Solubility Enhancement, Formulation & Evaluation of Hydrogel of Aceclofenac

Topical gel formulation is one of the most widely used dosage types to minimise systemic side effects. NSAIDs (non-steroidal anti-inflammatory drugs) are commonly utilised to treat inflammatory conditions like rheumatoid arthritis. When used orally they produce  stomach discomfort dur to irritation.

It acts as  analgesic and anti-inflammatory actions by inhibition of enzyme  cyclooxygenase. The cyclooxygenase is irradiated in synthesis of prostaglandin from archidonic acid. Osteoarthritis, rheumatoid arthritis, and other joint conditions are usually treated with it.

The aceclofenac (ACF) is used orally in the treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.^5,6  But oral administration of ACF causes  gastrointestinal ulcers and gastrointestinal bleeding .⁷  the half-life of ACF  is 3-4 yrs which requires oral administration at regular intervals. Topical administration of ACF would be a possible alternative offering distinct advantages such as elimination of the absorption variable rate, first pass intestinal and hepatic metabolism inherent with oral dosing and delivering the drug directly to the inflamed site and thereby, producing high local concentrations and avoiding the side effects.⁸ The hydrogel has the potential to trap a significant amount of water in its network structure while remaining impermeable to water. A appropriate hydrophilic polymer and solvent  utilised aling with drug  release the drug  gently from the core.^9,10

Hydrotropy is a term used to describe the process of increasing the solubility of a substance in water due to the presence of a significant amount of additives. The mechanism by which it improves solubility is more closely related to complexation comprising a mild interaction between the hydrotrophic substances like sodium benzoate, sodium acetate, sodium alginate, urea and the poorly water soluble drugs.^11,12Solid dispersion is the most effective technique for enhancing the release of poorly soluble drugs. The API in solid dispersions may be distributed as separate molecules, amorphous particles, or crystalline particles, whereas the carrier may be in a crystalline or amorphous state.¹³ Solid dispersion is that polymers used in solid dispersion may be stabilizing drugs in amorphous state and retarding crystallization after ingestion and dispersion. Solid dispersion of water insoluble drugs is the increase of chemical stability and shelf life compared to liquid formulations. Water-soluble polymers such as PVP and HPMC have a particular benefit in the science that they are known to prolong crystallization and stabilize the amorphous state or the solubilized state of the drug in the matrix.

MATERIALS AND METHODS

Aceclofenac was obtained as a gift sample from Arti pharmaceutical ltd Mumbai. Carbopol 934, HPMC, Guar gum, Propylene glycol, Glycerin, Triethanolamine, Methyl paraben, Urea, Sodium tricitrate (Modern Lab. Nashik) ( AR grade)were used in this investigation. Preparation of Hydrotropic solid dispersion was done by Solvent Evaporation method. It is a relatively new technique in which the drug and selected hydrotropes are used in various ratios in beaker, with distilled water being applied at a temperature between 80-85 ° C. The selected hydrotrope is then taken and added to the distilled water. Then slowly add the drug to the beaker and the teflon-coated magnetic bead is lowered in the beaker, the temperature is maintained for optimal stirring and the stirring is continued until the semi-solid mass is produced. This semi-solid mass is distributed over several watch glasses and is put in the oven at a temperature of 60-65 ° C. Then the crushing is done with the pestle and mortar and, after drying, it passes through the sieve no.100 and is held in the desiccators for 6 day.

Hydrotropic solid dispersion of Aceclofenac:

Urea, 3gm , sodium citrate 9 gm  and  10 ml of warm distilled were placed in beaker. It was stirred well with magnetic stirrer , 1.2gm of Aceclofenac (drug to carrier ratio was 1:3) was added in the above solution and temperature maintained in the range 55-56°c. The water evaporated after 30 min,  the wet solid dispersion was spread on watch glass which was kept in hot air oven at 50°c for 24 hrs. The hydrotropic solid dispersion were crushed using mortar and pestle and passed through sieve no.60 and finally stored in air tight glass bottle.

Determination of λ max of ACF:

Determination of λ max of Aceclofenac in phosphate buffer pH 7.4-The UV spectrum of Aceclofenac was determined in phosphate buffer pH 7.4 and maximum absorbance was recorded.

Solubility:

The solubility of Aceclofenac in water,ethanol and Hydrotopic Blend was determined.

FTIR Spectroscopy:

The IR  spectrum  of Aceclofenac in potassium bromide  was recorded by scanning in the wavelength region of 4000-400 cm using FTIR spectrophotometer.

Accuracy:

Accuracy was calculated in terms of % recovery for  (80%, 100% and 120%V/V solutions)

Intra- day and inter-day precision :

A standard solution containing (0.4, 1.2, 2.0 µg/mL) were analyzed three times on the same day for the determination of intra-day precision and on three different days for the determination of inter-day precision and % RSD was calculated.

Formula Design 

Formulation and Development topical hydrogel of Aceclofenac: 1% w/w

Table 1 Formula for préparation of Hydrogel of Aceclofenac

Preparation of ACF solution:

The propylene glycol 2ml was warmed in water bath  to 55 -60 °C  in this Aceclofenac  was dispersed with constant stirring.

Water phase:

Carbopol 934 was soaked in water for 24 hours. Separately, guar gum and HPMC powder were soaked in water for 24 hours. Then the  soaked  HPMC and guar gum were  transferred to the Carbopol mixture and stirred for 20 minutes.

Preparation of Hydrogel :

The solution of Aceclofenac in propylene glycol was  neutralized with triethanolamine , the water phase, glycerine , methyl paraben was added while stirring and volume was made to 10ml with purified water.

Evaluation of hydrogel

Physical characteristics:

The prepared hydrogel formulation was evaluated for  colour, homogeneity, consistency, grittiness, texture and phase separation.

Determination of pH:

The pH of hydrogel formulation was determined .One gram of gel was dissolved in 25 ml of distilled water and pH was determined.

Viscosity:

The viscosity of hydrogel was determined  by using Brookfield viscometer at 20rpm and 28°c.

Spreadability:

The spreadability was determined  using spreadability glass apparatus.

Drug content:

Accurately weighed hydrogel was dissolved in 100ml of phosphate buffer pH 7.4. It was filtered using Whatman filter paper. Suitable dilutions were done and drug content was determined at  λ max 273nm using UV spectophotometer.

Extrudability:

The extrudability was determined by calculating weight in grams required to extrude at least 0.5cm ribbon of hydrogel in 10sec from the collapsible aluminium tube.

In-vitro drug release:

In vitro drug release study of aceclofenac was carried out in a Franz diffusion call, by using cellophane membrane. The membrane was soaked in media for 12hrs, and placed in the space between the donor and receiver compartment of the Farnaz diffusion cell. 1gm of hydrogel was applied on donor side. phosphate buffer pH 7.4 was used as diffusion media. the temperature of cell was maintained constant 37 + 0.5°c by using circulating jacket. The solution was stirred continuously using magnetic bead. 2ml sample were withdrawn after 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420min and replaced with equal amount of fresh media. similar procedure was carried out for formulation F1 to F4. Sample was analysed by spectrophotometrically at 273nm and % CDR was calculated.

RESULT AND DISCUSSION

UV spectroscopic analysis for the Aceclofenac was performed in phosphate buffer pH 7.4 and in spectrum Aceclofenac showed absorbance maximum at 273nm.

Accuracy :

Table 2 Results for Accuracy determination of Aceclofenac

Precision of intra-day and inter-day

Intra-day precision

Table 3 Results for Intraday precision  determination of Aceclofenac

Inter-day precision

Table 4 Results for Inter day precision  determination of Aceclofenac

Solubility Enchancement: Hydrotropic Blend has shown 60.21% solubility enhancement as compared to Aceclofenac in  water

Compatability Study : To study compatibility between accelophenac and exciepients used for formulation compatbility study was performed using FTIR.

FTIR of Accelophenac pure drug and Aceclofenac drug and excipients was performed and checked for the peaks obtained.

EVALUATION OF ACECLOFENAC HYDROGEL USING GELLING AGENT:

Physical appearance:

The result of physical appearance i.e. colour, odour, homogeneity, phase separation, consistency, texture, grittiness of all batches are in shown in table. All batches of hydrogel were found to be transparent, characteristics odour with good homogeneity, consistency and texture. All formulation was non-gritty and without phase separation.

Physical appearance of hydrogel:

Table 5 Physical appearance of hydrogel of Aceclofenac

The pH value of hydrogel batches were found in the range of 5.7-6.2 which is similar to skin pH .

Table 6 pH of hydrogel formulation

Viscosity:

The tests were performed by using Brook-field viscometer. Highest viscosity was found in formulation F3and F4. It may be due to low concentration of gelling agent. The viscosity range observed for all formulation was 10102-15057Cps.

Table 7 viscosity of hydrogel formulation

Viscosity of F4 found have significant viscosity.

Spreadability:

The spreading coefficient of various hydrogel formulation are given below. It was concluded ‘that all the developed formulation showed acceptable spreadability, F3 and F4 formulation has more spreadability as compare to other formulation i.e. 14.30 and 12.93 respectively.

Table 8 Spreading coefficient of the formulation

Spreadability of F4 found to have significant spreadability.

Drug content :

The drug content of different hydrogel formulation was estimated by using UV spectrophotometer at 200-400 nm rang. The release of drug through prepared formulation was to be 99.25, 83.83,88,99.25 respectively. The result was found to be satisfactory.

Table 9 Drug content of F1 and F4 batch

Drug content of F1 and F4 batch found to have significant drug content

In-vitro diffusion study:

Table 10 In-vitro diffusion study of three batches F1,F2,F3

The drug release through the hydrogel formulation without solid-dispersion batches F1,F2,F3 was shown in above table ,F1 could up to 71.82 % at the end of 4hr .

Table 11 Cumulative % drug release of F1,F3 batch and marketed preparation

The drug release through the hydrogel formulation without solid dispersion (batch F1) was slower and could reach up to 93.5% at the end of 7 hr. Hydrogel batch (F4) with solid dispersion showed 100% in 5hr. Drug release which higher than batch F1 without solid dispersion. F4 batch was compared to marketed gel product, it reached up to 92.62% in 5hr. Optimize formulation F4 showed significantly improved  drug release rate compared to marketed preparation.

Fig.1 Cumulative % of Aceclofenac release