Journal of Pharmaceutical and Biomedical Analysis Letters. Analysis Letters

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1 Kishor et al, JPBMAL, 2015, 3(2): ISSN: Journal of Pharmaceutical and Biomedical Analysis Letters Journal Home Page: Research Article Open Access Design and Characterization of Chronotherapeutic Drug Delivery System of Dexibuprofen for the Treatment of Arthritis Kishor* 1, Bindu Madhavi 2, K. Someshwar 2 1 Department of Pharmceutics, St. Pauls College of Pharmacy, Hyderabad, Telangana, India 2 Manager, Formulation R&D, KP Labs (A Division of KDPL), Kothapet, Hyderabad Telangana, India A B S T R A C T In the present research work, chronotherapeutic drug delivery of Dexibuprofen was carried out. Chronotherapeutics refers to a treatment method in which in-vivo drug availability is timed to match rhythms of disease, in order to maximize the health benefits and minimize the adverse effects. Literature review was carried out regarding chronotherapeutic tablets, from that Dexibuprofen was selected as model drug and various grades of HPMC and Eudragit were selected as polymers. Analytical profile of drug molecule was established in 0.1 N HCL, 6.8 ph phosphate buffer and 7.4 ph phosphate buffer and standard calibration curve was plotted by taking different concentrations. The drug and excipient compatibility studies were carried out by using FTIR spectroscopy. From the studies it was evident taht the drug and excipients are compatible with each other. Core tablets were formulated with varying concentrations of HPMC K100, HPMC E15M and Ethyl cellulose. The formulated core tablets were evaluated for various evaluation parameters. The optimized formulation was being coated with the different coating formulations Eudragit L 100 and Eudragit S 100 ( 1:1) in combination (7.5 %), in the form of compressed coating polymers. The compressed coated were evaluated for various evaluation parameters. Analysis of drug release mechanism showed that the drug release from the formulations followed non-fickian diffusion and the best fit model was found to be Korsmeyer-Peppas and Zero order. Based on the results of evaluation tests formulation coded CF 10 was concluded as best formulation. Keywords: Dexibuprofen, HPMC, Ethyl cellulose, Eudragit L 100 & Eurdagit s 100, Cumulative % of drug release, Chronotherapeutic drug delivery. A R T I C L E I N F O CONTENTS 1. Introduction Materials and Methods Results and discussion Conclusion Acknowledgement References Article History: Received 25 April 2015, Accepted 29 May 2015, Available Online 18 July 2015 *Corresponding Author Kishor Department of Pharmaceutics, St. Pauls College of Pharmacy, Hyderabad, Telangana. India Manuscript ID: JPBMAL2855 PAPER-QR CODE Journal of Pharmaceutical and Biomedical Analysis Letters 294

2 Citation: Kishor, et al. Design and Characterization of Chronotherapeutic Drug Delivery System of Dexibuprofen for the Treatment of Arthritis. J. Pharm. Biomed. A. Lett., 2015, 3(2): Copyright 2015 Kishor. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. 1. Introduction Chronotherapeutic Drug Delivery System [1-4] The term "chrono" basically refers to the observation that every metabolic event undergoes rhythmic changes in time. Researchers have concluded that all living organisms are composites of rhythms with varying frequencies that may range from seconds to seasons. Perhaps the best-known and studied chronobiologic frequency is the circadian rhythm, which approximates the earth's 24-hour rotation around the sun. Researchers have recently concluded that both disease states and drug therapy are affected by a multitude of rhythmic changes that occur within the human body. Chronotherapeutics refers to a treatment method in which in vivo drug availability is timed to match rhythms of disease in order to optimize therapeutic outcomes and minimize side effects. It is based on the observation that there is an interdependent relationship between the peak-to-trough rhythmic activity in disease symptoms and risk factors, pharmacologic sensitivity, and pharmacokinetics of many drugs. As more continues to be learned about chronobiology and chronotherapeutics, it is becoming increasingly more evident that the specific time that patients take their medication may be even more significant than was recognized in the past. The tradition of prescribing medication at evenly spaced time intervals throughout the day, in an attempt to maintain constant drug levels throughout a 24-hour period, may be changing as researchers' report that some medications may work better if their administration is coordinated with day-night patterns and biological rhythms. Diseases and chronotherapeutics Up to now, design of drug delivery systems have been governed by the homeostatic theory. This theory is based on the assumption of biological functions that display constancy over time. However, chronobiological studies have established circadian rhythm for almost all body functions, e.g., heart rate, blood pressure, body temperature, plasma concentration of various hormones, gastric ph and renal function. It has become apparent that rhythmic processes are indispensable for the treatment of human diseases. Just as physiological functions vary over time, pathological states of disease have circadian rhythms. minimize the undesired ones. Study of influence of biological rhythm on the effects of medication is known as chronopharmacology while the science of study of biological rhythms is known as chronobiology. With the understanding of biological time keeping the idea came that these rhythms must affect how the body responds to drugs administered over the course of the day [1]. In order to increase the effectiveness of drug there are many approaches have been applied, here one of the technique is described which chronotherapeutic drug delivery system is. Many functions of the human body vary considerably in a day. These variations cause changes both in disease state and in plasma drug concentrations. Human circadian rhythm is based on sleep activity cycle, is influenced by our genetic makeup and hence, affects the body s functions day and night (24-hour period) chronopharmaceutical drug delivery systems (ChrDDS) should embody time-controlled and sitespecific drug delivery systems. The goal in drug delivery research is to develop formulations to meet therapeutic needs relating to particular pathological conditions. Research in the chronopharmacological field has demonstrated the importance of biological rhythms in drug therapy, and his brought a new approach to development of drug delivery system. Chronotherapy Coordinating biological rhythms with medical treatment is known as chronotherapy, which allows for appropriate dosing of actives at the most suitable times of the day, thus improving efficacy and reducing undesirable side effects. Advantages of Chronotherapy Chronotherapy is more effective when aperson sleeps for several hours. While Chronotherapy patients often fall asleep this improves their condition and confidence as well. Chronotherapy is different from other treatments because it got the beginning, middle, and an end. So one can predict easily the point at which it will work. It gives you a new schedule like getting up and sleeping early which will be quite unusual for some days but it will give u a period to adjust psychologically. Epidemiological studies have documented the elevated risk Improved stability of disease symptoms during the 24-hour cycle. The No risk of dose dumping [7] potential benefits of chronotherapeutics have been Disadvantages of Chronotherapy demonstrated in the management of a number of diseases. It develops a non 24 hours sleep wake syndrome In particular there is a great deal of interest in how after the treatment as the person sleeps or over 24 chronotherapy can particularly benefit patients suffering hours during the treatment. from allergic rhinitis, rheumatoid arthritis and related Person become less productive during disorders, asthma, cancer, cardiovascular diseases, and chronotherapy and staying awake till the other peptic ulcer disease. Chronotherapy considers a person s schedule will be bit uncomfortable. biological rhythms in determining the timing and amount of Medical supervision is mandatory for this therapy. medication to optimize a drug s desired effects and Large number of process variables. Journal of Pharmaceutical and Biomedical Analysis Letters 295

3 Trained /skilled person is needed for manufacturing [8]. 2. Materials and Methods Materials: Dexibuprofen, Ethyl Cellulose, Eudragit L-100, Eudragit S- 100, Eudragit RSPO, Hydroxy Propyl Methyl Cellulose K100M, Lactose, Mg. Stearate, Talc. Methodology: Standard Calibration Curve for Dexibuprofen: Buffers Used: 1. Preparation of 0.1N Hydrochloride: 8 ml of Hydrochloric acid (conc.) make up to 1000 ml with Distilled water this gives 1000 ml of 0.1N HCl. 2. Preparation of simulated Intestinal fluid (ph 7. 4 Buffer): 50 ml of 0.2M Potassium Dihydrogen Ortho Phosphate and add 39.1 ml of 0.2M Sodium Hydroxide Make up to 200 ml with Distilled water, this gives 200 ml o f ph 7.4 Simulated intestinal fluid. 3. Preparation of 6.8 ph Buffer: 50 ml of 0.2 M Potassium Dihydrogen Ortho Phosphate and add 22.4 ml of 0.2M Sodium Hydroxide Make up to 200 ml with Distilled water, this gives 200 ml o f ph 6.8 Buffer. Preparation of 0.2 M potassium Dihydrogen Ortho Phosphate: Dissolve o f Potassium dihydrogen ortho phosphate in Distilled water and make up to 1000 ml with Distilled water. II. Preparation of 0.2 M Sodium hydroxide: Dissolve 8.0 gm of Sodium hydroxide in Distilled water and make upto 1000 ml with Distilled water. Determination of absorption maxima: A solution of Dexibuprofen containing the concentration 10 µg/ ml was prepared in 0.1N HCl, 7.4 PH & phosphate buffer 6.8 PH respectively, UV spectrum was taken using Double beam UV/VIS spectrophotometer. The solution was scanned in the range of Calibration Curve for Dexibuprofen (in 0.1N HCl, 6.8 PH, 7.4 ph buffers) Preparation of stock solutions For Dexibuprofen: 10 mg of Dexibuprofen drug was accurately weighed and dissolved in 10 ml of 0.1N HCl, 7.4 PH, and 6.8 PH in 10 ml volumetric flask, to make (1000 µg/ml) standard stock solution (1). Then 1 ml stock solution (1) was taken in another 10 ml volumetric flask to make (100 µg/ml) standard stock solution(2), then again 1 ml of stock solution (2) was taken in another 10 ml volumetric flask and then final concentrations were prepared 2, 4,6, 8, 10, 12, 14, 16, 18, and 20 µg/ml with 0.1N HCl, 7.4 PH, and 6.8 PH. The absorbance of standard solution was determined using UV/ VIS spectrophotometer at 228nm and 232nm. Linearity of standard curve was assessed from the square of correlation coefficient (r 2 ) which determined by least-square linear regression analysis. Preparation of blend for Dexibuprofen Core: The composition of the blend includes (Table 5) Dexibuprofen, Ethyl cellulose, HPMCK100M, HPMCE15, Eudragit RSPO which were passed through sieve 80 individually and were mixed with already sieved Talc, Magnesium stearate, Lactose in mortar and pestle and were subjected to different pre formulation parameters. Pre-formulation Parameters: The quality of tablet, once formulated by rule, is generally dictated by the quality of physicochemical properties of blends. There are many formulations and process variables involved in mixing and all these can affect the characteristics of blends produced. The various characteristics of blends tested as per Pharmacopoeia. Angle of repose: The frictional force in a loose powder can be measured by the angle of repose. It is defined as, the maximum angle possible between the surface of the pile of the powder and the horizontal plane. If more powder is added to the pile, it slides down the sides of the pile until the mutual friction of the particles producing a surface angle, is in equilibrium with the gravitational force. The fixed funnel method was employed to measure the angle of repose. A funnel was secured with its tip at a given height (h), abo ve a graph paper that is placed on a flat horizontal surface. The blend was carefully pored through the funnel until the apex of the conical pile just touches the tip of the funnel. The radius (r) of the base of the conical pile was measured. Bulk density: Density is defined as weight per unit volume. Bulk density, is defined as the mass of the powder divided by the bulk volume and is expressed as gm/cm 3. The bulk density of a powder primarily depends on particle size distribution, particle shape and the tendency of particles to adhere together. Bulk density is very important in the size of containers needed for handling, shipping, and storage of raw material and blend. It is also important in size blending equipment. 10 gm powder blend was sieved and introduced into a dry 20 ml cylinder, without compacting. The powder was carefully leveled without compacting and the unsettled apparent volume, Vo, was read. Tapped density: After carrying out the procedure as given in the measurement of bulk density the cylinder containing the sample was tapped using a suitable mechanical tapped density tester that provides 100 drops per minute and this was repeated until difference between succeeding measurement is less than 2% and then tapped volume, V measured, to the nearest graduated unit. Measures of powder compressibility: The Compressibility Index (Carr s Index) is a measure of the propensity of a powder to be compressed. It is determined from the bulk and tapped densities. In theory, the less compressible a material the more flowable it is. As such, it is measures of the relative importance of interparticulate interactions. In a free- flowing powder, such interactions are generally less significant, and the bulk and tapped densities will be closer in value. For poorer flowing materials, there are frequently greater inter particle interactions, and a greater difference between the bulk and tapped densities will be observed. Preparation of dexibuprofen core tablets: Each core tablet (average weight 400 mg) for in-vitro drug release studies consisted of Dexibuprofen, Ethyl cellulose, Eudragit RSPO, HPMC K 1OO M, HPMC E 15, Talc, Lactose and Magnesium stearate, Dicalcium phosphate Journal of Pharmaceutical and Biomedical Analysis Letters 296

4 (Table 5). The materials were weighed, mixed and passed through a mesh no 60 to ensure complete mixing. The thoroughly mixed materials were then directly compressed into tablets using 12 mm round, flat punches on a tabletpunching machine. Tablet quality control tests such as weight variation, hardness, friability, thickness, and dissolution in different media were performed on the core tablets. Preparation of dexibuprofen compressed coated tablets: Coating of Dexibuprofen core tablets: The optimized core tablets (F5 and F6) were compressed coated with different quantities (Table 6) of coating material containing of Eudragit L 100 and Eudragit S 100 indifferent ratios such as 1:1, 1:2, 2:1 in different concentrations like 5 %, 7.5 %. Tablet quality control tests such as weight variation, hardness, friability, thickness, and drug release studies in different media were performed on the compression coated tablets. Evaluation of Tablets The designed formulation score and compression coated Dexibuprofen tablets were studied for their physicochemical properties like tablet appearance, weight variation, hardness, thickness, friability and drug content. Tablet appearance: The general appearance of tablet, its visual identity & overall elegance is essential for consumer acceptance, for control of lot-to-lot uniformity & for monitoring troublefree manufacturing. It includes size, shape, colour, presence or absence of an odour, taste, surface texture, physical flows & consistency & legibility of identifying markings. Weight variation test: To study the weight variation, twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was determined from the collective weight. The weight variation test would be a satisfactory method of deter mining the drug content uniformity. Not more than two of the individual weights deviate from the average weight by more than the percentage shown in the following table and none deviate by more than twice the percentage. The mean and deviation were determined. Hardness: Hardness of tablet is defined as the force applied a cross the diameter of the tablet in order to break the tablet. The resistance of the tablet to chipping, abrasion or breakage under condition of storage transformation and handling before usage depends on its hardness. For each formulation, the hardness of three tablets was determined using Monsato hardness tester and the average is calculated and presented with deviation. Thickness: Tablet thickness is an important characteristic in reproducing appearance. Tablet thickness & diameter is influenced by the amount of fill material in the die-cavity, die diameter & compaction force applied. Average thickness for core and coated tablets is calculated and presented with deviation. It is carried out by Vernier calipers. Friability: It is measured of mechanical strength of tablets. Roche friabilator was used to determine the friability by following procedure. Pre weighed tablets were placed in the friabilator. The tablets were rotated at 25 rpm for 4 minutes (100 rotations). In -Vitro Drug Release Studies Drug release studies of Dexibuprofen core tablets: The core tablets containing 400 mg Dexibuprofen of were tested in (ph 6.8), for their dissolution rates. Dissolution studies were performed using USP paddle type sample of 5 ml was withdrawn and replaced with equal volume of fresh medium. The samples were analyzed spectrophotometrically at respective 232 nm. Drug release studies of compressed coated Dexibuprofen tablets: The release of Dexibuprofen from coated tablets was carried out using USP paddle-type dissolution apparatus at a rotation speed of 50 rpm, and a temperature of 37±0.5 C. For tablets, simulation of gastrointestinal transit conditions was achieved by using different dissolution media. Thus, drug release studies were conducted in simulated gastric fluid (SGF, ph 1.2) for the first 2 hours as the average gastric emptying time is about 2 hours. Then, the dissolution medium was replaced with enzyme- free simulated intestinal fluid ( SIF, ph 7.4 ) and tested for drug release for 3 hours, as the average small intestinal transit time is about 3 hours, and finally enzymefree colonic ph 6.8 was used up to 12 hours to mimic colonic ph conditions. Drug release was measured from compressed coated Dexibuprofen tablets, added to 900 ml of dissolution medium. 5 ml of sample was withdrawn every time and replaced with fresh medium, samples withdrawn at various time intervals were analyzed spectrophotometrically at 228 nm and 232 nm respectively. All dissolution runs were performed for six batches. The results were given with deviation. Evaluation of Release Rate Kinetics Various models were tested for explaining the kinetics of drug release. To analyze the mechanism of the drug release rate kinetics of the dosage form, the obtained data were fitted into zero-order, first order, Higuchi, and Korsmeyer- Peppas release model. Zero order release rate kinetics: To study the zero order release kinetics the release rate data ar e fitted to the following equation. F = K o t Where, F is the drug release at time t, and K o is the zero order release rate constant. The plot of % drug release versus time is linear. First order release rate kinetics: The release rate data are fitted to the following equation Log (100-F) = kt A plot of log cumulative percent of drug remaining to be released vs. Time is plotted then it gives first order release. Higuchi release model: To study the Higuchi release kinetics, the release rate data were fitted to the following equation. F = k t1/2 Where, k is the Higuchi constant. In higuchi model, a plot of % drug release versus square root of time is linear. Korsmeyer and Peppas release model: The mechanism of drug release was evaluated by plotting the log percentage of drug released versus log time according to Korsmeyer- Journal of Pharmaceutical and Biomedical Analysis Letters 297

5 Peppas equation. The exponent n indicates the mechanism of drug release calculated through the slope of the straight Line. M t /M = K t n Where, M t /M is fraction of drug released at time t, k represents a constant, and n is the diffusional exponent, which characterizes the type of release mechanism during the dissolution process. For non-fickian release, the value of n falls between 0.5 and 1.0; while in case of Fickian diffusion, n = 0.5; for zero-order release (case II transport), n=1; and for super case II transport, n > 1. In this model, a plot of log (M t /M ) versus log (time) is linear [33]. 3. Results and Discussion The present study was aimed to developing compressed coated Dexibuprofen formulations for colon targeting using ethyl cellulose and enteric coating polymers like Eudragit L100 and Eudragit S 100. All the formulations were evaluated for physicochemical properties and in-vitro drug release studies. Experimental Method: Graphs of Dexibuprofen was taken in Simulated Gastric fluid (ph 1.2) and Simulated Intestinal Fluid (ph 6.8 and 7.4) Calibration curve of Dexibuprofen in 0.1N HCl (228 nm). Table 3: Observations for graph of Dexibuprofen in 0.1 N HCl. Conc [µg/ml] Abs Figure 2: Standard graph of Dexibuprofen in ph 7.4 Calibration curve of Dexibuprofen in colonic ph 6.8 ph (232 nm) Table 5: Observations for graph of Dexibuprofen in 6.8 ph Conc [µg/ml] Abs Figure 3: Standard graph of Dexibuprofen in 6.8 ph buffer. FT-IR Graphs Figure 1: Standard graph of Dexibuprofen in 0.1N HCl Calibration curve of Dexibuprofen in 7.4 ph Simulated Intestinal Fluid (232 nm) Table 4: Observations for graph of Dexibuprofen in 7.4 ph Conc [µg/ml] Abs Figure 4: FT-IR of Pure Drug Journal of Pharmaceutical and Biomedical Analysis Letters 298

6 ± 0.1 to 3.4 ± 0.21 kg/cm. The core tablets of Dexibuprofen were also found to comply with the friability test since the weight loss was found to be in the range of 0.25 ± to 0.55 ± %.The tablets thickness was found to be in the range of 2.81 ± to 2.96 ± mm. All formulations were complying with the standard Pharmacopoeial specifications. Thus the core tablets of Dexibuprofen formulated in the study were found to have the required characteristics for compression coating with Eudragit L100 and Eudragit S 100. Figure 5: FT-IR of Optimized Formula Pre-formulation Parameters Of Core Material Dexibuprofen blend was subjected to various preformulation parameters. The apparent bulk density and tapped bulk density values ranged from 0.52 to and to respectively. According to Tables 3 and 4, the results of angle of repose and compressibility index (%) ranged from 32.74±0.12 to 37.08±0.96 and 13.37±0.38 to 14.72±0.62 respectively. The results of angle of repose (<35) and compressibility index (<23) indicates fair to passable flow properties of the powder mixture. These results show that the core powder mixture has good flow properties. The formulation blend was directly compressed to tablets and in-vitro drug release studies were performed. In-Vitro Drug Release Studies Drug Release Studies of Dexibuprofen Core Tablets The core tablets containing 200 mg of Dexibuprofen were tested in 6.8 ph phosphate buffer solution for their dissolution rates. Dissolution studies were per formed using USP dissolution apparatus [2], with 50 rpm, at 37±0.5 C. At various time intervals, a sample of 5 ml was withdrawn and replaced with equal volume of fresh medium. The samples were analyzed spectrophotometrically at 232 nm. Figure 6: Drug release profile of core formulations F1, F2, F3 The dissolution results of Dexibuprofen core tablets in SIF(pH 6.8)solutions were shown in Table. From the above drug release profiles of core tablets it was interpreted that among all the formulations, formulations such as F5 and F6 with Ethyl cellulose: Dexibuprofen ratio (1:2 and 1:4) have shown ± 0.39 % and ± 0.30 % drug release respectively. These were subjected to compressed coating using enteric coating polymers such as Eudragit L 100 and Eudragit S 100. The optimized core tablets (F5 and F6) were compressed coated with different quantities (Table 7) of coating material containing of Eudragit L 100 and Eudragit S 100. Tablet quality control tests such as weight variation, hardness, friability, thickness, and drug release studies in different media were performed on the compression coated tablet. Figure 7: Drug release profile of core formulations F4, F5, F6 Evaluation report of Dexibuprofen coated tablets Quality control test soft tablets such as Weight variation (500.51±0.16), Thickness (3.78 ± 0.062), Hardness (6.96 ± 0.20), Friability (0.26 ± 0.015), Drug content (99.54 ±0.27) were performed to compressed coated Dexibuprofen tablets and the results were found to be within the Indian pharmacopoeial specifications. Resulted tablets were evaluated for drug release by using USP dissolution apparatus [2]. Assay of tablets shown that tablets are of required purity and matches with Indian pharmacopoeial specification. In-Vitro Drug Release Studies of Dexibuprofen of Coated Tablets: The coated tablets containing 200 mg of Dexibuprofen were tested in Simulated Gastric Fluid (ph 1.2), Simulated Intestinal Fluid (ph 7.4) and colonic Ph 6.8 buffer for their dissolution rates. Dissolution studies were performed using USP dissolution test apparatus [2], with 50 rpm, at 37±0.5 C. At various time intervals, a sample of 5 Quality Control Parameters for Core and Coated Formulation Evaluation report of Dexibuprofen core tablets Dexibuprofen powder was compressed directly into a core tablet by using direct compression vehicle such as magnesium stearate and talc. The hardness of the core tablets of Dexibuprofen was found to be in the range of 2.4 Journal of Pharmaceutical and Biomedical Analysis Letters 299

7 ml was withdrawn and replaced with equal volume of fresh medium. The samples were analyzed spectrophotometrically at 228 nm and 232 nm respectively. Figure 8: Drug Release Profile of Coated Formulations CF1 to CF6 Figure 11: First Order Kinetic Model of coated formulation CF10 Figure 9: Drug Release Profile of Coated Formulations F7 to F12 Figure 12: Higuchi Kinetic Model of coated formulation CF10 In-vitro drug release studies were conducted to the compressed coated Dexibuprofen tablets and drug release studies shown that formulation F10 have shown good release behavior in colon (98.54 ± 0.20) in 12 hour with limited drug release in stomach and intestine. This indicates that Eudragit L 100 and Eudragit S100 (1:1) in 7.5 %concentration were able to release maximum drug in the colon at 12 hour.this study confirms that Eudragit L 100, Eudragit S 100 act as carrier by using ethyl cellulose as binder to deliver drug to the colon effectively. Kinetic Studies of Coated Formulations Figure 13: Peppas Kinetic Model of coated formulation CF10 4. Conclusion Chronotherapeutics refers to a treatment method in which in vivo drug availability is timed to match rhythms of disease, in order to maximize the health benefits and minimize the adverse effects. Literature review was carried out regarding chronotherapeutic tablets, from that Dexibuprofen was selected as model drug and various grades of HPMC, Ethyl cellulose and Eudragit were selected Figure 10: Zero Order Kinetic Model of coated formulation as polymers. CF10 Journal of Pharmaceutical and Biomedical Analysis Letters 300

8 Analytical profile of drug molecule was established in 0.1 N HCL, 6.8 ph phosphate buffer and 7.4 ph phosphate buffer and standard calibration curve was plotted by taking different concentrations with lambda max of 228 nm and 232 nm. The drug and excipient compatibility studies were carried out by using FTIR spectroscopy. From the studies it was evident that the drug and excipients are compatible with each other. Eudragit L 100 and Eudragit S 100 (1:1) in combination (7.5 %),in the form of compressed coating polymers were capable of protecting S. No Journal of Pharmaceutical and Biomedical Analysis Letters 301 Dexibuprofen from being released in the upper region of Gastro Intestinal system, i.e. Stomach and small intestine. The in-vitro drug release studies indicated that formulation CF10 was a promising system to provide targeting of Dexibuprofen to the colon. Analysis of drug release mechanism showed that the drug release from the formulations followed non- Fickian diffusion and release pattern of the above formulation was best fitted to Korsmeyer Peppas model and zero-order model. Based on the results of evaluation tests formulatio n coded CF 10 was concluded as best formulation. Table 1: Composition of Dexibuprofen core tablets Quantity/tablet(mg) S.No Ingredients Formulation codes F1 F2 F3 F4 F5 F6 1 Dexibuprofen HPMCK 100M HPMC E Ethyl cellulose Lactose Magnesium stearate Talc Total Weight of tablet(mg) Table 2: Composition of coating material of Coated Tablets. Ingredients 5% 7.5% 1:1 1:2 2:1 1:1 1:2 2:1 Eudragit L 100(mg) 2.5 mg 1.7 mg 3.4 mg 3.75 mg 2.5 mg 5 mg Eudragit S 100(mg) 2.5 mg 3.4 mg 1.7 mg 3.75 mg 5 mg 2.5 mg Talc 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg 0.5 mg MCC Qs Qs Qs Qs Qs Qs Total (percentage) Table 6: FTIR interpretation Wave number in formulation (cm -1 ) Pure drug Optimized formulation Characteristic Wave number range (cm -1 ) Bond nature and bond attributed O-H stretching Carboxylic acids C=O stretching Carboxylic acids C-C stretch in ring aromatics C-O stretch Esters C-H oop aromatics =C-H bend Alkenes Table 7: Pre-formulation parameters of Core blend Formulation Code Angle of Repose Bulk density (gm/ml) Tapped density (gm/ml) Carr s index (%) Hausner s Ratio F ± ± ± ± F ± ± ± ± F ± ± ± ± F ± ± ± ±

9 F ± ± ± ± F ± ± ± ± Table 8: In-vitro Drug Release Studies of Dexibuprofen core tablets Time (Hours) F1 F2 F3 F4 F5 F ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.30 Formulation codes Table 9: Quality control parameters for (core and coated tablets) Weight variation(mg) Hardness(kg/cm 2 ) Before coating After coating Before coating After coating CF ± ± ± ±1.08 CF ± ± ± ±0.15 CF ± ± ± ±0.17 CF ± ± ± ±0.11 CF ± ± ± ±0.05 CF ± ± ± ±0.11 CF ± ± ± ±0.15 CF ± ± ± ±0.13 CF ± ± ± ±0.11 CF ± ± ± ±0.20 CF ± ± ± ±0.25 CF ± ± ± ±0.20 Formulation codes Table 10: Quality control parameters for (core and coated tablets) Thickness Thickness Friability before before coating after coating coating (%loss) (mm) (mm) Friability after coating (%loss) Drug content (%) CF1 2.82± ± ± ± ±0.69 CF2 2.83± ± ± ± ±1.03 CF3 2.85± ± ± ± ±0.59 CF4 2.89± ± ± ± ±1.02 CF5 2.87± ± ± ± ±0.69 CF6 2.81± ± ± ± ±0.59 CF7 2.86± ± ± ± ±1.88 CF8 2.91± ± ± ± ±0.49 CF9 2.87± ± ± ± ±0.67 CF ± ± ± ± ±0.27 CF ± ± ± ± ±0.41 CF ± ± ± ± ±0.52 Table 11: In- vitro Drug Release profile for coated formulations (CF1- CF6) Time (hrs) CF1 CF2 CF3 CF4 CF5 CF ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.20 Journal of Pharmaceutical and Biomedical Analysis Letters 302

10 5 1.38± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±S0.32 Table 12: In-vitro Drug Release profile for coated formulations (CF7-CF12) Time (hrs) CF7 CF8 CF9 CF10 CF11 CF ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.19 Table 13: Kinetic Studies of coated formulations Formulation codes Zero order First order Higuchi model Peppas model CF CF CF CF CF CF CF CF CF CF CF CF Acknowledgement The authors sincerely acknowledge the KP Labs (A Diviison of Karthikeya Drugs & Pharmaceuticals Private Limited), Kotahpet, Hyderabad, for providing Drugs and support to carry out this research work.. 6. References [1] Obitte et al. Ibuprofen self-emulsifying drug delivery system. World Journal of Pharmacy and Pharmaceutical Sciences Vol 4, Issue 02, [2] Jharana Mallick et al. Alginate beads of ibuprofen for oral sustained drug delivery: an in vitro evaluation issn: IJPCBS 2013, 3(3), [3] Rehnasalim et al. Biowaiver monographs of dexibuprofen issn: IJPCBS 2013, 3(2) [4] ISSN: Journal of Global Trends in Pharmaceutical Sciences Volume 3, Issue 3, pp , Chronotherapeutics drug delivery systems challenges to pharmaceutical field July-September 2012 [5] Studies on the development of colon specific drug delivery system of ibuprofen using polysaccharide extracted from Abelmoschus esculentus L. (Moench.) Asian Journal of Pharmaceutical Sciences 2012, 7 (1): [6] Alpana Ram et al. Preparation and characterization of ibuprofen loaded transferosome as a novel carrier for transdermal drug delivery system Asian J Pharm Clin Res, Vol 5, Issue 3, 2012, [7] Asian Journal of Pharmaceutical Sciences, Formulation and evaluation of dexibuprofen alginate clay composite microbeads for oral controlled drug delivery 2012, 7 (1): Journal of Pharmaceutical and Biomedical Analysis Letters 303

11 [8] Chronotherapy: a concept, pauperism and approches International Journal of Pharmaceutical Development & Technology Vol 1 Issue 1 Jan Jun [9] V S Chopra et al Chronotherapy: A Novel Concept In Drug Delivery Der Pharmacia Lettre, 2010, 2(3): [10] Chronotherapeutic Drug Delivery of Pectin Vs. Guar Gum, Xanthan Gum Controlled Release Colon Targeted Directly Compressed Propranolol Hcl Matrix Tablets SAJ Pharmacy and Pharmacology Volume 1 Issue 2 [11] Development and evaluation of a chronotherapeutic drug delivery system of torsemide Brazilian Journal of Pharmaceutical Sciences vol. 47, n. 3, jul./sep., 2011 [12] Chronotherapeutics and Chronotherapeutic Drug Delivery Systems Tropical Journal of Pharmaceutical Research, October 2009; 8 (5): [13] Formulation and Optimization of Chronotherapeutic Drug Delivery from Carvedilol Sulphate Compression Coated Tablets by using Design of Experiment Approach Journal of Applied Pharmaceutical Science Vol. 3 (10), pp , October, [14] Formulation and Evaluation of Timed Delayed Capsule Device for Chronotherapeutic Delivery of Terbutaline Sulphate Ars Pharm, 2010, Vol.50 nº 4; [15] International Journal of Current Pharmaceutical Research Vol 2, Issue 3, 2010 S+ Bbuprofen (dexibuprofen): the superior non steroidal antiinflammatory agents for development of pharmaceuticals issn [16] Tropical Journal of Pharmaceutical Research, Chronotherapeutics and Chronotherapeutic Drug Delivery Systems October 2009; 8 (5): Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, Nigeria. [17] Archives of Pharmacal Research Formulation of a extended release tablet containing dexibuprofen December 2008, Volume 31, Issue 12, pp [18] J Clin Periodontol 2005; The effect of a dexibuprofen mouth rinse on experimental gingivitis in humans 32: doi: /j X x [19] Anesthetic pharmacology international society for anaesthetic pharmacology section editor james g. bovill Dexibuprofen (S(_) -Isomer Ibuprofen) Reduces Gastric Damage and Improves Analgesic and Antiinflammatory Effects in Rodents Anesth analg anesthetic pharmacology bonabello et al. Anesth Analg 2003;97: / ;97:402 8 [20] L. Srinivas et al Formulation and evaluation of ibuprofen pulsin cap technique for controlled release Der Pharmacia Lettre, 2013, 5 (1):60-68 [21] RajendraAwasthi, Chronotherapy: Science and Technology of drug scheduling on the basis of Biological rhythm, Journal of Chronotherapy and Drug Delivery, vol.-1,issue-1, [22] J Sajan, TA Cinu, AJ Chacko, J Litty and T Jaseeda, Chrono-therapeutics and Chronotherapeutic Drug Delivery Systems, Tropical Journal of Pharmaceutical Research, 8 (5): , [23] Youan BIBC. Chronopharmaceutics: Science and Technology for Biological Rhythm-Guided Therapy and Prevention of Diseases. John Wiley & Sons, Inc. pp [24] Michael.H.Smolensky and Nicholas A. Peppas, Chronobiology, drug-delivery and Chronotherapeutics, Advanced Drug Delivery Reviews, 59(2007) Journal of Pharmaceutical and Biomedical Analysis Letters 304