Formulation Development and Evaluation of Carbamazepine Fast Dissolving Tablets

Journal of Pharmacy Research Vol.10 Issue 5 May 2016

Raghavendra Kumar Gunda et al. / Journal of Pharmacy Research 2016,10(5),216-225

216-225

Research ArticleISSN: 0974-6943

Available online throughhttp://jprsolutions.info

*Corresponding author.Mr. Raghavendra Kumar Gunda M.PharmAssistant Professor,Department of Pharmaceutics,Narasaraopeta Institute of Pharmaceutical Sciences,Narasaraopet, Guntur(D.t), A.P. India-522601.

Formulation Development and Evaluation of Carbamazepine Fast Dissolving Tablets

Raghavendra Kumar Gunda*1, J. N. Suresh Kumar1, V. Satyanarayana2, Swathi Batta3, Ch . Meher Harika1

1Department of Pharmaceutics, Narasaraopeta Institute of Pharmaceutical Sciences, Narasaraopet, Guntur (Dt), Andhra Pradesh-522601, India.

2Department of Pharmacy Practice, Narasaraopeta Institute of Pharmaceutical Sciences,Narasaraopet, Guntur (Dt), Andhra Pradesh-522601, India.

3Department of Pharmaceutics, Priyadarshni Institute of Pharmaceutical Education and Research,Guntur , Andhra Pradesh-522017, India.

Received on:14-02-2016; Revised on: 20-03-2016; Accepted on: 29-04-2016

ABSTRACTBackground: The main objective of present research work is to formulate the Carbamazepine Fast Dissoving tablets. Carbamazepine, anantiepileptic, belongs to BCS Class-II and used to control some types of seizures in the treatment of epilepsy and Neuropathic Pain byblocking use-dependent sodium channels. Methods: The Fast Dissoving tablets of Carbamazepine were prepared employing differentconcentrations of Crospovidone and Croscarmellose sodium in different combinations as a Sperdisintegrants by Direct Compression tech-nique using 32 factorial design. The concentration of Crospovidone and Croscarmellose sodium was selected as independent variables, X1

and X2 respectively whereas, wetting time, Disintegration time, t50% ,t90%were selected as dependent variables. Results and Discussion:Totally nine formulations were designed and are evaluated for hardness, friability, thickness, Assay, Wetting time, Disintegration time, In-vitro drug release. From the Results concluded that all the formulation were found to be with in the Pharmacopoeial limits and the In-vitrodissolution profiles of all formulations were fitted in to different Kinetic models, the statistical parameters like intercept (a), slope (b) &regression coefficient (r) were calculated. Polynomial equations were developed for Wetting time, Disintegration time, t50%, t90%. Validity ofdeveloped polynomial equations were verified by designing 2 check point formulations (C1, C2). According to SUPAC guidelines theformulation (F5) containing combination of 9.375% Crospovidone and 9.375% Croscarmellose, is the most similar formulation (similarity factorf2=82.675, dissimilarity factor f1= 2.049 & No significant difference, t= 0.041) to marketed product (TEGRETOL-100). Conclusion: Theselected formulation (F5) follows First order, Higuchi’s kinetics, mechanism of drug release was found to be Non-Fickian Diffusion (n= 0.665).

KEYWORDS: Carbamazepine, 32Factorial Design, Crospovidone , croscarmellose Sodium, Wetting Time, Disintegration Time.

INTRODUCTIONDifficulty in swallowing (Dysphasia) is a common problem of all agegroups, especially elderly and pediatrics, because of physiologicalchanges associated with these groups of patients. Researchersthroughout the world are focusing intensively on the methods for thedevelopment of new drug delivery systems to enhance patient’s com-pliance. Tablets are the most popular oral solidformulations availablein the market and are preferred by patients and physicians alike. Re-cently fast dissolving formulation is popular as Novel Drug DeliverySystems because they are easy to administer and lead to PatientCompliance.

Fast dissolving tablets become an emerging trend in the Pharmaceu-

tical industry. Fast dissolving tablets are ideal for all types of people,including for people who have swallowing difficulties, pediatric, geri-atric, and bedridden patients. It is also for active patients who arebusy, travelling and may not have access to water. Fast dissolvingtablets are also known as orodispersible tablets, mouth-dissolvingtablets, orally disintegrating tablets, melt-in mouth tablets, rapimelts,porous tablets, quick dissolving etc. Many drugs have the potentialsto be made into orodispersible tablets. They vary from analgesics toneuroleptics and anti-psychotic drugs. However only a small per-centage of them are researched on and some have been manufacturedand marketed.

Fast-dissolving drug-delivery systems were initially developed in thelate 1970s as an alternative to tablets, capsules, and syrups for pedi-atric and geriatric patients who experiences difficulties in swallowingtraditional oral solid-dosage forms1. The speed of solubility of drugaffects the rate of absorption of the drug. The faster the drug dissolveinto solution, quicker the absorption and onset of clinical effect. They



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should readily dissolve or disintegrate in the saliva generally within<60 seconds. Some drugs are absorbed from the mouth, pharynx andesophagus as the saliva passes down into the stomach. The signifi-cance of orodispersible dosage forms are progressively being recog-nized in both, industry and academics2,3. The small volume of saliva isusually sufficient to result in tablet disintegration in the oral cavity.The medication can then be absorbed partially or entirely into thesystemic circulation from blood vessels in the sublingualmucosa, orit can be swallowed as a solution to be absorbed from the gastrointes-tinal tract. Thesublingual route usually produces a faster onset ofaction than orally ingested tablets and theportion absorbed throughthe sublingual blood vessels bypasses the hepatic first-passmetabolicprocesses4. The performance of ODT depends on the tech-nology used in their manufacture. The orally disintegrating propertyof the tablet is attributable to a quick intake of water into the tabletmatrix, which creates porous structures and resultin rapid disintegra-tion. Hence the basic approaches to develop ODT include maximizingthe porous structure of the tablet matrix, incorporating the appropri-ate disintegrating agent and using highly water soluble excipients inthe formulation. Orally disintegratingtablets are formulated by utiliz-ing several processes, which differ in their methodologies and theODTsformed vary in various properties such as, mechanical strengthof tablet, taste and mouth feel, swallowability, drug dissolution insaliva, bioavailability and stability. Various processes employedinformulating ODTs include Freeze-Drying or Lyophilization, cottoncandy process, molding, spray drying,mass extrusion and compac-tion (wet granulation, dry granulation, direct compression)5.

In the present study the direct compression method was adopted tomanufacture the ODT tablets, since it is very simple and do not re-quire any sophisticated equipment’s. The direct compression repre-sents the simplest and most cost effective tablet manufacturing tech-nique.

Criteria for Fast Disintegrating Drug Delivery System6

v Not require water to swallow, but it should dissolve ordisintegrate in the mouth in matter of seconds.

v Be harder and less friable.v Be compatible with taste masking.v Be portable without fragility concern.v Have a pleasant mouth feel.v Leave minimum or no residue in the mouth after oral admin-

istration.v Exhibit low sensitive to environmental condition as tem-

perature and humidity.v Allow the manufacture of the tablet using conventional pro-

cessing and packaging equipment’s at low cost.

Criteria for excipient used in the formulation of FDTs7

§ It must be able to disintegrate quickly.§ Their individual properties should not affect the FDTs.§ It should not have any interactions with drug and other

excipients.§ It should not interfere in the efficacy and organoleptic prop-

erties of the product.§ When the final integrity and stability of the product.§ The melting points of excipients used will be in the range of

30-350C.

The binders may be in liquid, semi liquid, solid or Polymeric mixtures.(Ex: Polyethylene glycol, coca butter, hydrogenated vegetable oils)ODT by direct compression technique is a simple approach of drugdelivery systems that proved to be rational in the pharmaceuticalarena for its ease, compliance, faster production, avoid hydrolytic oroxidative reactions occurred during processing of dosage forms.

Drug Profile and Rationality For Experimental Design:Carbamazepine, a dibenzapine derivative with structure resemblingthe tricyclic antidepressants, is used to control some types of sei-zures in the treatment of epilepsy. One of the major problems with thisdrug is its very low solubility in biological fluids and its biologicalhalf-life between 18 to 65 h that results into poor bioavailability afteroral administration8-9. It shows erratic dissolution profile in gastricand intestinal fluid due to its poor water solubility. The peak plasmaconcentration (C max) and the time taken to reach C max (t max) de-pend upon extent and rate of dissolution of drug respectively. Therate of dissolution can be increased by increasing the surface areaof available drug by various methods (micronization, complexationand solid dispersion)10. The dissolution of a drug can also beinfluenced by disintegration time of the tablets. Faster disintegra-tion of tablets delivers a fine suspension of drug particlesresulting in a higher surface area and faster dissolution.Thebioavailability of the extended-release tablet is 89%, compared to thesuspension. Plasma levels of carbamazepine are variable. The time topeak concentration for the different formulations are as follows: Sus-pension = 1.5 hours; Conventional tablets = 4-5 hours; Extended-release tablets = 3-12 hours. Hence the drug is selected for formulat-ing Fast Dissolving Tablets by Direct compression method.

It is an important issue is to design an optimized formulation with anappropriate dissolution rate in a short time period and minimum trials.Many statistical experimental designs have been recognized asuseful techniques to optimize the process variables. For this pur-pose, response surface methodology (RSM) utilizing a polynomial



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Carbamazepine Fast Dissolving Tablets. The time required for 50%(t50%), 90% (t90%) drug dissolution, Disintegration Time and WettingTime were selected as dependent variables. Significance terms werechosen at 95% confidence interval (p<0.05) for Final Equations. Poly-nomial equations were developed for t50%, t90%, Disintegration Timeand Wetting Time (step-wise backward Linear Regression Analysis).

The three levels of factor X1 (Crospovidone) at a concentration of6.25%, 9.375%, 12.5%.three levels of factor X2 (Croscarmellose) at aconcentration of 6.25%, 9.375%, 12.5%. (% with respect to averageweight of Tablet, i.e200 mg) was taken as the rationale for the designof the Carbamazepine Fast Dissolving tablet formulation. Totally nineCarbamazepine Fast Dissolvingtablet formulations were preparedemploying selected combinations of the two factors i.e X1, X2 as per

equation has been widely used. Different types of RSM designs in-clude 3-level factorial design, central composite design (CCD), Box-Behnken design and D-optimal design. Response surface methodol-ogy (RSM) is used when only a few significant factors are involved inexperimental optimization. The technique requires less experimenta-tion and time, thus proving to be far more effective and cost-effectivethan the conventional methods of formulating sustained release dos-age forms11-14.

Hence an attempt is made in this research work to formulate FastDissolving Tablets of Carbamazepine using Crospovidone andCroscarmellose sodium . Instead of normal and trial method, a stan-dard statistical tool design of experiments is employed to study theeffect of formulation variables on the release properties. Large scaleproduction needs more simplicity in the formulation with economicand cheapest dosage form. The Fast Dissolving tablets formulationby direct compression method is most acceptable in large scale pro-duction.

Formulation Development of Carbamazepine Fast DissolvingTablets:The factorial design is a technique that allows identification of fac-tors involved in a process and assesses their relative importance. Inaddition, any interaction between factors chosen can be identified.Construction of a factorial design involves the selection of param-eters and the choice of responses15.

A selected three level, two factor experimental design (32 factorialdesign) describe the proportion in which the independent variablesCrospovidone and Croscarmellose were used in formulation of

MATERIALS AND METHODSMaterials used in this study were obtained from the different sources.Carbamazepinewas a gift sample from Dr.Reddy’s Laboratories,Hyderabad, India. Crospovidone, Croscarmellose, Di Calcium Phos-phate, were procured from LobaChemiePvt.Ltd, Mumbai. Other ex-cipients such as Magnesium Stearate and talc were procured fromS.D. Fine Chem. Ltd., Mumbai.

A 32 full factorial design was employed to systematically study thedrug release profile . A 32 full factorial design was employed to inves-

tigate the effect of two independent variables (factors), i.e the amountsof Crospovidone and Croscarmellose on the dependent variables,i.e. Disintegration time, Wetting Time, t50%, t90%, ( Time taken to re-

lease 50%, 90% respectively)

Experimental Design:Experimental design utilized in present investigation for the optimiza-tion of Superdisintegrant concentration such as, concentration ofCrospovidone was taken as X1 and concentration of Croscarmellosesodium was taken as X2. Experimental design was given in the Table1. Three levels for the Concentration of Crospovidone were selectedand coded as -1= 6.25%, 0=9.375%, +1=12.5%. Three levels for theConcentration of Croscarmellose sodium were selected and coded as-1= 6.25%, 0=9.375%, +1=12.5%. Formulae for all the experimentalbatches were given in Table 216.

Preparation of Carbamazepine Fast Dissolving Tablets:Carbamazepine Tablets were prepared by direct compression method.The composition of each tablet is shown in Table No 2 . The drug,diluents, superdisitegrants were passed through sieve #40. All theabove ingredients were properly mixed together (ina poly-bag). Talcand Magnesium stearate were passed through mesh #80, mixed andblended with initial mixture in a poly-bag. The powder blend wascompressed into tablets on a 8 station rotary punch tableting ma-chine (minipress) using 8 mm circular punches and same hardnesswas used for the required number tablets. Compressed tablets wereexamined as per official standards and unofficial tests. Tablets werepackaged in well closed light resistance and moisture proof contain-ers.

32 Factorial and evaluated to find out the significance of combined

effects of X1, X2to select the best combination and the concentrationrequired to achieve the desired Fast release/ Dissolution of drug (by

providing large Surface area and Improved Solubility) from the dos-

age form.



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Formulation Code X1 X2

F1 1 1F2 1 0F3 1 -1F4 0 1F5 0 0F6 0 -1F7 -1 1F8 -1 0F9 -1 -1C1 -0.5 -0.5C2 +0.5 +0.5

Table 1: Experimental Design Layout

Table 2: Formulae for the Preparation of Carbamazepine FastDissolving Tablets as Per Experimental DesignName of Ingredients Quantity of Ingredients per each Tablet (mg)

F1 F2 F3 F4 F5 F6 F7 F8 F9

Carbamazepine 100 100 100 100 100 100 100 100 100Di Calcium Phosphate 46 52.25 58.5 52.25 58.5 64.75 58.5 64.75 71Crospovidone 25 25 25 18.75 18.75 18.75 12.5 12.5 12.5Croscarmellose sodium 25 18.75 12.5 25 18.75 12.5 25 18.75 12.5Magnesium Stearate 2 2 2 2 2 2 2 2 2Talc 2 2 2 2 2 2 2 2 2Total Weight 200 200 200 200 200 200 200 200 200

Evaluation of carbamazepine fast dissolving tablets:

Hardness 17

The hardness of the tablets was tested by diametric compressionusing a Monsanto Hardness Tester. A tablet hardness of about 2-4Kg/cm2 is considered adequate for mechanical stability.

Friability17

The friability of the tablets was measured in a Roche friabilator (Camp-bell Electronics, Mumbai). 20 Tablets were taken, Weighed and Initialweight was noted (W0)arededusted in a drum for a fixed time (100revolutions, in a Roche Friabilator) and weighed (W) again. Percent-age friability was calculated from the loss in weight as given in equa-tion as below. The weight loss should not be more than 1 %.

Friability (%) = [(Initial weight- Final weight) / (Initial weight)] x 100

Content Uniformity17

In this test, 20 tablets were randomly selected and the percent drugcontent was determined, the tablets contained not less than 85% ornot more than 115% (100±15%)of the labeled drug content can beconsidered as the test was passed.

Assay 18

Drug content was determined by weighing randomly selected

tablets, pulverizing to a fine powder. The powder equivalent to 10 mgCarbamazepine was weighed and dissolved in 10 ml of methanol involumetric flask using magnetic stirrer, the volume was adjusted to100 ml with Phosphate buffer pH 6.8and the solution was filtered. Analiquot of 1.0 ml of solution were diluted to 10 ml Phosphate buffer pH6.8 in separate volumetric flask. The drug content in was determinedspectrophotometrically at 285 nm.

Thickness17

Thickness of the all tablet formulations were measured using verniercalipers by placing tablet between two arms of the vernier calipers.

Wetting time19,20

To measure Wetting time of the Tablet , a piece of Tissue paper foldedtwice was placed in a small petri dish (Internal Diameter is= 6.5 cm)containing 5 ml of Distilled water. A Tablet placed on the paper, andthe time for complete wetting of the tablet was measured in seconds.

In-vitro Dissolution Study 18

The In-vitro dissolution study for the Carbamazepine Fast Dissolv-ing tablets were carried out in USP XXIII type-II dissolution testapparatus (Paddle type) using 900 ml of Phosphate buffer pH 6.8 asdissolution medium at 50 rpm and temperature 37±0.5°C. At predeter-mined time intervals, 5 ml of the samples were withdrawn by means ofa syringe fitted with a pre-filter, the volume withdrawn at each intervalwas replaced with same quantity of fresh dissolution medium. Theresultant samples were analyzed for the presence of the drug releaseby measuring the absorbance at 285 nm using UV Visible spectropho-tometer after suitable dilutions. The determinations were performedin triplicate (n=3).

Disintegration test 21-22

Disintegration of fast disintegrating tablets is achieved in the mouthowing to the action of saliva, however amount of saliva in the mouthis limited and no tablet disintegration test was found in USP and IP tosimulate in vivo conditions. A modified method was used to deter-mine disintegration time of the tablets. A cylindrical vessel was usedin which 10 mesh screen was placed in such way that only 2 ml ofdisintegrating or dissolution medium would be placed below the sieve.To determine disintegration time, 6 ml of Sorenson’s buffer (pH 6.8),was placed inside the vessel in such way that 4 ml of the media wasbelow the sieve and 2 ml above the sieve. Tablet was placed on thesieve and the whole assembly was then placed on a shaker. The timeat which all the particles pass through the sieve was taken as a disin-tegration time of the tablet. Six tablets were chosen randomly from thecomposite samples and the average value was determined. FollowingFigure shows modified disintegration apparatus.



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Figure for Modified Disintegration Apparatus 21

Kinetic modeling of drug release 23-26

The dissolution profile of all the formulations was fitted in to zero-order, first-order, Higuchi and Korsmeyer-peppas models to ascertainthe kinetic modeling of drug release.

RESULTS AND DISCUSSION:Fast Dissolving tablets of Carbamazepine were prepared and opti-mized by 32 factorial design in order to select the best combination ofdifferent Superdisintegrants, Crospovidone, Croscarmellose sodiumand also to achieve the desired rapid release of drug from the dosageform (by Disintegrating quickly). The two factorial parameters in-volved in the development of formulations are, quantity ofCrospovidone & Croscarmellose sodium as independent variables(X1, X2), and In vitro dissolution parameters such as t50% , t90%

andWetting time, Disintegrating Time as dependent variables. To-tally nine formulations were prepared using 3 levels of 2 factors andall the formulations containing 100 mg of Carbamazepinewere pre-pared as a Fast Dissolving tablet dosage form by Direct Compres-sion technique as per the formulae given in Table 2.

All the prepared tablets were evaluated for different post compres-sion parameters, drug content, mean hardness, friability, mean thick-ness, Weight variation as per official methods and results are given inTable 3. The hardness of tablets was in the range of 3.1-3.5 Kg/cm2.Weight loss in the friability test was not more than 0.65%. Drugcontent of prepared tablets was within acceptance range only. TheWetting Time of tablets was in the range of 12.18-88.04 sec. TheDisintegration Time of tablets was in the range of 9.13-

Table 3: Post-Compression Parameters for the Formulations

S.No Formulation Hardness Thickness Friability Weight Drug Wetting Time DisintegrationCode (kg/cm2) (mm) (%) Variation Content (%) ( sec) Time (sec)

1 F1 3.1±0.12 3.4±0.8 0.58±0.2 200.69±0.9 99.45±1.1 12.18±1.3 9.13±0.52 F2 3.2±0.15 3.45±0.7 0.64±0.3 201.46±1.9 99.28±0.7 14.09±1.3 9.32±0.63 F3 3.2±0.11 3.6±0.5 0.62±0.1 200.67±1.1 99.41±0.5 18.10±1.7 10.30±0.74 F4 3.2±0.14 3.5±0.6 0.62±0.19 200.55±2.2 99.53±0.4 38.23±1.5 12.5±0.95 F5 3.1±0.16 3.55±0.4 0.52±0.30 201.48±1.1 99.39±0.6 42.31±1.1 12.8±0.86 F6 3.5±.10 3.7±.2 0.65±0.04 201.04±2.0 99.92±0.4 48.2±1.2 13.21±0.77 F7 3.3±0.15 3.55±0.6 0.61±0.3 200.48±1.4 99.23±1.0 51.16±1.5 28.18±1.28 F8 3.3±0.12 3.6±0.4 0.57±0.4 199.68±0.3 99.51±0.8 78.11±1.9 42.39±0.59 F9 3.2±0.13 3.75±0.1 0.62±0.4 200.45±0.9 99.49±0.9 88.04±1.2 53.20±2.2

Table 4: Regression Analysis Data of 32 Factorial Design Formulations of Carbamazepine Fast Dissolving Tablets

S.No Formulation Kinetic ParametersCode Zero Order First Order Higuchi Korsmeyer-Peppas

a b r a B r a b r a b r

1 F1 49.509 1.150 0.689 1.678 0.031 0.948 24.919 12.157 0.876 0.732 0.830 0.7462 F2 46.956 1.178 0.710 1.678 0.027 0.912 22.494 12.282 0.889 0.699 0.847 0.7553 F3 44.339 1.212 0.733 1.730 0.026 0.934 20.077 12.420 0.903 0.671 0.861 0.7644 F4 48.065 1.173 0.696 1.630 0.028 0.879 23.282 12.334 0.879 0.705 0.847 0.7495 F5 45.183 1.240 0.731 1.776 0.035 0.967 20.307 12.723 0.901 0.665 0.872 0.7636 F6 42.482 1.261 0.749 1.762 0.028 0.941 17.915 12.765 0.911 0.634 0.886 0.7707 F7 46.380 1.178 0.710 1.682 0.025 0.914 21.993 12.266 0.888 0.694 0.849 0.7538 F8 43.237 1.233 0.739 1.737 0.025 0.931 18.836 12.570 0.905 0.648 0.876 0.7669 F9 42.399 1.217 0.739 1.725 0.022 0.906 18.324 12.406 0.904 0.644 0.874 0.766

10 M P 44.971 1.219 0.727 1.757 0.030 0.950 20.433 12.524 0.898 0.675 0.862 0.763

F1 to F9 are factorial formulations, r-correlation coefficient, a-Intercept, b-Slope and MP-Marketed Product.



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53.20sec.Results for all Post-compression parameters were tabulatedor shown in Table 3. In-vitro Dissolution studies were performed forprepared tablets using Phosphate buffer pH 6.8 as a dissolution mediaat 50 rpm and temperature 37±0.5°C. The In-vitro dissolution profilesof tablets are shown in Fig.1 and the dissolution parameters are givenin Table 4. Cumulative % Drug release of Factorial Design Formula-tions F1-F9 at 1 Hr were found to be in the range of 95.34-99.24 %.From the result it reveals that the release rate was higher for formula-tions containing High level of Crospovidone / Croscarmellose so-dium compared with other Formulations containing Lower level, dueto High concentration of Superdisintegrant in combination, showsvarious disintegration mechanism such as wicking and swelling etcmore compared with lower concentration and alone, drug may re-lease rapidly and shows improved bioavailability. Therefore, requiredrelease of drug can be obtained by manipulating the composition ofCrospovidone and Croscarmellose sodium.

Much variation was observed in the Wetting time, Disintegratingtime, t50%and t90% due to formulation variables. Formulation F5 con-taining 18.75 mg of Crospovidone, 18.75 mg of Croscarmellose so-dium showed promising dissolution parameter (Wetting time=

42.31±1.1 sec , Disintegrating time = 12.8±0.8 sec , t50% = 8.671 min ,t90% = 28.813 min). The difference in burst effect of the initial time is aresult of the difference in the Concentration of Superdisintegrantsmixtures. This reveals that increased concentration of superdisinte-grants resulted in a corresponding decrease in the Wetting Time,which might be due to the result of wicking and other possible disin-tegrating mechanisms. Disintegration time is directly proportional towetting time.

The In -vitro dissolution data of Carbamazepine Fast Dissolving for-mulations was subjected to goodness of fit test by linear regression

analysis according to zero order and first order kinetic equations,Higuchi’s and Korsmeyer-Peppas models to assess the mechanismof drug release. The results of linear regression analysis includingregression coefficients are summarized in Table 4 and plots shown infig.1-4. It was observed from the above that dissolution of all thetablets followed First order kinetics with co-efficient of determination(R2) values in the range of 0.879-0.967. The values of r of factorialformulations for Higuchi’s equation was found to be in the range of0.876-0.911, which shows that the dissolution data fitted well toHiguchi’s square root of time equation confirming the release fol-lowed diffusion mechanism. Kinetic data also treated for Peppas equa-tion, the slope (n) values ranges from 0.634-0.732 that shows Non-Fickian diffusion mechanism. Polynomial equations were derived forWetting time, Disintegrating time, t50% and t90% values by backwardstepwise linear regression analysisusing PCP Disso software andResponse surface plots were constructed using SIGMAPLOTV13software.The Linear Contour plots and Response surfaceplotswere shown in Fig.7-14 for Wetting time,Disintegrating time, t50%

and t90% using X1 and X2 on both the axes respectively. The dissolu-tion data (Kinetic parameters) of factorial formulations F1 to F9 areshown in Table 5.

COMPARATIVE ZERO ORDER PLOTS FOR FORMULATIONS F1-F9

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70

Time(min)

%CD

R F1 F2

F3 F4

F5 F6

F7 F8

F9

Fig.1 Comparative Zero order plots for Formulation F1-F9

COMPARATIVE FIRST ORDER PLOTS FOR FORMULATIONS F1-F9

-0.5

0

0.5

1

1.5

2

2.5

0 20 40 60 80

Time(min)

Log%

UR

F1 F2

F3 F4

F5 F6

F7 F8

F9

Fig.2 Comparative First order plots for Formulation F1-F9

COMPARATIVE KORSMEYER-PEPPAS PLOTS FOR FORMULATIONS F1-F9

0

0.5

1

1.5

2

2.5

0 0.5 1 1.5 2Log Time

Log%

CDR F1 F2

F3 F4

F5 F6

F7 F8

F9

Fig.3 Comparative Higuchi plots for Formulation F1-F9



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Fig.4 Comparative Korsmeyer-Peppas plots for Formulation F1-F9

WETTING TIME CHART

0

20

40

60

80

100

F1 F2 F3 F4 F5 F6 F7 F8 F9

Formulations

Wet

ting

Tim

e (S

ec)

Fig.5 Wetting Time Chart for Formulation F1-F9

Fig.6 Disintegration Time Chart for Formulation F1-F9

Disintegration Time Chart

Fig.7 Linear Contour plot for Wetting Time

Fig.8 Linear Contour plot for Disintegration Time

Fig.9 Linear Contour plot for t50%

Fig.10 Linear Contour plot for t90%

C O M PARATIVE K O RS M EYER-PEPPAS PLO T S F O R F O R M U L A T I O N S F 1-F9

0

0 .5

1

1 .5

2

2 .5

0 0 .5 1 1 .5 2Log Time

Log%

CDR

F1 F2

F3 F4

F5 F6

F7 F8

F9



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Fig.11 Response Surface plot for Wetting Time

Response Surface plot for Wetting Time

Fig.12 Response Surface plot for Disintegration Time

Response Surface plot for Disintegration Time

Fig.13 Response Surface plot for t50%

Response Surface plot for t50%

Fig.14 Response Surface plot for t90%

Response Surface plot for t90%

Table 5: Dissolution Parameters of Carbamazepine Fast DissolvingTablets 3² Full Factorial Design Batches

S.No Formulation Kinetic Parameterscode t10% (Min) t50% (Min) t75% (Min) t90%(Min)

1 F1 1.464 9.630 19.260 32.0012 F2 1.724 11.344 22.687 37.6953 F3 1.784 11.739 23.479 39.0104 F4 1.652 10.870 21.740 36.1215 F5 1.318 8.671 17.342 28.8136 F6 1.648 10.841 21.682 36.0247 F7 1.832 12.051 24.101 40.0448 F8 1.805 11.872 23.744 39.4519 F9 2.092 13.762 27.525 45.73210 M P 1.526 10.042 20.084 33.370

Polynomial equation for 3² full factorial designs is given in EquationY= b0+b1 X1+b2 X2+b12 X1X2+b11 X1²+b22 X2²…

Where, Y is dependent variable, b0 arithmetic mean response of ninebatches, and b1 estimated co-efficient for factor X1. The main effects(X1 and X2) represent the average result of changing one factor at atime from its low to high value. The interaction term (X1X2) showshow the response changes when two factors are simultaneouslychanged. The polynomial terms (X1² and X2²) are included to investi-gate non-linearity. Validity of derived equations was verified by pre-paring Two Check point Formulations of Intermediateconcentration(C1, C2).

The equations for Wetting time, Disintegrating time, t50% and t90%

developed as follows,

Y1= 43.380-28.823X1-8.795X2+7.740X1X2+0.70 X12-2.185X2

2 (forWetting time)Y2= 21.225-15.837X1-4.483X2+5.963 X1X2+12.583 X1

2-0.417 X22 (for



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Disintegration time)Y3= 11.197-0.828X1-0.632X2-0.0995 X1X2+1.605 X1

2+0.853 X22 (for t50%)

Y4 = 37.210-2.754X1-2.1X2-0.33 X1X2+5.336 X12+2.836 X2

2 (for t90%)

The positive sign for co-efficient of X1 in Y1, Y2, Y3 and Y4 equationsindicates that, as the concentration of Crospovidone decreases,Wetting time, Disintegrating time, t50%and t90% value increases. In otherwords the data demonstrate that both X1 (amount of Crospovidone)and X2 (amount of Croscarmellose sodium) affect the time requiredfor drug release (Wetting time, Disintegrating time, t50%and t90%). Fromthe results it can be concluded that, and increase in the amount of theSuperdisintegrant leads to decrease in Disintegration time of theDosage form and drug release pattern may be changed by appropriateselection of the X1 and X2 levels. The Dissolution parameters forpredicted from the polynomial equations derived and those actualobserved from experimental results are summarized in Table 6. Thecloseness of Predicted and Observed values for Wetting time,

Disintegrating time,t50%and t90% indicates validity of derived equa-tions for dependent variables. The Response surface Plots were pre-sented to show the effects of X1 and X2 on Wetting time,Disintegratingtime,t50%and t90%. The final best (Optimized) formulation (F5) is com-pared with marketed product (TEGRETOL-100) shows similarity fac-tor (f2) 82.675, difference factor (f1) 2.048907 (There is no significantdifference in drug release because tcal is<0.05).

Formulation Predicted valueCode WT DT t50% t90%

(Sec) (Sec) (min) (min)

C 1 63.753 35.917 12.517 41.597C 2 26.135 15.597 11.057 36.744

Formulation Actual observed valueCode WT DT t50% t90%

(Sec) (Sec) (min) (min)

C 1 63.80 35.75 12.48 41.613C 2 26.50 16.20 11.09 36.852

Table 6: Dissolution Parameters for Predicted and Observed Val-ues for Check Point Formulations

CONCLUSIONThe present research work envisages the applicability ofSuperdisintegrants such as Crospovidone and Croscarmellose so-dium in the design and development of Fast Dissolving tablet formu-lations of Carbamazepineutilizing the 32 factorial design. From theresults it was clearly understand that as the concentration ofSuperdisintegrant increases the release rate of drug was RAPID (Im-proved Solubility) and both of these Superdisintegrants can be usedin combination since do not interact with the drug which may be morehelpful in achieving the desired fast Dissolving of the dosage formfor rapid action and improved Bioavailability. The optimized formula-tion followed Higuchi’s kinetics while the drug release mechanism

was found to be Non-Fickian Diffusion, first order release type. Onthe basis of evaluation parameters, the optimized formulation F5 maybe used for the effective management of Epilepsy, convulsions, Trem-ors and Neuropathic Pain.This may improve the patient complianceby showing rapid action via disintegration without difficult in swal-lowing and side effects which will ultimately improve the therapeuticoutcome.we could be able to minimize the per oral cost of the Formu-lation.

ACKNOWLEDGEMENTS:The author would like to thank Management, Principal, Teaching,Non-teaching Staff of Narasaraopeta Institute of Pharmaceutical Sci-ences, Narasaraopet, Guntur (D.t), A.P., India for providing supportfor successful completion of research work.

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Formulation Development and Evaluation of Carbamazepine Fast Dissolving Tablets