American-Eurasian Journal of Scientific Research 5 (4): 264-269, 2010 ISSN 1818-6785 IDOSI Publications, 2010

Formulation and Evaluation of Fast Dissolving Tablets of Amlodipine Besylate Using Different Super Disintegrants and Camphor as Sublimating Agent
Vineet Bhardwaj, Mayank Bansal and P.K. Sharma Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology Meerut-250005 (U.P.) India
Abstract: Amlodipine Besylate is used commonly for the treatment angina pectoris, commonly known as angina, is chest pain due to ischemia of the heart muscle, generally due to obstruction or spasm of the coronary arteries (the heart's blood vessels). Dosing to elderly patients is improved by mouth dissolving tablets it also provides convenience to whom that have trouble in swallowing tablets. The objective of the present study was to prepare the mouth dissolving tablet of Amlodipine using different superdisintegrants by sublimation method. Different concentrations (2%, 4% and 6%) of superdisintegrants such as Ac-Di-Sol, sodium starch glycolate, Kollidon-CL were used respectively. Camphor was used as an sublimating agent. Tablets are prepared by direct compression and mannitol is used as bulking agent. The compressed tablets are dried for 5 hours to allow sublimation of camphor to increase the porosity of the fast dissolving tablets to improve the dissolution. The tablets were evaluated for hardness, friability, weight variation, wetting time, thickness, water absorption ratio, disintegrating time, uniformity of content and in-vitro drug release. All the tablets had hardness 2.3-3.7 kg/cm2 and friability of all formulations was less than 1%, weight variation and drug content were within official limit. Amongst all formulations, formulation F9 prepared by 6% Ac-Di-Sol showed least disintegrating time of 11sec. and faster dissolution. Formulation F9 was then studied for accelerated stability studies as per ICH guidelines for 60 days that shows no remarkable change in the formulation. Key words: Angina pectoris Ac-Di-Sol Sodium starch glycolate Kollidon-CL ICH guidelines

NTRODUCTION A fast dissolving tablet system can be defined as a dosage form for oral administration, which when placed in mouth, rapidly dispersed or dissolved and can be swallowed in form of liquid. Recently fast dissolving formulation is popular as Novel Drug Delivery Systems because they are easy to administer and lead to better patient compliance. Paediatric and geriatric patient have difficulty in swallowing the conventional dosage forms these dosage forms dissolve or disintegrate in the oral cavity within a minute without the need of water or chewing. For these formulations, the small volume of saliva is usually sufficient to result in tablet disintegration in the oral cavity. The medication can then be absorbed partially or entirely into the systemic circulation from blood vessels in the sublingual mucosa, or it can be swallowed as a solution to be absorbed from the gastrointestinal tract [1-3].

Angina pectoris, commonly known as angina, is chest pain due to ischemia of the heart muscle, generally due to obstruction or spasm of the coronary arteries (the heart's blood vessels). Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and non dihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extra cellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells [4]. In this study, an attempt has been made to formulate fast dissolving tablet formulations of Amlodipine Besylate

Corresponding Author: Vineet Bhardwaj, Department of Pharmaceutical Technology, Meerut Institute of Engineering andTechnology Meerut-250005 (U.P.) India.

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by using sublimation method.[5] The independent variables were selected as the quantities of, sodium starch glycolate (SSG) [6, 7], Kollidon-CL and Ac-Di-Sol. Camphor is used as an sublimating agent, mannitol is used as diluent. Camphor is a good subliming agent and in many formulations it is used as subliming agent [8, 9, 10]. Water wicking and swelling are the two most important mechanisms of disintegrant action for Ac-Di-Sol [11]. Water wicking is the ability to draw water into the tablet matrix. Both the extent of water uptake and the rate of water uptake are critically important. Exposure to water can cause ingredients to swell and exert pressure against surrounding tablet or capsule ingredients, causing existing bonds between particles to break. The fibrous nature of Ac-Di-Sol provides many sites for fluid uptake and gives it excellent water wicking capabilities. The cross-linked chemical structure of Ac-Di-Sol creates an insoluble, hydrophilic and highly absorbent excipient that results in exceptional swelling properties. The solubility of Kollidon CL [5] varies considerably from one solvent to another. Sodium starch glycolate [12] is a commonly used super disintegrant employed to promote rapid disintegration and dissolution of solid dosage forms. It is manufactured by chemical modification of starch, i.e., carboxymethylation to enhance hydrophilicity and cross-linking to reduce solubility. MATERIAL AND METHOD Amlodipine Besylate is procured from Strides Arco Lab Pvt. Ltd, Bangalore, India, Kollidon CL, Ac-Di-Sol, Sodium starch glycolate are gifted by Signet chemical corporation Mumbai, Mannitol, Sodiam saccharin, Talc, Magnesium Stearate are procured by Loba Chemie, Cochine. Other materials used are of analytical grade. Preparation: The superdisintegrants (Kollidon-CL, Ac-disol, Sodium starch glycolate) in varying concentration (02%, 04% & 06%) used to develop the tablets. In this study fast-dissolving tablet were prepared by using camphor as sublimating agent. Nine formulations of Amlodipine Besylate containing camphor [6, 13] in different proportions were prepared by using Mannitol as a diluent. All the ingredients were passed through # 60 mesh separately. The drug and the diluents was mixed in small portion of both each time and blending it to get uniform mixture and set aside. The other ingredients were 265

weighed and mixed in geometrical order, mixed thoroughly with lubricant. The tablets of weight 150 mg were prepared by direct compression technique using 8 mm punch in cadmech tablet punching machine weighing 150 mg each. [14] After that the compressed tablets are dried for 5 hours for the sublimation of camphor. Evaluation of Fast Dissolving Tablets Fourier Transform Infrared Spectroscopy: FTIR spectra were obtained on a Perkin-Elmer 1600 FTIR spectrometer (1600 series, Perkin-Elmer Inc, Norwalk, CT). Samples were prepared in KBr disks (2 mg sample in 200 mg KBr). The scanning range was 400 to 4000 cm 1 and the resolution was 1 cm 1. Uniformity of Weight [15]: The weights were determined to within 1mg by using Sartorious balance (Model CP- 224 S). Weight control is based on a sample of 20 tablets. Determinations were made in triplicate. Tablet Hardness [16]: The crushing tolerance of tablets was measured using an Electrolab hardness tester model EL 500. Determinations were made in triplicate. Tablet Friability [16]: The friability of the tablets was measured in a Roche friabilator. Tablets of a known weight or a sample of 20 tablets are dedusted in a drum for a fixed time (100 revolutions) and weighed again. Percentage friability was calculated from the loss in weight as given in equation as below. The weight loss should not be more than 1%. Determination was made in triplicate.
Friability = [(Initial weight- Final weight) / (Initial weight)] x 100%

Drug Content: Ten tablets were powered and the blend equivalent to 5 mg of Amlodipine Besylate was weight and dissolved in suitable quantity of pH 1.2 solutions. Solution was filtered and diluted and drug content analyzed spectrophotometrically at 239 nm using Shimadzu Corporation, UV-1601, Japan. In-vitro Disintegration Test [17]: The test was carried out on 6 tablets using Tablet disintegration tester ED-20 (Electrolab, Mumbai, India) distilled water at 37C2C was used as a disintegration media and the time in second taken for complete disintegration of the tablet with no palable mass remaining in the apparatus was measured in seconds.

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Wetting Time [17]: The wetting time of the tablets can be measured using a simple procedure. Five circular tissue papers of 10 cm diameter are placed in a petridish with a 10 cm diameter. 10 mL of water-containing amaranth a water soluble dye is added to petridish. A tablet is carefully placed on the surface of the tissue paper. The time required for water to reach upper surface of the tablet is noted as a wetting time. Tablet Thickness [16]: Tablet thickness can be measured using a simple procedure. 5 tablets were taken and their thickness was measured using Varnier callipers. The thickness was measured by placing tablet between two arms of the Varnier callipers (Mitutoyo). Water Absorption Ratio [18]: A piece of tissue paper folded twice was placed in a small Petri dish containing 6 ml of water. A tablet was put on the tissue paper and allowed to completely wet. The wetted tablet was then weighted. Water absorption ratio, R was determined using following equation. R = 100 _Wa Wb/Wa Where, Wa = Weight of tablet after water absorption Wb = Weight of tablet before water absorption. In-vitro Dissolution Study: The release rate Amlodipine Besylate from fast dissolving tablets was determined using United State Pharmacopoeia (USP) XXIV dissolution testing apparatus II (paddle method). The dissolution test was performed using 900 ml of 0.1 N HCl (PH=1.2), at 37 0.50C and 50 rpm. A sample (5 ml) of the solution was withdrawn from the dissolution apparatus at regular intervals for 10 min. The samples were replaced with fresh dissolution medium of same quantity. The samples were filtered through a 0.45 membrane filter. Absorbance of these solutions was measured at 239 nm using a Shimadzu UV/Vis double beam spectrophotometer. Cumulative percentage of drug release was calculated using an equation obtained from a standard curve. Accelerated Stability Study of Best Batch [19, 20, 21]: In order to determine the change in in-vitro release profile on storage, stability study of batch F5 was carried out at 40 0C in a humidity chamber having 75% RH. Samples were withdrawn at regular intervals during the study of 60 days. Formulation is evaluated for change in in-vitro drug release pattern, hardness and disintegration time. 266

RESULT AND DISCUSSION The powder blend for all formulation containing various concentration of Kollidon-CL (2,4,6%), Ac-Di-Sol (2,4,6%) and sodium starch glycolate (2,4,6%) as superdisintegrant was prepared and then the FTIR studies were done that suggests incompatibility (Fig. 3), the study suggests that the drug and excipients are compatible to each other. Water insoluble diluents such as microcrystalline cellulose and dicalcium phosphate were omitted from the study as they are expected to cause an unacceptable feeling of grittiness in the mouth. Among the soluble diluents, mannitol was selected as a diluent considering its advantages in terms of easy availability and negative heat of dissolution. Table 2 shows that all the formulated tablets exhibited low weight variation that varies between 2.1 to 3.9 from different batches. Addition of a subliming agent had no pronounced effect on hardness and increased friability of the tablets. The wetting time (Fig 2) of the tablets were also considerably reduced in tablets. The drug content of all the formulations was found to be between 96.4-98.23% which was within the acceptable limits as per USP XXVII. The porous structure is responsible for faster water uptake; hence it facilitates wicking action of superdisintegrants in bringing about faster disintegration. Tablets with lower friability (0.5%) may not break during handling on machines. The use of a sublimation agent resulted in increased friability probably due to increased porosity. It was decided to incorporate colloidal silicon dioxide, extragranularly, at a level of 1% to decrease the friability of the tablets. Batches F1 to F9 showed good mechanical integrity, but the disintegration time was found to be less than 40 seconds. The results shown in Table 2 reveal that sublimation of camphor from tablets resulted in faster disintegration. The low value of wetting time and disintegration time indicate that the porosity of tablets of batch F9 would be greater than batches F1 to F8. The longer drying time was required in the case of tablets probably because of the decreased surface area and porosity. The thickness of tablets varies from 2.95 to 3.15 mm. In vitro release studies were carried out using USP XXIII tablet dissolution test apparatus paddle method at 370.5 C, taking 900 ml of pH-1.2 dissolution medium. Speed of rotation of the paddle was set at 50 rpm. Aliquots of 5 ml were withdrawn after 2, 4, 6, 8, 10 min and analyzed spectrophotometrically at 239 nm. The in vitro dissolution profile (Fig.1) indicated faster and maximum drug release from formulation F9. Formulation F9 prepared by direct sublimation of camphor from final tablets showed release 97.19% drug at the end of 10 min.

Am-Euras. J. Sci. Res., 5 (4): 264-269, 2010

Fig. 1: In-vitro Dissolution Curve between Cumulative % Release Vs Time

Fig. 2:

State of Tablet while measuring Wetting Time (A) Initial stage, (B) Intermediate, (C) Completely Wetted Tablet

Fig. 3:

FTIR spectra of Amlodipine Besylate (A), Ac -Di-Sol (B), Sodium starch glycolate (C), Kollidon-CL (D), Mixture (E)

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Table 1: Formulation composition for tablets prepared by Using Superdisintegrants Ingredients Amlodipine Besylate Kollidon CL SSG Ac-Di-Sol Mannitol Avicel Camphor Mg. Stearate Talc Total Wt. ofTablet F1 10 2 100 26 10 1 1 150 F2 10 4 100 24 10 1 1 150 F3 10 6 100 22 10 1 1 150 F4 10 2 100 26 10 1 1 150 F5 10 4 100 24 10 1 1 150 F6 10 6 100 22 10 1 1 150 F7 10 2 100 26 10 1 1 150 F8 10 4 100 24 10 1 1 150 F9 10 6 100 22 10 1 1 150

Table 2: Evaluation of Fast Dissolving Tablets Hardness Formulation F1 F2 F3 F4 F5 F6 F7 F8 F9 Weight variation 2.40.51 3.30.29 4.10.28 2.50.35 3.70.12 2.20.46 3.90.23 2.10.15 3.10.33 (Kg/cm2) 2.30.14 2.60.11 3.20.15 3.10.14 3.20.27 3.50.26 2.80.30 3.20.13 3.70.22 Friability 0.430.29 0.520.13 0.740.32 0.330.16 0.470.25 0.690.27 0.370.16 0.520.32 0.750.33 Drug content 97.28 96.4 96.86 97.84 98.15 97.73 96.57 98.19 98.23 Wetting time (Sec.) 200.9 211.1 161.7 311.9 231.2 301.7 150.9 131.0 100.8 Water Absorption ratio 28.912.1 39.301.9 59.001.7 41.231.4 58.111.2 69.891.4 42.921.9 64.472.2 81.732.4 Thickness (mm) 3.10.5 3.10.4 3.00.6 2.950.5 3.30.2 3.10.3 3.150.3 2.950.2 3.150.5 Disintegration time (Sec.) 272.1 232.8 182.0 332.2 262.3 321.0 172.0 142.5 112.2

Table 3: Physical Characteristics of Amlodipine Besylate fast disintegrating tablet of optimised Batch F 9 at Temperature (40C2C / 75% RH5%) Batch F9 -------------------------------------------------------------------------------------------------------------------------------------------Physical Parameter Weight gain (mg) Percent drug content (%) Hardness (Kg/cm2) Disintegration time (Sec) Wetting time (Sec) 0 days 100 99.8 3.7 11 10 15 Days 100 98.2 3.7 11 11 30 Days 103 97.65 3.6 14 11 60 Days 103 97.23 3.6 15 12

Table 4: Drug release% at 40C2C/75% RH5% S.No 1 2 3 Time ( Days) 0 30 60 40C / 75% RH 99.8 97.2 96.8

Stability studies performed on batch F9 as per ICH guidelines for 60 days at 40C2C / 75% RH5%. That shows no remarkable changes in the physical properties of the tablets as well as no remarkable changes in the drug content and the release profile as indicated in Table 3 and Table 4. The studies shows tablets after stability studies are in acceptable range. CONCLUSION The use of superdisintegrants for preparation of fast dissolving tablets is highly effective and commercially 268

feasible. These superdisintegrants accelerate disintegration/dissolution of tablets by virtue of their ability to absorb a large amount of water when exposed to an aqueous environment. Camphor used as a sublimating agent increases the porosity of the tablets due to which the absorption of water takes place at high rate that results in breaking of tablets and therefore faster disintegration/dissolution. This disintegration is reported to have an effect on dissolution characteristics as well. Prepared fast disintegrating tablet gets dispersed in the mouth quickly and releases the drug fast. Fig. 1 show the cumulative percentage of Amlodipine Besylate released

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from formulated tablet with different concentration of Kollidon- CL, Sodium Starch Glycolate and Ac-Di-Sol. It is clear that the dissolution and disintegration of Amlodipine Besylate has improved considerably in batch F9 as compared to rest of formulations, Batch F9 tablet showed good dissolution efficiency and rapid dissolution. The study shows that the dissolution rate and disintegration time can be improved by using camphor as the sublimating agent and with the addition of superdisintegrants. Formulation F9 during accelerated stability studies shows no remarkable changes in their characteristics. ACKNOWLEDGEMENT The authors are thankful to Chairman of MIET, Meerut for providing the necessary facilities and help author is also thankful to Director of Department of Pharmaceutical Technology for providing his kind guidance. REFERENCES 1. Berner, B., R. Birudaraj, S. Shen and X. Li, 2005. Buccal permeation of buspirone: mechanistic studies on transport pathways. J. Pharm. Sci, 94: 70-78. Ishikawa, T., N. Koizumi and B. Mukai, 2001. Pharmacokinetics of acetaminophen from rapidly disintegrating compressed tablet prepared using microcrystalline cellulose (PH-M-06) and spherical sugar granules. Chem Pharm Bull (Tokyo), 49: 230-232. Price, T.M., K.L. Blauer, M. Hansen and F. Stanczyk, 1997. Single-dose pharmacokinetics of sublingual versus oral administration of micronized 17 beta-estradiol. Obstet Gynecol, 89: 340-345. Available at http://www.drugs.com/pdr/amlodipinebesylate.html. Masareddy, R.S., R.V. Kadia and F.V. Manvi, 2008. Development of mouth dissolving tablets of Clozapine using two different techniques. Indian J. pharm. sci., 70: 526-8. Sharma, S. and G.D. Gupta, XXXX. Formulation and characterization of fast- dissolving tablet of promethazine theoclate. Asian J. Pharmaceutics, 8(2): 70-72. Aryal, S. and N. Skalko-basnet, 2008. Stability of Amlodipine besylate and Atenolol in MultiComponent tablets of mono-layer and bi-layer types. Acta pharm., 58: 299-308. 269

8.

9.

10.

11. 12. 13.

14. 15. 16. 17.

2.

3.

4. 5.

18.

19.

6.

20. 21.

7.

Ishikawa, T., N. Kuizumi, B. Mukai, N. Utoguchi, M. Fujii, M. Matsumoto, H. Endo, S. Shirrotake and Y. Watanabe, 2001. Preparation of rapidly disintegrating tablet using new types of microcrystalline cellulose. Chem.Pharm. Bull, 49: 134-139. Adel, M., M. Aley, J. Semreen and K. Mazin, 2005. To produce rapidly disintegrating Tenoxicam tablet via Camphor sublimation. Pharmaceutical Technology, pp: 68-78. Koizumi, K., Y. Watanabe, K. Morita, N. Utoguchi and M. Matsumoto, 1997. New method of preparing high porosity rapid saliva soluble compressed tablet using mannitol with camphor, a subliming material.Int. J. Pharm., 152: 127-131. Weller, P.J., 1994. Croscarmellose Sodium. Ainely Wade and Paul (London), 2: 141-142. Banker, G.S., 1994. Sodium Starch Glycolate. Ainely Wade and Paul, London. Zade, P.S., P.S. Kawtikwar and D.M. Sakarkar, 2009. Formulation, Evaluation and optimization of fast dissolving tablet containing Tizanidine hydrochloride. Int. J. phr tech Res., 1(1): 34-42. Sarasija, S., V. Pandit and H.P. Joshi, 2007. Mouth dissolving tablets of Salbutamol sulphate. Indian J. Pharm. Sci., 69: 467- 469. Indian Pharmacopoeia, 1996. 4th Ed, Ministry of Health and Family Welfare, Govt. of India. The controller of publications, New Delhi, A-54. Lachman, L., A. Lieberman and J.L. Kinig, 1991. The Theory and Practice of Industrial Pharmacy, Varghese Publishing House, pp: 67-68. Battue, S.K., M.A. Repay, S. Maunder and M.Y. Rio, 2007. Formulation and evaluation of rapidly disintegrating tablet Fenoverine tablets: Effect of superdisintegrants. Drug. Dev. Ind. Pharm., 33: 1225-1232. Bi, Y., H. Sunada, Y. Yonezawa, K. Danjo, A. Otsuka and K. Iida, 1996. Preparation and evaluation of a compressed tablet rapidly disintegrating in the oral cavity. Chem Pharm Bull (Tokyo), 44: 2121-2127. Swamy, P.A., S.H. Areefulla, S.B. Shrisand, S. Gandra and B. Prashanth, 2007. Orodispersible tablets of meloxicam using superdisintegrant blends for improved efficiency. Ind. J. Pharm. Sci., 69(6):836-840. Malke, S., S. Shidhaye and V.J. Kadam, 2007. Formulation and evaluation of oxcarbazepine fast dissolving tablets, Ind. J. Pharm. Sci, 69(2): 211-214. Patel, M.M. and D.M. Patel, 2006. Fast dissolving valdecoxib tablets containing solid dispersion of valdecoxib, Ind. J. Pharm. Sci, 68 (2): 222-226.