Noor Ahmed VH. et al. / International Journal of Biopharmaceutics. 2013; 4(1): 1-9. International Journal of Biopharmaceutics

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1 1 e- ISSN Print ISSN International Journal of Biopharmaceutics Journal homepage: IJB FORMULATION DESIGN, CHARACTERISATION AND IN VITRO EVALUATION OF BILAYERED TABLETS CONTAINING TELMISARTAN AND HYDROCHLORTHIZIDE Noor Ahmed VH 1*, Niharika G 2, Deepak P 3, Shaaz Nazan 4, Soheib Afroz Mohammed 5 Department of pharmaceutics, 1* Sree Vidyanikethan College of pharmacy, A.Rangampet, Tirupati , AP, India. 2 Bharat College of Pharmacy, Ibrahimpatnam, Hyderabad, AP, India. 3 Sree Padmavathi School of Pharmacy, Tirupati, AP, India. 4 Shadan College of Pharmacy, Peerancheru, Hyderabad, AP, India. 5 Vaagdevi College of Pharmacy, Hanamkonda, Warangal, AP, India. ABSTRACT The primary aim of this development is to have a stable formulation of antihypertensive drugs of the Telmisartan and Hydrochlorothiazide bilayer tablet, and to study the dissolution profile. The Formulation development work was initiated with Wet granulation for telmisartan and direct compression for hydrochlorothiazide. Telmisartan is converted to its sodium salt by dissolving in aqueous solution of Sodium hydroxide, to improve solubility and drug release. Various grades of Polyethylene oxide was used as polymers for the modified release profile over a period of 3 h. In the direct compression of Hydrochlorothiazide, microcrystalline cellulose is used as binder and crospovidone as super disintegrant. Tablets were evaluated for physical properties, drug content and in vitro drug release. The excipients used in this formulation did not alter physicochemical properties of drug, conformed by FTIR studies. This formulation also exhibited the best fitted formulation into zero order kinetics and non-fickian transport of the drug from the tablets was confirmed. Bilayer tablets prepared from optimised formula (T4H5) was found to be best suited method for fixed dose combination of Telmisartan and Hydrochlorothiazide. Key words: Bilayer tablets, Telmisartan, Hydrochlorothiazide, Super disintegrant, Non-Fickian transport. INTRODUCTION The study was under taken with an aim to formulate combination of antihypertensive agents for better bioavailability as bilayer tablets. The aim of drug delivery system was to provide therapeutic amount of drug to targeted site in body to achieve promptly and then maintain the desired concentration (Nagaraju et al., 2009) Corresponding Author Noor Ahmed VH noor.pharmacon@gmail.com Taste masking of rapidly disintegrating tablets is accomplished by using sutable dilunts and superdisintegrants (Shailesh et al., 2010). Bilayered tablets are intented for sequential release of two drugs in combination and separate two incompatable substances, (Shiyani et al., 2008). Hypertension is designated as primary hypertension and secondary hypertension (Mullaicharam et al., 2010). Telmisartan is an angiotensin II receptor antagonist (ARB) used in the management of hypertension. Generally, angiotensin II receptor blockers (ARBs) such as telmisartan bind to the angiotensin II type 1 (AT1) receptors with high affinity, causing inhibition of the action of angiotensin II on

2 2 vascular smooth muscle, ultimately leading to a reduction in arterial blood pressure. Bioavailability was found to be 45% only it is due to extensive first pass effect (Ashutosh kumar et al., 2010). Hydrochlorothiazide is a thiazide diuretic, half-life was found to be 6-8 hrs (Rangole et al., 2008), which reduces the reabsorption of electrolytes from the renal tubules. This results in increased excretion of water and electrolytes, including sodium, potassium, chloride and magnesium. It has been used in the treatment of several disorders including edema, hypertension, diabetes insipidus and hypoparathyroidism. Using a low dosage of two different drugs minimises the clinical effects that occurs with large doses of single drug of combined tablet and thus dosage of single drug can be reduced (Ramya et al., 2010). MATERIALS Telmisartan and Hydrochlorothiazide was obtained as gift sample from Aurabindo pharma Pvt Ltd,Hyderabad, Polyethylene oxide N80 Polyethyleneoxide WSR 303, Mannitol, Aerosilwas obtained as gift sample from MMC Health Care, Chennai, Hydroxy Propyl Methyl Cellulose K15M,Microcrystalline cellulose, Povidone K 30, was obtained as gift sample from A-Z Pharmaceuticals, Chennai, And all other chemicals used in formulations are analytical grade. METHODS FORMULATION DEVELOPMENT Formulation Development of Telmisartan and Hydrochlorothiazide bilayered tablets The formulation of telmisrtan and hydrochlorothiazide bilayered tablets for the treatment of hypertension were developed by using various swellable polymers such as PEO N80, PEO WSR Coagulant, PEO WSR 303, HPMC K15M to attain modified drug release to the first layer. And hydrochlorothiazide layer was formulated by using super disintegrants like crospovidone to show immediate release of the drug. The blend for Bilayer tablet was compressed using 13mm size oval shaped punch STEPS INVOLVED IN MANUFACTURING OF BILAYER TABLETS Granulation of first layer Step 1: Sifting and mixing: Telmisartan and mannitol are passed through sieve No.40# and mixed thoroughly with the help of mortar and pestle. Step 2: Preparation of binder:dissolve sodium hydroxide, followed by povidone in required quantity of purified water Step 3: Wet granulation:granulate step 1 mixture with step 2 binder. Step 4: Drying:Dry the step-4 wet mass in a tray dryer at 60 0 C for about 15 minutes. Step 5: Pass the dried granules through 25# and the granules are formed. Step 6: Polyoxy ethylene is passed through 40# and then mix step-5 dried granules with PEO.. Step 7: Lubrication: Pass magnesium stearate through 60# and lubricate the step-6 with magnesium stearate. Preparation of second layer Step 8: Hydrochlorothiazide, microcrystalline cellulose, aerosol, crospovidone are passed through 40# and are mixed thoroughly. Step 9: Also pass magnesium stearate through 60# and add to the above mixture. Step10: To the final blend add iron oxide and mix properly. BILAYER TABLET COMPRESSION Introducing the granules of the first layer formed in step 6 into the tablet press and compress to form a tablet layer. Introducing the other tablet layer composition i.e, the final blend formed in step 9 into the tablet press. The punch size of the press is 13mm and is oval in shape. Compressing both the tablet layers first layer followed by second layer to form a bilayer tablet. Table 1. Formulation of first layer using various polymers S.No Ingedients (mg) T1 T2 T3 1 Telmisartan Mannitol Povidone K Sodium hydroxide Purified water Qs Qs Qs 6 PEO WSR PEO WSR coagulant HPMC K15M Magnesium stearate TOTAL

3 3 Table 2. Formulation of first layer using various concentrations of polyethylene oxide S.No Ingredients (mg) T4 T5 T6 1 Telmisartan Mannitol Povidone k Sodium hydroxide Purified water Qs Qs Qs 6 PEO N Magnesium stearate TOTAL Table 3. Formulation of second layer S.No Ingredients(mg) H1 H2 H3 1 Hydrochlorthiazide Microcrystalline cellulose Aerosil Crospovidone Iron oxide Magnesium stearate Total EVALUATION Powder flow properties Angle of repose In order to determine the flow property, the Angle of repose was determined. It is the maximum angle that can be obtained between the free standing surface of the powder heap and the horizontal plan = tan - 1 (h/r) Where, h= height, r = radius, = Angle of repose. Determination of bulk density and tapped density A quantity of 5g of the powder (W) from each formula was introduced into a 25 ml measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall under its own weight onto a hard surface from the height of 2.5 cm at 2 sec intervals. The tapping was continued until no further change in volume was noted. The bulk density, and tapped density were calculated using the following formulas Bulk density = W / V O Tapped density = W / V f Where, W = weight of the powder, V O = initial volume, V f = final volume Compressibility index (carr s indices) Compressibility index is an important measure that can be obtained from the bulk and tapped densities. In theory, the less compressible a material the more flow able it is. A material having values of less than 20 to 30% is defined as the free flowing material. C I = 100 (V O V f )/V Where, C I = Compressibility index, V O = initial volume, V f = final volume. Hausner s ratio It indicates the flow properties of the powder and is measured by the ratio of tapped density to the bulk density. SHAPE OF TABLETS The compressed tablets were examined under the magnifying lens for the shape of the tablet. TABLET DIMENSIONS Thickness and were measured using a calibrated vernier caliper. Three tablets of each formulation were taken randomly and thickness was measured individually. HARDNESS Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablets was determined using Monsanto hardness tester. It is expressed in KiloPascals. Three tablets were randomly picked and hardness of the tablets was determined. FRIABILITY TEST The friability of tablets was determined using Roche friabilator. It is expressed in percentage (%). Twenty tablets were initially weighed (w 0 initial) and transferred into friabilator. The friabilator was operated at 25rpm for 4 minutes or run up to 100 revolutions. The tablets were weighed again (w). The % friability was then calculated by Percentage of Friability = 100 (1-w/w 0 ) Percentage friability of tablets less than 1% is considered acceptable. WEIGHT VARIATION TEST Twenty tablets were selected at random and the average weight was determined. Not more than two of the individual weights deviate from the average weight

4 4 by more than the percentage deviation shown in table and none deviates by more than twice the percentage. USP official limits of percentage deviation of tablet are presented in the table. SWELLING STUDIES The swelling behavior of dosage unit can be measured either by studying its dimensional changes, weight gain or water uptake. The water uptake study of the dosage form was conducted by using USP dissolution apparatus-ii in a 900ml of distilled water which was maintained at 37 o o c, rotated at 50 rpm. At selected regular intervals the tablet was withdrawn and weighed. Percentage swelling of the tablet was expressed as percentage water uptake (%WU) (Chavanpatil et al., 2006). %WU = (Wt - Wo) * 1= (Wt - Wo) * 100 / Wo Where, Wt is the weight of tablet at time t. Wo is initial weight of tablet. DISSOLUTION STUDIES Preparation of solutions Standard solution Weigh accurately and transfer 40 mg of Telmisartan and 12.5 mg of Hydrochlorthiazide into a 100ml volumetric flask and add sufficient amount of diluent, sonicate to dissolve and make up to the volume with diluent.from this pipette out 1ml and make upto 10ml using diluent. Sonicate the solution and filter it and transfer it to a HPLC vial. Sample solution Six tablets are kept individually in six dissolution flasks with sinkers containing 900ml of the medium that has been equilibrated to 37±0.5 0 C. care is taken to exclude air bubbles from the surface of the tablet, apparatus is started immediately. Samples have been collected after the specified time, from a zone midway between the surface of the medium and top of the rotating blade and not less than 1 cm from the vessel wall and filter through 0.23μ membrane filter, and inject the solution directly into HPLC vial. Procedure Separately inject equal volume of standard and sample preparation,,record the chromatograms, and measure the areas for the telmisartan and hydrochlorthiazide.calculate the quantity of telmisartan and hydrochlorthiazide RESULTS AND DISCUSSION Drug-Polymer compatibility studies by Fourier transform infrared spectroscopy Fig 1. FTIR scan of pure Telmisartan Fig 2. FTIR scan of pure Hydrochlorothiazide

5 5 Fig 3. FTIR scan of Telmisartan mixed with Hydrochlorothiazide Fig 4. FTIR scan of Telmisartan mixed with Mannitol Fig 5. FTIR scan of Hydrochlorothiazide mixed with Crospovidone

6 6 Fig 6. FTIR scan of Hydrochlorothiazide mixed with Aerosil Table 4. Flow propeties of telmisartan granules S.No Parameters T1 T2 T3 T4 T5 T6 1 Angle of repose(ɵ) Bulk density (g/cm3) Untapped Tapped Compress- ibility index Hausner s ratio Table 5. Flow properties of hydrochlorothiazide blend S.No Parameter H1 H2 H3 H4 H5 1 Angle of repose(ɵ) Bulk density (g/cm3) Untapped Tapped Compressibility index (%) Hausner s ratio Table 6. Assay values Assay BP specification Results Telmisartan of LA % Hydrochlorothiazide of LA 99.6% Table 7. Evaluation parameters S. No Formulations Tablet Hardness Thickness Friability Disintegration weight (mg) (neutons) (mm) (%) (seconds) Drug Content (%) 1 T4H T H T4H T H T4H T H T4H T H T4H T H Table 8. Percentage swelling for various formulations Time(mins) T1 T2 T

7 7 Table 9. Percentage swelling for various formulations Time(mins) T4 T5 T Table 10. Percentage drug release of Telmisartan formulations Time(min) % Drug release T1 T2 T3 T4 T5 T Table 11. Dissolution profile of bilayered tablets Time(min) %Drug release T4H1 T4H2 T4H3 T4H4 T4H Fig 7. Dissolution profile of bilayered tablets Fig 8. Zero order plot for T4 Table 12. Drug release kinetics R 2 values Batch no. Korsemeyer Zero order First order Higuchi R 2 value n value Hixon Crowell T T T T T T H Fig 9. First order plot for T4 Fig 10. Higuchi plot for T4

8 8 Fig 11. Krosmeyer peppas plot for T4 Fig 12. Hixson-Crowel plot for T4 The FTIR spectra of both the drugs, drug loaded optimized formulation were shown in Fig no (1-6). The characteristic peaks of the optimized formulation followed the same trajectory as that of the drug alone with minor differences. Thus there was no drug-excipient interactions found. Flow properties of the granules can be judged from the angle of repose, compressibility index and hausner ratio shown in Table no (4-5). The angle of repose <30 indicates free flowing material and >40 with poor flow properties. The compressibility index (%) <10 indicates excellent flow properties and >38 with poor flow properties. The hausner ratio indicates free flowing and >1.60 with poor flow properties. Values for angle of repose, compressibility index (%) and hausner ratio for all prepared granules were found to be in the range of to 27.93, 7.3 to 7.5, and 1.07 to 1.09 which showed that the granules was free flowing and can be used for compression. Bulk density was found to be between gm/cm 3 and tapped density between and gm/cm3 for all formulations. From density data % compressibility was calculated and was found to be between 16.67% %. Angle of repose was found to be in the range of Hausner ratio was found below All the formulation shows the good blend properties for direct compression and hence tablets were prepared by using direct compression technology. The swelling of the polymers used were determined by water uptake of the tablet. The percent swelling of the tablet was determined at the end of 3 h. Increase in percent swelling was found with increasing concentration of polymers, The formulation with PEO N80 showed good swelling when compared with others. With increasing concentration, the swelling was also increased. The swelling index of T1-T3 and T4-T6 are shown in table (8-9). Assay results shown in Table no (6) were % for Telmisartan and 98.85% for Hydrochlorothiazide. The drug release studies were performed by dissolution apparatus, shon in (Fig 7). In T1-T6 formulations, PEO WSR 303, PEO WSR Coagulant, PEO N80,HPMC K 15M were used as a hydrophilic swellable polymers to attain better bioavailability. From drug release profile T4 formulation using PEO N80 (100mg) showed better release and was found to be optimized. The T4 optimised formulation of first layer was then allowed for direct compression with various formulations for second layer. Here crospovidone was used as super disintegrant. Disintegrant when used in 5%w/w concentration showed better release. Hence T4H5 formulation was the final formulation for which various other parameters were also evaluated. Average weight of all the formulations were within the range of

9 mg. Friability was also within the range of %. Disintegration for all the formulations were in the range of sec.drug content in each of the formulations were within the limits.in all the formulations T4H5 showed better results and hence considered as the best formulation. The R 2 values of zero order kinetics shown in Table no (12) ranged from for formulations T1 H5. The values for first order kinetics for T1 H5 ranged from The values for Higuchi model ranged between The values for Hixsoncrow model ranged between and the values for Peppas model ranged between All formulations showed diffusion coefficient less than 1.For the optimized formulation T4, showed zero order release kinetics with the R 2 value of and the R 2 value of Krosmeyer Peppas is (nearer to 1) is dominant than the other models which indicates drug release depended on the log of time. Hence the drug release follows zero order and non fickian release mechanism. CONCLUSION In the present study, PEO N80 was found to play a major role in increasing the bioavailability of telmisartan. PEO N80, a hydrophilic polymer, swells and increases the size of the tablet thereby retains in the stomach for much time and releases the drug over a period of time, thus enhancing the bioavailability. With the data from tables and graphs, the formulation of telmisartan layer with good drug release profile was taken as optimized formulation and was compressed with various formulations of hydrochlorothiazide blends. Here telmisartan layer is prepared by wet granulation method and hydrochlorothiazide is prepared by direct compression method. From the results, it can be concluded that formulation T4H5 showed the desired results. Accordingly, it can be concluded that the final formulation is a robust one and the performance is less likely to be affected by various study factors. REFERENCES Aushutosh kumar A, Arunanachalam A, Karkikeyan M, Mandipa S, Ravishankar V, Senthilaraj R. Design and evaluation of sustained release tablets of Telmisartan. Int J Pharm Sci, 2010; 8(1): Kroge I and Bodmeier R. Development of a multifunctional matrix drug delivery system surrounded by an impermiable cylinder. J. Controlled Release. 1999; 61(1): Mullaicharam AR, Shumo PM, Muthuprasanna P. Sustained release matrix Metaprolol tartarate with Inlay Hydrochlorthiazide tablet. Int J Pharma Biosciences. 2010; 1(2): Nagaraju R and kaza R. Formulation and evaluation of bilayered sustained release tablets of Salbutamol and Theophylline. Int J Pharmal Sci Nanotech. 2009; 2(3): Shailesh S and guptha GD. Formulation design and optimisation of mouth dissolving tablets of Dompiridone using sublimation technique. Int J Pharm Sci. 2010; 1(1): Shiyini B, Gattani S, Sharana S. Formulation and evaluation of bilayered tabets of Metaclopramide hydrochloride and Ibuprofen. AAPS Pharma Sci Tech. 9(3): Stepenksky D, Friedman M, Srour W, Raz I, Hoffman A. Preclinical evaluation of pharmacokinetic - pharmacodynamic rationale for oral CR metformin formulation. J Control Rel. 2001; 71: Uday S Rangole, Kautikwar PS and Sankar DM. Formulation and invitro evaluation of rapidly disintegrating tabets using Hydrochlorthiazide as model drug.research J Pharma And Tech. 2010; 1(4):