IN-VITRO RELEASE STUDY OF IBUPROFEN FROM DIFFERENT TOPICAL FORMULATIONS

IN-VITRO RELEASE STUDY OF IBUPROFEN FROM DIFFERENT TOPICAL FORMULATIONS Riyaz Md. Sakhiyani *, Pasha Mohamed Irshad and Mondal Md. Sahidullah M.M.U College of Pharmacy, K.K Doddi, Ramadevera Betta Road, Ramanagaram-Karnataka. Abstract: Topical route of drug delivery has gained popularity because it avoids lots of disadvantages associated with oral administration. Topical formulations provide a suitable delivery system for drugs because they are greasy and can be easily removed from the skin. Percutaneous absorption of drugs from topical formulations involves the release of the drug from the formulation and permeation through skin to reach the target tissue. The release of the drug from topical preparations depends on the physicochemical properties of the vehicle and the drug employed. In order to enhance drug release and skin permeation, suitable vehicle have been studied. The three bases were chosen for their hydrophilic, hydrophobic and viscosity characteristics. And prepare an Ointment (F1), Cream (F2) and Gel (F3) which contain Ibuprofen as model drug. In vitro diffusion (release) of Ibuprofen from three different bases to an aqueous receptor phase through cellophane membrane was monitored spectrophotometrically at 221 nm. It is established that gel formulations are superior topical formulation for the topical delivery of Ibuprofen over the other two topical formulations, because it gives higher drug release than the cream and ointment formulations. Key words: Topical, Ibuprofen, Formulations, In vitro diffusion. [1-3] INTRODUCTION Delivery of drugs to the skin is an effective and targeted therapy for local dermatological disorders. When technically feasible, topical delivery of drug products, both for local and systemic use, may offer advantages over the oral route. Topical delivery of a drug product which is currently approved as an oral dosage form allows for: Ease of delivery Increased compliance Avoidance of first pass metabolism by the liver Delivery of a more even level of the therapeutic agent over time The possibility of reduced side effects Enhanced efficacy and safety for locally manifested disease Corresponding Author Riyaz Md. Sakhiyani 8 P a g e

Avoids gastrointestinal irritation and metabolic degradation associated with oral administration. large surface area Vast exposure to the circulatory The Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are commonly used as topical analgesic/antirheumatic agents because of the decrease in the incidence of side-effects associated with systemic delivery. Ibuprofen [2-(4- isobutylphenyl)propionic acid], a potent non-steroidal anti-inflammatory (NSAID) drug that is often used for the treatment of acute and chronic arthritic conditions, has ph dependent solubility and permeability. Although ibuprofen is highly permeable through the stomach, its poor water solubility (log P value 3.6) limits its entry into systemic circulation before gastric emptying (30 min to 2 hr) occurs. During gastric empting, ibuprofen enters the small intestine, where it cannot permeate through the membrane despite being solublised. Since dissolution is the rate-limiting step during drug absorption, the poor water solubility in oral forms of ibuprofen results in low bioavailability due to erratic or incomplete absorption from the gastrointestinal tract. In addition to absorption difficulties, oral formulations of ibuprofen can cause gastric mucosal damage, which may result in ulceration and bleeding. Stratum corneum is the principal barrier for cutaneous penetration allowing slow absorption for the majority of drugs. The objective of the present investigation was to deliver the Ibuprofen topically by the use of different formulations e.g; ointment, cream and gel, and to conclude the superior topical formulation for Ibuprofen penetration. MATERIAL AND METHOD: Ibuprofen was gifted sample by Natco Pharma Ltd; Emulsifying wax was supplied by Microfine chemicals; White soft paraffin, Liquid paraffin, Sodium hydroxide, Potassium hydroxide, Glycerin, Carbopol 934, Triethanol amine was supplied by Nice Chemicals Pvt. Ltd. (Kerala, India); Cetyl alcohol, Propylene glycol, Stearic acid was supplied by Loba Chemie Pvt. Ltd. (Mumbai, India); Methyl p-hydroxy benzoate was supplied by Rolex Laboratory Reagent. Preformulation Studies of Pure Ibuprofen: Preformulation study is one of the important prerequisite in development of any drug delivery system. It gives the information needed to define the nature of the drug release is either dissolution or diffusion. Hence, preformulation studies on the obtained sample of drug for identification including solubility analysis, melting point determination, FTIR study of drug, Determination Of λ max and Development of Calibration Curve. a) Solubility Analysis [4] : Preformulation solubility analysis was done, which include the selection of suitable solvent, to dissolve the respective drug. The solubility was done by adding the solute in small incremental amounts to the fixed volume of solvents, after each addition, the system was vigorously Shaken and examined visually for the 9 P a g e

undissolved solute particles. When some amount of the solute remains undissolved, the total amount added up to the point served as a good and rapid estimate of solubility. b) Melting Point Determination [4] : Melting point determination of the obtained sample was done as it is a good first indication of purity of the sample. The presence of relatively small amount of impurity can be detected by a lowering as well as widening in the melting point range. Melting point of drug sample was performed by using Thieles tube method. A fine powder of Ibuprofen was filled in a capillary tube, previously sealed at one end and the capillary tube was tied to the bottom of the thermometer. The thermometer and capillary tube were immersed in to the liquid paraffin taken in the tube. Bottom of the tube was heated gently by means of burner. When the sample starts to melt the reading was recorded. c) FTIR study of Ibuprofen: FTIR study is another identification test for Ibuprofen. The FTIR spectra of pure Ibuprofen was shown in the Figure 1. d) Determination Of λmax [5] : A stock solution of Ibuprofen was prepared by dissolving 10mg of drug in 25ml of NaOH (0.1 N) to obtained stock solution of 400 μg/ml. From this stock solution working standard are prepared. Then scanned in spectrum mode in the range of 400-200 nm using UV-visible spectrophotometer to determine the max (wavelength of maximum absorption) of the drugs. Spectrum was presented in the Figure 2. e) Development of Calibration Curve for Ibuprofen [5] : 10 mg of Ibuprofen was dissolved in Sorenson s Phosphate Buffer (ph 6.8) and made up volume to 100 ml by same solvent. This give the concentration of 100 mcg/ml (stock solution). The stock solution was further diluted to get different concentrations (mcg/ml): 5, 10, 15, 20, 25. Absorbances were taken at the wavelength of 221 nm. The standard curve was obtained by plotting absorbance Vs. concentration in µg/ml. The concentration ranges and absorbance data were reported in Table 1, Calibration graph was plotted using the data and presented in the Figure 3. Formulation of cream, gel and ointment The Ibuprofen was incorporated into the three different Formulations (ointment F1, cream F2 and gel F3) at a concentration of 10 percent by geometric trituration. The three bases were chosen for their different hydrophillic, hydrophobic and viscosity characteristics. Preparation procedure of Ointments [6, 7] : Melt required quantity of emulsifying wax in a porcelain dish, on a water bath. To this melt, incorporate liquid paraffin, white soft paraffin and add other ingredient & drug (10%) one by one with continuous stirring. Remove the foreign particle if present by decanting to a hot vessel and stir until product becomes cool and a semisolid mass is obtained. Formulation of Ointment was designed according to Table 2. Preparation procedure of Cream [6, 7] : Take ingredients of oil phase and heat at 70 c in container. Take ingredients of aqueous phase add heat also at 70 c in 10 P a g e

container. Now add aqueous phase in to organic phase with constant Stirring, cool the solution. Add perfuming agent when temperature is 35 c. Formulation of Cream were designed according to Table 3. Preparation procedure of gels [6-9] : Specific amount of Carbopol 934 was socked in water overnight. The required amount of drug (10%) was dissolved in this solution with stirring at 500 rpm by magnetic stirrer for 1 hour. Carbopol was than neutralized with 0.5% triethanolamine (TEA) with stirring until the desired ph value was approximately reached (6.8-7). Methyl p-hydroxy benzoate was added as preservative. Glycerin was added slowly with stirring to obtain a clear gel. Samples were allowed to equilibrate for at least 24 hours at room temperature prior to performing rheological measurements. Formulation of Gel were designed according to Table 4. Evaluation parameters for prepared formulations [6, 8] : a) Stability study: All three products were placed for stability study for three months at room temperature and at refrigerator temperature for the evaluation of physical characteristics of products like colour change, phase separation, consistency & development of disagreeable odour. b) In vitro release study of Ibuprofen: Release of Ibuprofen from various Formulations was studies using a diffusion cell. A standard cellophane membrane (soaked in ph 6.8 for two hours before use) was fixed to one end of the cylinder with the aid of an adhesive to result in permeation cell. One gram of gel was taken in the cell (donor compartment) and the cell was immersed in beaker (100 ml) containing drug free phosphate buffer ph 6.8 (100 ml) as receptor compartment. The cell was immersed to a depth of 1 cm below the surface of phosphate buffer in the receptor compartment and was agitated using a magnetic stirrer and a temperature of 37 o C ± 0.5 o C was maintained. Sample (1 ml) of the receptor compartment was taken at various interval of time (30, 60, 90, 120, 150, 180 minutes) over a period of 3 hours and assayed for Ibuprofen at 221 nm. The volume withdrawn at each time was replaced with drug free phosphate buffer. Withdrawn amount of sample was suitably diluted with fresh medium and Ibuprofen released at various intervals of time was calculated and plotted against time. Release pattern of all three different formulations are shown in Figure 4 and Table 5. RESULTS : Result of Preformulation Tests for Pure Ibuprofen: a) Solubility Analysis: Freely soluble in acetone, chloroform, ethanol and ether; practically insoluble in water. b) Melting Point Determination: M.P of Ibuprofen was found to be 76 o C. c) FTIR study of Ibuprofen: FTIR spectra was given in the Figure 1. d) Determination Of λ max : Absorption maximum ( max ) was found 221 nm. Spectrum was given in the Figure 2. e) Development of Calibration Curve for Ibuprofen: 11 P a g e

The concentration ranges and absorbance data were reported in Table 1. Calibration graph was plotted using the data and presented in the Figure 3. Result of Evaluated Ibuprofen Ointment (F1), Cream (F2), and Gel (F3): a) Stability study: There was no evidence of phase separation, development of disagreeable odour, change in colour and consistency of the all three products during stability study for three months at both room temperature and at refrigerator temperature. b) In-vitro release studies: Different release profile of Ibuprofen was observed due to the different Formulations examined, which are given in the Table 5 and Figure 4. DISCUSSION: After preformulation test of Ibuprofen, it can say that the Ibuprofen which has used in this experiment is pure. The prepare formulations [Ointment (F1), Cream (F2), and Gel (F3)] has sufficient stability. And according to the release study, the highest drug release obtained with gel formulation. The gel formulation appears to present the ideal combination of solubility and physical diffusivity through the vehicle, yielding the highest drug release rate. CONCLUSION: In the present study, topical delivery of Ibuprofen in ointment, cream and gel base were studied. From the above study, gel topical Formulations could be suggested as a good candidate for the topical delivery of Ibuprofen, giving higher drug release compared to the cream and ointment formulations. REFERENCES: [1] Mitchel JT. Topical Delivery of Oral Drugs: Designing The Path to the Patient. American Academy of Dermatology, 59th Annual Meeting. March 2 6: 2001. [2] Aukunuru1 J, Bonepally C, Guduri V. Preparation, Characterization and Optimization of Ibuprofen Ointment Intended for Topical and Systemic Delivery. Tropical J. Pharm. Res. Dec. 2007; 6 (4): 855-860. [3] Lakshmi PK, Kumar MK, Sridharan A, Bhaskaran S. Formulation and Evaluation of Ibuprofen topical gel: A novel approach for penetration enhancement. Int. J. Applied Pharm. 2011; 3(3): 25-30. [4] Aravindaram AS, Nandan RVS, Gowda DV, Khan MS. Development And Evaluation Of Ketoprofen Loaded Biopolymer Based Transdermal Film. Der Pharmacia Lettre. 2011; 3 (3): 233-244. [5] Swansi B, Gupta V, Dr. Prasad C.M, Moolchand. Formulation and Evaluation of Controlled release Ibuprofen Liposphere. J. Natura Conscientia. 2011; 2(2): 363-374. [6] Shah NV, Sheth NS, Mistry RB, Seth AK, Shah PM, Shah NC. In- Vitro Release of Diclofenac Sodium From Different Topical 12 P a g e

Formulations. Pharm. Sci. monitor. 2010: 478-786. [7] Jain H, Patel A, Gediya S, Upadhyay U. In vitro release of diclofenac sodium from different topical Formulations. Int. J. Res. Pharm. Sci. 2011; 2(1): 26-29. [8] Patel J, Patel B, Banwaith H, Parmar K, Patel M. Formulation And Evaluation of Topical Aceclofenac Gel Using Different Gelling Agent. Int. J. Drug Dev. & Res. Jan-March 2011; 3(3): 156-164. [9] Debnath SK, Sarkar S, Janakiraman K, Chakraborty S. Formulation and Evaluation of Aceclofenac Gel. Int. J. ChemTech Res. April-June 2009; 1(2): 204-207. Table 1: Standard Curve Data of Ibuprofen at 221 nm: S.No Concentration (µg/ml) Absorbance (nm) 1. 5 0.202 2. 10 0.426 3. 15 0.615 4. 20 0.820 5. 25 1.002 Table 2: Formula for Ointment (F1) Ingredients Quantity Ibuprofen 2.006 g Emulsifying wax 6g White soft paraffin 10g Liquid paraffin 4g Sodium hydroxide 0.02g Methyl p-hydroxy 0.04g benzoate Table 3: Formula for Cream (F2) Ingredients Quantity Ibuprofen 2.006g Stearic acid 15g Potassium hydroxide 0.50g Sodium hydroxide 0.18g Cetyl alcohol 0.5g Propylene glycol 3g Glycerin 1ml Methyl p-hydroxy benzoate 0.04g Water 14.88ml 13 P a g e

Table 4: Formula for Gel (F3) Ingredients Quantity Ibuprofen 2.006g Carbopol 934 0.2g Triethanol amine 0.1g Methyl p-hydroxy benzoate 0.04g Glycerin 2ml Purified water 17.4ml Table 5: In-vitro Release of formulations Formulation % drug release in Time (minutes) 30 60 90 120 min. min. min. min. (F1) 0.439 0.589 1.473 2.902 0.585 0.908 5.777 8.999 (F2) (F3) 4.545 10.820 16.441 21.501 Figure 1: FTIR Spectra of Ibuprofen (KBr) 14 P a g e

Cumulative % release Absorbance (nm) INTERNATIONAL JOURNAL OF 1.2 1 0.8 0.6 0.4 0.2 0 R² = 0.999 0 20 40 Concentration (µg/ml) Figure 2: max determination of Ibuprofen: Figure 3: Calibration Curve of Ibuprofen at 221 nm: 25 20 15 10 5 0 0 20 40 60 80 100 120 140 Time (minutes) F1 F2 F3 Figure 4: In-vitro Release Curve of prepared formulations 15 P a g e