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167
Current Applied Polymer Science, 2019, 3, 167-188

REVIEW ARTICLE
ISSN:2452-2716
eISSN: 2452-2724

Oral Soluble Films: Attributes of the Polymeric Material and Critical

Process Parameters for Designing Good Quality Films

Suhani Sinha1 and Rohit Dutt1,*

1
Department of Pharmacy, School of Medical and Allied Sciences, G D Goenka University, Gurugram-122103, India

Abstract: Background: Soluble films prepared using polymeric matrices have gained prominence in
drug delivery because of its multifarious merits. They are emerging as a momentous technology for
designing precision medicines using printing technology, wherein the drugs, proteins/peptides and
Current Applied Polymer Science

ARTICLE HISTORY
Received: October 16, 2019
Revised: November 17, 2019
Accepted: November 26, 2019
DOI:
10.2174/2452271603666191210121944
hormones in printing ink solution can be printed on placebo films targeted for specific age group
dosage administration. Advances made in 3D printing technology in biomanufacturing for sophisti-
cated tailor-made scaffolds of bone and tissue have further given impetus to digitally-controlled de-
positing of materials to create freeform geometries in the field of dosage form development.
Objective: The patent expiry of a significant number of existing chemical entities is an encouraging
factor for the possible market potential of these films as a novel drug delivery system through the
oral route, topical route and ocular route. Most prominent amongst them is the oral route simply be-
cause of its substantial advantages over other pre-existing oral dosage forms.
Method: Oral soluble films can be tailored for both local action in the buccal cavity as well as for
systemic action to other parts of the body by direct absorption into the systemic circulation through
the buccal mucosa. Depending upon the material attributes of its polymeric components, they can be
targeted for buccal, sublingual, ocular or topical administration and can also be loaded inside hard
gelatin capsule shells for administration into the gastrointestinal tract. Polymeric oral film technology
has been exploited to address gaps in varied therapeutic segments including pain and inflammation
management to provide instant relief, anti-emesis following chemotherapy, central nervous system
disorders due to ease of administration to the caregivers and patient compliance, cardiovascular dis-
eases due to faster onset of action, cancer therapy with enhanced safety and efficacy due to direct
systemic absorption bypassing the first pass metabolism effect.
Conclusion: This review summarizes the research works done to address gaps in varied therapeutic
areas with an emphasis on critical material attributes of its polymeric components and the critical
process parameters to be considered for manufacturing robust good quality medicinal films.

Keywords: Buccal films, hot-melt extrusion, inkjet printing, orodispersible films, solvent casting, sublingual films.

1. INTRODUCTION Different types of film formulations have been developed

Oral soluble films contain active pharmaceutical ingredi-
ents and excipients dispersed in thin polymeric matrices or
strips intended to be placed on the tongue for rapid dissolu-
tion in saliva prior to absorption. The regulatory agencies use
different terms to define them, for example US Food and
Drug Administration (USFDA) describes them as ‘Oral Sol-
uble Films’ while the European Medicines Agency (EMA)
describes them as ‘Orodispersible Films’ [1-3]. The na-
ture/type of soluble and biodegradable polymers substantial-
ly influence the quality and therapeutic activity of films.
*Address correspondence to this author at the Department of Pharmacy,
School of Medical and Allied Sciences, G D Goenka University, Gurugram-
122103, India; Tel: +919896732222; E-mail: rohitdatt23@rediffmail.com
depending upon the type and grade of polymer used to pre-
pare films. Dominant amongst them are:
1.1. Buccal Films
They are fabricated either as bilayer or multilayer films
containing a permeability enhancer and/or a mucoadhesive
polymer to adhere to buccal mucosa for efficient permeation
of drug. These films can be tailored for either local action in
buccal cavity or systemic action and for either immediate or
prolonged release of drug loaded on these films. The in-
volvement of an insoluble polymer backing layer facilitates
one way absorption and prevents rapid dissolution and loss
of drug in the oral cavity [4-7]. Ethyl cellulose and chitosan
have gained an upper edge as the backing layer and permea-

2452-2724/19 $58.00+.00 © 2019 Bentham Science Publishers

168 Current Applied Polymer Science, 2019, Vol. 3, No. 3
bility enhancing polymer respectively. Polymer backing film
of ethyl cellulose containing antibacterial agent ornidazole
was developed for the treatment of periodontitis. These pol-
ymeric films showed a sustained release of ornidazole over a
period of 9 days and in vitro antibacterial activity against
oral bacteria Streptococcus mutans [8]. Buccal films gained
immense compliance from pediatric, geriatric to dysphagic
patients due to their thin structure, adaptability towards buc-
cal mucosa and choice of exact dose modulation [9-12].
Vakili et al. [13] prepared bilayered buccal films of propran-
olol hydrochloride for the pediatric population by solvent
casting method using a polymer mix of polyvinylpyrroli-
done, polyvinyl alcohol, with different weight ratios of gela-
tin and or chitosan. Bilayer xanthan gum based mucoad-
hesive buccal patches of zolmitriptan were reported in the
literature with a 40-50% initial drug release followed by sus-
tained drug release for over 5 hours [14]. Fluticasone propi-
onate buccal films were prepared with different concentra-
tions of sodium carboxymethylcellulose and carbopol 971P
to achieve sustained release of the drug for 10 hours. Roy et
al. [15] reported different bioadhesive polymers with desired
characteristics, various sites suitable for mucoadhesive drug
delivery system and factors affecting bio/ mucoadhesion.
Sosnik et al. [16] expressed the benefits of the incorporation
of mucoadhesive polymers into the structure of these prod-
ucts to prolong their residence time at the site of administra-
tion. Chitosan is the most widely reported polymer for the
buccal film preparation as it improves the drug bioavailabil-
ity by facilitating the drug permeation of molecules across
the mucosal surface. Makhlof et al. [17, 18] elaborated vari-
ous mucoadhesive polymers, including poly (acrylates), chi-
tosan, thiolated polymers used in the formulation of mucosal
drug delivery. Buccal film of tramadol hydrochloride was
prepared by the solvent casting method using two different
grades of Polyvinylpyrrolidone (PVPK-90 and PVP K-70)
and chitosan as mucoadhesive polymers. Polymeric solution
of chitosan was prepared by dissolving chitosan in acetic
acid and distilled water with constant stirring. PVP was add-
ed to the solution of chitosan with stirring. Propylene glycol
(5%, V/V) was added as a plasticizer. Tramadol HCl was
added to polymeric solution and cast to films [19]. Mucoad-
hesive films containing curcumin-loaded nanoparticles coat-
ed with chitosan were successfully prepared using the sol-
vent casting method, after incorporation of nanoparticles into
plasticized chitosan solutions. The nanoparticle loaded films
offer controlled and prolonged delivery of drugs with desired
absorption, distribution, metabolism and elimination (AD-
ME) profile. Influenced by the multiple roles of cyclodex-
trins in polymeric systems Miroa, Agnese et al. [20] fabri-
cated polymeric matrices of polyethylene oxide (PEO) with
different concentrations of (2-hydroxypropyl)-cyclodextrin
(CD) using triamcinolone acetonide (TrA), a lipophilic syn-
thetic corticosteroid which is sparingly water soluble. The
formulation containing 54% by weight of CD was observed
as the optimized composition with acceptable mechanical
properties, in terms of tensile strength and elasticity, with
good wettability. The experiment strongly supports applica-
tions of PEO/CD films in buccal drug delivery. The oral bio-
availability of C-glycosyl flavonoid enriched fraction of Ce-
Sinha and Dutt
cropia glaziovii (EFF-Cg) was significantly improved by
preparing chitosan buccal films impregnated with EFF-Cg-
loaded nanospheres for labial herpes treatment [21]. Batista
et al. [22] prepared buccal delivery systems, using nanopar-
ticles of proteins and peptides to provide an alternative to
cumbersome parenteral delivery systems. Low molecular
weight heparin was also prepared as polymeric nanoparticles
and loaded on polymethacrylate polymeric film matrices.
The observations from these experiments suggested that the
surface charge on nanoparticulate systems significantly in-
fluence the permeation of drug through the buccal mucosa.
In another study nanoparticles of heparin loaded on
polymethacrylate polymeric film showed longer contact
times and deeper diffusion and transport of drug through the
buccal mucosa [23]. Alexander et al. [24] also described the
potential application of mucoadhesive polymers in formulat-
ing different types of mucoadhesive drug delivery systems.
Buccal insulin liposomes showed promising results in terms
of insulin delivery with significantly greater bioavailability
than conventional and subcutaneous insulin solution [25].
1.2. Sublingual Films
They are the second most popular category among film
dosage form. They are designed to be placed on the upper or
lower surface of vascular tongue to achieve rapid peak plas-
ma concentration for faster onset of action. They also help
maintain constant drug absorption profile while switching
from large volume parenteral drip to oral solid dosage form.
Sublingual films have the capabilities to accelerate the onset
of drug action, reduce the dose frequency and enhance drug
efficacy. Literature reveals the improved rate and extent of
absorption of meloxicam in the form of sublingual films pre-
pared by simple process integration of nanoprecipitation and
loading onto the fast dissolving films by solvent casting
method [26]. Similarly, Lai F. et al. [27] formulated nano-
suspension of quercetin using a high pressure homogenizer
followed by loading on films by a casting method. Free and
film loaded quercetin nanocrystals showed a comparable
dissolution rate, much higher than that of bulk quercetin.
Bhavesh et al. [28] prepared fenofibrate nanocrystals and
studied in vivo pharmacokinetics in rabbits. They observed a
significant difference in the pharmacokinetic parameter (1.4
fold increase bioavailability) of Fenofibrate nanocrystals-
loaded oral soluble films as compared to the marketed for-
mulation "Tricor" (pristine) drug.
1.3. Orodispersible Films
These films are fabricated with low molecular weight and
low viscosity single hydrophilic polymer or a combination of
polymers to achieve desired diffusion and solubility after
administration in oral cavity [29]. Rapid absorption through
vascular mucosa avoids the first-pass metabolism and im-
proves bioavailability of drug formulated in this type drug
delivery system [30]. Microparticles of prednisolone pre-
pared as orodispersible films showed good mechanical re-
sistance while maintaining excellent disintegration properties
[31]. Pawar et al. [32] prepared orodispersible films of
risperidone demonstrating improved bioavailability and rapid
Oral Soluble Films: Attributes of the Polymeric Material and Critical Process Parameters
onset of action for effective treatment of schizophrenia. High
relative bioavailability was shown by fast dissolving films of
antipsychotic drug, flupentixol dihydrochloride as compared
to the marketed preparation [33].
1.4. Ophthalmic Films
The ocular route of film drug delivery has gained im-
mense popularity in the last decade owing to their inherent
advantage of reduced dosing frequency and constant release
of drug. The drug permeability is guided by characteristics of
the polymer used. They are fabricated using a combination
of polymers for local application in the eye resulting in the
reduction of dose frequency and less systemic side effects,
while also achieving high therapeutic success and patient
adherence through local administration [34].
The other categories of film include films for topical ap-
plication on skin for inflammation or films prepared as diag-
nostic kits. These ideas are however in nascent stages of es-
tablishment of proof of concept. The all-embracing ad-
vantage of various film types is that they provide a large
surface area for dissolution, permeation, absorption by pass-
ing first pass metabolism and hence improving bioavailabil-
ity and reducing side effects. The soluble polymers used
therein cause quick disintegration and dissolution in saliva.
They are flexible not fragile and hence need no special pack-
aging for protection during transportation unlike orodispersi-
ble tablets, mouth dissolving tablets or mouth melt tablets.
The other advantages are, no fear of chocking, no need of
water for administration and more accurate dosing. Potent
drugs with low solubility, permeability and proteins/peptides
can also be incorporated as nanoparticles, microspheres and
liposomes, added to polymeric matrix preparation and then
cast to films [35-37]. A simple process integration of mixing
the drug with polymer and casting to films is very economi-
cal rather than other contemporary techniques used for oro-
dispersible tablets in the industry like lyophilization or freeze
drying to cause rapid dissolution in the mouth. Lercanidipine
nano-particles were loaded on fast dissolving oral films by
simple technique devoid of lyophilization or spray drying
technique which rapidly dissolved in the buccal cavity. In-
corporation of nanoparticles in ‘fast dissolving oral films'
addressed the major issues associated with the drug, viz.
poor dissolution and first pass metabolism [37]. The colloi-
dal systems such as nanocrystals, nanoemulsions and poly-
meric nanoparticles showed great promise in drug delivery
by improving the therapeutic index of drugs, thus increasing
their efficacy and/or reducing their toxicity [38]. Alongside
all above advantages, it is also to be noted that since oral
soluble films also have an altered pharmacokinetic profile,
they are categorised as ‘new dosage forms’ and hence a new
drug application (NDA), and a 505 (b) (2) application proce-
dure for registration in the US market is to be followed [39].
Also, in case of absence of a comparator, a new clinical
study would be required to be done by the sponsor. Howev-
er, a new clinical study towards establishing enhanced effi-
cacy awards a three year marketing exclusivity to the product
by the USFDA.
Current Applied Polymer Science, 2019, Vol. 3, No. 3 169
2. ESSENTIAL COMPONENTS OF ORALLY DISIN-
TEGRATING FILMS AND THEIR CRITICAL MA-
TERIAL ATTRIBUTES
Polymers are the essential components of film and their
critical material attributes are discussed below.
2.1. Polymers
They are multifunctional macromolecular compounds
which apart from their primary function to serve as a drug
loading matrix offers other advantages for oral film prepara-
tions like mucoadhesion, inhibition of enzymes, permeation
enhancement, efflux pump inhibition, increased buffer ca-
pacity, sorptive properties, taste masking ability, no pharma-
cological activity, and ability to form conjugates with drugs.
The critical material attributes of polymers that significantly
contribute to the film quality are; molecular weight, viscosi-
ty, hydrophilicity, pH and compatibility with the drug.
Commonly used polymers of natural origin are pullulan,
starch, pectin, sodium alginate, maltodextrin, gelatin, chi-
tosan and polymerized rosin while synthetic polymers widely
used are different grades of hydroxypropylmethylcellulose
(HPMC), hydroxypropylcellulose (HPC), polyvinyl alcohol
(PVA), modified starches, polyethylene oxide (PEO), eu-
dragit and polyvinylpyrrolidone (PVP). The natural and syn-
thetic polymers are being discussed briefly below along with
their influence on film quality.
2.2. Natural Polymers
2.2.1. Pullulan
Pullulan is a water soluble, neutral, linear polysaccharide
consisting of α-1, 6-linked maltotriose residues. It is a fungal
exopolysaccharide produced from starch by Aureobasidium
pullulan. [40, 41] It can be produced commercially by the
fermentation process. The regular occurrence of alpha-(l, 6)
linkage pattern is believed to be responsible for its structural
flexibility and solubility, resulting in highly water soluble
and flexible films. Pullulan films are thermally stable and
possess anti-static and elastic properties [42]. Films made
from pullulan are colorless, tasteless, odorless, transparent,
and heat sealable. Films made up of pullulan are clear and
highly oxygen-impermeable. The oxygen resistance of pullu-
lan films is suitable for the protection of readily oxidized fats
and vitamins in food. Pullulan film has 300 times stronger
oxygen barrier than HPMC film and 9 times stronger oxygen
barrier than gelatin film of the same thickness [43].
2.2.2. Starch / Modified Starches
Starch is the major carbohydrate reserve in plant tubers
and endosperm of seeds, containing several million amylo-
pectin molecules accompanied by a much larger number of
smaller amylose molecules. Amylose is responsible for the
film-forming capacity of starch [44]. The largest source of
starch is corn (maize) with other commonly used source be-
ing wheat. New film-forming polymer Lycoat NG 73 is an
excellent film forming polymer from pea starch prepared by
chemical and physical treatments [45]. Lycoat is a novel
granular hydroxypropyl starch polymer that has been de-
170 Current Applied Polymer Science, 2019, Vol. 3, No. 3
signed especially for orodispersible films as it disperses easi-
ly in cold water without the formation of lumps. It gives a
homogenous viscous solution by cooking without the for-
mation of lumps and agglomerates. Thus, it has excellent
film forming functionality without the need of additional
agent.
2.2.3. Sodium Alginate
Sodium alginate consists of sodium salt of alginic acid,
which is a mixture of polyuronic acids composed of residues
of D-mannuronic acid and L-guluronic acid. Alginate is a
biopolymer produced by brown seaweeds (Phaeophyceae,
mainly Laminaria). It is present in the cell walls of brown
algae as the calcium, magnesium and sodium salts of alginic
acid. Alginate has unique colloidal properties, which include
thickening, stabilizing, suspending, gel forming, emulsion
stabilizing and film forming property [46]. Edible films pre-
pared from alginate exhibit poor water resistance because of
their hydrophilic nature. The water permeability and me-
chanical attributes can be considered as moderate compared
to synthetic polymer films. Mechanical properties of alginate
film can be improved by the addition of starch [47].
2.2.4. Pectin
Pectin is a high-molecular-weight, complex anionic poly-
saccharide composed of β-1, 4-linked d-galacturonic acid
residues, wherein the uronic acid carboxyls are either fully or
partially methyl esterified. Pectin is found in fruit and vege-
tables and mainly prepared from citrus peel and apple pom-
ace. Pectins are good film formers with good capacity to
carry drugs and depending upon the molecular weight of
pectin used in formulation, it dissolves slowly in the oral
cavity. In a study, it was found that degradation of pectin
reduces its intrinsic viscosity from 4.9dl/g to 2.5dl/g making
it more suitable for use in oral films [48].
2.2.5. Gelatin
Gelatin is a mixture of purified protein fractions obtained
either by partial acid hydrolysis (type A gelatin) or by partial
alkaline hydrolysis (type B gelatin) of animal collagen. It is
prepared by the thermal denaturation of collagen, isolated
from animal skin, bones and fish skins. These protein frac-
tions consist almost entirely of amino acids joined together
by amide linkages to form a linear polypeptide chain. It is
readily soluble in water at temperatures above 40°C, forming
a viscous solution. The film-forming ability of gelatin is di-
rectly related to the molecular weight, i.e., the higher the
average molecular weight, the better the quality of the film.
Gelatin films were found to dissolve rapidly, producing a
smooth mouth feel [49].
2.2.6. Polymerized Rosin
Rosin is resin obtained from pines and some other plants,
mostly conifers, produced by heating fresh liquid resin to
vaporize the volatile liquid terpene components [50]. Rosin
and its esters are reported to have excellent film forming
properties and can be used for enteric coating and delayed
release of drugs. Being natural in origin, rosin and its deriva-
tives are expected to be biodegradable in-vivo. It has many
Sinha and Dutt
excellent properties including anti-oxidation, non-crystalli-
zing and good compatibility with film-forming agents [51].
2.2.7. Maltodextrin
Maltodextrin consists of D-glucose units connected in
chains of length varying from three to nineteen glucose units
[52-54]. The glucose units are primarily linked with α (1→4)
glycosidic bond. Maltodextrin is typically composed of a
mixture of chains and accordingly classified by DE (dextrose
equivalent) and having DE between3-20. The higher the DE
value, the shorter the glucose chains, the higher the sweet-
ness, the higher the solubility. It is used as a film forming
agent.
2.3. Synthetic Polymers
2.3.1. Hydroxypropyl Cellulose
Hydroxypropyl cellulose (HPC) is a non-ionic water sol-
uble thermoplastic polymer. Hydroxypropyl cellulose is a
partially substituted poly (hydroxypropyl) ether of cellulose.
HPC is commercially available in a number of different
grades that have various solution viscosities. Because of rela-
tively high glass transition temperatures (compared to other
film forming polymers) of HPC, the formed films were
shown to exhibit brittle fracture and were found to be stiff,
with a high elastic modulus and a very low percent elonga-
tion (less than 5%). HPC has a good film forming property.
It was chosen as the primary matrix-forming polymer since it
is the only water soluble cellulose derivative that is thermo-
plastic. HPC has a softening temperature in the range of 100-
1500C, depending on its molecular weight. It imparts low
surface and interfacial tension to its solution and thus can be
used for the preparation of flexible films alone or in combi-
nation with hypromellose.
2.3.2. Hydroxypropyl Methyl Cellulose
Hydroxypropyl Methyl Cellulose (HPMC) or hypro-
mellose is a partly O-methylated and O-(2-hydroxypropy-
lated) cellulose. It is known for its good film-forming prop-
erties and has excellent acceptability. Lower O- methylated
substituted grades of HPMC like Methocel E3, E5, and E15
are particularly used for film formation because of their low
viscosity. HPMC forms transparent, tough and flexible films
from aqueous solutions [55]. Additives are often incorpo-
rated to improve specific properties of formulated films.
Several studies have been focused on the influence of addi-
tives on physico-chemical properties of HPMC films. While
HPMC of varying grades is the most widely studied and
suggested polymer for film preparation, it has been observed
that thermal processing of the films containing HPMC in-
duces the crystallinity in hypromellose E15/E5. However,
the incorporation of plasticizer reduces this crystallinity to
some extent. The inclusion of PVA suppressed this crystal-
linity to a greater extent as compared to plasticizers like PEG
and TPGS [25].
2.3.3. Sodium Carboxy Methyl Cellulose
Sodium carboxy methyl cellulose (Na CMC) is prepared
from cellulose by treatment with alkali and mono-chloro-
Oral Soluble Films: Attributes of the Polymeric Material and Critical Process Parameters
acetic acid or its sodium salt. The enzymatically modified
carboxymethyl cellulose has good film forming property. It
is non-toxic and has the ability to accommodate high drug
loadings. Formulations comprising Na CMC or other hydro-
philic polymers such as HPMC and xanthan have great po-
tential for the delivery of drugs to moist surfaces. It is re-
ported for use in combination with other film forming poly-
mers for the preparation of oral films.
2.3.4. Polyvinyl Alcohol
Polyvinyl alcohol is produced by the polymerization of
vinyl acetate to poly vinyl acetate followed by hydrolysis of
poly vinyl acetate to poly vinyl alcohol. Commercial PVA
grades are available with partial or complete degree of hy-
drolysis depending upon which its solubility varies. The par-
tially hydrolyzed PVA is hydrophilic and soluble in water
[56] and yield transparent films with excellent flexibility.
2.3.5. Polyethylene Oxide
Polyethylene oxide (PEO) or POLYOX is a synthetic
polyether or water soluble resin that is readily available in a
wide range of molecular weights. Materials with MW
<100,000 are usually called PEGs, while higher molecular
weight polymers are classified as Poly ethylene oxides. It is a
non-ionic, water soluble resin, highly hydrophilic with good
lubricating, binding and film forming properties. The inter-
esting properties of PEO are its relatively high melting point,
good structural integrity, low glass transition temperature
and low toxicity.
2.3.6. Kollicoat
Kollicoat, a polyvinyl alcohol-polyethylene glycol graft
copolymer is a hydrophilic polymer readily soluble in water.
The polyvinyl alcohol moiety provides good film forming
properties and the polyethylene glycol part acts as an internal
plasticizer leading to excellent flexibility. In contrast to other
film formulations, the plasticizer cannot migrate because it is
covalently bound in the molecule and the film flexibility is
maintained during storage as crystallization is prohibited.
The mechanical properties of the Kollicoat films are retained
even at high relative humidity levels of upto 75%. The film
formed by Kollicoat is transparent in nature.
2.3.7. Poly Vinyl Pyrrolidone (PVP)
Polyvinyl pyrrolidone (PVP), also commonly called Pol-
yvidone or Povidone, is a water soluble polymer made from
the monomeric units of N-vinyl pyrrolidone [57]. It is hydro-
philic and readily forms films. It is non-ionic biocompatible,
non-toxic, essentially chemically inert, temperature resistant,
pH-stable and colorless. Polyvinyl pyrrolidone films are brit-
tle in nature and therefore co-povidone is mixed with poly
vinyl pyrrolidone for the preparation of flexible and fast dis-
integrating films.
It has been observed that films prepared using a combina-
tion of polymers exhibit improved mechanical strength, sta-
bility and dissolution. Oral films of granisetron hydrochlo-
ride were prepared using a combination of synthetic polymer
HPMC and natural polymer Pullulan. In this study, it was
Current Applied Polymer Science, 2019, Vol. 3, No. 3 171
observed that pullulan with 40-45% concentration was not
able to produce films with good strength however, when
used in combination with HPMC at 40% concentration
yielded film with better tensile strength but appeared sticky
[58, 59]. It is to be noted that while low viscosity and low
molecular weight polymers dissolve rapidly, polymers with
high viscosity and molecular mass result in films with better
tensile strength. Therefore, a mixture of polymers is prefera-
bly used, instead of a one polymer based-film, in an attempt
to optimize the final polymeric matrix characteristics. It is
preferred to couple PVA with HPMC and or PVP and or
HPC. Films made up of only sodium alginate exhibit brittle-
ness. Films fabricated with HPMCE15 (1%), HPMC
E5+PVA (0.5-1% + 0.5%) and sodium alginate (HV) (1%)
when plasticized with PEG 400 (1%) were found to possess
superior flexibility and disintegration properties [41]. Films
made up of HPMC E15 and HPMC E5-PVA exhibited supe-
rior characteristics compared to other polymeric composi-
tions when plasticized with TPGS 1000 [20]. TPGS 1000 is
hydrophilic and PVA is also hydrophilic, therefore an excess
amount of TPGS in Hypromellose E5-PVA films leads to the
formation of hygroscopic films [20]. Hifumi et al. [42] pre-
sented the novel application of attenuated total reflection-
Fourier transform infrared (ATR-FTIR) spectroscopic imag-
ing technique to study the correlation between the drying
process and dissolution behavior of polymer-based films.
They concluded that water ingress into the films influenced
the physicochemical state of the drug and dissolution behav-
ior.
Other than polymers discussed above, the other essential
excipients used in film formulation include:
2.3.8. Plasticizers
As already discussed, a plasticizer is added to polymeric
matrix to ensure the flexibility and desired mechanical
strength. It prevents racemization and increases the stability
of polymer in matrix. The most commonly used plasticizer
include, Glycerol, Polyethylene glycol (PEG), Propylene
glycol, Di-butylpthallate, Triethyl citrate, Tocopherol poly-
ethyleneglycol (TPGS) etc. Vuddanda et al. [60] in their
study concluded that glycerol is a suitable plasticizer com-
pared to others for manufacturing Pullulan based oral films.
2.3.9. Surfactants
Sometimes it is desired to include a surfactant as solubil-
ising, wetting or stabilizing agent in the formulation. Some
of the commonly used surfactants are sodium lauryl sulfate,
polyethylene glycols, polysorbates, polyols and polyethylene
glycol 1000 succinate (TPGS). However, if the desired film
attributes are achieved without the use of surfactant, it
should be excluded in the final formulation. Krull et al. [61]
fabricated films of fenofibrate, griseofulvin, naproxen, phe-
nylbutazone, and azodicarbonamide which were considered
as a model poorly water-soluble drugs. Their aqueous nano-
suspension was cast to films. A comparative study using
sodium dodecyl sulfate (SDS) as a surfactant was formulat-
ed, however, it was observed that SDS did not aid in achiev-
ing significant improvement in the dissolution for all five
drugs.
172 Current Applied Polymer Science, 2019, Vol. 3, No. 3
Table 1. Representative examples of drugs formulated as films.
Active Ingredient
Omeprazole, Esomeprazole
Salbutamol
Meloxicam, Ibuprofen, Diclofenac potassium, Benzydamine hydrochloride
Montelukast sodium, Chlorpheniramine Maleate, Cetrizine hydrochloride
Valdecoxib, Diclofenac
Rizatriptan, Sumatriptan
Lopinavir
Heparin, Insulin, Linaclotide, Plecanatide, Octreotide, Buserelin
Metformin, Dapagliflozin, Empagliflozin
Propranolol Hydrochloride, Tri-metazine dihydrochloride
Carbamazepine, Clonazepam, diazepam
Atorvastatin, Lovastatin, Rosuvastatin
Nystatin
Loperamide
Tramadol
Progesterone
Warfarin
Donepezil Hydrochloride
Acetazolamide, Ofloxacin, Levofloxacin, Natamycin
Ondansetron, Granisetron hydrochloride, Metoclopramide, Dimenhydrinate
Fenofibrate
Fluoxetine, Sertraline, Paroxetine, Fluvoxamine, Citalopram
2.3.10. Sweetening Agents
Sweetening agents like saccharin or aspartame can be
added for good mouth feel and aftertaste; however, it should
be noted that a careful selection of filler or diluents like
mannitol, dextrose, fructose, sucrose, isomaltose, sorbitol,
can also impart sweet taste and hence if not required, should
be avoided. Nevertheless, in the case of bitter drugs, the
sweeteners like Aliatame, Neotame, Acesulfame-K, Su-
cralose and Rebina can be experimented.
2.3.11. Saliva Stimulating Agent
Excipients that stimulate saliva production and facilitate
faster disintegration of films can be included in the formula-
tion like citric acid, malic acid, lactic acid and ascorbic acid.
Co-crystals of the drug with citric acid can be prepared.
2.3.12. Flavor
Since the product is intended to be dissolved in the
mouth, a pleasant mouth feel is desired. Any US-FDA ap-
proved flavour can be added, such as intense mints or sour
fruit flavors.
Sinha and Dutt
Therapeutic Category
Antiulcer [65]
Antitussive, expectorant [66]
Antiinflammatory [6, 13]
Antiallergic, antihistamine [67, 68]
Non-steroidal antiinflammatory [69]
Antimigraine [70]
Antiretroviral
Peptides [71-73]
Antidiabetic [74]
Antihypertensive, anti-angina [75-77]
Antiepileptics [78]
Statins [79]
Antifungal [80]
Antidiarrheal [81]
Opiate (narcotic analgesics)
Hormone [82]
Anticoagulant [83]
Reversible acetyl choline esterase inhibitor [84]
Ocular film
Antiemetic [85]
Antihyperlipidemic
Selective serotonin reuptake inhibitors
2.3.13. Permeability Enhancers
It has been reported that the permeability of the buccal
mucosa is approximately 4000 times greater than that of the
skin [1]. However, if desired, the permeability enhancers like
chitosan, 23-lauryl ether, azone, sodium EDTA, cetylpyri-
dinium chloride, cyclodextrins, polyoxyethylene cetyl ether,
menthol, sodium glycocholate and sodium taurodeoxycho-
late can be used depending upon the compatibility with drug
[62-63]. Formulating the drug as liposomes have also been
demonstrated to improve permeability and bioavailability.
Abd El Azim et al. [64] prepared vitamin B6 entrapped in
liposomes, which was then formulated as a mucoadhesive
film. Ex vivo permeation of vitamin B6, across chicken
pouch mucosa indicated increased permeation from liposome
systems compared to corresponding controls.
2.3.14. Active Ingredient
Several classes of drugs can be formulated as oral dis-
solving films and some of them are listed in Table 1.
The ideal candidates for film formulation are drugs of bi-
opharmaceutics classification system (BCS) class I, II and
Oral Soluble Films: Attributes of the Polymeric Material and Critical Process Parameters Current Applied Polymer Science, 2019, Vol. 3, No. 3 173

III, and this technology is a useful platform for the delivery
of drugs which are potent with low bioavailability due to
extensive first-pass metabolism. The major limitation with
this technology is a low amount of drug loading in films,
since the size and weight of films are small. The maximum
concentration achieved is upto 50% using simethicone in
Gas-X strips [86]. Certain tailored excipients that improve
solubility and permeability could be used to prepare film
formulation with BCS IV drugs.
A typical composition of the film as mentioned below [87]:
• Active Ingredient 5% to 50% w/w (ideal candidate is
potent low dose)
• Water soluble polymer 25% to 65% w/w (optimal
concentration is between 25- 40% w/w)
• Plasticizers 1% to 25% w/w(optimal concentration is
between 20-25%w/w)
• Surfactants 1% to 2% w/w (not essential)
• Saliva stimulating agent 2% to 6% w/w (not essen-
tial)
• Fillers, colors, flavors etc. q.s. (as per desired film
properties)
It is imperative to establish the correlation of raw materi-
al attributes and critical quality attribute (CQA) of films
[88]. Merits and demerits of involved raw material should be
considered as a part of risk assessment. Table 2 discusses
some example of critical material attributes for a typical film
formulation.

Table 2. Critical materials attributes of film forming polymers and plasticizers.

S. No. Excipients Functionality Critical Material Attributes Influence on Film Quality References

Yields uniform mucoadhesive films at 2-20% w/w

concentrations.
It has several mol. wt. substituent group due to
Type E, has low viscosity and optimal glass transi-
which different grades are available (type E
It is a synthetic non-ionic, tion temperature suitable for oral film matrices.
Hydroxypropyl methyl- and type K) It is a hydrophilic water soluble [1, 41, 58, 89,
1. hydrophilic polymer and The film strength increases with mol. weight
cellulose (HPMC) resin and is stable at pH 3.0 to 11.0. It has 90]
drug loading matrix. (E3<E5<E15<E50).
relatively high melting point, good structural
integrity and low glass transition temperature. E3 and E5 may lead to thin brittle films, whereas
E15 yields flexible films of desired tensile strength
and disintegration time and has palatable taste.

Yield films with good elasticity, dissolution rate,

It has relatively high melting point, low glass and mucoadhesion.
It is a self-plasticizing,
Poly (ethylene oxide) transition temperature, low toxicity and bio- Has the potential to incorporate higher drug load as
2. synthetic polymeric film [20, 41, 89, 90]
(PEO) compatibility. It is highly hydrophilic with lesser additives required in the formulation. Films
forming resin
good lubricating and film forming properties. with PEO have faster disintegration and better
elegance.

When used at concentration of 4% w/w, yields

It is a synthetic film form-
ing polymer
available with varying
3. Polyvinyl alcohol degree of hydrolysis.
- Fully hydrolyzed
-Partially hydrolyzed
- PEG incorporated
flexible films with high tensile strength, mucoad-
hesive properties and fast drug release profile. When
Fully hydrolyzed and is not suitable for fast
used in combination with HPMC or PVP yields
dissolving oral films as not soluble in cold
films with excellent mechanical strength and fast
water. [1, 41, 89]
drug release.
Partially hydrolyzed is soluble in cold water, Ideal polymer for ophthalmic films also at concen-
useful for preparing fast dissolving films. tration of 3-5% w/w.
PEG incorporated and is more suitable film forming
matrix as it contains plasticizer incorporated.

Film Plasticizer, Wide molecular weight range with

4. Polyethylene Glycol Imparts elasticity and flexibility to the films. [89]
Surfactant varying viscosities.

Combining PVP with PVA and HPMC improves

film forming capability. Combining PVP with ethyl
Polyvinyl Pyrrolidone It is a synthetic non-ionic
5. Soluble in cold water cellulose and HPC produces films with increased [1, 41, 58]
(PVP) film forming polymer
flexibility. Promote stabilization of peptides from
heat.

Hydroxypropyl Soluble in cold and hot polar organic solvents.

It is a synthetic film form- Used in a polymer matrix to improve solubility.
6. Cellulose Broad viscosity range. [1, 41, 58]
ing polymer It has a good film forming property.
(HPC) Moderate mucoadhesive properties.

(Table 2) contd…
174 Current Applied Polymer Science, 2019, Vol. 3, No. 3 Sinha and Dutt

S. No. Excipients Functionality Critical Material Attributes Influence on Film Quality References

Has good compatibility with starch forming single-

It is easily dispersed in water to form a clear or phase polymeric matrix films with improved me-
Carboxymethyl
colloidal solution. chanical and mucoadhesive properties. Formulations
7. Cellulose Film forming polymer [1, 41, 58]
Has broad viscosity ranges and high swelling comprising Na CMC or other hydrophilic polymers
(CMC)
properties such as HPMC and xanthan have great potential for
delivery of drugs to moist surfaces.

Good film forming capacity at low temperature with

A yellowish white, odorless powder with
mucilaginous taste. Molecular weight range
Natural film forming
8. Pectin 30,000-100,000 KDa and soluble in water.
polymer
Moisture content is approximately 10% w/w.
Aqueous solution has pH 6.0-7.2.
mucoadhesive properties. Modified pectins yielded
films with fast dissolution rates. Pectins have good
capacity to carry drugs and are particularly suitable
[1, 41, 91]
for low pH applications.
Degradation of pectin reduces its intrinsic viscosity
from 4.9dl/g to 2.5dl/g making it more suitable for
use in oral films

Chitosan has excellent film forming ability. En-

Sparingly soluble in water; other organic hances the transport of polar drugs across epithelial
Natural film forming
9. Chitosan solvents, and neutral or alkali solutions at pH surfaces. Possesses cell-binding activity due to [58]
polymer
above 6.5 polymer cationic polyelectrolyte structure that binds
to the negative charge of the cell surface.

Pullulan is white or yellowish white powder,

odorless, and tasteless.
Molecular weight range 100-250KDa.
It is a non-ionic, They are thermally stable and possess anti-static and
Soluble in hot as well as cold water.
10. Pullulan biocompatible, film form- elastic properties. Films have good disintegration [1, 41, 91]
Viscosity ranges from100-180 mm2/s (10%
ing polymer. time, and drug uniformity in the film.
aqueous solution at 30 °C). Contain approx. 6%
w/w of moisture. The pH of solution ranges
between 5-7.

Maintains uniformity of weight and acts as antioxi-

Tocopherol polyeth-
Film plasticizer, Degree of methylation of the phenol moiety of dant in films.
11. ylene glycol 1000 [37]
Stabilizer the chromanol ring. Useful for nanoparticles dispersed films as prevents
succinate (TPGS 1000)
aggregation of particles in solutions.

White to pale yellowish-brown colored pow-

der, soluble in water, forming a viscous colloi-
dal solution. Insoluble in organic solvents and Used as immobilization matrices
12. Sodium Alginate Film forming polymer acids for cells and enzymes. Controlled release of bioac- [58, 89]
Viscosity range 20-400 Cps (1% aqueous tive substances.
solution). Aqueous solution has pH of 7.2.
Moisture content is approximately 15%.

Three structural types exist: Iota, Kappa, and

Lambda, differing in solubility and rheology
Imparts mucoadhesive properties to films. Act as
13. Carrageenan Film forming polymer The sodium form of all three types are soluble [58, 75]
protein/peptide stabilizer.
in both cold and hot water
The best solution stability occurs at pH 6 to 10

Amber colored and brittle solid. Has molecular

weight between 15,000-250,000 KDa
Gelatin has good film forming ability for pro-
Soluble in glycerin, acid, alkali and hot water
teins/peptides films as it prevents aggregation.
14. Gelatin Film forming polymer Viscosity ranges between 4.3-4.7 mPa⋅s [41, 91]
Gelatin films dissolve rapidly and produce a smooth
(6.67% (w/v) aqueous solution at 60 °C).
mouth feel.
Moisture content does not exceed 10%.
pH for type B gelatin lies between 5- 7.4

Films prepared using starch have fast disintegration.

Hydrolyzed /substituted Natural film forming High molecular weight, forms strong hydrogen Forms non sticky smooth surface. The films are
15. [92-94]
starches polymer bonds. transparent or translucent, flavorless, tasteless and
colorless.
Oral Soluble Films: Attributes of the Polymeric Material and Critical Process Parameters Current Applied Polymer Science, 2019, Vol. 3, No. 3 175

Table 3. Advantages and disadvantages of different manufacturing processes.

Solvent Casting Hot Melt Extrusion Inkjet Printing

Suitable for thermally unstable drugs. Not suitable for thermally unstable drugs. Suitable for thermally unstable drugs.

Solvents are present in the process, hence health and Solvents are completely absent in this process, Solvents may be present hence health and environ-
environment hazard. hence no health or environment hazard. ment hazard.

Not preferred technology for producing personal-
Not suitable for producing personalized medicines
ized medicines or loading proteins/peptides and
or loading proteins/peptides and hormones.
hormones.
Promising technology for producing personalized-
dose medicines [96] or loading proteins/peptides
and hormones.

Comparatively less economical process as compared

Economical and less time consuming process Not economical
to solvent casting.

Residual moisture remains in the final product, No residual moisture remains in the final product Residual moisture remains in the final product,
hence stability issues. hence no stability issues. hence stability issues.

Manufacturing process ensures uniformity of dose Manufacturing process ensures uniformity of dose Most appropriate manufacturing process for ensur-
in each unit. in each unit. ing uniformity of dose in each unit [97].

Since drug and polymer solid dispersion is prepared

by melting, this process is the most suitable process
Both water soluble and water insoluble API can be
to improve the solubility and bioavailability of Not suitable for water insoluble API.
prepared as films by solvent casting.
poorly soluble drugs. Suggested process for taste
masking of bitter active substances [98].

No change of form of drug or polymer during the Chances of change of form of drug or polymer No change of form of drug or polymer during the
process. during melting at high temperature. process.

The amount of drug that can be loaded on film is

As compared to hot melt extrusion less amount of
drug can be loaded depending upon the solubility of
drug.
directly proportional to the saturation solubility of
Higher doses of the drug can be loaded
drug in ink hence, low doses can be loaded on films
[99]

The drug and polymer should be sufficiently stable The drug and polymer should be sufficiently stable
in solution/suspension as the manufacturing process Is a dry process, no such problem exist in solution/suspension as the manufacturing process
continues for several days. continues for several days.

Die swell phenomenon is observed, i.e. an increase

in the cross-section of the film after ejection from
No such phenomenon is observed. No such phenomenon is observed.
the die depending on the viscoelastic characteristics
of polymers.

Speed and duration of stirring of drug and polymer Speed and duration of mixing of co-rotating/counter
Speed and duration for stirring not critical for pre-
solution should be monitored to prevent foam for- rotating screw inside barrel should be critically
paring placebo films.
mation which could lead to dose non-uniformity. monitored.

3. TYPICAL MANUFACTURING PROCESS FOL-
LOWED IN INDUSTRY
The second important factor that influences the film qual-
ity is the process parameters during its manufacturing [95].
The manufacturing process selected for film fabrication is
mainly based on the physical and chemical properties of the
drug substance. However, each process has its own limita-
tions and advantages details of which have been discussed in
Table 3. If the active substance is susceptible to degradation
at high temperature, then hot melt extrusion process is
avoided and solvent casting process is adopted only if drying
temperature is critically monitored and controlled. To fabri-
cate films of proteins/peptides, printing technology is suita-
ble. Printing technology is suitable for most of the actives,
except when the dose of the drug is high. There are several
technical issues associated with each process and hence pro-
cess parameters should be critically monitored. Raphael et
al. reviewed the technical issues and possible remedy per-
taining to the viscosity of the casting liquid, mechanical
properties of the film, up-scaling and the stability issues of
the casting solution in the solvent casting process. The vari-
ous manufacturing processes (categorized into three major
categories) followed in the industry along with process pa-
rameters critical to quality are discussed in detail.
3.1. Process-I-Solvent Casting
A detailed flowchart describing the steps involved in
manufacturing films using the solvent casting technology
along with the critical process parameters is explained in
Fig. (1).
176 Current Applied Polymer Science, 2019, Vol. 3, No. 3 Sinha and Dutt

Dissolve the polymer /polymer mix in aqueous or hydroalcoholic solvent mixture

under continuous stirring so as to form a solution.
Parameters Critical to Quality:
Viscosity, hydrophilicity and solubility of the polymer, temperature, time and speed
of stirring.

Add the drug powder / solution / nano suspension / micelles to polymeric solution
under continuous stirring. If required add diluent, disintegrant, solubilizer,
permeability enhancer
Parameters Critical to Quality:
Compatibility and solubility of drug and excipients.
Temperature of process.

Stir the drug and polymer solution for a few hours under slow stirring to remove air
bubbles.
Parameters Critical to Quality:
Speed and Time of stirring

Spread the solution on glass plate and cast to thin uniform films using micrometer film
applicator.
Parameters Critical to Quality:
Viscosity of drug and polymer solution
Humidity of the environment
Accuracy of film applicator

0
Dry the film in oven at temperature 40-50 C
Parameters Critical to Quality:
Drying Temperature and time

The dried films are peeled and cut into uniform sizes based on dose desired in each
unit and packed in suitable packs.
Parameters Critical to Quality:
Material of packing container
Humidity of the environment

Fig. (1). Flow chart: process I-solvent casting.

In a large scale manufacturing in industry, the strips of
films are rolled known as ‘roll stock’ and stored for a certain
time before cutting, but since the film is prone to damage, if
possible, it should be cut and packed immediately after the
preparation. This process is suitable for both water soluble
and water insoluble actives. Visser et al. [100] prepared cast-
ing solutions containing water-soluble APIs (enalapril male-
ate and prednisolone disodium phosphate) and a poorly wa-
ter-soluble API (diazepam) for which ethanol 96% was used
as co-solvent. Both these categories of films met the criteria
of uniformity of mass and content set by the European
Pharmacopoeia.
Translating the production of films from a bench scale to
a production scale is one of the biggest challenges because
many critical factors as discussed in the flowchart such as
mixing speed, duration, and temperature during processing
could bring variability, and result in non-uniform films at
commercial scale. Therefore, all critical process parameters
should be optimized before scale-up. Fig. (2) depicts the
machine that is used for a large-scale production of a film
based on the solvent casting technique.
3.2. Process-II-Hot-Melt Extrusion (HME)
This process is not preferred in industry for the prepara-
tion of thin films as it involves high power consumption due
to high temperature involved in the process. HME is a pro-
cess of shaping a mixture of polymers, drug substance, and
other excipients into a film by melting the polymeric compo-
nent. The molten material is then charged through an orifice
(the die) to obtain homogeneous matrices. Eventually, the
films are cut into particular shapes and dimensions. A de-
tailed flowchart describing the steps involved in manufactur-
ing films using hot melt extrusion technique along with the
critical process parameters are explained in Fig. (3).
Large scale industry equipment for the HME process is
illustrated in Fig. (4), which consists of the hopper, a static
cylindrical barrel with varying temperature range zones with
single or twin screws (co-rotating or counter rotating),
Oral Soluble Films: Attributes of the Polymeric Material and Critical Process Parameters Current Applied Polymer Science, 2019, Vol. 3, No. 3 177

Fig. (2). Commercial manufacturing process of solvent casting.

Add the drug and polymer mixture to the hopper of hot melt extruder machine
Parameters Critical to Quality:
glass transition temperature of polymer, melting point of drug,
thermal stability of drug and polymer
compatibility of drug and polymer.
Physical form of drug (crystalline or amorphous)

The drug and polymer mixture is subjected to high shear mixing by rotating
screws inside the barrel of the hot melt extruder.
Parameters Critical to Quality:
Speed of rotating screws,
Temperature of process, time duration in each zone of barrel

The drug polymer mixture is made to pass through a die so as to form a thin film
of uniform thickness
Parameters Critical to Quality:
rheological properties of the molten drug and polymer mixture, die diameter.

The films emerging out of the machine is cut to uniform sized strips and packed in
suitable containers
Parameters Critical to Quality:
material of the packing container,
humidity of the environment

Fig. (3). Flowchart: Process II-hot melt extrusion.

extruder, film die, and roller. The barrel is divided into sec-
tions to shorten the residence time of the molten material.
The end of the barrel is connected to the end-plate die, which
is interchangeable dependand upon the required shape [34].
Jani, R et al. [101] in their extensive review explained the
identification of critical quality attributes, quality target pro-
file of product, criticality in the selection of process parame-
ters and material for substantial simulation in laboratory
scale and production for successful technology transfer using
hot melt extrusion process.
3.3. Process -III-Printing Technologies
This technology uses inkjet printers in which drug-loaded
inks are deposited on polymeric films to yield accurately
dosed units of pharmaceutical ingredients. A combination of
inkjet and flexographic technologies has been practiced. The
178 Current Applied Polymer Science, 2019, Vol. 3, No. 3
Fig. (4). Commercial manufacturing process of hot-melt extrusion.
Fig. (5). Commercial manufacturing process of printing on oral films.
inkjet printing was used for printing of actives on a substrate,
whereas the flexographic printing was employed to coat the
drug loaded-substrate with a polymeric thin film. Commer-
cial manufacturing of printed oral films and critical process
parameters are depicted in Figs. (5 and 6).
Printing technology produces films with more homoge-
neous distribution and accurate dose of the drug throughout
the film and it is more superior process than the other pro-
cess. It has been observed during stress testing that the drug
crystallizes out of solvent casted films but remains un-
changed in printed films [101, 102]. Jamróz et al. [103] pre-
pared films by using 3D printing technology using poorly
water soluble drug, aripiprazole (amorphous) printed on po-
rous structure of Polyvinyl alcohol film. Key findings of the
study were, increased dissolution rate in comparison to cast-
ed films, which, however, have slightly better mechanical
properties due to their continuous structure. Buanz, et al.
[96] prepared clonidine films with cellulose polymers by
both solvent casting as well as printing process and com-
pared their mechanical properties and physical stability. Me-
chanical testing showed that the printed films had Young's
moduli and tensile strength values similar to the free film,
but solvent cast films were significantly more brittle.
Though we have categorised the manufacturing processes
into three major categories, a combination of excipients and
processing steps for formulating to films have also been
studied by various scientists [104]. Maher et al. [105] pre-
pared co-amorphous dispersions of olanzapine at 1:2 molar
ratio and cast into films. It was observed that there was a
600-fold increase in solubility of Olanzapine. The model
optimized fast dissolving film prepared from the dispersion
which was physically and chemically stable, demonstrated
short disintegration time (8.5 s), fast dissolution (97% in 10
min) and optimum tensile strength (4.9 N/cm2). The results
of in vivo data indicated high bioavailability (144 ng h/mL)
and maximum plasma concentration (14.2 ng/mL) compared
with the marketed references.
Sinha and Dutt
Having summarized the critical material attributes of film
components and critical process parameters that should be
considered during formulation development and optimization
of films, it is imperative to discuss the quality attributes that
are expected for this type of dosage form. Quality by design
(QbD) approach should be followed to build quality into the
product during the development stage only. Visser et al.
[106] explained QbD approach for optimizing the formula-
tion of extemporaneously prepared orodispersible films us-
ing Design-Expert® Software. Chengying et al. [107] de-
signed and optimized a novel drug nanoparticles-loaded oral
fast dissolving film (NP-OFDF) using Box-Behnken design-
response surface methodology.
In the absence of any official guidance, it is important
that the requirements and specifications of each attribute be
defined at the beginning of the product development as a
quality target product profile. The correct way to define this
is based on the physical, chemical and pharmacokinetic
properties of the active ingredient as well as the desired re-
lease profile and impurity standards in the product. Subse-
quent to this, a deep dive into the critical material attributes
and process parameters should be done to determine those
factors which influence the film quality. Appropriate quality
risk management tool should be employed to determine
which factor would contribute most to quality and should be
mitigated or reduced in case they have adverse effect on any
quality parameter.
4. DESIRED CRITICAL QUALITY ATTRIBUTES OF
FILMS AND INVITRO TESTING TECHNIQUES
The critical quality attributes of the oral films which sig-
nificantly impact the safety and efficacy of film dosage form
are discussed below.
4.1. Mechanical Strength
The oral film should possess sufficient flexibility and
tensile strength so it can be pulled out from the pouch,
Oral Soluble Films: Attributes of the Polymeric Material and Critical Process Parameters Current Applied Polymer Science, 2019, Vol. 3, No. 3 179

Placebo polymeric films are prepared by either solvent casting or hot melt
extrusion technique.
Parameters Critical to Quality:
Processing temperature, stirring/mixing speed, stirring/mixing time,
humidity of environment,
Hydrophilicity and viscosity of polymers.

The saturated solution of drug in printing ink is prepared.

Parameters Critical to Quality:
• Solubility of drug in ink

Accurately dosed units of drug in ink are printed on the films.

Parameters Critical to Quality:
• Speed of printing
• Dwell time

The films are then accurately sized to uniform pieces around the printed drug and
liners are peeled off. Each unit is packed.
Parameters Critical to Quality:
• Material of packing container
• Humidity of environment

Fig. (6). Flowchart: Process III- printing technology.

peeled from the release liner, and rolled out after casting and
drying. However, too high mechanical strength may make
the cutting process difficult. Depending upon the polymeric
matrix of the film the mechanical strength may vary, hence it
is difficult to establish the strict range and a wide variation
may be observed. It is essential to test this attribute during
product accelerated stability and long-term stability. The
most widely accepted test for confirming tensile strength of
film includes elongation at break and Young's modulus.
4.2. Stability
Compatibility study of drugs with other excipients should
be performed during early formulation development. This is
done by evaluating drug and each excipient mixture for any
impurities by FTIR or DSC or related substances by HPLC.
Optimizing the process parameters during manufacturing and
selection of an adequate packaging material helps to mitigate
any unforeseen stability issues. The complexity of polymeric
matrices may trigger reactions/interactions at high tempera-
tures. Some excipients may inadvertently function as reac-
tion catalyzers, compromising the product stability. A
change in pharmaceutical form may be anticipated partially
or completely at high temperatures especially when hot melt
extrusion is employed. Since the films have a large surface
area, they have a tendency to oxidize more easily. The Sub-
oxone® sublingual film is a good example, in which nalox-
one may be more easily oxidized in the film compared to the
sublingual tablets available. Therefore, the shelf-life is lim-
ited to 12 months and the storage temperature is reduced
from 30°C to 25°C [108].
4.3. Appearance and Description
The size and the shape should be carefully selected de-
pending on the strength of the drug and site of application.
Sublingual formulations have a small available area to ad-
here, so the film should be of a comparatively smaller size.
Buccal films generally tend to be placed in the mouth for
long periods of time, so they should also have suitable di-
mensions to be comfortable for the patient. The prepared
film should have a uniform smooth texture.
4.4. Drug Release or Dissolution
Depending upon the quality target product profile, it is
intended to either have a bioequivalent dosage form or dos-
age form with enhanced bioavailability which may be a rap-
idly dissolving or a combination of initial 20-40% rapid re-
lease followed by sustained release. In the absence of specif-
ic guidelines for films, one can adopt the FDA guidance on
orodispersible tablets, which mentions disintegration time as
less than 30 seconds. This shall however not apply for modi-
180 Current Applied Polymer Science, 2019, Vol. 3, No. 3
fied release films. Preis et al. [109] developed a modified
set-up of the existing dissolution apparatus and also demon-
strated the electronic end point for the orodispersible prod-
ucts.
Krampe et al. [110] studied dissolution methods for oro-
dispersible films, considering the in vivo conditions in the
oral cavity - namely the mechanical force of the tongue, sali-
va flow, salivary volume and composition. He also observed
that the dissolution profile obtained in the biorelevant media
was slower than the dissolution profile observed in the non-
biorelevant media. This information is of high interest for the
development of orodispersible films, as less amount of dis-
solved API, may indicate a better release than expected by
using a conventional dissolution method.
4.5. Moisture Content
The residual moisture content of the films is critical and
range should be defined for a specific formulation, depend-
ing upon the inherent bound water contribution by each in-
gredient in the product. An excess or deficit of water content
may affect the mechanical properties of the polymeric ma-
trix. The loss of water content may contribute to brittle pol-
ymeric matrices whereas an excess of water absorption by
the polymeric matrix may cause sticky films. Water mole-
cules in the polymeric chains may also influence the dissolu-
tion of the films. The loss of water molecules would contrib-
ute to tightening the polymeric chain links, making the water
penetration difficult and therefore the disintegration time.
Preis, M et al. [11] in their findings showed high tempera-
tures and high humidity affected some of the investigated
orodispersible films, resulting in higher disintegration time
or even no disintegration within the tested time period. It is
also crucial to monitor and control the relative humidity con-
ditions during the process of film fabrication. Finally, an
appropriate primary packaging material should be provided
to prevent water permeation to the product.
Table 4. Critical quality attribute of films and their relative risk levels in determining the quality.
CQA Target
Suitable color and shape, no visual defects, ensure
Appearance, Odor, Taste
patient acceptability, no unpleasant odor
Size Suitable for site application and target population
Disintegration time As per the desired product profile
Must comply with Pharmacopoeial specification
Assay
100%w/w per film
Uniformity of weight /content Must comply with Pharmacopoeial specification
Should be defined in quality target product profile
Dissolution profile
(rapid release or delayed release desired)
Degradation product Must comply with Pharmacopoeia or ICH
Should be defined according to the water content of
Residual water content
drugs and excipients.
Sufficient tensile strength to resist breakage during
Mechanical properties
peeling or packing [115].
Sinha and Dutt
4.6. Organoleptic Characteristics
The oral films have a relatively high surface area in con-
tact with the oral mucosa; thus it is essential to focus on the
development of a pleasant and palatable system. Usually, the
disagreeable taste is due to the drug substance characteris-
tics, bitterness, particle size/shape, solubility, ionisation and
concentration in the oral film. Therefore, depending on these
properties, it is essential to define an effective strategy to
assure an agreeable taste, aftertaste and mouth feel. From the
formulation point of view, it is essential to consider the re-
gional and aged group tastes. For example, children general-
ly prefer fruit flavors, while adults tend to prefer slightly acid
flavors and older people frequently prefer mint or wine fla-
vored products. Solid dispersion of drugs with cyclodextrins
or drug-resin complexation can be done to mask the bitter
taste of drugs [111, 112].
4.7. Dose Uniformity
The weight variation influence the uniformity of dosage
units so adequate weight variation range should be specified
during the process. It is also essential to have an in-depth
knowledge of the process and the product so that slight ad-
justments may be performed during manufacturing if neces-
sary.
4.8. pH
pH value measurements for the film are essential to de-
termine drug absorption or stability in salivary pH. Moreo-
ver, the pH is also important to predict possible mucosal
irritation, since acidic or alkaline pH may cause some dis-
comfort.
The critical quality attributes (CQA) of films with rela-
tive risk levels in determining the film performance and in
vitro quality testing requirements of orodispersible films is
discussed in Tables 4 and 5 respectively.
Risk Level Rationale for Criticality
Medium Not directly linked to safety and efficacy
Low For ease of administration to oral cavity
Has a direct impact on safety and efficacy due to
High
direct onset of action
High
Has a direct impact on safety and efficacy
High
Has a direct impact on safety and efficacy due to the
High
influence on product bioavailability [113, 114].
It has a direct impact on safety and efficacy and
High
prevents adverse and toxic effects.
The water content may trigger chemical reactions
High
within the film and cause instability.
Inappropriate mechanical properties may lead to
High
films that may easily break or difficult to cut or pack
Oral Soluble Films: Attributes of the Polymeric Material and Critical Process Parameters Current Applied Polymer Science, 2019, Vol. 3, No. 3 181

Table 5. In vitro quality testing requirements of orodispersible films.

S. No. CQA of Films Testing Instrument and Method Requirements References

1. Film thickness Micrometer screw gauge /Vernier Calipers 50-200µm [1, 116]

Drug content and content (Borges, Silva, & Celho,

2. By HPLC, UV Spectrophotometer Complies as per Pharmacopoeia
uniformity 2015), [19, 116]

4-10 mL of a phosphate buffer pH6.8 (artificial (Borges, Silva, & Celho,

3. Disintegration time Preferred is less than 30 sec.
saliva) to be added on a Petri dish 2015), [19, 116]

(Borges, Silva, & Celho,

4. Weight variation Analytical balance Complies as per Pharmacopoeia
2015), [116]

Caco-2 Permeability Cell/Franz diffusion appa- (Borges, Silva, & Celho,

5. Permeability Meets requirements
ratus 2015), [116]

(Borges, Silva, & Celho,

6. Folding endurance By folding repeatedly >200-300
2015), [116]

No agglomeration of drug (Borges, Silva, & Celho,

7. Particle distribution By SEM
particles. 2015), [116]

No change of form of active or (Borges, Silva, & Celho,

8. Crystallinity By XRD and DSC
excipient 2015), [116]

No specific range, varies as per

Tensile strength (Borges, Silva, & Celho,
9. By Texture Analyzer polymer grade in matrix and drug
(% Elongation) 2015), [116]
concentration in film.

By Type I/Type II Dissolution apparatus in 6.8 Complete release within 15-30 (Borges, Silva, & Celho,
10. Dissolution
pH buffer (simulated saliva) min. 2015), [116]

Evaluated by test panel, based on taste and mouth (Borges, Silva, & Celho,
11. Organoleptic characterization Acceptable taste and mouth feel
feel characteristics 2015), [116]

(Borges, Silva, & Celho,

12. Handling characterization Detach from liner Ability to peel off easily
2015), [116]

As per active and excipient contri- (Borges, Silva, & Celho,

13. Moisture content Water by KFR
bution. 2015), [116]

Table 6. Various technological platforms for the manufacture of films.

Technology Name Company Name Drug Loading Capacity

Pharm Film Mono Sol Upto 80 mg

Rapid Film Labtec Upto 30 mg

Versa Film Intel Genx Technologies Corp. Upto 40 mg

Orally and Adhesive disintegrating films KyuKyu Pharmaceuticals Comp. Upto 15 mg

Smart Film Seoul Pharma Upto 140 mg

5. VARIOUS TECHNOLOGICAL PLATFORMS 6. MARKETED ORAL FILM PRODUCTS

Listed below in Table 6 are the various technological Some of the famous commercially available oral products
platforms for this type of dosage form and also some popular are listed in Table 7.
marketed film products manufactured using these technolo- Some of the noted formulation patents pertaining to oral
gies. film formulations have been presented in Table 8 below
182 Current Applied Polymer Science, 2019, Vol. 3, No. 3 Sinha and Dutt

Table 7. Examples of marketed products of fast dissolving films [117].

Formulations Brand Name Manufacturer/Marketed

Zolmitriptan
Fast dissolving oral film Labtec's production site in Hamburg, Germany.
Rapid film®

Ondansetron ODF Set film® BioAlliance Pharma

MonoSol Rx
Ondansetron ODF Zuplenz(R)
Marketed by Strativa Pharmaceuticals United

Oral films of
T Methylcobalamin
T Diphenhydramine HCl
T Dextromethorphan -- Hughes Medical Corp.
T Folic Acid
T Loratidine
T Caffeine

d-Amphetamine film KP106 MonoSol Rx and KemPharm

Listerine Pocket Packs -- MonoSol Rx

MonoSol Rx
Buprenorphine/ Naloxone film Suboxone Marketing partner
Reckitt Benckiser
®
Donepezil film Donepezil Rapidfilm Labtec

Vitamins, hormones, nutraceuticals films -- Paladin Labs

Table 8. Formulation patents on fast dissolving oral films/strips.

Title Patent No. Grant Inventors Assignee Filed

Film-like form of administration for the M.Muller, C.M. Hammes,

Lohmann Therapie-
transmucosal delivery of antidiabetic WO2017186563A1 - C.Schmitz, M.Linn, M. Sameti April 20, 2017
Systeme
peptides. and P. Klaffenbach

Quickly soluble oral film dosage con- Jin-Kyu Park

Cmb Pharmaceutical
taining steviosides as an unpleasant taste US9492379B2 Nov 15, 2016 Won-suk Yang -
Co Ltd
masking agent Kyoung Tae Jung

Andrew Ingram
Soluble Film WO2012025730A3 - Biofilm Limited July 26, 2012
Alan Gibson

Yong Hee Cho

Won Young Jang
Tadalafil oral dispersible film and prepa- Jin Hee UM
WO2016036093A1 - Seoul Pharma. Co., Ltd. March 10, 2016
ration method thereof Dong Woon Choe
Hyun Soo Kim
Jung Hoon Kim

Dexamethasone oral film WO2016071395A1 - Bengt Arvid Westrin Acucort Ab May 12, 2016

New oral dissolving films for insulin

EP2670368 A1 - Y.Rubin, S. Cohen and E.Ron Pharmedica Ltd. April 15, 2015
administration, for treating diabetes

(Table 8) contd…
Oral Soluble Films: Attributes of the Polymeric Material and Critical Process Parameters Current Applied Polymer Science, 2019, Vol. 3, No. 3 183

Title Patent No. Grant Inventors Assignee Filed

October 24, Roderike Pohl

Rapid acting drug delivery compositions EP2106790B1 Biodel, Inc. -
2012 Solomon S. Steiner

Abuse resistant transmucosal drug Andrew Finn BioDelivery

WO2007070632A3 - October 11, 2007
delivery device Niraj Vasisht Sciences

Phillip Williams

Combination peptide-nanoparticles and ThomasRademacher

US8790704B2 - Monosol Rx LLC July 29, 2014
delivery systems incorporation Alexander Mark Schobel
Eric Dadey

Methods for modulating dissolution,

bioavailability, bioequivalence delivery
Robert Davidson Cure Pharmaceutical
profile of thin film drug delivery sys- US8999372B2 April 7, 2015 -
Gary Kehoe Corporation
tems, controlled release dosage formats
methods for their manufacture and use.

Nanoparticle-insulin and insulin Thomas Rademacher

US9352026B2 May 31, 2016 Midatech Limited -
analogue compositions Phillip Williams

Markus Müller
Claudia Maria Hammes
New oral dissolving films for Insulin Christoph Schmitz Lohmann Therapie- November 02,
WO2017186563A1 -
administration, for treating diabetes Michael Linn Systeme 2017
Mohammad Sameti
Peter Klaffenbach

Bess; William S. (Edison, NJ),

Kulkarni; Neema (Randolph,
Fast dissolving orally consumable films NJ), Ambike; Suhas H.
McNeil-PPC, Inc.
containing an ion exchange resin as a EP1267829B1 May 03, 2006 -
(West Hill, CA), (Skillman, NJ)
taste masking agent
Ramsay; Michael
P. (Ajax, CA)

Aupac
Process for manufacturing thin film strip US6824829B2 Nov. 30, 2004 Craig j.berry Walter klauser -
packaging, inc.

Sau Hung Spence Leung,

Robert S.
Leone, Lori D. Kumar, Warner Lambert
Fast dissolving orally consumable film US7025983B2 Apr.11, 2006 -
Company LLC.
Neema Kulkarni,
Albert F. Sorg

David R. Friend

Fast dissolving film for oral Aaron W. Levine Sarnoff

WO2004060298A3 - Oct.21, 2004
administration of drugs Kerrie L. Ziegler Corporation.
Emmanuel Manna

Fast dissolving orally consumable film

David John Fadden Neema Warner Lambert Com-
containing a modified starch for im- EP1622595A1 - Feb. 8, 2006
Kulkarni, Albert F. Sorg pany LLC
proved heat and moisture resistance

Oral Film Formulations Comprising Sanovel Ilac Sanayi ve

EP2698147B1 Jul 22, 2015 Ramesh Bangalore -
Dapoxetine and Tadalafil Ticaret AS

The Dial
Water soluble sheet composition US7387787B2 June. 17, 2008 Priscilla S. Fox -
Corporation

(Table 8) contd…
184 Current Applied Polymer Science, 2019, Vol. 3, No. 3 Sinha and Dutt

Title Patent No. Grant Inventors Assignee Filed

Gary L. Myers
Ondansetron film compositions EP2253224A1 - Madhusudan Hariharan MonoSol Rx LLC Nov.24, 2010
Pradeep Sanghvi

William G.Meathrel, Nathan A.

Meyer, Scott D.Barnhart, Cathy

Disintegrable films for diagnostic M.Moritz, Andrew Adhesives

US7727466B2 Jun. 01, 2010 -
devices P.Full, Susan Research, Inc.
R.Newsom,
Mary Robertson

Film comprising nitroglycerin US20100215774A1 August 26, 2010 Maibach, Todd Acaderm Inc. -

Robert Scott, Dominique Cade,

Pullulan film composition US7267718B2 Sep. 11, 2007 Capsugel Belgium NV -
Xiongwei He

Rapidly disintegrating oral film formula- Armin Breitenbach

WO2012110222A1 Aug 23, 2012 Labtec, GmbH -
tion for olanzapine Nina Schwier

Philip Morris Products

Smokeless tobacco product CA2702222C Aug 30, 2016 Richard Fuisz -
SA

to further emphasize the popularity of this dosage form sions thus reducing the burden on the environment. Consid-
[117]. ering formulation development, it is expected that some
common guidance be outlined in the pharmacopoeia to miti-
CONCLUSION gate the technical hurdles regarding product performance to
facilitate product manufacturing and registration in all mar-
Formulations as ‘Oral Soluble Films’ have been emanat-
kets [118]. Printing technologies offer a solution for thermo-
ing for manifold categories of drugs including anti-ulcer,
labile drugs and proteins /peptides, however, the process
antitussive, anti-inflammatory, anti-allergic, anti-cancer, anti-
should be critically monitored during dose loading. Since the
migraine, anti-retroviral, anti-diabetic, anti-hypertensive,
pharmaceutical treatments are evolving and the approach is
anti-emetic, anti-epileptics, anti-fungal, anti-retroviral and
becoming quality based and patient centric, so eventually, it
peptides. The type, grade and quantity of polymeric compo-
would be necessary to demonstrate the advantages of this
nents significantly impacts the quality of the films. The ade-
dosage form as portable, suitable for individualized pharma-
quate design of experiments should be done to optimize the
cotherapy [119-121], with enhanced bioavailability and re-
polymer and plasticizer level in the final formulation to be
duced side effects. Considering the aspect of providing a
further scaled to the manufacturing level so as to achieve
wholesome solution to patients' needs, other classes of
adequate mechanical strength. The most widely experiment-
dosage forms can be developed, including topical films for
ed and developed film category is buccal films and sublin-
local applications on wound, gastro-retentive dosage forms
gual films and the most preferred process in the industry is
and diagnostic devices. Printing technology when combined
solvent casting since it is easy and economical. Two quality
with solvent casting, a stacked and multilayer system
attributes namely ‘tensile strength’ and ‘drug release’ influ-
containing bioactive components or fixed dose combination
ences film performance significantly and should be studied
products could be developed. 3D printing technology has
carefully. This technology comes with the limitation of pro-
brought paradigmn shift in the formulation development of
cessing under controlled conditions at low relative humidity
personalized oral films.
as even a slight increase in the moisture content of films
would result in sticky films and cause stability issues. Since
CONSENT FOR PUBLICATION
oral films come with improved bioavailability, there is a
scope of dose reduction, hence drugs with higher doses can Not applicable.
also be formulated as films, e.g. rifampicin (600 mg), met-
formin (1000 mg) etc. This fact coupled with nanonization of FUNDING
drug, solid dispersion of drug with cyclodextrins or co-
crystal of drug with permeation enhancers like citric acid can None.
improve the efficacy and contribute to dose reduction. The
hydrophilic polymers used to prepare these films are biode- CONFLICT OF INTEREST
gradable, biocompatible, and inert and leave no residue. The The authors declare no conflict of interest, financial or
methods for manufacture are comparatively simple and envi- otherwise.
ronment friendly with less energy consumption and emis-
Oral Soluble Films: Attributes of the Polymeric Material and Critical Process Parameters
ACKNOWLEDGEMENTS [18]
Declared none.
[19]
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