Journal of Thermal Analysis and Calorimetry (2018) 133:1521–1533

https://doi.org/10.1007/s10973-018-7195-x (012 3456789().

,- volV)(0123456789().,-volV)

Physical–chemical characterization studies of ketoprofen

for orodispersible tablets
Laiane J. Oliveira1 • Nayana C. F. Stofella1 • Andressa Veiga1 • Suélyn Féderle1 • Maria da Graça T. Toledo1 •

Larissa S. Bernardi2 • Paulo R. Oliveira2 • Marco Aurélio S. Carvalho Filho3 • Itamar F. Andreazza1 •
Fábio S. Murakami1

Received: 14 November 2017 / Accepted: 11 March 2018 / Published online: 27 March 2018
Ó Akadémiai Kiadó, Budapest, Hungary 2018

Abstract
The development of orodispersible tablets containing ketoprofen (KTP) offers versatility in administration to patients with
swallowing difficulties. The rational development of a medication requires characterization studies for the solid state of the
active ingredient and compatibility with excipients to thus ensure a high-quality, safe and effective pharmaceutical form.
Therefore, compatibility studies were performed by differential scanning calorimetry (DSC) and thermogravimetry/
derivative thermogravimetry (TG/DTG), spectroscopy techniques (DRIFT, DRX, Raman), and morphological analysis by
scanning electron microscopy in order to obtain thermal characterization of the drug. The DSC curve demonstrated an
endothermic, symmetrical and evident fusion event (Tpeak = 96.37 °C, DH = -120.92 J g-1) and the TG/DTG curve
showed mass loss of Dm = 92.45% relative decomposition. For stability analysis, the non-isothermal kinetic study was
carried out. The granulate KTP showed higher Ea = 77.30 ± 0.25 kJ mol-1, hence being more stable than pure KTP
(Ea = 54.69 ± 1.53 kJ mol-1). Regarding the compatibility study, a displacement of the drug’s melting point to lower
temperatures was observed. However, a more significant interaction was evident with magnesium stearate. Further studies
were performed using spectroscopic techniques of DRIFT, Raman, X-ray diffraction and by scanning electron microscopy,
which demonstrated that there was no change in physicochemical properties of pure KTP. Therefore, through this study it
is possible to produce orodispersible tablets by compression and freeze-drying methods containing ketoprofen.

Keywords Ketoprofen  Orodispersible tablets  Kinetics analysis  Compatibility studies  Solid-state interactions

Introduction empirical formula is C16H14O3, and the chemical structure

The KTP (ketoprofen, 2-(3-benzoylphenyll)-propionic) is a
drug derived from the arylpropionic acid belonging to
nonsteroidal anti-inflammatory drugs (NSAIDs). Its
& Fábio S. Murakami
fsmurakami@gmail.com
1 the synthesis of prostaglandins and leukotrienes. Thus, it
Departamento de Farmácia, Universidade Federal do Paraná,
Av. Pref. Lothário Meissner, 632 - Jardim Botânico, Curitiba,
PR 80210-170, Brazil
2
Programa de Pós Graduação em Ciências Farmacêuticas,
Universidade Estadual do Centro-Oeste (UNICENTRO), Rua
Simeão Camargo Varela de Sá, 03 -Vila Carli, Guarapuava,
PR 85040-080, Brazil
3
Universidade Positivo – UP, R. Prof. Pedro Viriato Parigot de
Souza, 5300, Curitiba, PR 81280-330, Brazil
is shown in Fig. 1 [1]. The molecular mass of KTP is
254.29 g mol-1, and its melting range is from 94 to 97 °C.
It presents itself as a crystalline powder, practically insol-
uble in water, easily soluble in acetone, ethanol and
methylene chloride [2, 3]. Chemically, ketoprofen is a
weak acid due to the presence of a chiral carbon atom in
the side chain of the propionic acid [4]. In relation to the
pharmacological activity, KTP has an inhibitory effect on
presents anti-inflammatory, antipyretic and analgesic
activities [5, 6].
This drug has been used in the treatment of muscu-
loskeletal disorders and clinical studies show that the KTP
is as effective as other anti-inflammatory drugs in reducing
postoperative pain and discomfort. According to the Bio-
pharmaceutical Classification System, the KTP is classified

123
1522
O CH3
OH
O
Fig. 1 Ketoprofen chemical structure
as Class II, due to its high permeability and poor solubility
[7, 8].
The development of new pharmaceutical forms proposes
adherence to treatment and versatility to the patient.
Therefore, orodispersible tablets are an additional possi-
bility of pharmaceutical form to meet the needs of the
elderly and children who have major difficulty in swal-
lowing, since these tablets do not require co-administration
with water. In addition to that, orodispersible tablets pro-
vide precise dosages of the drug and, since there is
immediate release of the drug in the oral cavity, optimizes
pharmacotherapy [9].
The production of orodispersible tablets can be accom-
plished through several techniques. However, the charac-
teristics are common to all: high porosity, low
disintegration time and low hardness [10]. Meeting these
characteristics requires the combination of excipients
which make the formulation viable without interfering with
the pharmacological activity of the active substance.
Thus, the drug-excipient compatibility study during the
development of a product is an easy procedure which
verifies the possibility of chemical or physical interaction
between the components, which may compromise the
quality of the final product [11]. For this purpose, several
analytical techniques must be used in order to evaluate the
physical–chemical interaction between drug and excipient.
Among the available techniques, we point out the thermal
analysis, which makes it possible to verify physical or
chemical changes to the sample as a result of temperature.
Therefore, thermal analysis becomes an important tool for
a compatibility study in the ratio of 1:1 (w/w), comparing
the thermal curve of the pure drug to the other components
of the formulation [12]. To confirm the results of the
compatibility study obtained by DSC, there are comple-
mentary techniques such as: diffuse reflectance infrared
fourier transform (DRIFT) spectroscopy, X-ray diffraction
and raman spectroscopy, in addition to scanning electron
microscopy (SEM) [13, 14].
The kinetics of degradation study is also important for
both pure substances and mixtures. In this work, such study
is significant to define the issues of miscibility/incompati-
bility and their effects on thermal stability [15, 16].
Thus, the objective of this work was to carry out the pre-
formulation study for rational development of orodis-
persible tablets. This was accomplished through the
123
L. J. Oliveira et al.
physical–chemical study of KTP in solid state, evaluating
purity and drug-excipient compatibility by differential
scanning calorimetry (DSC), non-isothermal kinetic anal-
ysis, spectroscopy techniques and scanning electron
microscopy.
Materials and methods
Pre-formulation study for tablets obtained
by compression
The pre-formulation study was undertaken to facilitate
production of orodispersible tablets by the compression
method. This method was carried out by the wet granula-
tion method, using the drug ketoprofen (Fragon, Guarul-
hos-SP/Batch: 15073789A) and excipients.
Because the chosen method was wet granulation, the
ketoprofen was granulated using a solution of alcohol 70%
(v/v) to form a moist mass and incorporate the excipients.
The excipients used for the compression method were:
glycine (Alphatec), mannitol (All ChemistryÒ),
croscarmellose sodium (Blanver-ColorcomÒ), crospovi-
done (Blanver-ColorcomÒ), sodium starch glycolate
(Blanver-ColorcomÒ) magnesium stearate (Pharmachemi-
cal), and colloidal silicon dioxide (EvonikÒ). After the
ketoprofen, alcohol 70% (v/v) and excipients mixture, a
mass was formed, which then was extruded on tamils-by-
16 mesh with an aperture of 1 mm (BertelÒ, Caieiras-SP)
to obtain granules. This was followed by drying and stan-
dardization of the granules, ending with compression and
obtaining the tablets.
Pre-formulation study for tablets obtained
by freeze-drying
Pre-formulation studies were also performed in order to
develop the tablets by the freeze-drying method. This
method was supported by a suspension containing a mix-
ture of ketoprofen with the following excipients: glycine
(Alphatec), mannitol (All ChemistryÒ), croscarmellose
sodium (Blanver-ColorcomÒ), crospovidone (Blanver-
ColorcomÒ), sodium starch glycolate (Blanver-Color-
comÒ) xanthan gum (Pryme Foods), microcrystalline cel-
lulose (Blanver-ColorcomÒ) and sodium lauryl sulfate
(BiotecÒ).
For the production of freeze-drying orodispersible
tablets, the use of a suspending agent (xanthan gum) was
necessary. Consequently, a suspension with the Ketoprofen
mixture, a solution of xanthan gum, and other excipients
was performed, followed by weighing (approximately 1 g)
of this suspension in a blister with an average size of
15 mm in diameter. These were frozen at - 80 °C for 2 h
Physical–chemical characterization studies of ketoprofen for orodispersible tablets
and then freeze-dried (Benchtop Freeze-Dryer) in con-
denser at - 79 °C, under pressure of 16 mT for 24 h.
Characterization in the solid state
For analysis of purity and kinetic study, the bulk KTP was
compared to the granulated KTP.
The compatibility study by DSC was performed by
physically mixing KTP and excipients in proportional
amounts (1:1 w/w). In order to confirm the compatibility
studies between drug and excipients, the formulations were
subjected to spectroscopy and microscopy analyses. Both,
drug and excipients, were contained in proportions that will
be used in the production of the tablets.
Thermal analysis
Bulk ketoprofen, granulated ketoprofen and the mixture of
ketoprofen with excipients were investigated by thermo-
analysis techniques using thermogravimetry/derivative
thermogravimetry (TG/DTG) and differential scanning
calorimetry (DSC).
Thermogravimetric analysis/kinetics analysis
The thermogravimetric curves were obtained in the Shi-
madzu DTG-60 thermal analyzer by using platinum cru-
cibles with a sample mass of * 3 mg, under a dynamic
synthetic air atmosphere (50 mL min-1), with heating rate
of 10 °C min-1 in the temperature range of 30–400 °C.
For the non-isothermal kinetic study, curves were
obtained at a heating rate of 5, 10, 15, 20, 25 °C min-1.
The equipment was calibrated with reference standard of
calcium oxalate with declared purity of 99.99% [13].
Differential scanning calorimetry analysis
Regarding the purity study of pure and granulated KTP,
DSC curves (drug/excipient) were obtained in a Shimadzu
DSC-60 equipment under a dynamic synthetic air atmo-
sphere (50 mL min-1). The equipment was previously cal-
ibrated with reference standards of zinc and indium.
Approximately 3 mg of the drug-excipient mixture (1:1 w/w)
was placed in aluminum capsules and then sealed. The
analysis was carried out in the temperature range of
30–400 °C, in heating rate of 2 °C min-1 for purity analysis
and of 10 °C min-1 for compatibility analyses.
Diffuse reflectance infrared Fourier transform spectroscopy
The DRIFT spectra were performed using a Shimadzu
Europe spectrometer (model FTIR-8400S) in a scan range
of 500–4000 cm-1, with 45 scans and a spectral resolution
1523
of 4 cm-1 in KBr. A background spectrum for each
experimental condition was obtained. Each sample (pure
KTP, excipients for compression and excipients for freeze-
drying) was prepared by mixing 2% (w/w) in potassium
bromide (KBr). The data processing was conducted by the
Shimadzu Hyper IRÒ.
Raman spectroscopy
For the Raman spectroscopy, a Witec-Alpha 300 L was
used (source of di-iodine-3 mW, diffraction grating
600 g mm-1, laser wavelength of 532 nm). The results of
the spectra were processed by the OringinPro software
(version 8.5).
X-ray powder diffraction
The analyses of X-ray diffraction were obtained from the
X-ray diffractometer PANalytical (EMPYREAN, with
X’Celerator detector). The software used was X’Pert High
Score Plus, PDF-2 database. Monochromatic radiation Cu
´
Ka (k = 1.5406 Å) was also used, operating at 40 kV and
50 mA over a range of 2h of 3.5°–70°, generating a
spectrum every 10 s.
Scanning electron microscopy
A JEOL (JSM-6060LV) was used for the analyses of
scanning electron microscopy. The samples were previ-
ously metalized with gold and analyzed in low vacuum
mode with acceleration voltage of 15 kV in the magnifi-
cations of 10K9, 6K9, 3K9, and 2K9.
Results and discussion
Thermal characterization of ketoprofen
The TG/DTG and DSC curves of the pure KTP are shown
in Fig. 2. From the DSC curve, an endothermic event can
be observed, with a significant peak (Tpeak = 96.37 °C;
Tonset = 94.11 °C; DH = 120.92 J g-1) indicating drug
fusion. These data are in agreement with those in the lit-
erature (94–97 °C) [3]. Thus, the melting point confirms
that ketoprofen is in pure crystalline state.
The TG/DTG curves indicate that there was a thermal
decomposition in a single step, in only one endothermic
event with only one very evident peak in the range between
169 and 300 °C (Dm = 92.45%, DTGpeak = 281.61 °C).
Thus, the TG/DTG curves confirm that ketoprofen is
thermostable up to 169 °C. No significant losses occur up
to this temperature. At the end of the analysis, there was
another mass variation between 303–400 °C (Dm = 1.33%)
123
1524 L. J. Oliveira et al.

DrTGA/ DSC/ the pure and granulate KTP were used [13]. Thus, the DSC
–1
mg min–1 mW mg Mass/% curves obtained for pure and granulate KTP are presented
–2.00 in Fig. 3. Purity was calculated by applying the Van’t Hoff
100.00
2.00 equation, in the linearization of the melting event. Thus,
–4.00
the purity calculated for pure and granulate KTP was
1.00 99.20% ± 0.01, presenting melting enthalpy for pure
50.00
ketoprofen (DHf = -120.53 J g-1) and granulate ketopro-
DTG
0.00 –6.00
fen (DHf = -118.95 J g-1).
DSC Therefore, through this analysis, melting events were
–1.00 –8.00 observed, with well-defined and symmetrical endothermic
TG 0.00 peaks. This indicates that the drug granulation process, in
–2.00 one of its solvents, did not modify the characteristics of
–10.00
purity or crystallinity.
Endo

–3.00
–50.00
–12.00 Kinetics analysis
–0.00 100.00 200.00 300.00 400.00
Temperature/°C
It is valid to carry out a stability study analyzing storage
Fig. 2 The DSC and TG/DTG curves of ketoprofen obtained under conditions and expiration period of the product. In order to
synthetic air atmosphere (50 mL min-1) at heating rate of 10 °C do so, we performed non-isothermal kinetic analysis with
min-1
KTP samples, both pure and granulate. This method is
carried out by means of controlled temperature increase.
and the DSC endothermic peak at 339.46 °C refers to
Thus, the effect of the temperature on the samples was
carbonaceous materials, thus not a loss inherent to the drug.
analyzed in relation to the order of reaction and speed of
the degradation process [17].
Purity study
The non-isothermal method, initially derived by Ozawa
(1965), Flynn and Wall (1966), determines the value of the
The determination of purity is based on the hypothesis of
activation energy through various thermogravimetric
identifying impurities through the melting point of a pure
curves obtained at different heating rates [18, 19].
material. The melting point is characterized by an
The solid-state kinetic study has the purpose of calcu-
endothermic range and a melting enthalpy. The melting
lating the activation energy through the Arrhenius equation
transitions of a pure substance, i.e., a material that is 100%
(Eq. 1), which relates the constant rate of a simple reaction
crystalline, will generate DSC curves with narrow and very
stage to the temperature, through the activation energy (E)
evident peaks. The presence of small amounts of impurities
and pre-exponential factor (A), in which T is the absolute
in certain substances can interfere with the crystalline
temperature and R is the gas constant [20].
structure, generating a reduction in the melting point and
extending the overall melting range. For purity analysis,

Fig. 3 The DSC curves to:

(a) KTP pure and (b) granulate
ketoprofen with alcohol 70%
(v/v), obtained under synthetic (b)
air atmosphere (50 mL min-1) (a)
at heating rate of 2 °C min-1
Heat flow/mW

Endo

2.00 mW 99.2% ± 0.01

100 200 300

Temperature/°C

123
Physical–chemical characterization studies of ketoprofen for orodispersible tablets 1525

k ¼ AeðEa=RTÞ : ð1Þ variation was 0.32%, pre-exponential factor (A) 5.682 9

To obtain some kinetic parameters (activation energy,
order of reaction and pre-exponential factor), these were
calculated through the Ozawa equation (Eq. 2), in which a
is the fraction of decomposition, T is temperature, b is
heating rate, E is the activation energy, A is the pre-ex-
ponential factor, and R is the gas constant [20].
log b ¼ lg½AE=R; ga  2:315  0:4567 E=RT:
Non-isothermal kinetic data were calculated through mass
loss by the temperature of five TG curves obtained at dif-
ferent heating rates. The superposition of the TG curves for
the two samples was offset to a higher temperature in
proportion to the increase in the heating.
The TG curves obtained for the kinetic analysis are
described in Figs. 4 and 5. The insets in the figures show
the correlation of the curves, presenting a linear tendency
for both pure and granulate KTP. The activation energy
was obtained from a graph that represented the logarithms
of the heating rates as a function of inverse temperature (1/
T) for constant G (an integrated dependence form of the
conversion function f(x)).
The kinetic parameters obtained for pure KTP (Fig. 4)
were: activation energy (Ea) of 54.69 ± 1.52 kJ mol-1,
variation coefficient of 2.791%, pre-exponential factor
(A) of 2.877 9 104 min-1 and order of reaction zero
(n = 0).
In relation to the granulate KTP (Fig. 5), the activation
energy (Ea) was 77.30 ± 0.251 kJ mol-1, coefficient of
106 min-1 and order of reaction zero (n = 0).
According to a non-isothermal study, the parameters of
activation energy demonstrate that granulate KTP points to
a higher activation energy, that is, the process of granula-
tion has made the drug thermally more stable. This increase
in thermostability can be attributed to a reaction of the
alcohol molecule with carbon from the ketone group,
ð2Þ which separates the two rings of the ketoprofen structure.
On that account, according to Vueba et al. (2006), the
preferred and most stable conformations present ‘‘sub-
stituents’’ with synthesis or inclination guidance in relation
to the connection C=O. On the other hand, the order of the
reaction was the same for both samples (n = 0) [21].
Compatibility studies with excipients
DSC
In the development of the orodispersible tablets through
freeze-drying and compression by wet granulation, the
compatibility study between KTP and the excipients was
performed using differential scanning calorimetry (DSC).
The thermally analytical data of pure KTP and the 1:1
w/w mixture are presented in Tables 1 and 2 according to
the production technique, with the respective comparative
DSC curve (Figs. 6, 7).
The DSC curves analysis between the drug and sugars,
mannitol and glycine, has shown that these excipients are
compatible, since they did not to interfere with the
endothermic peak of pure KTP.

Fig. 4 TG of pure KTP

obtained at different heating
rates under dynamic synthetic
100.00
air atmosphere. The inset shows
the linear tendency and 5 °C min–1 (a)
correlation of the Ozawa plots 10 °C min–1 (b)
of the curves 15 °C min–1 (c)
80.00 20 °C min–1 (d) (a)
25 °C min–1 (e) (b)
(c)
Mass/%

(d)
(e)
60.00
Log A
1.45

1.25
40.00
1.05

0.85

20.00 0.65

×10
–3
1.80 1.90 2.00 2.10
1/T/K–1
–0.00
100.00 200.00 300.00
Temperature/°C

123
1526 L. J. Oliveira et al.

Fig. 5 TG of granulated
ketoprofen with alcohol 70%
(v/v) obtained at different
heating rates under dynamic 100.00
synthetic air atmosphere. The
inset shows the linear tendency 5 °C min–1 (a)
and correlation of the Ozawa 10 °C min–1 (b)
15 °C min–1 (c) (a)
plots of the curves 80.00 20 °C min–1 (d) (b)
25 °C min–1 (e) (c)
(d)
(e)

Mass/%
60.00
Log A
1.45

1.25
40.00
1.05

0.85

0.65
20.00
1.80 1.90 2.00 ×10–3
1/T/K–1

100.00 200.00 300.00

Temperature/°C

Table 1 The DSC

Drug/excipients Tpeak/°C T Onset/°C Tendset/°C DH/J g-1
measurements showing Tonset,
Tpeak and enthalpy values of (a) KTP 96.37 94.03 100.74 - 120.28
ketoprofen and various drug–
excipient binary mixtures, (b) Mannitol ? KTP 96.11 93.31 99.79 - 56.89
corresponding to the (c) Glycine ? KTP 95.73 93.48 98.75 - 38.25
compression formulation (d) Croscarmellose sodium ? KTP 86.41 81.10 91.79 - 71.70
(e) Crospovidone ? KTP 82.37 79.25 86.23 - 57.17
(f) Sodium starch glycolate ? KTP 85.66 76.32 89.76 - 64.41
(g) Microcrystalline cellulose ? KTP 87.84 81.67 92.97 - 64.15
(h) Magnesium stearate ? KTP 76.64 71.65 84.58 - 134.91
(i) Colloidal silicon dioxide ? KTP 92.18 86.77 96.21 - 53.83

Table 2 The DSC

Drug/excipients Tpeak/°C Tonset/°C Tendset/°C DH/J g-1
measurements showing Tonset,
Tpeak and enthalpy values of (a) KTP 96.19 94.03 100.74 - 120.28
ketoprofen and various drug–
excipient binary mixtures, (b) Mannitol ? KTP 95.75 93.31 99.79 - 56.89
corresponding to the freeze- (c) Glycine ? KTP 95.54 93.48 98.75 - 38.25
drying formulation (d) Croscarmellose sodium ? KTP 86.25 81.10 91.79 - 71.70
(e) Crospovidone ? KTP 82.20 79.25 86.23 - 57.17
(f) Sodium starch glycolate ? KTP 83.88 76.32 89.76 - 64.41
(g) Sodium lauryl sulfate ? KTP 90.43 81.85 95.02 - 52.78
(h) Xanthan gum ? KTP 86.26 81.50 92.28 - 53.64

Regarding the superdisintegrants croscarmellose,
crospovidone and starch glycolate: the DSC curves for the
two formulations had larger peaks corresponding to dehy-
dration with endothermic event. Thus, the melting peaks of
ketoprofen were offset to lower temperature, which may
have occurred due to the melting of the drug with the peak
of water loss of the superdisintegrants. Cellulose micro-
crystalline (CMC 101) was used as a diluent in the for-
mulation by compression. The mixture also shifted the
event of KTP melting. Hence, there was also melting of the
drug with water loss from the CMC 101 [14].

123
Physical–chemical characterization studies of ketoprofen for orodispersible tablets 1527

(a)
96.37 °C

96.11 °C
(b)
Heat flow/mW
(c)
95.73 °C
(d)
86.41 °C

(e)
82.37 °C
(f)
Endo

85.66 °C
(g)
87.84 °C
(h)
76.64 °C
(i)
2.00 mW 92.18 °C
100 200 300
Temperature/°C

Fig. 6 DSC curves of ketoprofen and binary mixture of KTP with excipients for formulation compression, according to Table 1. The data were
obtained in dynamic synthetic air atmosphere (50 mL min-1) and heating rate of 10 °C min-1

Fig. 7 DSC curves of

ketoprofen and binary mixture
of KTP with excipients for (a)
freeze-drying formulation,
96.19 °C
according to Table 2. The data
were obtained in dynamic
synthetic air atmosphere (b)
95.75 °C
(50 mL min-1) and heating rate
Heat flow/mW

of 10 °C min-1 (c)
95.54 °C
(d)
86.25 °C
(e)
82.20 °C
(f)
Endo

83.88 °C
(g)
90.43 °C
(h)
86.26 °C
2.00 mW

100 200 300

Temperature/°C

As for the lubricants used for compression, the silicon
dioxide showed no interference in the melting peak, due to
the fact that the melting point of silicon dioxide is 1600 °C,
i.e., it does not interfere in the endothermic event of the
drug. It is also silica, which does not retain water easily and
therefore does not dehydrate or decompose [22]. The
magnesium stearate, however, when compared to KTP,
presented visible differences. The DSC curve shows an
offset of the melting peak (Tpeak = 76.64 °C) of the KTP to
a low temperature. This is due to the fact that the magne-
sium stearate in its production process is composed of
different fatty acids (mainly stearic acid and palmitic acid)
with different melting points (range 60–70 °C). This
composition implies different melting points with multiple
endothermic melting events, thus affecting the values of
Tpeak, Tonset and drug enthalpy over these binary mixtures.
The offset can be attributed to the production of impurity
(salt of palmitate) caused by the eutectic mixture between

123
1528 L. J. Oliveira et al.

the two components when subjected to high heating [23].
Some authors have published compatibility studies using
magnesium stearate. Among them, a similar behavior was
observed by Veiga et al. (2017), Peres-Filho et al. (2011)
and Mura et al. (1995) [24–26].
For the production of tablets through freeze-drying, the
formulation used xanthan gum as a thickening agent and
sodium lauryl sulfate (LSS) as a surfactant, contributing to
the incorporation of KTP into the formulation. The DSC
curve (Fig. 7) of the thickener and the drug mixed had an
offset of Tpeak and can be attributed to drug melting with
the peak of water loss. As for the LSS, it also presented a
small reduction in the Tpeak of the drug, though not an
expressive one.
Drift
Diffuse reflectance for the transformation of Fourier
infrared is part of the spectroscopic analysis that can be
applied as complementary technique in compatibility
studies between drug and excipient, in order to confirm the
results obtained from thermal analysis. This technique was
used in this study since it is the most appropriate one
among the spectroscopic nondestructive methods, making
it a particularly attractive method in the analysis of solid

Fig. 8 Comparative DRIFT spectra

of pure KTP (a), KTP with (a)
excipients for compression (b)
and KTP with excipients for
freeze-drying (c)
Transmitance/%

(b)

(c)

4000.0 2000.0 1500.0 1000.0 500.0

Wavenumber/cm–1

Table 3 Chemical groups of

Compound IR data/cm-1 Band position/cm-1
KTP according to the bands of
absorption Masked O–H O–H stretching 3200–2500
C–H stretching of aromatic 3053, 3061, 3069, 3088
C–H stretching of CH3 2981
C–H stretching of *C 1448
C=O carboxylic acid stretch 1697
C=O ketone stretch 1654
C=C aromatic ring 1598, 1580, 1455
C–H deformation of *C asymmetrical 1440
C–H deformation of CH3 symmetrical 1370
C–C–C rings joined by the ketone group 1283
C=C deformation of aromatic rings 860–690

123
Physical–chemical characterization studies of ketoprofen for orodispersible tablets 1529

Fig. 9 RAMAN spectra

(a)
(250–3250 cm-1). a KTP,
b KTP with excipients for
compression formulation,
c KTP with excipients for
freeze-drying formulation and
d Structure KTP identified

250 500 750 1000 1250 1500 1750 2000 2250 2500 2750 3000 3250

(b)

250 500 750 1000 1250 1500 1750 2000 2250 2500 2750 3000 3250

(c)

250 500 750 1000 1250 1500 1750 2000 2250 2500 2750 3000 3250

Wavenumber/cm–1

(d) 1705 cm–1

O CH3

OH

1281 cm–1

O
1657 cm–1
1491 cm–1 a 1601 cm–1
3058 cm–1 a 3073 cm–1

pharmaceuticals. This is due to the fact that the materials KTP spectra were obtained and formulations of each
are not subject to thermal or mechanical energy during the method (compression and freeze-drying) containing
preparation of the sample, thus avoiding changes in the excipients and the drug in proportion to the production of
state of matter [13]. the tablets (Fig. 8). After the readings, the spectra were

123
1530
8000
(a)
6000
4000
2000
Intensity/a.u.
0
10 20 30
(b)
6000
4000
2000
0
10 20 30
2θ /°
Fig. 10 DRX: a bulk KTP, b KTP with excipients
compared in order to identify a possible chemical inter-
action between them.
It is possible to observe the bands of absorption with
high intensity in the first spectrum of Fig. 8. These can be
related to the functional groups that characterize KTP as
provided in Table 3. It is relevant to focus on the main
bands of absorption, which are related to the functional
groups and/or connections that characterize the KTP.
Among these bands, the highlights are: 1697 cm-1 related
to the carboxylic acid. There are also 1654 cm-1 related to
the ketone group that is attached to two aromatic rings, the
first of which is identified in the bands from 3053 to
3088 cm-1, and the second is characterized in 1598, 1580
and 1455 cm-1. The two aromatic rings attached to the
ketone group in 1283 cm-1 make up part of the chemical
structure that is intrinsic to ketoprofen [21, 27, 28].
After the identification of bands of absorption that
characterize the KTP, the study of compatibility was per-
formed. According to the spectra obtained for both for-
mulations (freeze-drying and compression), shown in
Fig. 8, it can be observed that the excipients have not
modified the bands of the absorption characteristic of the
drug structure.
Therefore, the DRIFT technique complements the
compatibility study between drug and excipient, proving
that the excipients did not change the physical–chemical
structure of KTP. The removals occurred at the same
wavelengths, thus confirming that the formulations were
planned with inert excipients.
123
L. J. Oliveira et al.
40 50 60
40 50 60
Raman
The Raman technique is based on the principle of disper-
sion, that is, the emission of radiation from a monochrome
laser focusing on the sample, causing vibration of the
molecules contained in it. Thus, the Raman spectrum is
obtained between the inelastic collision of incident
monochromatic radiation (laser) and the molecules present
in the study sample [29].
Raman’s spectroscopy was performed on samples of
pure KTP and mixture of all the excipients in proportions
formulated for a tablet. The spectra obtained are presented
in Fig. 9, with analysis in the range of 250–3250 cm-1,
yielding a spectrum every 3 s, with an integration time of
30 s. Figure 9d shows the frequencies assigned to the
organic groups such as: ketone, carboxylic acid and phenyl,
which consist, in part, of the molecule of the KTP.
The ketoprofen molecule can take on different confor-
mations, and the difference between the least stable and
most stable conformation energy is 7 kJ mol-1. Thus,
among the groups that characterize KTP are the carboxylic
acid with frequency at 1657 cm-1 and the ketone group at
1705 cm-1, which joins two aromatic rings, the first being
identified between 1491 and 1601 cm-1, and the second
between 3058 and 3073 cm-1, while the connection
between the three carbons, particular to KTP, is identified
in the frequency of 1281 cm-1 [22].
After identifying the KTP structure, the Raman spec-
trum of the drug and excipient mixture for the compression
and freeze-drying method was obtained, as shown in
Fig. 9b and c, respectively. According to the comparison of
Physical–chemical characterization studies of ketoprofen for orodispersible tablets 1531

the spectra, no offset occurred nor any disappearance of

bands that might characterize a possible incompatibility
between drug and excipient. Therefore, the mixture of KTP
with all excipients did not alter the physical characteristics
of the drug. Thus, a compatibility study through Raman
analysis contributes to the viability of the proposed
formulations.

DRX

The diffraction of an X-ray (DRX) beam by a crystalline

material is formed by the process of constructive interfer-
ence, caused by the incidence of an X-ray beam toward a
material with periodically arranged atomic structure. The
X-ray powder diffraction technique was used for qualita-
tive purposes for the identification of crystallinity [30].
The diffractograms of ketoprofen and of the mixture
between ketoprofen and all excipients can be observed in
Fig. 10.
According to the diffractograms, the X-ray pattern of
pure KTP (Fig. 10a) characterizes it as a crystalline
material with characteristic diffraction peaks. Showing
diffraction pattern peaks at 6.33°, 13.16°, 14.42°, 16.22°,
17.308 18.42°, 19.15°, 20.04°, 22.91°, 23.95°, 27.23°,
27.73°, 29.49°, with the main peaks at 6.33°, 18.42° and
23.95°. Dragan et al. (2016) and Yadav et al. (2013)
described similar X-ray pattern of pure crystalline of
ketoprofen [28, 31].
The DRX study showed peaks corresponding to the
ketoprofen molecule inside the excipient diffractogram
(Fig. 10b) with no interference occurring, that is, the
diffraction peaks at 2h angles at 6.33°, 18.42° and 23.95°
and same intensity are evident, even though it is in the
mixture with all excipients.
Hence, results obtained by DRX showed that the
excipients are inert in relation to the crystalline charac-
teristic of the drug, showing no interaction in the solid
state.
Scanning electron microscopy
The physical characteristics of pure KTP and of the
excipients are shown in photomicrographs obtained by
scanning electron microscopy (SEM), in Fig. 11.
The form of the crystals directly influences character-
istics such as fluidity, compressibility, stability of suspen-
sion and powder dissolution. Therefore, micrographies
were obtained by high-resolution microscopy (6K9 and
10K9) of KTP in its pure state (Fig. 11a1/a2). The pho-
tomicrographs showed that pure KTP presents crystalline
forms with sizes of 1–10 lm, regularly shaped as
orthorhombic crystals [32].
Fig. 11 Photomicrographs obtained by scanning electron microscopy
(SEM): a1 KTP 6K9 and a2 KTP 10K9; b1 KTP with excipients
3K9 e b2 KTP with excipients 10K9; c1 and c2 show the granulate
KTP in increments of 2K9 and 3K9, respectively
In relation to the physical mixture of pure KTP and
excipients, the photomicrographs are shown in Fig. 11b1/
b2. It is possible to observe that the excipients of the for-
mulations for compression (mannitol, glycine,
croscarmellose, crospovidone, starch glycolate, CMC 101,
magnesium stearate and silicon dioxide) and for freeze-
drying (mannitol, glycine, croscarmellose, crospovidone,
starch glycolate, xanthan gum and sodium lauryl sulfate)
presented irregular forms, predominantly as amorphous
substances [33]. Therefore, the mixture of KTP and
excipients showed no interaction, given that maintenance
of the morphology of the drug can be verified.
The thermostability of pure KTP in relation to granu-
lated KTP can also be confirmed by photomicrographs by
scanning electron microscopy, as shown in Fig. 11c1/c2.
In the preparation of tablets through the compression
method, the formulation containing the excipients and drug
in the desired proportions goes through a granulation pro-
cess. Therefore, it is possible to compare the differences in
the physical mixtures (Fig. 11b1/b2) in relation to the
granules in Fig. 11c1/c2. Comparatively, what can be
observed is that, whereas crystalline structures of the drug
preferably occur in the physical mixture, there is a pref-
erence for amorphous structures in the granules. This may
be attributed to the process of mass extrusion that produces

123
1532
drug–excipient agglomerates and makes this characteristic
more thermally stable, which was verified through non-
isothermal kinetic analysis.
Conclusions
From the characterization of the solid-state KTP, it was
possible to perform the rational development of orodis-
persible tablets using the wet compression method and
freeze-drying.
DSC purity analysis for pure KTP and granulated KTP
showed fusion events with well-defined and symmetrical
endothermic peaks, indicating that the drug granulation
process, in one of its solvents, did not alter the character-
istics of purity or crystallinity. In relation to thermosta-
bility, granulated KTP presented a higher activation
energy, which was confirmed by the SEM photomicro-
graphs that show the granules with preference for amor-
phous structure, due to the process of extrusion of mass
producing drug–excipient agglomerates, and thus con-
firming that granulated KTP is more thermostable.
As for the compatibility study, the differential scanning
calorimetry (DSC) technique showed only one possible
incompatibility between KTP and magnesium stearate.
However, this incompatibility is attributed to the compo-
sition of the excipient. To corroborate the compatibility
and feasibility studies of the formulations, spectroscopy
techniques such as DRIFT, Raman and DRX were per-
formed, showing comparative spectra between pure KTP
and KTP with excipients. In general, there was no dis-
placement, disappearance or even interference in the
absorption bands in the spectra. It is also worth noting that
the absorption bands characteristic to KTP remained in the
mixture spectrum, confirming that there was no interaction
in the solid state, and therefore the excipients are inert.
Regarding the physical characteristics of pure KTP and
its mixture with excipients, pure KTP was observed in
acicular form in SEM photomicrographs, whereas the
excipients presented irregular forms. The KTP–excipients
mixture showed no interaction, considering maintenance of
the morphology of the drug was verified.
Thus, pharmaceutical characterization studies made it
possible to produce orodispersible tablets containing the
ketoprofen drug safely, effectively and with quality.
Acknowledgements The authors would like to thank the Brazilian
National Research Council (CNPq) by their financial support and the
Academic Publishing Advisory Center (CAPA) of Federal University
of Parana for assistance with English language editing.
123
L. J. Oliveira et al.
References
1. Rençber S, Karavana Y, Özyazici M. Bioavailability file: keto-
profen. J Pharm Sci. 2009;34:203–16.
2. United States Pharmacopeia and National Formulary (USP 32 -
NF 27). Rockville: United States Pharmacopeia Convention;
2009, p. 2739.
3. BRASIL. Agência Nacional de Vigilância Sanitária (ANVISA).
Farmacopeia Brasileira. 5th ed. Distrito Federal Brası́lia: Agência
Nacional de Vigilância Sanitária (ANVISA); 2010.
4. Asensio C, Levoin N, Guillaume C, Guerquin MJ, Rouguieg K,
Chrétien F, Chapleur Y, Netter P, Minn A, Lapicque F. Irre-
versible inhibition of glucose-6-phosphate dehydrogenase by the
coenzyme A conjugate of ketoprofen: a key to oxidative stress
induced by non-steroidal anti-inflammatory drugs? Biochem
Pharmacol. 2007;73(3):405–16.
5. Levoin N, Blondeaua C, Guillaumea C, Grandcolas L, Chretien
F, Jouzeau JY, Benoit E, Chapleur Y, Netter P, Lapicque F.
Elucidation of the mechanism of inhibition of cyclooxygenases
by acyl-coenzyme A and acylglucuronic conjugates of ketopro-
fen. Biochem Pharmacol. 2004;68(10):1957–69.
6. Seymour RA, Kelly PJ, Hawkesford JE. The efficacy of keto-
profen and paracetamol (acetaminophen) in postoperative pain
after third molar surgery. Br J Clin Pharmacol. 1996;41(6):581–5.
7. Pora_zka J, Karbownik A, Murawa D, Spychala A, Firlej M,
Grabowski T, Murawa P, Grześkowiak E, Szałek E. The phar-
macokinetics of oral ketoprofen in patients after gastric resec-
tion. Pharmacol Rep. 2017;69(2):296–9.
8. Shohin IE, Kulinich JI, Ramenskaya GV, Abrahamsson B, Kopp
S, Langguth P, Polli JE, Shah VP, Groot DW, Barends DM,
Dressman JB. Biowaiver monographs for immediate-release solid
oral dosage forms: ketoprofen. J Pharm Sci.
2012;101(10):3593–603.
9. Prabhu P, Malli R, Koland M, Vijaynarayana K, D’Souza U,
Harish NM, Shastry CS, Charyulu RN. Formulation and evalua-
tion of fast dissolving oral film of levocetirizine di hydrochloride.
Int J Pharm Investig. 2011;4(1):337–441.
10. Goel H, Rai P, Rana V, Tiwary AK. Orally disintegrating sys-
tems: innovations in formulation and technology. Recent Pat
Drug Deliv Formul. 2008;2(3):258–74.
11. Verma RK, Garg S. Compatibility studies between isosorbide
mononitrate and selected excipients used in the development of
extended release formulations. J Pharm Biomed Anal.
2004;35(3):449–58.
12. Araujo AAS, Cides LC, Storpirtis S, Matos JR, Bruns RE. Effects
of experimental conditions on the estimation of kinetic parame-
ters of the thermal decomposition of AZT using factorial design.
J Therm Anal Calorim. 2005;79(3):697–701.
13. Murakami FS, Lang KL, Mendes C, Cruz AP, Carvalho Filho
MAS, Silva MAS. Physico-chemical solid-state characterization
of omeprazole sodium: thermal, spectroscopic and crystallinity
studies. J Pharm Biomed Anal. 2009;49(1):72–80.
14. Tiţa B, Fuliaş A, Bandur G, Marian E, Tiţa D. Compatibility
study between ketoprofen and pharmaceutical excipients used in
solid dosage forms. J Pharm Biomed Anal. 2011;56(2):221–7.
15. Ortega A. A simple and precise linear integral method for iso-
conversional data. Termochimica Acta. 2008;474(1–2):81–6.
16. Budrugeac P. Differential non-linear isoconversional procedure
for evaluating the activation energy of non-isothermal reactions.
J Therm Anal Calorim. 2002;68(1):131–9.
17. Pomerantsev AL, Kutsenova AV, Rodionova OY. Kinetic anal-
ysis of non-isothermal solid-state reactions: multi-stage modeling
without assumptions in the reaction mechanism. Phys Chem
Chem Phys. 2017;19:3606–15.
Physical–chemical characterization studies of ketoprofen for orodispersible tablets
18. Ozawa T. A new method of analyzing thermogravimetric data.
Bull Chem Soc Jpn. 1965;38(11):1881–6.
19. Flynn JH, Wall LA. General treatment of the thermogravimetry
of polymers. J Res Natl Bur Stand. 1966;70(6):487–523.
20. Murakami FS, Bernardi LS, Pereira RN, Valente BR, Vascon-
celos EC, Carvalho Filho MAS, Silva MAS. Comparative
behavior studies of cinnamic acid using isothermal and non-
isothermal kinetic methods. Pharm Chem J. 2009;43(12):716–20.
21. Vueba ML, Pina ME, Veiga F, Sousa JJ, de Carvalho BLAE.
Conformational study of ketoprofen by combined DFT calcula-
tion and Raman spectroscopy. Int J Pharm. 2006;307(1):56–65.
22. Fruijtier-Pöllot C. The toxicological mode of action and the
safety of synthetic amorphous sı́lica—a nanostructured material.
Toxicology. 2012;294:61–79.
23. Mura P, Gratteri P, Faucci MT. Compatibility studies of multi-
component tablet formulations. DSC and experimental mixture
design. J Therm Anal Calorim. 2002;68(2):541–51.
24. Veiga A, Oliveira PR, Bernardi LS, Mendes C, Silva MS, Sangoi
MS, Janissek PR, Murakami FS. Solid-state compatibility studies
of a drug without melting point: the case of omeprazole sodium.
J Therm Anal Calorim. 2017. https://doi.org/10.1007/s10973-
017-6756-8.
25. Peres-Filho MJ, Gaeti MPN, Oliveira SR, Marreto RN, Lima EM.
Thermoanalytical investigation of olanzapine compatibility with
excipients used in solid oral dosage forms. J Therm Anal
Calorim. 2011;104(1):255–60.
26. Mura P, Manderioli A, Bramanti G, Furlanetto S, Pinzauti S.
Utilization of differential scanning calorimetry as a screening
1533
technique to determine the compatibility of ketoprofen with
excipients. Int J Pharm. 1995;119(1):71–9.
27. Bannach G, Arcaro R, Ferroni DC, Siqueira AB, Treu-Filho O,
Ionashiro M, Schnitzler E. Thermoanalytical study of some anti-
inflammatory analgesic agents. J Therm Anal Calorim.
2010;102:163–70.
28. Dragan F, Kacso I, Martin F, Borodi G, Bratu I, Costuleanu M,
Sandu IG, Poroch V. Solid state interactions between ketoprofen and
excipients in solid dosage forms. Rev Chim. 2016;67(10):2043–8.
29. Bumbrah SG, Sharma RM. Raman spectroscopy—basic princi-
ple, instrumentation and selected applications for the characteri-
zation of drugs of abuse. Egypt J Forensic Sci.
2016;6(3):209–2015.
30. Bunaciu AA, Udriştioiu EG, Aboul-Enein HY. X-ray diffraction:
instrumentation and applications. Crit Rev Anal Chem.
2015;45(4):289–99.
31. Yadav PS, Kumar V, Singh PU, Bhat RH, Mazumder B.
Physicochemical characterization and in vitro dissolution studies
of solid dispersions of ketoprofen with PVP K30 and D-mannitol.
Saudi Pharm J. 2013;21(1):77–84.
32. Dixit M, Parthasarathi KK, Rudra SV. Effect of different crys-
tallization techniques on the dissolution behavior of ketoprofen.
Trop J Pharm Res June. 2013;12(3):317–22.
33. Shohin IE, Kulinich JI, Ramenskaya GV, Vasilenko GF. Evalu-
ation of in vitro equivalence for drugs containing BCS class II
compound ketoprofen. Dissolution Technol. 2011;19(1):26–9.
123