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Physical-Chemical Characterization Studies of Ketoprofen
Physical-Chemical Characterization Studies of Ketoprofen
Larissa S. Bernardi2 • Paulo R. Oliveira2 • Marco Aurélio S. Carvalho Filho3 • Itamar F. Andreazza1 •
Fábio S. Murakami1
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
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L. J. Oliveira et al.
as Class II, due to its high permeability and poor solubility Materials and methods
[7, 8].
The development of new pharmaceutical forms proposes Pre-formulation study for tablets obtained
adherence to treatment and versatility to the patient. by compression
Therefore, orodispersible tablets are an additional possi-
bility of pharmaceutical form to meet the needs of the The pre-formulation study was undertaken to facilitate
elderly and children who have major difficulty in swal- production of orodispersible tablets by the compression
lowing, since these tablets do not require co-administration method. This method was carried out by the wet granula-
with water. In addition to that, orodispersible tablets pro- tion method, using the drug ketoprofen (Fragon, Guarul-
vide precise dosages of the drug and, since there is hos-SP/Batch: 15073789A) and excipients.
immediate release of the drug in the oral cavity, optimizes Because the chosen method was wet granulation, the
pharmacotherapy [9]. ketoprofen was granulated using a solution of alcohol 70%
The production of orodispersible tablets can be accom- (v/v) to form a moist mass and incorporate the excipients.
plished through several techniques. However, the charac- The excipients used for the compression method were:
teristics are common to all: high porosity, low glycine (Alphatec), mannitol (All ChemistryÒ),
disintegration time and low hardness [10]. Meeting these croscarmellose sodium (Blanver-ColorcomÒ), crospovi-
characteristics requires the combination of excipients done (Blanver-ColorcomÒ), sodium starch glycolate
which make the formulation viable without interfering with (Blanver-ColorcomÒ) magnesium stearate (Pharmachemi-
the pharmacological activity of the active substance. cal), and colloidal silicon dioxide (EvonikÒ). After the
Thus, the drug-excipient compatibility study during the ketoprofen, alcohol 70% (v/v) and excipients mixture, a
development of a product is an easy procedure which mass was formed, which then was extruded on tamils-by-
verifies the possibility of chemical or physical interaction 16 mesh with an aperture of 1 mm (BertelÒ, Caieiras-SP)
between the components, which may compromise the to obtain granules. This was followed by drying and stan-
quality of the final product [11]. For this purpose, several dardization of the granules, ending with compression and
analytical techniques must be used in order to evaluate the obtaining the tablets.
physical–chemical interaction between drug and excipient.
Among the available techniques, we point out the thermal Pre-formulation study for tablets obtained
analysis, which makes it possible to verify physical or by freeze-drying
chemical changes to the sample as a result of temperature.
Therefore, thermal analysis becomes an important tool for Pre-formulation studies were also performed in order to
a compatibility study in the ratio of 1:1 (w/w), comparing develop the tablets by the freeze-drying method. This
the thermal curve of the pure drug to the other components method was supported by a suspension containing a mix-
of the formulation [12]. To confirm the results of the ture of ketoprofen with the following excipients: glycine
compatibility study obtained by DSC, there are comple- (Alphatec), mannitol (All ChemistryÒ), croscarmellose
mentary techniques such as: diffuse reflectance infrared sodium (Blanver-ColorcomÒ), crospovidone (Blanver-
fourier transform (DRIFT) spectroscopy, X-ray diffraction ColorcomÒ), sodium starch glycolate (Blanver-Color-
and raman spectroscopy, in addition to scanning electron comÒ) xanthan gum (Pryme Foods), microcrystalline cel-
microscopy (SEM) [13, 14]. lulose (Blanver-ColorcomÒ) and sodium lauryl sulfate
The kinetics of degradation study is also important for (BiotecÒ).
both pure substances and mixtures. In this work, such study For the production of freeze-drying orodispersible
is significant to define the issues of miscibility/incompati- tablets, the use of a suspending agent (xanthan gum) was
bility and their effects on thermal stability [15, 16]. necessary. Consequently, a suspension with the Ketoprofen
Thus, the objective of this work was to carry out the pre- mixture, a solution of xanthan gum, and other excipients
formulation study for rational development of orodis- was performed, followed by weighing (approximately 1 g)
persible tablets. This was accomplished through the of this suspension in a blister with an average size of
15 mm in diameter. These were frozen at - 80 °C for 2 h
123
Physical–chemical characterization studies of ketoprofen for orodispersible tablets
and then freeze-dried (Benchtop Freeze-Dryer) in con- of 4 cm-1 in KBr. A background spectrum for each
denser at - 79 °C, under pressure of 16 mT for 24 h. experimental condition was obtained. Each sample (pure
KTP, excipients for compression and excipients for freeze-
Characterization in the solid state drying) was prepared by mixing 2% (w/w) in potassium
bromide (KBr). The data processing was conducted by the
For analysis of purity and kinetic study, the bulk KTP was Shimadzu Hyper IRÒ.
compared to the granulated KTP.
The compatibility study by DSC was performed by Raman spectroscopy
physically mixing KTP and excipients in proportional
amounts (1:1 w/w). In order to confirm the compatibility For the Raman spectroscopy, a Witec-Alpha 300 L was
studies between drug and excipients, the formulations were used (source of di-iodine-3 mW, diffraction grating
subjected to spectroscopy and microscopy analyses. Both, 600 g mm-1, laser wavelength of 532 nm). The results of
drug and excipients, were contained in proportions that will the spectra were processed by the OringinPro software
be used in the production of the tablets. (version 8.5).
Bulk ketoprofen, granulated ketoprofen and the mixture of The analyses of X-ray diffraction were obtained from the
ketoprofen with excipients were investigated by thermo- X-ray diffractometer PANalytical (EMPYREAN, with
analysis techniques using thermogravimetry/derivative X’Celerator detector). The software used was X’Pert High
thermogravimetry (TG/DTG) and differential scanning Score Plus, PDF-2 database. Monochromatic radiation Cu
´
calorimetry (DSC). 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
Thermogravimetric analysis/kinetics analysis spectrum every 10 s.
The thermogravimetric curves were obtained in the Shi- Scanning electron microscopy
madzu DTG-60 thermal analyzer by using platinum cru-
cibles with a sample mass of * 3 mg, under a dynamic A JEOL (JSM-6060LV) was used for the analyses of
synthetic air atmosphere (50 mL min-1), with heating rate scanning electron microscopy. The samples were previ-
of 10 °C min-1 in the temperature range of 30–400 °C. ously metalized with gold and analyzed in low vacuum
For the non-isothermal kinetic study, curves were mode with acceleration voltage of 15 kV in the magnifi-
obtained at a heating rate of 5, 10, 15, 20, 25 °C min-1. cations of 10K9, 6K9, 3K9, and 2K9.
The equipment was calibrated with reference standard of
calcium oxalate with declared purity of 99.99% [13].
Results and discussion
Differential scanning calorimetry analysis
Thermal characterization of ketoprofen
Regarding the purity study of pure and granulated KTP,
DSC curves (drug/excipient) were obtained in a Shimadzu The TG/DTG and DSC curves of the pure KTP are shown
DSC-60 equipment under a dynamic synthetic air atmo- in Fig. 2. From the DSC curve, an endothermic event can
sphere (50 mL min-1). The equipment was previously cal- be observed, with a significant peak (Tpeak = 96.37 °C;
ibrated with reference standards of zinc and indium. Tonset = 94.11 °C; DH = 120.92 J g-1) indicating drug
Approximately 3 mg of the drug-excipient mixture (1:1 w/w) fusion. These data are in agreement with those in the lit-
was placed in aluminum capsules and then sealed. The erature (94–97 °C) [3]. Thus, the melting point confirms
analysis was carried out in the temperature range of that ketoprofen is in pure crystalline state.
30–400 °C, in heating rate of 2 °C min-1 for purity analysis The TG/DTG curves indicate that there was a thermal
and of 10 °C min-1 for compatibility analyses. decomposition in a single step, in only one endothermic
event with only one very evident peak in the range between
Diffuse reflectance infrared Fourier transform spectroscopy 169 and 300 °C (Dm = 92.45%, DTGpeak = 281.61 °C).
Thus, the TG/DTG curves confirm that ketoprofen is
The DRIFT spectra were performed using a Shimadzu thermostable up to 169 °C. No significant losses occur up
Europe spectrometer (model FTIR-8400S) in a scan range to this temperature. At the end of the analysis, there was
of 500–4000 cm-1, with 45 scans and a spectral resolution another mass variation between 303–400 °C (Dm = 1.33%)
123
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,
Endo
123
Physical–chemical characterization studies of ketoprofen for orodispersible tablets
(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
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
Regarding the superdisintegrants croscarmellose, of water loss of the superdisintegrants. Cellulose micro-
crospovidone and starch glycolate: the DSC curves for the crystalline (CMC 101) was used as a diluent in the for-
two formulations had larger peaks corresponding to dehy- mulation by compression. The mixture also shifted the
dration with endothermic event. Thus, the melting peaks of event of KTP melting. Hence, there was also melting of the
ketoprofen were offset to lower temperature, which may drug with water loss from the CMC 101 [14].
have occurred due to the melting of the drug with the peak
123
Physical–chemical characterization studies of ketoprofen for orodispersible tablets
(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
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
As for the lubricants used for compression, the silicon a low temperature. This is due to the fact that the magne-
dioxide showed no interference in the melting peak, due to sium stearate in its production process is composed of
the fact that the melting point of silicon dioxide is 1600 °C, different fatty acids (mainly stearic acid and palmitic acid)
i.e., it does not interfere in the endothermic event of the with different melting points (range 60–70 °C). This
drug. It is also silica, which does not retain water easily and composition implies different melting points with multiple
therefore does not dehydrate or decompose [22]. The endothermic melting events, thus affecting the values of
magnesium stearate, however, when compared to KTP, Tpeak, Tonset and drug enthalpy over these binary mixtures.
presented visible differences. The DSC curve shows an The offset can be attributed to the production of impurity
offset of the melting peak (Tpeak = 76.64 °C) of the KTP to (salt of palmitate) caused by the eutectic mixture between
123
L. J. Oliveira et al.
the two components when subjected to high heating [23]. small reduction in the Tpeak of the drug, though not an
Some authors have published compatibility studies using expressive one.
magnesium stearate. Among them, a similar behavior was
observed by Veiga et al. (2017), Peres-Filho et al. (2011) Drift
and Mura et al. (1995) [24–26].
For the production of tablets through freeze-drying, the Diffuse reflectance for the transformation of Fourier
formulation used xanthan gum as a thickening agent and infrared is part of the spectroscopic analysis that can be
sodium lauryl sulfate (LSS) as a surfactant, contributing to applied as complementary technique in compatibility
the incorporation of KTP into the formulation. The DSC studies between drug and excipient, in order to confirm the
curve (Fig. 7) of the thickener and the drug mixed had an results obtained from thermal analysis. This technique was
offset of Tpeak and can be attributed to drug melting with used in this study since it is the most appropriate one
the peak of water loss. As for the LSS, it also presented a among the spectroscopic nondestructive methods, making
it a particularly attractive method in the analysis of solid
(b)
(c)
123
Physical–chemical characterization studies of ketoprofen for orodispersible tablets
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
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
L. J. Oliveira et al.
8000
(a)
6000
4000
2000
Intensity/a.u.
0
10 20 30 40 50 60
(b)
6000
4000
2000
0
10 20 30 40 50 60
2θ /°
123
Physical–chemical characterization studies of ketoprofen for orodispersible tablets
DRX
123
L. J. Oliveira et al.
123
Physical–chemical characterization studies of ketoprofen for orodispersible tablets
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