The present research work is to formulate and optimize Aceclofenac gel. Fourier Transfer Infrared Spectroscopy (FT-IR) study revealed no chemical interaction between drug and polymers. The formulations were prepared by using various polymers like Carbopol 934 and HPMC K15M. The formulated gels were evaluated for several physicochemical parameters like drug-polymer interaction, pH, Viscosity, Spredability, Drug content uniformity, In vitro drug release. The formulation F9 Showed maximum drug diffusion rate. The optimization study was carried out to find out effect of two independent variable on diffusion rate at 3 hour and diffusion rate at 6 hour. Optimization was performed by the help of software DESIGN EXPERT 8.0.6 trial. From this study, it was find out that as the concentration of polymer increases, the drug release will decreases

R Shabaraya, Arun Gokul T.S, Krishnananda Kamath K, A

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 Research in Pharmacy 3(1): 14-22, 2013                                                                 ISSN : 2231-539X www.researchinpharmacy.com  Received: 30.12.2012; Revised: 12.2.2013; Accepted: 18.2.2013  Regular Article Formulation and optimization of Aceclofenac gel  Arun Gokul T.S*, Krishnananda Kamath K, A.R Shabaraya  Department of Quality Assurance, Srinivas College of Pharmacy, Valachil, Mangalore, Karanataka Corresponding Author e-mail id: arungokul1989@gmail.com  The present research work is to formulate and optimize Aceclofenac gel. Fourier Transfer Infrared Spectroscopy (FT-IR) study revealed no chemical interaction between drug and polymers.  The formulations were prepared by using various polymers like Carbopol 934 and HPMC K15M. The formulated gels were evaluated for several physico-chemical parameters like drug-polymer interaction, pH, Viscosity, Spredability, Drug content uniformity, In vitro drug release.  The formulation F9 Showed maximum drug diffusion rate. The optimization study was carried out to find out effect of two independent variable on diffusion rate at 3 hour and diffusion rate at 6 hour. Optimization was performed by the help of software DESIGN EXPERT 8.0.6 trial. From this study, it was find out that as the concentration of polymer increases, the drug release will decreases.  Keywords: Aceclofenac, Carbopol 934, HPMC K15M, Optimization  Topical drug delivery systems are gaining increase in popularity and several drugs have been successfully delivered by this route for both local and systemic action. In recent years, most of non-steroidal anti inflammatory drugs (NSAID’s) have been designed to deliver the drug in the form of topical gels, to avoid gastrointestinal irritation, to overcome “first pass” effect and to maximize the drug concentration at the site of action. Gels have better potential as a vehicle to administered drug topically in comparison to ointment, because they are non-sticky requires low energy during the formulation (Chein, 1992). The purpose of this research work was to formulate and evaluate Aceclofenac gel and find out effect of Carbopol 934 and HPMC K15M on formulation. Formulation chart was prepared by applying 32 full factorial design using two independent variables, i.e. concentration of Carbopol 934 and HPMC K15M (Aukunuru et al., 2007 ) The formulations were prepared by using various polymers like Carbopol 934and HPMC. The formulated gels were evaluated for several physico-chemical parameters like drug-polymer interaction, pH, Viscosity, Spreadability, Drug content uniformity, In vitro drug release. The best formulation was selected. The formulation F9 Showed maximum drug diffusion rate. The optimization study was carried out to find out effect of two independent variable on diffusion rate at 3 hour and diffusion rate at 6 hour. Optimization was performed by the help of software DESIGN EXPERT 8.0.6 trial (Vishnumoorthy, 2011).    Arun Gokul et al. / Research in Pharmacy 3(1): 14-22, 2013   15  Materials and methods Materials: Aceclofenac was obtained as a gift sample from Yarrow chemical Ltd, Bombay .Carbopol 934 and HPMC K15M were obtained from Yarrow chemical Ltd, Bombay. All the other chemicals used in the formulations were of analytical grade. Methods: Preparation of Standard Curve: 100 mg of Aceclofenac was accurately weighed and dissolved using pH 7.0 phosphate buffer solution in 100 ml standard flask and 5, 10, 15, 20 and 25 µg/ml were prepared by suitably diluting the stock solutions with pH 7.0 PBS, each sample was then analyzed spectrophotometrically at 275 nm using UV Visible spectrophotometer. Drug - Excipients compatibility study: Compatibility of the drug with excipients was determined by FT-IR spectral analysis, this study was carried out to detect any changes on chemical constitution of the drug after combined it with the excipients. Designing of formulations: Formulation of gel of Aceclofenac was designed using design expert software trial version 8.0.1 by applying 32factorial design. Amount of polymer used was taken as an independent variables i.e, amount of Carbopol 934(X1) and HPMC K15M (X2) as independent variables and percentage drug release at 3hrs(Y1) and at 6hrs(Y2) was considered as dependent variables. By using this data total nine preliminary were prepared (i.e, F1 to F9) as shown in the table Table 1(A) and 1 (B).   Table 1A: 32 full factorial design layout for Aceclofenac gel             Table 1B: amount of independent variables         Formulation of gel: Accurately weighed amount of Carbopol 934&HPMC K15M was placed in known amount of distilled water. After complete dispersion, the polymer solution was kept in dark for 8 hours for complete swelling. Accurately weighed amount of Aceclofenac was dissolved in a specified quantity of propylene glycol. The drug solution was added slowly to the aqueous dispersion of polymer with continuous stirring. Menthol was dissolved in Iso Propyl Alcohol. Finally, the remaining ingredients were added to obtain a homogeneous dispersion BATCH NO. X1 X2 F1 0 +1 F2 +1 +1 F3 +1 -1 F4 -1 0 F5 0 0 F6 -1 +1 F7 +1 0 F8 0 -1 F9 -1 -1 INDEPENDENT VARIABLES LOW(-1) MEDIUM(0) HIGH(+1) Conc. of  Carbopol 934(gm) (X1) 1 1.75 2.5 Conc. of HPMC K15M(gm) (X2) 1.5 2 3 Arun Gokul et al. / Research in Pharmacy 3(1): 14-22, 2013   16  of gel. The formed gel was then neutralized by sufficient quantity of triethanolamine. Final volume was adjusted by water.  Evaluation of gels  1. Appearance The appeared gels were inspected visually for Clarity, Colour, and presence of any particle. The test is important regarding patient compliance 2. pH Ph of the gel was determined sing digital pH meter. About 1 gm of gel was stirred in distilled water till a uniform suspension effected. The volume was made up to 40 ml and pH of the solution was measured. 3. Skin irritation Test for irritation was performed on human volunteers.  About 1.0 gm of gel was applied on an area of 2 square inch to the back of hand and observed for lesions or irritations. 4. Drug content A specific quantity of developed gel was taken and dissolved in 100 ml of phosphate buffer of pH 6.8. From that 1 ml was taken and made up to 10 ml. This solution was filtered and estimated spectrophotometrically at 275nm using phosphate buffer pH 6.8 as blank. 5. Viscosity Viscosity of the gel was determined by using Brookfield viscometer, using spindle No.4. 6. Spreadability Spreadability of formulations was determined by woodwn block and glass slide apparatus, consist of slide fixed on wooden block and upper slide with one end tide to a weight pan. An excess of gel (2-5gm) was placed in between the glass slide. A fixed weight was added to pan. The time in seconds required to separate the two slides was taken as a measure of spreadability. It is calculated by    S=M.L/T Where S=spreadability;  M=weight tied to upper slide;         L =length of glass slide T=time taken 7. In vitro drug diffusion study The membrane permeability studies of various formulations of Aceclofenac gel can be carried out using Kesharychien diffusion cell. The receptor compartment is filled with saline phosphate buffer of pH 7.4 and methanol (90:10) and keeps at 32±0.5oc stirred with the help of magnetic stirrer. Methanol 10% is added to maintained sink condition. About 200-300mg of gel is placed on cellulose chamber. One ml of sample is withdrawn from receptor compartment at 1, 2, 3, 4, 5, 6 hour and replaced with same volume of medium. All samples are diluted up to 10ml with medium and analysed at 275nm. Optimization: Results obtained from the preliminary formulations are applied in design expert software and analyzed for two responses i.e release rate at 3Hrs (Y1) and Release rate at6 Hrs (Y2).  Results and discussion In the present study the UV absorption maxima was observed at 275 nm. The obtained results revealed that the maximum absorbance appeared at 275nm. (Figure 1)The comparison of the IR spectrum of pure drug and polymers revealed that there is no appreciable change in the positions of characteristic absorption bands of groups and bonds. Even though slightly differ in appearance but no change is observed in the positions of the   bandpolym    Batch no. AnF1 F2 F3 F4 F5 F6 F7 F8 F9 BanFFFFFFFFFs in spectra,er used forceclofeac (gm) Carol (g1 1.1 21 21 1 1.1 1 21 1.1 tch o. Appeara1 Clea2 Clea3 Clea4 Clea5 Clea6 Clea7 Clea8 Clea9 cleaArun Goku this clearly this study (TaTabop934  m) HPMC(gm) 75 3 .5 3 .5 1.5 1 2 75 2 1 3 .5 2 75 1.5 1 1.5 nce Homor Gr Gr Gr Gr Gr Gr Gr Gr Gl et al. / Rese suggests thFigure 2 a, bFigure 1: ble 2: Formulble 3: Various Methyl salicylate(ml) 10 10 10 10 10 10 10 10 10 genesity irood  ood ood ood ood ood ood ood ood arch in Phar17 at there is n, c).   UV absorptionation chart of  physico chem  Menthol (gm) 1 1 1 1 1 1 1 1 1 Skin ritation SprNil Nil Nil Nil Nil Nil Nil Nil Nil macy 3(1): 1o interactio maxima Aceclofenac gical parameteTri ethanolamine (ml) Mp1 1 1 1 1 1 1 1 1 eadability 40.35 39.75 42.05 43.65 42.60 41.40 42.00 42.65 43.70 4-22, 2013 n between tel rs ethyl araben (gm) IP(m0.1 60.1 60.1 60.1 60.1 60.1 60.1 60.1 60.1 6pH Drug content7.1 95.2 % 7.3 95.8 % 6.9 95.1 % 7.1 95.4% 7.0 96.4 % 7.2 95.3 % 7.2 95.9 % 7.3 95.6 % 7.3 97.00% he drug an A l) Propylenglycol (m 10  10  10  10  10  10  10  10  10  Viscosity(c31400 34200 31100 29900 30400 31500 33600 30800 29600  d the e l) water  Up to 100 p) Arun Gokul et al. / Research in Pharmacy 3(1): 14-22, 2013   18  a4500 4000 3500 3000 2500 2000 1500 1000 500-0.020.000.020.040.060.080.100.120.140.16% transmittancewavenumber (cm-1) B        b 4500 4000 3500 3000 2500 2000 1500 1000 5000.000.050.100.150.20% transmittanceWavenumber B  c 4500 4000 3500 3000 2500 2000 1500 1000 500-0.020.000.020.040.060.080.100.120.14% transmittanceWavenumber B Figure 2. FTIR Spectra of (a)-pure drug, (b)-drug+Carbopol 934, (c)-drug+HPMC  The prepared gels were inspected visually for the clarity, colour and presence of any particle.  The test important regarding patient compliance. All gels were clear and transparent. All developed (F1-F9) gels showed good homogeneity with absence of lumps. Arun Gokul et al. / Research in Pharmacy 3(1): 14-22, 2013   19  The pH value of all developed formulations of gels (F1-F9) were in the range of 6.9 to 7.3. All the formulations showed no significant skin irritation on intact skin. Thus observations indicate acceptability of these gels for topical use. The value of spreadability indicates that the gel is easily spreadable by small amount of shear. Spreadability of gels were in the range of 39.75-43.65 gm/sec. Formulation F2 shows least Spreadability and F9 shows highest. The percentage drug content of all prepared gel formulations were found to be 93.2 % to 97 %. The percentage drug content of formulations were found satisfactory. Hence methods adopted for gels formulations were found suitable. The viscosity of various formulated Aceclofenac gels was measured using a Brookfield viscometer. The rheological behavior of all formulated gels systems was studied. In gel system, consistency depends on the ratio of solid fraction, which produces the structure to liquid fraction. Viscosity of various formulated Aceclofenac gels was found in range of 29600 to 34200 centipoises.(Table 3).Diffusion profile of preliminary formulations compared at two check points i.e. percentage cumulative drug release at 3 hours and percentage cumulative drug release at 6 hours. Formulations F2 and showed least percentage cumulative drug release value 40.19 % at 3 hours and formulation F9 showed highest percentage of drug release value 43.19% in 3 hours.  Percentage cumulative drug release value of all formulations ranges from 40.19 % to 43.19% at 3 hours. Formulation F2 showed least percentage cumulative drug release value 75.14 % at 6 hours and formulation F9 showed highest percentage of drug release value 79.93 % in 6 hours.  Percentage cumulative drug release value of all formulations ranges from 75.14 % to 79.93 % at 12 hours (Table 4).  Table 4: Cumulative drug release of formulations                         It was clear from the above table that the drug release decreased with increase in concentration of gelling agents. In addition viscosity increased as polymer concentration increased. Viscosity is negatively related to the release of active substances from the formulations and its penetration through the diffusion barriers. Formulation F9 and F4 showed fast drug release because of lower concentration of polymers. For the factorial study based on 32 full factorial design nine experimental runs are conducted  and responses for the nine formulations are given in the Table No 5.4. Range of responses Y1, the cumulative% drug release after 3 hrs was 40.19 %( minimum) in formulation No.2 (F1) and 43.19%(maximum) in formulation No.9 (F9). Similarly response Y2 was maximum in formulation No9 (F9) and minimum in formulation No.2 (F2).ANOVA was performed to estimate the significance of the model. The ANOVA analysis for both the  responses shown that the both the models are significant. The software analyse the datas and generated 3D plots showing the effect of independent variables on dependent variables.(Figure No. 3(a), 3(b)  Time (hr) % Cumulative Drug Release F1 F2 F3 F4 F5 F6 F7 F8 F9 1 9.585 10.462 11.36 10.415 10.722 9.992 9.397 10.785 10.673 2 32.055 30.925 31.112 29.385 31.738 29.075 30.605 32.255 29.89 3 40.56 40.19 40.441 42.592 40.797 41.966 40.269 40.956 43.19 4 51.35 51.12 51.573 54.345 52.415 53.28 52.169 51.823 54.751 5 68.02 66.02 65.88 68.129 66.504 68.650 66.060 66.252 67.577 6 76.19 75.14 75.921 78.35 77.181 77.913 75.35 78.865 79.931 Arun Gokul et al. / Research in Pharmacy 3(1): 14-22, 2013   20                                          a                                                                     b Figure  3 (a): effect of Carbopol 934 and HPMC K15M on drug release rate at 3 hour Figure 3 (b): effect of Carbopol 934 and HPMC K15M on drug release rate at 6 hour  After generating the model equations to relate the dependent and independent variables, the process was optimized for two responses (Y1 and Y2). Optimum formulation was selected based on the constraints set on independent variables: Y1 (40.19 – 43.19%), Y2 (75% – 79.93%). The final optimal experimental parameters were calculated using the extensive grid search and feasibility search provided in the Design Expert software. The 8 solutions provided by the software from which 4 formulations are randomly selected which was tabulated in the Table 5. Four check point formulations were selected, for which the results of all the dependent variables were found to be within the limits. Table No 6 lists the obtained and predicted values of the check point formulations along with the % prediction error. Linearity correlation plots between the observed experimental values and the predicted values are shown in Fig. 4 and Fig. 5. The accelerated stabilities studies were carried for developed formulations (OF1 TO OF4). Formulations were analyzed for homogeneity, pH, spreadability and drug content. After six weeks studies, it is revealed that there were no changes observed in homogeneity. Formulations showed slight changes in pH, but it were in acceptable limits (± 0.5). Study of drug content remaining in all Arun Gokul et al. / Research in Pharmacy 3(1): 14-22, 2013   21  formulations reveals that there was no definite change observed for drug degradation as shown in Table 7.  Table 5: Solutions provided by Design Expert software           Table 6: The obtained and predicted values   Table 7: Stability studies of the optimized formulations (OF1 – OF4)   Time (Hours) % CUMULATIVE DRUG RELEASE OF OPTIMIZED FORMULATIONS OF1 OF2 OF3 OF4 1 11.321 10.001 9.761 11.291 2 30.349 29.45 31.934 33.177 3 40.923 40.160 40.451 41.101 4 52.810 51.416 50.12 52.350 5 68.541 66.254 65.671 65.913 6 79.119 77.213 76.11 76.943 Optimized formulation Release at 3 hours Release at 6 hours Predicted Actual %Error Predicted Actual %Error OF1 41.0789 40.663 -1.01% 78.4433 79.01 0.722 OF2 40.7656 40.576 -0.463% 77.1667 77.213 0.0691 OF3 40.4556 40.481 0.064% 76.62 76.251 -0.481% OF4 40.6089 40.554 -0.132% 76.5033 76.943 0.575% Sr. no Formulations Weak pH Spreadability Drug  content  1  OF1 0 7.3 42.65 95.6% 2 7.2 42.05 95.2% 4 7.1 40.74 95.1% 6 7.1 39.79 94.2%   2   OF2 0 7.0 42.6 96.4% 2 7.1 41.63 96.3% 4 7.0 41.22 95.7% 6 7.0 40.51 95.0%   3   OF3 0 6.9 42.05 95.1% 2 7.0 41.54 94.8% 4 6.9 41.19 94.2% 6 6.9 40.35 93.2%   4   OF4 0 7.1 40.35 95.2% 2 7.1 40.12 95.1% 4 7.0 38.63 93.4% 6 7.0 37.29 91.7% Arun Gokul et al. / Research in Pharmacy 3(1): 14-22, 2013   22        Figure 4 & 5: the predicted vs Actual plots   Conclusion From this study, it was concluded that the polymers used in the formulation have great effect on various parameters, as the concentration of polymer increases, the drug release will decreases.  References Aukunuru J, Boneppally C, Gunduri V. 2007. Preparation, Characterization and Optimization of  Ibuprofen ointment intended for Topical and Systemic delivery  Tro J Pharm Res;6(4):855-860. Bhosale UV, Kusum Devi V2010.. Formulation and Optimization of Mucoadhesive nano drug delivery system of Acyclovir. Pharmbit; XXII (2):94-104. Carter SJ. Disperse system. In: Cooper and Gunn’s Tutorial Pharmacy. 2000. 6 Delhi: CBS    Publishers and Distributors; 68-72. Chein YW. Novel drug delivery systems. 1992. 2nd ed. Vol. 50, Marcel Dekker, Inc.;New  York,;301-306 Pandya SJ. Statistically Optimization of Drug Formulation Using Factorial Design. [Updated  2008 March 15; cited 2011 Nov 16]. Avaible from: http://www.pharmainfo.net/ reviews/statestically-optimization-drug-formulation-using-factorial-design  40.4540.540.5540.640.6540.740.4 40.6 40.8 41 41.2actualpredicted7676.57777.57878.57979.576 77 78 79actualpredicted

Formulation and optimization of Aceclofenac gel

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Formulation and optimization of Aceclofenac gel

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