International Journal of Innovative Pharmaceutical Sciences and Research www.ijipsr.com FORMULATION AND EVALUATION OF ORAL DISPERSIBLE TABLETS OF ZOLMITRIPTAN 1 Jalendhar Nakka *, 2 M.Srujan Kumar, 3 Dr.K.V.Subrahmanyam 1 M.Pharmacy Scholar, Samskruti College of Pharmacy, Hyderabad, India. 2 Faculty, Samskruti College of Pharmacy, Hyderabad, India. 3 Principal, Samskruti College of Pharmacy, Hyderabad, India. Abstract Objective of this study was to formulate orally disintegrating tablets of Zolmitriptan with sufficient mechanical integrity, content uniformity, and acceptable palatability to assist patients of any age group for easy administration by Melt granulation method and direct compression method. Effect of varying concentrations of different superdisintegrants such as crospovidone, Precirol and Sorbitol on disintegration time was studied. Tablets were evaluated for weight variation, thickness, hardness, friability, drug content, in vitro disintegrating time and in vitro drug release. Other parameters such as drug-excipient compatibility were also evaluated. The disintegration time of the optimized batch was <25 sec.. Release of drug was faster from formulations containing Precirol and crospovidone (F9) compared to the marketed convetional zolmitriptan tablet. FTIR studies did not indicate any excipient incompatibility, either during mixing or after compression. F9 formulation is showing better dissolution results at 30 th minutes so that it was concluded that direct compression method was showing more solubility then melt granulation method, when compared to marketed product at 30 th minute percentage of drug release is more. Key words:, Melt Compression, Precirol, Crospovidone, Disintegration, FTIR. Corresponding Author: Jalendhar Nakka Samskruti college of Pharmacy Department of Pharmaceutics Email: jalendhar0006pharma@gmail.com Contact: +91-949278078 Available online: www.ijipsr.com October Issue 308
INTRODUCTION Tablets dosage forms [1] which rapidly disintegrate in the mouth and can be taken without water have become extremely popular in recent years. These products offer the convenience of a tablet with the ease of swallowing a liquid. These dosage forms are of particular advantage in certain patients group such as children, elderly and psychiatric patients. Certain medical conditions such as pain, migraine, nausea, panic attack, allergic conditions, cough or cold, and Alzheimer s may benefit from these dosage forms. Despite of tremendous innovations in drug delivery, the oral route remains the preferred route for administration of therapeutic agents because of accurate dosage, low cost therapy, self medication, non invasive method and ease of administration leading to high level of patient compliance. However, traditional tablets and capsules administered with a glass of water may be inconvenient or impractical for some geriatric patients because of changes in various physiological and neurological conditions associated with aging including difficulty in swallowing/dysphasia, hand tremors, deterioration in their eyesight, hearing, memory, risk of choking in addition to change in taste and smell. For these reasons, it is said that age is a convenient red flag [2] that pharmacists can use to alert themselves for patients who may have special counseling needs [1]. Solid dosage forms also present significant administration challenges in other patient groups, such as children, mentally challenged, bed ridden and uncooperative patients. Pediatric patients may suffer from ingestion problems as a result of underdeveloped muscular and nervous control. Moreover, patients traveling with little or no access to water, limit utility of orally administered conventional tablets or capsules. Therefore, to cater the needs of such patients, recent advancements in technology have resulted in development of viable dosage alternatives popularly known as orally disintegrating tablets (ODTs). These dosage forms are preferable alternative for oral medication in improving the quality of life and patient acceptability. ODTs are also known as oro dispersible tablets, mouth dissolving tablets, rapimelts, melt-in-mouth tablets, fast disintegrating tablets and rapid dissolving tablets. ODTs are the solid unit dosage forms/entities containing medicinal substances which disintegrate or dissolve rapidly in oral cavity usually within a few seconds even without the need of water or chewing. As the tablet disintegrates in mouth, this can enhance the clinical effect of drug through pregastric absorption from the mouth, pharynx and esophagus. In such Available online: www.ijipsr.com October Issue 309
cases, bioavailability of drug is significantly enhanced by avoiding first pass hepatic metabolism than those observed with conventional tablets Superdisintegrants [3, 4] Disintegrants are substances routinely included in tablet formulations and in some hard shell capsule formulations to promote moisture penetration and dispersion of the matrix of dosageform in dissolution fluids. An oral solid dosage form should ideally disperse into the primary particles from which it was prepared. Super disintegrants are generally used at a low concentration, typically 1-10% by weight relative to total weight of dosage unit. Generally employed super disintegrants are croscarmellose sodium (Ac-Di-Sol), crospovidone (CP), sodiumstarchglycolate (SSG) etc. which represent example of crosslinked cellulose, crosslinked polymer and crosslinked starch respectively.selection of appropriate formulation excipients and manufacturing technology is necessary for obtaining the optimized design features of orally disintegrating dosage forms. Ideally, superdisintegrants should cause the tablet to disrupt, not only into the granules from which it was compressed but also into powder particles from which the granules were prepared. Zolmitriptan binds with high affinity to human recombinant 5-HT1D and 5-HT1B receptors. Zolmitriptan exhibits modest affinity for 5-HT1A receptors, but has no significant affinity (as measured by radioligand binding assays) or pharmacological activity at 5-HT2, 5- HT3, 5-HT4, alpha1-, alpha2-, or beta1- adrenergic; H1, H2, histaminic; muscarinic; dopamine1, or dopamine2 receptors. The N-desmethyl metabolite also has high affinity for 5-HT1B/1D and modest affinity for 5-HT1A receptors. ZOMIG is indicated for the acute treatment of migraine with or without aura in adults.zomig should only be used where a clear diagnosis of migraine has been established. ZOMIG is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine Safety and effectiveness of ZOMIG have not been established for cluster headache, which is present in an older, predominantly male population.the medical and pharmaceutical communities are seeing increasing opportunities and benefits from the ability to deliver immediate release dosage forms. To formulate and evaluate zolmitriptan orally disintegrating Tablets (100mg). Available online: www.ijipsr.com October Issue 310
MATERIALS AND METHOD Zolmitriptan, Sorbitol, PEG6000, Precirol, Aerosil, Mannitol, Crosspovidone, Pippermint, Magnesium Stearate, Ace sulfate were obtained from Pharma Train Research Lab Ltd. 1. Preformulation Study [5]: A. Colour, odor, taste and appearance: The drug sample was evaluated for its colour and odor. The results are shown in Table. B. Melting point determination: Melting point of the drug sample was determined by capillary method by using melting point apparatus. C. Determination of solubility The solubility of the Zolmitriptan was determined by adding excess amount of drug in the solvent and equilibrium solubility was determined by taking supernatant and analyzing it on Perkin Elmer Lambda35, double beam spectrophotometer. D. Fourier Transform Infrared Spectroscopy (FTIR) Interpretation: The infrared spectra of pure Ritonavir samples were recorded by SHIMADZU 84005 FTIR spectrometer, equipped with an Inferometer detector. Samples were prepared by KBr disc method (2 mg sample in 100 mg KBr) and examined in the transmission mode. Each spectrum was measured over a frequency range of 4000 400 cm 1.The software used for the data analysis was Perkin-Elmer Spectrum 3.02. The peaks obtained in the spectra were then compared with corresponding functional groups in the structures of Ritonavir. E. Ultraviolet Visible (UV-visible) spectroscopy: Construction of Calibration Curve: Standard Stock solution: Accurately weighed 100 mg of Zolmitriptan was dissolved in 100 ml of different buffers (1.2pH 0.1N HCl). The resultant solutions were having concentration of 1000 µg/ml (1.1 mg/ml). 10 ml of this solution was further diluted up to 100.0 ml with buffer and to give a solution of Concentrations 100 µg/ml. This resultant solution is used as working stock solution for further study. Further dilutions were prepared from the same solution. Available online: www.ijipsr.com October Issue 311
Preparation of calibration curve for Zolmitriptan [6]: Appropriate aliquots were pipetted out from the standard stock solution in to a series of 10 ml volumetric flasks. The volume was made up to the mark with buffer to get a set of solutions having the concentration range of 2,3,4,5, and 6 µg/ml for Zolmitriptan. Absorbances of the above solutions were measured at 225 nm and a calibration curve of absorbance against concentration was plotted and the drug follows the Beer s & Lambert s law in the concentration range of 2-6 µg/ml. The regression equation and correlation coefficient was determined. 2. Formulation development [7, 8] Procedures: The Purpose of key ingredients included in the formulation. Table1: Composition of Zomitriptan Oral Dispersibe Tablets Melt Granulation S.NO. Ingredients F1(mg) F2(mg) F3(mg) F4(mg) F5(mg) 1 Zolmitriptan (mg) 10 (mg) 10 (mg) 10 (mg) 10 (mg) 10 2 Sorbitol 20 10 7.5 15 15 3 Peg6000 3 1.5 1.125 2.25 2.25 4 Precirol 0 0 0 0 0 5 Aerosil 1 1 1 1 1 6 Mannitol 56.25 67.75 70.625 62 59.25 7 Crosspovidone 7.5 7.5 7.5 7.5 10 8 Pippermint 0.25 0.25 0.25 0.25 0.25 9 Magnesium stearate 0.5 0.5 0.5 0.5 0.5 10 Ace sulfate pt 1.5 1.5 1.5 1.5 1.5 Table2: Composition of Zomitriptan Oral Dispersibe Tablets Direct Compression SNO Direct F6(mg) F7(mg) F8(mg) F9(mg) F10(mg) 1 Zolmitriptan 10 10 10 10 10 2 Precirol 5 7.5 10 15 7.5 3 Aerosil 1 1 1 1 1 4 Mannitol 74.25 71.75 69.25 64.25 69.25 5 Crosspovidone 7.5 7.5 7.5 7.5 10 6 Ace sulfate pt 1.5 1.5 1.5 1.5 1.5 7 Pippermint 0.25 0.25 0.25 0.25 0.25 8 Magnesium 0.5 0.5 0.5 0.5 0.5 Available online: www.ijipsr.com stearate October Issue 312
Steps in Formulation: Preparation of Meltgranulation: 1. Melt granulation [8] Melt granulation technique is a process by which pharmaceutical powders are efficiently agglomerated by a melt able binder. The advantage of this technique compared to a conventional granulation is that no water or organic solvents is needed. For accomplishing this process, high shear mixers are utilized, where the product temperature is raised above the melting point of binder by a heating jacket or by the heat of friction generated by impellerblades. This approach to prepare FDT with sufficient mechanical integrity, involves the use of a hydrophilic waxy binder (Superpolystate, PEG-6-stearate). Superpolystate is a waxy material with a melting point of 33 37 C and a HLB value of 9. So it will not only act as a binder and increase the physical resistance of tablets but will also help the disintegration of the tablets as it melts in the mouth and solublises rapidly leaving no residues. 2. Preparation of Direct compression: 1. Drug and polymer pass through 40 # mesh separately and then transfer it to poly bag and mix it for 3 minutes. 2. Add other excipients to the above mixture. Finally add the Glidant (Magnesium Stearate) to the above blend mix it for 2min. 3. Compressed the above lubricated blend by using 7mm round punches. Pre-Compression Parameters: Pre-compression parameters like bulk density, Tapped density, Angle of repose, compressibility Index, Hausner s ratio were evaluated for the Formulation powder. Post Compression Parameters: Post compression parameters like physical appearance, shape, weight variation, content uniformity, hardness, friability, In vitro Drug Release studies and Drug release kinetics for the optimized formulation were evaluated. Available online: www.ijipsr.com October Issue 313
RESULTS AND DISCUSSION 1. Preformulation: Table 3: Preformulation studies of Pure Drug S.no API Characterisation Results 1 Physical appearance Zolmitriptan is a pale yellow powder 2 Melting point 139 c 3 Solubility It is freely soluble in methanol and 4 Bulk density 0.34 gm/ml 5 Tapped density 0.546 gm/ml 6 Carr s index/compressibility index 15.05 7 Hausner s ratio 1.57 Table 4: List of Micromeritic properties of directly compressible powder: Parameter F1 F2 F3 F4 F5 F6 F7 F8 F9 Angle of repose 27 0 55 29 o 39 23.31± 0.1 28 0 81 28 0 65 26 0 74 28 o 39 21 0 81 24 0 81 Bulk density 0.63 0.55 0.51 0.47 0.60 0.57 0.46 0.42 0.61 Tapped density 0.66 0.63 0.54 0.52 0.64 0.63 0.51 0.53 0.69 % Compressibility 4.76 14.54 5.88 10.63 6.66 10.52 10.86 26.19 13.11 Hausner s ratio 1.047 1.14 1.05 1.10 1.06 1.10 1.10 1.15 1.13 2. Calibration of Standard Graph of Zolmitriptan: Standard graph of Zolmitriptan in 0.1N HCl (1.2 ph buffer): The construction of standard calibration curve of Zolmitriptan was done by using 0.1N HCl as the medium. Zolmitriptan was found to have the maximum absorbance at 225 nm. The Available online: www.ijipsr.com October Issue 314
standard graph of Zolmitriptan in 0.1N HCl was constructed by making the concentrations of 2µg/ml, 3µg/ml, 4 µg/ml, 5 µg/ml and 6 µg/ml solutions. The absorbance of solutions was examined under UV- spectrophotometer at an absorption maximum of 225 nm. The standard graph of Zolmitriptan was constructed by taking the absorbance on Y-axis and concentrations on X-axis Table 5: Standard Graph of Zolmitriptan S. No. CONCENTRATION(µg/ml) ABSORBANCE 1 0 0 2 2 0.221 3 3 0.321 4 4 0.415 5 5 0.535 6 6 0.624 Fig 1: Calibration curve Of Zolmitriptan in 0.1N HCl (1.2 ph buffer) Available online: www.ijipsr.com October Issue 315
Fourier Transformation Infrared (FTIR) analysis: Infra-red spectroscopy analysis was performed by Fourier Transformation Infrared Spectrophotometer Alpha Brooker FTIR (Tokyo, Japan).The instrument was calibrated by using polystyrene film. Table 6: IR Interpretation of drug, other excipients and physical mixture of drug-sorbitol: S.NO INTERPRETATION PURE DRUG ( - CM) DRUG+SORBITOL ( - CM) 1 C-O 1258.27 1082.45 2 C=O 1736.29 1735.96 3 N-H 1290.09 3406.52 4 C-C 3410.19 1259.00 Fig 2: Spectra of Zolmitriptan Fig 3: Spectra of Zolmitriptan and Sorbitol Fig 4: Spectra of Zolmitriptan & PEG6000 Fig 5: Spectra of Zolmitriptan & Precirol Available online: www.ijipsr.com October Issue 316
Fig 6: Spectra of Zolmitriptan & Aerosil Fig 7: Spectra of Zolmitriptan & Mannitol Fig 8: Spectra of Zolmitriptan & Ace Sulfate Fig 9: Spectra of Zolmitriptan &Peppermint Fig 10: FTIR Spectra for pure drug and all the Excipients Available online: www.ijipsr.com October Issue 317
Evaluation of the Prepared Tablets for Physical Parameters: All formulations were tested for Physical parameters like Hardness, thickness, Weight Variation, Friability and found to be within the Pharmacopoeial limits. The results of the tests were tabulated. The drug content of all the formulations was determined and was found to be within the permissible limit. This study indicated that all the prepared formulations were good. Table 7: Results for Evaluation parameters of all formulations: parameter F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 Weight 97 99 97 98 98 101 100 99 101 variation 101 Thickness (mm) 15 15.7 23 26.5 29 34 32 41 41 42 Hardness (kg/cm 2 ) 2.4 2.3 2.5 2.3 2.4 2.5 2.3 2.6 2.5 2.5 Friability (%W/W) Content uniformity (%) 0.3 0.35 0.4 0.3 0.4 0.5 0.6 0.8 0.9 0.9 98 98.4 98.6 98.8% 99 99.17 99 99.88 99.68 100 In vitro Dissolution studies: The dissolution conditions used for studying the drug release from tablet of zolmitriptan are: Apparatus Agitation speed (rpm) Medium Volume Temperature Time Wavelength : USP apparatus II (Paddle) : 50rpm : 0.1N HCl. : 900 ml : 37.0 ± 0.5 0 C : 5, 10,15,20,30 and 45 min. : 225 nm Available online: www.ijipsr.com October Issue 318
The samples were withdrawn at predetermined time points, and were analyzed spectrophotometrically at 225 nm. Table 8: Results of Dissolution profile for F1-F10: Time (min) F1 F2 F3 F4 F5 F-6 F-7 F-8 F-9 F10 0 0 0 0 0 0 0 0 0 0 0 5 41 55 40 46 50 51 41 38 55 60 10 50 70 51 62 65 65 61 55 71 74 15 65 85 69 80 82 85 76 75 88 89 20 81 94 87 91 91 92 85 85 95 95 30 95 94 95 94 94 96 94 91 96 95 45 95 95 96 96 96 96 96 92 98 97 Fig 11: Dissolution Profile Comparison of Formulations F1-F4 Fig 12: Dissolution Profile Comparison of Formulations F1-F4 Fig 13: Dissolution Profile Comparison of F9 & F10 Available online: www.ijipsr.com October Issue 319
Table 9: Results of Dissolution Profile for Marketed Formulation TIME(min) % OF DRUG RELEASE 5 77 10 89 15 95 20 96 30 97 Fig 14: Comparision of Marketed Vs Optimised Formulation KINETIC MODELS: Dissolution data of above methods was fitted in Zero order. Table 10: Regression Coefficient of Optimised and Marketed Formulations Formulation Code Optimised Formulation Marketed Formulation Regression Coefficient (R 2 )Zero Order 0.582 0.552 Fig 15: Release Kinetics of Optimized Formulations Available online: www.ijipsr.com October Issue 320
CONCLUSION In Vitro Disintegration Time Considering wetting time, R value, in vitro DT, %friability and cumulative % drug released, formulations containing F9 (Precirol and Crospovidone) was considered to be better than those containing Sorbotol and SSG. F9 was considered as the optimal orally disintegrating tablet formulation among all. REFERENCES 1. Hart, C. (2008) Literature Reviewing and Argumentation. In The Postgraduate's Companion, (eds.) Gerard Hall and Jo Longman. UKGrad. United Kingdom. London: Sage ISBN 978-1-4129-3026-0 research". Journal of Mixed Methods Research; Vol. 1, No. 4, pp. 309 332. 2. Green, B. N., Johnson, C. D., and Adams, A. (2006) "Writing Narrative Literature Reviews for Peer-Reviewed Journals: Secrets of the Trade". Journal of Chiropractic Medicine; 5(3), pp. 101 11413. 3. Indian Pharmacopoeia 2010 Volume 1,Volume 2 and Volume 3 4. Raymond C Rowe, Paul J Sheskey, Handbook of Pharmaceutical Excipients, 6th edition, published in 2009. 5. Zanchin G, Dainese F, Mainardi F, Maggioni F. Clinical experience with triptans. Journal of Headache & Pain. 2001;2(SUPPL 1):S107 112. 6. Salonen R, Scott A. Triptans: do they differ? Current Pain & Headache Reports. 2002;6(2):133 139 7. Belsey J. The clinical and financial impact of oral triptans in the management of migraine in the UK: A systematic review. Journal of Medical Economics. 2000;3:35 47. 8.Pham B. A systematic review of the use of triptans in acute migraine. Canadian Journal of Neurological Sciences. 2001;28(3):272. Available online: www.ijipsr.com October Issue 321