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Journal of Pharmacy Research Vol.5 Issue 7.July 2012

Ajay Kumar Tiwari et al. / Journal of Pharmacy Research 2012,5(7),3506-3514

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Research ArticleISSN: 0974-6943

Available online throughhttp://jprsolutions.info

*Corresponding author.Ajay Kumar TiwariSinghania University,Pacheri Bari, District.Jhunjhunu, Rajasthan-333515,India

INTRODUCTIONFor decades an acute or chronic illness is being clinically treated throughdelivery of drugs to the patients in form of some pharmaceutical dosageforms like tablets, capsules, liquids, creams, pills, aerosols, injectable, andsuppositories. However, these conventional dosage forms have some draw-backs. Multiple daily dosing is inconvenient to the patient and can result inmissed doses, made up doses and patient incompliance with the therapeuticregimen. When conventional immediate release dosage forms are taken onschedule and more than once daily, there are sequential therapeutically bloodpeaks and valley associated with taking each dose. It should be emphasizedthat the plasma level of a drug should be maintained within the safe marginand effective range2.

For this proper and calculated doses of the drug need to be given at differenttime interval by conventional dosage form. To achieve and maintain theconcentration of administered drug within therapeutically effective range, itis often necessary to take drug dosage several times and this result in afluctuating drug level in plasma. A simple dosing scheme with a once- ortwice daily administration of the antihypertensive agent is known to increasepatient compliance For this reason, the pharmaceutical industry is inten-sively searching for longer-acting antihypertensive drugs, either by the de-velopment of novel agents with a longer elimination half-life, or by theimprovement of the dosage form of existing shorter-acting compounds, sothat plasma concentrations compatible with a blood-pressure-lowering ac-tivity are maintained during the whole day. The present research endeavorwas directed towards the development of a sustained release Floating drugtablet formulation containing diltiazem hydrochloride tablet taken once ratherthan two or three times a day1.

Formulation and optimization of effervescent floating tabletof diltiazem hydrochloride using response surface methodolgy

*Ajay Kumar Tiwari1, Nirav Rabadia2, Nirav Rabadia2,1Singhania University, Pacheri Bari, District. Jhunjhunu, rajasthan-333515

2Department of Pharmaceutics, School of Pharmaceutical Science, Jaipur National University, Jagatpura, Jaipur-302025

Received on:07-04-2012; Revised on: 12-05-2012; Accepted on:16-06-2012

ABSTRACTThe purpose of this research was to prepare a floating drug delivery system of Diltiazem Hydrochloride. Floating tablets of Diltiazem were developed toprolong gastric residence time, increase its bioavailability and patient compliance. Rapid gastro-intestinal transit could result in incomplete drug release fromthe drug delivery system above the absorption zone leading to diminished efficacy of the administered dose. The tablets were prepared by directcompression technique, using polymers such as HPMC K 100 M, Xanthan gum, Guar gum , alone or in combination and other standard excipients. Sodiumbicarbonate was incorporated as a gas generating agent and citric acid was incorporated as a release rate enhancer. The effect of Sodium bicarbonate, tablethardness and content of citric acid on drug release profile and floating properties were investigated. A 32 full factorial design was applied to systematicallyoptimize the drug release profile. The ratio of HPMC K100 M to Xanthan gum (X1) and amount of guar gum (X2) were selected as independent variables.The time required for 50 % (t50), percentage drug release at 1 hr (Q1), Hardness and Floating lag time were selected as dependent variables. The results offactorial design indicated that ratio of HPMC K100 M to Xanthan gum had dominant role on drug release from floating tablets. The linear regression analysisand model fitting showed that all these formulations followed Korsmeyer and Peppas model, which had a higher value of correlation coefficient (r).

Keywords: Diltiazem hydrochloride, factorial design, response surface methodology

The gastroretentive drug delivery system can be retained in the stomach andassists in improving the oral sustained delivery of drugs that have and ab-sorption window in a particular region of the GI tract. These systems help incontinuously releasing the drug before it reaches the absorption window,thus ensuring optimal bioavailability. Several approaches are currently usedto prolong gastric retention time. These include floating drug delivery sys-tems, swelling and expanding systems, polymeric bioadhesive systems, high–density systems and other delayed gastric-emptying devices. The principleof buoyant preparation offers a simple and practical approach to achieveincreased gastric residence time for dosage form and sustained drug release.The present investigation describes the formulation development of anintragastric floating drug delivery system of Diltiazem Hydrochloride.

MATERIALS AND METHODS

MaterialsDiltiazem hydrochloride was received as a gift sample from J.B Pharmaceu-ticals, Ankleshwar, India. Hydroxypropyl methylcellulose (HPMC K100M), Xanthan gum, Sodium bicarbonate, Citric acid, and Stearic acid werereceived as gift samples from Unique Pharmaceuticals Pvt Ltd, Ankleshwar,India. Talcum powder and magnesium stearate were gift samples from Vijayminerals Corporation Pvt. Ltd. All the other chemicals used were of analyti-cal reagent grade.

Preparation of standard curve of diltiazem hydrochloride:100 mg of Diltiazem Hydrochloride was accurately weighed and transferredto a 100ml volumetric flask containing 100 ml of 0.1 N HCl solution andshaked to dissolve. The solution resulted is ˜1000 µg/ml. Then 10 ml of thissolution is transferred to another volumetric flask to obtain solution of 100µg/ml served as stock. Then again 10 ml of this solution is transferred toanother volumetric flask to obtain solution of 10 µg/ml and the absorbancewas taken on double beam U.V. spectrophotometer using λmax at240nm.Similarly solution of 1,2,3,4……10 µg/ml was prepared and absor-



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bance was taken. The absorbance values were plotted against concentration(µg/ml) to obtain the standard calibration curve.

Preparation of 0.1 N HCl: Dilute 8.5 ml of concentrated HCl in 1000 ml ofdistilled water to get 0.1 N HCl.

Standard calibration curve of diltiazem hydrochloride:Standard calibration curve of Diltiazem Hydrochloride was determined byplotting absorbance V/s concentration at 240 nm. And it follows the Beer’slaw.

Y = 0.049X + 0.001

Graph 1: Standard curve for Diltiazem Hydrochloride in 0.1N HCl

Formulation of floating tablets:Diltiazem Hydrochloride was used with various grades of HPMC, XanthanGum and Guar Gum in varying concentration to formulate the floating tab-lets. Lactose was used as diluents in the preparation of the tablets. Sodiumbicarbonate was incorporated into the tablets to aid buoyancy of the tabletsdue to liberation of CO2 when tablets come in contact with acidified dissolu-tion medium. The level of the drug in all of the formulation was kept constantat 30% and tablet weight was adjusted so as to contain 90 mg of DiltiazemHydrochloride in each tablet. Different tablets formulations were preparedby direct compression technique. All the powders were passed through #80mesh sieve. Required quantity of drug and various polymers were mixedthoroughly. Talc (2% w/w) and magnesium stearate (2% w/w) were finallyadded as glident and lubricant respectively. The blend was directly com-pressed (8mm diameter punches) using tablet compression machine. Thetablet weight was adjusted to 276 mg and 25 tablets for each batch wereprepared.

EXPERIMENTAL DESIGNFactorial design is an experimental design technique, by which the factorinvolved and their relative importance can be assessed. In the present study,the formulations, which are designed based on 32 full factorial design contain-ing 2 factors evaluated at three levels and the experimental trials were per-formed at all possible combinations. Hardness, time to release 1st hour, T50%,floating lag time were taken as dependent variables and values were fitted todesign expert software version 8.01.

The two independent formulation variables evaluated include:Factor A: Different ratios of polymers in milligrams (HPMC: Xanthan Gum)(X1) (0:110, 55:55, 110:0)

Factor B: Amount of guar gum in milligrams (X2). (0, 5, 10)32 full factorial design was considered and according to the model totallyeleven experiments were conducted with three replicates of center point.

Table 1: Actual and coded values of the factors

MODEL VALUES ACTUALVALUES CODED VALUESFactor Low Mid High Low Mid High

level level level level level level

Factor A=HPMC:Xanthan gum X1s 0:110 55:55 110:0 -1 0 1Factor B=Guar gum X2 0 5 10 -1 0 1

The coded levels are calculated using the following formula:Level= X- the average of two level/half the difference of the level

Table 2: Runs designed in actual and coded valuesFormulation Type Coded values Actual values

Table 3: Formulations based on 32 full factorial designsINGREDIENTS D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11

DILTIAZEM 90 90 90 90 90 90 90 90 90 90 90HYDROCHLORIDEHPMC K100M 0 55 110 0 55 110 0 55 110 55 55XANTHANGUM 110 55 0 110 55 0 110 55 0 55 55GUARGUM 0 5 10 5 10 0 10 0 5 5 10LACTOSE 9 9 9 9 9 9 9 9 9 9 9STARCH 22 22 17 17 12 22 17 22 22 17 22SODIUM BICARBONATE 35 30 30 35 35 35 30 35 30 35 25MAGNESIUM STEARATE 4 4 4 4 4 4 4 4 4 4 4TALC 6 6 6 6 6 6 6 6 6 6 6TOTAL WEIGHT 276 276 276 276 276 276 276 276 276 276 276

PREFORMULATION STUDIES

Infrared Spectroscopic StudiesIdentification of the pure drug and polymer were performed using infraredspectroscopy. IR spectroscopy (using Perkin Elmer) by KBr pellet methodwas carried out on drug and polymer. They are compressed under 10 tonespressure in a hydraulic press to form a transparent pellet. The pellet wasscanned from 4000 to 400 cm-1 in a spectrophotometer and peaks obtainedwere identified.

Drug Excipient Compatibility StudiesAbout 90 mg of diltiazem hydrochloride with various excipients in 1:1 ratioin glass vials were taken and kept at various accelerated condition (300C/65%RH,400C/75%RH and 600C/80%RH) in stability chamber (OswaldStability Chamber, India) for one month in open and closed condition. Thesample were withdrawn on 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 14th, 21st and30th day and physical characteristics like color change, if any was recorded.Finally the mixtures with no color change were selected for formulation. Thefinal confirmation to check the excipient compatibility can be done by DSC,TLC or IR Spectroscopy respectively.

EVALUATION OF FLOATING TABLETS OF DILTIAZEM HYDRO-CHLORIDE

1) Pre-compression parameters: 4, 5

A) Determination of bulk density and tapped densityBoth bulk density (BD) and tapped density (TD) was determined. A quan-tity of 2 gm of powder blend from each formula, previously shaken to break

1 Fact -1 -1 0:110 02 Cent edge 0 -1 55:55 53 Fact 1 -1 110:0 104 Cent edge -1 0 0:110 55 Center 0 0 55:55 106 Cent edge 1 0 110:0 07 Fact -1 1 0:110 108 Cent edge 0 1 55:55 09 Fact 1 1 110:0 510 Center 0 0 55:55 511 Center 0 0 55:55 10

Factor A Factor B Factor A Factor B



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any agglomerates formed, was introduced in to 10 ml measuring cylinder.After that the initial volume was noted and the cylinder was allowed to fallunder its own weight on to a hard surface from the height of 1.5 cm at secondintervals. Tapping was continued until no further change in volume wasnoted. BD and TD were calculated using the following equations.

Bulk density = W/VoTapped density = W/Vf

Where,W = wt. of powder,Vf = final volumeV0 = initial volume,

B) Compressibility indexThe Compressibility index and Hausner’s ratio are measures of the propen-sity of a powder to be compressed. As such, they are measures of the relativeimportance of interparticulate interactions. In a free-flowing powder, suchinteractions are generally less significant, and the bulk and tapped densitieswill be closer in value. For poorer flowing materials, there are frequentlygreater interparticle interactions, and a greater difference between the bulkand tapped densities will be observed. These differences are reflected in theCompressibility Index and the Hausner’s Ratio. The compressibility indexand Hausner’s ratio may be calculated using measured values for bulk density(Db) and tapped density (Dt) as follows:

Compressibility index = Dt-Db/Dt X 100

Hausner’s ratio =Dt/DbWhere Db= Bulk density, Dt= Tapped density

Table 4. Effect of Carr’s index and Hausner’s ratio on flow property

Carr’s Flow Hauser’sIndex (%) Character Ratio

< 10 Excellent 1.00–1.1111–15 Good 1.12–1.1816–20 Fair 1.19–1.2521–25 Passable 1.26–1.3426–31 Poor 1.35–1.4532–37 Very poor 1.46–1.59>38 Very, very poor >1.60

C) Angle of reposeThe angle of repose of powder blend was determined by the funnel method.The accurately weight powder blend were taken in the funnel. The height ofthe funnel was adjusted in such a way the tip of the funnel just touched theapex of the powder blend. The powder blend was allowed to flow throughthe funnel freely on to the surface. The diameter of the powder cone wasmeasured and angle of repose was calculated. The flow characteristics aremeasured by angle of repose. Improper flow of powder is due to frictionalforces between the particles. These frictional forces are quantified by angleof repose. Angle of repose is defined as the maximum angle possible betweenthe surface of a pile of the powder and the horizontal plane.

Tanθ = h/r θ = tan-1 h/r

Where h = height of pile, r = radius of the base of the pile, θ = angle of repose

Table 5. Effect of angle of repose (θ) on flow property

Angle of Repose (θ) Type of Flow

< 20 Excellent20-30 Good30-34 Passable>35 Very poor

2). Post- compression parameters: 6, 7, 8

A). Tablet HardnessThe crushing strength Kg/cm2 of prepared tablets was determined for tabletsof each batch by using Monsanto tablet hardness tester. Hardness indicatesthe ability of a tablet to withstand mechanical shocks while handling.

B). Tablet ThicknessThe thickness of the tablets was determined by using vernier calipers. Fivetablets were used, and average values were calculated.

C). Friability Test.The friability of tablets was determined using Roche Friabilator. It is ex-pressed in percentage (%). Ten tablets were initially weighed (W0 initial) andtransferred into friabilator. The friabilator was operated at 25rpm for 4 min-utes or run up to 100 revolutions. The tablets were weighed again (W final).The % friability was then calculated by:

%F = (1-W/W0 ) x 100Where, W0 = weight of tablet before test, W = weight of tablet after test.

D). Weight variation testTo study weight variation twenty tablets of the formulation were weighedusing a Sartorius electronic balance and the test were performed according tothe official method. Twenty tablets were selected randomly from each batchand weighed individually to check for weight variation.

Table 6. IP standard for uniformity of weight

Sr.no Average weight % standardof tablet deviation

1 80 mg or <80 102 >80 to <250 mg 7.53 >250 or more 5

E). Uniformity of Content 9

Five randomly selected tablets were weighed and powdered. The powderequivalent to average weight of tablets was weighed and drug was transferredin a 250ml flask containing 100ml of 0.1N HCl (pH 1.2). The flask wasshaken on a flask shaker for 24 hours and was kept for 12 hours for thesedimentation of undissolved materials. The solution was filtered throughWhatman filter paper. 10ml of this filtrate was taken and appropriate dilu-tion was made. The samples were analyzed at 240 nm using UV visiblespectrophotometer. The drug content was determined from the standardcurve prepared at λ max 240 nm.

F). In Vitro Buoyancy Test 10,

The prepared tablets were subjected to in vitro buoyancy test by placingthem in 250 ml beaker containing 200ml 0.1 N HCl (pH 1.2, temp. 37±0.5oC).The time between introduction of the dosage form and its buoyancy in themedium and the floating durations of tablets was calculated for the determi-nation of lag time and total buoyancy time by visual observation. The Timetaken for dosage form to emerge on surface of medium called Floating LagTime (FLT) or Buoyancy Lag Time (BLT) and total duration of time bywhich dosage form remain buoyant is called Total Floating Time (TFT).

G). Swelling indexSwelling of tablet excipients particles involves the absorption of a liquidresulting in an increase in weight and volume. Liquid uptake by the particlemay be due to saturation of capillary spaces within the particles or hydrationof macromolecule. The liquid enters the particle through pores and bind to



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large molecule; breaking the hydrogen bond and resulting in the swelling ofparticle. The extent of swelling can be measured in terms of weight gain bythe tablet. Each tablet from all formulations are pre-weighed and allowed toequilibrate with 0.1N HCL (pH-1.2) for 5hr, was then removed, blottedusing tissue paper and weighed. The swelling index was then calculated usingthe formula:

Swelling indexWU = (Wt – W0) x 100 Where, Wt = Weight of tablet at time t, W0 = Initial weight of tablet

H). Effect of hardness on Buoyancy Lag Time:-Formulation D7 was selected to study the effect of hardness on buoyancylag time. The tablets of batch 7 were compressed at different compressionpressures to get the hardness of 5kg/cm2, 6kg/cm2, 7kg/cm2 ,8kg/cm2and9kg/cm2. The tablets were evaluated for Buoyancy Lag Time. The methodfollowed is same as that of Buoyancy test.

I). In vitro Dissolution Study 9, 10

The dissolution study was carried out using USP II (paddle method) appara-tus in 900 ml of 0.1 N HCl (pH 1.2) for 24 hours. The temperature of thedissolution medium was kept at 37± 0.5oC and the paddle was set at 50 rpm.5 ml of sample solution was withdrawn at specified interval of time andfiltered through Whatman filter paper. And the samples were replaced withfresh dissolution medium. The sample diluted to a suitable concentrationwith 0.1 N HCL. The absorbance of the withdrawn samples was measured atλmax 240 nm using a Shimadzu UV-1601 UV/VIS double beam spectropho-tometer.

KINETIC MODELING OF DRUG RELEASEThe dissolution profile of all the batches was fitted to zero order, first order,Higuchi, Korsmeyer and Peppas, equations to ascertain the kinetic modelingof drug release.11-15

STABILITY STUDIESStability studies were carried out for optimized formulations. The tabletswere packed in aluminum foil placed in airtight container and kept at 40C inrefrigerator, 400C /75% RH in stability chamber (Oswald, Mumbai) and600Cin incubator for 3 month. At the interval of 15 days, the tablets were with-drawn and evaluated for physical properties, In-vitro drug release.16

OPTIMIZATION DATA ANALYSIS AND VALIDATION OF OPTIMI-ZATION MODELVarious RSM computations for the current optimization study were per-formed employing Design Expert software (Version 8.0.1, Stat-Ease Inc, andMinneapolis, MN). Polynomial models including interaction and quadraticterms were generated for all the response variables using multiple linearregression analysis (MLRA) approach. The general form of the MLRAmodel is represented as Equation 1.

Y = β0+ β1? 1+β2? 2+β3X1X2+β4X12+β5X2

2+ β6X1X22+ β7X2

1X2 --- e.q. (1)

where, ß0is the intercept representing the arithmetic average of all quantita-tive outcomes of 11 runs; ß1to ß7are the coefficients computed from theobserved experimental values of Y; and X1and X2are the coded levels of theindependent variable(s). The terms X1X2and Xi2 (i = 1 to 2) represent theinteraction and quadratic terms, respectively. Statistical validity of the poly-nomials was established on the basis of ANOVA provision in the DesignExpert software. Subsequently, the feasibility and grid searches were per-formed to locate the composition of optimum formulations. Also, the 3-Dresponse surface graphs were constructed in MS-Excel environment usingthe output files generated by the Design Expert software.17, 18

RESULT AND DISCUSSION Preformulation studies A. IR spectroscopic studies

Graph 2: IR graph of pure Diltiazem hydrochloride

Graph 3: IR graph of sample drug Diltiazem Hydrochloride



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Table 7: Interpretation of studied FTIR peaks with theircharacteristics functional groups

Sr.no Peaks Characteristic functional group

1 1700 – 1650 -CO stretching2 1750 Esteric – CO stretching3 3350 – 3200 -NH stretching4 3000 – 2900 Aliphatic (CH3,CH2,CH ) stretching5 3100 – 3000 Aromatic CH stretching

B. Drug- Excipient compatibility studies

C. Evaluation of tablet

I. Pre-compression Parameters:a. Angle of Repose (θ): The angle of repose for the formulated blend wascarried out and the results were shown in table no.3. It concludes all theformulations blend was found to be in the range 190 to 270

b. Compressibility Index: Compressibility index was carried out, it foundbetween 12% to 18 % indicating the powder blend has the required flowproperty for compression.

Table 8: Pre-compression parameters of designed formulationsParameter D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11

Bulk densityg/cc 0.422 0.413 0.438 0.43 0.457 0.434 0.423 0.448 0.413 0.43 0.436Tapped densityg/cc 0.483 0.477 0.501 0.513 0.511 0.539 0.493 0.521 0.477 0.523 0.524Angle of repose 19.32 22.25 22.74 23.13 23.04 25.26 25.87 27.41 21.16 26.03 20.19Carr’s index 12.73 13.45 14.42 14.92 14.83 15.37 15.68 17.21 13.41 15.67 13.12Hausner’s ratio 1.14 1.15 1.14 1.19 1.11 1.24 1.16 1.16 1.15 1.21 1.13

II. Post-compression Parameters:a) Shape of the tablet: Microscopic examinations of tablets from D1 toD11 were found to be circular shape with no cracks.

b) Hardness test: The measured hardness of tablets of each batch rangedbetween 4 to 5kg/cm2 .This ensures good handling characteristics of all batches.

c) Friability Test: - The values of friability test were tabulated in Tableno.12. The % friability was less than 1% in all the formulations ensuring thatthe tablets were mechanically stable.d) Weight Variation Test: - The percentage weight variations for all formu-lations were tabulated. All the formulated (D1 to D11) tablets passed weightvariation test as the % weight variation was within the Pharmacopoeial limitsof ± 5% of the weight. The weights of all the tablets were found to be uniformwith low standard deviation values.

e) Drug Content Uniformity: - The percentage of drug content for D1 toD11 was found to be between 97.35% to 99.75% of Diltiazem Hydrochlo-ride, it complies with official specifications.

f) In vitro Buoyancy Study:- On immersion in 0.1N HCL solution pH (1.2)at 370C, the tablets floated, and remained buoyant without disintegration.Table no.9 shows the results of Buoyancy study from the results it can beconcluded that the entire batch containing HPMC K100M and Xanthan gumshowed good Buoyancy lag time (BLT) and Total floating time (TFT). For-mulation D1, D4, D6, D8, and D9 showed good BLT of 1.43, 1.75, 1.43,1.19, 1.49 min. respectively .The gas generated cannot be entrapped insidethe gelatinous layer, and it escapes leading to variation in BLT and TFT.

Table 9: Post compression parameters for designed formulations

A. IR Spectrum of Diltiazem hydrochlorideB. IR spectrum of Diltiazem hydrochloride and HPMC K100MC. IR spectrum of Diltiazem hydrochloride and Xanthan gumD. IR spectrum of optimized formulation F7

Parameter D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11

Hardness 4.33 4.0 4.66 4.33 4.33 4.89 5.0 4.8 4.93 4.33 4.93Friability 4.43 0.42 0.36 0.28 0.29 0.41 0.36 0.33 0.43 0.36 0.39Thickness 3.23 3.12 3.18 3.01 3.13 3.23 3.12 3.04 3.14 3.16 3.19Weight variation 276 275 275 276 275 276 276 276 276 276 276Uniformity ofdrug content 97.35 ± 1.25 98.93 ± 1.01 99.75 ± 0.36 98.12 ± 0.76 98.12 ± 1.30 97.35 ± 0.29 98.93 ± 0.87 99.75 ± 1.10 97.35 ± 0.43 98.93 ± 0.37 97.35 ± 0.21Floating lag time in min 1.43 2.01 2.05 1.75 1.98 1.43 1.87 1.19 1.49 2.34 2.21Invitro buoyancy test >24 >24 >24 >24 >24 >24 >24 >24 >24 >24 >24% cumulative drug release 99.36 in 18 hr 99.08 in 20 hr 99.46 in 22 hr 98.39 in 24 hr 98.46 in 22 hr 99.23 in 22 hr 99.82 in 24 hr 97.83 in 20 hr 99.60 in 24hr 99.31 in 22 hr 98.58 in 22 hr



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Graph 5: % CDR Vs time in hr for formulation D1 to D6

Graph 6: % CDR Vs time in hr for formulation D7 to D11

g) Swelling Study: - Swelling study was performed on all the batches (D1to D11) for 5 hr. From the results it was concluded that swelling increases asthe time passes because the polymer gradually absorb water due to hydro-philicity of polymer. The outermost hydrophilic polymer hydrates and swellsand a gel barrier are formed at the outer surface. As the gelatinous layerprogressively dissolves and/or is dispersed, the hydration swelling releaseprocess is continuous towards new exposed surfaces, thus maintaining theintegrity of the dosage form.

In the present study, the higher swelling index was found for tablets of batchD6 containingHPMC K100M having nominal viscosity of more than 1, 04,000 cps. Thus,the viscosity of the polymer had major influence on swelling process, matrixintegrity, as well as floating capability, hence from the above results it can beconcluded that linear relationship exists between swelling process and vis-cosity of polymer.

5.3.3. SWELLING STUDIES

Table 10: Observation table for swelling study

Formulations 0hr 1hr 2hr 3hr 4hr 5hr

D1 0 39% 55% 60% 72% 90%D2 0 44 59 74 84 95D3 0 42 60 71 83 102D4 0 40 62 77 85 99D5 0 38 49 61 68 85D6 0 46 60 74 86 104D7 0 41 55 69 82 96D8 0 44 56 70 78 93D9 0 38 53 68 85 99D10 0 43 57 73 82 95D11 0 49 61 72 82 93

h) Effect of hardness on Buoyancy Lag Time: The effect of hardness onbuoyancy lag time for batch F6 was studied. The results of floating lag timeof tablets with hardness of 4 kg/cm2 ,5kg/cm2, 6kg/cm2, 7kg/cm2 and 8 kg/cm2 were 85,120,158,220 and 310 sec. respectively. Buoyancy of the tabletwere influenced by both the swelling of the hydrocolloid particle on surfacewhen it contacts the gastric fluid which in turn results in an increase in thebulk volume and porosity buoyancy lag time will increases when the hard-ness increases, at high compressed, reduces of porosity of tablets occurs, thecompacted hydrocolloid particles on the surface of the tablet cannot hydraterapidly when the tablet reaches the gastric fluid and as a result, the capabilityof the tablet to float is significantly reduced.

Table 11: Hardness vs Floating lag time

Hardness Kg/cm2 Floating lag time in secs

4 855 1206 1587 2208 310

DATA ANALYSIS

Kinetic Modeling of Drug ReleaseThe curve fitting results of the release rate profile of the designed formula-tions gave an idea on the release rate and mechanism of drug release. Fitting ofthe release data to the Korsmeyer and Peppas equation and found that, thedrug release rate at 1st hour (%) ranges from 16.3- 20.65, the diffusioncoefficient (n) ranges from 0.516 to 0.652 and the T50% ranges from 5.11 to6.55 hours. These results indicated that, the release mechanism is by diffu-sion. The diffusion coefficient values indicate that the drug release followsnon-Fickian transport. The response dependent variables such as drug re-lease at 1st hr, time required for 50% of drug release, floating lag time, andhardness was considered. These responses were subjected to multiple re-gression analyses of variance and the following observations were made.

Table 12: Curve fitting data of release profile for designed formulations

Formulation Zero First Higuchi Korsmeyer-order order Peppas

D1 R2 0.910 0.884 0.986 0.986K(h-1) 5.205 -0.2233 25.47 1.271n 0.609

D2 R2 0.907 0.917 0.988 0.990K(h-1) 4.58 -0.1911 23.7 1.278n 0.578

D3 R2 0.912 0.896 0.985 0.985K(h-1) 4.213 -0.1865 23.06 1.254n 0.577

D4 R2 0.922 0.929 0.979 0.978K(h-1) 4.245 -0.1727 22.52 1.227n 0.585

D5 R2 0.930 0.887 0.988 0.985K(h-1) 3.716 -0.1727 21.78 1.267n 0.550

D6 R2 0.946 0.879 0.985 0.972K(h-1) 4.225 -0.1727 22.71 1.228n 0.578

D7 R2 0.930 0.830 0.986 0.985K(h-1) 3.951 -0.1911 22.5 1.182n 0.616

D8 R2 0.934 0.889 0.992 0.986K(h-1) 4.159 -0.1773 22.58 1.258n 0.562

D9 R2 0.915 0.879 0.978 0.983K(h-1) 3.837 -0.1773 22.03 1.240n 0.571

D10 R2 0.930 0.885 0.984 0.978K(h-1) 4.2220 -0.1175 22.88 1.237n 0.579

D11 R2 0.916 0.896 0.989 0.987K(h-1) 3.811 -0.1727 21.9 1.252n 0.516



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DESIGN SUMMARY AND RESPONSESTable 13: Design summary and responses

Formulation Factor Factor ResponseA B Hardness Release at T50% Floating lag

Kg/cm2 1st hr in % in hrs time in min

D1 -1 -1 4.33 19.05 5.11 1.43D2 0 0 4.0 19.18 5.45 2.01D3 1 1 4.66 19.47 6.09 2.05D4 -1 0 4.33 18.96 6.44 1.75D5 0 1 4.33 20.09 6.24 1.98D6 1 -1 4.89 20.16 6.65 1.43D7 -1 1 5.0 16.93 6.56 1.87D8 0 -1 4.8 20.65 6.25 1.19D9 1 0 4.93 19.32 6.23 1.49D10 0 0 4.3 20.06 6.48 2.34D11 0 1 4.93 19.34 6.21 2.1

RSM Optimization ResultsMathematical Modeling Mathematical relationships generated using MLRAfor the studied response variables are expressed as Equations 2 to 5 and aswell as ANOVA statistic is mentioned below.

RESULTS OF STATISTICAL ANALYSISResponse: Hardness

Table 14: ANOVA for Response Surface Quadratic Model

Source Sum of square DF Mean square F value Prob> F

Model 0.74 5 0.15 2.05 0.2242A 0.11 1 0.11 1.55 0.2688B 3.651E-003 1 3.651E-003 0.050 0.8313Residual 0.36 5 0.072 —— ——-Lack of fit 0.32 3 0.11 4.65 0.183Pure error 0.045 2 0.023 ——- ———Cor Total 1.11 10 ————— ——- ———-

Statistically significant at a < 0.05Polynomial equation obtained for response Hardness: = 4.23+0.14*A -0.023*B

Response: Release at 1st hour

Table 15: ANOVA for Response Surface Quadratic Model


Model 7.61 5 1.52 3.96 0.0785A 2.68 1 2.68 6.98 0.0459B 2.28 1 2.28 5.94 0.0588Residual 1.92 5 0.38 ——- ——-Lack of fit 1.25 3 0.42 1.25 0.4736Pure error 0.67 2 0.33 ——— ————Cor Total 9.53 10 ——— ———- ————

Statistically significant at a < 0.05Polynomial equation obtained for response Release at 1st hour: = 19.88+0.67*A-0.58*B

Response: T50% in hours

Table 16: ANOVA for Response Surface 2FI Model


Model 1.26 3 0.42 3.08 0.0997A 0.12 1 0.12 0.90 0.3733B 0.13 1 0.13 0.93 0.3677AB 1.01 1 1.01 7.41 .0297Residual 0.95 7 0.14 —- ———Lack of fit 0.42 5 0.085 0.32 0.8689Pure error 0.53 2 0.27 —— ———-Cor Total 2.21 10 ——- ———-

Response: floating lag time in minute

Table 17: ANOVA for Response Linear Model

Statistically significant at a < 0.05Polynomial equation obtained for response T 50% in hour:= 6.14+0.14*A+0.14*B


Model 0.68 2 0.34 4.62 0.0464A 1.067E-003 1 1.067E-003 0.015 0.9071B 0.68 1 0.68 9.22 0.0162Residual 0.59 8 0.074 ——- ———-Lack of fit 0.53 6 0.088 0.2.85 2.85Pure error 0.062 2 0.031 ——- ————Cor Total 1.27 10 ———- ——- ————

Statistically significant at a < 0.05Polynomial equation obtained for response Floating lag time: = 1.76-0.013*A+0.31*B

Design-Expert® SoftwareFactor Coding: Actualhardness

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Graph 7: Response surface plot for hardness

Design-Expert® SoftwareFactor Coding: Actualtime to release 50%

Design points above predicted valueDesign points below predicted value6.65

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Graph 8: Response surface plot for release at 1st hour

Design-Expert® SoftwareFactor Coding: Actualrelease at 1 hour


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Graph 9: Response surface plot for time to release 50% drug



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Design-Expert® SoftwareFactor Coding: Actualfloating lag time


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Graph 10: Response surface plot for floating lag time in min

Effect of formulation variables on hardness of the tabletIn this case model term for hardness of the tablet was not found to besignificant with an F value 0.2242, indicating adequate fitting of the surfacequadratic model. Both the factors are not significantly effective on thehardness of the tablet.

Effect of formulation variables on release at 1st hourThe model term for Diltiazem HCl release at 1st hr was found to be signifi-cant with a probability value of 0.0459, indicates the adequate fitting tosurface quadratic model. In this model, factor A, was found to be significant.As the ratio of polymers (X1) increased, the amount of drug release at 1st hrfound to be increased. Such a behavior of increase in the drug release at 1st hrmay be attributed due to the formation of gel layer with low viscosity ofpolymer matrix of HPMC alone, which in turn increases the influx of waterin to gel matrix leading to increased drug diffusion. Whereas in this modelfactor B was found to be significant, the concentration of guargum may alsocontribute to change in release at 1st hr.

Effect of formulation variables on time required for 50% of drug release.The model term for T50% was found to be highly significant with an F valueof 0.0297 indicating the adequate fitting of the surface 2 factor models. Boththe factor when used in combination found to increase or decrease in T50%depending upon combination used for the formulation.

Effect of formulation variables on floating lag timeThe model term for floating lag time was found to be very significant with theF value of 0.0297, indicating adequate fitting of the 2 factor model. Bothfactors AB found to be significant indicating that different combination ofpolymer may result in increase and decrease of floating lag time.

Validation of RSM ResultsFor checkpoint formulations, the results of the physical evaluation and tab-let assay were found to be within limits. Table 4 lists the compositions of thecheckpoints, their predicted and experimental values of all the responsevariables. Upon validation, the optimum formulation exhibited percentageerror for various response variables, varying between -0.% and 0.601% to1%. Thus, the low magnitudes of error as well as the significant values in thecurrent study indicate a high prognostic ability of RSM.Table 18: comparison chart of predicted and actual values for optimizedFormulation

Formulations Hardness Release at 1 hr T50% in hr Floating lagtime in min

Optimized Actual Predicted Actual Predicted Actual Predicted Actual Predictedformulation 4.96 4.99 20.09 20.15 6.38 6.55 1.56 1.43

CONCLUSIONThe effervescent-based floating drug delivery is a promising approach toachieve in vitro buoyancy by using gel-forming polymer HPMC K100M,Xanthan gum and gas-generating agent sodium bicarbonate. Combination ofHPMC K100M and Xanthan gum has resulted in minimal variation in drugrelease. A systematic study using a 32full-factorial design revealed that byselecting a suitable composition of HPMC K100M and Xanthan Gum, thedesired dissolution profile could be achieved. The optimized formulationgives the best result in terms of the required lag time (1.53 minutes) andfloating duration of 24 hours, and drug release was in accordance with theUSP dissolution criteria for extended release tablet for DTZ and matchedwith marketed formulation. Regulated drug release in zero-order mannerattained in the current study indicates that the hydrophilic matrix tablets ofDiltiazem Hydrochloride, prepared using HPMC K100M and Xanthan gum,can successfully be employed as a once-a-day oral controlled release drugdelivery system. However, appropriate balancing between various levels ofthe 2 polymers is imperative to acquire proper controlled release. Highdegree of prognosis obtained using RSM corroborates that a 2-factor CCD isquite efficient in optimizing drug delivery systems that exhibit non-linearityin response(s).

ACKNOWLEDGMENTSThe authors are thankful to J.B. Pharmaceuticals, Ankleshwar for providingthe gift sample of Diltiazem HCl and to Colorcon Asia Pvt Ltd (Goa, India)for providing the gift sample of HPMC K100M and Hindustan gum Pvt ltdfor providing Xanthan gum.

REFERENCES:1. Gennaro AR (Ed.) Remington, The Science and Practice of

Pharmacy, 19th Edition, Vol. II, 1995: 1662.2. Krishnaiah YSR and Patross, Pharma Times, Feb. 2001; 33: 16-18.3. Bahskaran S and Remiz M. Novel approach to zero order drug

delivery via hydrogel for diltiazem hydrochloride. Indian J. Pharm.Sci., 2002; 64(4): 357-361.

4. Marshall K, In; Lachman L, Liebermann H.A, The Theory andpractice of industrial pharmacy, 3rd edn, Varghese publishing house,Mumbai, 1987, 66-69.

5. Lindberg N, Palsson M, Pihl A, Freeman R, Enstad G, Flow abilitymeasurements of pharmaceutical powder mixtures with poor flowusing five different techniques. Drug.Dev. Ind. Pharm, 2004, 30(7),785-79.

6. Indian Pharmacopoeia (IP), Vol. II, Published by the Controller ofPublications Delhi, pp. 470

7. United States Pharmacopoeia 24, NF, 1999. ,United States Phar-macopoeia Convention Rockville.MD Asian edition.2000:-325

8. Lachman Leon, Liberman H.A. and Kanig J.L. “The Theory andPractice of Industrial Pharmacy”(20th Ed.). vol. I, Mack Publish-ing Company, Easton,PA,(2000),986-987

9. Desai S, Bolton S. A floating controlled release system: In-vitro –In-vivo evaluation. Pharm. Res. 1993; 10: 1321-1325.

10. Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mecha-nism of solute release from porous hydrophilic polymers. Int. J.Pharm. 1983; 15: 25-

11. Peppas NA. Analysis of Fickian and non-Fickian drug releasefrom polymers Pharm. Acta Helv. 1985; 60: 110-111.

12. Higuchi, W. I., Diffusional models useful in biopharmaceutics drugrelease rate processes. J. Pharm. Sci., 1967, 56: 315-324.

13. Lakshmi, P.K. Dissolution testing is widely used in the pharma-ceutical industry for optimization of formulation and quality con-trol of different dosage forms, Pharma info.net 2010

14. Siepmann, J. and Peppas, N.A. Modeling of drug release fromdelivery system based on hydroxypropyl methylcellulose(HPMC). Adv. Drug Deliv. Rev. 48, 2001, 139-157.



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15. Costa P.et.al, Modelling and comparison of dissolution profiles,European Journal of Pharmaceutical Sciences, 13, 2001, pp 123-133.

16. Nur AO, Zhang JS. Captopril floating and/or bioadhesive tablets:design and release kinetics. Drug Dev Ind Pharm. 2000 .26:965Y969.

17. Singh B, Ahuja N. Response surface optimization of drug delivery

system. In: Jain NK, ed. Progress in Controlled and Novel DrugDelivery Systems. New Delhi, India: CBS Publishers and Dis-tributors; 2004.

18. Singh B, Ahuja N. Development of controlled-release buccoadhesivehydrophilic matrices of diltiazem hydrochloride: optimization ofbioadhesion, dissolution, and diffusion parameters. Drug Dev IndPharm. 2002; 28:431Y442.

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

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