J Therm Anal Calorim (2014) 118:12931304
DOI 10.1007/s10973-014-3986-x
Compatibility study between indomethacin and excipients in
their physical mixtures
Bogdan Tita Ionut Ledeti Geza Bandur
Dumitru Tita
Received: 13 December 2013 / Accepted: 20 June 2014 / Published online: 24 July 2014
Akademiai Kiado, Budapest, Hungary 2014
Abstract Thermal analysis is a routine method for analysis of
drugs and substances of pharmaceutical interest. Thermo-
gravimetry/derivative thermogravimetry (TG/DTG) and dif-
ferential scanning calorimetry (DSC) are thermoanalytical
methods which offer important information about the physical
and chemical properties of drugs (purity, stability, phase
transition, polymorphism, compatibility, kinetic analysis, etc.).
This work exemplifies a general method of studying the drug-
excipient interactions with the aim of predicting rapidly and
inexpensively the long thermal stability of their mixtures. The
TG/DTG and DSC were used as screening techniques for
assessing the compatibility between indomethacin (IND) and its
physical associations as binary mixtures with some com-mon
excipients. Based on their frequent use in preformula-tions eleven
different excipients: corn starch, microcrystalline cellulose (PH
101; PH 102), colloidal silicon dioxide, lactose (monohydrate and
anhydre), polyvinilpyrrolidone K30, magnesium stearate, talc,
stearic acid, and manitol were blended with IND. The samples
were prepared by mixing the analyte and excipients in a
proportion of 1:1 (w:w). In order to
investigate the possible interactions between the components,
the thermal curves of IND and each selected excipient were
compared with those of their 1:1 (w/w) physical mixtures. FT-
IR spectroscopy and X-ray powder diffraction were used as
complementary techniques to adequately implement and
B. Tita (&) I. Ledeti D. Tita
Faculty of Pharmacy, University of Medicine and Pharmacy
Victor Babes, Eftimie Murgu Square 2, 300041 Timisoara,
Romania
e-mail: bogdantita@yahoo.com
G. Bandur
Industrial Chemistry and Environmental Engineering Faculty,
Politehnica University of Timisoara, Victoriei Square 2,
300006 Timisoara, Romania
assist in interpretation of thermal results. On the basis of
thermal results, confirmed by FT-IR and X-ray analyses, a
possible interaction was found between IND with polyvinyl-
pyrrolidone K30, magnesium stearate, and stearic acid.
Keywords Indomethacin Thermal analysis
Excipients Drug-excipient compatibility
Introduction
A wide range of non-steroidal anti-inflammatory com-
pounds (NSAIDs) have been in clinical practise for the
treatment of inflammatory disorders including arthritis and
cancer as well as for prevention of myocardial infarction
and Alzheimers disease.
Indomethacin [1-(4-chlorobenzoyl)-5-methoxy-2-
methyl-1 H-indole-3-acetic acid] with the formula
CH
O 3
OH
N
O
CI
O CH3
a non-steroidal anti-inflammatory drug (NSAID), have
been shown to be potent inhibitors of prostaglandin syn-
thesis through inhibition of one of the obligatory enzyme,
in the inflammatory cascade viz. cyclooxygenase, which
exists in two isoforms referred as COX-1 and COX-2,
respectively [13].
Compounds inhibiting COX-1 enzymes have been
shown to cause gastrointestinal irritations and kidney
damages since the enzyme is involved in the physiological
function of protecting gastric mucosa. Consequently,
123
1294
research efforts have been directed toward evolving com-
pounds which are specific COX-2 inhibitors, which can
minimize deleterious effects of NSAIDs [4, 5].
The development of controlled release dosage form has
been investigated to improve the treatment efficacy and
reduce the limitations of existing therapies. The successful
formulation of a stable and effective solid dosage form
depends on careful excipients selection. The most drugs
intended for oral administration require formulation with
excipients to allow adequate administration, to facilitate
the product manufacture, to increase the formulation sta-
bility, and for esthetic reasons.
Thermal methods of analysis are widely used for
checking thermal decomposition, thermal stability, poly-
morphism, reactions in solid state, drug formulations,
purity, evolved gas analysis using simultaneous TGFTIR,
and other properties of solid compounds used in pharma-
ceutical industry [611].
The evaluation of drug stability and their possible
physical and chemical interaction involves the incompati-
bility study, as it can affect the chemical nature, the sta-
bility and bioavailability of drugs and, consequently,
therapeutic efficacy, and their safety.
Differential scanning calorimetry (DSC) has been pro-
posed as a rapid method to examine the possibility of
physiochemical interactions, between drug(s), and drugs
and excipient(s), predicting entectic behavior of drugs and
excipients for preparation of a phase diagram. Differential
thermal analysis (DTA) predicting polymorphic forms and
study thermal behavior kinetic analysis through thermo-
gravimetry/derivative thermogravimetry curves (TG/
DTG), since it is often necessary to predict degradation
rates at marketing temperatures on accelerated processes
studied at elevated temperatures [1218].
In our previous papers we provided the importance of
the thermal stability and compatibility for different
pharmaceuticals.
However, the interpretation of the thermal data is not always
easy and, to avoid misinterpretations and misleading of thermal
analysis results, it must be emphasized that the interactions
observed at high temperatures may not always be relevant under
ambient conditions. Moreover, the presence of a solid solid
interaction does not necessarily indicates pharmaceutical
incompatibility, but it might instead be advantageous, e.g., as a
more desirable form of drug delivery system [1922]. There-fore,
the use of other analytical techniques, such as FT-IR
spectroscopy, X-ray powder diffractometry, and scanning electron
microscopy (SEM) as complementary tools to assist in the
interpretation of TA findings is greatly advisable [2326].
The main purpose of the present paper is to evaluate the
compatibility of indomethacin with common pharmaceu-
tical excipients, used in the solid dosage form, by thermal
123
B. Tita et al.
analysis (TA), Fourier transformed infrared spectroscopy
(FT-IR), and X-ray powder diffraction patterns (XRPD).
Experimental
Materials and samples
The indomethacin drug (IND) was supplied by Euro OTC
Pharma Gmb. H. Bonen, Germany, lot: 700111 Ch. B.
The excipients were as follows: corn starch hydrated
(Roquette Freres, France, lot: E1209); microcrystalline
cellulose PH 101 (MC101) and PH 102 (MC102) from
J.Rettenmaier & Sohne GmbH, Germany (lot:6610173917
and 5610273320); colloidal silicon dioxide (CSD-Aerosil
200) from Degussa AG., Germany (lot:3157040314); lac-
tose monohydrate (a-lactose) and lactose anhydre (b-lac-
tose) from Friesland Foods Domo, Holland (lot:620831
and 620214); polyvinylpyrrolidone K30 (PVP K30 or
PVP) from BASF Aktiengesellschaft, Germany
(lot:65658675LO); magnesium stearate (MS) from Undesa,
Spain (lot:484931); talc (Luzenac Val Chisone, Italy
(lot:S1094106); stearic acid (AcSt) from Euro OTC
Pharma GmbH, Bonn, Germany, lot: 2040) and mannitol
(Mn) from Merk, Germany (lot:43725604).
Physical mixtures of indomethacin with each selected
excipient were prepared in the 1:1 (w:w) ratio by simple
mixture of the components in an agate mortar with pestle
for *5 min.
The 1:1 (w/w) ratio was chosen in order to maximize
the probability of observing any interaction.
Methods
Thermal analysis
The TG/DTG/DTA curves were recorded using a Netzsch-
STA 449 TG/DTA instrument in the temperature range of
20500 LC, under a dynamic atmosphere of nitrogen (20
-1 -1
mL min ) and at a heating rate (b) of 10 LC min , using
platinum crucibles and weighed *20 mg of samples.
DSC experiments were carried out with a Netzsch dif-
ferential scanning calorimeter, model DSC204, using alu-
minum crucibles with approximately 3 mg of samples, under
-1
dynamic nitrogen atmosphere (50 mL min ) and a heating
-1
rate of 10 LC min , up to a temperature of 500 LC.
Fourier transformed infrared spectroscopy (FT-IR) and X-
ray diffraction
FT-IR spectra of drug, excipients and drug-excipients
blends were recorded on a PerkinElmer Model 1600
-1
apparatus using KBr disks in the range of 4000400 cm .
Compatibility study between indomethacin and excipients 1295

Fig. 1 TG/DTG/DTA curves of Flow/mL min

1
indomethacin TG/% DTA/mW mg
1
DTG/% min
1

100 250 0
[1] 0.0
90 2
0.5 200
[1] IND50010Kminazot Pt.dsu
80 Purge1
Purge2
4
Protective

70 1.0
Exo 6
150
60
1.5 8
50 100 10

2.0
40 [1]
12

30 2.5 50 14

[1]
20 [1]

3.0 16
[1]
10 0
50 100 150 200 250 300 350 400 450
Temperature/C

X-ray diffraction patterns (XRPD), for the same cate-
gory of substances, were obtained with a Bruker D8
Advance X-ray diffractometer using MoKa radiation (Zr
filter on the diffracted beam, 50 kV and 40 mA) in a
BraggBrentano h:2h configuration, with Soller and fixed
slits and a NaI (Tl) scintillation detector. The measure-
ments of 2h ranged between 0L and 30L. Data analysis and
plus
acquisition were performed using DIFFRACT software
from Bruker AXS.
Results and discussion
Thermal behavior of indomethacin
The thermoanalytical curves of indomethacin are presented
in Fig. 1.
The TG/DTG curves show that indomethacin is stable
up to 230 LC and presents a single stage of mass loss
between 230 and 450 LC (Dm = 90 %) and DTG peak =
373.0 LC.
The DTA curve has shown a sharp endothermic peak
(Tpeak = 162.7 LC; Tonset = 154.3 LC) indicating the
melting and which corresponds to the values indicated in
literature (159163 LC, followed by other endothermic
peak due to decomposition (Tpeak = 373.0 LC).
Compatibility study with excipients
In fact, DSC has been proposed to be a rapid method for
evaluating physico-chemical interactions between compo-
nents of the formulation through the comparison of thermal
curves of pure substances with the curve obtained from a
1:1 physical mixture and therefore select adequate excipi-
ents with suitable compatibility.
Figures 2 and 3 show the TG and DSC curves of the
substances used in the compatibility study. The DTG
curves do not appear as figure separate, because their
characteristics are presented in text, together with those of
the TG curves.
The TG/DTG curves of starch show a dehydration
between 33 and 120 LC (Dm = 7.2 %; DTG peak = 65 LC),
followed by the process of decomposition between 295 and
375 LC (DTGpeak = 325 LC; Dm = 79.7 %). Initially the
DSC curve exhibits a wide endothermic peak representing
dehydration (Tpeak = 94 LC) [6, 12, 15].
The thermal behavior of microcrystalline cellulose PH
101 and respectively PH 102 is the same. Absorbed water
(about 5 %) is lost below 110 LC, between 35 and 110 LC,
apparently in a single, endothermic, and spread-out process
(DSCpeak = 72 LC). No other thermal phenomena are
observed before the beginning of decomposition, between
307 and 385 LC (DTGpeak = 355 LC and Dm = 88 %),
respectively DSCpeak = 320 LC [12, 13, 16, 27].
In the case of the colloidal silicon dioxide, on the
thermoanalytical curves, no peak was observed in the
range of 25500 LC [12, 14, 16].
The amorphous form of lactose was identified by the
presence of an exothermic peak at 167 LC, which repre-
sented the transformation of amorphous to crystalline form.
It is followed by two endothermic peaks, one at 210 and
the other at 216 LC. These melting peaks belong to alpha
and beta-lactose respectively. It confirmed the
transformation of the amorphous form of lactose to the two
types of crystalline form by heating [17, 27, 28].
The 100 % crystalline lactose, according to XRPD,
contains a and b forms.

123
1296 B. Tita et al.

Fig. 2 TG curves of all

substances used in compatibility 1
2
study 3
4 1.IND

loss/a.u.
5 2.Starch
6 3. lactose
4. lactose
5.MCM101
7 6.MCM102

Mass
8 7.CSD
9
10 8.Talc
11 9.PVP
12 10.MS
11.Mn
12.AcSt
0 100 200 300 400 500

Temperature/C
1 1.IND

Fig. 3 DSC curves of all

substances used in compatibility 2 2.Starch
study
3 3.MCM102
4 4.MCM101
5 7. lactose
flow/a.u.

6 5.CSD
9

7 6.lactose
8
Heat

10 8.PVP

11 9.MS
12 10.Talc
11.AcSt
12.Mn
0 50 100 150 200 250 300 350 400

Temperature/C

According to the TG curve, the water-content
(Dm = 4.5 %) of a-lactose monohydrate is evolved
between 100 and 170 LC (DTGpeak = 161 LC). The water-
free compound is stable up to about 265 LC, then it
decomposes up to 365 LC and DTGpeak = 315 LC. The
DSC curve shows a first sharp endothermic peak (Tpeak =
145 LC) corresponding to the dehydration reac-tion,
followed by two endothermic peaks, from the first sharp
endothermic peak (DSCpeak = 215 LC), which cor-
responds to the melting of a-lactose, the second weak peak
(DSCpeak = 224 LC) represents the melting of b-lactose
[12, 16, 17, 29].
On the DSC curve, the b-lactose presents a small endo-
thermic peak (Tpeak = 145 LC) with an insignificant mass
loss on the TG curve, followed by two peaks, the first light
corre-sponding to the melting of a-lactose (Tpeak = 215
LC), and the second representing the melting of the b-
lactose (Tpeak = 224 LC). The decomposition process takes
place in the temperature range of 275 and 365 LC
(DTGpeak = 312 LC), accompanied by an endothermic
event on the DSC curve (Tpeak = 318 LC) [12, 16, 30, 31].
The TG/DSC curves of PVP, below 150 LC display on
initial mass loss of &9 %. This mass loss is accompanied
by a broad endothermic phenomena (DSC peak = 82 LC)
over an ill-defined baseline which makes evaluation of the
dehydration enthalpy quite uncertain. The sample readily
dehydrates and its initial mass depends upon the moisture
content of the atmosphere. Apparently, dehydration is
completed at 110 LC (DTGpeak = 164 LC) in N2. However,
a second loss stage (&2 %) begins past 150 LC and com-
pletes around 250 LC. Thermal analysis, SEM, and XRPD
all show that the compound is in a vitreous phase with
glass transition near 200 LC. Decomposition begins around
384 LC (DTGpeak = 442 LC, Dm = 86 %) up to 485 LC
[13, 27, 3234].
Simultaneous TG/DSC curves of magnesium stearate
show several dehydration stages below 110 LC. The first
endothermic effect is due to release of a small amount of
surface water. Around 50 LC begins the first dehydration
stage of structural water, which partially overlaps with a
second stage at higher temperature. The overall mass loss
due to surface water and to the first stage is &3 %, while
the amplitude of the second stage is &1.5 % of the initial
mass. DSC curve of magnesium stearate initially shows
wide endothermic effect (Tpeak = 75 LC), representing
dehydration. Melting begins at &110 LC and produces an

123
Compatibility study between indomethacin and excipients 1297

Fig. 4 TG curves of IND

1 IND
indomethacin and its 1:1
2
physical mixtures 3
1.IND + Starch

4 2.IND + lactose
5 3.IND + lactose
6

TG/a.u.
7 4.IND + MCM 102
8 5.IND + MCM 101
9
10 6.IND + CSD
11 7.IND + Talc
8.IND + PVP
9.IND + MS
10.IND + Mn
11.IND + AcSt

0 100 200 300 400 500

Temperature/C

Fig. 5 DSC curves of 1

indomethacin and its 1:1 1.IND
physical mixtures 2.IND + Starch
2
3 3.IND + MCM102
4
4.IND + MCM101
5
DSC/a.u.

5.IND + CSD
6
7 6.IND + lactose
8 7.IND + lactose
9
8.IND + PVP
10
11 9.IND + MS

12 10.IND + Talc
11.IND + AcSt
12.IND + Mn
0 50 100 150 200 250 300 350 400 450 500
Temperature/C

endothermic peak with a shoulder in the high temperature
side which is caused by melting of magnesium palmitate or
high-melting polymorphs. The decomposition of the sam-
ple begins around 311 LC (DTGpeak = 362 LC) and to 480
LC, 92.5 % of sample mass is lost. Corresponding to the
decomposition process, the DSC curve presents a sharp
endothermic with Tmax = 372 LC [12, 13, 27, 30, 31, 34].
The TG/DTG and DSC curves of talc present any sig-
nificant events under the conditions in the present work
[12, 16, 30, 31, 34].
The DSC curve of stearic acid shows two distinct
endothermic peaks. The first corresponds to the melting
process (Tpeak = 64 LC), process which flows without mass
variation on the TG curve. After melting, the decomposi-
tion occurs in the 200450 LC temperature range, with
Tpeak DTG = Tpeak DSC = 326 LC. The final residue is about
10 %.
The mannitol is an excipient with a well-defined thermal
profile, which shows the melting peak at 172.2 LC, char-
acteristic for the crystallinity and the anhydrous state. The
decomposition occurs after melting in the 275475 LC
temperature range, with Tpeak DTG = 372 LC and Dm =
98.3 %, which is recorded slightly endothermic on the
DSC curve with Tpeak = 376 LC.
TG and DSC curves of the pure indomethacin and the
1:1 drug:excipient physical mixture are shown in Figs. 4
and 5.
In the 1:1 physical mixtures, when there is no interaction
between drug and excipient, the Tpeak value of melting event
(DSC curve) and the first stage of the decomposition (T onset
and Tpeak of TG/DTG curves) should remain prac-tically
unchanged, similarly when the drug is alone. In this case the
thermal profiles of the mixture can be considered as a
superposition of the curves of the indomethacin and
excipients. In the DSC curve the Tpeak values of melting of the
drug is alone, or in its mixtures when there is no interaction
between drug and excipient.
According to the thermal curves (Figs. 4, 5), especially
DSC curves that provide the most complete information, there
have been found some smaller or larger differences (the case
of the mixtures with PVP, MS, and AcSt) in terms of the
melting temperature values and those of the thermal

123
1298 B. Tita et al.
Table 1 Thermoanalytical data of indomethacin and drug:excipient physical mixtures

Samples DSC -1 DTG Dm/%

DHfusion/J g
T /LC T /LC T /LC T /LC
onset (fusion) peak (fusion) onset peak DTG

Drug
IND 154.3 162.7 371.3 235 373 90
Drug/excipient
Starch 153.0 160.9 174.3 30; 250 70; 295 5; 71
MC102 153.1 161.0 177.9 30; 248 60; 352 3; 79
MC101 153.1 161.8 165.4 30; 248 60; 351 3; 78
CSD 147.1 160.7 99.7 450 348 41
a-lactose 155.6 161.6 204.8 125; 200 150; 305 3; 77
b-lactose 153.4 162.0 207.0 200 302 76
PVP 105.2 118.2 78.1 30; 250; 375 75; 345; 480 8; 34; 49
a a a a
30; 200 70; 350; 380 3; 82
MS
Talc 154.4 161.8 176.1 200 350 43
Acid stearic 134.0 147.9 99.0 200 320 92
Manitol 152.1 159.4 179.2 200 350 96
a
The value not calculated due to the absence of drugs melting event or undefined peak

1
decomposition ranges. Basically, all the other excipients DSC/mW mg
Exo
present some differences, however small, on the melting 15
temperature, respectively the value of the melting enthal-
pies (Table 1). These differences may be due to the small
10
interactions that have not been confirmed by FTIR spec-
troscopy and X-ray diffraction patterns.
5
In the case of mixtures with povidone (PVP), magne-
sium stearate, and stearic acid, the DSC curves demon-
0
strated differences in the thermal profile of the IND, such
as the absence of drugs melting event. The TG curves 50 100 150 200 250 300 350 400
demonstrated that excipients influence the decomposition Temperature/C
process of the IND by displacing the Tonset, respectively
DTGpeak of the first mass loss event at a lower temperature Fig. 6 DSC curves of IND (green), PVP (blue) and its 1:1 physical
mixture (red). (Color figure online)
than the isolated drug. Frequently, this displacing is due to
structural change and indicates interaction and incompati-
bilities between the compounds.
By the comparison of the DSC curves (Fig. 6) of pure
IND and PVP with their 1:1 physical mixture, the differ- 1
ences are well visible and these can be attributed to any DSC/mW mg
Exo
incompatibility (interaction) between the two components. 15
The endothermic peak of the melting point of IND (T peak
10
fusion = 162.7 LC) disappeared and the signal of PVP was
changed. A new one appears below 44.5 LC. The DSC 5
curve of the binary mixture IND-PVP indicates a chemical
interaction between substances due to heating. 0

The same behavior was described in the literature for 5

the mixtures of PVP with other drugs such as naproxen,
cetoprofen, captopril, sodium diclofenac, ibuprofen, and 50 100 150 200 250 300 350 400
ketoprofen [12, 13, 27, 3436]. Temperature/C
The differences of the DSC curves (Fig. 7) of IND, MS,
Fig. 7 DSC curves of IND (green), MS (blue) and its 1:1 physical
respectively their 1:1 physical mixture, are well visible and mixture (red). (Color figure online)

123
Compatibility study between indomethacin and excipients
DSC/mW mg
1
25 Exo
20
15
10
5
0 FT-IR spectra were drawn for indomethacin, excipients,
50 100 150 200 250 300 350 400
Temperature/C
Fig. 8 DSC curves of IND (green), AcSt (blue) and its 1:1 physical
mixture (red). (Color figure online)
these can be attributed to any incompatibility (interaction)
between the two components.
In the DSC curve of binary mixture was evidenced the
disappearance of characteristic IND fusion peak. In the
literature, other interactions between drugs and magnesium
stearate are detailed [6, 15, 16, 27, 32].
The DSC curve of the physical mixture of IND with AcSt
(Fig. 8) shows a similar behavior as in the case of IND-PVP
mixture. So, the endothermic peak of the melting point of IND
(Tpeak fusion = 162.7 LC) disappeared and a new one appears
below 14.8 LC. The DSC curve of the binary mixture IND-
AcSt indicates a chemical interaction between substances due
to heating [16, 3537].
The results taken from the TG/DTG and DSC curves for
the binary mixtures are collected in Table 1.
Generally, the melting peak of IND was preserved and
the enthalpys values are reduced to half, less for the two
binary mixtures mentioned. The slight lowering and/or
broadening of the melting temperature, respectively
beginning and maximum temperature of decomposition
may be attributed to the mixing process, which lower the
purity of each component in the mixture.
Decreasing values of DHfus suggest that the process (in
this case melting) is moved and takes place with low
intensity (the case of IND with PVP and AcSt mixtures) or
even disappears (the case of IND with MS mixture for
which DHfus was not calculated).
Unlike the small differences of the melting tempera-
tures, the values of DHfus even less than half of the value
corresponding to the indomethacin show the possibility of
one physical interaction, especially for the CSD, but does
not determine an incompatibility.
The FT-IR spectroscopy was used as a supplementary
technique in order to investigate the possible chemical
interaction between drug-excipient and to confirm the
results obtained by the thermal analysis. It is the most
suitable technique of the non-destructive spectroscopic
1299
methods and has become an attractive method in the ana-
lysis of pharmaceutical solids, since the materials are not
subject to thermal or mechanical energy during sample
preparation, therefore preventing solid-state transforma-
tions. The appearances of new absorption band(s), broad-
ening of band(s), and alteration in intensity are the main
characteristics to evidence interactions between drug and
excipients [12, 16, 30, 3840].
and respectively for the corresponding mixtures. Further,
only the spectra for the cases where the thermal analysis
indicates a possible interaction, namely: indomethacin,
povidone, and the mixture indomethacin:povidone (Fig. 9),
indomethacin, magnesium stearate, and the corresponding
mixture (Fig. 10), respectively indomethacin, stearic acid,
and the corresponding mixture (Fig. 11), were presented
[17, 28, 32, 33, 35, 40].
For the other mixtures, the FT-IR spectra can be con-
sidered as the superposition of the individual ones without
the absence, shift or broadening in the vibration bands of
IND. It demonstrated the absence of chemical interactions
between IND and the corresponding excipients.
The main absorption bands of FTIR spectrum for IND,
with proper attribution, are as follows:
an absorption band of moderate-low intensity, with the
-1
maximum absorption at 2923 cm , which corresponds
to mCH (CH3) vibration;
the most intense absorption band showing almost two
-1
absorption maximum at 1717 and 1691 cm , corre-
sponds to mC=O vibration from carboxyl and ketone;
-1
the band at 1480 cm , intense with a right shoulder at
-1
1455 cm , corresponds to mC=C aromatic vibration;
-1
the band at 1361 cm , of average intensity corre-sponds
to mCN vibration;
-1
the intense band at 1308 cm , corresponds to
d(asym., sym.) CH vibration
-1
at 1227 cm , an intense band appears which charac-
terizes the m(asym) COC vibration;
the m(sym) COC vibration is characterized by the band at
-1
1067 cm , of an average intensity;
-1
the band at 837 cm , of an average intensity, charac-
terizes the rocking vibration in the dCH plan;
-1
at 752 cm , there appears a band of medium intensity
which corresponds to mCHCl vibration.
In respect of the povidone, it presents the bands at:
-1
3460 cm a large band attributed to the OH group from
the crystallization water;
-1
2977 cm that corresponds to the C = O binding;
-1
1669 cm that corresponds to the carbonyl amidic
group;
-1
1495; 1465; 1422 cm these correspond to asym-
metrical vibration (das CH3);
123
1300 B. Tita et al.

Fig. 9 IR spectra of PVP, IND,

and 1:1 blend as simple mixture IND + PVP
of IND and PVP

Transmitance/a.u.
PVP

IND

4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 2000 1800 1600 1400 1200 1000 800 600 400
1
Wavenumber/cm

Fig. 10 IR spectra of MS, IND,

and 1:1 blend as simple mixture
IND + MS
of IND and MS
Transmitance/a.u.

MS

IND

4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 2000 1800 1600 1400 1200 1000 800 600 400
1
Wavenumber/cm

Fig. 11 IR spectra of AcSt,

IND, and 1:1 blend as simple
mixture of IND and AcSt IND + Ac. St
Transmitance/a.u.

Ac. St

IND

4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 2000 1800 1600 1400 1200 1000 800 600 400
1
Wavenumber/cm

123
Compatibility study between indomethacin and excipients 1301

-1 2000
1291 cm that corresponds to the in-plane CH 1900
bending.
1800
For the binary mixture, it shows the following 1700
differences: 1600
1500
the considerably reduction of the width and intensity of 1400 IND + PVP
-1 -1
bands at 3447 cm (PVP) from 2955 to 2928 cm 1300
,respectively, (PVP);

Intensity/a.u.
1200
-
the
1 disappearance of the most intense band at 1622 cm
1100
(PVP); 1000
-1
the bands of 1719 and 1692 cm have changed their 900
intensity: the first has increased by about 10 % and the 800
second has fell by about 28 %; 700
-1 600 IND
the intensity of the main bands from the 1480700 cm
500
region (1480; 1360; 1311; 1233; 1087; 1068; 837; 753
-1 400
cm ) increased by about 1020 %. 300
200
Because of these differences it can be considered that 100 PVP
IND interacts with PVP.
0
Magnesium stearate presents a strong ethyl vibration in 2 10 20 30
-1 -1
the region of 2921 up to 2850 cm . In the 15691468 cm 2/
region, it showed an asymmetric stretch corresponding to
the carboxyl anion.
Other bands that must be maintained have their peaks at Fig. 12 X-ray diffractogram of PVP, IND, and 1:1 blend as simple
-1 mixture of IND and PVP
2958 cm corresponding to asymmetric vibration of CH
-1
bond in methyl group, respectively those at 721 cm
which corresponds to rocking deformation (HCH) n. n
-1
[ 3. has two low intensity bands at 933, 720 cm , corre-
FT-IR spectrum of indomethacinmagnesium stearate sponding to OH vibration outside the plan and to the
mixture shows the following changes: rocking vibration of the CH2 group.
-1 The main changes that occur in the spectrum of the
the disappearance of the 3421 cm broad band (MS); IND-AcSt binary mixture are as follows:
-1
the absorption maximum at 2917 cm maintains its -1
-1
intensity (maximum), while the one from 2850 cm the emergence of a broad band (37003300 cm ) of low
-1
decreases its absortion by about 15 %; intensity and absorption maximum at 3458 cm ;
-1 -1
the peaks in the region 1717752 cm reduce their maintaining the intensity of bands at 2918 and 2849 cm ;
intensity between 15 and 35 %; -1
the appearance of a single band at 1693 cm , instead
-1 -1 -1
the peak at 721 cm (MS) disappears. of those from 1717 to 1691 cm (IND) and 1701 cm
(AcSt);
From the above observations obtained after comparing -1
the spectra, it may be considered that magnesium stearate the bands in the 1475752 cm region reduce their
intensity by about 1520 %.
interacts with indomethacin.
The stearic acid spectrum shows a broad band in the Based on these changes, it can be considered that IND
-1 interactions with AcSt.
33002750 cm range, with two very intense absorption
-1
maximum at 2918 and 2849 cm , corresponding to mOH To investigate the possible interaction of indomethacin
and mCH stretching vibrations. Axial deformation bands of with povidone, magnesium stearate and stearic acid, besides
the CH appear superimposed on the broad band of OH. the FT-IR spectroscopy which is a qualitative analysis
-1
The band at 1701 cm corresponds to the mC=O (sym- technique, the X-ray powder diffraction has been used for
metric) stretching vibration. The bands at 1464 and 1296 qualitative and quantitative identification of crystallinity. The
-1
cm ,respectively, characterize the deformations of the C number of the speciality papers which uses the X-ray powder
O and OH from the COH group. The stearic acid
diffraction is growing [17, 28, 32, 33, 36, 41].
The X-ray diffraction patterns of indomethacin, povi-
done and indomethacin-povidone mixture, indomethacin,

123
1302 B. Tita et al.

2100 The additional prominent DSC peaks in the mixtures of

2000
the drugs and excipients are a positive indication of
1900
1800
chemical interaction of the drugs with excipients. Such
1700
interaction should result in the partial or complete disap-
1600 pearance of the reactant phases and appearance of new
1500 IND + MS phases, which can be inferred from X-ray diffraction pat-
1400 terns. X-ray diffraction patterns of the mixture, prepared at
.Intensity/a.u

1300
room temperature, when compared with those of its indi-
1200
vidual components showed appearance of new lines and
1100
1000
disappearance of some of the lines present in the individual
900 components.
800 From examining the characteristic data of the recorded
700 IND diffraction spectra, it was found that
600
500 40 % of the diffraction lines, present in the diffraction
400 spectrum of the IND-PVP mixture, are new, and their
300 intensity varies from 11 to 55.5 %;
200 in the case of the mixtures IND-MS and IND-Ac.St.
100 MS about 10 % of the lines are new;
0 a certain number of lines present in the XRD patterns of
2 10 20 30
the individual components disappear in the case of
2/ mixtures, especially for mixture IND-PVP;
generally, the number of lines present in the XRD
Fig. 13 X-ray diffractogram of MS, IND, and 1:1 blend as simple
mixture of IND and MS patterns of the individual components was found
missing in the similar pattern recorded for the mixture.

The significant difference in the X-ray patterns of the

drugexcipient mixtures compared to those of individual
drugs and excipient indicates possible incompatibility of the
3000 drugs with the excipient, even at room temperature. The
presence of majority of the lines of the parent substances in
the thoroughly ground mixture prepared at room tempera-ture,
corresponding to the significant increase of the peaks
Intensity/a.u.

IND + Ac.St. intensities indicates the interaction of IND with PVP, MS, and
2000 Ac. St. at room temperature, which could increase with
the increased temperature.

IND Conclusions
1000
This paper presents an issue of great importance, met more
and more often in the speciality literature: the compatibility
of the drugs with different excipients.
Ac.St. The study refers to the thermal stability of the IND,
0 respectively the compatibility of this substance with a
2 10 20 30 range of excipients mentioned in the paper. As methods of
2/ study, the following were used: the thermal methods of
Fig. 14 X-ray diffractogram of AcSt, IND, and 1:1 blend as simple analysis as main technique, respectively the FT-IR spec-
mixture of IND and AcSt troscopy and X-ray diffraction patterns as supplementary
techniques.
magnesium stearate and indomethacin-magnesium stearate The results confirmed the utility and reliability of ther-
mixture, respectively indomethacin, stearic acid, and mal analysis, especially DSC technique, at the earliest
indomethacinstearic acid mixture are shown in stage of preformulation studies as a valuable tool for a
Figs.1214. rapid screening of a wide range of candidate excipients,

123
Compatibility study between indomethacin and excipients
allowing a rapid evaluation of possible active substance-
excipient interactions.
The changes in the profile of thermoanalytical curves (TG/
DTG and DSC) in the case of some binary mixtures indicate
the formation of some interaction as a function of heating.
According to the thermal curves, especially DSC
curves, one can say that all tested excipients, less PVP,
MS, and AcSt, present compatibility with IND. This fact is
sup-ported by the differences between the values of T fusion
and of the enthalpies of melting (DHfusion).
Considering that the enthalpies of melting are quanti-
tative data since they may be expressed as a fractional
change, it could be said that PVP, MS, and AcSt certainly
interact chemical with IND. In the same context, the small
variations of DHfusion for the other binary mixtures can be
attributed to some heterogeneity in the small samples.
For the binary mixture IND-CSD, it can be considered
that a physical interaction takes place, an interaction which
is not supposed to the corresponding compatibility.
The interaction of PVP, MS, respectively AcSt with IND
was confirmed by FT-IR spectroscopy and by X-ray
diffraction patterns. For the other excipients, as CSD, the two
mentioned techniques do not indicate an incompati-bility with
IND, probably because of limited modifications.
This study shows the incompatibility of IND with PVP,
MS, and AcSt.
References
1. Chennamaneni S, Zhong Bo, Lama R, Su B. COX inhibitors
indomethacin and sulindac derivatives as antiproliferative agents:
synthesis, biological evaluation, and mechanism investigation.
Eur J Med Chem. 2012;56:1729.
2. Kafarska K, Czakis-Sulikowska D, Wolf WM. Novel Co(II) and
Cd(II) complexes with non-steroidal anti-inflammatory drugs.
Synthesis, properties and thermal investigation. J Therm Anal
Calorim. 2009;96:61721.
3. Zhong Bo, Cai X, Chennamaneni S, Yi X, Liu L, Xu Y, Zhou A,
Su B. From Cox-2 inhibitor nimesulide to potent anti-cancer
agent: synthesis, in vitro, in vivo and pharmacokinetic
evaluation. Eur J Med Chem. 2012;47:43244.
4. Teslyuk OI, Beltyukova SV, Yegorova AV, Yagodkin BN.
Complex compounds of terbium(III) with some nonsteroidal
anti-inflammatory drugs and their analytical applications. J Anal
Chem. 2007;62:3305.
5. Ying YC, Yi L, Cheng ZJ, Dan Z. Inhibitory effect of copper
complex of indomethacin on bacteria studied by microcalorime-
try. Biol Trace Elem Res. 2008;122:828.
6. Neto HS, Novak Cs, Matos Jr. Thermal analysis and compati-
bility studies of prednicarbate with excipients used in semi solid
pharmaceutical form. J Therm Anal Calorim. 2009;97:36774.
7. Mora PC, Cirri M, Mura P. Differential scanning calorimetry as a
screening technique in compatibility studies of DHEA extended
release formulations. J Pharm Biomed Anal. 2006;42:310.
8. Moura EA, Correia LP, Pinto MF, Procopio JVV, de Sousa FS,
Macedo RO. Thermal characterization of the solid state and raw
material fluconazole by thermal analysis and pyrolysis coupled
to GC/MS. J Therm Anal Calorim. 2010;100:28993.
1303
9. Picciochi R, Diogo HP, da Piedade MEM. Thermochemistry of
paracetamol. J Therm Anal Calorim. 2010;99:391401.
10. Juhasz M, Kitahara Y, Takahashi S, Fujii T. Thermal stability of
vitamin C: thermogravimetric analysis and use of total ion
monitoring chromatograms. J Pharm Biomed Anal. 2012;59:
1903.
11. Fini A, Fazio G, Benetti L, Chedini V. Thermal analysis of some
diclofenac salts with alkyl and alkylhydroxy amines. Thermo-
chim Acta. 2007;464:6574.
12. Bertol CD, Cruz AP, Stulzer HK, Murakami FS, Silva MAS.
Thermal decomposition kinetics and compatibility studies of
primaquine under isothermal and non-isothermal conditions. J
Therm Anal Calorim. 2010;102:18792.
13. Zhao L, Li Q, Cui Y, Wang J, Chen X, Bi K. Thermal kinetic
studies on the decomposition of cefuroxime lysine in different
atmospheres and heating rates. J Therm Anal Calorim.
2012;108:26973.
14. Moyano MA, Broussalis AM, Segall AI. Thermal analysis of
lipoic acid and evaluation of the compatibility with excipients. J
Therm Anal Calorim. 2010;99:6317.
15. Bernardi LS, Oliveira PR, Murakami FS, Silva MAS, Borgmann
SHM, Cardoso SG. Characterization of venlafoxine with phar-
maceutical excipients. J Therm Anal Calorim. 2009;97:72933.
16. Barboza F, Vecchia DD, Tagliari MP, Silva MAS, Stulzer HK.
Differential scanning calorimetry as a screening technique in
compatibility studies of acyclovir extended release formulations.
Pharm Chem J. 2009;43:3638.
17. Desai SR, Shaikh MM, Dharwadkar SR. Preformulation com-
patibility studies of etamsylate and fluconazole drugs with
lactose by DSC. J Therm Anal Calorim. 2003;71:6518.
18. Findorakova L, Svoboda R. Kinetic analysis of the thermal
decomposition of Zn(II)2-chlorobenzoate complex with caffeine.
Thermochim Acta. 2012;543:1137.
19. Lavor EP, Duarte Freire F, Aragao CFS, Raffin FN, de Lima e
Moura TFA. Application of thermal analysis to the study of anti-
tuberculosis drug compatibility. Part 1. J Therm Anal Calorim.
2012;108:20712.
20. Singh AV, Nath LK. Synthesis, characterization, and compati-
bility study of acetylated starch with lamivudine. J Therm Anal
Calorim. 2012;108:30713.
21. Singh AV, Nath LK. Evaluation of compatibility of tablet ex-
cipients and novel synthesized polymer with lamivudine. J
Therm Anal Calorim. 2012;108:2637.
22. Bruni G, Sartor F, Berbenni V, Milanese C, Maietta M, Franchi
D, Marini A. Compatibility of paroxetine hydrochloride and
GW597599B. A physico-chemical approach. J Therm Anal Cal-
orim. 2012;108:3818.
23. Zimmermann B, Baranovici G. Thermal analysis of paracetamol
polymorphs by FT-IR spectroscopies. J Pharm Biomed Anal.
2011;54:295302.
24. Zhang GC, Lin HL, Lin SY. Thermal analysis and FTIR spectral
curve-fitting investigation of formation mechanism and stability
of indomethacin-saccharin cocrystals via solid-state grinding
process. J Pharm Biomed Anal. 2012;66:1629.
25. Mocanu MA, Moldoveanu C, Odochian L, Neculau R. Study on
the thermal behavior of casein under nitrogen and air atmosphere
by means of the TG-FTIR technique. Thermochim Acta.
2012;546:1206.
26. Pani NR, Nath LK, Acharya S, Bhuniya B. Application of DSC,
IST, and FTIR study in the compatibility testing of nateglinide
with different pharmaceutical excipients. J Therm Anal Calorim.
2012;108:21926.
27. Marini A, Berbenni V, Moioli S, Bruni G, Cofrancesco P, Mar-
gheritis C. Drugexcipient compatibility studies by physico
chemical techniques. The case of indomethacin. J Therm Anal
Calorim. 2003;73:52945.
123
1304
28. Gombas A, Szabo-Revesz P, Kata M, Regdon G Jr, Eros I.
Quantitative determination of crystallinity of a-lactose monohy-
drate by DSC. J Therm Anal Calorim. 2002;68:50310.
29. Balestrieri F, Magri AD, Magri AL, Marini D, Sacchini A.
Application of differential scanning calorimetry to the study of
drug-excipient compatibility. Thermochim Acta. 1996;285:337
45.
30. Cides LCS, Araujo AAS, Santos-Filho M, Matos JR. Thermal
behaviour, compatibility study and decomposition kinetics of
glimepiride under isothermal and non-isothermal conditions. J
Therm Anal Calorim. 2006;84:4415.
31. Oliveira GGG, Ferraz HG, Matos JSR. Thermoanalytical study
of glibenclamide and excipients. J Therm Anal Calorim.
2005;79:26770.
32. Marini A, Berbenni V, Pegoretti M, Bruni G, Cofrancesco P,
Sinistri C, Villa M. Drug-excipient compatibility studies by
physico-chemical techniques. The case of atenolol. J Therm Anal
Calorim. 2003;73:54761.
33. Bruni G, Amici L, Berbenni V, Marini A, Orlandi A. Drug-
excipient compatibility studies. J Therm Anal Calorim. 2002;68:
56173.
34. Nunes RS, Semaan FS, Riga AT, Cavalheiro ETG. Thermal
behavior of verapamil hydrochloride and its association with
excipients. J Therm Anal Calorim. 2009;97:34953.
35. Stulzer HK, Rodrigues PO, Cardoso TM, Matos JSR, Silva MAS.
Compatibility studies between captopril and pharmaceutical ex-
cipients used in tablets formulations. J Therm Anal Calorim.
2008;91:3238.
123
B. Tita et al.
36. Stulzer HK, Rodrigues PO, Cardoso TM, Matos JSR, Silva
MAS. Compatibility studies between captopril and
pharmaceutical ex-cipients used in tablets formulations. J Therm
Anal Calorim. 2008;91:3238.
37. Aigner Z, Heinrich R, Sipos E, Farkas G, Ciurba A, Berkesi O, Szabo
-Revesz P. Compatibility studies of aceclofenac with retard tablet
excipients by means of thermal and FT-IR spectroscopic methods. J
Therm Anal Calorim. 2011;104:26571.
38. Verma RK, Garg S. Selection of excipients for extended release
formulations of glipizide through drug-excipient compatibility
testing. J Pharm Biomed Anal. 2005;38:63344.
39. Neto HS, Novak Cs, Matos Jr. Thermal analysis and compati-
bility studies of prednicarbate with excipients used in semi solid
pharmaceutical form. J Therm Anal Calorim. 2009;97:36774.
40. Freire FD, Aragao CFS, de Lima e Moura TFA, Raffin FN.
Compatibility study between chlopropamide and excipients in
their physical mixtures. J Therm Anal Calorim. 2009;97:3557.
41. Abbas D, Kaloustian J, Orneto C, Piccerelle P, Portugal H,
Nicolay A. DSC and physico-chemical properties of a substituted
pyridoquinoline and its interaction study with excipients. J
Therm Anal Calorim. 2008;93:35360.