formulation and evaluation of inlay tablet of...

Journal of Pharmacy Research Vol.8 Issue 11.November 2014

Palanisamy. P et al. / Journal of Pharmacy Research 2014,8(11),1592-1607

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Research ArticleISSN: 0974-6943

Available online throughhttp://jprsolutions.info

*Corresponding author.Mr. Palanisamy.p*.,M.Pharm,Department of Pharmaceutics,Vinayaka Mission’s College of Pharmacy,Yercaud Main Road,Kondappanaickenpatty,Salem (D.T),Tamil Nadu (State),Pin. Code: 636 008-India

Formulation and evaluation of inlay tablet of metformin hydrochloride assustained release and pioglitazone with glibenclamide as immediate release

Palanisamy. P*1, R. Margret Chandira1, B. Jaykar2, A.Pasupathi1, B. S. Venkateshwarlu1, M. Kumar2, M. V. Kumudhavalli3

1Department of Pharmaceutics, 2Department of Pharmaceutical Chemistry, 3Department of Pharmacutical Analysis, Vinayaka Mission’sCollege of Pharmacy,Vinayaka Missions University, Yercaud Main Road, Kondappanaickenpatty, Salem (D.T) 636 008,Tamilnadu,India

Received on:16-09-2014; Revised on: 12-10-2014; Accepted on:14-11-2014

ABSTRACTThe present research endeavor is directed towards the development of once daily sustained release matrix tablet of metformin hydrochloridewith inlay tablet of pioglitazone glibenclamide as immediate release. Combination therapy concluded that Pioglitazone is effective in improv-ing the glycemic control when added to a combination of glibenclamide and metformin in type 2 DM. Matrix system was based on swellablepolymer were selected for sustained the drug release. Different polymers Viz., HPMC, Xanthan Gum, Guar gum, to get the desired releaseprofile over a period for 12 hours. Different batches of both Immediate release(IR) and Sustained release (SR) were prepared by Directcompression and Wet granulation method respectively. In the immediate release layer formulation, disintegration such as sodium starchglycolate at three different concentration (5%, 7.5% and 10% w/w) with 5% concentration crosspovidone of tablet weight were tried to get adesired release profile within 30 minutes. The in-vitro dissolution studies were performed for all the IR formulations. Formulation IR1 to IR3released of pioglitazone and glibenclamide respectively at the end of 30 minutes with SSG concentration of 10%. So IR3 were selected for finalformulation. SR formulations F3 showed release profile were complies with USP at 40% concentration of HPMC-K100M with respect to drugcompared with another 11 formulations. Inlay tablet formulation were prepared using Optimum formulation of sustained granules andimmediate release granules.The tablets assay, weight variation, hardness, thickness friability, disintegration time and in-vitro dissolutionwere found to be within the official limits. The dissolution data of the optimized batch was subjected to study the in-vitro release kinetics. Theresult showed that the IR layer of inlay tablet formulation followed the first order release kinetics and the drug release kinetics of SR layer ofInlay tablet formulation correspond best to Higuchi’s model and drug release mechanism as per n value of Korsmeyer&Peppas Modelappeared to be a complex mechanism of swelling, diffusion and erosion with zero order release kinetics.

KEY WORDS: Metformin hydrochloride, pioglitazone, glibenclamide and triple combination tablet.

INTRODUCTION:The convenient oral drug delivery has been known for decades is themost widely utilized route of administration among all the routes. Itremains the preferred route of administration in the discovery anddevelopment of new drug candidates. The popularity of oral route isattributed to patient acceptance, ease of administration, accurate dos-ing, cost effective manufacturing methods and generally improve theshelf life of the product[1].

Immediate release tablets are designed to disintegrate and release thedrug in absence of any controlling features such as coating or otherformulation techniques. Despite a rising interest in controlled-re-

lease drug delivery systems, the most common tablets are those in-tended to be swallowed whole, disintegrating and releasing their me-dicaments rapidly in the gastrointestinal tract.The potential benefitsthat a sustained release system may bring to us can be appreciated bya consideration of prolonged and efficient delivery of therapeuticallyeffective dosages, patient compliance and localization of thetherapy.The bioavailability of drug molecules to the ailing tissue cellsis governed by a sequence of pharmacokinetics processes-release,absorption, distribution, metabolism and elimination. In some cases,these processes result in the inefficient bioavailability of the drug tothe target tissue cells. The bioavailability to a target tissue can bemaximized and the adverse side effects in non-target tissue can beminimized by applying the principles of sustained release system[2-4].Diabetes is a chronic disease marked by high levels of sugar in theblood. Diabetes mellitus often referred to simple as diabetes, whichroughly translates to excessive sweet urine. It is a noninfectious dis-ease. The body systems affected by diabetes mellitus are thenervous, digestive, circulatory, endocrine and urinary systems, butall body system are in some way affect. The formulation once daily



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sustained release (SR) Matrix tablet of Metformin Hydrochloride withInlay tablet of Pioglitazone Hydrochloride with Glibenclamide as Im-mediate release (IR).

To obtain the beneficial anti-diabetic effect of triple drug combinationon a single tablet with dual release mechanism.To improve the patientcompliance by giving the triple combination as a single dosage form.To reduce the dosing frequency, the patient already receiving theGlibenclamide 5mg, Metformin 500mg that two times a day to oncedaily dosage form.To provide effective, Safe and stable pharmaceuti-cal oral formulation containing both immediate release and sustainedrelease of three anti-diabetic drugs with different mechanism of actionto improve glycemic control(5).

MATERIALS AND METHODS:Metformin hydrochloride was procured by Alekya Chemicals(Mumbai, India); Glibenclamide and Pioglitazone Hydrochloride wasprocured by Sri Krishnan Drug Ltd (Bangalore, India); HPMC K 100M,Xantham Gum and Guar Gum was gifted by Laffans Petrochem (Ban-galore, India); Povidone K30, Sodium Starch Glycolate, Sodium Lau-ryl Sulphate, Magnesium stearate, Crosspovidone, Colloidal silicondioxide, Talc and MCCP pH-102 was gifted by Amishi Drugs (Banga-lore, India).

PREFORMULATION STUDIES OF PURE DRUG ANDEXCIPIENTS [6-7]:Preformulation study relates to pharmaceutical and analytical inves-tigation carried out proceeding and supporting formulation develop-

ment efforts of the dosage form of the drug substance. Preformulationyields basic knowledge necessary to develop suitable formulationfor the toxicological use. It gives information needed to define thenature of the drug substance and provide frame work for the drugcombination with pharmaceutical recipients in the dosage form.Hence, the following Preformulation studies were performed on theobtained sample of drug. The results are shown in Table. No: 4 & 7.

COMPATIBILITY STUDIES [8]:The Active ingredients and excipients were mixed and taken in 2 mLglass vials and sealed. These glass vials are kept at Room Tempera-ture and 40°C / 75% RH for about 1 month. At the interval of 10 days,the samples were withdrawn and analyzed for color change.

SPECTRAL IDENTIFICATION [9]:Excipients are integral components of almost all pharmaceutical dos-age forms. The successful formulation of a stable and effective soliddosage form depends on the careful selection of the excipients, whichare added to facilitate administration, to promote the consistent re-lease and bioavailability of the drug and protect it from degradation.Infra red spectroscopy is one of the most powerful analytical tech-niques to identify functional groups of a drug.

In the present study, the potassium bromide disc (pellet) method wasemployed. Chemical stability was confirmed by IR spectrometry. Theresults are shown in Figure. No: 4-14

FORMULATION DEVELOPMENT

Table. No: 1. Formulation of SR Matrix metformin Hydrochloride Tablet

Batch. No: F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12Ingredients (mg / tablet)

Metformin HcL 500 500 500 500 500 500 500 500 500 500 500 500HPMC K100M 150 175 200 225 - - - - - - - -Xanthan Gum - - - - 150 175 200 225 - - - -Guar Gum - - - - - - - - 150 175 200 225PVP k30 40 40 40 40 40 40 40 40 40 40 40 40MCCP Ph-102 100 75 50 25 100 75 50 25 100 75 50 25Crosspovidone 5 5 5 5 5 5 5 5 5 5 5 5Magnesium stearate 10 10 10 10 10 10 10 10 10 10 10 10Talc 10 10 10 10 10 10 10 10 10 10 10 10Aerosil 5 5 5 5 5 5 5 5 5 5 5 5Total Weight 820 820 820 820 820 820 820 820 820 820 820 820

Table. No:2 Formulation of IR Pioglitazone with Glibenclamide

Batch. No: IR1 IR2 IR3Ingredients (mg / tablet)

Glibenclamide 5.05 5.05 5.05Pioglitazone HcL 16.7 16.7 16.7Sodium Starch Glycolate 3.5 5.25 7Crosspovidone 3.5 3.5 3.5Sodium Lauryl Sulphate 2 2 2Crosspovidone 1 1 1MCCP pH-102 36.75 35 33.25Talc 1 1 1Magnesium Stearate 0.5 0.5 0.5Total Weight 70 70 70

Formulation of the Inlay Tablet:Final Inlay tablets were prepared using optimized sustained formula-tions of Metformin HCL and immediate release Pioglitazone withGlibenclamide. Initially the granules of metformin was filled in thetablet die optimized tablets of the IR are being placed on the metformingranules and it is compressed as an inlay tablet.

POST COMPRESSION PARAMETERS [10-13]:a) Weight Variation Test:Twenty tablets were selected randomly from each batch and weighed



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individually to check for weight variation. A little variation wasallowed in the weight of a tablet according to U.S. Pharmacopoeia.The following percentage deviation in weight variation wasallowed.The results are shown in Table. No: 5& 8.

Average weight of a tablet Percentage deviation

130 mg or less ± 10>130 mg and <324 mg ± 7.5

324mg or more ± 5

b) Tablet Dimensions:Thickness and diameter were measured using calibrated Vernier cali-pers. Five tablets of each formulation were picked randomly and thick-ness and diameter was measured individually. The results are shownin Table. No: 5 & 8.

c) Thickness:The thickness of the tablets was determined by Vernier calipers. Fivetablets from each batch were used and the average values were calcu-lated. The results are shown in Table. No: 5 & 8.

d) Hardness:Hardness indicates the ability of a tablet to withstand mechanicalshocks while handling. The hardness of the tablets was determinedusing Monsanto hardness tester. It is expressed in kg/cm2. Five tab-lets were randomly picked and hardness of the tablets was deter-mined. The results are shown in Table. No: 5 & 8.

e) Friability test:The friability of tablets was determined by using Roche friabilator. Itis expressed in percentage (%). Twenty tablets were initially weighed(Wt) and transferred into friabilator. The friabilator was operated at 25rpm for 4 minutes or run up to 100revolutions. The tablets were weighedagain (WF). The % friability was then calculated by-

W (initial)-W (final)%F =........................................... ×100

W (initial)

The results are shown in Table. No: 5 & 8.

f) Disintegration test:The disintegration time for immediate release layer was determinedusing the disintegration apparatus. One tablet was placed in each ofsix tubes placed in a beaker containing 1000 ml of purified watermaintained at 37 ± 20 C and the apparatus was operated. The timetaken for the tablets to disintegrate and pass through the mesh wasnoted. The results are shown in Table. No: 5 & 8.

ASSAY:

For SR Metformin hydrochloride Tablets:

Standard preparation:Prepare a solution of metformin hydrochloride in water having a knownconcentration of about 10 µg per mL.

Sample preparation:Weigh and finally powder 20 tablets. Transfer an accurately weighedof the powder, equivalent to about 100mg of metformin hydrochlorideto a 100ml volumetric flask. Add 70 ml of water shake by mechanicalmeans for 15 minutes, Dilute with water to volume and filter, discard-ing the first 20 ml of the filtrate. Dilute 10ml of the filtrate with water to100ml and dilute 10ml of the resulting solution with water to 100ml.

For IR Pioglitazone & Glibenclamide tablets:

Standard preparation:Dissolve 165 mg of Pioglitazone and 50 mg of Glibenclamide in 10 mlof methanol with the aid of ultrasound for 20 minutes, add sufficientmethanol to produce 100ml and dilute 5ml of this solution to 50mlstandard flask and make up to the mark with methanol.

Sample preparation:Weigh and fine powder of 20 tablets transfer an accurately weighedportion of the powder, equivalent to about Pioglitazone 15mg with amixture of 2ml of water and 50ml of methanol in 100ml of standardflask shake until fully dissolved, and make up to volume with metha-nol.

Chromatographic Conditions:Apparatus : HPLC systemColumn : C18, 4.6mm × 250 cm. 5µWavelength : 254nmInjection volume : 20µl.Flow rate : 1.0ml/minColum Temperature : Ambient

Uniformity of content:Content uniformity is based on the assay of the individual content ofdrug substance in a number of individual dosage units to determinewhether the individual content is within the limits. Uniformity of con-tent needed for the dosage unit containing less than 25mg of API orless than 25% of total tablet weight. Content uniformity of the dosageunit was analyzed by as directed in the assay of tablet instead ofequivalent weight taken as a whole tablet.



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IN-VITRO DISSOLUTION STUDIES:Dissolution study of sustained release and immediate release of dif-ferent tablet formulations were carried out separately.

Dissolution SR Tablets:Apparatus : USP Type II (Paddle)Medium : 6.8 Phosphate bufferMedium Volume : 900mlSpeed : 100 RPMTime intervals : 1, 3, 6, 9 & 12 hour.Temperature : 37 ± 0.5°C.Apparatus : UV-VIS SpectrophotometerWavelength : 232nmThe results are shown in Table. No: 10

Dissolution of IR Pioglitazone & Glibenclamide tablets:Dissolution of IR tablets done in two parts. Dissolution medium isseparately chosen for two drugs. API based on their individual solu-bility and their absorption site in the G.I.T.

For PioglitazoneApparatus : Dissolution Apparatus USP Type I

(Basket Type)Medium : 0.1 HCLMedium Volume : 900mlSpeed : 100 RPMTime : 30 MinutesTime intervals : 5, 10, 15, 20& 30 MinutesTemperature : 37 ± 0.5°C.

Chromatographic Conditions:Apparatus : HPLC systemColumn : C18, 4.6mm × 250 cm. 5µWavelength : 254nmDetector : UV/PDAInjection volume : 20µl.Flow rate : 1.0ml/minSample cooler temp. : 30°C

For GlibenclamideApparatus : Dissolution Apparatus USP Type I

(Basket Type)Medium : 0.05 M boric acid and 0.05 M potassium

chloride solution, prepared by dissolving3.09 g of boric acid and 3.73g of potas-sium chloride in approximately 250 mlof water, adjusting with 1 N sodiumhydroxide to a pH of 9.5 and diluting withwater to 1 L.

Medium Volume : 900mlSpeed : 100 RPM

Time : 30 MinutesTime intervals : 5, 10, 15, 20& 30 MinutesTemperature : 37 ± 0.5°C.

Chromatographic Conditions:Apparatus : HPLC systemColumn : C18, 4.6mm × 250 cm. 5µWavelength : 254nmDetector : UV/PDAInjection volume : 20µl.Flow rate : 1.0ml/minSample cooler temp. : 30°CThe results are shown in Table. No: 10

For Inlay Tablet

Swelling and Erosion Studies:The rate of test medium uptake by the polymer was determined byequilibrium weigh gain method. The inlay tablets were accuratelyweighed (W0), Placed in the basket of dissolution apparatus, rotatingat 100 rpm, 37 ± 0.5°C temperature, using pH 6.8 phosphate buffer.After 1, 2, 3, 5, 7, 9 and 12 hours, each basket was removed from thedissolution apparatus, the tablet with the pre-weighted mesh waswithdramn from the medium and lightly blotted with tissue paper toremove excess test liquid and then reweighed (W1). After the swell-ing studies, the wet samples were then dried in an oven at 80°C for 12Hours time period, allowed cooling in desiccators and finally weigheduntil constant weight was achieved (final dry weight, W2). The ex-periment was performed in 6 times for each time point and fresh sampleswere used for each individual time point. The percentage increase inweight due to absorbed liquid or water uptake was estimated at eachtime point from the following quation.

Swelling % = W1 – W0/W0 × 100, Erosion % = W0 – W2/W0 × 100The results are shown in Table. No: 12 & Fig. no: 18 & 19

Assay of Inlay tablet:Assay of Inlay tablet containing Metformin HCL and Pioglitazonewith Glibenclamide done by two steps. The assay of inlay tablet SRlayer containing metformin HCL was analyzed by UV method as di-rected in the Assay as of SR tablet. The assay of inlay tablet IR layercontaining Pioglitazone with Glibenclamide was analyzed by HPLCmethod as directed in the assay as of IR tablet.

Uniformity of content:Content uniformity of the dosage unit was analyzed by as directed inthe assay of tablet instead of equivalent weight taken as a wholetablet.

In-Vitro Dissolution profile of Inlay tablet:Dissolution medium is separately chosen for all three drugs. API



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based on their individual solubility and their absorption site in theG.I.T.

Separate dissolution condition were decide, one for each API.1. The dissolution of immediate release layer was studies with

dissolution medium of Pioglitazone in 0.1HCL for 30 minutesand Glibenclamide in 9.5 Buffer for 30 minutes. As directedin the assay of IR tablet.

2. The dissolution of sustained release layer was studied withdissolution medium of 6.8 pH phosphate buffer for 12 hours.As directed in the assay of SR tablet.

The results are shown in Table. No: 13 & 14

Evaluation of In-Vitro release kinetics:To study kinetics, data obtained from in-vitro release were plotted invarious kinetic models.

In-vitro Drug Release Kinetic Studies [18]:The dissolution data were subjected to release kinetic study. Drugdissolution from solid dosage form has been described by kineticmodels in which the dissolved amount of drug (Q) is compared to theDrug content (%) function of the test time (t). some analytical andkinetic models of the Q versus t commonly used are Zero order, Firstorder, Hixson – Crowell, Higuchi and Korsmeyer – Peppas model tostudy the in-vitro kinetic release mechanism. The results are shownin Table.No: 15 & 16 Figure.No: 20 to 28

Stabilty Study:Stability study of optimized inlay tablet was carried out at room tem-perature and an accelerated condition of 40°C ± 2°C/75%RH± 5%RHfor a period of 6 months. Samples were withdrawn at an interval of 1,2, 3 & 6 month for evaluation with respect to physical parameters,assayand dissolution studies. The results are shown inTable.no: 17 & 18

RESULT AND DISCUSSION:

Table. no: 3 calibration curve of API materials

Metformin Pioglitazone Glibenclamide Hydrochloride HydrochlorideConc. Absorbance Conc. Area Conc. Area(µg/ml) at 232nm (µg/ml) (MAU) (µg/ml) (MAU)

0 0 0 0 0 02 0.152 40 586.48218 10 112.748964 0.327 80 1075.3542 20 230.307926 0.489 120 1645.335 30 341.538218 0.651 160 2151.4565 40 454.2855210 0.827 200 2724.8735 50 572.2378512 0.955 240 3272.6106 60 682.2033714 1.11 300 3999.0288 70 792.5611016 1.288 320 4360.0147 80 911.6030318 1.458 360 4896.645 90 1107.000620 1.623 400 5299.6294 100 1137.2675

Calibration curve

Fig. no: 1 Linearity of Metformin Hydrochloride

Fig. no: 2 Linearity of Pioglitazone Hydrochloride

Fig. no: 3 Linearity of Glibenclamide



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Preformulation studiesThe overall objective of preformulation studies is to generate usefulinformation to the formulator in developing stable and bioavailabledosage forms that can be mass produced.

Physical Drug – Excipients compatibility studies:The successful formulation of a stable and effective solid dosageform depends on the careful selection of the excipients that are addedin the formulation. The drug and excipients must be compatible withone another to produce a product that is stable, Efficacious and easyto administer and safe.

The physical compatibility evaluation was performed in visual basis.

Fig. no :4 Metformin Hydrochloride

The study implies that the drug, polymer and other excipients werephysically compatible with each other as there was no change ofphysical description.

Chemical compatibility studies by FT-IR:The FT-IR spectral analysis of the Metformin hydrochloride,Pioglitazone, Glibenclamide, polymers and other excipients was shownfrom Fig. no: 4 to Fig. no:14. All the characteristic peaks appear for thepure Metformin, Pioglitazone, Glibenclamide and its physical mixtureindicating no interaction between the three drugs. All three drugswith polymer also show characteristic peaks so, No interaction be-tween the drug and excipients.

Fig. no: 5 Pioglitazone

Fig. no: 6 Glibenclamide



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Fig. no:7 Metformin Hydrochloride + Pioglitazone

Fig. no:8Metformin Hydrochloride + Glibenclamide

Fig. no: 9 Pioglitazone + Glibenclamide



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Fig. no:10 Metformin Hydrochloride + Pioglitazone + Glibenclamide

Fig. no:11 Metformin Hydrochloride + Pioglitazone + Glibenclamide + HPMC K100M

Fig. no:12 Metformin Hydrochloride + Pioglitazone + Glibenclamide + Guar Gum



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Fig. no:13 Metformin Hydrochloride + Pioglitazone + Glibenclamide + Xanthan Gum

Fig. no: 14 Metformin Hydrochloride + Pioglitazone + Glibenclamide + All excipients (Inlay Tablet)

Pre compression study SR formulation

Table. No: 4 pre compression study SR formulation

Batch Bulk density* Tapped density* Compressibility Harner’s Angle of Moisturecode g/cm3 g/cm3 index g/cm3 Ratio* Repose* Content* %w/w

F1 0.478±0.004 0.612±0.002 20.88±0.028 1.245±0.001 31.77±0.568 3.21±0.568F2 0.468±0.024 0.622±0.004 21.78±0.032 1.252±0.001 31.78±0.762 2.32±0.324F3 0.493±0.011 0.664±0.003 21.89±0.038 1.221±0.001 32.27±0.208 3.45±0.212F4 0.471±0.012 0.629±0.005 22.94±0.048 1.222±0.001 31.23±0.218 3.11±0.234F5 0.501±0.001 0.628±0.006 23.23±0.038 1.255±0.003 31.07±0.121 3.01±0.434F6 0.504±0.006 0.632±0.004 22.01±0.018 1.272±0.004 31.22±0.211 3.61±0.768F7 0.512±0.001 0.642±0.001 23.07±0.013 1.265±0.003 30.72±0.232 2.11±0.868F8 0.521±0.002 0.710±0.005 25.28±0.048 1.345±0.001 31.34±0.332 4.21±0.676F9 0.507±0.003 0.698±0.007 25.18±1.122 1.321±0.023 31.23±0.213 4.09±0.988F10 0.504±0.005 0.723±0.006 20.81±2.034 1.325±0.021 31.32±0.323 3.44±0.121F11 0.523±0.001 0.743±0.005 26.78±2.021 1.245±0.051 32.34±0.320 3.22±0.333F12 0.521±0.006 0.718±0.007 20.12±0.011 1.21±0.021 30.32±0.213 3.44±0.889

*Mean ± SD (n=6)



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Post compression study of a SR tablets

Batch Weight Hardness* Thickness* Friability* Diameter* Drug content*code variation**

F1 821±6.35 6.09±0.435 6.49±0.021 0.210±0.201 13.11±0.006 101.12±0.04F2 815±6.76 5.99±0.423 6.11±0.023 0.123±0.056 13.10±0.007 102.23±0.07F3 820±6.34 6.29±0.565 6.23±0.098 0.213±0.076 13.11±0.005 101.20±0.03F4 823±7.32 6.59±0.566 6.12±0.021 0.120±0.091 13.11±0.004 99.12±0.04F5 831±6.75 6.29±0.333 6.32±0.043 0.110±0.031 13.11±0.005 100.12±0.01F6 835±6.80 6.44±0.444 6.57±0.081 0.111±0.041 13.10±0.005 101.18±0.03F7 818±6.87 6.23±0.234 6.56±0.007 0.114±0.051 13.11±0.003 101.13±0.02F8 820±4.52 6.29±0.335 6.21±0.098 0.140±0.052 13.11±0.004 100.12±0.03F9 823±7.25 6.44±0.454 6.32±0.043 0.123±0.031 13.11±0.005 100.11±0.05F10 817±5.23 6.55±0.345 6.29±0.056 0.110±0.011 13.10±0.004 101.02±0.03F11 824±6.45 6.69±0.543 6.32±0.087 0.211±0.031 13.11±0.003 101.02±0.03F12 828±5.44 6.23±0.321 6.21±0.082 0.140±0.041 13.10±0.004 101.02±0.02

Table. No: 5 post compression study of SR tablets

*Mean ± SD (n=6),**Mean ± SD (n=20)

Iv-Vitro Dissolution study:

Table. No: 6. In-Vitro Dissolution profile SR tablets*

Time in hrs 1 3 6 9 12

F1 52.67±1.23 74.54±1.18 86.67±1.78 94.23±1.98 99.23±1.12F2 38.78±0.76 68.78±1.89 82.54±1.23 90.89±1.02 98.78±2.14F3 30.32±1.18 52.89±1.19 71.98±1.21 82.98±1.14 97.98±1.21F4 27.78±0.87 42.56±0.78 58.89±1.14 73.89±0.78 86.56±0.98F5 62.78±1.98 82.89±1.89 94.23±0.98 95.98±1.12 98.78±1.12F6 59.98±1.21 73.67±0.98 90.12±1.29 94.45±0.65 98.45±0.67F7 57.89±0.98 71.78±1.32 87.98±0.89 90.54±1.12 98.78±1.23F8 51.78±1.21 67.89±0.87 81.98±0.78 89.98±0.28 97.89±1.67F9 58.98±0.89 84.78±1.21 96.89±1.77 98.89±1.78 99.67±0.78F10 56.76±1.21 81.89±0.78 94.89±0.98 97.23±0.89 99.12±1.34F11 50.78±0.78 76.87±1.24 90.34±0.78 96.23±0.56 98.56±0.87F12 47.89±1.43 74.89±0.34 87.67±1.23 95.21±1.23 97.76±1.75

*Mean ± SD (n=6)

Fig. No: 15 In-Vitro Dissolution profile SR tablets



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Table.no: 7 pre compression study for IR formulation

Batch Bulk density* Tapped density* Compressibility Harner’s Ratio* Angle of Repose* Moisturecode g/cm3 g/cm3 index g/cm3 Content* %w/w

IR1 0.418±0.004 0.512±0.002 21.88±0.028 1.285±0.001 37.77±0.368 4.21±0.168IR2 0.416±0.024 0.522±0.003 20.78±0.032 1.292±0.013 38.78±0.462 3.32±0.124IR3 0.413±0.021 0.564±0.002 22.89±0.038 1.281±0.015 36.27±0.308 4.45±0.112

*Mean ± SD (n=6)

Post compression study of IR tablets

Table. No:8 post compression study of IR tablets

Batch Weight Hardness* Thickness* Friability* Diameter* Disintegrationcode variation** Time in Sec

IR1 70.023±0.35 2.09±0.435 2.49±0.021 0.110±0.201 5.61±0.006 30.00±0.04IR2 70.221±0.76 2.99±0.423 2.98±0.023 0.123±0.056 5.58±0.007 21.23±0.07IR3 70.341±0.34 3.29±0.565 2.83±0.098 0.113±0.076 5.87±0.005 13.58±0.03

*Mean ± SD (n=6), **Mean ± SD (n=20)

Table.no: 9 Assay and Content uniformity of the IR formulation

S. No Batch .No Pioglitazone GlibenclamideAssay* Uniformity of content** Assay* Uniformity of content**

1 IR1 100.89±0.589 101.89±0.809 100.78±1.089 99.97±0.5672 IR2 101.02±0.783 100.78±0.432 101.12±0.587 99.98±0.7893 IR3 101.02±0.893 101.65±0.765 101.16±0.903 99.56±1.765

*Mean ± SD (n=6),**Mean ± SD (n=10)

In – Vitro Dissolution release Profile and Optimization IR tablets

Table. No: 10. In-Vitro dissolution profile of IR tablets

Time in Minutes IR1 IR2 IR3Pioglitazone Glibenclamide Pioglitazone Glibenclamide Pioglitazone Glibenclamide

5 61.38±2.37 13.23±1.34 67.98±1.77 21.89±1.54 77.98±3.67 38.89±1.4510 83.75±1.56 38.89±1.56 85.87±1.78 52.45±1.20 94.87±2.76 76.89±1.4215 95.34±2.67 74.89±2.78 95.46±1.36 77.57±2.09 95.56±2.06 92.54±2.5420 94.78±2.87 87.44±1.79 95.63±2.44 94.44±1.67 95.83±3.04 99.78±2.6730 95.78±2.45 97.34±1.65 96.49±1.78 100.06±1.76 96.89±2.68 100.56±2.65

*Mean ± SD (n=6)

Fig. no: 16In-Vitro Dissolution profile of Pioglitazone IR1 - IR3

Fig. no: 17In-Vitro Dissolution profile of Glibenclamide IR1 - IR3



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FORMULATION AND EVALUATION OF INLAY TABLETS

Sustained Release mg/ tablet Immediate Release mg/ tabletLayer (F3) layer (IR3)

Metformin HCL 500 Glibenclamide 5.05HPMC K100M 200 Pioglitazone HCL 16.7PVP k30 40 Sodium Starch Glycolate 7MCCP Ph-102 50 Crosspovidone 3.5Crosspovidone 5 Sodium Lauryl Sulphate 2Aerosil 2.5 Crosspovidone 1Magnesium stearate 10 MCCP pH-102 33.25Talc 10 Talc 1Aerosil 2.5 Magnesium Stearate 0.5Total Weight 820 Total Weight 70

Evaluation of Inlay tablets

Parameters Results

Uniformity of Weight** 890.67±7.989Tablet Thickness* 6.987±0.0567Diameter* 13.098±0.012Hardness* 6.98±0.567Friability* 0.0678±0.065Dinintegration Time* 2.16±0.065

** Mean ± SD (n=20),*Mean ± SD (n=6)

Time in Hours % of swelling % of erosion

0 0 01 6.149±0.0242 2.089±0.0582 6.443±0.222 3.035±0.2643 8.750±0.113 3.265±0.0895 11.064±0.028 4.398±0.0497 12.643±0.043 4.483±0.0899 12.368±0.047 4.923±0.09812 11.689±0.087 4.989±0.169

Fig. no:18 Swelling Behavior of Inlay Tablet

Fig. no:19 Erosion Behavior of Inlay Tablet

The result showed in the table says that the SR tablet maintainedtheir integrity and gave increased swelling through the course ofstudy. Thus the extent of swelling increases with amount of swellablepolymer.

Assay and content uniformity of the Inlay tablet

Table. No: 13Assay and Drug content uniformity of the Inlay tablet

Inlay tablet % of Drug (Assay)* Content uniformity**

Metformin Hydrochloride 99.98±0.142 - Pioglitazone 101.42±0.576 100.765±0.245 Glibenclamide 100.245±0.564 100.657±0.675

*Mean ± SD (n=20),**Mean ± SD (n=10)

In-Vitro Dissolution Release profile of Inlay tablet

Time in Immediate Release Layer Sustained Release LayerMinutes Cumulative % Time Cumulative %

of Drug release in hours of Drug releasePioglitazone Glibenclamide Metformin Hydrochloride

5 46.98±1.87 46.23±1.34 1 28.14±0.8710 73.12±1.21 61.10±5.01 3 47.98±0.78615 94.23±1.98 80.23±0.87 6 69.89±0.87920 96.87±1.78 95.78±1.98 9 84.05±1.87930 98.89±0.23 98.78±1.89 12 98.98±0.809

*Mean ± SD (n=6)In-Vitro Kinetic Study of Inlay Tablet

Table. No: 11Formulation of Inlay tablets

Swelling and Erosion behavior of Inlay TabletsTable. No: 12 Swelling and Erosion behavior of Inlay Tablets

Table. No: 15 Data for various kinetic modelsTime % cum. Drug % cum drug Log % cum. Square root Log time Log % cum. Cube root of(hours) release remaining Drug of time Drug % drug

remaining release remaining

0 0 100 2 0 0 0 4.64161 28.14 71.88 1.8566 1 0 1.449 4.15783 47.98 51.19 1.709 1.732 0.477 1.688 3.71306 69.89 30.9 1.4899 2.449 0.778 1.839 3.13799 84.05 16.14 1.2079 3 0.954 1.923 2.527112 98.97 1.03 0.0128 3.464 1.079 1.995 1.009

For Metformin hydrochloride

Table. No: 14 In-Vitro Dissolution profile of SR and IR layer*



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Fig. no: 20 Zero order kinetics

Fig. no: 21First order kinetics

Fig. no: 22 Higuchi diffusion kinetics

Fig. no: 23 Hixson Crowell

Fig. no: 24Korsmeyer Pappas equation

The results showed that the formulation followed the Zero orderrelease kinetics. Drug release kinetics of this formulation correspondbest Higuchi’s model drug release mechanism as per n value ofKorsmeyer& Pappas model appeared to be a complex mechanism ofswelling, diffusion and erosion.

FOR PIOGLITAZONE & GLIBENCLAMIDE

Table. No: 16 data for various kinetic models

For Pioglitazone For Glibenclamide

Time % % Log % % Log (Min) Cumulative to be Cumulative Cumulative to be Cumulative

Drug released % Drug Drug released % DrugRelease Remaining Release Remaining

0 0 100 2.000 0 100 2.000 5 47.58 52.42 1.719 46.02 53.98 1.732 10 73.04 26.96 1.431 61.16 38.84 1.589 15 94.67 5.33 0.727 81.18 18.82 1.275 20 97.73 2.3 0.362 96.9 3.1 0.491 30 98.51 1.49 0.173 98.63 1.37 0.136

Fig. no: 25. First order kinetics for Pioglitazone

Fig. no: 26. First order kinetics for Glibenclamide



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Fig. no: 27 Zero order kinetics for Pioglitazone

Fig. no: 28 Zero order kinetics for Glibenclamide

From the above results obtained for Pioglitazone and Glibenclamidehas been observed that the order of release of the drug was followedthe First order kinetics.

Stability Study:The optimized Inlay tablets were subjected to stability studies andthe results were showed in the tables.

Table. No: 17 Stability Study at 40°C ± 2°C/75%RH± 5%RH

Parameters 1st Month 2nd Month 3rd Month 6th MonthRT 40°C RT 40°C RT 40°C RT 40°C

Uniformity of Weight** 890.55±1.56 890.45±1.23 890.45±1.56 890.52±1.23 890.45±1.56 890.53±1.23 890.44±1.56 890.55±1.23Thickness* 7.1±0.087 7.1±0.076 7.1±0.089 7.1±0.176 7.1±0.091 7.1±0.179 7.1±0.097 7.1±0.183Diameter* 13.04±0.023 13.04±0.013 13.04±0.013 13.05±0.08 13.04±0.011 13.04±0.05 13.04±0.011 13.05±0.021Hardness* 6.25±0.654 6.25±0.534 6.25±0.642 6.25±0.514 6.25±0.641 6.25±0.514 6.25±0.641 6.25±0.541D. Time* 2.34±0.432 2.34±0.321 2.34±0.262 2.34±0.352 2.34±0.352 2.24±0.352 2.34±0.352 2.34±0.352Friability* 0.12±0.034 0.12±0.044 0.12±0.064 0.12±0.274 0.12±0.074 0.12±0.284 0.12±0.074 0.12±0.989

**Mean ± SD (n=20), *Mean ± SD (n=6)

Table. No: 18 Assay and Dissolution profile of Inlay tablet at stability study 40°C ± 2°C/75%RH± 5%RH

Intervals in Months Drug % of Drug Content* % of Cum. Release*RT 40°C RT 40°C

1st Month Metformin HCL 101.34±0.32 101.64±0.76 98.21±0.98 99.02±0.78Pioglitazone 100.48±0.76 100.51±0.87 98.89±1.34 97.76±0.67Glibenclamide 99.7±0.78 100.32±0.78 100.76±0.98 100.23±0.76

2nd Month Metformin HCL 101.27±0.22 101.22±0.46 98.13±0.78 99.00±0.28Pioglitazone 100.25±0.73 100.32±0.67 98.49±0.34 97.36±0.37Glibenclamide 99.8±0.88 99.5±0.43 100.26±0.69 100.14±0.64

3rd Month Metformin HCL 101.21±0.21 101.21±0.42 98.11±0.65 98.45±0.21Pioglitazone 100.15±0.71 100.22±0.62 98.21±0.21 97.24±0.25Glibenclamide 99.6±0.68 99.4±0.41 100.12±0.42 99.78±0.43

6th Month Metformin HCL 101.01±0.11 101.10±0.22 98.01±0.23 98.12±0.01Pioglitazone 100.05±0.71 99.98±0.32 98.01±0.01 97.14±0.15Glibenclamide 99.2±0.38 99.2±0.24 99.89±0.42 99.43±0.43

* Mean ± SD (n=6)



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No significant changes were observed in the physical appearance,colour, hardness, drug content and dissolution studies of Inlay tabletof the optimized batch for both at room temperature (RT) and40°C ±2°C/75%RH± 5%RH.

SUMMARY AND CONCLUSIONThe present research endeavor is directed towards the developmentof once daily sustained release matrix tablet of metformin hydrochlo-ride (500mg) with inlay tablet of pioglitazone (15mg) glibenclamide(5mg) as immediate release.

Combination therapy concluded that Pioglitazone is effective in im-proving the glycemic control when added to a combination ofglibenclamide and metformin in type 2 DM. Matrix system was basedon swellable polymer were selected for sustained the drug release.

Different polymers Viz., HPMC, Xanthan Gum, Guar gum, to get thedesired release profile over a period for 12 hours. Different batches ofboth Immediate release(IR) and Sustained release (SR) were preparedby Direct compression and Wet granulation method respectively.

In the immediate release layer formulation, disintegration such assodium starch glycolate at three different concentration (5%, 7.5%and 10% w/w) with 5% concentration crosspovidone of tablet weightwere tried to get a desired release profile within 30 minutes.

All the formulations were evaluated for physical characteristics, dis-integration, In-Vitro dissolution study and stability. Following con-clusions have been made from the present study.

The possibility of Drug – Excipients interaction was investigated byFT-IR.

The physical characteristics of all blended formulations were satis-factory.

The prepared tablets evaluated for weight variation, hardness, thick-ness, friability and dinintegration time were found to be within theofficial limits.

The dinintrrgration studies showed that the immediate release formu-lation IR3 prepared by direct compression technique using SSG of10% w/w concentration was 14 seconds.

The in-vitro dissolution studies were performed for all the IR formula-tions. Formulation IR1 to IR3 released 95.53%, 96.45% and 96.65% ofpioglitazone and 100.01%, 96.72% and 100.78% of glibenclamide re-spectively at the end of 30 minutes with SSG concentration of 10%.So IR3 were selected for final formulation.

SR formulations F3 showed release profile were complies with USP at

40% concentration of HPMC-K100M with respect to drug comparedwith another 11 formulations.

Inlay tablet formulation were prepared using Optimum formulation ofsustained granules and immediate release granules. Initially metformingranules were filled in the die cavity over that immediate release tab-let was placed on it and then compressed finally to get a inlay tablet.The tablets assay, weight variation, hardness, thickness friability,disintegration time and in-vitro dissolution were found to be withinthe official limits. The dissolution data of the optimized batch wassubjected to study the in-vitro release kinetics.

The result showed that the IR layer of inlay tablet formulation fol-lowed the first order release kinetics and the drug release kinetics ofSR layer of Inlay tablet formulation correspond best to Higuchi’smodel and drug release mechanism as per n value of Korsmeyer&Peppas Model appeared to be a complex mechanism of swelling,diffusion and erosion with zero order release kinetics.

The triple combination of inlay tablet containing pioglitazone withglibenclamide in immediate disintegrating layer and metformin hydro-chloride in sustained release layer were successfully formulated andevaluated.

ACKNOWLEDGEMENTS:Authors are thankful to Prof (Dr.).B.Jaykar, Principal VinayakaMission’s College of Pharmacy, Salem, Tamil nadu and providing allthe facilities for this research project.

REFERENCES:1. Remington, The Science and pharmacy practice of pharmacy,

21st edition volume I & II, Page. no: 869-870.2. AnisulQuardir, Karl Kolter, A comparative study of current

Super disintegrents, pharmaceutical technology, October2006.

3. Aulton M.E. The science of dosage form design, interna-tional edition, second, Churchill Livingston (2006.

4. Brahmankar DM and Jaiswal SB. “Biopharmaceutics andPharmacokinetics”, VallabhPrakashan 1st Edition; 1995: 347-352.

5. Colombo PR, BettiniManima. Journal of Parma Science; 1991-1992: 8-86.

6. Clarke’s “Isolation and Identification of drugs”, 2nd edition,The pharmaceutical press, London, 1986; Page.No:838.

7. Regmington : The Science and practice of Pharmacy. 20th

Edition; 2000; Page. No: 903-929.8. Amidon, G. E.; Augsburger, L. L.; “Physical test methods

for powder flow characterizationof pharmaceutical materi-als :areviewofmethods”PharmacopeialForum 25,1999; Page.No:8298-8308

9. Swarbrick J, Boylan J.C., Encyclopedia of PharmaceuticalTechnology, Second Volume-1992; Page. No: 531-536.



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10. Banker G.S. Anderson N.R., “Tablets” chapter 11 in “Thetheory and practice of industrial pharmacy” edited BYLachman Edition, Varghese Publishing House, 1991; Page.No: 296-317.

11. Fonner “Characterization of Granulation” in “Pharmaceuti-cal dosage forms: Tablets”, Volume. No:2, edited by

Lieberman H.A., Lachman L., Marcel Dekker; Page.No: 240-249.

12. Carver,L.D.:ParticleSizeAnalysis,Industrial Research, Au-gust1971; Page.No:39–43.

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

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