P.Varatharajan et al.

/ Journal of Pharmacy Research 2012,5(2),

Research Article ISSN: 0974-6943

Available online through www.jpronline.info

Formulation and evaluation of voglibose mouth dissolving tablets by direct compression method
P.Varatharajan*1, K.Sabarikumar2, M. Anto Shering 3, P.Iavarasan4 1.Department of Pharmaceutics, Actavis Pharma Manufacturing Pvt.Ltd, Alathur, Tamilnadu, India. 2.Department of Pharmaceutics, Apex Laboratories Pvt.Ltd, Alathur, Tamilnadu, India. 3.Department of Pharmaceutics, Medisas Pharmaceuticals, Puducherry, India. 4.Department of Pharmaceutics, College of Pharmacy, Mother Theresa Post Graduate and Research Institute of Health Sciences, Puducherry, India.

Received on:19-11-2011; Revised on: 17-01-2011; Accepted on:28-01-2012 ABSTRACT

The present work was carried out to design and evaluate mouth dissolving tablets of Voglibose. The mouth dissolving tablets were prepared different formulation by direct compression technique using Microcrystalline cellulose, Pregelatinised starch (Starch 1500), Starlac as diluent combined with three superdisintegrants like Crospovidone (Polyplasdone XL10), Sodium starch glycollate (Primojel) and Croscarmellose sodium (Primellose). All the formulations were evaluated for physical characteristics, disintegration, in vitro dissolution and stability. The in vitro dissolution studies were performed for the F5 , F6 , F8 , F9 formulations. The formulations F5 , F6, F8 and F9 released 68.5, 99.4%, 68.4%, and 88.5% respectively at the end of 30 mins. Formulation F6 showed the maximum cumulative percentage drug release (99.4%). The accelerated stability studies were conducted for 3 months under 400 C/75%RH condition as per ICH guidelines in blisters. Finally after the duration, the product was analyzed for physical appearance, loss on drying, disintegration, dissolution and assay. The results obtained were found to be within the specification limits. Mouth dissolving tablets of Voglibose formulated by using direct compression technique were found to be stable. Key words: Voglibose, Superdisintegrants, Direct Compression Technique, Mouth Dissolving Tablets, Vitro Dissolution Studies and Stability Studies.

INTRODUCTION
Voglibose is an alpha glucosidase inhibitor used for lowering post prandial blood glucose levels in people with diabetic mellitus1-3 . Hence the present study is mainly focused on the development of Voglibose mouth dissolving tablets4, 5 . Mouth dissolving tablets has gained more advantages when compared to that of conventional dosage forms these tablets disintegrate in the saliva without the need of water and no need to swallow which is more beneficial for geriatric and dysphagia patients. Mostly mouth dissolving tablets shows increased bioavailability may be due to oral transmucosal absorption and avoidance of the first pass hepatic metabolism. Hence the mouth dissolving tablets has gained much attention as a preferred alternative to conventional oral dosage forms such as tablets and capsules, the present work was carried out to design and evaluate mouth dissolving tablets of Voglibose, an alpha glucosidase inhibitor. The mouth dissolving tablets were prepared by direct compression technique6 using Microcrystalline cellulose, Pregelatinised starch (Starch 1500), Starlac as diluent combined with three Superdisintegrants like Crospovidone (Polyplasdone XL10), Sodium starch glycolate (Primojel) and Croscarmellose sodium (Primellose) to cater the needs of pediatric, geriatric and patients with dysphagia. (Poly plastoneXL10)Kawarlal Ltd, Ahemadabad. Sodium starch glycollate (Primojel), Croscarmellose sodium (Primellose), Colloidal silicon dioxide (Aerosil-200), Aspartame, peppermint flavor, Magnesium stearate were of analytical grade. METHOD The method followed to prepare the fast disintegrating tablet of Voglibose in the present study avoids the use of expensive and non conventional equipment like freeze dryer (or) spray dryers. It is particularly suitable for moisture sensitive drugs because the process does not involve the use of any solvent medium. Directly compressible grades of diluents like microcrystalline cellulose, Pregelatinised starch (starch 1500), Starlac were used to fabricate tablets by direct compression method. Based on the Drug and Excipients compatibility study the disintegrants used in the present study is Primellose (Croscarmellose sodium), Crospovidone, Primojel (Sodium starch glycolate) which acts mainly by high capillary action and pronounced hydration capacity7, 8 . EVALUATION PARAMETERS

MATERIALS PRE-COMPRESSION PARAMETERS 9 Voglibose Biocon Ltd, Bangalore. Microcrystalline cellulose (RANQ) Reliance cellulose Ltd, Mumbai. Pregelatinised starch (Starch 1500)) Colorcon, Flow Property Measurements: Mumbai. Maize starch and Lactose monohydrate (Starlac), Mannitol DC It is very important parameter to be measured since it affects the mass of (Pearlitol SD 200), Signet chemical corporation, Mumbai. Cross povidone uniformity of the dose. It is usually predicted from Angle of repose, Density, Tapped density, compressibility index and Hausner Ratio.

*Corresponding author.
P.Varatharajan Department of Pharmaceutics, Actavis Pharma Manufacturing Pvt.Ltd, Alathur, Tamilnadu, India.

a) Density :(g/ml) Granule density, True Density, Bulk density may influence compressibility, tablet porosity, flow property, dissolution and other properties. Higher compression load is required in case of dense and hard granules which in turn increase the table disintegration and drug dissolution time. Density is usually determined by Pycnometer.

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Table.No.1 Composition of various Formulations of Mouth dissolving Tablets (per tablet)
Ingredients (mg) Voglibose Microcrystalline cellulose Pregelatinised starch (Starch 1500) Starlac Mannitol DC Crospovidone Croscarmellose sodium(Primellose) Sodium starch glycollate(Primojel) Aerosil Aspartame Trusil peppermint Flavour Magnesium Stearate F1 0.200 59.15 60.00 6.00 0.65 1.00 2.00 1.00 F2 0.200 59.15 60.00 6.00 0.65 1.00 2.00 1.00 F3 0.200 59.15 60.00 6.00 0.65 1.00 2.00 1.00 F4 0.200 59.15 60.00 6.00 0.65 1.00 2.00 1.00 F5 0.200 59.15 60.00 6.00 0.65 1.00 2.00 1.00 F6 0.200 59.15 60.00 6.00 0.65 1.00 2.00 1.00 F7 0.200 59.15 60.00 6.00 0.65 1.00 2.00 1.00 F8 0.200 59.15 60.00 6.00 0.65 1.00 2.00 1.00 F9 0.200 59.15 60.00 6.00 0.65 1.00 2.00 1.00

Bulk density: Weighed quantity of Voglibose granules was transferred into a 50ml measuring cylinder without tapping during transfer the volume occupied by granules was measured. Bulk density was measured by using formula.

and is the measure the flow ability of powder /granules. = tan 1 (h/r) (or) = tan 1 (height /0.5 Base) Where, h - Height of the heap of pile, r - Radius of base of pile POST-COMPRESSION PARAMETERS 10-12 a) Shape of tablets: The compressed tablets were examined under the magnifying lens for the shape of the tablet. b) Tablet dimensions: Thickness and diameter were measured using a calibrated dial caliper. Three tablets of each formulation were taken randomly and thickness was measured individually. c) 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 kg/cm2 . Three tablets were randomly picked and hardness of the tablets was determined. d) Friability test: The friability of tablets was determined using Roche friabilator, it is expressed in percentage (%). ten tablets were initially weighed (w0 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 final). The % friability was then calculated by Percentage of friability = 100 (1-w0 /w) Percentage friability of tablets less than 1% is considered acceptable. e) Weight variation test: Twenty tablets were selected randomly from each batch and weighed individually to check for weight variation. f) Tablet disintegration time: Tablet disintegration time is one of the most important characteristic required for the fast dissolving tablets .These dosage forms are required to disintegrate within a minute. The disintegration time was determined using disintegration test apparatus. A tablet was placed in each of the six tubes of the apparatus and one disc was added to each tube. The time in seconds taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured in seconds. In-vitro Dissolution Studies: The USP 2 Paddle apparatus is used for this purpose which is the most suitable and common choice for orally-disintegrating tablets, with a paddle speed of 100 rpm, medium-water at 37 0.5 o C commonly used.

Pi = m/Vo
Where, m : Mass of the blend Vo: Untapped Volume Tapped density: (Pt) Weighed quantity of Voglibose granules was taken into a graduated cylinder, volume occupied by granules was noted down. Then cylinder was subjected to 500/ 750 and 1250 taps in tapped density tester (Electro Lab USPII) According to USP , the blend was subjected for 500 taps the % Volume variation was calculated by following formula.

Pt = m/Vi
Where, m: Mass of the blend Vi: Tapped Volume. (b) Compressibility Index: (CI) (Carrs Index) Compressibility is the ability of powder to decrease in volume under pressure. Compressibility is a measure that obtained from density determination, the percentage of compressibility Index is calculated by using formula. CI=Vo-Vi/V*100 Where, Vo : Untapped density Vi: Tapped density (C) Hausner Ratio: It is measurement of frictional resistance of the drug. The Ideal range should be 1.2 1.5, it was determined by the ratio of tapped density and bulk density.

Hausner Ratio = Vo/Vi

Where, Vo : Untapped density Vi : Tapped density (d) Angle of repose: Angle of Repose (?) is the maximum angle between the surface of a pile of powder and horizontal plane. It is usually determined by fixed funnel method

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Evaluation of in vitro release kinetics To study the release kinetics, data obtained from in vitro drug release were plotted in various kinetic models. Zero Order equation The graph was plotted as cumulative % drug released Vs Time in mins. C = Ko t Where, Ko is the Zero order rate constant expressed in units of concentration/time,T is the time in mins. The graph would yield a straight line with a slope equal to Ko and intercept the origin of the axis. First order equation The graph was plotted as log cumulative % drug remaining Vs Time in mins. Log C = Log Co Kt / 2.303 Co - initial concentration of drug, K - First order rate constant,T -Time STABILITY STUDIES OF THE TABLET FORMULATIONS Stability is an important parameter evaluated for the formulations to assess the stability of the drug in the formulation at the probable storage conditions. A batch of 2000 tablets was prepared using final optimized formula (F6 ).Tablets were packed in Alu/PVC blister packing and kept in stability chambers maintained at 300 c /65% RH (3 month) 400 c/75%RH (1,2,3 month) for evaluation with respect to assay and dissolution studies. RESULTS AND DISCUSSION IR SPECTRAL ANALYSIS IR Spectral analysis for drug alone and in combination with other excipients was carried out. If there is no change in peaks of mixture when compared to pure drug, it indicates the absence of interaction. The principal peaks of pure Voglibose and Voglibose Excipient mixture are shown in Table.No.2 considerable changes in the IR peaks of the drug were observed when mixed with excipient which indicates the absence of any chemical incompatibility between drug and excipients.
Table.No.2 Major IR peaks of Voglibose and Voglibose- Excipient mixture
Samples A Composition Voglibose standard Major peaks(Wave numbers, cm-1 ) 1717.80, 1684.94 ,1653.40, 1636.26, 1559.31, 1465.73, 1437.42, 1368.06,. 1113.81, 1087.90, 880.48, 514.66, 463.67 1717.88, 1684.40, 1653.16, 1636.02, 1558.89, 1465.97, 1436.87, 1368.01, 1113.60, 1087.85, 880.36, 515.47, 460.52. 1717.88, 1684.80, 1654.17, 1636.78, , 1559.49, 1436.07, 1082.57, 881.72, 519.52 460.06.

Fig. No.2 IR Spectral Analysis Sample mixture

PRE-COMPRESSION PARAMETERS Flow Property Measurements: The flow property measured by suitable parameters such as Angle of repose, Density, Tapped density, compressibility index and Hausner Ratio and the results shown good. See below table.no.3. Table.No.3 Flow Property Measurements of various formulations by using various parameters
S.No Formulations Bulk Density Angle of Repose 31.2 o 0.1581 31.8 o 0.1141 28.4 o 0.3646 32.1 o 0.2863 31.5 o 0.4000 29.5 o 0.3361 30.5 o 0.7700 31.6 o 0.3361 29.6 o 0.4861 Compressibility Hausners Index Ratio 8.30.1923 9.70.3361 7.60.1673 7.90.2588 8.50.3049 8.00.1483 8.80.2387 9.60.1923 8.40.4037 0.91 0.0273 0.88 0.0230 0.72 0.01581 0.98 0.0288 0.79 0.0240 0.99 0.0277 0.89 0.0258 0.95 0.0194 0.96 0.02073

1 2 3 4 5 6 7 8 9

F1 F2 F3 F4 F5 F6 F7 F8 F9

0.64 0.0158 0.61 0.016 0.61 0.0181 0.59 0.0240 0.62 0.0114 0.61 0.01581 0.60 0.0130 0.59 0.0114 0.63 0.0158

Voglibose MD Tablets

Voglibose placebo

Evaluation of Post Compression Parameters: The tablets of different formulations were subjected to various in vitro evaluation tests like hardness, friability, uniformity of weight, drug content, disintegration time, in vitro dissolution studies and stability studies and the results shown below tables.no.4
Table.No.4 Evaluation of Post Compression Parameters for the Tablets of different formulations
S.No Formulations Weight variation (%) F1 F2 F3 F4 F5 F6 F7 F8 F9 1.28 0.0158 1.30 0.02588 1.32 0.01140 1.31 0.0230 1.34 0.0207 1.48 0.0402 1.35 0.02881 1.33 0.0249 1.42 0.0207 Hardness (kg/cm2 ) 6.0 0.6519 4.5 0.4183 4.0 0.4183 3.5 0.4183 5.0 0.4472 4.0 0.4183 3.5 0.4183 4.0 0.4180 4.0 0.5000 % Friability Disintegration Time (secs) 112 2.607 105 0.8366 100 1.1401 75 2.0493 58 1.6733 22 1.1401 95 1.3038 52 1.5811 50 2.000

1 2 3 4 5 6 7 8 9

0.15 0.0378 0.18 0.0316 0.20 0.0374 0.23 0.0585 0.21 0.0311 0.16 0.0228 0.30 0.0697 0.21 0.0498 0.25 0.0194

In vitro Dissolution testing The values of the in-vitro dissolution testing of various formulations are depicted in table.no.5.
Fig. No.1 IR Spectral Analysis Pure Voglibose

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Table.No.5 in vitro release profile various Formulations of Mouth dissolving tablets of Voglibose
% Cumulative Drug Release Time(min) F5 F6 0 5 10 15 20 25 30 0 60.4 60.6 62.9 65.1 66.5 68.5 0 95.5 96.6 97.3 98.1 98.7 99.4 F8 0 59.9 61.9 64.1 65.8 67.3 68.4 F9 0 66.5 68.5 70.0 72.7 74.2 88.5

Invitro Release Profile of Mouth Dissolving Tablets of Voglibose

120 % Drug Release 100 80 60 40 20 0 0 5 10 15 20 25 30 35 Time(mins) F5 F6 F8 F9

Slope R2

: 2.1864 : 0.4093

Fig.No.4 Zero order kinetics From the results obtained it has been observed that the order of release of the drug was found to be first order in which the R2 value was close to 1. First order equation
Table.No.7 First order kinetics
Time in mins % CDR % To be released 0 4.5 3.4 2.7 1.9 1.3 0.6 Log cumulative % drug remaining 0 0.6532 0.5314 0.4313 0.2787 0.1139 -0.2218

Fig.No.3 In Vitro Release Profile Various Formulations of Mouth Dissolving Tablets of Voglibose

From the results obtained it has been observed that the formulations F 5 , F 6, F8 and F9 released 68.5, 99.4%, 68.4%, and 88.5% respectively at the end of 30 mins. S.No significant difference found between formulation F5 and F8 . However there was significant difference found between F6 and F9 , F8 , F5 formulations. The form Sulation F6 formulated by using super disintegrant Primellose (Croscarmellose sodium) combination with Starlac shows the increased dissolution rate compared all formulations. This increase in the dissolution rate may be due to water uptake and swelling mechanism of the Primellose (Croscarmellose sodium). Exposure to water causes starch grains to swell and exert pressure against surrounding tablet ingredients causing existing bonds between particles to break. Water uptake (or) wicking is the ability to draw water into the tablet matrix which one is another possible mechanism of action for Primellose (Croscarmellose sodium). However the % CDR was found to be maximum (99.4%) in F 6 , while in F 5 , F8 , F 9 it is the least. Hence formulation F 6 shows a good dissolution, which had also shown a good disintegration. Evaluation of in vitro release kinetics Zero order equation Table.No.6 zero order kinetics
Time(mins) % Cumulative Drug Release( F6 ) 0 95.5 96.6 97.3 98.1 98.7 99.4

0 5 10 15 20 25 30

0 95.5 96.6 97.3 98.1 98.7 99.4

Slope R2

: -0.0266 : 0.9907

0 5 10 15 20 25 30

Fig.No.5 First order release kinetics

From the results obtained it has been observed that the order of release of the drug was not followed the zero order kinetics in which the R 2 value was not close to 1.

ACCELERATED STABILITY STUDIES Based on the finalized formula and manufacturing process, a lab scale batch was taken and the formulated tablets were packed in Blisters and loaded in stability chambers for accelerated stability studies at 400 C/75%RH, and 300 C/65%RH .The required quantity of tablets in 400 C/75%RH were analyzed at the end of 1 st,2nd and 3 rd month and for tablets in 300 C/65%RH were analyzed at the end of 3 rd month for its physical appearance, Hardness, Average weight, disintegration time, dissolution and Assay.

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Table No.8 Accelerated Stability Studies
Parameters Initial 1 Month 2 Months 3 Months 40 0 C/75%RH 40 0 C/75%RH 30 0 C/65%RH 40 0 C/75%RH # 1300.2 4 22 97.96 98.9 # 1310.2 4.5 24 97.1 97.6 # 1300.2 4 23 98.4 98.6 # 1310.2 4.5 24 96.4 97.2

tion and assay. The results obtained were found to be within the specification limits. Mouth dissolving tablets of Voglibose formulated by using direct compression technique was found to be stable. REFERENCES
1. 2. 3. 4. 5. Raja Ponnambalam Pavithra V S., Diabetes Mellitus a review, The Asian Journal of Diabetology., 2007; 9(2): 17-21. Satoskar R S., Bhandarkar S D., Ainapure S S., Pharmacology and pharmaco therapeutics. 2001; 17 th edition: 905. K D Tripathi, Essentials of medical pharmacology 1999; 4th edition: .281. Sugihara M. Development of oral dosage form for elderly patients: Use of agar as base of rapidly disintegrating oral tablets. Chem Pharm Bull 1996; 44:2132-2136. Hanawa T,Watanabe A, Tsuchiya T, Ikoma R, Hidaka M, Sugihara M. New oral dosage form for elderly patients II. Release behaviour of benfotiamine from silk fibroini gel, Chem Pharm Bull 1995; 43:872-876. F. Ndindayino, D. Henrist , F. Kiekens , G. Van den Mooter ,C. Vervaet , J.P. Remon. Direct compression properties extruded iso malt. Int. J. Pharma 2002; 235: 149-157. William P,Tapash K G, Orally disintegrating tablets Products technologies and development issues, Pharm. Technol 2005; 29:136150. Brown D. Orally Disintegrating Tablets: Taste over Speed. Drug Deliv. Technol. 2001; 3: 58-61. Preformulation testing in Pharmaceutical Dosage forms Tablets; Edited by Herbert A. Lieberman; Leon Lachmann and Joseph. B. Schwartz; 1, 2 edition; .57-68. Makino T., Yamada M. and Kikuta J., Fast dissolving tablet and its production, 1998; European Patent, 0553777 A2. Reddy L H., Ghosh B., and Rajneesh, Fast dissolving drug delivery systems: A review of the literature, Indian J. Pharm. Sci. 2002; 64(4): 331-336. Koh N, Sakamoto S, Chino F, Improvement in medication compliance and glycemic control with voglibose oral disintegrating tablet, Koh Medical Clinic, Nagoya, Japan, 2008 Nov;216(3):249-57.

Description Average weight (mg) Hardness (kg/cm2 ) Disintegration Time (mins) Dissolution (% release) Assay (Drug Content) %w/w

# 130 0.2 4 22 98.7 99.38

# White, flat, circular, bevel edged uncoated Tablet.

CONCLUSION In the present study mouth dissolving tablets of Voglibose was prepared by using Direct compression technique. Different formulations were made by using three super disintegrants Croscarmellose sodium, Sodium Starch Glycolate, Crospovidone combination with directly compressible grade diluent like Microcrystalline cellulose, Pregelatinised starch (Starch 1500), and Starlac. All the formulations were evaluated for physical characteristics, disintegration, in vitro dissolution and stability. The in vitro dissolution studies were performed for the F 5 , F 6, F 8 , F 9 formulations. The Formulation F6 has shown the maximum cumulative percentage drug release (99.4%) at the end of 30 mins. The dissolution data of the optimized batch (F6 ) was subjected to study the in vitro release kinetics. The result shows that the formulation followed the first order release kinetics. The accelerated stability studies were conducted for 3 months under 400 C/75%RH condition as per ICH guidelines in blisters. Finally after the duration, the product was analyzed for physical appearance, loss on drying, disintegration, dissolu-

6. 7. 8. 9. 10. 11. 12.

Source of support: Nil, Conflict of interest: None Declared

Journal of Pharmacy Research Vol.5 Issue 2.February 2012