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1 Available Online through ISSN: X CODEN: IJPTFI Research Article ENHANCEMENT OF DISSOLUTION OF IRBESARTAN USING LIQUISOLID TECHNOLOGY P. Santosh, C. Aparna *, Dr. Prathima Srinivas, Dr.M. Sadanandam Department of Pharmaceutics, Sri Venkateshwara College of Pharmacy, Madhapur, Hyderabad. Received on Accepted on Abstract Irbesartan is a non peptide, specific competitive antagonist of the angiotensin II receptor antagonist, used orally for the treatment of hypertension. The drug exhibits low bioavailability owing to its poor water solubility. According to BCS, Irbesartan is class II compound i.e. water insoluble and lipophilic, highly permeable drug. Therefore IRB bioavailability can be improved by increasing its solubility and dissolution rate 1.In order to improve solubility by way of dissolution enhancement, we have formulated a liquisolid system of IRB. This method involves dissolving water insoluble drugs in nonvolatile vehicles, which are then converted into free flowing and compressible powders by blending with suitable excipients. Several liquisolid formulations were prepared based on an mathematical model which was used to calculate the required quantities of powder and liquid ingredients, to produce acceptably flowing and compressible admixture. The prepared LS systems were evaluated for the flow properties such as Bulk density, tapped density, Carr s index, Hausner s ratio and angle of repose. Both DSC and XRD results suggested loss of crystallinity of irbesartan upon convertion into a liquisolid formulation. The results showed that liquisolid systems demonstrated considerably higher dissolution rates than plain drug and DCT. This might be due to increased wetting properties and surface of drug available for dissolution. Key words: Dissolution, Irbesartan, Liquisolid systems, Solubility. Introduction Among various methods for improving dissolution rates, liquisolid compact technology is a novel, technique for dissolution enhancement 2. A liquisolid system is a powdered form of liquid drug formulated by IJPT April-2012 Vol. 4 Issue No Page 3811

2 converting liquid lipophilic drug or drug suspension or solution of water insoluble drug in suitable nonvolatile solvent system into dry looking, non adherent, free flowing and readily compressible powdered mixtures by blending with selected carrier and coating materials 3. However, in the liquisolid systems the drug might be in a solid dosage form, it is held within the powder substrate in solution, or in a solubilised, almost molecularly dispersed state. Therefore, due to their significantly increased wetting properties and surface area available for dissolution, liquisolid compacts of water insoluble drugs may be expected to display enhanced drug release properties and consequently improved bioavailability 4. Various grades of celluloses, lactose, and starch can be used as carrier materials where as very fine silica powder is used as the coating material 3. Silica particles possessing large surface areas, and different grades of celluloses of fine particle size produced good flow and compression properties, resulting in acceptable tablets 5. Mathematical model by spireas et al of liquisolid systems described the calculation of the appropriate amounts of both carrier and coating material to be added to produce acceptable flowability and compressibility 5. Glibenclamide 11,Indomethacin 12, Methylclothiazide 13, Carbamazepine 14,Hydrocortisone 15, BromohexineHCl 16 etc. These are few drug used in the formulation of liquisolid systems. Materials and Methods Materials: Irbesartan was a kind gift from Dr. Reddy s (Hyderabad), Avicel PH 102 was procured from Zhaveri pharmakhem pvt ltd (Mumbai). Croscarmellose sodium (CCS) was supplied as a gift sample from Aizant Drug Research Solutions (Hyderabad). Propylene glycol and other excipients were procured from S.D Fine chemicals (Mumbai). Solubility studies: Solubility study of irbesartan was carried out in distilled water, propylene glycol (PG), tween 80, PEG 400. Saturated solutions of Irbesartan were prepared by adding excess of Irbesartan to all solvents and kept on the mechanical shaker for 48 hrs at 25 o C. After this period, the solutions were filtered, diluted and analysed by UV spectrophotometer at 245nm. Three determinations were carried out for each sample to calculate the solubility of irbesartan. IJPT April-2012 Vol. 4 Issue No Page 3812

3 Application of Mathematical Model for Design of Liquisolid Compacts: To achieve good flow and compressibility of liquisolid systems, a mathematical model designed by Spireas et al 6, was used in the present work. In this study, propylene glycol was used as liquid vehicle, Micro crystalline cellulose phosphate ( Avicel PH102), colloidal silicon dioxide Aerosil(200) were used as carrier and coating material respectively. Concentration of the drug in propylene glycol was taken as 100%, 75%, 62.5% and carrier to coating material ratios were selected, ranging from Liquid Loading Factor (L f ): It is defined as the maximum weight of liquid that can be retained per unit weight of powder material in order to produce acceptable liquid powder admixture. L f = Ǿ CA + Ǿ CO (1/R) (1) Ǿ CA - Flowable liquid retention potential of the carrier material Ǿ CO - Flowable liquid retention potential of the coating material R - Excipient ratio Liquid loading factor is also defined as ratio of weight of liquid medication (W) to the weight of carrier material (Q) L f =W/Q (2) Excipient ratio R of a powder is defined as the ratio of the weight of the carrier material (Q) to the weight of the coating material (q), present in formulation. R= Q/q (3) In this study, excipient ratios were selected as ranging from 5-50, For calculation of L f, Ǿ values are required, The Ǿ values for Avicel PH 102 and Aerosil 200 with Propylene glycol were reported as 0.16 & 3.31 respectively. 7 According to the ratio of the carrier/coating material (R), Ǿ CA, Ǿ CO values, L f was calculated (From Eq 1). From the liquid vehicle concentration(w), Liquid loading factor (L f ) values, appropriate quantities of carrier and coating materials were calculated by using eq. 2, and eq. 3 respectively. IJPT April-2012 Vol. 4 Issue No Page 3813

4 The drug concentrations (w/w), liquid load factors(l f ), amounts of carrier (Q), and coating materials(q), are given in Table 1. Table no 1: Formulation of liquisolid systems. Formulation Code %w/w of Excipient Liquid Carrier Coating Unit wt of Drug in Ratio(R) Loading Material Material Propylene glycol(w) Factor (Lf) (gms) Q=W/L f (gms) q= Q/R Tablet (gms) LS-1 100% LS-2 100% LS-3 100% LS-4 100% LS-5 100% LS-6 100% LS-7 100% LS-8 75% LS-9 75% LS-10 75% LS-11 75% LS-12 75% LS-13 75% LS-14 75% LS % LS % LS % LS % LS % LS % LS % In all formulations having 5% of CCS. IJPT April-2012 Vol. 4 Issue No Page 3814

5 Preparation of liquisolid compacts and liquisolid micro systems: Measured quantities (Table No. 1) of solid drug and the liquid vehicle (PG) were mixed and heated to o C with constant stirring and the mixture is sonicated for 15mins, until a homogenous suspension was obtained. Next the calculated weights of the hot liquid medication were incorporated into the calculated quantities of carrier (Avicel PH 102) and after mixing the resultant wet mixture was then blended with calculated amount of coating material (Aerosil 200) using a standard mixing procedure that was described by Spireas and Bolton 9,10. Later on, the liquisolid formula was blended with 5% disintegrant croscarmellose sodium (CCS) and the prepared liquisolid systems that were proven to have the acceptable flowability and compressibility. The formulated powder was divided into two portions, one portion was compressed into tablets using a 12mm circular concave punches plain on both sides using a 12 station compression tablet press machine (Rimek) 9, 10. The other portion was filled into 0 size capsules and were called liquisolid micro systems. Characterization: Flow Properties of liquisolid systems: Flow properties of liuisolid systems were estimated by Tapped density, Bulk density, Angle of repose, Carrs index, Hausners ratio. These properties were determined by using the following equations 8. Bulk Density (ρ b ) = mass (gms)/ bulk volume Tapped density (ρ t ) = mass (gms)/ tapped volume Carrs Index = ρ t ρ b / ρ t X 100 Angle of repose Tan θ = h/r Hausners ratio = ρ t / ρ b Evaluation of liquisolid systems: The prepared Liquisolid compacts were evaluated for carrying out various tests assay, content uniformity, uniformity of tablet thickness, friability, weight variation, hardness and dissolution. All tests were carried out according to the USP compendial specifications. IJPT April-2012 Vol. 4 Issue No Page 3815

6 Dissolution Studies: The dissolution studies were performed in dissolution apparatus using paddle method (USP II) using 1000ml of 0.1N HCl (ph-1.2) at 37± 0.5 o C at 50 rpm. IRB 75mg or its equivalent amount of tablet was added to 0.1N. The volume of dissolution medium was adjusted to 1000ml by replacing with 5ml of fresh 0.1N HCl. The samples were analyzed spectrophotometrically at 245nm. Differential Scanning Calorimeter: Thermograms of IRB, excipients, LS formulation were recorded by using Perkin-Elmer differential scanning calorimeter with a pyris6 workstation. The accurately weighed sample was placed on aluminium pan and an empty aluminium pan was used as reference. Thermal behaviour of the samples was investigated under a scanning rate of 10 o C/ min, covering a temperature range of o C. X- Ray Powder Diffraction: X ray diffractograms of IRB, and LS formulation were recorded by using PAN analytical X pert pro. The cross section of the samples was exposed to X ray radiation with scanning range of 0-50 θ. Directly compressible tablets of irbesartan: The tablets were prepared using dry granulation. Irbesartan, lactose monohydrate (Granulac and Flowlac ) and a portion of the sodium starch glycolate were sized and mixed. (Give exact quantities) The powder blend was compacted into slugs. The slugs obtained were milled and mixed with sodium starch glycolate. The blend obtained was lubricated with magnesium stearate and compressed into tablets using circular concave 12mm punches plain on both sides. Results and Discussions Solubility studies: Solubility studies were performed to select the solvent for liquisolid systems (Table No 3). Irbesartan shows maximum solubility in propylene glycol, hence the same was selected as non volatile solvent. (Fig 1). IJPT April-2012 Vol. 4 Issue No Page 3816

7 Figure 1: Solubility study of IRB in different solvents. Flow property evaluation: Flow properties such as angle of repose, Carr s index and Hausner s ratio were estimated and are represented in Table. 4. Based on the results LS-7, LS-13, LS-14 were selected as optimized formulations for further studies. Proportion of carrier material in formulations LS-13 & LS-14 (0.428gms & 0.459gms respectively) is greater than the solvent system (75%). Hence these formulations showed good flow properties. Table 3: Solubility study of irbesartan in different solvents. Solvent Solubility (%w/w) Dis. Water Tween Propylene glycol PEG IJPT April-2012 Vol. 4 Issue No Page 3817

8 Table no 4: Flow property evaluation. Formulation Tapped Code Bulk density density Avg. Carr s Hausner s Angle of (gm/ml) (gm/ml) index (%) ratio repose (θ) DCT 0.333± ± ± ± ±1.46 LS ± ± ± ± ±1.61 LS ± ± ± ± ±0.73 LS ± ± ± ± ±0.45 LS ± ± ± ± ±0.58 LS ± ± ± ± ±0.56 LS ± ± ± ± ±0.80 LS ± ± ± ± ±1.21 LS ± ± ± ± ±0.42 LS ± ± ± ± ±1.18 LS ± ± ± ± ±0.74 LS ± ± ± ± ±0.62 LS ± ± ± ± ±0.46 LS ± ± ± ± ±0.56 LS ± ± ± ± ±0.71 LS ± ± ± ± ±0.67 LS ± ± ± ± ±.0.74 LS ± ± ± ± ±1.54 LS ± ± ± ± ±0.69 LS ± ± ± ± ±1.42 LS ± ± ± ± ±0.70 LS ± ± ± ± ±1.51 Each value represents mean ± SD (n=3) Evaluation of optimized Liquisolid compacts The optimized liquisolid formulations LS-7, LS-13, LS-14 were compressed into tablets and evaluated for assay, weight variation, hardness and friability. The results are given in Table 5. The results indicated that all the formulations complied with USP specifications. (Limits: Assay %, friability < 1%, and weight variation --). IJPT April-2012 Vol. 4 Issue No Page 3818

9 Formulations LS-7, LS-13 could not achieve the required hardness of 3Kgs and therefore only LS-14 formulation with hardness more than 3Kgs/Sq.cm was selected for further studies. Table No 5: Evaluation of Optimized Liquisolid Compacts And Dct n = 6. CODE ASSAY ± SD Wt VARIATION HARDNESS FRIABILITY ±SD LS ± ( ) ±0.23 LS ± ( ) ±0.19 LS ± ( ) ±0.015 DCT 98.34± ( ) ±0.12 Each value represents mean ± SD (n=6) Evaluation of Liquisolid micro systems The optimized LS-14 formulation was filled into empty capsule and evaluated for assay. The Assay for LS-14 microsystems was found to be 98.35±0.36%,. Evaluation of directly compressible tablets of irbesartan Irbesartan powder mixture comprising of drug Lactose monohydrate, Sodium starch glycolate, Magnesium stearate and Talc (Table No.2) were evaluated for flow properties and compressed into tablets by direct compression method. The tablets were also evaluated for the properties like assay, weight variation, hardness and friability. The results of flow properties and evaluation of directly compressible tablets are given in the Table 4 and 5 respectively. The directly compressible tablets complied with the USP specifications. Table no 2: Formulation of directly compressible tablets. COMPOSITION Weights(mg) Irbesartan 75 Lactose monohydrate 67.5 Sodium starch glycolate 4.5 Mg. stearate 1.5 Talc 3 IJPT April-2012 Vol. 4 Issue No Page 3819

10 In vitro dissolution studies: The optimized formulations were subjected to in vitro dissolution studies in 0.1 N HCl. The dissolution studies of LS-14 (compact), LS-14 (micro systems), LS -14 (in capsule), pure drug, directly compressible tablet (DCT) are shown in Figure 2. The dissolution profiles of LS-14 micro systems formulation exhibited highest drug release compared to pure drug, DCT and LS- Dissolution profiles 14 compact. % Drug release Time (min) LS microsystems LS compact DCT Pure drug Fig: 2 Dissolution profiles of Plain Drug and formulations of LSC. Dissolution rate of pure Irbesartan was less because of hydrophobic nature of drug. The pure drug had shown 100% drug release in 180 min. The directly compressible tablet has shown 100% drug release in 60 min. In case of LS-14 compact >90% drug release was seen in 60 min, and LS-14 microsystems shown 100% of drug release in 45 min. Hence LS microsystems have shown higher dissolution profiles than LS-14 compact, DCT, Pure drug. This might be due to increased wetting properties and increased surface area available for dissolution. Powder X-ray diffraction analysis: X-ray diffraction patterns revealed that pure irbesartan was in crystalline state (Fig 3), as it showed sharp distinct peaks notably at 2θ diffraction angles of 4.75 o, o, o, o. Avicel PH 102 showed a peak at 2θ diffraction angles of o. Aerosil 200 is does not show any peak in the angle range from 2θ to 50θ, indicating the amorphous state. The reflections (specific peaks) corresponding to the drug and other excipients were also found in the formulation diffractogram with reduced intensity as compared to drug alone. The reduced intensity and reduced number of peaks in formulation diffractogram suggest that reduction in crystalline nature of drug conversion to IJPT April-2012 Vol. 4 Issue No Page 3820

11 amorphous form. This lack of crystallinity in the formulation might be due to solubilization of drug in liquid vehicle. Fig: 3 XRD spectrums of LS 14 formulation of irbesartan. Fig 4: DSC thermogram of LS 14 formulation of irbesartan. IJPT April-2012 Vol. 4 Issue No Page 3821

12 Differential Scanning Calorimeter: The thermogram of pure irbesartan showed a sharp endothermic peak at 185 o C (T onset = o C; H=84.4 J/gm), indicating the crystalline nature of the drug. Avicel PH102, Aerosil 200 displayed broad peaks at o C & o C. DSC thermogram of liquisolid formulations revealed a characteristic drug peak at 189 o C, as the area and sharpness of the peak was decreased. This indicated reduction in crystalline nature of the drug and conversion to amorphous form. There was no change in the peak temperature of the optimized formulation, when compared to the pure drug, which indicates no interaction between drug and excipients. Conclusion Liquisolid technique could be a promising strategy in improving dissolution of poorly water soluble drugs like Irbesartan and formulating immediate release dosage forms. Various non volatile solvents and excipients were used in the preparation of Liquisolid systems. Liquisolid systems were prepared by using propylene glycol as the liquid medicament as the drug shows maximum solubility in propylene glycol. Avicel PH102, Aerosil 200, Croscarmellose sodium were selected as carrier, coating material and superdisintegrants respectively. Based on flow properties LS-7, LS-13 & Ls-14 were selected as optimized formulations for further studies. Carrier to coating 50:1 ratio formulations of liquisolid microsystems, had shown higher dissolution profiles than LS-14 compact, DCT, pure drug. The optimized formulation was evaluated and characterized. The results of XRD showed reduction of crystalline properties of drug and DSC showed there is no interaction between drug and excipients during formulation process. In conclusion it can be stated that the objective of the study was met. The technique was successful in improving the dissolution rate of Irbesartan. Acknowledgements: We would like to M/s Dr. Reddy s laboratories Hyderabad, India for their kind gift samples of the drug, Irbesartan. References 1. Rajashree hirlekar and vilasrao kadam, preformulation study of the inclusion complex irbesartan-β-cyclodextrin, AAPS pharmasci tech, 2009, Vol 10, pp IJPT April-2012 Vol. 4 Issue No Page 3822

13 2. V.B yadav et al. liquisolid granulation technique for tablet manufacturing: an over view, Journal of Pharmacy Research, 2009, Vol 2, pp Y. Javadzadeh, M R Siahi-shadbad, M Barzegar-jalali,A Nokhodchi, enhancement of dissolution rate of piroxicam using liquisolid compacts, II farmaco 2005,Vol 60, pp Rania H fahmy, mohammed A kassem enhancement of Famotidine dissolution rate through liquisolid tablets formulation: invitro and invivo evaluation Europen journal of pharmaceutics and Biopharmaceutics, 2008, Vol 69, pp Saadia A. Tayel, Iman, I,Soliman, Dina Louis improvement of dissolution properties of carbamzepine through application of liquisolid tablet technique. European journal of Pharmaceutics and Biopharmaceutics, 2008,Vol 69, pp Amrit B karmarkar et al. Liquisolid tablets: A novel approach for drug delivery, International Journal of Health Research 2009, Vol 2, pp Indrajeer D Gonjari, Amrit B.karmarkar, Avinash H.Hosmani. evaluation of in vitro dissolution profile comparision methods of sustained release tramadol hydrochloride liquisolid compact formulations with marketed sustained release tablets, Digest Journal of Nano Materials And Biostructures, 2009, Vol 4, pp VB Yadav, AV yadav, Improvement of solubility and dissolution of indomethacin by liquisolid and compaction granulation technique, J.Pharm.sci & res. 2009,Vol 1, pp S.Spireas, M Bolton, liquisolid systems and methods of preparing same, U.S. patent, 5,968,550, S.Spireas, M Bolton liquisol5id systems and methods of preparing same, U.S. patent 6,423,339 B1, Darwish, I.A.E, EI-Kameel, Dissolution enhancement of glibenclamide using liquisolid tablet technology, Acta Pharma, 2001,Vol 51, pp Ali Nokhodchi, Y.Javadzadeh, Mohammad Reza Siahi-Shadbad, Mohammad Barzegar-Jalali, The effect of type and concentration of vehicles on the dissolution rate of a poorly soluble drug (indomethacin) from liquisolid compacts, J.Pharm Pharmaceut Sci, 2005,Vol 8, pp IJPT April-2012 Vol. 4 Issue No Page 3823

14 13. S.Spireas, T.Wang, R.Grover, Effect of powder substrate on the dissolution properties of methyclothiazide liquisolid compacts, Drug Dev Ind Pharm, 1999, Vol 25,pp Yousef javadzadeh, Liquisolid technique for dissolution rate enhancement of high dose water-insoluble drug (carbamazepine), International journal of pharmaceutics, 2007, Vol 341,pp Spiro Spireas, S.Sadu and Rakesh Grover, In-vitro release evaluation of hydrocortisone liquisolid tablets, J of Pharmaceutical Sciences, 1998, Vol 87, pp Sanjeev gubbi and ravindra jarag liquisolid technique for enhancement of dissolution properties of Bromohexine HCL, Research journal of pharmacy and technology, 2009, Vol 2, pp Corresponding Author: C. Aparna *, caprn123@yahoo.co.in IJPT April-2012 Vol. 4 Issue No Page 3824