Assessment of Hupu Gum for Its Carrier Property in the Design and Evaluation of Solid Mixtures of Poorly Water Soluble Drug - Rofecoxib

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1 Send Orders for Reprints to 62 Current Drug Delivery, 2014, 11, Assessment of Hupu Gum for Its Carrier Property in the Design and Evaluation of Solid Mixtures of Poorly Water Soluble Drug - Rofecoxib Harini Chowdary Vadlamudi a*, Y. Prasanna Raju a, G. Asuntha b, Rahul Nair a, K.V. Ramana Murthy c and Jayasri Vulava a a Sree Vidyanikethan College of Pharmacy, A. Rangampet, Tirupati , India; b SPW Polytechnic, Tirupati , India; c College of Pharmaceutical Sciences, Andhra University, Visakhapatnam , India Abstract: There are no reports about the pharmaceutical applications of hupu gum (HG). Hence the present study was undertaken to test its suitability in the dissolution enhancement of poorly water soluble drug. Rofecoxib (RFB) was taken as model drug. For comparison solid mixtures were prepared with carriers such as poly vinyl pyrrolidone (PVP), sodium starch glycollate (SSG) and guar gum (GG). Physical mixing (PM), co-grinding (CG), kneading (KT) and solvent evaporation (SE) techniques were used to prepare the solid mixtures, using all the carriers in different carrier and drug ratios. The solid mixtures were characterized by powder X-ray diffraction (XRD) and Fourier-transformed infrared spectroscopy (FTIR). There was a significant improvement in the dissolution rate of solid mixtures of HG, when compared with the solid mixtures of other carriers. There was an increase in dissolution rate with increase in concentration of HG upto 1:1 ratio of carrier and drug. No drug-carrier interaction was found by FTIR studies. XRD studies indicated reduction in crystallinity of the drug with increase in HG concentration. Hence HG could be a useful carrier for the dissolution enhancement of poorly water soluble drugs. Keywords: Carriers, Dissolution parameters, Dissolution rate, Drug release kinetics, Hupu gum, Rofecoxib, Solubility. INTRODUCTION The improvement in dissolution characteristics of poorly water soluble drugs by solid dispersion technique was attributed to the reduction in particle size of drug, reduction in crystallinity of drug, improvement of drug wettability by carriers and direct solubilization or a co-solvent effect of carriers on drug. Along with the above reasons, the improvement in dissolution rate of poorly water soluble drugs that deposited on the carriers is due to the distribution of drug on relatively large surface area of carrier particles fairly and evenly, which prevents reagglomeration and increase in the effective surface area for dissolution. The frequently used techniques in improving the dissolution rate of poorly soluble drugs are decreasing particle size of solid compound [1] and/or by optimizing the wetting characteristics of the compound surface [2], decreasing boundary layer thickness, to ensure sink conditions for dissolution and improving the apparent solubility of the drug under physiologically relevant conditions [3]. The usage of natural polymers as drug carriers in the improvement of solubility of poorly soluble drugs has recently attracted considerable attention in pharmaceutical field due to their low cost, biocompatibility and biodegradability [1]. Many natural polymers such as gelatin, egg albumin and chitosan have been evaluated for their suitability as carriers in enhancement *Address correspondence to this author at the Department of Pharmaceutics, Sree Vidyanikethan College of Pharmacy, A.Rangampet, Tirupati, , Andhra Pradesh, India; Tel: ; vadlamudi.harini@gmail.com of dissolution rate of poorly water soluble drugs. Because of its low viscosity and comparable swelling capacity, which are beneficial properties for overcoming the processing and handling problems which commonly occur in the preparation of solid mixtures containing high viscous carriers [2]. Hupu gum, a natural polysaccharide is having good swelling index and moderate viscosity with many applications as food additive, in the printing industry, in chemical industry as adhesive. HG was found to be non toxic up to 5% and can be used safely as a food additive. Therefore hupu gum was selected for its application in the design of solid mixtures of poorly soluble drugs. Hupu gum (Kondagogu, Kolha or Silk-cotton) is the dried gummy exudate obtained from the deciduous tree of Cochlospermum religiosum (L.) Alston (synonym Cochlospermum gossypium (L) D.C.), Family Cochlospermaceae (synonym Bixaceae). Hupu gum tree is abundantly found in hills and forests of Chittoor, East Godavari districts in Andhra Pradesh, Mayurbhanj district in Orissa, India [3]. Its applicability is reported for industries like paper, printing gum, nicotine sprays and in the preparations of lotions and pastes, it was not investigated for its applicability in the pharmaceutical field. Few investigations have been conducted on HG as a potential food additive in food and nutrition industries [4]. Rofecoxib was taken as model drug in this study. Rofecoxib is chemically 4-[4-(methylsulfonyl) phenyl]-3- phenyl-2 (5H)-furanone. It is a diaryl substituted pyrazole derivative containing a sulfonamide substituent. It is a selective inhibitor of the COX-2 isoform of prostaglandin endop- /14 $ Bentham Science Publishers

2 Assessment of Carrier Property of Hupu Gum in Design and Evaluation of Solid Mixtures Current Drug Delivery, 2014, Vol. 11, No eroxide synthase and exhibits many of the pharmacological actions of prototypical NSAIDS, including anti-inflammatory, analgesic and antipyretic activity. RFB shows insolubility in water, partial solubility in alcohols such as methanol and ethanol [5]. Since RFB is meant for treatment of acute and chronic pains [6] it requires rapid absorption and high bioavailability in patient point of view. To study the carrier effect of HG on RFB, different weight ratios of carrier and drug solid mixtures were prepared and evaluated. And these were compared with the solid mixtures of RFB with wellestablished carriers such as polyvinyl pyrrolidone (PVP, sodium starch glycollate (SSG) and guar gum (GG). Physical mixing (PM), co-grinding (CG), kneading technique (KT) and solvent evaporation (SE) methods were employed in the preparation of carrier-drug solid mixtures. MATERIALS AND METHODS Hupu gum of Grade-I quality was purchased from M/s. Girijan Co-op Corporation Ltd., Visakhapatnam, India. Rofecoxib was received as a gift sample from Cadila Pharmaceuticals Limited, Ahmedabad. Polyvinyl pyrrolidone as PVP K30, SSG and GG were procured from S.D.Fine Chem. Ltd., Mumbai. All the other chemicals used were of AR grade satisfying pharmacopoeial specifications. PREPARATION OF SOLID MIXTURES Solid mixtures of HG and RFB were prepared in 1:1, 1:5 and 1:10 weight ratios. The solid mixtures of other polymers were prepared in same weight ratios for comparison. Physical mixtures (PM) were prepared by simple blending of accurately weighed quantities of drug and the carrier(s) in a cylindrical closed glass bottle. Co-grinding mixtures (CG) were prepared by transferring weighed quantities of drug and carrier(s) into a dry and clean glass mortar and triturated well with pestle for 20 min. Kneading mixtures (KT) were prepared by taking weighed quantities of drug and carrier were triturated in a mortar with a small volume of methanol. The thick slurry was kneaded for 45 min and then dried at 50 C until it reached uniform weight. Solid dispersions of RFB and selected carriers were prepared using solvent evaporation (SE) method. The appropriate weighed amounts of drug were dissolved in sufficient quantity ( 60 ml) of solvent/solvent blend to get clear solution. The carriers (HG, PVP, SSG and GG) were dispersed in drug solution. Both were mixed together on a cyclo mixer for two minutes and solvent/solvent blend was then removed by evaporation in a water bath at 45 o C under reduced pressure. The resulting residue was then transferred to glass dessicator and dried under vacuum to constant weight. The dried products were powdered and sifted through sieve #100. All these samples prior to be used for the analysis were stored in dessicator. In each case 2 gm of dispersion was prepared. PHASE SOLUBILITY STUDY Drug solubility study was performed according to Higuchi and Connors method [7]. Excess drug (50 mg) was added to 15 ml of distilled water (ph 6.8) containing various concentrations of HG (5-200 mg) taken in a series of 50 ml stoppered conical flasks and the mixtures were shaken for 72 hours at room temperature (28 C) on a rotary flask shaker. After 72 hours of shaking, 2 ml aliquots were withdrawn at 1 hour interval and filtered immediately using a 0.45 nylon disc filter. The filtered samples were diluted suitably and assayed for drug content by measuring the absorbance against blanks prepared in the same concentration of HG in water so as to cancel any absorbance that may be exhibited by the HG molecules. Shaking was continued until three consecutive estimations are the same. The solubility experiments were conducted in triplicate. DRUG CONTENT UNIFORMITY From each batch of the prepared solid mixtures, 4 samples were taken and analyzed for drug content. The solid mixture (50 mg) was transferred into a 50 ml volumetric flask and methanol was added. The contents were thoroughly mixed and kept aside for 4 hrs with occasional shaking to facilitate the extraction of drug from the solid mixture into solvent. The solution was made up to volume with methanol and filtered through a 0.45 membrane filter (Millipore*, nylon discs). The solutions were suitably diluted with methanol and assayed for their drug content spectrophotometrically by measuring the absorbance at 211 nm. FOURIER TRANSFORM INFRARED SPECTROS- COPY (FTIR) FTIR spectra of Hupu gum, pure rofecoxib and solid mixture were obtained on a Perkin-Elmer 841 FTIR spectrometer equipped with a DTSG detector. Samples were prepared in KBr discs. The scanning range was cm -1 and the resolution was 1 cm -1. X-RAY DIFFRACTION STUDIES (XRD) Powder X-ray diffraction patterns of RFB and solid mixture of Hupu gum and rofecoxib was recorded on a Seifert 303, Germany, X-Ray Diffractometer with Rayflex software using Ni-filtered, CuK radiation, a voltage of 40 kv and a current of 25 ma. The instrument was operated in the continuous scan mode over a 2 range of 10 to 70. IN-VITRO DISSOLUTION STUDIES Dissolution experiments of pure drug and solid mixtures were carried out in triplicate with USP XXIII Dissolution Rate Test Apparatus (M/S. Campbell Electronics) using the paddle method at a rotation speed of 50 rpm. Samples of each preparation equivalent to 50 mg of drug were added to the dissolution medium [8]. At appropriate time intervals, 5 ml of the sample was withdrawn, filtered through a 0.45 membrane filter. The initial volume of the dissolution medium was maintained by replacing with 5 ml of the medium. The filtered solutions were suitably diluted and assayed for its drug content spectrophotometrically at 211 nm. The mean percent of drug dissolved and the standard deviation were calculated. COMPARISON OF DISSOLUTION PROFILES AND DRUG RELEASE MECHANISMS AND KINETICS OF DISSOLUTION RATE Model-independent approaches are based on the ratio of area under the dissolution curve (dissolution efficiency) or

3 64 Current Drug Delivery, 2014, Vol. 11, No. 1 Vadlamudi et al. on mean dissolution time. In the model-dependent approaches, some mathematical models are employed to successfully fit the individual dissolution data. As a modelindependent approach, comparison of the time taken for the given proportion of the active drug to be dissolved in the dissolution medium and figures such as T 50 and T 90 calculated by taking the time points of 50% and 90% of the drug dissolved and another parameter Dissolution Efficiency (DE) was employed [9, 10]. DE is defined as the area under the dissolution curve up to the time t expressed as a percentage of the area of the rectangle described by 100% dissolution in the same time. DE 30 and DE 60 values were calculated from the dissolution data of each formulation and used for comparison. First-order release kinetics were studied by lnq()= t lnq 0 k 1 t, the first order equation describes the release from systems where release rate is concentration dependent. Where (Q o ) is the initial amount of the drug, (t) is in minutes and (k 1 ) describes the dissolution rate constant for first order release kinetics. A plot of the logarithm of the percent drug remained against time will be linear if the release obeys first-order release kinetics. Values of release rate constant (k 1 ) were obtained in each case from the slope of the log % drug remained versus time plots. The Hixson-Crowell cube root model was applied with W 13 0 W 13 t = K HC t equation, where W 0 is the initial amount of drug in the dosage form, W t is the remaining amount of drug at time t. Hixson-Crowell cube root law describes the release from systems where there is a change in surface area and diameter of the particles. K HC is the release rate constant for Hixson-Crowell rate equation. Then a graphic of the cubic root of the unreleased percent of drug versus time will be linear if the equilibrium condition are not reached and if the geometrical shape of the dosage form diminishes proportionally over time and the release rate constant (K HC ) corresponds to the slope. This model has been used to describe the release profile from the diminishing surface of the drug particles during the dissolution. RESULTS AND DISCUSSION PHASE SOLUBILITY STUDIES The phase solubility diagram of rofecoxib in various concentrations of HG aqueous solutions is shown in (Fig. 1). Since the molecular weight of HG is not defined clearly, the concentrations are expressed in %w/v units. The aqueous solubility of these drugs was increased as a function of the concentration of hupu gum. Hupu gum concentrations beyond 0.5% w/v resulted in the formation of viscous gel and Fig. (1). Phase solubility diagram of HG-RFB.

4 Assessment of Carrier Property of Hupu Gum in Design and Evaluation of Solid Mixtures Current Drug Delivery, 2014, Vol. 11, No Table 1. Percent drug content of RFB in solid mixtures. Type of Solid Mixture Percent RFB Content [n=4 (c.v.)] 1:1 1:5 1:10 PM (0.87) (0.77) (0.89) HG:RFB CG (0.95) (0.83) (0.96) KT (0.95) (0.97) (0.97) SE (0.97) (0.87) (0.98) PM (0.87) (0.77) (0.88) PVP:RFB CG (0.98) (0.86) (0.95) KT (0.90) (0.97) (0.87) SE (0.97) (0.87) (1.12) PM (0.77) (0.96) (1.18) SSG:RFB CG (0.95) (0.96) (0.96) KT (0.98) (0.97) (0.97) SE (0.87) (0.97) (0.99) PM (0.87) (0.96) (0.88) GG:RFB CG ) (0.96) (0.97) KT (0.95) (0.97) (0.98) SE (0.97) (0.97) (0.87) solubility of the drugs could not be determined. The phase solubility studies thus clearly indicated the role of hupu gum in improving the solubility of the above poorly soluble drugs. DRUG CONTENT UNIFORMITY The percent drug contents of all the solid mixtures with c.v. values are given in Table 1. Low c.v. values in the percent drug content ensured uniformity of drug in each batch. There was no significant loss of drug during the preparation of solid mixtures with all carriers. It was found that the ratios and methods used to prepare solid mixtures have shown no effect on the drug content uniformity of solid mixtures. FTIR STUDIES IR spectra of spectra of RFB, HG and solid mixture prepared from HG prepared by solvent evaporation method at 1:1 weight ratios are given in (Fig. 2). The principle absorption peaks of RFB were observed at 1764 cm -1 (lactone carbonyl), 1405 cm -1 (methyl sulfonyl) and 1304 cm -1 (methyl sulfonyl). Same peaks of lactone carbonyl and methyl sulfonyl were present without much shifting in the spectra of solid mixture, suggested no interaction between the drug and the carrier. X-RAY DIFFRACTION STUDIES Characteristic peaks of rofecoxib were observed at diffraction angle of , , , , and as depicted in (Fig. 3). These observations suggest that RFB is present in crystalline state. Solid mixtures of HG-RFB with 1:1 weight ratio of solvent evaporation technique showed drastic reduction in the intensity of peaks indicating improvement in the amorphous nature of RFB in the solid mixture. DISSOLUTION STUDIES Dissolution profiles of rofecoxib showed that 100% drug dissolved in 60 min in case of HG-RFB-1:1-SE solid mixture whereas in pure RFB it was 81.52% only (Table 2 & 3). The DE 30 and DE 60 values of RFB and its solid mixtures are given in Table 4. Out of four methods employed in the preparation of HG-RFB solid mixtures, solvent evaporation method gave highest DE values. However, physical mixing (PM), co-grinding (CG), kneading technique (KT) and solvent evaporation (SE) employed for the preparation of HG- RFB solid mixtures, gave marked improvement in the dissolution rate as compared to pure drug as evidenced by DE values. Solid mixtures of RFB that are prepared with HG in all weight ratios showed the order of drug dissolved in SE>KT>CG>PM. The solid mixtures RFB prepared with other carriers (PVP, SSG and GG) have showed the same order of drug dissolution profiles. In solid dispersion, fine suspension of drug and carrier particles will be formed. With the smaller particle size and better wettability of the drug particle in the suspension contributes for faster dissolution rate of the drug. The swelling index of Hupu gum was 3800%. High value of swelling index revealed the high swelling ability of Hupu gum. This might be attributed for the enhancement of solubility of rofecoxib. The solid mixtures of HG-RFB gave better dissolution profiles when compared

5 66 Current Drug Delivery, 2014, Vol. 11, No. 1 Vadlamudi et al GT ROFECOXIB A Hupu gum %Tw %T Rofecoxib +Hupu gum Fig. (2). FTIR spectra of RFB, HG and solid mixture.

6 Assessment of Carrier Property of Hupu Gum in Design and Evaluation of Solid Mixtures Current Drug Delivery, 2014, Vol. 11, No Table 2. Dissolution profiles of RFB solid mixtures with HG and PVP. Time (Min) Pure RFB PM CG KT SE ± ± ± ± ± 0.55 HG:RFB-1: ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.88 HG:RFB-1: ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.49 HG:RFB- 1: ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.81 PVP:RFB-1: ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.98 PVP:RFB 1: ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.13 PVP:RFB 1: ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.69

7 68 Current Drug Delivery, 2014, Vol. 11, No. 1 Vadlamudi et al. Table 3. Dissolution profiles of RFB solid mixtures with SSG and GG. Time (Min) Pure RFB PM CG KT SE ± ± ± ± ± 0.97 SSG:RFB-1: ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.47 SSG:RFB-1: ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.54 SSG:RFB- 1: ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.92 GG:RFB-1: ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.65 GG:RFB 1: ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.52 GG:RFB 1: ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.69

8 Assessment of Carrier Property of Hupu Gum in Design and Evaluation of Solid Mixtures Current Drug Delivery, 2014, Vol. 11, No Fig. (3). Powder XRD of RFB and HG: RFB-1:1-SE solid mixture. Table 4. Dissolution parameters of solid mixtures of HG-RFB dissolution profiles. Type of Solid Mixture Dissolution Parameters DE 30 DE 60 T 50 T 90 Pure RFB PM :1-HG:RFB 1:5-HG:RFB 1:10-HG:RFB CG KT SE PM CG KT SE PM CG KT SE

9 70 Current Drug Delivery, 2014, Vol. 11, No. 1 Vadlamudi et al. Table 5. Rate constant (K) values & coefficient of correlation (r) values in dissolution rate Test of HG: RFB solid mixtures. Type of Solid Mixture First-Order Model Rate Constant (K) Values Hixson-Crowell's Cube Root Model Correlation Coefficient (r) Values First-Order Model Hixson-Crowell's Cube Root Model Pure RFB PM :1-HG:RFB CG KT SE PM :5-HG:RFB CG KT SE PM :10-HG:RFB CG KT SE Table 6. First order kinetics (correlation of correlation value r ) of RFB solid mixtures with HG and PVP, SSG and GG. Type of Solid Mixture PM GG KT SE HG:RFB-1: HG:RFB-1: HG:RFB-1: PVP:RFB-1: PVP:RFB-1: PVP:RFB-1: SSG:RFB 1: SSG:RFB 1: SSG:RFB 1: GG:RFB 1: GG:RFB 1: GG:RFB 1: to all other carriers used for the preparation of solid mixtures. This confirms the effectiveness of HG in the improvement of dissolution rate of RFB by the solvent evaporation method. The T 50 and T 90 values also confirmed the effect of HG in improving the dissolution rate of RFB compared to pure drug. KINETICS The correlation coefficient (r) values for pure RFB and its solid mixtures are given in Table 5 after fitting the data to various kinetic models the correlation coefficient (r) values showed good correlation for First order and Hixson-Crowell cube root equation. First-order rate constant value and K HC of HG-RFB-1:1-SE solid mixture, were significantly more compared to other solid mixtures of HG/other carriers. Hence HG: RFB in the ratio of 1:1 is the optimum concentration and the optimum method is solvent evaporation. Kinetics can be seen in (Table 6). CONCLUSIONS Thus, the results of the present investigation clearly indicated that the dissolution rate of poorly water soluble drugs

10 Assessment of Carrier Property of Hupu Gum in Design and Evaluation of Solid Mixtures Current Drug Delivery, 2014, Vol. 11, No can be enhanced markedly by their solid mixtures with hupu gum prepared by physical mixing, co-grinding, kneading and solvent evaporation. HG was found to be non toxic up to 5% and can be used safely. The swelling index of Hupu gum was found to be 3800%. High value of swelling index revealed the high swelling ability of Hupu gum. HG, with high swelling index can be used as an effective carrier in improving the dissolution of the poorly soluble drugs. However, variation in the improvement of dissolution was observed for different methods of preparation of solid mixture and difference in the ratio of drug and polymer. This may be due to the nature of the drug, its solubility characteristics and efficacy of polymers at different ratio. Our results supported that HG is well suitable natural polysaccharide and carrier to improve the solubility and dissolution rates of poorly water soluble drugs. CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest. ACKNOWLEDGEMENTS Declared none. PATIENT CONSENT Declared none. REFERENCES [1] Acartürk, F.; Kislal, O.; Çelebi, N. The effect of some natural polymers on the solubility and dissolution characteristics of nifedipine. Int. J. Pharm., 1992, 85, 1-6. [2] Bolhuis, G.K.; Zuurman, K.; Te Wierik, G.H.P. Improvement of dissolution of poorly soluble drugs by solid deposition on a super disintegrant II. The choice of super disintegrants and effect of granulation. Eur. J. Pharm., 1997, 5, [3] Janaki, B.; Sashidhar, R.B. Subchronic (90-day) Toxicity studies in Rats Fed Gum Kondagogu (Cochlospermum gossypium). Food Toxicol., 2000, 38, [4] Janaki, B.; Sashidhar, R.B. Physico-Chemical analysis of gum kondagogu (Cochlospermum gossypium): a potential food additive. Food Chem., 1998, 61, [5] Sean, C. S. Martindale: The Complete Drug Reference, 33 rd Ed.; Pharmaceutical Press, London, [6] Pinheiro, R.M.; Calixto, J.B. Effect of the selective COX-2 inhibitors, celecoxib and rofecoxib in rat acute models of inflammation. Inflamm. Res., 2002, 51, [7] Higuchi, T.; Conners, K.A. Phase-solubility Techniques, In: Advances in Analytical chemistry and Instrumentation; Reilly, C.N, Ed.; Wiley-Interscience, New York, 1965, 4, 117. [8] Prasanna, R.Y.; Asuntha, G.; Sreenivasa, R.B.; Ramana, M.K.V. Development of dissolution medium for rofecoxib in pharmaceutical formulations. Asian J. Chem., 2005, 17, [9] Mura, P.; Bettinetti, G.P.; Manderioli, A.; Faucci, M.T.; Bramanti, G.; Sorrenti, M. Interactions of ketoprofen and ibuprofen with -cyclodextrins in solution and in the solid state. Int. J. Pharm., 1998, 166, [10] Mura, P.; Manderioli, A.; Bramanti, G.; Ceccarelli, L. The properties of solid dispersions of naproxen in various polyethylene glycols. Drug Dev. Ind. Pharm., 1996, 22, Received: March 13, 2013 Revised: April 09, 2013 Accepted: June 08, 2013