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/cm 2 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 Angina pectoris, commonly known as angina, is chest pain due to ischemia of the heart muscle, generally A fast dissolving tablet system can be defined as a due to obstruction or spasm of the coronary arteries dosage form for oral administration, which when placed in (the heart's blood vessels). Amlodipine is a mouth, rapidly dispersed or dissolved and can be dihydropyridine calcium antagonist (calcium ion swallowed in form of liquid. Recently fast dissolving antagonist or slow-channel blocker) that inhibits the formulation is popular as Novel Drug Delivery Systems transmembrane influx of calcium ions into vascular because they are easy to administer and lead to better smooth muscle and cardiac muscle. Experimental data patient compliance. Paediatric and geriatric patient have suggest that amlodipine binds to both dihydropyridine difficulty in swallowing the conventional dosage forms and non dihydropyridine binding sites. The contractile these dosage forms dissolve or disintegrate in the oral processes of cardiac muscle and vascular smooth muscle cavity within a minute without the need of water or are dependent upon the movement of extra cellular chewing. For these formulations, the small volume of calcium ions into these cells through specific ion saliva is usually sufficient to result in tablet disintegration channels. Amlodipine inhibits calcium ion influx across in the oral cavity. The medication can then be absorbed cell membranes selectively, with a greater effect on partially or entirely into the systemic circulation from vascular smooth muscle cells than on cardiac muscle blood vessels in the sublingual mucosa, or it can be cells [4]. swallowed as a solution to be absorbed from the In this study, an attempt has been made to formulate gastrointestinal tract [1-3]. 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. 264
by using sublimation method.[5] The independent weighed and mixed in geometrical order, mixed thoroughly variables were selected as the quantities of, sodium starch with lubricant. The tablets of weight 150 mg were prepared glycolate (SSG) [6, 7], Kollidon-CL and Ac-Di-Sol. by direct compression technique using 8 mm punch in Camphor is used as an sublimating agent, mannitol is cadmech tablet punching machine weighing 150 mg each. used as diluent. Camphor is a good subliming agent and [14] After that the compressed tablets are dried for 5 in many formulations it is used as subliming agent hours for the sublimation of camphor. [8, 9, 10]. Water wicking and swelling are the two most Evaluation of Fast Dissolving Tablets important mechanisms of disintegrant action for Fourier Transform Infrared Spectroscopy: FTIR spectra Ac-Di-Sol [11]. Water wicking is the ability to draw water were obtained on a Perkin-Elmer 1600 FTIR spectrometer into the tablet matrix. Both the extent of water uptake and (1600 series, Perkin-Elmer Inc,Norwalk, CT). Samples were the rate of water uptake are critically important. Exposure prepared in KBr disks (2 mg sample in 200 mg KBr). The to water can cause ingredients to swell and exert pressure scanning range was 400 to 4000 cm 1 and the resolution against surrounding tablet or capsule ingredients, causing was 1 cm 1. existing bonds between particles to break. The fibrous nature of Ac-Di-Sol provides many sites for fluid uptake Uniformity of Weight [15]: The weights were and gives it excellent water wicking capabilities. The determined to within ±1mg by using Sartorious balance cross-linked chemical structure of Ac-Di-Sol creates an (Model CP- 224 S). Weight control is based on a sample insoluble, hydrophilic and highly absorbent excipient that of 20 tablets. Determinations were made in triplicate. results in exceptional swelling properties. The solubility of Kollidon CL [5] varies considerably from one solvent to Tablet Hardness [16]: The crushing tolerance of tablets another. Sodium starch glycolate [12] is a commonly used was measured using an Electrolab hardness tester model super disintegrant employed to promote rapid EL 500. Determinations were made in triplicate. disintegration and dissolution of solid dosage forms. It is manufactured by chemical modification of starch, i.e., Tablet Friability [16]: The friability of the tablets was carboxymethylation to enhance hydrophilicity and measured in a Roche friabilator. Tablets of a known cross-linking to reduce solubility. weight or a sample of 20 tablets are dedusted in a drum for a fixed time (100 revolutions) and weighed again. MATERIAL AND METHOD Percentage friability was calculated from the loss in weight as given in equation as below. The weight loss Amlodipine Besylate is procured from Strides should not be more than 1%. Determination was made in Arco Lab Pvt. Ltd, Bangalore, India, Kollidon CL, triplicate. Ac-Di-Sol, Sodium starch glycolate are gifted by Signet chemical corporation Mumbai, Mannitol, Sodiam Friability = [(Initial weight- Final weight) / (Initial weight)] x 100% 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 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 37 C±2 C 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. 265
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 0.45ì 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 0 40 C 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. 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 37±0.5 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. 266
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) 267
Table 1: Formulation composition for tablets prepared by Using Superdisintegrants Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9 Amlodipine Besylate 10 10 10 10 10 10 10 10 10 Kollidon CL 2 4 6 - - - - - - SSG - - - 2 4 6 - - - Ac-Di-Sol - - - - - - 2 4 6 Mannitol 100 100 100 100 100 100 100 100 100 Avicel 26 24 22 26 24 22 26 24 22 Camphor 10 10 10 10 10 10 10 10 10 Mg. Stearate 1 1 1 1 1 1 1 1 1 Talc 1 1 1 1 1 1 1 1 1 Total Wt. oftablet 150 150 150 150 150 150 150 150 150 Table 2: Evaluation of Fast Dissolving Tablets Hardness Wetting time Thickness Disintegration time Formulation Weight variation 2 (Kg/cm ) Friability Drug content (Sec.) Water Absorption ratio (mm) (Sec.) F1 2.4±0.51 2.3±0.14 0.43±0.29 97.28 20±0.9 28.91±2.1 3.1±0.5 27±2.1 F2 3.3±0.29 2.6±0.11 0.52±0.13 96.4 21±1.1 39.30±1.9 3.1±0.4 23±2.8 F3 4.1±0.28 3.2±0.15 0.74±0.32 96.86 16±1.7 59.00±1.7 3.0±0.6 18±2.0 F4 2.5±0.35 3.1±0.14 0.33±0.16 97.84 31±1.9 41.23±1.4 2.95±0.5 33±2.2 F5 3.7±0.12 3.2±0.27 0.47±0.25 98.15 23±1.2 58.11±1.2 3.3±0.2 26±2.3 F6 2.2±0.46 3.5±0.26 0.69±0.27 97.73 30±1.7 69.89±1.4 3.1±0.3 32±1.0 F7 3.9±0.23 2.8±0.30 0.37±0.16 96.57 15±0.9 42.92±1.9 3.15±0.3 17±2.0 F8 2.1±0.15 3.2±0.13 0.52±0.32 98.19 13±1.0 64.47±2.2 2.95±0.2 14±2.5 F9 3.1±0.33 3.7±0.22 0.75±0.33 98.23 10±0.8 81.73±2.4 3.15±0.5 11±2.2 Table 3: Physical Characteristics of Amlodipine Besylate fast disintegrating tablet of optimised Batch F 9 at Temperature (40 C±2 C / 75% RH±5%) Batch F9 -------------------------------------------------------------------------------------------------------------------------------------------- Physical Parameter 0 days 15 Days 30 Days 60 Days Weight gain (mg) 100 100 103 103 Percent drug content (%) 99.8 98.2 97.65 97.23 Hardness (Kg/cm2) 3.7 3.7 3.6 3.6 Disintegration time (Sec) 11 11 14 15 Wetting time (Sec) 10 11 11 12 Table 4: Drug release% at 40 C±2 C/75% RH±5% S.No Time ( Days) 40 C / 75% RH 1 0 99.8 2 30 97.2 3 60 96.8 Stability studies performed on batch F9 as per ICH feasible. These superdisintegrants accelerate guidelines for 60 days at 40 C±2 C / 75% RH±5%. That disintegration/dissolution of tablets by virtue of their shows no remarkable changes in the physical properties ability to absorb a large amount of water when exposed to of the tablets as well as no remarkable changes in the drug an aqueous environment. Camphor used as a sublimating content and the release profile as indicated in Table 3 and agent increases the porosity of the tablets due to which Table 4. The studies shows tablets after stability studies the absorption of water takes place at high rate that are in acceptable range. results in breaking of tablets and therefore faster disintegration/dissolution. This disintegration is reported CONCLUSION to have an effect on dissolution characteristics as well. Prepared fast disintegrating tablet gets dispersed in the The use of superdisintegrants for preparation of fast mouth quickly and releases the drug fast. Fig. 1 show the dissolving tablets is highly effective and commercially cumulative percentage of Amlodipine Besylate released 268
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