Development and Evaluation of High Loading oral dissolving film of aspirin and acetaminophen

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DevelopmentandEvaluationofHighLoadingOralDissolvingFilmofAspirinandAcetaminophen

ARTICLEmiddotJUNE2014

DOI101166jpsp20141014

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PiyushPatel

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DhavalShah

USFoodandDrugAdministration

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Copyright copy 2014 American Scientific PublishersAll rights reservedPrinted in the United States of America

ArticleJournal of

Pharmaceutical Sciencesand Pharmacology

Vol 1 112ndash122 2014wwwaspbscomjpsp

Development and Evaluation of High Loading OralDissolving Film of Aspirin and Acetaminophen

Rutesh H Davelowast Dhaval A Shah and Piyush G PatelArnold and Marie Schwartz College of Pharmacy and Health Sciences Long Island University Brooklyn 11201 NY USA

The objective of this research was to develop and evaluate physicochemical properties of acetaminophen and aspirinorally disintegrating strips with high loading dose The strips were compared with conventional over the counter strips andchewable tablets for their mechanical and chemical properties Aspirin (81 mg) and acetaminophen (80 mg) oral dissolvingfilms were developed with 50ndash55 of drug loading and were compared with GAS-Xreg (625 mg) and chewable tablets(aspirin and acetaminophen) Orally dissolving films were developed using a solvent casting method Sonication wasproven to be a more competent step in order to load a high amount of active drug substance in the thin film strips Differentfilm formulations were prepared by varying concentration of polymers and plasticizers Optimization of formulation wasdone by conducting studies for various mechanical properties using TA-XT plus texture analyzer Dissolution of optimizedformulation was performed in 250 ml of pH 12 and artificial saliva (pH 68) The study was conducted by stirring thedissolution media at 50 rpm 37 C for 30 minutes and was analyzed using UVVis spectroscopy The dimensions oforally dissolving films were determined with the help of vernier calipers Modulated Differential Scanning Calorimetry(MDSC) was also performed for the filmstrips to check the compatibility The film strip was evaluated for imperfectionsand cuts peelability without rupturing folding and cracking endurance surface roughness tensile strength film burst anddisintegration time with the help of TA-XT plus texture analyzer Moisture content was performed on the fresh as wellas stability samples Dissolution of filmstrips showed much faster release as compared to respective chewable tablets inartificial saliva as well as in pH 12 Disintegration times for filmstrips were also comparable to Gas-Xreg and ListerineregAfter one month stability of filmstrips at room temperature dissolution profiles perceived with negligible change Othermechanical properties of the filmstrips were also comparable to Gas-Xreg DSC results suggest miscibility in polymer whichexplains the increase in dissolution rate of filmstrips at high dose loading Hence in conclusion we develop a new inhouse method to formulate a stable and more efficient formulation for high loading dose of aspirin and acetaminophen

KEYWORDS Orally Dissolving Films ODT Aspirin APAP Ultra Sonication Dissolution

INTRODUCTIONDrug delivery via oral cavity is the most common routeof administration it has always been an urgency for thepharmaceutical companies to prepare patient compliantdosage forms which in most cases are the oral dosageforms (Srikonda V Sastry 1997) Besides expansion indrug delivery in the last decade oral route of drug admin-istration is counted as the universally preferred routeof drug administration due to self-medication Moreoverit helps in eliminating the generation of pain associatedwith parenteral administration (Siddiqui 2011) As per

lowastAuthor to whom correspondence should be addressedEmail ruteshdaveliueduReceived 4 February 2014Accepted 19 February 2014

the current scenario most pharmaceutical new chemicalentities (NCEs) are falling into the BCS class II and IVcategories (Lipinski 2000) Today the greatest challengethat scientists are facing is due to the lipophilic natureand poor aqueous solubility of chemical entities Suchdrugs can be targeted via oral cavity as they are lipophilicin nature which enhances the uptake of lipophilic drugThe mucosal cavity is highly preferred due to its richblood supply (Rathbone and Hadgraft 1991) The exercisefor the patient compliance led to the development of theoral fast-dispersing dosage forms They are also knownas quick dissolvingquick disintegrating dosage forms Bydefinition these are solid dosage forms which disintegrateor dissolve within a few seconds to a minute in the oralcavity (Sastry et al 2000) After disintegration the film-strip is transformed in to solution or suspension This is

112 J Pharm Sci Pharmacol 2014 Vol 1 No 2 2333-371520141112011 doi101166jpsp20141014



Dave et al Development and Evaluation of High Loading Oral Dissolving Film of Aspirin and Acetaminophen

Table I Special features and advantages of ODFs

Special features Advantages

bullThin elegant films bullConvenient dosingbullVarious shapes and sizes bullNo water neededbullUnobstructive bullNo risk of chokingbullMucoadhesion bullTaste maskingbullQuick dissolving bullQuick absorption and bioavailibilitybullFast disintegrating bull Improved patient compliancebullRapid release bullLife cycle management

the key advantage of ODFs (Table I) among other oraldosage forms (Borsadia 2003) ODFs when put on thetongue or in the buccal cavity come in contact with themucosal saliva and hydrates rapidly due to wetting It isthen followed by quick dispersion andor dissolution in thesaliva Depending upon the permeability some drugs canbe absorbed in the mouth pharynx and esophagus as thesaliva passes down the stomach In these cases bioavail-ability of drugs can be amplified significantly as comparedto the tablet and capsule dosage forms (Biradar 2005)It offers quick onset of action within a few seconds due tomucosal absorption of the drug in to the systemic circu-lation (Reema US 20070042023 A1) In addition orallydisintegratingdissolving films successfully eliminate thecomplications of swallowing and choking by effectivelydelivering the medication to the elderly and children (NitinSaigal 2008) The fast dissolvable film perception wasfirst introduced to consumers in 2001 by Pfizer in the formof ldquoListerineregrdquo-mouth dissolving strips It was a novelroute of delivering breath freshener product through theoral cavity (Alicia Hambleton 2008 Wu et al 2002)Pharmaceutical companies have quickly followed the trendby developing oral strip formats for the popular over-the-counter (OTC) cold and antacid drugs to promote easyand accurate dosing for children and the elderly patientsBesides this strip technologies have a few more advan-tages listed below(1) Availability of large surface area in the oral cavity(2) Precise and accurate dosing(3) Avoidance of first pass metabolism(4) Increase the bioavailability and by reducing conven-tional dose which leads to reduction of side effects to thepatient

Todate the thin film technology includes all wide spectrumof drug products including drugs for cold and coughsmoking cessation antiemetic (Nishimura et al 2009)pain (Vasisht 2010) nausea antiepileptic acidity andconstipation Extensive research has been done in meth-ods of manufacturing thin filmstrips Solvent castingsemisolid casting hot-melt extrusion solid dispersionextrusion and rolling methods are very well establishedfrom small scale to manufacturing scale One or a combi-nation of any of these methods can be used to successfully

formulate the ODFs (Arun Arya 2010) Technologieslike SOLULEAVEStrade WAFERTABtrade FOAM BURSTtradeXGELtrade have been successfully developed for the for-mulation and manufacturing of thin film strips (Mishra2007) The first material employed to produce ediblefilms was Pullulan Pullulan is a glucan consisting ofmaltotriose units obtained from starch by fungus Auri-obasidium pullulans (Leathers 2003) Pullulan howeveris expensive as compared to conventional film formingpolymers which are available in the market They foundnoticeable success with hydrocolloids and developed themas film forming agents Modified starches gums cellu-lose ethers alginates polyvinyl alcohols polyvinylpyrroli-dones have been established as a film forming agents(Ali 2007) Among them a blend of hydroxypropyl cel-lulose (HPC) of low viscosity hydroxypropyl methyl-cellulose E5 (HPMC) and polyvinylpyrrolidone K 2932(PVP) are considered superior for developing a highloading (50ndash55) ODFs Focus of the present researchwork was to design a fast-dissolving filmstrip consist-ing of hydroxypropyl cellulose polyvinylpyrrolidone andhydroxypropyl methylcellulose using glycerin and triacetinas plastisizers Interplay between types and amounts of thepolymers and plasticizers plays a critical role on mechan-ical strength as well as in-vitro performance of the ODFs(Kunte and Tandale 2010) The critical issues in the devel-opment of a fast-dissolving film are mainly related to itsmechanical properties Therefore the impact of the con-centration of the plasticizers andor polymers on flexi-bility disintegration time tensile strength and stickinesswere preliminarily evaluated Acetaminophen (APAP) andaspirin were used as model drugs The 80 mg chewabletablet for APAP is currently available in OTC and mar-keted for the treatment of pain and 81 mg of aspirin chew-able tablet is also available in OTC and prescription forpatients with the risk of heart attack The strips were devel-oped and evaluated with loading of 81 mg80 mg by asolvent casting method Physicochemical properties of thestrips were compared with marketed OTC strips and chew-able tablets for its effectiveness in improving dissolutionrate and stability

MATERIALS AND METHODSMaterialsAPAP was supplied by Mallinckrodt Inc (HazelwoodMO) Hydroxypropylcellulose LF was obtained fromAshland (Wilmington DE) PVP K 2932 was obtainedfrom ISP Technologies Inc (Wayne NJ) Triacetin andGlycerin were supplied by Mutchler chemicals Inc(Harrington Park NJ) Aspirin was purchased from Spec-trum chemicals (New Brunswick NJ) Sucralose and man-nitol were obtained from Sigma Aldrich (St Louis MO)and Roquette Inc (Keokuk IA) respectively PoloxamerF68 was obtained from BASF (Florham Park NJ) andHPMC E5 was obtained from Dow chemicals (Midland

J Pharm Sci Pharmacol 1 112ndash122 2014 113



Development and Evaluation of High Loading Oral Dissolving Film of Aspirin and Acetaminophen Dave et al

API (APAP Aspirin) + Polymer (ie PVP k2932 Polaxamer F-68) + Sugar(ie sucralose mannitol) in organic solvent (ie Ethanol)

Stirred at a high speedUltra sonication

HPC LF + Plasticizer (ie Triacetin Glycerin) + HPMC E5

Remove air bubbles and Poured solution on Teflonplate with film liner

Dried in oven till a flexiblefilm formed

Figure 1 Common formulation method for APAP and Aspirin ODFs

MI) Ethanol 190 proof (EtoH) was obtained from Phar-maco Products Inc (Brookfield CT)

MethodsPreparation of APAP FilmsSolvent casting method was employed for developingAPAP ODFs (Fig 1) Here the solution was prepared bydissolving required amount of drug sucralose and PVPK 2932 in ethanol followed by the addition of HPCLF The solution was sonicated for 45 seconds usingSonicator 3000 equipped with using ultrasonic converterprobe (Serial R1809Misonix Misonix Inc Farming-dale NY) After sonication triacetin was added and it wasallowed to stir until a clear solution was formed (ie30 minutes) The entrapped air bubbles were removedusing degasser (Cole-palmer Vernon Hills IL) The pre-pared solution was poured onto a teflon plate coated withfilm liner and spread uniformly using a casting knife(BYK- Gardner Columbia MD) After casting the filmswere allowed to dry in an oven at 70 C for 2 hours Thefilms were cut into 4times24 cm2 size using sharp blade andstored in plastic zip lock bag at room temperature

Preparation of Aspirin FilmsAspirin ODFs were also prepared using the solvent castingmethod (Fig 1) In this case solution was prepared bydissolving required amount of drug mannitol poloxamerF68 PVP K 29ndash32 sucralose and HPMC E5 in ethanol

The solution was stirred for approximately 15 min until itbecame clear HPC LF and glycerin were added and thesolution was again stirred at high speed for 30 minutesThe remainder of the procedure was same as APAP exceptthe size of filmstrips were of 38times26 cm2

Evaluation of APAPAspirin Containing FilmsFilms of all formulation (Tables II and III) were weighedaccurately on an analytical balance (Model 1712MP8Sartorious Bohemia NY) The thickness of films was mea-sured using vernier calipers (Rakesh Patel 2009) Moisturecontent of the ODFs was determined by OHUS instrument(Model MB200 Switzerland) in which chamber was setat 80 C for 1 min during the measurement Percentage ofthe moisture was calculated by measuring the differencebetween the sample weights The tests were performed intriplicate (Dinge 2008)

Folding EnduranceFolding endurance is defined as the logarithm of the num-ber of double folds that are required to make a test piecebreak under standardized condition

F = log10 d

Where F = folding endurance d = number of doublefoldsIt is also a measure of brittleness This test was per-

formed by cutting ODFs in predetermined size containing

114 J Pharm Sci Pharmacol 1 112ndash122 2014




Table II Formulation

APAP ODFs Aspirin ODFs

APAP (50ndash55) Aspirin (50ndash55)HPC LF (15ndash28) HPC LF (10ndash17)PVP K 2932 (2ndash6) PVP K 2932 (5ndash8)Traicetine (5ndash14) Glycerin (1ndash6)Sucralose (3ndash8) Sucralose (4ndash8) Mannitol (1ndash3)Ethanol HPMC E5 (2ndash6)ndash Poloxamer F68 (4ndash7)ndash Ethanol

80 mg and 81 mg of APAP and aspirin The strip wasfolded at the same place until it broke and the number offolds was noted (Patel 2009)

Drug Content UniformityTen films of equal size and weights were randomlyselected They were completely dissolved in 150 ml ofpurified water and 30 ml of ethanol solution From this1 ml of solution was pipetted out in a volumetric flaskand diluted to 100 ml with water In order to determinethe concentration the absorbance was measured usingUVVisible spectrophotometer at 243 and 273 nm forAPAP and aspirin respectively Concentration of APAPand aspirin was calculated using standard calibrationcurves (Dinge 2008)

Tensile StrengthTensile strength is defined as a measurement of maxi-mum amount of force a material can take without break-ing Tensile strength was evaluated using a TA-XT plustexture analyzer (Texture Technologies Scarsdale NY)equipped with a 5 kg load cell The tensile test was per-formed according to the International test method for plas-tic sheeting (ASTM-D882-10) Each test strip was cut intoa desired size and placed longitudinally in a tensile gripprobe (TA-96B) on the texture analyzer Initial grip sepa-ration was 5 mm and cross head speed was 10 mm minminus1The test was considered concluded at the film break Thetensile strength was evaluated using the following equation

Table III Formulations of Aspirin ODFs using different concentration of HPC LF HPMC E5 and glycerin

Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9

Aspirin 5573 5447 5564 5354 5303 5560 5432 5280 5492HPC LF 14 14 14 156 155 12 14 16 13HPMC E5 8 12 10 4 6 4 4 4 4PVP K 2932 467 410 443 537 534 560 547 531 553Sucralose 509 447 483 634 582 610 597 580 603Glycerin 6 28 28 12 12 28 12 12 6Mannitol 220 388 209 410 252 427 417 406 422Poloxamer F-68 467 410 443 556 534 560 547 5319 553Alcohol QSlowast QS QS QS QS QS QS QS QSTotal 100 100 100 100 100 100 100 100 100

Notes lowastThe given amount of excipients are in ww lowastQS=Quantity sufficient

(Dixit and Puthli 2009) Results were expressed in a forceper unit area

Tensile strength = Force at breaktimes100Thicknesstimeswidth

Film BurstFilm burst is a measure of a resistance to rupture It mea-sures the film behavior before and after being stretchedbeyond its point of deformation or burst point The studieswere conducted using texture analyzer The instrument wascalibrated with a 5 kg load cell and fitted with a stainlesssteel probe (TA-8A) The methodology consists of attach-ing the film to a platform which was tightened with screwsInitially the probe was set at a pre-speed of 1 mmsecwith 1 g trigger force and post speed of 10 mmsec Thetest measures the penetration distance as the film is com-pressed Each experiment was performed in triplicate

AdhesionAdhesion testing was conducted using the texture analyzerequipped with a 5 kg load cell and fitted with an acrylicprobe (TA-10) The probe moved until a trigger force wasdetected at that point the instrument was set to maintaina predetermined force for a given period of timeThe test strip was placed on the flat surface of the tex-

ture analyzer Initially the probe was placed at a pre-speedof 05 mmsec and at an applied force of 500 g with a postspeed of 10 mmsec The force was applied for 15 sec Thetest measures the force required to pull the strip placed ona flat surface of a texture analyzer Each experiment wasperformed in triplicate

In-Vitro Disintegration TestThere is no official guideline available for the deter-mination of disintegration time of orally disintegratingtablets and oral fast disintegrating filmstrips However theEP (European Pharmacopoeia) specifies DT for ODTs as3 min This can be varied from 10 s to 30 s depending onin-house standards from industries Disintegration testingwas conducted using a texture analyzer equipped with a5 kg load cell The methodology consists of attaching the





film to a platform which was tightened with screws Theprobe (TA-108S5) moved until a trigger force was detectedat that point the instrument was set to maintain a predeter-mined normal force for a given period of time Initially theprobe was placed at a pre-speed of 05 mmsec with 5 gtrigger force and a post speed of 10 mmsec As soon asthe probe touched the film 1 ml of artificial saliva (pH 68)was introduced to the film The probe was set to mimicartificial oral cavity pressure (Yamini Morjaria 2004) Thistest measures the in-vitro disintegration time of the filmEach experiment was performed in triplicate

In-Vitro Dissolution StudyDissolution studies were carried out using the Distekdissolution system (Model 2100C-Distek Inc NorthBrunswick NJ) equipped with USP- II (Paddle) apparatusDissolution tests were performed at 37 plusmn05 C and at aspeed of 50 rpm in 250 ml of simulated saliva (pH 68) andat a gastric pH (pH 12) 5 ml was withdrawn at 1 3 5 and6 minutes of time intervals and filtered through 045 msize PTFE pall syringe filters Samples were diluted andanalyzed using UV-VIS spectrophotometer (Model UV-1700 UV Visible spectrophotometer Shimadzu Japan) at243 nm for APAP and 273 nm for aspirin An equal vol-ume of fresh dissolution medium maintained at the sametemperature was added after each withdrawal the sampleto maintain a perfect sink condition Dissolution tests wereperformed in triplicate

Differential Scanning Calorimetry DSCDSC studies were performed to characterize film formu-lation for excipient compatibility testing with APAP andaspirin using a DSC Q100 (TA instruments NewcastleDE) The DSC instrument was calibrated using an indiumstandard Approximately a 5ndash10 mg of sample wasweighed accurately in small hermetically sealed aluminumpans The sample pans were then heated from 10 C to200 C at a rate of 10 Cminute Nitrogen gas was usedas a purging gas with a flow of 50 mlmin

RESULTSVarying different concentration of polymers and plas-ticizers several formulations were developed Each

Table IV Formulations of APAP ODFs using different concentration of HPC LF PVP K 2932 and triacetin

Formulation A B C D E F G H I J K

APAP 566 551 531 513 479 537 526 516 558 507 491HPC LF 150 172 202 229 280 204 199 196 212 193 186PVP K2932 32 31 30 29 27 19 41 58 31 28 27Sucralose 152 148 142 137 128 144 141 138 149 136 131Triacetin 101 98 95 92 86 96 94 92 50 136 164Alcohol QS QS QS QS QS QS QS QS QS QS QSTotal 100 100 100 100 100 100 100 100 100 100 100

Notes lowastThe given amount of excipients are in ww

formulation was evaluated for tensile strength film burstcapacity disintegration time folding endurance and otherphysicochemical parameters Tables III and IV representdifferent formulation approaches that were used to opti-mize APAP and aspirin ODFs

Physical CharacterizationPhysicochemical and mechanical parameters associatedwith ODFs were evaluated and compared with the mar-keted orally dissolving films and chewable tablets Ana-lyzed data are tabulated in Table V Moisture content isvery vital for the film formulation as it can affect themechanical properties like tensile strength adhesion andchemical properties like in-vitro dissolution and disinte-gration performance after storage Listerinereg and Gas-Xreg

have LOD values around 9ndash10 while in the case ofODFs LOD values were in the range of 6ndash7 The ODFshave relatively less LOD value which signifies their sta-bility with respect to environmental change

Tensile StrengthModerate tensile strength is mandatory for the ODFs for-mulation (Mashru et al 2005) as it is responsible for theflexibility of the film by maintaining desired plasticity andbrittleness The study focused on the effect of various con-centrations of HPC LF and PVP K 2932 on the tensilestrength of APAP ODFs and the effect of HPC LF andHPMC E5 on aspirin ODFs Observations showed changein all variables as the concentration of polymers increasesThe variables were measured using texture analyzer andcompared with marketed products After a systematicstudy polymer concentrations were optimized Proportion-ally as the concentration of polymer increases viscosityof a casted solvent system increases It affects the thick-ness and brittleness of the film An optimal film formu-lation was observed with HPMC E5 for aspirin and PVPK 2932 for APAP ODFs along with HPC LF Increasedconcentration of triacetin in APAP ODFs and glycerin inaspirin ODFs resulted in increased flexibility and plasticityof the ODFs The texture of the film observed was smoothand plasticized All the measured variables were comparedwith commercially marketed products such as Listerinereg





Table V Comparison of various physical parameters of ODFs and chewable tablet

Parameters Listerinereg Gas-Xreg APAP chewable tablet APAP (ODFs-C) Aspirin (ODFs-F7) Aspirin chewable tablet

Dose (mg) NA 625 80 80 81 81Weight (mg) 35 109 750 150 160 190Thickness (m) 60 140 NA 140 160 NASize (cm) 33times22 36times22 NA 4times24 38times26 NATensile strength (Kgmm2) 65plusmn374 274plusmn121 NA 25plusmn0047 27plusmn293 NAFoldinglowast endurance 181 047 NA 047 047 NADisintegration time (sec) 7plusmn11 58plusmn27 10plusmn12 67plusmn513 70plusmn313 90plusmn42Stickinesslowastlowast 0 0 NA 0 0 NALODlowast 10 91 14 60 65 8Dissolution in pH 68 NA NA 18 in 5 min 100 in 5 min 50 in 10 min 30 in 10 minDissolution in pH 12 NA NA 28 in 3 min 100 in 3 min 100 in 10 min 60 in 10 min

Notes lowastLOD and folding endurance are average value of triplicate experiment lowastlowastNo stickiness observed in all the cases

and Gas-Xreg The comparison data was used to optimizethe final concentration of polymers and plasticizers Theobserved data suggests (Fig 2) that the tensile strength ofODFs are comparable with the marketed products

Film BurstStudies were done on the film burst property of APAP andaspirin ODFs using various concentrations of HPLC LFHPMC E5 PVP K 2932 triacetine and glycerin Analysiswas performed on the resulting ODFs using texture ana-lyzer The measured data (Fig 3) from a texture analyzerresembled similar patterns of tensile strength in terms ofincreasing the concentration of ingredients Comparison offilm burst was done with Listerinereg and Gas-Xreg

Folding EnduranceFolding endurance of a film is frequently used to assessthe ability of the film to withstand repeated bending

Figure 2 Comparison of tensile strength between ListerineregGas-xreg APAP ODFs and Aspirin ODFs

folding and creasing It is also considered a measure ofthe quality of films in terms of brittleness The foldingendurance was varied from batch to batch The foldingendurance increased proportionally with the concentrationsof polymers andor plasticizers Comparison of the foldingendurance values were done with Listerinereg and Gas-XregThe observed data for Listerinereg showed higher foldingendurance as compared to ODFs while in the case of Gas-Xreg Aspirin and APAP ODFs folding endurance numberswere similar due to the presence of an API Hence ODFshave satisfactory folding endurance values that gives itflexibility and permits for easy and comfortable applica-tion (Bindu 2010)

Disintegration TimeDisintegration time (DT) of APAP and aspirin ODFs wasalso affected by concentrations of polymers and plasticiz-ers (Fig 4) ODFs have been evaluated for the effect of

Figure 3 Comparison of film burst between Listerinereg Gas-xreg APAP ODFs and Aspirin ODFs





Figure 4 Comparison of disintegration time betweenListerinereg Gas-xreg APAP ODFs and Aspirin ODFs

various concentrations of polymers and plasticizers on thedisintegration time The study was carried out using thetexture analyzer using probe TA-108S5 and 1 ml of arti-ficial saliva with a pH of 68 The experimental data sug-gests that as the concentration of HPC LF increases theDT varied from 60ndash180 sec As the concentration of HPCLF increases it forms hard films that take a longer timeto disintegrate From various experiments optimized con-centration of HPC LF was selected to achieve comparableDT with commercially marketed products was determinedThe ODFs prepared with different concentrations of PVPK 2932 and HPMC E5 showed proportionality betweenthe viscosity of the polymeric solution and concentrationsof polymers In response it forms a thick film whichtakes longer time to disintegrate As the concentration ofplasticizer increases it imparts plasticity to the formula-tion Experiments were performed using lower to higherconcentrations of plasticizer to study the effect on disinte-gration time of the ODFs At higher concentrations plas-ticizers impart more plasticity to the formulation whichleads to increase in DT Plasticizer concentration was opti-mized to formulate ODFs that are comparable to marketedproducts Listerinereg showed rapid disintegration as com-pared to other ODFs Hence we can conclude that thepresence of an API has significant impact on DT of ODFsAs we can see from Gas-Xreg it contains 625 mg of API inthe form of simethicone it directly reflects on its measure-ment of DT The DT of Gas-Xreg was 58 seconds The DTof the final formulations for aspirin and APAP ODFs were68 and 60 seconds respectively after optimizing the con-centrations of excipients The loading amount of an APIcan be counted as the possible reason for small increase inDT as compared to Gas-Xreg (McLaughlin 2009) Hencethe conclusion was made that the loading of a drug has a

Figure 5 Comparison of stickiness between Listerinereg Gas-xreg APAP ODFs and Aspirin ODFs

direct relationship with disintegration time The final for-mulation for aspirin and APAP ODFs respectively contains81 mg and 80 mg of API

StickinessFigure 5 reflects that all the formulations were lacking instickiness In other words the final dosage form packedin individual sachets will not stick to the packing materialduring the period of the time before its use Stickiness wasnot affected by concentration of polymers and plasticizersin ODFs

In Vitro Dissolution StudiesIn vitro dissolution performance of particular formulationgives a better understanding about the behavior of the sys-tem It is a very essential tool for the optimization of for-mulation as well as to evaluate the in vitro performance ofoptimized formulation From the results of the observedmechanical and physicochemical parameters the formu-lation with 14 ww HPC LF 4 ww HPMC E5 and12 ww of glycerin was selected as an optimized for-mulation for the development of aspirin ODFs In the caseof APAP ODFs the formulation with 17 ww HPC LF3 ww PVP K 2932 and 98 ww of triacetin wasselected as an optimal formulation Dissolution was per-formed in artificial saliva (pH 68) and pH 12 at 100 rpmIn the case of artificial saliva 50 of the drug was dis-solved within 10 minutes while in the case of pH 12100 of drug dissolved within 5 min A dissolution com-parison was done with an 81 mg Aspirin chewable tabletDissolution of aspirin chewable tablet (81 mg) showedthat 48 of the drug dissolved within 20 min in the case





Figure 6 Dissolution of APAP ODFs versus chewable tabletin artificial saliva at pH 68

of an artificial saliva and 58 of drug dissolved within10 minutes in the case of pH 12 (Figs 8 and 9) APAPODFs showed complete dissolution within five minutes inboth pH 12 and an artificial saliva In the case of APAPODT 25 of drug dissolved in artificial saliva and 40of drug dissolved in pH 12 (Figs 6 and 7) The improve-ment in dissolution performance can be attributed to thesolubility of API and presence of hydrophilic polymersThe presence of highly water soluble hydrophilic poly-meric carriers are responsible for the generation of watersoluble binary (drug+polymer) dispersion which leads toa quicker drug dissolution than the conventional formula-tions (Chakravorty 2008)

Content Uniformity of ODFsContent uniformity is critical for the uniform performanceof any formulation Hence in case of small postage stampsize thin filmstrip with the thickness of 100ndash180 m it is

Figure 7 Dissolution of APAP ODFs versus chewable tabletat pH 12

Figure 8 Dissolution of Aspirin ODFs versus chewable tabletin artificial saliva at pH 68

very essential to have API dispersed uniformly in to thepolymeric matrix in order to achieve good stability as wellas dissolution profile In the current study the API wasuniformly distributed throughout the film formulation andthe content uniformity for APAP was found to be 8072 mg(1008) and for aspirin it was found to be 8137 mg(10045)

Stability Study of ODFsStability studies were performed by comparing dissolutionprofiles in artificial saliva at pH 68 and pH 12 betweenfresh ODFs formulation and one month old ODFs stored atroom temperature The data of the fresh sample resembledthe data of the old sample (Figs 10ndash13) Therefore we canconclude that the formulated ODFs were stable at roomtemperature

DSC Study of ODFsDSC is a thermal analysis technique used to determinethe extent of drug miscibility with the polymer by looking

Figure 9 Dissolution of Aspirin ODFs versus chewable tabletat pH 12





Figure 10 Dissolution of fresh aspirin ODFs versus stabilitysample at pH 68

at the depression in the heat of melting (area under thecurve of endothermic peak caused due to drug melting)As per DSC (Figs 14 and 15) thermogram conclusioncan be made that both Acetaminophen and Aspirin weremiscible with their polymers Moreover absence of degra-dation peak in the DSC endotherm at higher temperaturesuggested compatibility of excipients with the API Henceboth the formulations were observed to be stable

DISCUSSIONThe overall objective of this research was to develop a sta-ble orally disintegrating film with high loading dose Tilltoday only 625 mg of high active drug substance contain-ing ODFs (Gas-Xreg) is available in the market There area few ODFs that are available in the market with lowerloading of API (ie suboxone) Aspirin and APAP wereused as model drugs for this study Both aspirin 81 mg and

Figure 11 Dissolution of Fresh aspirin ODFs versus stabilitysample at pH 12

Figure 12 Dissolution of Fresh APAP ODFs versus stabilitysample at pH 68

APAP 80 mg are available over the counter in the drugstore as a chewable tablet ODFs are made for disintegrat-ing andor dissolving in the oral cavity They are innova-tive and promising dosage forms for the patient having afear of choking and for a pediatric having difficulties inswallowing the tablet Taste masking of aspirin and APAParose a further requirement to avoid refusal of new dosageform Drug free films were prepared with the help of pub-lished literatures to evaluate the effect of different filmformers such as HPC-LF HPMC E5 and PVP K-2932Use of plasticizer can reduce the stiffness and increasethe formability of the polymer (Banker 1966 Sakellariou1995) The optimized formulation contains specific ratioof HPC LF HPMC E5 and glycerin in thecase of aspirinwhile in the case of APAP optimized formulation wasdeveloped by using HPC LF PVP K 2932 and triacetinThe taste and palatability of the films were found to be






Figure 14 DSC thermogram overlay of aspirin ODFs andpure aspirin

improved with sweeteners (sucralose mannitol) and fla-vors (raspberry) The dissolution behavior of APAP andaspirin ODFs were also comparable with chewable APAPand aspirin tablet in both artificial saliva (pH 68) andpH 12 media The in-vitro results of APAP and aspirinODFs showed much higher dissolution rate compared tothe APAP and aspirin chewable tablets The improved dis-solution rates attributed to the presence of micronize par-ticles in ODFs Moreover MDSC confirmed that APAPand aspirin in the ODFs were miscible with polymer(Figs 14 15) (Gaisford et al 2009) The micronizationwas achieved by ultra-sonication which helped to develophighly loaded formulation

Figure 15 DSC thermogram overlay of APAP ODFs and pureAPAP

CONCLUSIONODFs of APAP and aspirin developed by the solvent cast-ing method showed acceptable mechanical characteristicand satisfactory drug release even after one month of thestability study Recently the WHO (world health organiza-tion) has recommended solid oral dosage forms includingoral films for global use due to their better stability andlower cost (Mohit 2013) Many of pharmaceutical com-panies are switching their product franchises form ODTsto ODFs (Subashvijaya Kumar 2010) This technologyalso provides a patent non-infringement product develop-ment platform It is a good tool for life cycle manage-ment to increase patent life of existing molecules andproducts The ODFs are easy to fabricate and also cost-effective in terms of manufacturing as compared to ODTformulation Recently few scientist had started focusingon developing film strip by incorporating nanoparticles andevaluating their mechanical properties in-vitro character-istics and change in other physical properties for poorlysoluble drugs (Sievens-Figueroa et al 2012) It suggeststhat there is still huge room for more research in thisarea

Conflict of InterestThe authors report no conflict of interest

ABBREVIATIONSAPAPmdashAcetaminophen

HPC-LFmdashLow viscosity Hydroxypropyl cellulosePVP-Polyvinylpyrrolidone

ODFsmdashOrally dissolvingdisintegrating film stripODT-Orally disintegrating tablet

HPMCmdashHydroxypropyl methylcelluloseMDSCmdashModulated differential scanning calorime-

ter LODmdashLoss on dryingUV-VISmdashUltraviolet visible spectroscopy

REFERENCESAditya Dinge M N (2008) Formulation and evaluation of fast dissolv-ing films for delivery of triclosan to the oral cavity AAPS PharmSciTech9 349ndash356

Ali S Q A (2007) High molecular weight povidone polymer-basedfilms for fast-dissolving drug delivery application Drug Deliv Technol7 36ndash43

Alicia Hambleton F D R D Laurent B Thomas K and AndreacuteeV (2008) Protection of active aroma compound against moisture andoxygen by encapsulation in biopolymeric emulsion-based edible filmsBiomacromolecules 9 1058ndash1063

Arun Arya A C Vijay Sharma and Kamla Pathak (2010) Fast dis-solving oral films An innovative drug delivery system and dosage formInternational Journal of ChemTech Research 2 576ndash583

ASTM-D882-10 httpwwwastmorgDatabaseCartHistoricalD882-10htm [Online] [Accessed January 31 2014]

Banker G S (1966) Film coating theory and practice Journal of Phar-maceutical Sciences 55 81ndash89





Biradar S S S T B and Kuppasad I J (2005) Fast dissolving drugdelivery systems A brief overview The Internet Journal of Pharmacol-ogy 4

Borsadia S B (2003) Quick-dissolving filmsmdashA novel approach todrug delivery Drug Development and Delivery 3 63ndash66

Dixit R P and Puthli S P (2009) Oral strip technology Overview andfuture potential J Control Release 139 94ndash107

Gaisford S Verma A Saunders M and Royall P G (2009) Monitor-ing crystallisation of drugs from fast-dissolving oral films with isothermalcalorimetry International Journal of Pharmaceutics 380 105ndash111

Hima Bindu T V L V M Kavitha K Sastry T P and Suresh KumarR V (2010) Preparation and evaluation of ciprofloxacin loaded chitosan-gelatin composite films for wound healing activity International Journalof Drug Delivery 2 173ndash182

Kunte S and Tandale P (2010) Fast dissolving strips A novel approachfor the delivery of verapamil J Pharm Bioallied Sci 2 325ndash8

Leathers T D (2003) Biotechnological production and applications ofpullulan Appl Microbiol Biotechnol 62 468ndash73

Lipinski C A (2000) Drug-like properties and the causes of poor solu-bility and poor permiability Journal of Pharmacological and Toxicolog-ical Methods 44 235ndash249

Mashru R C Sutariya V B Sankalia M G and Parikh P P (2005)Development and evaluation of fast-dissolving film of salbutamol sul-phate Drug Dev Ind Pharm 31 25ndash34

Mishra R A A (2007) Quick API delivery Pharmaceutical TechnologyEurope httpwwwpharmtechcompharmtechDosage+FormsQuick-API-deliveryArticleStandardArticledetail464314 Accessed on January 212014

Mohit V I J Praveen Kumar H G Lalit Kumar Jyoti Monga DR Rajashree S Hirlekar (2013) Paediatric dispersible tablets con-taining cefdinir (CEF)-cyclodextrin inclusion complex Formulation andevaluation International Journal of Pharmaceutical Research and Bio-Science 2 81ndash94

Nishimura M Matsuura K Tsukioka T Yamashita H Inagaki NSugiyama T and Itoh Y (2009) In vitro and in vivo characteris-tics of prochlorperazine oral disintegrating film Int J Pharm 36898ndash102

Nitin Saigal S B Alka Ahuja and Javed Ali (2008) Fast-dissolvingintra-oral drug delivery systems Expert Opinion on Therapeutic Patents18 769ndash781

Rakesh Patel N S Jigar Patel and Ashok Baria (2009) Formulationdevelopment and evaluation of mouth melting film of ondansetron ArchPharm Sci Res 1 212ndash217

Rathbone M J and Hadgraft J (1991) Absorption of drugs from thehuman oral cavity International Journal of Pharmaceutics 74 9ndash24

Reema P R G US 20070042023 A1 Dissolvable Film US20070042023 A1

Rosie M S B and Kieran C (2009) The effect of recent FDA guidanceon ODT technologies and applications Pharmaceutical Technology

Saibal Chakravorty V H (2008) Mouth Dissolvable and Meltable andWater Dispersable Delivery Formulation 20080269223

Sakellariou P R R (1995) Interactions in cellulose derivative films fororal drug delivery Prog Polym Sci 20 889ndash942

Sastry S V Nyshadham J R and Fix J A (2000) Recent techno-logical advances in oral drug deliverymdasha review Pharm Sci TechnoloToday 3 138ndash145

N Siddiqui G G and Sharma P K (2011) A short review on a novelapproach in oral fast dissolving drug delivery system and their patentsAdv Biol Res 5 291ndash303

Sievens-Figueroa L Bhakay A Jerez-Rozo J I Pandya NRomantildeAch R J Michniak-Kohn B Iqbal Z Bilgili E and DaveacuteR N (2012) Preparation and characterization of hydroxypropyl methylcellulose films containing stable BCS Class II drug nanoparticles forpharmaceutical applications International Journal of Pharmaceutics423 496ndash508

Srikonda V Sastry M D D Lndra K Reddy and Mansoor A K(1997) Atenolol gastrointestinal therapeutic system I screening offormulation variables Drug Development and Industrial Pharmacy23 157ndash165

Subashvijaya Kumar B G Gurusharan Y and Madhusudan Rao(2010) Overview on fast dissolving films International Journal of Phar-macy and Pharmaceutical Sciences 2 29ndash33

Vasisht N Gever L N Tagarro I and Finn A L (2010) Single-dose pharmacokinetics of fentanyl buccal soluble film Pain Med11 1017ndash1023

Wu Y Weller C L Hamouz F Cuppett S L and Schnepf M (2002)Development and application of multicomponent edible coatings andfilms A review Advances in Food and Nutrition Research 44 347ndash94

Yamini Morjaria W J I Paul X B Rick S C and Barbara R C(2004) In vitro release of nicotine from chewing gum formulations Dis-solution Technologies 12ndash15




Copyright copy 2014 American Scientific PublishersAll rights reservedPrinted in the United States of America

ArticleJournal of

Pharmaceutical Sciencesand Pharmacology

Vol 1 112ndash122 2014wwwaspbscomjpsp

Development and Evaluation of High Loading OralDissolving Film of Aspirin and Acetaminophen

Rutesh H Davelowast Dhaval A Shah and Piyush G PatelArnold and Marie Schwartz College of Pharmacy and Health Sciences Long Island University Brooklyn 11201 NY USA

The objective of this research was to develop and evaluate physicochemical properties of acetaminophen and aspirinorally disintegrating strips with high loading dose The strips were compared with conventional over the counter strips andchewable tablets for their mechanical and chemical properties Aspirin (81 mg) and acetaminophen (80 mg) oral dissolvingfilms were developed with 50ndash55 of drug loading and were compared with GAS-Xreg (625 mg) and chewable tablets(aspirin and acetaminophen) Orally dissolving films were developed using a solvent casting method Sonication wasproven to be a more competent step in order to load a high amount of active drug substance in the thin film strips Differentfilm formulations were prepared by varying concentration of polymers and plasticizers Optimization of formulation wasdone by conducting studies for various mechanical properties using TA-XT plus texture analyzer Dissolution of optimizedformulation was performed in 250 ml of pH 12 and artificial saliva (pH 68) The study was conducted by stirring thedissolution media at 50 rpm 37 C for 30 minutes and was analyzed using UVVis spectroscopy The dimensions oforally dissolving films were determined with the help of vernier calipers Modulated Differential Scanning Calorimetry(MDSC) was also performed for the filmstrips to check the compatibility The film strip was evaluated for imperfectionsand cuts peelability without rupturing folding and cracking endurance surface roughness tensile strength film burst anddisintegration time with the help of TA-XT plus texture analyzer Moisture content was performed on the fresh as wellas stability samples Dissolution of filmstrips showed much faster release as compared to respective chewable tablets inartificial saliva as well as in pH 12 Disintegration times for filmstrips were also comparable to Gas-Xreg and ListerineregAfter one month stability of filmstrips at room temperature dissolution profiles perceived with negligible change Othermechanical properties of the filmstrips were also comparable to Gas-Xreg DSC results suggest miscibility in polymer whichexplains the increase in dissolution rate of filmstrips at high dose loading Hence in conclusion we develop a new inhouse method to formulate a stable and more efficient formulation for high loading dose of aspirin and acetaminophen

KEYWORDS Orally Dissolving Films ODT Aspirin APAP Ultra Sonication Dissolution

INTRODUCTIONDrug delivery via oral cavity is the most common routeof administration it has always been an urgency for thepharmaceutical companies to prepare patient compliantdosage forms which in most cases are the oral dosageforms (Srikonda V Sastry 1997) Besides expansion indrug delivery in the last decade oral route of drug admin-istration is counted as the universally preferred routeof drug administration due to self-medication Moreoverit helps in eliminating the generation of pain associatedwith parenteral administration (Siddiqui 2011) As per

lowastAuthor to whom correspondence should be addressedEmail ruteshdaveliueduReceived 4 February 2014Accepted 19 February 2014

the current scenario most pharmaceutical new chemicalentities (NCEs) are falling into the BCS class II and IVcategories (Lipinski 2000) Today the greatest challengethat scientists are facing is due to the lipophilic natureand poor aqueous solubility of chemical entities Suchdrugs can be targeted via oral cavity as they are lipophilicin nature which enhances the uptake of lipophilic drugThe mucosal cavity is highly preferred due to its richblood supply (Rathbone and Hadgraft 1991) The exercisefor the patient compliance led to the development of theoral fast-dispersing dosage forms They are also knownas quick dissolvingquick disintegrating dosage forms Bydefinition these are solid dosage forms which disintegrateor dissolve within a few seconds to a minute in the oralcavity (Sastry et al 2000) After disintegration the film-strip is transformed in to solution or suspension This is

112 J Pharm Sci Pharmacol 2014 Vol 1 No 2 2333-371520141112011 doi101166jpsp20141014



























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Documents

Development and Evaluation of High Loading oral dissolving film of aspirin and acetaminophen