Journal of Biomaterials and Nanobiotechnology, 2011, 2, 582-595
doi:10.4236/jbnb.2011.225070 Published Online December 2011 (http://www.scirp.org/journal/jbnb)
Formulation Development of a Carrageenan Based
Delivery System for Buccal Drug Delivery Using
Ibuprofen as a Model Drug
Farnoosh Kianfar, Milan D. Antonijevic, Babur Z. Chowdhry, Joshua S. Boateng*
School of Science, University of Greenwich at Medway, Kent, UK.
Received September 20th, 2011; revised October 26th, 2011; accepted November 20th, 2011.
ABSTRACT
Solvent cast films are used as oral strips with potential to adhere to the mucosal surface, hydrate and deliver drugs
across the buccal membrane. The objective of this study was the formulation development of bioadhesive films with
optimum drug loading for buccal delivery. Films prepared from κ-carrageenan, poloxamer and polyethylene glycol or
glycerol, were loaded with ibuprofen as a model water insoluble drug. The films were characterized using texture
analysis (TA), hot stage microscopy (HSM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA),
scanning electron microscopy (SEM), x-ray powder diffraction (XRPD), high performance liquid chromatography
(HPLC) and in vitro drug dissolution. Optimized films were obtained from aqueous gels containing 2.5% w/w κ-car-
rageenan 911, 4% w/w poloxamer 407 and polyethylene glycol (PEG) 600 [5.5% w/w (non-drug loaded) and 6.5% w/w
(drug loaded)]. A maximum of 0.8% w/w ibuprofen could be incorporated into the gels to obtain films with optimum
characteristics. Texture analysis confirmed that optimum film flexibility was achieved from 5.5% w/w and 6.5% (w/w)
of PEG 600 for blank films and ibuprofen loaded films respectively. TGA showed residual water content of the films as
approximately 5%. DSC revealed a Tg for ibuprofen at −53.87˚C, a unified Tm for PEG 600/poloxamer mixture at
32.74˚C and the existence of ibuprofen in amorphous form, and confirmed by XRPD. Drug dissolution at a pH simulat-
ing that of saliva showed that amorphous ibuprofen was released from the films at a faster rate than the pure crystalline
drug. The results show successful design of a carrageenan and poloxamer based drug delivery system with potential for
buccal drug delivery and showed the conversion of crystalline ibuprofen to the amorphous form during film formation.
Keywords: Carrageenan, Drug Dissolution, Physical Characterization, Plasticizer, Poloxamer
1. Introduction
The oral route is the most common means of admi-
nistering pharmacological agents [1] because of advan-
tages such as economy, convenience and patient compli-
ance. However, it also presents major disadvantages such
as first pass effect, gastrointestinal enzymatic degrada-
tion and delay between the time of administration and
absorption which is detrimental in the case of drugs with
rapid onset requirements. The foregoing factors have
resulted in the exploration of alternative routes for the
delivery of drugs [2] such as the buccal mucosa which
may help to overcome the aforementioned challenges and
improve drug bioavailability. Buccal delivery avoids
liver first pass metabolism and GI enzymatic degradation
and able to transfer drug relatively quickly via the
systemic circulation to the site of action [3,4]. Since the
drug content within the buccal formulations can be
considerably lower than tablets and capsules, toxicity or
undesired side effects will potentially be significantly
reduced.
However, there are other limiting factors which need
careful consideration, including drug solubility and for-
mulation bioadhesivity to achieve efficient drug delivery
and the desired systemic bioavailability. Films have po-
tential as buccal drug delivery systems owing to their
ease of administration (currently used as fast dissolving
oral strips) and ease of hydration on contact with
mucosal surfaces to allow drug diffusion out of the
swollen gel [5]. However, they are limited by low drug
loading capacity because of their thin nature [6]. In
addition, not all film forming polymers are bioadhesive
and improvements in bioadhesivity of such formulations

Formulation Development of a Carrageenan Based Delivery System for Buccal Drug Delivery 583
Using Ibuprofen as a Model Drug
can be achieved by employing hydrogel polymers with
several hydrogen bonding sites which interact with
functional groups of high molecular weight glycoproteins
located on the surface of buccal tissues [7,8].
The current report discusses the development, opti-
mization and characterization of a polymeric solvent cast
film containing carrageenan and poloxamer (polymers),
polyethyleneglycol (PEG) and glycerol (GLY) (plastici-
zers) and ibuprofen as a model drug for buccal drug
delivery. Ibuprofen has been reported to be a suitable
model drug in terms of its permeability (log P) properties
[9]. Formulation development involved determining the
amounts of carrageenan, poloxamer and the plasticizer
(PEG or glycerol) required to achieve optimum films. In
addition experiments were conducted in order to achieve
maximum drug loading in the optimized films prior to
tensile characterization (TA), water content thermogra-
vimetry (TGA), stability and the physical form of the drug
(DSC, HSM, XRPD) as well as drug dissolution studies.
Hydrogel polymers used included various grades of
carrageenan: NF911, 812 (κ) and 379 (ι) with the mono-
mer chemical structure shown in Figure 1(a). Carragee-
nan is a sulphated polysaccharide produced from red
seaweed (Rhodophyceae). Based on the number of
sulphate groups per repeat unit of polysaccharide, it is
classified into three different grades: kappa (κ), iota (ι)
and lambda (λ) with one, two or three sulphate groups,
respectively [10]. All grades of carrageenan produce a
thermo reversible sol-gel in aqueous solution which
undergoes dispersion following random-coil formation in
the sol stage. Carrageenan as a natural polymer has been
widely employed in the food industry. However, it has
not been used extensively in pharmaceutical applications,
although κ-carrageenan has previously been demon-
strated to have desirable properties for use in pharma-
ceutical formulations. At low temperature, galactose se-
quences within the carrageenan chains twist in a double
helix fashion [11]. The sweet taste of galactose may help
to mask the bitter taste of some drugs thus avoiding the
need for flavoring and sweetening agents. Previous
reports have also confirmed an increase in drug bioavail-
ability [12] of κ-carrageenan. However, the major reason
for its selection was the availability of several sites for
hydrogen bonding which impart bioadhesive properties
to the final formulation. In addition, the mucoadhesive
property could be further enhanced by the negative
charge of the sulphate group in the carrageenan structure
forming ionic bonds with the positively charged mucin
present on the buccal mucosa.
The other polymer employed was poloxamer 407 with
the molecular formula [HO(C2H4O)101(C3H6O)56 (C2H4O)
101H] and chemical structure shown in Figure 1(b). It is a
block co-polymer containing ethylene and propylene
oxide. Poloxamer 407 is a non-ionic surfactant with the
ability to increase the solubility of drugs (e.g. ibuprofen)
with high log P and has been employed to achieve
different drug release profiles [13-16]. Previous studies
have shown that the erosion of poloxamer-based gels, in
aqueous media, is relatively fast and it also exhibits
mucosal permeation enhancing properties [17]. Plasti-
cizers employed were polyethylene glycol 600 (Figure
1(c)) which is a hydrophilic polymer constituted of oxye-
thylene monomers [18] and glycerol (Figure 1(d)), with
three hydroxyl groups, that dissolves in water and dis-
rupts the hydrogen bonding between carrageenan chains.
2. Materials and Methods
2.1. Materials
κ-carrageenan (Gelcarin NF 911, batch number: 50102070
and Gelcarin 812 batch number: 80402170) and ι-carra-
geenan (Gelcarin NF379, batch number: 40021170) were
gifts from BASF (Surrey, UK). Poloxamer 407 (batch
number: 038k0071) polyethylene glycol 600, batch num-
ber: 0001409391 (PEG), ibuprofen (batch number:
026H1368) and glycerol (batch number: RB12720) were
all purchased from Sigma-Aldrich (Gillingham, UK) and
used as received.
2.2. Formulation Development
Initial experiments involved investigating optimum gel
preparation prior to film formation. These initial experi-
ments were performed to determine the optimum com-
binations of the various polymers and plasticizers to
produce films for drug incorporation (Table 1(a)).
Gel formulation involved three main approaches.
1) Carrageenan (911, 812 or 379) was added to mag-
netically stirred hot deionised water (80˚C) and stirring
continued until a uniform gel was obtained. Poloxamer
407 and PEG 600 or glycerol, were then added to the
resulting carrageenan gel and stirring continued with
heating for 30 minutes.
2) The required amount of deionizer water was divided
into two equal portions. One portion was heated to 60˚C
and carrageenan added with continuous stirring for 10
minutes. Poloxamer and plasticizer (PEG 600 or glycerol)
were dissolved in the second portion, stirred for 5 min-
utes to produce a clear solution and then gently added to
the initially prepared carrageenan gel.
3) Poloxamer 407 was dissolved in cold water (<15˚C)
for two hours before addition of carrageenan to the re-
sulting solution and left overnight at 40˚C - 50˚C to en-
sure complete hydration of carrageenan. The final gel
was obtained by addition of plasticizer (PEG 600 or

Formulation Development of a Carrageenan Based Delivery System for Buccal Drug Delivery
Using Ibuprofen as a Model Drug
584
O
OH
O
O
O
OSO 3-
O
O
OH
O3SO-
O
O
O
OH
OH OO
HH
H
H
HH
HH
H2
C
H
HO
H
3ß1
H
H
H
H
H
H
H
H
H2C
H
H
4
3ß1
4
a1
a1
Figure 1. Chemical structures of the raw materials (a) κ-carrageenan 911; (b) poloxamer 407; (c) polyethylene glycol; (d)
glycerol and (e) ibuprofen used for formulating the optimized films.
glycerol) at a temperature of 40˚C - 50˚C with continu-
ous stirring.
Selected formulations comprising 2.5% w/w carra-
geenan 911, 4% w/w poloxamer 407 and varying con-
centrations of PEG 600 (5.0% - 6.5% w/w) or GLY
(4.5% - 5.5% w/w) were identified for drug incorporation
(Table 1(b)). Two strategies were evaluated based on the
maximum amount of ibuprofen that could be loaded
without being visible (to the naked eye) on the film sur-
face.
1) Ibuprofen (0.3% - 1.0% w/w) was added to 4% w/w
poloxamer 407 solution (<15˚C), kept for 2 hours before
addition of carrageenan 2.5% w/w and plasticizer PEG
600 (5.0% - 6.5% w/w) or GLY (4.5% - 5.5% w/w) and

Formulation Development of a Carrageenan Based Delivery System for Buccal Drug Delivery 585
Using Ibuprofen as a Model Drug
Table 1. Composition of the gels prepared (approach 3)
during film formulation development and optimization pro-
cess.
(a) % composition of gels containing poloxamer 407 (POL) with
various grades of κ-carrageenan (CAR 812, 911, 379) PEG 600 or
GLY (NB: The formulations contained no ibuprofen)
CAR (% w/w) POL 407 (% w/w) Plasticizer (%w/w)
2.5 (911) 4 3.5 PEG
1.5 (812, 911, 379) 2 4.5 PEG
1.5 (812, 911, 379) 3 4.5 PEG
1.5 (812, 911) 5 4.5 PEG
1.5 (812, 911) 6 4.5 PEG
1.5 (812, 911) 7 4.5 PEG
2.5 (812, 911) 4 5.0 PEG
1.5 (812, 911) 4 5.5 PEG
2.5 (812, 911) 4 5.5 PEG
2.5 (812, 911) 4 6.0 PEG
2.5 (812) 4 6.5 PEG
2.5 (911) 4 6.5 PEG
1.5 (812, 911) 4 5.0 GLY
1.5 (812, 911) 4 5.5 GLY
2.5 (812, 911) 4 5.0 GLY
2.5 (812, 911) 4 5.5 GLY
(b) Selected optimised gels containing 2.5% w/w κ-carrageenan
(911 & 812) (CAR), 4% w/w poloxamer 407 (POL) and plasticizers
(GLY or PEG 600) loaded with different amounts of ibuprofen
CAR (% w/w) POL407 (% /w) plasticizer% w/w) ibuprofen (% w/w)
2.5 (911) 4 5.0 PEG 0.3
2.5 (812) 4 5.0 PEG 0.3
2.5 (911) 4 5.0 PEG 0.4
2.5 (812) 4 5.0 PEG 0.4
2.5 (812, 911) 4 5.5 PEG 0.3
2.5 (812, 911) 4 5.5 PEG 0.4
2.5 (911) 4 5.5 PEG 0.4
2.5 (911) 4 5.5 PEG 0.8
2.5 (911) 4 5.5 PEG 1.0
2.5 (911) 4 6.5 PEG 0.8
2.5 (911) 4 6.5 PEG 1.0
2.5 (812, 911) 4 4.5 GLY 0.3
2.5 (812) 4 5.0 GLY 0.3
2.5 (911) 4 5.0 GLY 0.3
2.5 (812) 4 5.0 GLY 0.3
2.5 (911) 4 5.0 GLY 0.3
2.5 (812, 911) 4 5.5 GLY 0.4
2.5 (812, 911) 4 5.5 GLY 0.8
2.5 (812, 911) 4 5.5 GLY 1.0
left for 24 hours. This was undertaken with the aim of
increasing drug incorporation based on the surfactant
properties of poloxamer 407.
2) Ibuprofen (0.3% - 1.0% w/w) was dissolved sepa-
rately in 2 ml of ethanol and the resulting solution added
to the gel comprising 2.5% w/w carrageenan 911, 4%
w/w poloxamer 407 and 5.0% - 6.5% PEG 600 or 4.5% -
5.5% w/w GLY prepared as in (III) above.
The resulting gels were poured into Petri dishes and
placed in a vacuum oven at 60˚C. To determine the
maximum time required for complete drying, the weight
loss of the films was measured every 24 hours up to 72
hours until a constant weight was achieved.
2.3. Texture Analysis (TA)
Texture analysis was used to investigate the tensile prop-
erties (tensile strength, elastic modulus and percentage
elongation) of the films (PEG plasticised) selected from
initial formulation development. The results were used to
aid in the selection of optimised films (as described
above) with acceptable flexibility for drug loading and to
determine effect of increasing drug content. Films con-
taining 3.5% - 6.5% w/w PEG 600 were stretched to de-
termine the effect of PEG 600 on tensile properties. Be-
fore tensile measurements, the thickness of the films was
measured by a micrometer screw gauge in five different
areas of each sample (four edges and one in the middle)
and showed thickness ranging from 0.33 - 0.37 mm. The
exact thickness of each particular specimen was entered
into the texture analyser software prior to stretching. The
films were cut into dumb-bell shaped strips and stretched
between tensile rigs of the texture analyser (HTI, Houns-
feild, Germany) to break point. The following settings
were used: load range—10 N; extension—40 mm; gauge
length—30 mm; approach speed—5 mm/min; test speed
—50 mm/min; and a preload force—0 N. The tensile
properties were calculated using the following equations.


2
N
Elastic modulusmm



2
Force corresponding strain N
cross-sectional mmcorresponding strain

(1)


% Elongation
Increase in length mm100
Orginal length of the sample mm

(2)


2
N
Tensile strengthmm
Force at break N



2
Inital cross-sectional area of sample mm

(3)

Formulation Development of a Carrageenan Based Delivery System for Buccal Drug Delivery
Using Ibuprofen as a Model Drug
586
2.4. Thermal Analysis
1) Hot stage microscopy (HSM)
Analyses were carried out using a Mettler Toledo
HSM instrument (Leicester-UK). A small sample of
starting materials or film was placed on a glass slide lo-
cated in a furnace below the microscope lens. Samples
were subjected to a dynamic heating cycle from 30 to
300˚C at a rate of 10˚C/min and all phase transitions
were recorded as a video file.
2) Thermogravimetric analysis (TGA)
TGA was used to determine the residual water in the
films (Table 2) and the effect of plasticizer and ibupro-
fen concentration and storage on the moisture content of
the films. About 3 - 10 mg of sample was weighed,
placed in aluminium pans (100 µL) and weight loss de-
termined using a high resolution TGA 2950 instrument
(TA Instruments, Crawley, UK). The experimental pro-
gram involved heating the samples from 25˚C to 150˚C
at a heating rate of 10˚C/min.
3) Differential scanning calorimetry (DSC)
DSC analysis of physical mixtures of the starting ma-
terials and the optimized films was performed using a
Q2000 instrument (TA Instruments, Crawley, UK). The
instrument was calibrated with indium and sapphire be-
fore analyzing samples under a nitrogen atmosphere. T
zero aluminium pans (75 µL) were packed with 3 - 10
mg of sample and hermetically sealed. The thermal cycle
involved cooling the sample to −80˚C and maintaining
this temperature for 5 minutes. The samples were then
heated at a rate of 10˚C/min up to 180˚C, and kept at this
temperature for 3 minutes to allow complete melting.
The run proceeded with quench cooling of the sample at
a rate of −10˚C/min to return to a temperature of −80˚C.
This process was repeated twice to investigate the stabil-
ity of carrageenan, PEG and ibuprofen during the heating
cycle. Further experiments were performed based on the
possible interaction between PEG 600 and poloxamer
407. This was due to an extra melting transition observed
in the films’ DSC thermogram. The two polymers were
mixed in ratios corresponding to those present in the
films and melted before loading into the T zero DSC
pans. The analysis involved a heating cycle from −80˚C
Table 2. Water content for different films produced during the formulation development and optimization process, con-
taining various κ-carrageenan grades (911 & 812), plasticizers (GLY or PEG 600) and poloxamer 407 with or without
ibuprofen. The last two rows show the final optimised films containing κ-carrageenan 911 (CAR), PEG 600 and poloxamer
407 (POL) freshly prepared and ibuprofen (IBU) loaded equivalents either freshly prepared or stored for a month. The %
concentrations of the components refer to the amounts present in the original gels used to prepare the corresponding films.
CAR (% w/w) POL (% w/w) Plasticizer (% w/w) IBU (% w/w) Water content (%)
2.5(812) 4 5.0 GLY - 16.4 ± 0.8
2.5 (911) 4 5.0 GLY - 6.9 ± 0.4
2.5 (812) 4 5.0 GLY 0.3 19.9 ± 1.1
2.5 (911) 4 5.0 GLY 0.3 23.5 ± 1.2
2.5 (812) 4 5.0 PEG - 10.3 ± 0.6
2.5 (911) 4 5.0 PEG - 2.3 ± 0.3
2.5 (812) 4 5.0 GLY 0.3 17.1 ± 0.7
2.5 (911) 4 5.0 GLY 0.3 13.9 ± 0.8
2.5 (812) 4 5.0 PEG 0.4 12.1 ± 0.7
2.5 (911) 4 5.0 PEG 0.4 3.7 ± 0.2
2.5 (812) 4 5.0 PEG 0.4 9.9 ± 0.5
2.5 (911) 4 5.0 PEG 0.4 8.1 ± 0.4
2.5 (911) 4 5.5 GLY - 23.5 ± 1.2
2.5 (911) 4 5.5 PEG - 5.1 ± 0.4
2.5 (911) 4 6.5 PEG 0.8 5.1 ± 0.1 (freshly prepared film)
2.5 (911) 4 6.5 PEG 0.8 1.0 ± 0.3 (after 6 month storage)

Formulation Development of a Carrageenan Based Delivery System for Buccal Drug Delivery 587
Using Ibuprofen as a Model Drug
to 80˚C at a rate of 10˚C/min followed by cooling at a
rate of −10˚C/min to −80˚C, and the cycle repeated. To
determine the detection limit of the instrument for ibu-
profen in the films, the equivalent amount of the pure
drug was loaded onto the DSC and analyzed as above.
2.5. Scanning Electron Microscopy (SEM)
SEM was used to examine the surface of the films to
determine their microscopic morphology. Samples were
uncoated and tested using a JEOL instrument (Japan) by
a back scattered electron technique with the aid of artifi-
cial shadowing in low vacuum (20 Pa) and an accelerat-
ing voltage of 20 kV.
2.6. X-Ray Powder Diffraction (XRPD)
X-ray diffraction patterns were recorded and used to de-
termine the physical form (crystalline or amorphous) of
the individual components present in the film. A D8 Ad-
vance XRPD diffractmeter (Bruker, Coventry, UK)
which was equipped with a Lyn X—Iris detector and 6.5
mm slit size was employed to obtain results in reflection
and transmission modes. The X-ray instrument was set at
40 kV and 40 mA with primary solar slit of 4˚ and a
secondary solar slit of 2.5 mm while the scattered slit
was 0.6 mm. Samples were scanned at a speed of 0.02˚,
2-theta step size every 0.1 seconds. The same was con-
ducted for pure PEG 600, poloxamer 407 and their
physical mixtures before and after heating on the DSC.
2.7. Stability Test
The formulations wrapped in paraffin film (to prevent
moisture absorption by κ-carrageenan 911, which is hy-
groscopic) were stored at room temperature and 45%
relative humidity (RH) over a six month period and the
drug content assayed monthly using HPLC. A standard
solution of ibuprofen (0.05 mg/ml) was used to develop a
suitable HPLC method. Different ratios of organic sol-
vents (methanol, acetonitrile) and the aqueous phase
(acetic acid, ortho-phosphoric acid) were investigated to
determine the optimum λmax. Based on the results the
final HPLC parameters were selected as follows: ODS
C18 reverse phase 5 μm particle size column (Hichrom
H50DS-3814), mobile phase methanol: water: ortho-
phosphoric acid (74:24:2), flow rate 1.5 mL/min and
diode array UV detection at 214 nm. A 0.5 mg/ml stan-
dard solution of ibuprofen was prepared, serially diluted
(0.05, 0.075, 0.1, 0.125 and 0.15 mg/ml) and analyzed by
HPLC and the data used to plot a calibration curve. Drug
stability over the storage period was analyzed by dis-
solving films in deionized water prior to running on the
HPLC. Pure crystalline ibuprofen powder stored at room
temperature as for the films was used as a control.
2.8. Drug Dissolution and Release Profile Studies
Before performing dissolution studies, the amount of
ibuprofen present within the film was assayed by HPLC
using the same conditions as for the stability studies.
Dissolution studies were performed using two different
dissolution media: 1) deionized water, pH of 5.6 as a
control, and 2) buffer solution (100 ml of KH2SO4 (0.1 M)
plus 13 ml of NaOH (0.1 M) with pH of 6.2 to simulate
that of saliva. As a further control, two 15 mg samples of
pure crystalline ibuprofen were weighed and dispersed
separately in 50 mL buffer solution and 50 ml deionized
water, respectively, at room temperature with continuous
stirring and the same procedure repeated as for the films.
Dissolution media were sampled at 5 minute intervals
starting from time zero till two hours and absorbance
(214 nm) measured using a Varian Spectro-photometer
(Yarnton, UK). Cumulative amounts of drug released
(mg) were calculated from the calibration curve and the
percentage drug release versus time profiles plotted. The
kinetics of ibuprofen release from the films were evalu-
ated by determining the best fit of the dissolution data
(percentage release vs. time) to the Higuchi, Korsmeyer-
Peppas, zero order and first order equations.
3. Results and Discussion
3.1. Formulation Development
The initial stages in the formulation of the films involved
polymer swelling, hydration and subsequent formation of
uniform and easily flowing gels for drying. κ-carra-
geenan 911 formed a firm gel which produced a flexible
film in the presence of PEG 600 while the κ-carrageenan
812 gel was strong; hence the resulting film was very
brittle even after the addition of plasticizer. Therefore,
κ-carrageenan 911 was the polymer of choice for further
studies. However, complete hydration and production of
a uniform gel was challenging due to its high molecular
weight and was also dependent on the temperature. One
means of overcoming this challenge was by prolonging
the hydration and swelling time of carrageenan 911 in
aqueous solution to 24 hours, which allowed complete
hydration at a lower temperature (40˚C - 50˚C). However,
this approach was very time consuming. The alternative
approach for obtaining films with acceptable characteris-
tics, involved dissolving poloxamer 407 in water for two
hours before addition of carrageenan. This gel formation
approach was used in all subsequent experiments for
investigating maximum drug loading.
The characteristics of an “ideal” film were evaluated
based on criteria such as transparency and homogeneity
(i.e. transparent without any entrapped air bubbles or
patches), plasticity (non-brittle films) and thickness (less

Formulation Development of a Carrageenan Based Delivery System for Buccal Drug Delivery 588
Using Ibuprofen as a Model Drug
than 1mm) [19] Based on the foregoing criteria, only
κ-carrageenan 911 produced films with acceptable char-
acteristics. Although glycerol plasticized films contain-
ing no drug showed ideal characteristics of transparency
and thickness less than 1mm, the corresponding ibupro-
fen loaded films did not exhibit the other desirable phy-
sical characteristics described above as the films showed
a patchy and uneven distribution of the various compo-
nents on the surface, resulting in an opaque appearance
(Figure 2(a)). This could be due to the higher amounts of
water retained by glycerol containing films, compared to
PEG (Table 2). As a result, glycerol was discontinued as
a plasticizer in drug loaded films. On the other hand,
PEG 600 (Figure 2(b)) at an optimum percentage (5.5%
- 6.5% w/w) within the gel produced flexible films with
sufficient rigidity and toughness under stress and during
handling and was therefore the plasticizer of choice for
all subsequent formulations.
The optimum concentrations of κ-carrageenan 911 and
poloxamer 407 within the gel were determined to be
2.5% and 4% w/w respectively. The maximum concen-
tration of ibuprofen that could be incorporated into the
gel was 0.8% w/w. This was achievable at a PEG 600
concentration of 6.5% w/w in the gel preparation using
the second drug loading approach, by initially dissolving
ibuprofen in ethanol. In addition, there was no significant
weight variation after an optimum drying time of 24
hours.
3.2. Texture Analysis
Texture analysis was used to measure tensile properties,
tensile strength (brittleness of films), elastic modulus
(rigidity) and elongation (flexibility and elasticity). The
elastic modulus was estimated from the initial linear por-
tion of the stress-strain curve (Equation (1)) whilst ten-
sile strength was calculated by dividing force at break by
(a) (b)
Figure 2. Digital images of ibuprofen loaded films pla-
sticized with (a) glycerol showing a non-uniform film with
patches of accumulated initial material and (b) PEG 600
which appears clear, transparent and exhibited acceptable
flexibility.
the initial cross-sectional area of the films specimen.
Figure 3(a) shows that the elastic modulus decreases
gradually with increasing PEG 600 concentration for
films containing no ibuprofen. According to the results,
the concentration of 5.5% w/w PEG 600 in gel (corre-
sponding to a κ-carrageenan 911/PEG 600 ratio of 5:11)
resulted in the elastic modulus reaching the minimum
value while the percent elongation remained at the
maximum.
Increasing the PEG 600 concentration to 6.5% w/w re-
sulted in a significant decrease in the percentage elonga-
tion and a corresponding increase in the elastic modu- lus
of the blank (non-drug loaded) films. However, different
observations were made when ibuprofen was present. Fol-
lowing the addition of ibuprofen, the elastic modulus
3.5 4.5 5.5 6.5
200
300
400
0
10
20
30
Elastic modulus (N/mm2)
PEG concentration (% w/w)
Elastic modulus
% Elongation
% Elongation
(a)
4.5 5.0 5.56.0 6.5
200
300
400
500
10
20
30
40
Elastic modulus (N/mm2)
PEGconcentration (/w)
Elastic modulus
% Elongation
% Elongation
(b)
Figure 3. Tensile results from texture analyses showing the
variations in elastic modulus and percentage elongation of
films with increasing concentration of PEG 600 for (a) op-
timized films containing no drug and (b) optimized films
prepared from gels containing 0.8 % w/w ibuprofen.

Formulation Development of a Carrageenan Based Delivery System for Buccal Drug Delivery 589
Using Ibuprofen as a Model Drug
values measured were higher than for the blank film and
required an increase in PEG 600 content to 6.5% w/w to
obtain films with desirable flexibility and toughness.
This increased concentration of PEG 600 allowed the
maximum 0.8% w/w ibuprofen loading in the gel, whilst
maintaining desirable film flexibility matching that of the
non-drug loaded films (Figure 3(b)). The tensile strength,
elongation and elastic modulus values are relevant as
they indicate the strength of the film under stress due to
stretching and have a direct effect on patient’s accep-
tance and clinical performance of the final dosage form.
Flexible films provide better patient compliance as they
are less likely to cause contact irritation. However, an
unduly elastic film is likely to cause problems with han-
dling such as folding and stickiness [19].
3.3. Thermal Analysis
1) Hot stage microscopy (HSM)
HSM results specified the degradation point for the
film samples loaded, which was about 190˚C. These re-
sults helped in developing suitable methods for TGA and
DSC analyses and determined the maximum temperature
to which samples could be heated.
2) Thermo gravimetric analysis (TGA)
TGA evaluation showed that the residual water in the
non-drug loaded films plasticized with glycerol was con-
siderably higher than films plasticized with PEG 600
(Table 2). This was attributed to the fact that glycerol
which is a known moisturizing agent retained more water
in the film matrix than PEG 600 owing to its higher af-
finity for water. Whilst this was not an issue with the
current model drug (ibuprofen), it could cause instability
especially for water sensitive drugs [20]. In the case of
films containing ibuprofen plasticized with PEG, the
residual (free) water content was considerably lower com-
pared to non-drug loaded films after storage for six
months due to loss in water during storage.
3) Differential scanning calorimetry (DSC)
To be able to evaluate the behavior of ibuprofen within
the films, based on its phase transition profiles, prelimi-
nary experiments of the pure compounds were conducted.
The results (Figures 4(a) and (b)) were used as the refer-
ence glass transition temperature and melting points of
the amorphous and crystalline forms of ibuprofen, re-
spectively. Figure 4(a) shows the glass transition of the
pure ibuprofen in amorphous form at a temperature of
−45.27˚C and Figure 4(b) shows the melting tempera-
ture of the crystalline form at 77.68˚C. Results of the
characterization of the thermodynamic behavior of films
formulated with carrageenan 911, poloxamer 407, PEG
600 and ibuprofen by DSC confirmed the absence of the
sharp melting point of the crystalline form of ibuprofen
at 77.68˚C. Instead the glass transition (Tg) correspond-
ing to the amorphous form of ibuprofen was detected at
-45.08°C
-0.45
-0.25
Heat Flow (W/g)
-65 -50 -35
Temperature (°C)
(a)
77.98°C
77.68°C
126.8J/g
-5.5
-3.5
-1.5
Heat Flow (W/g)
0 30609
Temperature (°C)0
(b)
-59.73°C
1.42°C
-15.63°C
17.19J/g
25.73°C
20.90°C
3.032J/g
40.42°C
34.11°C
23.93J/g
-1.8
-0.8
Heat Flow (W/g)
-75 -252575
Temperature (°C)
(c)
Figure 4. DSC profiles showing (a) glass transition of pure
amorphous ibuprofen; (b) melting point of pure crystalline
ibuprofen and (c) phase transitions of the film containing
ibuprofen.

Formulation Development of a Carrageenan Based Delivery System for Buccal Drug Delivery 590
Using Ibuprofen as a Model Drug
−59.73˚C (Figure 4(c)). It has been reported [21] that the
reason for the variation in glass transition point value is
the existence of plasticizer in the system which results in
the depression of the Tg. The results suggest that ibupro-
fen was present within the film matrix in an amorphous
form and was converted from the crystalline form origin-
nally added to the gel. Though amorphous forms are
known to be more soluble, they do present stability chal-
lenges owing to their tendency to convert back to the
crystalline form [22-24].
To investigate the stability of ibuprofen within the films,
further DSC experiments were conducted to determine
whether ibuprofen remained in an amorphous form or was
converted back to the crystalline form during storage. The
DSC results confirmed that ibuprofen remained in the
amorphous form within the film after storage at room
temperature for six months (Figure 5).
The results from mixing PEG 600 and poloxamer 407
[in the same ratio (56:34) as present in the film respect-
tively] showed another melting transition which ap-
peared between the transitions for PEG 600 and polox-
amer (Figure 6(a)). This is the reason for the DSC pro-
file of the film exhibiting three melting transitions in-
stead of two, corresponding to PEG 600 and poloxamer
407 (Figure 4(c)). It is plausible therefore that a mixture
of poloxamer and PEG 600 is formed within the film
which has a direct modifying effect on the melting point
of each compound as well. Instead of two melting points,
three melting peaks, representing the melting point of
PEG 600, poloxamer 407 and the mixture was detected
in films between 20˚C - 25˚C. There are two possible
reasons with regards to the identity of the mixture.
1) The first hypothesis is that poloxamer 407 solubilizes
-59.87°C
1.48°C
-16.14°C
15.43J/g
26.38°C
21.10°C
3.049J/g
40.53°C
34.93°C
30.82J/g
-2.2
-0.6
Heat Flow (W/g)
-75 -252575
Temperature (°C)
Figure 5. DSC profile of film containing ibuprofen after 6
month storage under room temperature conditions showing
three separate transitions attributed to poloxamer 407,
PEG 600 and the new entity comprising a mixture of both
compounds.
in the PEG 600 which could result in micelles of polox-
amer 407 in the core surrounded by PEG 600 in the shell.
However, comparison of XRPD diffractogram (Figure
6(b)) for pure PEG 600 and poloxamer 407 and their
mixtures before and after heating by DSC demonstrates
that this hypothesis is unlikely to occur as the only crys-
talline form present in the system was poloxamer 407.
Furthermore, the DSC results and the above hypothesis
relate to the non-drug loaded films but not the physical
mixtures or ibuprofen loaded films and therefore cannot
account for the incorporation of ibuprofen within such
micelles.
Although a shift in the melting transition of poloxamer
and PEG 600 was observed, it did not have any effect on
the thermal characteristics of ibuprofen. Therefore it can
be concluded that ibuprofen was not incorporated in mi-
celles comprising PEG and poloxamer.
2) The chemical structure of poloxamer 407 shows
that it comprises 79% PEG and 21% PPG (polypropylene
oxide). PEG has the ability to form inter-chain hydrogen
bonding as well as hydrogen bonding with water. It is
therefore possible that the presence of water may pro-
mote greater interaction of the PEG chains of poloxamer
407 and PEG 600 through greater hydrogen bonding. The
removal of water may weaken this interaction leading to
the formation of two distinct peaks during storage.
3.4. X-Ray Powder Diffraction (XRPD)
Figure 6(b) shows the XRPD spectra for physical mix-
tures of PEG 600 and poloxamer 407 as was analyzed on
the DSC. The spectra confirm the formation of a single
entity representing a mixture of poloxamer 407 and PEG
600 within the film. Figure 7 shows the XRPD spectra of
films containing ibuprofen. Figure 7(a) corresponds to
the film containing all components (carrageenan 911,
poloxamer 407, PEG 600 and ibuprofen). Since carra-
geenan 911, which is in amorphous form, was present in
a relatively high proportion within the film, a broad
XRPD spectrum was obtained. To eliminate this effect,
the spectra for carrageenan 911 were background sub-
tracted. The resulting spectrum represents all the crystal-
line molecules present within the film matrix. The results
demonstrate the absence of the main peak of crystalline
ibuprofen that should have appeared at 16.2 (2-theta)
according to the XRPD library data base. This confirmed
the DSC results and showed that the initial crystalline
ibuprofen originally added to the system was transformed
into amorphous form during film formation. The data in
Figure 7(b) shows that the relative percentage of PEG
600 changed during storage with an increase in the ratio
of crystalline to amorphous content as a consequence of
re-crystallization of PEG 60, with a resultant change in 0

Formulation Development of a Carrageenan Based Delivery System for Buccal Drug Delivery
Using Ibuprofen as a Model Drug
591
12.46°C
3.22°C
43.53J/g
30.75°C
25.60°C
13.78J/g
45.9 8°C
41.98°C
57.02J/g
-3
-1
Heat Flow (W/g)
-35 545
Temperature (°C)
(a)
(b)
Figure 6. (a) DSC results for the physical mixture of PEG 600 and poloxamer 407 during second heating cycle showing the
new melting point transition appearing between the two melting points of the individual components and (b) corresponding
XRPD diffractograms showing the spectra of the starting materials and physical mixtures.
the XRPD profile. However, amorphous ibuprofen did
not present any significant instability by way of recrys-
tallization back to the crystalline form during six months
of storage.
3.5. Scanning Electron Microscopy (SEM)
SEM was used to evaluate the surface characteristics
(morphology) of the films and how that could impart
other physico-chemical properties. The microscopic ap-
pearance of the film surface showed continuous sheet
which was also uniform with no obvious porous regions
(Figure 8(a)) and was maintained after incorporation of
ibuprofen (Figure 8(b)). This is important because the
rates of hydration, swelling and eventual drug dissolution

Formulation Development of a Carrageenan Based Delivery System for Buccal Drug Delivery 592
Using Ibuprofen as a Model Drug
(a)
(b)
Figure 7. XRPD profiles of (a) combined diffractograms of κ-carrageenan 911, poloxamer 407 and PEG 600 film’s showing
the absence of expected ibuprofen peak in the freshly prepared drug loaded film and (b) diffract gram for ibuprofen loaded
film after 1 month storage at room temperature conditions showing sharp crystalline peak of PEG 600 and absence of ibu-
rofen crystalline peak. p

Formulation Development of a Carrageenan Based Delivery System for Buccal Drug Delivery 593
Using Ibuprofen as a Model Drug
10 µm
x100
(a)
10 µm
x100
(b)
Figure 8. SEM images (×100 magnification) showing the
surface morphology of films prepared from carrageenan
911, poloxamer 407 and PEG 600 (a) containing no
ibuprofen and (b) that loaded with ibuprofen.
are dependent on the physical integrity of the film struc-
ture as it affects the initial rate of water ingress [6]. It
also shows a uniform distribution of the drug within the
film matrix which is highly desirable, in order to prevent
potential re-crystallization and crystal growth, which
could lead to instability.
3.6. Stability Studies
HPLC results showed that the actual concentration of
ibuprofen in the film sample did not change significantly
after six month storage at room temperature and 45% RH
(>90% assay). The pure crystalline ibuprofen used as
control also remained stable over 6 months. Though this
is highly desirable, longer term stability of ibuprofen
within the films will need to be studied under accelerated
conditions of higher temperature and relative humidity
[25] demonstrated that the degradation of ibuprofen in
bulk-drug samples ranged between 2.9% and 11.4%
following storage at the higher temperature of 80˚C.
Ibuprofen degradation under high temperature conditions
is likely given the alcohol functions present which could
result in possible ester formation between PEG 600 and
ibuprofen [26] have shown previously that polyethylene
glycol enhances the degradation of ibuprofen in tablets
under accelerated conditions of 70˚C and 75% RH and
such studies will be required to confirm this in the films.
3.7. Drug Dissolution and Release Profiles
The data in Figure 9 compares the dissolution profiles
for pure crystalline ibuprofen (control) and that within
the films using the two different dissolution media (deio-
nised water and buffer). Pure ibuprofen initially dis-
solved relatively quickly due possibly to the immediate
contact with the dissolution medium but reached a
plateau in 10 minutes. In contrast, ibuprofen was initially
released from the film matrix more quickly but showed
constant release profiles overall, reaching 65% and 58%
in 120 minutes for buffer and deionised water, respec-
tively. The dissolution profiles and gradient derived from
the initial linear portion of the drug release vs. time
curves confirmed the effect of pH on drug release rate
from the film matrix. These results showed that the rate
of drug release was accelerated in the simulated saliva
pH environment compared with the acidic pH condition
(deionized water). In addition, the maximum drug release
in buffer solution was about 8% higher than in acidic pH
(corresponding to stomach dissolution media). This
presents a potential advantage of buccal delivery over the
traditional oral route. This is an interesting finding for
films intended for buccal mucosa applications. However,
this needs further investigations as the difference obser-
ved could relate to ionization suppression of the acidic
ibuprofen at the lower pH of deionised water.
040801
0
30
60
20
% Drug release
Time (min)
Film + ibuprofen in water
Pure ibuprofen in water
Film + ibuprofen in buffer
Figure 9. Comparison of the dissolution profiles of pure
crystalline ibuprofen, and that contained within the film in
water and buffer dissolution media which simulated that of
saliva.

Formulation Development of a Carrageenan Based Delivery System for Buccal Drug Delivery 594
Using Ibuprofen as a Model Drug
These results indicate that ibuprofen was present in the
films in the amorphous form as compared to the pure
crystalline form used as a control. The amorphous form
of the drug being more water soluble is expected to have
a higher rate of dissolution according to Noyes-Whitney
equation and therefore may account for the higher rates
of release via diffusion and swelling of the polymer ma-
trix.
Dissolution data were fitted to different kinetic models
and the R2 values for the four models were calculated as
Higuchi (R2 = 0.98), Korsmeyer-Peppas (R2 = 0.98, n =
1.1), zero order (R2 = 0.99) and first order (R2 = 0.98)
which were not significantly different [27]. The Peppas
equation (Q = ktn) is generally used to analyze the release
of pharmaceutical polymeric dosage forms when the re-
lease mechanism is not well known (anomalous transport
release). It is also useful when more than one type of
release phenomenon could be involved, for example,
swelling and erosion of polymer. The equation becomes
more realistic in two main cases; pure diffusion con-
trolled drug release, n = 0.5 and swelling controlled drug
release, n = 1 (Case ІІ transport). Other values of n indi-
cate anomalous transport kinetics i.e. a combined mecha-
nism of pure diffusion and swelling and the magnitude of
n can be used as an indication of the type of transport
mechanism for the drug. A value of n ≤ 0.45 corresponds
to Fickian diffusion release (case І diffusional), (0.45 < n
≤ 0.89) to an anomalous (non-Fickian diffusion) trans-
port i.e. a gel erosion release mechanism, n = 0.89 to a
zero-order (case ІІ) release kinetics, and n > 0.89 to a
super case ІІ transport [28]. In the current study, the
value of n was found to be 1.1, indicating super case II
transport for drug release from the carrageenan based
films.
4. Conclusions
Optimized buccal films with ideal flexibility and tough-
ness were obtained from the gel comprising 2.5% w/w
κ-carrageenan 911 in combination with 4% w/w poloxa-
mer 407, 6.5% w/w PEG 600 and 0.8% w/w ibuprofen.
Thermal analysis showed that an interaction occurred
between PEG 600 and poloxamer 407 and such interac-
tions were dependent on the ratio of the two components
within the film. The key finding of this study lies in the
fact that ibuprofen, originally added as a crystalline
polymorph, was converted into a stable amorphous form
during film formation and this has an impact on the drug
release profiles from the film matrix in dissolution me-
dium simulating the pH of saliva. These films have po-
tential for buccal drug delivery and will be investigated
further for drug release and transport across ex vivo buc-
cal membrane in subsequent studies.
5. Acknowledgements
The authors will like to thank BASF (Surrey, UK) for
donating all grades of carrageenan used in this study.
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