International Journal of Pharmacy and Pharmaceutical Sciences

ResearchArticle FORMULATIONANDEVALUTIONOFMOUTHDISSOLVINGTABLETSOF AMITRIPTYLINEHYDROCHLORIDEBYDIRECTCOMPRESSIONTECHNIQUE

MOHSINA.A*1,NIMBALAKRN.E,SANAULLAHS,AEJAZA
1

Vol 2, Issue 1, 2010

DepartmentofPharmaceutics,LuqmanCollegeofpharmacy,Gulbarga,585102.Karnataka,India

ABSTRACT Fast dissolving drug deliverysystemoffers a solution for thosepatients havingdifficultyin swallowing tablet. In the present study, an attempt has been made to prepare fast dissolving tablets of the drug AmitriptylinehydrochlorideusingsuperdisintegrantssuchasCroscarmellosesodium(AcDiSol),Sodium starch glycolate (Explotab) and Crospovidone by direct compression technique. The prepared tablets wereevaluatedforhardness,friability,wettingtime,weightvariation, in vitrodisintegrationtimeand in vitrodissolutionstudy.Thehardnessofthetabletswasintherangeof2.04.0Kg/cm.Thepercentage friability of the tablets was less than one. Weight variation test results showed that the tablets were deviatingfromtheaverageweightwithinthepermissiblelimitsof7.5%.Drugcontentuniformitystudy resultsshowedthatuniformdispersionofthedrugthroughouttheformulationi.e.98.54%to101.23%. Tablets containing Crospovidone (DC9) showed better disintegrating character along with the rapid release(99.83%drugwithin7minutes).Noappreciabledifferencewasfoundbetweentheformulations containingothertwosuperdisintegrants.Crospovidonewasfoundtobebettersuitedfortheformulation ofmouthdissolvingtabletofAmitriptylinehydrochloridecomparedtoothersuperdisintegrarntsusedin thestudy. Keywords:Fastdissolvingtablets,AmitriptylineHydrochloride,Superdisintegrants.

INTRODUCTION Solid dosage forms and capsules are most popular and preferred drug delivery system because of they have a high patient compliance. Many patient find difficulty to swallow tablet and hard gelatin capsule, consequently they donottakemedicationasprescribed.It isestimatedthat50%ofthepopulation isaffectedbythisproblemwhichresult high incidence of noncompliance and ineffectivetherapy1. The difficulty is experienced in particular by pediatric and geriatric patients, but it is applicable to people who are ill in bed and those active working patients who are busy or traveling, mentally ill, developmentally disable and patients who are uncooperative. To overcome this problem fast dissolving tablet is prepared2. Amitriptyline HCl inhibits the reuptake ofnorepinephirenandserotoninalmost equally. These actions help in Amitriptyline HCl as an antidepressant andantipsychoticdrug3. With the view to all the above information,anattempthadbeenmade to develop a rapidly disintegrating Amitriptyline HCl mouth dissolving tablets ofwhich disintegrateintheoral cavitywithouttheneedofwaterwithin amatterofseconds.Thiswillleadtothe formationofsuspension/solutionform whichcanbeeasilyswallowed,thereby improving dissolution rate and bioavailability of drug and onset of pharmacologicalaction. MATERIALSANDMETHODS Materials Amitriptyline HCl was obtained as gift sample from Vasudha Pharma Chem Ltd., Hyderabad,India, Crospovidone, Croscarmellose sodium, Sodium starch glycolate and aspartame were gifted sample from Cipla, Kurkumbh,India, Lactose, Magnesium stearate was procured from S.D Fine Chemicals, Mumbai, India, were used and all other

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chemicals/solventsusedwereanalytical grade. Method Formulation of mouth dissolving tablets of Amitriptyline Hydrochloride Tablet each containing 25 mg Amitriptyline Hydrochloride were prepared as per composition given in Table1. The drug and excipients were passed through sieve (#80) to ensure the better mixing. Microcrystalline Cellulose was used as a direct compressible vehicle. Super disintigrants like Sodium Starch Glycolate, Crospovidone and Croscarmellose Sodium were used in different ratios. The powder was compressed using Rimek compression machine equipped with 8 mm round punchbydirectcompressiontechnique. A minimum of 50 tablets was prepared foreachbatch. PreCompressionParameters AngleofRepose Angle of repose was determined using funnel method4. The blend was poured through funnel that can be raised vertically until a maximum cone height (h)wasobtained.Radiusoftheheap(r) was measured and angle of repose was calculatedusingtheformula =tan1 h r

determined. The bulk density was calculatedusingtheformula b TappedDensity The measuring cylinder containing known mass of blend was tapped for a fixed time. The minimum volume (Vt ) occupiedinthecylinderandweight(M) oftheblend wasmeasured.Thetapped density (b) 4 was calculated using the followingformula t =
M

Vt

Vt

CarrsCompressibilityIndex The simplest way of measurement of free flow of powder is compressibility, an indication of the ease with which a materialcanbeinducedtoflowisgiven by compressibility. The compressibility index of the granules was determined by Carrs compressibility index4 (I), which is calculated by using the followingformula I HausnerRatio Hausner ratio5 is an indirect index of ease of powder flow. It is calculated by thefollowingformula Hausnerratio = t d = V0Vt Vo x 100

Where, is the angle of repose, h is height of pile; r is radius of the base of pile. BulkDensity Apparent bulk density (b) was determinedbypouringtheblendintoa graduated cylinder4. The bulk volume (Vb) and weight of powder (M) was

Where t is tapped density and d is bulk density. Lower Hausner ratio (< 1.25) indicates better flow properties thanhigherones6(>1.25). 205

Postcompressionparameter Hardness The hardness of the tablet from each formulation was determined using Pfizerhardnesstester4. WeightVariation Twenty tablets from each formulation were selected at a random and average weightwasdetermined.Thenindividual tablets were weighed and was comparedwithaverageweight4. Friability Friabilityofthetablets4wasdetermined using Veego Friabilator. This device subjects the tablets to the combined effectofabrasionandshockinaplastic chamber revolving at 25 rpm and dropping the tablets at a height of 6 inches in each revolution. Pre weighed sample of tablets was placed in the friabilator and were subjected to100 revolutions. Tablets were de dusted using a soft muslin cloth and re weighed.Thefriability(f)isgivenbythe formula. Friability(f) =(1 WhereW0isweightofthetabletsbefore thetestandWistheweightofthetablet afterthetest InvitroDisintegrationtime The disintegration time for all formulations was carried out using tablet disintegration test apparatus. Six tabletswereplacedindividuallyineach tube of disintegration test apparatus and discs were placed. The water was maintainedatatemperatureof372C and time taken for the entire tablet to disintegratecompletelywasnoted7. W0 W )x 100

Drugcontent Five tablets were powdered and the blend equivalent to 100 mg of Amitriptyline hydrochloride was weighed and dissolved in suitable quantityofdistilledwater.Thesolution was filtered, suitably diluted and the drug content was analyzed spectrophotometrically at 239nm. Each samplewasanalyzedintriplicate8. InvitroDissolutionstudies9 In vitro dissolution studies for all the fabricated tablets was carried out by using USP Type II apparatus (USP XXIII Dissolution Test Apparatus) at 50 rmp in 900 ml of phosphate buffer pH 6.8, maintained at 370.5C. 5 ml aliquot was withdrawn at the specified time intervals, filtered through whatmann filter paper and assayed spectrophotometrically at 239nm using Shimadzu 1700 spectrophotometer. An equal volume of fresh medium, which was pre warmed at 37 0C was replaced into the dissolution medium after each sampling to maintain the constant volumethroughoutthetest.Dissolution studieswereperformedintriplicate. Stabilitystudy10,11 The purpose of stability testing is to provideevidenceonhowthequalityofa drug substance or drug product varies with time under the influence of a varietyofenvironmentalfactorssuchas temperature, humidity, light and enables recommended storage conditions, retest periods and shelf livestobeestablished. ICH specifies the length of study and storageconditions: Longtermtesting25C2C/60% RH5%for12months

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 Accelerated testing 40C 2 C / 75 %RH5%for6months

% for a specific time period up to 30 days for the selected formulations. Tablets were evaluated for hardness, In the present study, stability studies weight variation, friability, content were carried out at 25C 2C / 60 % uniformity, disintegration and drug RH5%and40C2 C/75%RH5 release. Table1:Compositionofdifferentbatchesofmouthdissolvingtabletsof AmitriptylineHydrocholride
DC0 25 103 50 10 2 10 200 DC1 25 99 4 50 10 2 10 200 DC2 25 97 6 50 10 2 10 200 DC3 25 95 8 50 10 2 10 200 DC4 25 99 4 50 10 2 10 200 DC5 25 97 6 50 10 2 10 200 DC6 25 95 8 50 10 2 10 200 DC7 25 99 4 50 10 2 10 200 DC8 25 97 6 50 10 2 10 200 DC9 25 95 8 50 10 2 10 200

Ingredients(mg) Amitriptyline Hydrocholride Lactose(DC) Sodium starch glycolate (Explotab) Croscarmellose sodium (ACDiSol) Crospovidone (Polyplasdone) Microcrystallinecellulose Aspartame Magnesiumstearate Talc Totalweight

Table2:EvaluationofMixedBlendofDrugandExcipients
Angleof Formulation repose code () DC0 25.11 DC1 23.42 DC2 24.14 DC3 24.30 DC4 25.01 DC5 26.56 DC6 25.76 25.17 DC7 DC8 25.11 26.56 DC9
cumulative percent drug release

Tapped Bulk density density (g/cm) (g/cm) 0.454 0.522 0.451 0.542 0.459 0.539 0.438 0.523 0.447 0.539 0.473 0.565 0.46 0.553 0.427 0.508 0.478 0.567 0.442 0.537

Hausners ratio 1.14 1.201 1.173 1.194 1.205 1.194 1.202 1.189 1.186 1.21

Compressibility index (%) 13.03 17.01 14.18 16.28 17.01 16.31 16.79 15.93 15.72 17.68

100 90 80 70 60 50 40 30 20 10 0 0 2 4 6 Time (min)

DC1 DC2

10

12

Fig.1:ComparativedissolutionprofileofAmitriptylinehydrochloridetablets containingdifferentsuperdisintegrantsDC0,DC1,DC2&DC3 207

DC0

DC3

Table3:Evaluationoftablets
Formulation Code DC0 DC1 DC2 DC3 DC4 DC5 DC6 DC7 DC8 DC9 Weight Variation (mg) Hardness Kg/cm2 SD 4.10.311 3.40.401 3.10.209 3.20.216 3.60.513 3.20.291 3.40.316 3.50.263 3.90.315 3.70.277 Thickness (mm) SD 3.710.010 3.700.030 3.730.012 3.730.040 3.700.011 3.710.035 3.710.053 3.730.025 3.700.013 3.700.033 Friability (%) 0.42 0.52 0.56 0.67 0.71 0.63 0.60 0.68 0.42 0.47 Drug content (%) SD 99.180.72 99.811.07 98.540.50 99.120.72 99.30027 101.230.39 101.030.73 98.630.44 99.500.34 99.960.77 Invitro disintegration time(sec) SD 2420.73 390.90 230.68 200.64 240.71 220.27 310.55 230.94 180.57 130.76 Water absorption ratio (Sec) 83.010.26 72.30.31 77.640.54 75.150.11 68.150.31 68.770.45 59.250.78 70.170.70 68.790.32 57.770.55 Wetting time (Sec) 610.263 250.201 120.324 170.496 190.406 170.496 120.324 100.201 140.263 90.413 % Drug release 97.13 97.60 97.72 98.78 99.01 98.90 99.12 99.56 99.01 99.83

199205(within the IPlimitof7.5%)

cumulative percent drug release

100 90 80 70 60 50 40 30 20 10 0 0 2 4 6 Time (min)

DC 4

10

12

Fig.2:ComparativedissolutionprofileofAmitriptylinehydrochloridetablets containingdifferentsuperdisintegrantsDC0,DC4,DC5&DC6

DC 0

DC 5

DC 6

cumulative percent drug release

100 90 80 70 60 50 40 30 20 10 0 0 2 4 6 Time (min)

DC7

10

12

DC 0

DC8

DC9

Fig.3:ComparativedissolutionprofileofAmitriptylinehydrochloridetablets containingdifferentsuperdisintegrantsDC0,DC7,DC8&DC9

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RESULTSANDDISCUSSION Nine formulations of Amitriptyline Hydrochloride were prepared with concentration of three superdisintegrants: Sodium Starch glycolate, Croscarmellose sodium, Crospovidone and microcrystalline cellulose were used as a direct compressible vehicle. For each formulation, blend of drug and excipientswerepreparedandevaluated for various parameters as explained earlier. The powder blend was compressed using direct compression technique.Bulkdensitywasfoundinthe range of 0.4270.478 g/cm3 and the tapped density between 0.5080.567 g/cm3 (Table II). Using these two density data Hausners ratio and compressibility index was calculated. The powder blend of all the formulations had Hausners ratio of 1.2 or less indicating good flowability. The compressibility index was found between 13.03 and 17.68 % and the compressibility flowability correlation data12indicatedafairlygoodflowability of the blend. The good flowability of blend was also evidenced with angle of repose (range of 23 27 0), which is below400indicatinggoodflowability. Tablets were prepared using direct compressiontechnique.Thicknessofthe tablets was measured by screw gauge bypickingtabletsrandomlyfromallthe batches. The mean thickness was (n=3) almost uniform in all the formulations and values ranged from 3.70 0.013 mm to 3.73 0.040 mm. The standard deviation values indicated that all the formulations were within the range. Since the powder material was free flowing, tablets were obtained of uniform weight due to uniform die fill, withacceptableweightvariationsasper pharmaceutical specifications. The drug contentwasfoundintherangeof98.54 101.23 % (acceptable limit) and the

hardness of the tablets between 3.0 4.0 kg/cm2 (Table III). Friability of the tabletswasfoundbelow1%indicating agoodmechanicalresistanceoftablets. Wetting time is closely related to the inner structure of the tablet. This showed that wetting process was very rapid in almost all formulations. This may be due to ability of swelling and also capacity of water absorption and causesswelling.The invitrodispersion time is measured by the time taken to undergo uniform dispersion. Rapid dispersion within few minutes was observed in all the formulations. The results showed that tablet containing Crospovidone having low dispersion time as compare to other superdisintegrants.Thedispersiontime increases as the concentration of superdisintegrants increases. The in vitro disintegration time of the tablets wasfoundtobelessthan60sec.Allthe formulations showed enhanced dissolution rate as compared to Amitriptyline hydrochloride with out superdisintegrants. The maximum increase in the dissolution rate was observed with crospovidone amongst the three superdisintegrants. The order of enhancement of the dissolution rate with various superdisintegrants found to be Crospovidone >Cross carmellose>Sodiumstarchglycolate. Stability study shows no significant changes in values during onemonth study. CONCLUSION It was concluded that mouthdissolving tablets of Amitriptyline hydrochloride can be successfully prepared by direct compression technique using selected superdisintegrantsforthebetterpatient complianceandeffectivetherapy. ACKNOWLEDGEMENTS Authors thank Vasudha Pharma Chem Ltd., Hyderabad (India) Cipla, 209

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