Drug Development and Industrial Pharmacy, 34: 1036-1047, 2008
`Copyright © Infonna UK, Ltd.
`ISSN: 0363-9045 print / 1520-5762 online
`DOl: 10.1080103639040801928952
`
`informa
`I,ealtheare
`
`Investigating a New Approach to Film Casting for Enhanced
`Drug Content Uniformity in Polymeric Films
`
`V. A. Perumal and T. Govender
`School of Pharmacy and Pharmacology, University of KwaZulu-Natal, Durban, South Africa
`
`D. Lutchman
`Abbott South Africa, Abbott Place, Constantia Kloof, Gauteng, South Africa
`
`I. Mackraj
`School of Medical Sciences, University ofKwaZulu-Natal, Durban, South Africa
`
`Films prepared by conventional casting onto trays such as
`teflon-coated perspex trays (TCPTs) suffer from poor drug
`content uniformity. The aim of this study was to prepare a silicone(cid:173)
`molded tray (SMT) with individual wells for film casting and to
`evaluate it in terms of enhancing drug content uniformity. Films
`were prepared by solvent evaporation or emulsification and cast
`onto TCPT and SMT. Preparation of films by the SMT method
`was superior in terms of meeting drug content uniformity
`requirements. As compared with the TCPT method, the SMT
`casting method also reduced the variability in mucoadhesivity,
`drug release, and film thickness. Reproducibility of the SMT
`method was demonstrated in terms of drug content, mucoadhe(cid:173)
`sion, and drug release.
`
`Keywords
`
`films; buccal; drug uniformity; mucoadhesion; drug
`release
`
`left to dry to facilitate solvent evaporation. This forms a sheet
`of film which is cut into desired sizes to provide a specified
`dose of drug (Amnuaikit, Ikeuchi, Ogawara, Higaki, & Kimura,
`2005; Dhanikula & Panchagnula, 2004; Perugini, Genta, Conti,
`Modena, & Pavanetto, 2003; Remunan-Lopez, Portero, Vila(cid:173)
`Jato, & Alonso, 1998). Simultaneous optimization of mucoad(cid:173)
`hesivity and drug release profiles of mono layered films may
`require the blending of drug and polymer(s) of opposing solu(cid:173)
`bilities and therefore may not be simply dissolved in a single
`vehicle for film casting. Such films have been recently prepared
`by a novel emulsification/solvent evaporation method but were
`conventionally cast onto trays as mentioned above, which
`forms film sheets that can be cut into predetermined sizes to
`provide specified doses (Perugini et al., 2003). Preliminary
`investigations in our laboratories using both methods of film
`preparation and casting onto teflon-coated trays as above for
`cutting into specified sizes indicated nonuniform drug distribu-
`INTRODUCTION
`tion across the individual film units. A prerequisite for thera-
`peutic efficacy, safety, and regulatory approval of a medicine
`Mucoadhesive controlled release drug-loaded films are
`is drug content uniformity. Failure to achieve a high degree of
`being extensively studied for the buccal route (Ahmed, Barry,
`Williams, & Davis, 2004; Khoo, Frantzich, Rosinski, Sjostrom, &
`accuracy with respect to the amount of drug in individual unit
`Hoogstrate, 2003; Lin, Lee, & Lin, 1995; Okamoto, Taguchi,
`doses of the film can result in therapeutic failure, nonreproduc(cid:173)
`Iida, & Danjo, 2001; Yoo, Dharmala, & Lee, 2006). Films are
`ible effects, and, importantly, toxic effects to the patient.
`particularly advantageous for the buccal route because they
`An extensive literature search with respect to drug content
`uniformity in polymeric films showed that although the litera(cid:173)
`offer flexibility and comfort and may be preferred over adhe-
`ture is replete with formulation and several physicochemical
`sive tablets. Films can also circumvent the relatively short resi-
`dence time of oral gels on the mucosa, which is easily washed
`characterization studies on films, surprisingly, the majority of
`papers did not report any assay values (Table 1). Of the very
`away and removed by saliva (Peh & Wong, 1999). Films are
`=Conventionally~prepared by the solvent-casting method in" fewthit aid; iri·thiee researcI1ers had measureddn'Ig content by
`which the drug and polymer(s) of similar solubilities are dis-
`dissolving a known weight of the film for analysis (Ahmed
`solved in a single vehicle and cast onto trays, which are then
`et aI., 2004; Amnuaikit, Ikeuchi, Ogawara, Higaki, & Kimura,
`2005; Dhanikula & Panchagnula, 2004). This is not an accurate
`reflection of drug uniformity because sheets offilm are cut into
`unit doses. An assay of film area rather than weight would be
`more appropriate for assessing drug content uniformity in such
`
`Address correspondence to T. Govender, School of Pharmacy and
`Pharmacology, Private Bag X5400l Durban, 4000, KwaZulu Natal,
`South Africa. E-mail: govenderth@ukzn.ac.za
`
`1036
`
`Plaintiffs' Exhibit
`
`Reckitt Benckiser Pharms. Inc., et al.
`v. Watson Labs., Inc., et al.
`(1:13-cv-01674-RGA)(Con.)
`
`PTX 215
`
`MonoSol2012-0001
`
`Dr. Reddys v. MonoSol
`IPR2016-01111
`
`

`
`DRUG CONTENT UNIFORMITY IN POLYMERIC FILMS
`
`1037
`
`TABLE I
`Summary of Film Characterization Studies and Reported Drug Content Uniformity/Assay Results from a Literature Search
`
`Film Characterization
`Studies
`
`Assay
`Results
`
`Reference
`
`Polymer(s)
`
`Drug
`
`EUD ElOO
`
`Piroxicam
`
`EC,HPC
`
`Lidocaine HCl
`
`EC,CHT
`glutamate
`PCL
`
`PHCI, Nifedipine
`
`Chlorhexidine
`
`HPC
`
`Lidocaine
`
`Polycarbophil,
`EUD SIOO
`CHT,PVA,
`PEO, PVP
`
`Plasmid DNA,
`~-Galactosidase
`Model drug
`
`PLGA,CHT
`glutamate
`
`Ipriflavone
`
`Acyclovir
`
`Timolol, Sotalol-HCI
`
`C')
`
`0;
`
`oj
`
`~
`00
`0
`.::
`0 g
`:g
`-'" oj
`..c::
`U
`03
`oj
`..c::
`u
`~
`E
`S
`0 u
`~
`'"
`u
`-5
`OJ
`'" ~:>,
`s-;:;
`<8<1)
`.- '" s·
`.:: '"
`0
`<t::
`~~
`oj ~
`00
`~~
`0
`Q
`
`~o
`
`g
`§
`..c::
`0..
`OJ
`.~
`'"
`.s
`-0
`.::
`'"
`"
`'" s
`0.
`0
`03
`> '"
`
`oj
`
`-0
`
`Q
`bJl
`2
`Q
`
`PAA,CHT
`HCI
`Potato starch,
`potato starch
`acetate
`EUDNE30D,
`PVP
`CHT
`
`Gelatin,
`carrageenan
`CRT
`
`PVA,PVP
`
`Dextran-PCL
`co-polymer
`
`Transparency and SEM, peel adhesion
`test, drug-polymer interaction
`study, in vitro membrane
`permeation study
`In vitro dissolution, DSC, IR,
`measurement of pore size
`distribution, adhesion of films
`In vitro drug release, morphology
`(SEM)
`In vivo test
`
`In vitro permeation, dissolution
`studies, determination of penetration
`rate and release rate
`Release studies, rabbit immunization
`studies
`Swelling and erosion studies, in vitro
`drug release, in vivo animal studies,
`thermal transitions, Fourier
`transform infrared spectroscopy
`(FTIR), tensile testing
`Morphology, water absorption
`capability, degradation, in vitro
`dissolution, drug content uniformity,
`in vitro drug release
`Hydration, rheology, mucoadhesion,
`drug release, permeation
`In vitro release, weight loss and water
`content
`
`Not Reported
`
`Lin et ai., 1995
`
`Not Reported Kohda et ai., 1997
`
`Not Reported
`
`Remunan-Lopez et ai.,
`1998
`Not Reported Medlicott, Holborow,
`Rathbone, Jones, &
`Tucker, 1999
`Not Reported Okamoto et ai., 2001
`
`Not Reported Cui and Mumper, 2002
`
`Not Reported Khoo et ai., 2003
`
`Reported
`
`Perugini et ai., 2003
`
`Not Reported
`
`Rossi et ai., 2003
`
`Not Reported
`
`Tuovinen, Peltonen, &
`Jarvinen, 2003
`
`Reported
`
`Ahmed et ai., 2004
`
`Not Reported
`
`Aksungur et ai., 2004
`
`Not Reported Bonferoni et ai., 2004
`
`Reported
`
`Dhanikula&
`Panchagnula, 2004
`
`Not Reported
`
`Not Reported
`
`Seabra, Ganzarolli, &
`de Oliveira, 2004
`Shi and Burt, 2004
`
`( Continued)
`
`R ~ 0 H T g
`
`"'i)
`
`Penciclovir
`
`Nystatin
`
`Timolol
`
`Paclitaxel
`
`Drug content, microscopy, DSC, X-ray
`diffraction, Higuchi release kinetics
`Water uptake, in vitro release, gel
`stability, in vivo studies on hamsters
`Water uptake, drug release,
`washability test, mucoadhesion
`Stability of paclitaxel, content
`uniformity, release studies, film
`thickness, tensile strength, DSC,
`FTIR, SEM, X-ray diffraction, in
`Vivo il1lpICllltatioll,llis!ology
`S-nitrosogluta-thione DSC, mechanical properties, SEM,
`(GSNO)
`dissolution, diffusion of GSNO
`Paclitaxel
`Swelling, DSC, X-ray diffraction, in
`vitro release, morphology
`
`MonoSol2012-0002
`
`

`
`1038
`
`V. A. PERUMAL ET AL.
`
`TABLE I
`(Continued)
`
`Polymer(s)
`
`PLGA
`
`Drug
`
`Ethacrynic acid
`
`EC,PVP
`
`PHCI
`
`CHT,PAOMA
`co-polymer
`
`Sodium alginate,
`gelatin
`
`Model drug
`
`Ciprofloxacin HCl
`
`CHT, guar gum
`
`Celecoxib
`
`PLGA,
`PVA-g-PLGA
`
`Paclitaxel
`
`Carbopol, PEG,
`HPMC
`
`SDS
`
`Film Characterization
`Studies
`
`Assay
`Results
`
`Reference
`
`In vitro release, SEM, water uptake, pH
`value, weight loss, in vivo eye test
`Thickness, drug content, moisture
`uptake, in vitro drug release, in vitro
`skin permeation
`In vitro drug release, kinetic analysis,
`SEM,
`
`FTIR, X-ray diffraction, in vitro release,
`morphology, mechanical properties,
`swelling
`Swelling, mucoadhesion, in vitro and in
`vivo degradation, drug release
`
`DSC, wide angle X-ray diffraction, size
`exclusion chromatography, SEM, in
`vitro release, in vitro degradation
`Film thickness, drug content, tensile
`strength, measurement of contact
`angle, swelling, erosion, SDS release
`
`Not Reported Wang, Challa, Epstein,
`&Yuan,2004
`Amnuaikit et a!., 2005
`
`Reported
`
`Not Reported Y oshizawa, Shin-ya,
`Hong, & Kajiuchi,
`2005
`Not Reported Dong, Wang, & Du,
`2006
`
`Not Reported Haupt, Zioni, Gati,
`Kleinstem, &
`Rubinstein, 2006
`Westedt et a!., 2006
`
`Not Reported
`
`Reported
`
`Yoo et a!., 2006
`
`EUD, Eudragit; EC, ethylcellulose; HPMC, hydroxypropylmethyl cellulose; CRT, chitosan; PRCI, propranolol hydrochloride; PCL
`polycaprolactone; PLGA, poly(D,L lactide-co-glycolide); PAA, poly(acrylic acid); PEO, poly(ethylene oxide); PVP, polyvinylpyrrolidone; PAOMA
`polyalkyleneoxide-maleic acid; PV A, poly(vinyl alcohol); PEG, poly( ethylene glycol); HPC, hydroxypropyl cellulose; SDS, sodium dodecyl sulphate.
`
`films. In addition, Dhanikula and Panchagnula (2004) only
`stated that uniformity results in their study indicated that the
`variation in drug distribution was <15%, but they did not report
`any data, whereas Perugini et a!. (2003) reported assay values
`as a statement of drug content being more than 70%. The lack
`of reported data on this crucial characterization property of any
`novel drug delivery system led to the assumption that research(cid:173)
`ers in this field may also have been experiencing difficulty
`with this aspect of film characterization. Yet no paper to date,
`to the best of our knowledge, in the published pharmaceutical
`literature has highlighted this difficulty. It was only a search of
`patent applications that confirmed the assumption that difficul(cid:173)
`ties with achieving uniform drug distribution in films did
`indeed exist, as some patent applications that attempted to
`directly address the problems encountered with nonuniformity
`in films were identified. Although the identification of these
`patents confirmed the existence of this problem, it was intrigu(cid:173)
`ing that the published-pharmaceutical liteniture omitted the
`reporting of assay values, yet revealed the undertaking of other
`complex characterization studies (Table I) without focusing on
`overcoming this simple but mandatory prerequisite for devel(cid:173)
`opment of any drug delivery system. In these patent applica(cid:173)
`tions, it was explained that films prepared via the conventional
`casting technique, as used in the literature, suffered from the
`
`aggregation or conglomeration of particles, which rendered
`them inherently nonuniform in terms of all film components,
`including polymers and drug. It was found that the formation
`of agglomerates randomly distributed the film components as
`well as any active present, thus leading to the poor drug
`content uniformity (US Patent No. 60/443,741,2004). The for(cid:173)
`mation of agglomerates was attributed to the relatively long
`drying times, which facilitated intermolecular attractive forces,
`convection forces, and air flow which aided in the formation of
`such conglomerates (US Patent No. 60/443,741, 2004). Some
`approaches
`that attempted to prevent agglomeration are
`described briefly. Schmidt (US Patent No. 4,849,246 in US
`Patent No. 60/443,741, 2004) abandoned the concept that a
`mono layered film may provide accurate dosing and instead
`attempted to solve the problem of aggregation by forming a
`multilayered film. The incorporation of additional excipients,
`i.e. gel formers and polyhydric alcohols respectively, to
`iricrease the viscosity of the filinprioitodryiiig iri-ail'eff6rttCi C
`reduce aggregation of the components in the film is described
`(US Patent No. 60/443,741, 2004). These methods had the
`disadvantage of requiring additional components, which trans-
`lated to additional cost and manufacturing steps. Furthermore,
`these methods employed the use of time-consuming drying
`methods such as high-temperature air-bath using a drying oven,
`
`-
`
`.
`
`MonoSol2012-0003
`
`

`
`DRUG CONTENT UNIFORMITY IN POLYMERIC FILMS
`
`1039
`
`drying tunnel, vacuum dryer, or other such drying equipment,
`all of which aided in promoting the aggregation of firm compo(cid:173)
`nents and active. In addition, such processes subjected the
`active to prolonged exposure to moisture and elevated temper(cid:173)
`atures, which might render it ineffective or even harmful (US
`Patent No. 60/443,741, 2004). Also, approaches described in
`US Patent No. 60/443,741, 2004
`for enhancing drug
`uniformity, required sophisticated drying equipment and
`additional pharmaceutical excipients, which lead to unfeasible
`increased manufacturing costs and multi-step processing.
`Thus, a method that uses minimal additional excipients into the
`fonnulation, uses simple technology, and also provides uni(cid:173)
`form drug content throughout the film clearly needed to be
`identified. Instead of considering additional excipients or intro(cid:173)
`ducing new expensive and complicated drying technologies, a
`specially designed tray with built-in predetermined wells for
`forming polymeric films with uniform drug content was pro(cid:173)
`posed and evaluated in this study. It was expected that this sim(cid:173)
`ple approach, which would involve casting specified volumes of
`polymer-drug mixtures into wells, would lead to improved drug
`uniformity because the drug would be entrapped in each film
`unit, irrespective of the migration of the active within that well
`during drying. Such an improvement will not only be useful in
`the field of buccal drug delivery for formulation optimization,
`but it will also impact on other fields because mucosal films are
`used for a variety of other routes of administration, that is, vagi(cid:173)
`nal, rectal, and ocular.
`Therefore, the aim of this study was to develop and evaluate
`a specially designed silicone-molded tray (SMT) with built-in
`predetermined wells for film casting as a method for achieving
`drug uniformity. Propranolol hydrochloride (PHCl) was used
`as the model drug. Initially, the SMT was evaluated with a
`simple homopolymeric film containing drug and polymer of
`similar solubilities. Thereafter, its applicability to monolayered
`multipolymeric films with drug and polymers of both similar
`and opposing solubilities was also assessed. In addition to drug
`content uniformity, thickness, and morphology, the films from
`the trays were also characterized in terms of mucoadhesivity
`and in vitro drug release properties. These two properties
`measure retention on the mucosae and drug release behavior,
`respectively, and are essential in the evaluation of drug deliv(cid:173)
`ery systems for the buccal route.
`
`MATERIALS AND METHODS
`
`Materials
`Chit()san (CHT) (MW 110 000) (Primex Ingredients ASA,
`Avaldsnes, Norway), Hydroxypropylmethylcellulose (HPMC)
`(Fluka, Buchs, Switzerland), Propranolol HCI (PHCI) (Frankel
`Chemicals, Johannesburg, SA), Mucin (Sigma-Aldrich, Dorset
`UK), Lactic Acid (BDH Lab Supplies, Poole, UK), Perspex
`(Maizey Plastics, Durban, SA), and Teflon (Coated Fabrics,
`Johannesburg, SA) were purchased and used as received.
`
`Eudragit® RS I 00 (EUD I 00) (Rhom Pharma, Darmstadt,
`Germany) was donated by Degussa Africa (Pty) Ltd. Wacker
`Silicone M4514 (Elastosil®) (amt Composites, Durban, SA)
`was mixed with its supplied catalyst (T 26) prior to use. All
`other chemicals used were of analytical or reagent grade.
`
`Methods
`Preparation a/Trays/or Film Casting
`Drug containing polymeric solutions/emulsions were cast
`onto conventional teflon-coated perspex trays (TCPTs) as well
`as onto two other trays, that is, TCPTs with a removable cham(cid:173)
`ber system and SMTs with built-in wells. The description and
`preparation of these trays are presented hereunder. Digital
`photographs of the trays are presented below in Figure 1.
`
`(a)
`
`(b)
`
`(c)
`
`FIGURE I. Digital photographs of trays used for casting of drug-polymeric
`films. (A) Conventional teflon-coated perspex tray (TCPT); (B) TCPT with a
`removable chamber system, (i) separate components and (ii) chambers inserted
`into TCPT; (C) silicone-molded tray (SMD (i) without inserts and (ii) with
`teflon-coated perspex inserts.
`
`R j G H T S
`
`i(i)
`
`MonoSol2012-0004
`
`

`
`1040
`
`V. A. PERUMAL ET AL.
`
`Teflon-Coated Perspex Trays. TCPTs were prepared by
`gluing together pieces of 4-mm clear perspex (Maizey Plastics)
`to form a tray of dimensions 11 x 7 x 3 cm with an area of
`77 cm2
`. Thereafter, the trays were coated with a self-adhesive
`fabric teflon (Cofab, Johannesburg, SA) and were ready for
`immediate use. The TCPT yielded a sheet of film that was then
`cut into individual 1 x 3 cm2 film units for analyses. The tray
`is shown in Figure IA.
`TCPT with a Removable Chamber System. The TCPT was
`prepared as described in the Section "Teflon-Coated Perspex
`Trays," and the removable chamber system was prepared by
`gluing together pieces of perspex to form a grid that formed
`16 individual compartments of 1 x 3 cm2 each when inserted
`into the TCPT. These compartments were coated with teflon
`fabric (Cofab). Films that were of 1 x 3 cm2 size were retrieved
`from each compartment. The tray is shown in Figure lB.
`Silicone-Molded Trays. SMTs were prepared by combining
`Wacker silicone (150 mL) with its catalyst (T 26) (7.5 mL)
`(AMT Composites) in a glass beaker, by stirring with a glass
`rod for approximately 8 min to form a silicone mixture with a
`pot life of 20 min, and then pouring it into a greased wooden
`mold and allowing it to cure at room temperature (20°C) for 5 h.
`The cured silicone was then demolded to yield a flexible sili(cid:173)
`cone tray with 20 individual 1 x 3 cm2 wells. This tray was
`also investigated with the addition of teflon-coated perspex
`inserts into each tray. The inserts were prepared by cutting
`4-mm clear perspex pieces (Maizey Plastics) into 1 x 3 cm2
`rectangles and coating them with the self-adhesive fabric
`teflon (Cofab). These inserts were then firmly placed into each
`well of the SMT prior to film casting. The SMT yielded indi(cid:173)
`vidual film units of 1 x3 cm2 from each well. The tray is
`shown in Figure 1 C.
`
`the above CHT solution. The resulting drug containing poly(cid:173)
`meric solution was allowed to stand until air bubbles were
`removed before casting onto a TCPT or SMT. The quantities
`used ensured that each 1 x 3 cm2 film unit would theoretically
`comprise 15 mg PHCI.
`Multipolymeric Films. Multipolymeric films, in which drug
`and polymers were all of similar solubilities (i.e., PHCI+
`CHT+HPMC) and also those in which drug and polymers
`were of opposing solubilities (i.e., PHCI + CHT + EUDIOO),
`were prepared for evaluation. The films were prepared in a
`1 :0.5 :0.5 drug:polymer:polymer ratio. Plasticizer was added at
`30% wt/wt of polymer weight.
`Monolayered multipolymeric films, in which PHCI and the
`polymers (CHT and HPMC) were all hydrophilic, were pre(cid:173)
`pared as follows: CHT and glycerol as plasticizer (30%, wtlwt)
`were dissolved in a 1% lactic acid solution (15 mL), and
`thereafter PHCI was added and allowed to dissolve. HPMC
`was dissolved separately in water (15 mL) and then added to
`the PHCI-CHT preparation and allowed to mix under magnetic
`stirring. When this drug-containing multipolymeric solution
`was homogenously combined, it was cast onto the respective
`trays and dried as described above.
`Monolayered multipolymeric films with the hydrophilic
`drug PHCI and a hydrophilic (CHT) as well as a hydrophobic
`polymer (EUD100) were prepared as per a method modified
`from Perugini et al. (2003): CHT and glycerol (30%, wtlwt)
`were dissolved in a 1 % lactic acid solution (15 mL), and there(cid:173)
`after PHCI was added and allowed to dissolve. EUD 1 00 and tri(cid:173)
`ethyl citrate (30%, wtlwt, used as a plasticizer) were separately
`dissolved in acetone (15 mL). Both polymeric solutions were
`brought to the same temperature (20°C) and then combined
`by emulsification (IKA Homogenizer, 9,500 rpm for 5 min).
`During homogenization, the polymeric solution was maintained
`in an ice bath. The resulting drug-containing emulsion was cast
`onto the respective trays and dried as described above.
`
`Preparation of Polymer-Drug Solutions/Emulsions
`for Film Casting
`All PHCI-containing polymeric solutions/emulsions were Evaluation of Films
`Assay ofPHCI Polymeric Films. A 1 x3 cm2 film, either as a
`prepared at a concentration of 15 mg/mL to ensure that each
`1 x 3 cm2 film unit theoretically contained a 15 mg/3 cm2 dose.
`unit from the SMT or cut into this specified size with a scalpel
`The total volume of PHCI containing polymeric solution!
`from the film sheet of a TCPT, was cut into pieces with a surgi(cid:173)
`emulsion was cast onto the TCPT, whereas 1 mL of the solution
`cal blade in a mortar. Thereafter, the contents of the mortar
`was cast into each well ofthe SMT. All trays containing the cast were transferred into a 100 mL volumetric flask. The mortar
`polymeric solutions/emulsions were allowed to dry in an oven was washed several times with the selected solvent system
`(water or water/ethanol), which was also transferred into the
`(Series 2000, Scientific, South Africa) at 30°C for approxi-
`mately 24 h, until the solvent had evaporated (until constant
`flask after each washing. The mixture was then mechanically
`agitated in a shaking water bath maintained at 40°C for 24 h
`weight). Films were stored in foil bags in a tightly sealed
`:.imber bClttleat roOlntemperature (20°CLll~~iUurther use. T~~ ___ ~efore being brought up to volume with additional solvent.
`. preparidion of the polymeric soluiions7emuIsionsfoi-casting-- This-stock solution (0.15 mg/rriL) wasaJso agihitedfor 5min
`onto the different trays is described below.
`and then filtered (Millipore® Filter, 0.45 llm). A subsequent
`Homopolymeric Films. Homopolymeric films containing
`1 in 10 dilution was performed before UV analysis of the solu(cid:173)
`CHT and PHCI were prepared at a 1:1 ratio. The required
`tion at 290 nm (UV-Spectrophotometer, 1650 PC, Shimadzu,
`amount of CHT and plasticizer, that is, glycerol (30% wtlwt of Tokyo, Japan). It should be noted that at the outset, it was
`polymer weight), was dissolved in a I % lactic acid solution
`established that all solvents, polymers, and other excipients
`(30 mL) under magnetic stirring. PHCI was then dissolved in
`employed in this study did not interfere with drug analysis at
`
`MonoSol2012-0005
`
`

`
`DRUG CONTENT UNIFORMITY IN POLYMERIC FILMS
`
`1041
`
`the reported wavelengths. Precision and accuracy tests were
`undertaken and confirmed the validity of the assay method used.
`In Vitro Drug Release Profiles. A modified shaking water
`bath dissolution method was employed to determine drug
`release profiles of the films. The shaking water bath apparatus
`(100 strokes per minute) consisted of a water bath, thermostati(cid:173)
`cally controlled at 37 ± 0.5°C and a mechanical shaker
`platform onto which a bottle holder plate was positioned. Glass
`bottles (125 mL), the caps of which were modified to hold a
`stainless steel basket into which each film was placed so as to
`contain all fragments of the dosage form as it disintegrated dur(cid:173)
`ing the dissolution process, were secured in the holders of the
`holder plate. The baskets used were dissolution baskets with a
`height of 35 mm, a diameter of 20 mm, and a mesh size of
`0.4 mm. Phosphate-buffered saline (PBS) (100 mL) equili(cid:173)
`brated to 37 ± O.5°C was used as the dissolution medium.
`A minimum of three replicate determinations were performed
`for all dissolution tests. At specified time intervals (0.25; 0.5;
`0.75; 1; 2; 3; 4; 5; 6; 7; and 8 h), 2-mL aliquots of sample were
`removed from each vessel using a syringe and filtered through
`a MiIIipore® Filter (0.45 !-lm). An equal volume (2 mL) of fresh
`PBS was replaced into each dissolution vessel, to ensure a con(cid:173)
`stant volume of dissolution medium throughout the duration of
`the test. All dissolution samples were analyzed using a UV
`spectrophotometer (Shimadzu) at a wavelength of289 nm.
`Mucoadhesivity of Films. The mucoadhesivity of the films
`was measured with the aid of a software-controlled penetrometer,
`TA-XT2i texture analyzer (Stable Micro Systems, Surrey, UK)
`equipped with a 5-kg load cell, a force measurement accuracy
`of 0.0025%, and a resolution distance of 0.0025 mm. The pre(cid:173)
`test, test, and post-test speeds were set at 1.0, 0.5, and 1.0 mmls,
`respectively, with an acquisition rate of 200 points per second.
`A removable stainless steel probe with dimensions I x3 cm2
`was used for all measurements. A sample of the prepared poly(cid:173)
`meric film (1 x3 cm2
`) was attached to the base of the probe
`with cyanoacrylate (superglue) and prehydrated with PBS
`(PH 6.8, 20 !-lL) before being fixed to the mobile arm of the
`TA-XT2i, where the film was allowed to continue to undergo
`hydration for the remaining period of the 2 min prehydration
`phase. In the interim, 1 mL of mucin (30%, wtlwt at 37°C) was
`spread onto a glass slide that was firmly attached to the base
`plate of the TA-XT2i. Upon completion of the prehydration
`period (2 min), the film was brought into contact with the
`mucin for 30 s. The mucoadhesive performance of the samples
`was determined by measuring the maximum detachment force
`(MDF) (mN) and/or work (mJ). The MDF represents the force
`required to detach the film from themucin. The area under the
`... ·c force/ dista;icecurve wat:iIso determined to represent the work
`or energy required for detachment of the two systems (mucin!
`polymeric film) (Eouani, Piccerelle, Prinderre, Bouret, &
`Jaochim, 2001). A typical force/distance curve generated for
`each mucoadhesivity measurement from which the MDF and/
`or work performed was determined is illustrated in Figure 2.
`A minimum of 10 replicate determinations was performed.
`
`(N)
`Force
`1.4
`
`1.2
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0.0 t=====..-----.-r--,---.----,
`00
`0.6
`0.8
`1.0
`Distance (mm)
`
`-{).2
`
`-{).4
`
`FIGURE 2. A typical detachment profile (force-distance curve) for the
`mucoadhesivity testing of a polymeric film.
`
`Appearance and Morphology. Film surface was evaluated
`optically by a digital camera (Nikon Coolpix 5900, Tokyo,
`Japan). Film morphology was also characterized by scanning
`electron microscopy. Samples were mounted on round brass
`stubs (12 mm diameter) using double-backed adhesive tape
`and then sputter-coated for 8 min at 1.1 LV under argon atmo(cid:173)
`sphere with gold (Polaron SC 500 Sputter Coater, Watford,
`UK) before examination under the scanning electron micro(cid:173)
`scope (JEOL JSM-6100 Scanning Electron Microscope,
`Avaldsnes, Japan). The images were captured on an Ilford
`PANF 50 black and white 35-mm film.
`Thickness Measurements. The thickness of each film was
`measured at five different locations (center and four comers)
`using an electronic digital micrometer (Mitutoyo Co.,
`Kawasaki, Japan). Data are represented as a mean ± SD of five
`replicate determinations.
`Statistical Analysis. All statistical analyses of data were
`undertaken using GraphPad Instat, version 3.05 (GraphPad
`Software Inc., San Diego, CA, USA), whereas all mathemati(cid:173)
`cal calculations were undertaken with Microsoft Excel®
`(Version 2002, USA). The assay data were specifically
`analyzed using a Kruskal-Wallis test with Dunn's Post Hoc
`tests, whereas the mucoadhesivity data were analyzed using
`one-way ANOV A with Bonferroni Post Hoc tests. Data were
`considered statistically significant if p < 0.05.
`
`RESULTS AND DISCUSSION
`
`Development of Trays for Enhancing Drug Uniformity
`in Films
`Table 2 depicts the pictures of trays used in the study for
`film casting and a summary of the assay and morphology of
`films generated. Homopolymeric CHT films were initially
`
`R 1 G H T S
`
`i<~}
`
`MonoSol2012-0006
`
`

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`1042
`
`V. A. PERUMAL ET AL.
`
`TABLE 2
`Description of Tray Development and Film Characteristics
`
`Tray Type
`
`TCPT
`
`Picutre of Tray
`
`Assay (%)
`Mean±SD
`
`110.00 ± 66.63
`CV= 60.57%
`
`Electron Micrograph of Film
`
`TCPT with removable
`chambers
`
`lI6.33±28.31
`CV = 24.34%
`
`SMT
`
`104.06 ± 3.31
`CV = 3.18%
`
`SMT with teflon-coated
`perspex inserts
`
`104.84 ± 1.30
`CV =1.24%
`
`-- . TCPT;tef1on~coatedperspex tray; SMT, silicone-molded tray:
`
`prepared by employing the conventional casting technique
`whereby the polymeric solution is cast onto TCPTs to form a
`sheet of film that is cut into individual film units of desired
`sizes. This yielded films with uniform surface morphology but
`poor drug content uniformity values, i.e., 110.00 ± 66.63%,
`
`indicating a large coefficient of variation (CV) of60.57%. The
`poor drug uniformity with these TCPTs was attributed to the
`reasons given in several patent applications, that is, to the for(cid:173)
`mation of conglomerates and migration of drug throughout the
`tray during the drying process. To prevent this from occurring,
`
`R t G H T S
`
`i«>
`
`MonoSol2012-0007
`
`

`
`c
`o
`
`DRUG CONTENT UNIFORMITY IN POLYMERIC FILMS
`
`1043
`
`a TCPT with a removable unit that encompassed chambers
`
`(each chamber = 1 x 3 cm 2) was developed. This was an
`attempt to contain the drug-containing polymeric solution dis(cid:173)
`pensed into each chamber within that chamber. Although this
`method improved the drug uniformity as compared with the
`TCPT, that is, the CV decreased from 60.57 to 24.34%, the
`values were still unacceptable for regulatory approval. This
`poor drug uniformity may have been due to seepage of the
`polymeric mixture to adjacent chambers because it was detach(cid:173)
`able and the solution could seep from one chamber to the next.
`The difficulty also experienced with this type of tray was the
`inability to remove the dried films without damage due to
`rigidity of the tray This, coupled with the poor assay values,
`led to the realization that a flexible tray for easy film removal
`was required and that the tray should also possess individual
`predetermined wells completely separate from one another, to
`facilitate entrapment ofthe polymeric solution.
`One of the suitable materials that satisfy the abovemen(cid:173)
`tioned factors is silicone, as it can be easily molded to yield a
`flexible product. In addition, silicone products have a rela(cid:173)
`tive inert state that minimizes the risk of chemical reaction
`with dmg (Maillard-Salin, Becourt, & Couarraze, 2000).
`Silicones also resist acids, bases, solvents, chemicals, oils,
`and water. Furthermore, it has been previously used in the
`literature as a component of novel drug delivery systems
`(Maillard-Salin et aI., 2000; Schierholz, Jansen, Jaenicke, &
`Pulverer, 1994).
`Taking these factors into consideration, an SMT with
`20 individual separate wells was developed. Instead of being
`cast as a single film to be cut up into different sizes, a specified
`volume of dmg-polymeric solution/emulsion was cast into
`each well of the SMT and dried to form individual film
`units. Films prepared using this tray exhibited assay values of
`104.06± 3.31%, that is, a CV of3.18% (Table 2). Hence as
`compared with the TCPT method, the SMT method signifi(cid:173)
`cantly reduced the CV for assay values from 60.57 to only
`3.18%, thus confirming its suitability to enhance dmg content
`uniformity. Also, flexibility of the molded tray enabled the
`easy removal of films for evaluation. However, the films from
`this tray displayed poor surface morphology as they appeared
`
`porous (Table 2). This could possibly be due to the physical
`nature of silicone when it is heated and dried, that is, adhesion
`of the films directly onto the silicone surface may have resulted
`in the film porosity observed. Becaus