Asian J. Pharm. Res. 2012; Vol.

2: Issue 3, Pg 111-117

[AJPRes.]

ISSN- 2231–5683 (Print) www.asianpharmaonline.org ISSN- 2231–5691 (Online) 0974-3618

RESEARCH ARTICLE

Formulation and Characterization of Metformin Hydrochloride Floating Tablets
Ashok A. Hajare* and Vrushali A. Patil
Department of Pharmaceutical Technology, Bharati Vidyapeeth College of Pharmacy, Kolhapur-416013, MS, India *Corresponding Author E-mail: ashok.ahajare@bharatividyapeeth.edu

ABSTRACT:
The objective of the research work was to provide a gastroretentive system for sustained release of metformin HCl in proximal part gastrointestinal tract (GIT) in the form of oral floating tablet. Metformin HCl is an anti-diabetic biguanid with poor bioavailability and absorption window at the upper part of GIT. Floating tablets were prepared by wet granulation method incorporating natural polymers guar gum and k-Carrageen and a synthetic polymer HPMC K100 (HPMC) either alone or in combination. Sodium bicarbonate and citric acid was used as gas generating agent. Floating tablets were evaluated for weight variation, hardness, and friability, drug content, swelling index, in vitro buoyancy and in vitro drug release study. The formulation optimized based on floating ability, matrix integrity, and in vitro drug release in simulated gastric fluid pH 1.2. Formulation prepared with combination of 6% w/w k-carrageen and 11%w/w guar gum showed good gel strength, stable and persistent buoyancy for 12h, least floating lag time of 58 sec with good matrix integrity throughout dissolution period. The drug release of optimized formulation followed the Korsmeyer– Peppas model and the mechanism was non-Fickian/anomalous. PXRD and DSC studies revealed partial amorphization of drug. The mechanism of drug release was appears to be diffusion mechanism. Stability studies indicated absence of any drug degradation on storage for 3 months at 40oC. Comparison study with Glutamet® showed that the optimized formulation has better and complete release than the marketed product. Studies revealed usefulness of natural polymers over synthetic one.

KEYWORDS: Guar gum, K-carrageenan, HPMC K100, bioavailability, floating tablet INTRODUCTION:
The oral route considered as the most promising route of drug delivery. Effective oral drug delivery may depend upon the factors such as gastric emptying process, gastrointestinal transit time of dosage form, drug release from the dosage form and site of drug absorption. Most of the oral dosage forms possess several physiological limitations such as inability to restrain and locate the controlled drug delivery system within the desired region of the GIT due to variable gastric emptying and motility; shorter residence time of the dosage form in the stomach and incomplete absorption of drugs having absorption window especially in the upper part of the small intestine. As once the drug passes down the absorption site, the remaining quantity goes unabsorbed. The gastric emptying of dosage form in human is affected by several factors because of which wide inter and intra-subject variations are observed1. Hence, a beneficial delivery system would be one, which possesses the ability to control and prolong the gastric emptying time and can deliver drugs in higher concentrations to the absorption site. The controlled gastric retention of solid dosage forms may be achieved by the mechanism of mucoadhesion2,3, floatation4, sedimentation5,6, expansion7,8, modified shape systems9,10or by the administration of pharmacological agents11,12 that delaying gastric emptying. Based upon these approaches, floating drug delivery systems seems to be the promising delivery systems for control release of drugs. Floating drug delivery system (FDDS) possesses a bulk density lower than gastric fluids and thus remain buoyant in the gastric fluids for a prolonged period without affecting the gastric emptying rate. While the system is floating on

Received on 01.08.2012 Accepted on 20.08.2012 © Asian Pharma Press All Right Reserved
Asian J. Pharm. Res. 2(3): July-Sept. 2012; Page 111-117

111

1 N HCl at steel sieve (#40). 22 The test of the formulations are given in the Table 1. In effervescent systems a gas generating agent usually sodium bicarbonate or sodium carbonate is mixed with matrices prepared with swellable polymers. the drug released slowly at desired rate from the system. Pg 111-117 [AJPRes. Hardness of the tablets tested using a Monsanto hardness tester.6h and the main site of its absorption is proximal small intestines. Granules were dried in hot air oven at 50°C 112 . guar gum and κ-carrageenan as gelling hydrocolloids. IR spectrums of pure drug. Goa.This would lead to improvement in the bioavailability of the drug. It is an antihyperglycemic agent. uniformly mixed with drug and kept in sample holder and the spectra was recorded over the wave number 400-4000cm-1. The experiments were performed in triplicate and average value with SD werenoted.respectively. Infrared Spectra Analysis: FTIR studies were carried out in order to determine any possible interaction between drug and excipients used. Pharm. which improves glucose tolerance in type II diabetes.Asian J. Compression force adjusted to obtain hardness in the range of 3-5 kg/cm2. 20 MATERIALS AND METHODS: Materials: Metformin HCl was supplied by Cipla Pharmaceuticals Ltd. TD=Bulk density = Bulk mass / Bulk Volume. which needs to be administered twice or thrice a day. The resulting solution was further diluted with water prepared by conventional wet granulation method to achieve concentration 10µg/mL and the absorbance employing sodium bicarbonate and citric acid as gas measured at the 233 nm by UV spectrophotometer. HPMC obtained as a gift sample from Colorcon Asia Pvt. Sifted materials were dry mixed in rotation of 50 rpm at 37±0. PWeight variation was determined by weighing 20 tablets using an analytical balance and the deviation of individual tablet from the average weight of the tablets was determined. It has been reported that the absolute bioavailability of metformin when given orally is 50–60%. drug in 10 mL water.] the gastric content.Briefly. it stands an advantage over conventional dosage form. κ-Carrageenan was procured from Aquagri Processing Pvt. Drug content: Twenty tablets weighed and powdered.Tamil Nadu. Preliminary studies for optimizing the floating timewere carried out.5oC. The compositions and total floating timedescribed by Rosa et al.21. Gaur gum was purchased from SD Fine Chemicals. doughy mass passed through stainless steel sieve (#16) to form granules. Compressibility index and Hausner’s ratio of the granules was determined by using the formula: CI(%) = [(TDBD/BD)] ×100 and HR=TD/BD. Thickness and diameter measured by vernier caliper. has taken as the model drug for the present study. generating agents.3. physical mixture of ingredients of the formulation and optimized tablet wererecorded. A FDDS system was planned for metformin as such a system when administered would remain buoyant on the gastric fluids for a prolonged period of time and the drug would be available in the dissolved form at the main site of its absorption. Thus produces an upward motion of the system maintaining buoyancy.19. In this way. Once floating was optimized In -vitro buoyancy study: the same concentration of sodium bicarbonate and citric In vitro buoyancy was characterized from floating lag time acid was used in all other formulations. slowly and the wet dissolution medium wasrecorded as floating lag time and mass was mixed to get desired doughy consistency. respectively. The time required for the geometric dilution by spatulation without addition of tablet to rise to the surface of the dissolution medium and magnesium stearate and talc. All other chemicals were of analytical grades as required. Vol. Mumbai. Res. non-effervescent and effervescent systems have been utilized in the development of FDDS. when the systems comes in contact with gastric fluids. India) using a 13 mm flat punch. Ltd. Evaluation of Granules: The angle of repose of the granules was determined by using funnel method. completely dried KBr used as blank and before running the sample. 2: Issue 3. a BCS class III drug. the carbon dioxide is liberated by the acidity of gastric contents and the gas is entrapped in the viscous hydrocolloid. 2012. Weighed was performed using a USP dissolution test type II quantities of all the ingredients were sifted through stainless apparatus (Electro lab) using 900 mL of 0. Ltd. Friability of the tablets was determined in a Roche friabilator.5 to 1. Pure. Stock solution was sonicated for 20 Each floating tablet containing metformin HCl500mg was min. Biological half‐life of metformin is 1.14 Metformin hydrochloride. The total floating time. 16 The aim of the present study was to formulate and characterize floating drug delivery system for metformin HCl using HPMC.13Based on the mechanism of buoyancy. The lubricated granules were compressed on a ten station tablet mini press (Rimek.17 for 30 min and mixed with lubricant magnesium stearate and glidant talc. Distilled waterwas added to the duration of time the tablet constantly floated on the dry-mixed blend of drug and excipients. IR absorption spectrum of metformin HCl was determined using FTIR spectrophotometer (Jasco-V-530). about 2 mg of sample of was ground thoroughly with previously dried KBr at 120ºC for 30 min.15. Mumbai. Bulk density (BD) and tapped density (TD) were calculated by formulae:BD = Bulk mass / Bulk Volume. two distinctly different technologies. 10 Evaluation of Tablets: Uniformity of weight was determined according to method reported in I. The stock solution Methods: was prepared by dissolving powder equivalent to 10 mg of 18 Floating tablets were prepared by effervescent technology.

The test was performed using 900mL of 0. Res. respectively and evaluated for the different parameters.1 N HCl at 37 ± 0. 2: Issue 3. Analysis of data done was performed using PCP Disso V-3 software.23 Scanning Electron Microscopy: The SEM image of the tablet was used to examinesurface topography. Pharm. optimized tablet of batch (F5) and physical mixture of the same were irradiated with monochromatised CuKα radiation and analysed between 10° to 70°2θ. FTIR studies revealed that fundamental peaks of the metformin HCl retained in the optimized tablet and physical mixture. in 900 mL of 0. 1. Comparative study: Dissolution profile of optimized formulation (F5)compared with that of marketed formulation (Glycomet® SR-500mg). RESULTS AND DISCUSSION: Infrared Spectra Analysis: In vitro dissolution studies: In vitro dissolution studies were performed using USP typeII dissolution test apparatus (TDT 08L. 113 . Absorbance of these solutions were measured at λmax 233nm using UV spectrophotometer (JASCO UV530). Pg 111-117 Table 1: Composition of floating tablets of metformin HCl: Batch codes Ingredient (mg) F1 F2 F3 Metformin HCL 500 500 500 HPMC 166 106 K-Carrageenan 60 Guar gum 166 Sodium bicarbonate 230 30 230 Citric acid 10 10 10 Magnesium stearate 7 7 7 Talc 7 7 7 Total weight of tablets 920 920 920 [AJPRes. and morphology of fracturedsurface. these can be used in the formulation of floating tablet of metformin HCl. PW3710). Swelling characteristics were expressed as percentage water uptake (%WU).Asian J. Ltd. Inert atmosphere maintained by purging nitrogen at the flow rate of 150 mL/min.1N HCl. texture..5°C at 50 rpm. Vol. indicated absence of any significant interactions between the drug and polymers used in the formulation and hence. blotted to remove excess water and weighed. the tablet was withdrawn. The powder samples were hermetically kept in the aluminium pan and heated at constant rate 10°C/min over a temperature range of 35°C to 250°C. Mumbai.45µ membrane filter and diluted to a suitable concentration with 0. India). The samples of pure drug. Fig. SEM analysis conducted using JOEL JSMT330 scanning microscope for optimized formulation.1N HCl at 37±0.] F4 500 60 106 230 10 7 7 920 F5 500 60 106 230 10 7 7 920 F6 500 132 34 230 10 7 7 920 F7 500 34 132 230 10 7 7 920 F8 500 34 132 230 10 7 7 920 Water uptake study: The swelling properties of floating tablets were determined by placing the tablet in the dissolution test apparatus. Platinum crucible was used with an alpha alumina powder as reference to calibrate the DSC temperature and enthalpy scale. The results. After a specified time intervals. The sample was filtered through 0.5⁰C. 2012. Figure 1: Overlain FTIR spectrums: (a) pure drug (b) physical mixture and (c) optimized tablet formulation (F5) PXRD Studies: PXRD study was carried out to know any change in physical state of ingredients in the formulation has occurred using X-ray diffractometer (Philips X-ray diffractometer. Perkin Elmer) equipped with an intracooler.24 DSC Studies: Thermograms of physical mixture and optimized tablet formulation were obtained using DSC (Pyris Diamond TG/DTA. 60. Stability Studies: The optimized metformin hydrochloride floating tablets (batch F5) were packed and subjected to accelerated stability studies as per ICH guidelines (40°C ± 2 °C /75 % ± 5 % RH). 90 days.25 The sample were withdrawn periodically at the end of 30. Accurately 5 mL sample of dissolution medium was withdrawn from the vessel hourly for total 12h and the withdrawn sample was replaced with equal amount of fresh dissolution medium. Electro lab Pvt.

13 12.30±0.09±0.003 F5 0. Batch F5 with floating lag time <1 was optimized batch.02. This might be due to viscous nature of guar gum.93±0.52±0.17 4.82±0. Vol.25±0.004 g/cm3 as shown in Table 2.02 F7 917±1.83±0. 2012.84 4. Pg 111-117 Table 2: Granule Properties of all the batches: Batch code Bulk density(g/cm3) F1 0. which maintains the integrity of the tablets for longer duration by reducing the effect of erosion thus resulting in increase in floating time.02indicating good flowability.73±0. 2: Issue 3. F4.69±0.10 4.01±0.13 4.02 1.3333±0.61±0. respectively. Pharm.12 24.10±1.23 4. other hand.04 1.73±0.12 4.007 to 0.06 F6 918±1. transportation and other processing operations. 2.45 Hardness (Kg/cm2) 4. formulation F5.36 11.4598±0.02 0.31±0.55 19.43 22.4798±0.14 98.30± 0. F8 prepared as combination of HPMC and κ-Carrageen showed floating lag time of 135.1 M HCl).05 13.29 101.55 12.36±0.02 F3 918±0. and remain buoyant for 10.75±0. F6. Res. Floating lag times were in the range of 58 to 540 sec.09±0.06 0.007 [AJPRes.51±0. 8.12 mg.95±0.29 to101.03 1.4698±0.02±0.88 11.80±0. The angle of repose was within the range of 25º to 30°. complying drug content uniformity test.22 4. The observations suggest good flow ability of the granules.22 99.33±0.43±0.21 4.01 0.09 0.006 Carr’s index 11.35±0.24 14.45% whereas Hausnerratio was in the range of 1.77 11. The observation indicates good packing capacity of granules.36±0.4202±0.63±0.92±0.79 4.3998±0.17 97.43±0.05 0. F2 540 >12 Thickness was in range of 4.49±0. Fig.21 Table 3: Tablet properties of metformin HCl floating tablet: Batch code Average weight Thickness Diameter (mm) (mg) (mm) F1 917±0. As density of the tablet falls below one the tablet became buoyant.08 13.001 F3 0.55 to 19.12 4.85 4.3758±0.004 0. decreasing the density of the tablet.90±0.99 4.] Tapped density (g/cm3) 0. complying with pharmacopoeial specifications.53±0.4269±0.006 F6 0.32±1.59±0.89±0.08 Friability (%) 0. All formulations. Generated gas was trapped and protected within the gelformed by hydration of polymer.4202±0.78±0.89±0.12 24.003 F2 0.17±0.009 F8 0.39 ± 0.13 27.002 0.49 ± 0. Formulations F3.84 mg.95±0. Sodium bicarbonate induced CO2 generation in the presence of dissolution medium (0.Asian J.67±0.07 F8 921±0.02 13.4166±0.63±0.006-0.42±0.07±0.001 0. It ensures that the tablets can withstand mechanical impacts during packing. In Vitro Buoyancy Studies: All the tablets prepared by effervescent approach.39±0. Table 4: Floating Properties of metformin HCl tablets: Evaluation of Tablets: Batch Floating lag Matrix Floating duration (h) The weights of the tablet were varied between 917±0.79to code time (sec) integrity 921±0.32±0.04 13.53±0.007 g/cm3 and tap density in the range 0.39Kg/cm indicating satisfactory mechanical F5 58 > 12 210 > 12 strength.18±0.03 13.65±0.52±0. The selected formulation F5 showed floating lag time 58 sec.43±0. Hence. Table 4.14±0.009 0.07±0. The variation in weight was within the range 75 >12 F1 of ±5%.02±0.03 0.08±0.07 13. Figure 2: Photographs of in-vitro buoyancy study of F5 batch 5h.75±0.03 Drug content (% ) 97. Sodium bicarbonate was added as a gas-generating agent. 105.14 25.99±0. till completely eroded.18±0.14 4.05 F5 919±0.4591±0.14±0.1 99. F7 prepared with combination of κ-Carrageenan and guar gum showed decrease in floating lag time and increased floating duration time.13±0.73±0.07 F2 920±0.002 F4 0.86±0.17 20.02 F4 920±1. The F3 135 Disintegrated after 10 h hardness of found in the range 4.4031±0.05 to F8 370 Disintegrated after 5 hrs 0.4166±0. 370 sec.3333±0.07 Angle of repose (°) 27.17 to F4 105 Disintegrated after 8 h 2 4.07±0.51±0.60±0.Carr’s index was in the range of 11.003 0.73±0.27 Evaluation of Granules: The bulk density of granules was in the range 0. exhibited a weight loss F6 F7 430 > 12 of <1% and the loss were in the range of 0.4681±0.37±0. with floating duration time >12 h.10±1.The drug content was in the range of 97.09±0.69±1. respectively.02 1.87±1.99± 0.02 0.53±0.41 26.04to 1.007 F7 0.01 1. On the containing κ-Carrageenan and guar gum (60:106) 114 .07 13.07 to 4.40±0. Table 3.21 4.0471±0.04 1.003 0.07mm.31 98.4133±0.06 1.4033±0.39 4.4798±0.4505±0.04 13.96±0.35 Hausner’s ratio 1.001 0.20 98.

indicating the drug release govern by Fickian diffusion mechanism.3509 to 0. F5. because weight gain by tablet increased proportionally with rate of hydration. F6.Asian J.9811 0.7729 F3 81.8736 8.1292 F8 96. Table 5: Dissolution data and release kinetics of Korsmeyer-Peppas model: Batch code % Drug release after 12h n K F1 95.9091 0. dissolution period.80% and 85. batch F2 and F5 showed n values in the range of 0. In-vitro dissolution data gave us information about the effect of change in polymer type and concentration on drug release and swelling capability of formulation.3713 34. persistent buoyancy. of κ-Carrageenan and further decreases at its highest concentration employed.76 0. it was decreased gradually due to dissolution of outermost-gelled layer of tablet into dissolution medium. Later on.64 0.9906 0. F3. F6.3509 38. it was revealed that swelling indices were increased as the concentration of κ-Carrageenan increased.14% of drug. Res. As time increases.1381 F4 s99. F8 were in the range of 0. Hence. Formulation F1 and F2 released 95. Based on the dissolution profiles the formulations can be arranged in the following order of their controlling efficiency as F4>F5>F8>F1>F7>F2>F3>F6.3626 35. formulation F5 was considered as the best formulation.35 0. 3. KorsmeyerPeppas model found to be the best fit with higher values of correlation coefficient. The optimized formulations F5 show maximum swelling up to 5h followed by decrease in swelling index. in 12h. κ-Carrageenan binds with water extensively and get hydrated because of the high mobility of water molecules between polymer chains and sulphategroups24. Table 5. this might due to higher concentration of HPMC. F4. and good matrix integrity throughout Fig. On the other hand.76 0.3897 37. Vol.9480. Reason behind this may be erosion Figure 4: Dissolution profile of metformin HCl floating tablets process initiation at the end of 5h attributing gradual decrease in percent swelling after 5h.1116 F2 85. Dissolution data of formulation F3.94 0. Formulation F1 showed maximum swelling in 12h with sharp increase up to 5h. which has higher water absorption capacity and form thick swollen mass. Pharm. From observed swelling indices of batches F5. release than other formulations with least floating lag time. the swelling index was increased.14 0.κ-Carrageenan-guar gum Dissolution Studies: combination imparts good matrix integrity compared to κIn vitro drug release studies performed as per procedure Carrageenan-HPMC. The percentage drug release plotted against time to obtain drug release profile.9546 0.] Swelling Characteristics: The swelling indices were calculated with respect to times. F7 and F8 revealed increase in drug release with concentration Figure 3: Relationship between swelling index and time. By comparing the r-values of different models.9815 0.1290 F5 98.9783 0. F6 and F7.4265 34.4265.6127 20.9810 Best fit model Matrix Matrix Peppas Matrix Peppas Peppas Matrix Zero order 115 . indicating the drug release governed by Anomalous transport mechanism. The mean diffusion exponent values (n) for batches F1.9782 0.This difference may be due to lack of enough gelling strength of HPMC to control the drug release and less water permeability of guar gumcompared to HPMC. 2: Issue 3.0109 F6 79. 2012.6127 and 0. Formulation F5 showed better drug described in methodology section. F4.4.9480 10. Fig. Pg 111-117 [AJPRes.6181 r 0. 3.69 0.0946 F7 85.80 0. Fig. respectively.

thus concluded that effervescent floating tablet containing metformin HCl (F5) gives better and but complete drug release over 12h. shown in Table 6. but when it was incorporated into the polymer matrix.1ºC. Fig.07±0. showed sharp endothermic peak starting at 209ºC with melting peak at 225.57 98.40±0. it can be concluded that drug released from matrix by diffusion mechanism.07±0.75 After 90 days 4.08 4. Key: (a) before and (b) after dissolution Stability Study of Batch F5: The results of stability studies.98±0. Another peak observed in formulation at 160.1ºC and in the thermogram of optimized batch the endothermic peak appeared at 208. Vol. indicate no evident change in the physical properties of formulations after subjecting them to 30.89 97.10 13.40±0.3ºC may be due to polymer.03 Diameter (mm) 13.8% drug release in 12h. The optimized formulation F5 remained floatable in the stomach for 12h. Before dissolution tablet was with intact surface without any perforation.43±0. Figure 5: DSC thermograms. 2: Issue 3. 2012.12±0.43±0. Key: (A) Physical mixture (B) Optimized batch F5 and (C) Metformin HCl Table 6: Evaluation of optimized formulation F5 after stability period: Parameters Period Zero day After 30 days Thickness (mm) 4. it has one of the advantages over marketed formulation that it increases absorption of metformin HCl drug. Res.02 Hardness (Kg/cm2) 4.07±0.02 12. Scanning Electron Microscopy: SEM photographs of tablet of optimized batch taken before and after dissolution are shown in Fig. Key: (a) metformin HCl and (b) optimized tablet formulation PXRD Studies: The overlay of PX-RD pattern of Metformin HCl.Asian J.76 98. Figure 6: Overlain Powder X-ray diffractograms. Fig. After dissolution solvent enters the matrix and moves slowly towards the centre of the tablet. Pg 111-117 [AJPRes. Shifting of endothermic peaks to left side with decrease in its intensity indicates amorphization of drug. Hence. 5.98 116 . The image of tablet. It reveals that the intensity of the peaks for the pure drug was sharp. Comparison of Optimized Formulation with Marketed Product: The marketed product had showed 94.has showed that the optimized formulation F5 has better drug release in comparison to the marketed product as showed in Fig. Pharm.7-b. Figure 7: Scanning electron microscopy image of tablet surface. physical mixture and optimized formulation F5 showed in Fig. Comparison study with marketed product of Glutamet® SR 500mg. Thus.01 4. channels and troughs.17 Drug release (12h) 98.42±0.40±0.7.42±0. the intensities of the peaks decreases due to decreased crystallinity of the metformin HCl. It is.06 13.45±0.13 4.75 After 60 days 4.10 59 > 12 98.7% drug release in 12h.17 99. The drug diffuses out the matrix after it getsexposed to dissolution medium.15 Floating lag time (s) 58 58 Floating time (h) >12 >12 Drug content (%) 99. 60 and 90 days accelerated stability studies.08 4.6. itconcludes that the drug does not undergo degradation on storage. 8. Thus.77±0. shows formation of polymer network through which the drug diffused to the surrounding medium.41±0.] DSC Studies: DSC thermogram of pure metformin HCl.18 59 >12 99.73±0. where as the optimized formulation F5 showed 98.

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