Enhancement of Dissolution of Valsartan by Surface Solid Dispersion Technique

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1 Research Article ISSN: Janika Garg et al. / Journal of Pharmacy Research 2012,5(8), Available online through Enhancement of Dissolution of Valsartan by Surface Solid Dispersion Technique Janika Garg, Sadhna Khatry*, Sandeep Arora Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway, Rajpura , Patiala, Punjab, India. Received on: ; Revised on: ; Accepted on: ABSTRACT The main objective of the study was to enhance the dissolution of poorly water soluble drug Valsartan by Surface solid dispersion (SSD) technique. Water-insoluble carriers like Sodium starch glycolate (SSG), Crospovidone, Avicel PH 101, Pre-gelatinized starch, Avicel PH 102 and Aerosil 200 were used in different ratios to prepare SSD by solvent evaporation method. SSD prepared with SSG as carrier in the ratio of 1:9 showed the highest dissolution rate in 30 mins as compared to pure drug and physical mixture. The enhancement of dissolution rate depends on the nature and amount of the carrier and increases with the increase in the concentration of the carrier. Increase in the dissolution rate may be attributed to, the reduced particle size of drug deposited on the surface of carrier and enhanced wettability of the drug particles by the carrier. The optimized formulations were evaluated by X-ray diffractometry (XRD), Differential scanning colorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and Scanning electron microscopy (SEM). Tablets prepared from SSD complied with the official USP specifications and exhibited higher dissolution rate as compared to marketed tablets. Key words: Valsartan, Sodium starch glycolate, Crospovidone, Surface Solid Dispersion, In-vitro dissolution, Avicel PH 101. INTRODUCTION Formulation of poorly water soluble drugs for oral delivery is an ongoing challenge for scientists[1]. Oral bioavailability of a drug depends on its solubility and dissolution rate which is the rate determining step for the onset of therapeutic activity. Several methods have been introduced to increase dissolution rate and thereby oral absorption and bioavailability of such drugs. Among various approaches, solid dispersion has shown promising results in improving the solubility, wettability, dissolution rate and subsequently its bioavailability. Only a few commercial solid dispersion products are available inspite of the many advantages it offers[2]. Surface solid dispersion (SSD) technique overcomes the shortcomings of solid dispersion prepared like tackiness and difficulty in handling of the product[3]. This technique disperses one or more active ingredients on a water insoluble carrier of extremely high surface area to achieve increased dissolution rates of practically insoluble drugs[4]. The carriers used in surface solid dispersion are hydrophilic, water insoluble, porous materials [5]. Common tablet excipients like sodium starch glycolate, crospovidone, croscarmellose sodium, kyron T-314, cab-o-sil and silicified microcrystalline cellulose have been used as carriers for surface solid dispersions[6]. Deposition of drug on the surface of an inert carrier leads to reduction in the particle size of the drug thereby providing a faster dissolution rate. Larger the surface area of carrier available for adsorption of drug, better is the release rate[7]. This technique has been extensively used to increase the solubility, dissolution and bioavailability of many insoluble or poorly water soluble drugs such as Piroxicam[8], Ibuprofen[9], Domperidone, Nifedipine, Meloxicam[10] and Itraconazole[11]. Valsartan is an angiotensin II receptor antagonist effectively used in the management of hypertension. It is rapidly absorbed after oral dose with a *Corresponding author. Sadhna Khatry, Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway, Rajpura , Patiala, Punjab, India. bioavailability of about 23%. Peak plasma concentrations occur in 2 to 4 hours and its plasma half-life is about 7.5 hours. This drug has low aqueous solubility and high membrane permeability belonging to class II of the Biopharmaceutical Drug Classification system[12]. Improvement in its solubility and dissolution rate may lead to an enhancement in bioavailability. Studies on solid dispersion of valsartan have been done using various carriers such as soluplus[13], gelucire-50/13[14], cyclodextrin[15], HPMC, PVP K30 and skimmed milk powder[16]. The main objective of this study was to enhance the dissolution rate of poorly water soluble drug valsartan by using various hydrophilic carriers. SSDs were prepared by solvent evaporation method using different drug to carrier ratios. The optimized SSD was formulated into tablets and dissolution rate compared to that of pure drug and marketed tablets. MATERIALS AND METHOD Materials Valsartan was obtained as a gift sample from Ranbaxy Laboratories, Pontasahib (India). Sodium starch glycolate (SSG) and crospovidone (CP) were obtained as gift samples from Park Pharma, Baddi (India). All the reagents used were of analytical grade. Method Preparation of calibration curve 20 mg of drug was dissolved in methanol in a volumetric flask and volume made upto 100 ml with methanol (200µg/ml). From this stock solution, solutions of different concentrations were prepared with distilled water and absorbances measured at 250 nm using systronics UV-VIS spectrophotometer. Beer-Lambert law was obeyed in the concentration range of 4 to 28µg/ml. Preparation of valsartan surface solid dispersion (SSD) and physical mixture (PM) Surface solid dispersion of valsartan were prepared by solvent evaporation method using different hydrophilic carriers such as Sodium starch glycolate(ssg), Crosspovidone, Avicel PH 101, Pre-gelatinized starch, Avicel

2 Janika Garg et al. / Journal of Pharmacy Research 2012,5(8), PH 102 and Aerosil 200. Surface solid dispersion and physical mixtures were prepared with drug to carrier ratios of 1:1, 1:3, 1:6 and 1:9. The required amount of drug was dissolved in methanol to get a clear solution. Water insoluble carrier was added to this clear drug solution and dispersed. The solvent was removed by continuous trituration until a dry mass was obtained. The obtained mass was further dried at 500C for 4 hrs in an oven. This product was crushed, pulverized and sifted through a 60# sieve. The obtained product was stored in desiccators containing CaCl2. Physical mixtures (PM) containing one part of drug and different parts of carrier were prepared by mixing in a porcelain mortar. The prepared mixtures were sifted through 60# sieve and evaluated. Evaluation of Surface Solid Dispersion Saturation Solubility Studies Saturation solubility was determined by the shake-flask method. Excess quantity of drug and SSDs were kept in conical flasks containing 10 ml of distilled water. The samples were placed in an orbital shaker at 37 C and 100 rpm until equilibrium was achieved (24 h). The solutions were diluted and their concentration analysed by UV- VIS spectrophotometer at 250 nm. In-Vitro Dissolution Studies In-vitro dissolution studies for drug valsartan and prepared SSDs were carried out using USP Apparatus 2 (Paddle type). Sample equivalent to 40 mg of valsartan was placed in the dissolution vessel containing 900 ml of phosphate buffer (ph 6.8) at 37 ± 0.5 C and stirred at 50 rpm. Aliquots of 5 ml were withdrawn at specified time intervals and replaced with an equal volume of dissolution medium. The filtered samples were analyzed spectrophotometrically at 250 nm. Amount of drug released at 5, 15 and 30 minutes were calculated and tabulated as t10, t15 and t30 respectively. Dissolution data obtained was fitted into zero order, first order, Hixson-Crowell cube root and Higuchi model to analyze the mechanism of drug release rate kinetics from the prepared SSD and physical mixtures. Flow properties Flow properties must be optimum for the formulation and industrial production of tablet dosage form. The flow properties of surface solid dispersion were estimated by Tapped density, Bulk density, Angle of repose, Carr s index and Hausner s ratio. Angle of repose (θ) was measured using fixed funnel method and tapped density was determined using bulk density apparatus. Powder X-Ray Diffractometry (PXRD) XRD was necessary to study the polymorphic changes of drug in SSD. XRD spectra of formulations were recorded using a high-power powder x- ray diffractometer (XPERT-PRO, USA) with Cu as target. Samples were analyzed at a 2θ angle range of Operating voltage and current were 40 kv and 55 ma respectively. Differential Scanning Calorimetry (DSC) DSC was used to study the drug excipient interaction in surface solid dispersions. Thermograms of drug, physical mixture and SSD were recorded using a differential scanning calorimeter (Mettler Toledo, USA). The instrument was calibrated with indium standard. Approximately 2 5 mg of each sample was heated in a pierced aluminum pan from 30 to 300 C at a heating rate of 10 C/min under a stream of nitrogen at a flow rate of 50 ml/ min. Scanning Electron Microscopy (SEM) Drug and SSD were all mounted onto copper stubs with double-sided adhesive tape and coated with gold using the coated sputter. Samples were examined under a JSM-6100 electron probe microanalyzer (Jeol, USA). Gas chromatography The residual solvent concentration of the prepared solid dispersion of drug was studied by GC. GC analysis was performed using Agilent GC with head space sampler fitted with a flame ionization detector and employing nitrogen as carrier gas. Headspace GC is used to detect solvent residues. Preparation and evaluation of tablets SSD with SSG as the carrier was selected for the preparation of tablets based on the dissolution profile. The amount of SSD equivalent to unit dose of drug (40 mg) was incorporated into each tablet. The main ingredients i.e drug and carrier were thoroughly mixed in a mortar and pestle for 5 mins. Talc and magnesium stearate were added to this mixture and the blend was compressed into 400 mg tablet by direct compression method with punch size of 9 mm. The prepared and marketed tablets were evaluated for parameters such as hardness, friability, disintegration time, content uniformity and drug release. Evaluation of the prepared tablets All tests were carried out according to the USP compendial specifications. Uniformity of Weight Twenty tablets taken randomly were weighed individually and the average weight, the standard deviation and the coefficient of variation were calculated. Drug Content Surface solid dispersion equivalent to 40 mg of valsartan was weighed accurately and dissolved in 100 ml of methanol. This solution was further diluted with phosphate buffer ( ph 6.8) and analyzed by UV-VIS spectrophotometer at 250 nm. SSD having maximum saturated solubility and drug release was characterized by XRD, DSC, FTIR, SEM and compared with the pure drug. Fourier Transform Infrared Spectroscopy (FTIR) FTIR spectroscopy was used to study the structural changes and possible interactions between the drug and carrier in the SSD. IR spectra of drug, physical mixture and SSD were recorded using an FTIR spectrophotometer [BRUKER (Alpha E)]. Samples were scanned over the frequency range cm-1. The resultant spectra were compared for any spectral changes. Hardness and Friability Hardness and friability of prepared tablets were measured using a Monsanto hardness tester and Roche type apparatus respectively. Disintegration time DT was determined at 37 0C using disintegration apparatus (EI products, India). Dissolution Studies In-vitro release profile of SSD tablets was obtained using a dissolution test USP Apparatus 2 (Electro Lab). Dissolution was carried out in 900 ml of phosphate buffer (ph 6.8) as the dissolution medium at 37 C ± 2 C at 50 rpm. RESULTS AND DISCUSSION Water dispersible carriers like Sodium starch glycolate(ssg), Crospovidone(CP), Avicel PH 101, Pre-gelatinized starch, Avicel PH 102

3 Janika Garg et al. / Journal of Pharmacy Research 2012,5(8), and Aerosil 200 were selected for the study. All SSDs were found to be fine and free flowing powders. Saturated solubility Fig. 1 represents an increase in drug solubility of SSD over pure drug in distilled water. Surface solid dispersion containing SSG showed solubility (3.51±0.011 mg/ml) a 10 fold increase in solubility as compared to pure drug (0.393±0.028 mg/ml). This may be due to either the reduction in the crystallinity of drug or improved wetting of the drug particles. Fig. 2: Dissolution profile of drug valsartan compared with different formulations. SSG has a very fine particle size, hence large surface area. Surface area available for adsorption of drug crystals increases with increase in the concentration of carrier leading to increase in the interfacial area of contact between the drug particles and dissolution media. Fig. 1: Saturated solubility of different formulations. Dissolution All the carriers selected showed rapid and higher dissolution of valsartan as compared to pure drug. Dissolution rate observed with various carriers were in following increasing order: SSG> Crospovidone > Avicel PH 101> Aerosil 200> Avicel PH 102> Pre gelatinised starch. Table 1 shows the comparison of dissolution profile of different formulations of surface solid dispersions. Table 1: Dissolution profile of Drug and SSDs. S. No Excipients Ratio t 15 ± SD t 30 ± SD t 45 ± SD 1 Drug 13.16± ± ±.72 2 SSG 1: ± ± ±.68 1: ± ± ±.96 1: ± ± ±1.23 1: ± ± ± CP 1:1 61.7± ± ±1.32 1:3 65.8± ± ±1.74 1:6 71.2± ± ±.86 1: ± ± ±.94 4 Avicel PH 101 1:1 46.2± ± ±.75 1:3 51.2± ± ±.83 1: ± ± ±1.33 1: ± ± ± Aerosil 200 1:1 31.5± ± ±.96 1:3 36.4± ± ±.68 1: ± ± ±1.11 1: ± ± ± Avicel PH 102 1: ± ± ±1.21 1: ± ± ±.87 1: ± ± ±.73 1: ± ± ± Pregelatinized Starch 1: ± ± ±1.34 1: ± ± ±1.25 1: ± ± ±1.42 1: ± ± ±.88 Each value represents mean ±SD (n=3). The aqueous dissolution profile of the SSDs of valsartan with different carriers in the ratio of 1:9 is shown in Fig. 2. Surface solid dispersions prepared using various carriers showed different dissolution profile. SSD of drug with SSG as the carrier showed almost 98.84% drug release in 30 mins whereas CP as carrier showed 93.88% drug release indicating that SSG is the most suitable carrier giving better dissolution profile than CP. The drug release data obtained from in-vitro studies was fitted into various kinetic models plotted i.e zero order, first order, Higuchi model and Hixsoncrowell cube root law. The release of drug from different formulations followed first order kinetics and was found to be concentration dependent. Correlation coefficient (r) is reported in Table 2 Table 2: Correlation Coefficient (r) values of valsartan surface solid Dispersions. S.No Formulation Correlation Coefficient (r) Values Zero order First order Higuchi Hixson- Crowell 1 Drug+SSG Drug+CP Drug+Avicel PH Drug+Aerosil Drug+Avicel PH Drug+Pregelatinized Starch Correlation Drug Content Drug content for all SSDs were in the range of % which is acceptable according to the USP. Low coefficient of variation of the preparation indicated uniformity of drug content in each batch prepared. The content of drug in SSD was slight lower probably due to solvent evaporative losses. These losses were much higher when lower carrier ratios were used hence SSD were prepared with higher carrier ratios. Powder flowability Table 3 shows the flow properties of SSD and pure drug. All SSDs were free flowing powders. Inclusion of carrier in the formulations improved the flow properties as compared to the valsartan powder (Hausner s Factor is 1.5). Angle of repose of SSD confirmed the improvement in flow properties of drug.ssds produced good compressibility properties due to decrease in Carr s Index values as compared to the non-compressible powdered drug. Table 3: Flow properties of Drug and SSD. S.No Evaluation Tests Drug SSD 1 Bulk Density(g/cm 3 ) 0.444± ± Tapped Density(g/cm 3 ) 0.666± ± Hausner s Ratio 1.5± ± Carr s Index (%) 33.33± ± Angle of repose 38.65± ±0.5

4 Janika Garg et al. / Journal of Pharmacy Research 2012,5(8), FT-IR spectra FTIR spectrum of valsartan showed its characteristic IR absorption peaks at 3743, 2364, 1749 and 680 cm-1 whereas SSD and physical mixture peaks were observed at 3731, 2362, 1741 and 668 cm-1(figure 3). SSG showed characteristic absorption peaks at 3926, 3893, 2364, 1647 and 752cm-1 whereas CP shows showed characteristic absorption peaks at 3925, 3620, 2364, 1426 and 760cm-1. These spectrum observations indicated no interaction between the drug and carrier used in SSD and physical mixture. surface solid dispersion indicated that the drug is entrapped by the carrier thereby reducing the overall crystallinity of system. Change in the crystalline structure of drug in the surface solid dispersion resulted in an increase in solubility of the drug which is reflected by the enhanced dissolution rate of drug from solid dispersion. DSC studies also showed that there was no interaction between the drug and carrier at molecular level in both surface solid dispersion and physical mixture. Fig. 3: FTIR spectra of (A) Valsartan (B) Physical Mixture C) Surface solid dispersion. X-Ray Diffraction XRD patterns of pure drug, PM, SSG and surface solid dispersions are depicted in Figure 4. The diffraction pattern of pure drug valsartan showed a highly crystalline nature, indicated by numerous distinctive peaks at a diffraction angle of 2θ (17.92, 31.66, ) throughout the scanning range. XRD of surface solid dispersions showed disappearance of sharp distinctive peaks at a diffraction angle of 2θ (17.78, 31.73, ). The diffraction patterns of the physical mixture and SSD indicated changes in the crystalline nature of the drug. The relative 2θ angle of valsartan peaks remained unchanged but relative intensity of the peaks was decreased. Thus, the relative reduction in the diffraction intensities in the surface solid dispersions can be attributed to the change in orientation during the crystal growth phase. Fig. 5: DSC thermogram of A) Sodium starch glycolate B) Physical Mixture C) Valsartan D) Surface solid dispersion (from bottom). Scanning Electron Microscopy (SEM) The electromicrophotographs of pure valsartan and SSDs are shown in Fig. 6. Figure 6a shows the large smooth surface crystals of pure valsartan. Figure 6b shows SSDs of irregular matrices due to the porous nature of the carrier with fine particles of the drug deposited on it. SEM studies explained the surface morphological properties of the SSD indicating that the solid dispersion is in amorphous state. Fig. 6: SEM microphotographs of 6a) Drug valsartan 6b) Surface solid dispersion. Fig. 4: XRD spectra of A) Drug B) Physical Mixture C) Surface solid dispersion D) Sodium starch glycolate. Differential Scanning Colorimetry DSC of drug, PM, SSG and SSD prepared are shown in Fig 5. Thermogram of drug showed a single sharp endothermic peak at C corresponding to its melting point indicating the crystalline nature of the drug. SSG showed endothermic peak at C whereas SSD with SSG as carrier showed endothermic peak at C. The absence of melting peak of drug in the Residual solvent Levels of methanol were below the detectable limits. Hence, solvent deposition method was efficient in removal of solvents from SSD below permissible levels. Valsartan tablets from surface solid dispersion Valsartan tablets of drug with SSG as carrier were prepared by direct compression method. Table 4 reveals that all the prepared tablets have acceptable physical properties according to the USP. The uniformity of weight fulfills the requirement with less than ±5% in all cases.

5 Table 4: Evaluation tests of SSD and marketed tablet. Janika Garg et al. / Journal of Pharmacy Research 2012,5(8), S.No Evaluation Tests SSD tablet Marketed tablet 1 Weight Variation 404± ± Hardness (Kg/cm 2) 4.46± ± Friability (%) Disintegration Time(seconds) Content Uniformity (%) Fig. 7 shows the comparative dissolution studies of prepared SSD tablets with prepared physical mixture tablets and marketed product. Fig. 7: Dissolution profile of prepared SSD tablet with marketed tablet. Tablets prepared from SSD having SSG as the carrier exhibited higher dissolution rate as compared to marketed tablets and prepared physical mixture tablets. Marketed tablets showed 96.53% drug release in 30 mins whereas tablets prepared from SSD with SSG as the carrier showed % drug release. Hence, the formulated surface solid dispersion tablets can be recommended for management of hypertension. CONCLUSION Surface solid dispersion technique was successful in improving the dissolution rate of poorly water-soluble drugs like valsartan. SSDs of drug with SSG as carrier showed significantly higher dissolution rate as compared to pure drug and physical mixture. The nature and amount of carrier used played an important role in the enhancement of dissolution rate. FTIR and DSC studies showed no evidence of interaction between the drug and carrier. SSD tablets prepared with SSG as carrier showed an enhancement of dissolution rate of drug as compared to marketed tablets. ACKNOWLEDGEMENT The authors are grateful to M/S Ranbaxy Laboratories, Pontasahib (India) for their gift sample of the drug Valsartan. REFERENCES 1. Emara L.H., Badr R.M. Improving the dissolution and bioavailability of nifedipine using solid dispersion and solubilizers Drug Dev. Ind. Pharm. 28; 2002, Patidar Kalpana, Soni Manish, Sharma K. D. Solid dispersion: Approaches, Technology involved, need & Challenges. Drug Invention Today 2(7); 2010, Y. Lalitha, P. K. Lakshmi Enhancement of dissolution of nifedipine by surface solid dispersion technique Int J Pharm Pharm Sci. 3(3); 2011, Naga Aparna. T. Studies on enhancement of dissolution rate of domperidone by surface solid dispersion technology International Journal of research in pharmacy and chemistry IJRPC 1(2); 2011, Adrian C. Williams, Peter Timins, Mingchu Lu, Robert T. Forbes, Disorder and Dissolution Enhancement: Deposition of Ibuprofen onto Insoluble Polymers European Journal of Pharmaceutical Sciences. 26; 2005, T. Kiran, Nalini Shastri. Surface solid dispersion of glimepiride for enhancement of dissolution rate International Journal of PharmTech Research 1(3); 2009, K. Y. Yang, R. Glemza and C. I. Jarowski Effects of amorphous silicon dioxides on drug dissolution J. Pharm. Sci. 68; 1979, Barzegar-Jalali Enhancement of dissolution rate and antiinflammatory effects of piroxicam using solvent deposition technique Drug Dev. Ind Pharm. 28(6); 2002, Williams A.C., Timmins P., Lu M. & Forbes R.T. Disorder and dissolution enhancement: Deposition of ibuprofen on to insoluble polymers Eur. J. Pharm. Sci. 26; 2005, Sharma S., Sher P., Badve S., & Pawar A.P. Adsorption of meloxicam on porous calcium silicate: Characterization and tablet formulation AAPS PharmSciTech. 6(4); 2005, E618-E Chowdary, K.P.R., & Rao, Sk. S. Investigation of dissolution enhancement of itraconazole by solid dispersion in superdisintegrants Drug Dev. Ind. Pharm. 26(1); 2000, Brunella C.; Clelia D. M.; Maria I., A. Improvement of solubility and stability of valsartan by hydroxypropyl-beta-cyclodextrin J. Incl. Phenom. Macrocycl. Chem. 54; 2006, Raja rajeswari.k and Abbulu.K Development, characterization and solubility study of solid dispersion of Valsartan J. Chem. Pharm. Res. 3(1); 2011, Agnivesh R. Shrivastava, Bhalchandra Ursekar Design, Optimization, Preparation and Evaluation of Dispersion Granules of Valsartan and Formulation into Tablets Current Drug Delivery 6; 2009, Anjan K. Mahapatra, P. N. Murthy Dissolution Enhancement and Physicochemical Characterization of Valsartan in Solid Dispersions with ß-CD, HP ß-CD and PVP K-30 Dissolution Technologies February 2011; K.Venkates Kumar, N.Arunkumar Preparation and in vitro characterization of valsartan solid dispersion using skimmed milk powder as carrier International Journal of PharmTech Research July-Sept 1(3); 2009, Source of support: Nil, Conflict of interest: None Declared