HPMC viscosity can significantly affect the release rate of diclofenac potassium.

2.4 Influence of tableting pressure

Tablets were made with different pressures, and the hardnesses of the obtained tablets were 6.9 and 12 kg·cm-2, respectively. The cumulative drug release percentage was determined. It can be seen that when the hardness of the tablets is different, the drug release behavior is almost the same.

2.5 Influence of propeller speed

When the paddle speed was 50, 100 and 150 r·min-1, the cumulative drug release percentage was measured. It can be seen that the paddle speed has almost no effect on the release of diclofenac potassium sustained-release tablets.

2.6 Effect of release medium pH

When the release media were hydrochloric acid solution at pH 1.2, acetic acid-sodium acetate buffer at pH 4.5, and phosphate buffer at pH 6.8 and 7.4, the cumulative drug release percentages were determined. It can be seen that in the acidic release medium, the release amount of diclofenac potassium sustained-release tablets is low, and the release amount increases with the increase of pH; while in the neutral release medium (pH 6.8, 7.4), the release amount of diclofenac potassium from the condensed The release is faster in the glue matrix.

3.Discussion

The release of drugs from HPMC matrix tablets mainly depends on the diffusion of drugs in the gel layer formed by HPMC hydration and the erosion of the gel layer. The release mechanism of water-soluble drugs from HPMC matrix tablets is mainly the diffusion of dissolved drugs through the gel layer, and the release mechanism of insoluble drugs from HPMC matrix tablets is mainly the erosion of the gel layer. Diclofenac potassium is a water-soluble drug, and its release from HPMC matrix tablets is mainly based on the diffusion mechanism. When the drug/HPMC ratio is 1:0.8, the sustained release effect is better. The drug release data were processed according to Higuchi equation, and the regression coefficient was 0.998 8, which further indicated that the drug was released by diffusion mechanism.

3.1 Effect of drug/HPMC ratio

With the increase of HPMC dosage, the drug release rate decreased. This is because as the amount of HPMC increases, the viscosity of the gel layer after hydration increases, and the diffusion path of the drug in the gel layer becomes longer, resulting in a decrease in the effective diffusion coefficient of the drug and a decrease in the release rate.

3.2 Effect of HPMC particle size

It has been reported in the literature that the particle size of HPMC has little effect on the release of water-soluble drug matrix tablets, but has a certain impact on the release of insoluble drug matrix tablets. In this study, diclofenac potassium is a water-soluble drug, and the particle size of HPMC has little effect on the release of diclofenac potassium sustained-release tablets.

3.3 The influence of HPMC viscosity

When the viscosity of HPMC is low, it cannot control the release of diclofenac potassium; and when the viscosity of HPMC is K15M, it can effectively control the release of diclofenac potassium. This may be because when HPMC has a low viscosity, it cannot form an effective gel layer to retard drug release after hydration.

3.4 Influence of tableting pressure

When the pressure is different during tablet making, the hardness of the obtained tablet is obviously different, and the porosity in the tablet has a large difference, but the porosity in the gel layer formed by HPMC hydration has nothing to do with the initial porosity, so that the tableting pressure has no effect on the tablet. Drug release in the HPMC matrix has little effect.

3.5 Influence of propeller speed

Paddle rotation speed had little effect on the release of diclofenac potassium extended-release tablets. This may be because the paddle speed did not affect the HPMC hydration gel layer formation and the release of diclofenac potassium from the gel layer.

3.6 Effect of release medium pH

The pH of the release medium did not affect the wetting and swelling of HPMC, but it significantly affected the solubility of diclofenac potassium. As the pH of the medium increased, the solubility of diclofenac potassium increased, resulting in an increase in the cumulative release of diclofenac potassium HPMC matrix tablets.