Formulation and characterization of liquisolid compacts of valsartan

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1 Research Article Available online through ISSN: Formulation and characterization of liquisolid compacts of valsartan Govil Sharma, 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 Valsartan is a nonpeptide, orally active, and specific angiotensin II receptor blocker, used for the treatment of hypertension. It belongs to BCS class II i.e. low solubility and high permeability, thus exhibiting the problem of variable bioavailability. Liquisolid system involves dissolving water insoluble drugs in non-volatile solvents and then converting them into dry, non-adherent, free- flowing and compressible powder mixtures by blending with selected carriers and coating materials. Liquisolid compacts (LSC) of poorly water soluble drug valsartan were prepared to enhance its dissolution rate and bioavailability. Liquisolid tablets were prepared using Polyethylene Glycol (PEG-200) as the non-volatile solvent with selected carriers and coating materials. The prepared liquisolid (LS) systems were evaluated for the flow properties such as Bulk density, Tapped density, Carr s index, Hausner s ratio and Angle of repose. The physico chemical properties of liquisolid systems were evaluated by Infrared spectra analysis (IR), Differential scanning calorimetry (DSC) and X- ray diffraction (XRD). DSC studies revealed that there was no interaction between the drug and carrier. XRD studies demonstrated that there was a significant decrease in crystallinity of pure drug present in LS system. The liquisolid tablets were evaluated for Weight variation, Hardness, Drug content, Disintegration time and Dissolution rate. Liquisolid compact exhibited higher dissolution rate as compared to marketed tablet. This enhanced dissolution rate might be due to increased wetting properties and surface area of drug available for dissolution. KEYWORDS: Valsartan; Loading Factor; Liquisolid compacts (LSC); Dissolution rate; XRD; DSC. INTRODUCTION Dissolution properties of water insoluble drug and its release from a dosage form have a basic impact on the bioavailability (1). Solubility and dissolution rate of water-insoluble drugs are the major challenges to the development of pharmaceutical dosage forms (2-3). Dissolution acts as a rate limiting step in the absorption of drugs from oral route (3), therefore it is necessary to enhance the dissolution of these drugs to ensure its maximum therapeutic utility. Various methods employed to improve the dissolution characteristics of poorly water soluble drugs are solubilization, ph adjustment, cosolvancy, microemulsion, self emulsification, polymeric modification, drug complexation, and micronization, use of surfactant as a solubilizing agent, the prodrug approach and solid dispersion (3-4). The new technique developed by Spireas liquisolid system is the most promising method for improving the dissolution properties of poorly soluble drugs (3). A liquisolid system (LS) refers to formulations formed by conversion of liquid drugs, drug suspensions or drug solution in non-volatile solvents into dry, non-adherent, free- flowing and compressible powder mixtures by blending with selected carriers and coating materials (2). Drug present in the liquid medicament in LS is in the solubilized or molecularly dispersed state, so the dissolution can be enhanced by increased surface area and better wetting properties (5). The technique of liquisolid compacts has been successfully employed to improve the in vitro release of poorly water soluble drugs such as carbamazepine (3), Atorvastatin calcium (4), famotidine (6), Piroxicam (7), Indomethacin (8), Rofecoxib (9), Carvedilol (10), Irbesartan (11) etc. The advantages of Liquisolid techniques includes simplicity, low cost and capability of industrial production (5, 12). Valsartan is an angiotensin II receptor antagonist used in the management of hypertension (13). Valsartan has low aqueous solubility and high membrane *Corresponding author. Sadhna Khatry, Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway, Rajpura , Patiala, Punjab, India. permeability belonging to class II of the Biopharmaceutical Drug Classification system (14).It is rapidly absorbed after oral dose with a bioavailability of about 23%. It is a weakly-acidic drug that has tetrazole derivative containing acid and carboxylic acid groups with pka values of 4.73 and 3.9 respectively. Peak plasma concentrations occur in 2 to 4 hours and its plasma half-life is about 7.5 hours (13). Therefore, improvement in its solubility and dissolution rate may lead to enhancement in bioavailability. The main objective of this work was to develop a new formulation of Valsartan to enhance its bioavailability by preparing liquisolid compacts. In the present work, liquisolid compacts of Valsartan were formulated and evaluated for their precompression and postcompression parameters. MATERIALS AND METHODS Materials Valsartan was obtained as a gift sample from Ranbaxy Laboratories, Pontasahib (India). Avicel PH 102, Aerosil 200, Sodium starch glycolate (SSG) and Crospovidone (CP) were obtained as gift samples from Park Pharma, Baddi (India). All reagents used were of analytical grade. Spectrophotometric analysis: Preparation of calibration curve 20 mg of drug was dissolved in methanol in a volumetric flask. Volume was made upto 100 ml with methanol (200 µg/ml). From this stock solution, dilutions were made with distilled water in the concentrations of 4, 8, 12, 16, 20, 24 and 28 µg/ml. The absorbances were recorded at 250 nm using systronics UV-Visible spectrophotometer. Beer Lambert law was obeyed in the concentration range of 4 to 28 µg/ml. Solubility studies Solubility studies of Valsartan were carried out in Distilled water, Propylene glycol and Polyethylene glycol (PEG-200, 400, and 600) to determine the best non-volatile solvent. Saturated solutions were prepared by adding excess drug to the vehicles and kept on the orbital shaker for 48 h at 25 C. The solutions were diluted and their concentration analysed by UV-spectropho-

2 tometer at 250 nm. Three determinations were carried out for each sample to calculate the solubility of Valsartan. (2, 10) Application of mathematical model for design of liquisolid tablets The formulation design of liquisolid systems was done in accordance with the mathematical model described by Spireas et al. According to theories of liquisolid tablets, the carrier and coating powder materials can retain only certain amounts of liquid while maintaining acceptable flowability and compressibility. The excipient ratio R of the powder is defined as R = Q / q (1) Where R is the ratio of the weight of carrier (Q) and (q) coating materials present in the formulation. The liquid load factor (L f ) is defined as the ratio of the weight of liquid medication (W) to the weight of the carrier powder (Q) in the system, which should be present in an acceptably flowing and compressible liquisolid system, i.e. L f = W / Q (2) Flowable liquid retention potential ( θ value) of powder excipients was used to calculate the required ingredient quantities. Therefore, powder excipients ratios R and liquid load factors L f of the formulations are related as follows: L f = θ CA + θ CO (1/R) (3) Where, θ CA and θ CO are the θ values of carrier and coating materials, respectively. Q = W/ L f (4) q = Q/R (5) Where, Q is the Carrier and q is the Coating material. θ-value of carrier and coating material in the solvent PEG- 200 was determined experimentally and found to be and respectively. Precompression studies of the liquisolid system: Flow Properties of the liquisolid system Flow properties must be optimum for the formulation and industrial production of tablet dosage form. Flow properties of liquisolid systems were estimated by Tapped density, Bulk density, Angle of repose, Carr s index, Hausner s ratio. These properties were determined by using the following equations: Bulk Density (ρ b) = mass (g)/ bulk volume Tapped density (ρ t) = mass (g)/ tapped volume Carr s Index = ρt ρ b / ρ t X 100 Angle of repose Tan θ = h/r Hausner s ratio = ρt / ρ b Drug Content LS mixture equivalent to unit dose of drug (40mg) was weighed accurately and dissolved in 100 ml of methanol. The stock solutions were diluted with distilled water and analyzed by UV- spectrophotometry at 250 nm and drug content calculated accordingly. Fourier Transform Infrared Spectroscopy (FTIR) The IR spectra of drug, physical mixture and LS mixture were recorded using an FTIR spectrophotometer [BRUKER (Alpha E)]. The samples were scanned over the frequency range cm -1. The resultant spectra were compared for any spectral changes. X-Ray Diffractometry (XRD) Polymorphic changes in the drug are important since they might affect the dissolution rate and bioavailability, therefore, it was necessary to study the polymorphic changes of Valsartan in liquisolid compacts. XRD spectra of samples were recorded using a high-power powder x-ray diffractometer (Ru- 200B, Pune, India) with Cu as target at a scan speed of 4 /min. The samples were analyzed at a 2θ angle range of The operating voltage and current were 40 kv and 55 ma respectively. According to mathematical model equation for Avicel PH 102 and Aerosil 200 in PEG 200, Lf was calculated by using R values as follows: Lf = (1 / R) Preparation of liquisolid Compacts and conventional tablet Calculated quantities of Valsartan and Polyethylene glycol (PEG 200) were accurately weighed and mixed at 30 C. The mixture was sonicated for 10 mins to obtain a clear solution. Required quantities of carrier (Avicel PH 102) and coating materials (Aerosil 200) were incorporated to the admixture of drug-vehicle and mixed completely. The optimum concentrations of superdisintegrants (Crospovidone, Sodium Starch Glycolate) were added to prepared liquisolid systems for acceptable flowability and compressibility. The formulated powder was compressed into tablets using rotary press. Conventional tablets of Valsartan were prepared by direct compression containing 40 mg drug with Avicel PH 102, Aerosil 200. Table1: Explains the formulations of Liquisolid system with different R ratios. Formulation Wt. of Liquid Lf Avicel Aerosil Code medicament PH 102 (mg) 200 (mg) qo (mg) Qo = W/ Lf = Qo/R LS LS LS Differential scanning calorimetry (DSC) The possible interactions between the drug and excipients in liquisolid compacts were determined by DSC. Thermograms of drug, physical mixture and LS mixture were recorded using a differential scanning calorimeter. Accurately weighed 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. Evaluation of liquisolid compacts (Formulation) The prepared Liquisolid compacts were evaluated for carrying out various tests such as assay, content uniformity, friability, weight variation, hardness and disintegration. All tests were carried out according to the USP compendial specifications. Dissolution Studies Dissolution studies of LS tablets were carried out in USP Apparatus 2 (Paddle type) (Electro Lab). Tablets were placed in dissolution vessel containing 900 ml Phosphate buffer( ph 6.8 ) maintained 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 fresh dissolution medium. The samples were analyzed spectrophotometrically at 250 nm. RESULTS AND DISCUSSION Solubility Studies Solubility studies were performed to select the solvent for liquisolid system. Table 2 and Fig. 1 explains the results of solubility studies. Valsartan showed maximum solubility in PEG 200, hence the same was selected as non-volatile solvent.

3 Table 2: Solubility of Valsartan in different solvents Solvent Solubility(% w/w) Dis. Water Propylene glycol PEG PEG PEG Fig. 2: FTIR spectra of (A) Valsartan (B) Physical Mixture C) Liquisolid System (LS -1) Fig. 1: Solubility of Valsartan in different solvents Precompression studies for liquisolid systems: Flow properties Results of measurements such as angle of repose, Carr s index, and Hausner s ratio are represented in the Table 3. Table 3: Evaluation of Flow Properties (LS systems and Drug) X-Ray Diffraction Figure 3 shows the X-ray diffractogram of the Drug, LS-1 system and Physical mixture. Valsartan shows sharp peaks at 17.92, and at 2θ. The absence of characteristic peaks of Valsartan in the liquisolid system shows that drug is entirely converted into amorphous or solubilized form. The absence of crystallinity of the drug in the liquisolid system might be due to the result of solubilisation in the liquid vehicle which was absorbed into carrier material and adsorbed onto coating materials.the Liquisolid and physical mixture formulations have the same diffraction pattern and there were no other peaks. The amorphization or solubilisation of Valsartan has increased the dissolution rate. Formulation Bulk Tapped Hausner s Carr s Angle Angle Code Density Density Ratio Index of repose of Slide (g/cm 3 ) (g/cm 3 ) (%) Drug 0.444± ± ± ± ±0.5 42±0.5 LS ± ± ± ± ±0.5 33±0.5 LS ± ± ± ± ±0.5 36±0.5 LS ± ± ± ± ±0.5 39±0.5 Each value represents mean ±SD (n=3) Based on the results of flow properties, LS-1 was selected as optimized system for further studies. Proportion of carrier material in formulation LS- 1 is more than LS-2 and LS-3, therefore it showed good flow properties. FT-IR spectra FTIR spectroscopy was used to study the structural changes and possible interactions between the drug and LS-1 system. The FTIR spectrum (Fig. 2) of Valsartan showed its characteristic IR absorption peaks at 3741, 2872, 2315, 1963, 1734, 833 and 652 cm -1. The characteristic peaks for LS-1 and physical mixture were found at 3742, 2871, 2314, 1962, 1726,828 and 657 cm -1 (Fig. 2). These spectra observations indicated no interaction between the drug and carrier used (Avicel). Fig. 3: Characterization by XRD: A) Liquisolid System (LS-1) B) Physical Mixture C) Drug

4 Differential Scanning Colorimetry 120 % Cumulative drug release Time (min.) DRUG LSC- 1 LSC- 2 LSC- 3 Fig. 4: DSC thermogram of A) Valsartan Drug B) Aerosil C) Avicel D) Liquisolid (LS 1) system. Fig. 5: Dissolution profile of prepared different LS tablets (LSC) and drug Figure 5 shows the dissolution studies of the drug and the prepared different Liquisolid tablets. LSC- 2 or tablets with 4% CP exhibited higher dissolution rate as compared to LSC -3 with 5% SSG. Pure drug showed 40.49% drug release in 45 mins., optimized LS System (LSC-1 ) showed 90.57% drug release, LSC-2 with CP 4% showed % and LSC- 3 with 5% SSG showed % drug release in 45 mins. The thermogram of pure Valsartan in (Fig. 4) showed a sharp endothermic peak at C corresponding to its melting point, indicating the crystalline nature of the drug. Avicel PH 102 displayed broad peaks at C and Aerosil 200 displayed a small broad peak 90 0 C. DSC thermogram of liquisolid system revealed a broad peak at 85 0 C, indicating a reduction in the crystalline nature of drug and its conversion to amorphous form. There was a slight shift in the drug melting peak indicating dissolution of drug in the non-volatile solvent (PEG-200) before reaching its fusion temperature. It was concluded that the presence of the drug affects the lattice energy of the crystalline polymer leading to shifting of the peak. The disappearance of drug peaks upon formulation into a liquisolid system was in agreement with McCauley and Brittain (15) who declared that the complete suppression of all drug thermal features undoubtedly indicates the formation of an amorphous solid solution. There was no other observed interaction between the drug and excipients. Formulation and Optimization of Liquisolid Compacts (LSC-Tablets): Table 4: Composition of Valsartan liquisolid formulations S. No Composition LSC-1 (mg) LSC-2 (mg) LSC-3(mg) 1 Liq. Medicament Avicel PH Aerosil CP (4%) SSG (5%) Mg. Stearate (0.5%) Talc (0.5%) Total Weight Where CP is Cross-povidone and SSG is Sodium Starch Glycolate Table 5: Evaluation of Valsartan liquisolid tablets Code Hardness Friability Disintegration Drug (kg/cm 2 ) (g) time(min.) Content (%) LSC LSC LSC Each value represents mean (n=6) Fig.6: Dissolution profile of LS tablet (LSC-2), marketed tablet and conventional tablet. Figure 6 shows the comparative dissolution studies of LSC-2 tablets, marketed preparation and conventional tablets. Marketed preparation showed 97.6% drug release in 45 mins, conventional tablet showed 88.78% drug release and LSC -2 tablets showed % drug release. CONCLUSION Liquisolid technique was successful in improving the dissolution of poorly water-soluble drugs like Valsartan. It is a novel technique for formulating immediate release dosage form. Liquisolid systems were prepared by using PEG (200) as the liquid medicament as the drug showed maximum solubility in it. Avicel PH 102, Aerosil 200, Crospovidone (4%) and Sodium Starch Glycolate (5%) were selected as carrier, coating material and superdisintegrants respectively. LS-1 was selected as optimized system for further studies because it showed the best flow properties. The optimized LS-1 was evaluated and characterized. XRD studies showed complete inhibition of crystallinity in the Valsartan liquisolid system and conversion into amorphous form. DSC study confirmed the absence of any interaction between the drug and excipients used in the preparation of liquisolid compacts. Then LS-1 was formulated into Liquisolid compacts (tablets) using superdisintegrants and other excipients. LSC-2 tablets with (4%) CP showed significantly

5 higher dissolution as compared to pure drug, conventional tablet and marketed tablet. ACKNOWLEDGEMENTS: We would like to thank M/S Ranbaxy Laboratories, Pontasahib (India) for their kind gift sample of the drug, Valsartan. REFERENCES: 1. Gavali Sahil M., Pacharane Sharad S., Jadhav Kisan R. et al. Liquisolid compact: A new technique for enhancement of drug dissolution. International Journal of research in Pharmacy and Chemistry, 1(3): (2011). 2. Gubbi Sanjeev, Jarag Ravindra. Liquisolid Technique for enhancement of dissolution properties of Bromhexine Hydrochloride. Research J. Pharm. and Tech., 2 (2): April.-June. (2009), Javadzadeh Y., Nokhodchi A et. al. Liquisolid technique for dissolution rate enhancement of a high dose water-insoluble drug (carbamazepine). International Journal of Pharmaceutics, 341: (2007) G. Sanjeev Raghavendra, Jarag Ravindra. Formulation and Characterization of Atorvastatin Calcium liquisolid compacts. Asian Journal of Pharmaceutical Sciences, 5(2): (2010) Karmarkar Amrit B., Gonjari Indrajeet D et. al. Dissolution rate enhancement of Fenofibrate using Liquisolid Tablet Technique, Latin American Journal of Pharmacy, 28 (2): (2009) Fahmy R. H., Kassem M. A. Enhancement of famotidine dissolution rate through liquisolid tablets formulation: In vitro and in vivo evaluation. Eur J Pharm Biopharm, 69: (2008) Javadzadeh Y., Siahi-Shadbad M. R., Barzegar-Jalali M., Nokhodchi A. Enhancement of dissolution rate of piroxicam compacts. Farmaco, 60: (2005) Saeedi Majid, Akbari Jafar et al. Enhancement of dissolution rate of Indomethacin using liquisolid compacts. Iranian Journal of Pharmaceutical Research, 10 (1): (2011) Khalid M. El-Say, Ahmed M. Samy, Mohamed I. Fetouh. Formulation and evaluation of Rofecoxib liquisolid tablets. International Journal Of Pharmaceutical Sciences Review & Research, 1(3): (2010). 10. P. Dinesh M., S. Umesh D., Mathur. Vijay B., Bhusari K. P. Liquisolid Technique for enhancement of dissolution properties of Carvedilol. Der Pharmacia Lettre, 2(15): (2010) Santosh P., Aparna C., Srinivas P., Sadanandam M. Enhancement of dissolution of irbesartan using liquisolid technology. International Journal of Pharmacy and Technology, vol. 4, Issue no. 1: April (2012) Javadzadeh Y., Musaalrezaei L., Nokhodchi Ali. Liquisolid technique as a new approach to sustain propranolol hydrochloride release from tablet matrices. International Journal of Pharmaceutics, 362: (2008) Goodman and Gilman s the pharmacological basis of therapeutics. 10th ed. New-york; McGraw Hill medical publishing division. 14. 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) J. A. McCauley, H. G. Brittain. Thermal methods of analysis, in: H.G. Brittain (ed.). Physical Characterization of Pharmaceutical Solids, Drugs and Pharmaceutical Sciences, Marcel Dekker Inc., New York. 1995, 70: Source of support: Nil, Conflict of interest: None Declared