See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/278392041

Compatibility studies of trioxsalen with excipients by DSC, DTA, and FTIR

Article  in  Journal of Thermal Analysis and Calorimetry · March 2014

DOI: 10.1007/s10973-013-3216-y

CITATIONS READS

10 479

9 authors, including:

Thays S. Oliveira T.F.A.L. Moura

3 PUBLICATIONS   44 CITATIONS   
Universidade Federal do Rio Grande do Norte
43 PUBLICATIONS   423 CITATIONS   
SEE PROFILE
SEE PROFILE

Ana Cláudia Medeiros ANA PAULA Barreto Gomes

Universidade Estadual da Paraíba Universidade Federal do Rio Grande do Norte
81 PUBLICATIONS   447 CITATIONS    25 PUBLICATIONS   252 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Development of herbal medicines View project

New bioactives compounds of Brazilian Plants View project

All content following this page was uploaded by ANA PAULA Barreto Gomes on 26 October 2015.

The user has requested enhancement of the downloaded file.

J Therm Anal Calorim (2014) 115:2311–2318
DOI 10.1007/s10973-013-3216-y
Compatibility studies of trioxsalen with excipients
by DSC, DTA, and FTIR
Naiana G. P. B. Lima • Igor P. B. Lima • Denise M. C. Barros • Thays S. Oliveira
Fernanda N. Raffin • Túlio F. A. de Lima e Moura • Ana C. D. Medeiros •
Ana P. B. Gomes • Cı́cero F. S. Aragão
Received: 20 November 2012 / Accepted: 22 April 2013 / Published online: 21 May 2013
Ó Akadémiai Kiadó, Budapest, Hungary 2013
Abstract Psoralens are widely used for the treatment of
psoriasis. Trioxsalen is a drug prescribed low-dose,
belonging to the group of substituted psoralen. The aim of
this study was to evaluate the compatibility of trioxsalen
with pharmaceutical excipients used in the solid forms by
analytical techniques. Binary mixtures between the triox-
salen and pharmaceutical excipients (namely, magnesium
stearate, a-lactose, microcrystalline cellulose 102, pregelati-
nized starch, mannitol, sodium lauryl sulfate, sodium starch
glycolate, and croscarmellose sodium) were examined. The
trioxsalen–sodium lauryl sulfate mixture displayed some
physical interaction based on the DTA and DSC results, but
the FTIR study ruled out any chemical change.
Keywords Trioxsalen  Compatibility  DSC  DTA 
FTIR
Introduction
Psoriasis is a complex chronic non-infectious inflammatory
skin disease with many different presentations. The classic
presentation is well defined as red plaques with silver scale
N. G. P. B. Lima  I. P. B. Lima  D. M. C. Barros 
T. S. Oliveira  F. N. Raffin  T. F. A. de Lima e Moura 
A. P. B. Gomes  C. F. S. Aragão (&)
Programa de Pós-graduação em Desenvolvimento e Inovação
Tecnológica em Medicamentos, Universidade Federal do Rio
Grande do Norte, Caixa Postal 1524, Campus Universitário,
Lagoa Nova, Natal, RN 59078-970, Brazil
e-mail: ciceroaragao@ufrnet.br
N. G. P. B. Lima  A. C. D. Medeiros
Laboratório de Desenvolvimento e Ensaios de Medicamentos,
Universidade Estadual da Paraı́ba, Centro de Ciências Biológicas
e da Saúde, Campina Grande, PB 58.429-500, Brazil
•
[1]. This disease affects 2–4 % of the world’s population
[2]. Although psoriasis generally does not affect survival, it
certainly has a number of major negative effects on
patients, demonstrable by a significant detriment to life
quality that is similar to or worse than that presented in
patients with other chronic diseases [3].
Trioxsalen also known as 4,50 ,8-trimethylpsoralen is an
anti-psoriatic drug with the chemical name 2,5,9-trimethyl-
7H-furo[3,2-g]1]benzopyran-7-one (Fig. 1). It occurs as a
white to off-white or grayish, odorless, crystalline powder,
it is insoluble in water and slightly soluble in alcohol and
has a molecular mass of 228.24 g mol-1. The molecular
formula is C14H1203 [4, 5]. This is a low-dose prescription
drug: 5–10 mg.
Thermal analysis is a group of techniques in which a
sample property is measured against time or temperature
while the sample temperature, in a specified atmosphere is
heated or cooled at a fixed rate of temperature change or
held at constant temperature [6]. The most widely used
techniques for application in the pharmaceutical area are
thermogravimetry (TG), differential thermal analysis
(DTA), and differential scanning calorimetry (DSC) [7].
Chemical and physicochemical interactions in the solid
state between the active pharmaceutical ingredient(s) and
excipients in pharmaceutical formulations can strongly
influence the stability, dissolution rate, and bioavailability
of solid dosage forms (tablet, capsules, granules, or pow-
ders) [8]. There is no universally accepted protocol to
evaluate the compatibility between drugs and excipients.
Thermoanalytical methods are frequently used to investi-
gate and predict physicochemical incompatibilities between
drugs and pharmaceutical excipients [9, 10]. These tech-
niques are widely applied alone or combined with micros-
copy, spectroscopy (UV, IR), and X-ray powder
diffractometry [11–14].
123
2312 N. G. P. B. Lima et al.

CH3 were weighted out and placed in a sealed aluminum pan.

O O O
The analysis was carried out from 30 to 450 °C at a heating
CH3 rate of 10 °C min-1. The DSC cell was calibrated with
indium (156.6 °C). DSC curves were analyzed with the aid
of TA Instrument software Universal Analysis.
CH3

Fig. 1 Chemical structure of trioxsalen DTA

The DTA curves of samples were obtained on a Shimadzu

The aim of the present work was to evaluate the possible
interactions between trioxsalen and some pharmaceutical
excipients using thermoanalytical techniques (DSC/DTA)
and spectroscopic method.
Materials and methods
thermobalance, model DTG-60, using alumina crucible
(8 mg), at a heating rate of 10 °C min-1, temperature
interval of 35–900 °C, under atmosphere of nitrogen at
flow 50 mL min-1. DTA curves were analyzed with the
aid of Shimadzu software TASYS. DTA cell was calibrated
with indium (156.6 °C) and zinc (419.6 °C) standards
melting point.

Materials and samples Melting point apparatus

The trioxsalen and lactose monohydrate (a-lactose), were Capillary tubes (10 cm in length, 1.0 mm internal diame-
acquired by Galena. Magnesium stearate (MS), micro- ter) were charged with sufficient amount of the dry powder
crystalline cellulose PH 102 (MC-102), pregelatinized to form a column in the bottom of the tube 2.5–3.5 mm
starch (starch), mannitol, sodium lauryl sulfate (SLS), high. The procedure requires inserting the capillary with
sodium starch glycolate (SSG), and croscarmellose sodium the sample into the heating block (Quimis, Q340S model)
(CCS) were purchased from Henrifarma (Table 1). 5 °C below its expected melting point and ramping at
1 °C min-1 until the melt is complete. After the tempera-
Preparation of binary mixtures ture of 240 and 260 °C, samples were removed from the
capillary.
Physical mixtures of trioxsalen with each selected excipi-
ent were prepared at 1:1 (w/w) ratio by simple mixture of Fourier transform infrared spectroscopy (FTIR)
the components in an agate mortar with pestle for
approximately 5 min. The 1:1 (w/w) ratio was chosen to Fourier transform infrared spectroscopy spectra of drug,
maximize the probability of observing any interaction. excipients, and physical mixtures were recorded on a
Perkin-Elmer Model 65 apparatus using KBr-stressed disks
DSC in the range of 400–4,000 cm-1 at room temperature and
heat treated at 240 and 260 °C.
The DSC curves were obtained using a DSC Q20 (TA
instrument), under dynamic nitrogen atmosphere with the
flow rate of 50 mL min-1. Approximately 2 mg of samples Results and discussion
Table 1 Substances used in the compatibility study
Several reports in the literature demonstrate the importance
Sample Classification of thermal analysis by DSC in the characterization, poly-
morphism identification, purity evaluation of drugs, and
Drug Trioxsalen Active ingredient
compatibility studies for the pharmaceutical formulation
Excipients Magnesium stearate Lubricant
[15–17]. DTA is a thermal method of material investiga-
Lactose monohydrate Diluent, binder
tion. The results obtained from DTA curves depend on the
Microcrystalline cellulose Diluent, disintegrant,
PH 102 binder substance preparation and the instrument sensitivity. This
Pregelatinized starch Diluent, binder technique is helpful for better understanding of the results
Mannitol Diluent attained from X-ray diffraction, chemical analysis, and
Sodium starch glycolate Disintegrant
microscopy [18].
Croscarmellose sodium Disintegrant
Assessment of possible incompatibility between the
active component (i.e., trioxsalen—TX) and different
Sodium lauryl sulfate Wetting agent
excipients along with the evaluation of thermal stability are

123
Compatibility studies of trioxsalen
crucial parts of the normal study prior to the final formu-
lation setting of a solid dosage form [19].
Excipients are required to facilitate the administration,
promote consistent release, and drug bioavailability, and
protect the active ingredient from the environment. Even
though excipients are usually regarded as inert substance,
physical and chemical interactions with drugs are com-
monplace [20].
The DSC and DTA findings on trioxsalen, excipients
and binary mixtures are shown in Figs. 2, 3, 4, and 5. The
DSC curve of TX (Fig. 2a curve 1; Table 2) showed two
events. The first was a sharp endothermic event at 234 °C
(Tonset = 228 °C; DHfus = 245 J g-1) indicating the
melting, which corresponds to the values reported in lit-
erature (234–235 °C). The second presented event with
Tonset 244 °C Tpeak 310 °C Tendset 316 °C and energy
involved in 430 J g-1. The DTA curve of TX (Fig. 4a,
curve 1; Table 3) showed two events: the first, an endo-
thermic event between 233 and 245 °C (Tpeak = 237 °C)
and the second between 261 and 295 °C (Tpeak = 295 °C).
The energy involved in the first DTA event at 10 °C min-1
was 869 J g-1, while in the other event the energy involved
was 1,042 J g-1.
The DSC curve of MS (Fig. 2a, curve 2) presented two
endothermic events between 96 and 130 °C
(DH = 228 J g-1) and 297–362 °C (DH = 228 J g-1).
The DSC curves of trioxsalen, MS (Fig. 2a, curve 1 and 2)
and their physical mixture (Fig. 2b, curve 2) are almost
superimposable. The DTA curve of TX/MS BM showed
five events (Fig. 4b, curve 2), the third and fourth events
show the two peaks characteristic of the drug, and the
others represent the excipient. This curve has a slight
change in temperature (Tonset, Tpeak and Tendset) compared
with the DTA curve of pure TX; however, the energies
involved have reduced their values from 869 to 342 J g-1
in the first event and from 1,042 to 397 J g-1 in the second
one. The data indicate no interaction. Nebicapone a cate-
chol-O-methyltransferase inhibitor was incompatible with
MS using the techniques: DSC, high sensitivity DSC
(HSDSC) and conventional heat stress [21]. This excipient
also proved being incompatible with non-steroidal anti-
inflammatory aceclofenac and acetylsalicylic acid by the
DSC and FTIR [22, 23].
The DSC curve of lactose (Fig. 2a, curve 3) shows a peak
(endothermic event) corresponding to the dehydration
(bound water) at 146 °C, and melting point at 217 °C. The
DSC curve of trioxsalen/lactose monohydrate shows three
endothermic peaks, one corresponding to the drug at
232 °C, and the others to lactose monohydrate dehydration
and melting (Fig. 2b, curve 3). The DTA curve of the
physical mixture of TX with lactose showed four events,
with the first and second for the excipient (Fig. 4b, curve 3).
The third event was a slight decrease in temperatures Tonset
2313
from 233 to 230 °C, Tpeak from 237 to 234 °C and Tendset
from 245 to 242 °C. The fourth event also had decreased
temperatures and energies involved compared with the pure
drug. These results indicated no incompatibility. In one
study, it was observed that lactose monohydrate was
incompatible with promethazine hydrochloride by DSC and
chromatographic analysis [24].
The DSC curve of microcrystalline cellulose (Fig. 2a,
curve 4) indicates two consecutive endothermic events: one
at 28–118 °C (DH = 196 J g-1) corresponding to dehy-
dration and the other at 306–364 °C (DH = 562 J g-1).
The sum of representative curves of MC 102 and TX
(Fig. 2b, curve 4) correspond to the profile obtained from
the physical mixture of these components. In the case of
the TX/MC 102 mixture (Fig. 4b, curve 4), the DTA curve
showed four events, with the third and fourth being typical
of the excipient. The first event has a slight increase in
temperatures Tonset from 233 to 234 °C, Tpeak from 237 to
238 °C and Tendset from 245 to 246 °C. In the second event,
temperatures are anticipated to slightly lower values and
their energies are reduced. Therefore, data from DTA and
DSC curves indicate no interaction between them.
As seen in Fig. 2a, the pregelatinized starch sample
showed a major endothermic transition in the DSC curve
between 29 and 150 °C (DH = 641 J g-1), corresponding
to its dehydration (unbound water). The thermal behavior
(DSC and DTA) of the binary mixture of TX and starch
(Figs. 2b, 4b, curve 5) shows the endothermic character-
istic of drug. The results indicate the presumable absence
of incompatibility.
Other researchers have identified physical interaction of
the glimepiride with MS, lactose in the 1:1 physical mix-
tures [25]. Primaquine proved to be incompatible with
mannitol, lactose, and MS by the DSC and such incom-
patibility was confirmed by the FTIR [26].
Between 160 and 172 °C, there is an endothermic event
indicated by the sharp peak (Tpeak = 167.3 °C,
DH = 527 J g-1) corresponding to the melting process of
mannitol (Fig. 2a, curve 6). The DSC (Fig. 2b, curve 6)
and DTA (Fig. 4b, curve 6) curves of the physical mixture
trioxsalen/mannitol showed no change in the mixture
thermal profile, which corresponds to the sum of events
observed for the compounds individually, indicating no
interaction between them.
The DSC curve of SSG (Fig. 2a, curve 7) indicates one
broad endothermic peak due to the dehydration between 31
and 157 °C (DH = 389 J g-1) and an exothermic event at
264–355 °C (DH = 243 J g-1). The DSC curve of cros-
camellose sodium (Fig. 2a, curve 8) shows one broad
endothermic peak due the dehydration between 27 and
171 °C (DH = 971 J g-1) and an exothermic event
236–332 °C (DH = 1117 J g-1). The thermal profiles of
the mixtures trioxsalen/SSG and TX/CCS (Fig. 2b, curve 7
123
2314 N. G. P. B. Lima et al.

a 40
1 b 40
1
2 2
Heat flow/mW

Heat flow/mW
20 3 20 3
4 4
5 5
0 0
6 6

7
7
Endo

Endo
–20 –20
8
8

–40 –40
0 100 200 300 400 0 100 200 300 400
Temperature/°C Temperature/°C

Fig. 2 DSC curves of all substances used in compatibility study: TX/MS, 3 TX/lactose, 4 TX/MC-102, 5 TX/starch, 6 TX/mannitol,
a—(1 TX, 2 MS, 3 lactose, 4 MC-102, 5 starch, 6 mannitol, 7 SSG, 8 7 TX/SSG, 8 TX/CCS)
CCS); b—DSC curves of TX and its 1:1 physical mixtures (1 TX, 2

5 DTA
uV
1
200
0
2 1
100
Heat flow/mW

–5 3
2
0
–10
Endo

–100 3
Endo

–15

–200

–20 100 200 300 400

0 100 200 300 400 Temperature/°C
Temperature/°C
Fig. 5 DTA curves of (1) TX, (2) TX/SLS, (3) SLS
Fig. 3 DSC curves of (1) TX, (2) TX/SLS, (3) SLS

DTA
a uV b DTA
uV
500 1 500 1
2 2
3 3

4 4
0 0 5
5
6
6
Endo

Endo

7 7

8 8
–500 –500
100 200 300 400 100 200 300 400
Temperature/°C Temperature/°C

Fig. 4 DTA curves of all substances used in compatibility study: TX/MS, 3 TX/lactose, 4 TX/MC-102, 5 TX/starch, 6 TX/mannitol, 7
a—(1 TX, 2 MS, 3 lactose, 4 MC-102, 5 starch, 6 mannitol, 7 SSG, 8 TX/SSG, 8 TX/CCS)
CCS); b—DTA curves of TX and its 1:1 physical mixtures (1 TX, 2

and 8 respectively) can be considered a superposition of the The temperatures observed for the first event were very
curves of TX and excipients. The DTA curve of the binary similar to those of the pure drug, but the value found for the
mixture TX with SSG showed two events (Fig. 4b, curve 7). energy involved was lower (Table 3). In the second event,

123
Compatibility studies of trioxsalen 2315

Table 2 DSC data of TX and drug: excipient physical mixtures Table 3 DTA data of TX and drug: excipient physical mixtures
a
Samples Events Temperature/°C Energy/ Samples Eventsa Temperature/°C Energy/
J g-1 J g-1
Onset Peak Endset Onset Peak Endset

Drug Drug
Trioxsalen 1 228 234 236 191 Trioxsalen 1 233 237 245 869
2 244 310 316 430 2 261 295 303 1,042
Drug/excipient Drug/excipient
Trioxsalen/MS 2 222 234 237 161 Trioxsalen/MS 3 234 237 244 342
Trioxsalen/a-lactose 3 228 231 239 239 4 256 281 304 397
Trioxsalen/MC-102 1 230 234 238 246 Trioxsalen/a-lactose 3 230 234 242 415
Trioxsalen/starch 2 227 231 236 108 4 252 281 295 448
Trioxsalen/mannitol 2 226 231 235 214 Trioxsalen/MC-102 1 234 238 246 350
Trioxsalen/SSG 2 228 234 239 207 2 257 280 288 509
Trioxsalen/CCS 2 230 235 239 190 Trioxsalen/starch 1 234 238 246 351
Trioxsalen/SLS 4 227 237 255 222 2 261 282 289 461
a
Events correspondent to temperature interval of trioxsalen events Trioxsalen/mannitol 2 231 234 241 424
3 255 286 292 455
Trioxsalen/SSG 1 233 238 245 388
2 256 282 289 694
Trioxsalen/CCS 1 234 239 246 360
temperatures and the energy involved were lower if com-
2 257 280 292 826
pared with the drug alone. The DTA curve of trioxsalen/
Trioxsalen/SLS 3 217 225 246 1,120
CCS presented three events (Fig. 4b, curve 8). The first
event had an endothermic peak with a slight increase in 4 251 261 269 292
temperatures Tonset from 233 to 234 °C, Tpeak from 237 to a
Events correspondent to temperature interval of trioxsalen events
239 °C Tendset from 245 to 246 °C, and decreased energies
compared with relation to the pure drug. In the second curve, showing a probable interaction with SLS. The dis-
event, temperatures and their energies showed lower values appearance of the melting peak of drug is indicative of a
than those obtained for the single drug, at the end of this strong interaction, but not necessarily corresponding to
event, there is the start of the exothermic peak character- incompatibility. The compatibility study is based on the
istic of the excipient, third event. These results indicated no changes in the thermal profile of drug, especially its fusion
incompatibility with SSG and CCS. CCS is used in oral parameters (Tonset and DHfusion), which should remain
pharmaceutical formulations as disintegrant of capsules, constant in a binary mixture with appropriate excipient,
tablets and granules [27]. It has been shown by DSC like a superposition of isolated substances [29].
experiments that croscamellose sodium and starch are both Trioxsalen is practically insoluble in water [5]. SLS is an
compatible with ceftodoxime proxetil [28]. anionic surfactant/wetting agent employed in a wide range of
Figure 3 of the SLS shows five endothermic events. The nonparenteral pharmaceutical formulations to improve the
TX peak of fusion remains constant in major binary mix- solubility of poorly soluble drugs [27]. Freire et al. [30] in
tures (Fig. 2b). However, the TX peak of fusion has dis- 2009, published the study of the chemical and physical
appeared in mixtures with SLS (Fig. 3). By comparing the interactions of chlorpropamide with SLS by DSC. DSC
DSC and DTA curves of pure TX and SLS with their 1:1 curves of the drug and excipient alone were compared to
physical mixture, the differences are quite visible and can those of each drug–excipient 1:1 (w/w) mixtures. SLS
be attributed to any interaction between both components caused significant levothyroxine sodium pentahydrate deg-
(Fig. 5). The DTA curve of TX-SLS had four events, the radation evaluated by DSC, TG, and high performance liquid
first and second characteristic of the excipient. The third chromatography (HPLC) as analytical technique [31].
event observed has its temperature reduced compared with The thermoanalytical investigations (DSC and DTA) did
pure TX, Tonset from 233 to 217 °C, Tpeak from 237 to not reveal any interaction between trioxsalen and MS, lactose,
225 °C and a slight increase Tendset from 245 to 246 °C, the microcrystalline cellulose, starch, mannitol, SSG or CCS
energy involved increased from 869 to 1,120 J g-1. In the whereas interactions may be assumed in the case of SLS.
fourth event, temperatures are anticipated to lower values Differential thermal analysis similar to DSC is used to
and their energies are reduced. In this BM, DSC and DTA measure the melting point and fusion heat and has been
curves assumes most of the behavior of the excipient’s utilized for more than five decades to evaluate interactions

123
2316 N. G. P. B. Lima et al.

Fig. 6 IR spectra of (1) TX, (2) 1

TX/SLS, (3) SLS at 25 °C

Transmitance/%
2

4000 3500 3000 2500 2000 1500 1000 500 400

Wavelength/cm–1

Fig. 7 IR spectra of (1) TX, (2) 1

TX/SLS, (3) SLS at 240 °C Transmitance/%

4000 3500 3000 2500 2000 1500 1000 500 400

Wavelength/cm–1

Fig. 8 IR spectra of (1) TX, (2) 1

TX/SLS, (3) SLS at 260 °C
Transmitance/%

4000 3500 3000 2500 2000 1500 1000 500 400

Wavelength/cm–1

between substances [32, 33]. Several studies [34–36] have
confirmed that these techniques can be considered a valuable
tool in the first step of a formulation setting for the screening
of candidate excipients. There are some differences between
these two techniques. DTA detects temperature (temperature
difference) while the DSC detects enthalpy changes (heat
flow difference). DTA is a robust technique, older than the
DSC. On the other hand, the DSC is derived from the DTA,
more sensitive, use an amount of sample approximately four
times smaller than that used in DTA. For DTA, the unit is lV
and for DSC it related in watts. The open crucible most
frequently used in DTA is alumina (AI203) e for DSC sealed
aluminum pan. By combining the DTA or DSC with a
complementary technique, many overlapping stages may be
solved and interpreted [37].
Physical or chemical interactions between drugs and ex-
cipients do not necessarily indicate incompatibility, but
overall the authors agree that a change in the DTA and DSC
curves is an undeniable evidence of interaction [38]. The
results of the DSC and DTA indicated interaction in the solid-
state with temperature, but not necessarily corresponding to
incompatibility. The FTIR spectroscopy technique has been

123
Compatibility studies of trioxsalen
used for qualitative identification to investigate the possible
interaction of drugs and excipients [39, 40]. In this work, this
technique was used as a complementary tool to assist in the
interpretation of the DSC and DTA results.
The IR spectrum of TX, SLS and it 1:1 binary mixture is
shown in Figs. 6, 7 and 8. The IR spectral analysis of TX alone
at room temperature (Fig. 6) showed principal peaks at
wavenumbers 3,057 cm-1 (aromatic C–H stretch),
1,787 cm-1 (C=O stretching vibration of unsaturated lac-
tones), 1,609 cm-1 (C=C of ring), 1,310 cm-1 (C–O stretch-
ing vibration), 1,189 cm-1 (O–C–C band), 1,052 cm-1
(symmetric C–O–C stretch) and 753 cm-1 (out of plane C–H
bend). The presence of these representative bands in the IR
spectrum of TX heat treated at 240 °C this temperature was
after the fusion event (Fig. 7) and 260 °C (Fig. 8) where in
occurred within the second endothermic event, showed no
change in the spectral profile confirming the volatilization
trioxsalen, since there appeared degradation products.
Characteristic bands of trioxsalen were well retained in
the IR spectrum of the TX–SLS mixture without any new
bands, indicating no change in the structure of drug at
room temperature and heat treated at 240 and 260 °C
(Figs. 6, 7, 8). Based on the aforementioned results, it was
concluded that trioxsalen was compatible with SLS.
Group Bernardi conducted a study of compatibility by
DSC showing a possible physical interaction of the ven-
lafaxine hydrochloride, a third generation antidepressant,
with MS, microcrystalline cellulose and starch. Neverthe-
less, these results were not confirmed by diffuse reflectance
infrared fourier transform spectroscopy (DRIFT) and
Scanning electron microscopy (SEM) analyses [41].
Another study indicated incompatibility of acyclovir with
lactose by DSC, although The Fourier transform infrared
(FTIR) spectra were mostly unmodified due to the over-
lapping peaks [13]. Through the DSC technique some
degree of interaction of nateglinide was observed with MS,
but by FTIR the compatibility with this excipient [42] was
observed. Maximiano et al. [43] noted the incompatibility
of benznidazole (BNZ) with beta hydroxyethylcellulose,
polyethylene glycol and hydroxypropyl-b-cyclodextrin
using DSC as thermal screening technique. However, fur-
ther evaluation of these incompatible excipients with non-
thermal method such as FTIR showed the incompatibility
of BNZ with only the polyethylene glycol. FTIR method
was, thus, of help in interpreting DSC and DTA results and
excluding all relevant pharmaceutical incompatibilities.
Conclusions
The results of the compatibility of some binary mixtures
were analyzed using DSC, DTA, and IR. The data from DSC
and DTA indicated that the MS, lactose, microcrystalline
2317
cellulose, pregelatinized starch, mannitol, SSG, and CCS
showed no incompatibility between trioxsalen and these
excipients. However, changes in the thermal profile of the
curves were observed indicating possible physical interac-
tion between TX and SLS depending on heating. Based on
the results of FTIR analysis, any pharmaceutical incompat-
ibility between TX and SLS was ruled out. These results
support for the usefulness of DTA/DSC techniques as a
relevant screening tool during formulation development.
Acknowledgments The authors thank Fundação de Apoio à Pes-
quisa do Estado do Rio Grande do Norte (FAPERN), Conselho
Nacional de Desenvolvimento Cientı́fico e Tecnológico (CNPq), and
Coordenação de Aperfeiçoamento de Pessoal de Nı́vel Superior
(CAPES) for financial support and Laboratório de Certificação de
Biomateriais (CERTBIO).
References
1. Ryan S. Psoriasis: characteristics, psychosocial effects and
treatment options. Br J Nurs. 2008;17:284–90.
2. Davidovici BB, Sullivan-Whalen MM, Gilleaudeau P, Krueger
JG. Differing effect of systemic anti psoriasis therapies on
platelet physiology—a case report and review of literature. BMC
Dermatol. 2010;10(2):1–5.
3. Langley RGB, Krueger GG, Griffiths CEM. Psoriasis: epidemi-
ology, clinical features, and quality of life. Ann Rheum Dis.
2005;64(Suppl II):18–23.
4. Hadjipavlou-Litina D, Bariamis ES, Militsopoulou M, Athanassopoulos
CM, Papaioannou D. Trioxsalen derivatives with lipoxygenase
inhibitory activity. J Enzyme Inhib Med Chem. 2009;24(6):1351–6.
5. U.S. Pharmacopeia. USP 29. http://www.pharmacopeia.cn/v29
240/usp29nf24s0_alpha-2-32.html. Accessed 15 Oct 2011.
6. Giron D. Applications of thermal analysis and coupled techniques
in pharmaceutical industry. J Therm Anal Calorim. 2002;8:335–57.
7. Leite RS, Macedo RO, Torres SM, Batista CCN, Baltazar LO,
Lima Neto SA, Souza FS. Evaluation of thermal stability and
parameters of dissolution of nifedipine crystals. J Therm Anal
Calorim. 2013;111:2117–23.
8. Chaves LL, Rolim LA, Gonçalves Maria LCM, Vieira ACC,
Alves LDS, Soares MFR, Soares-Sobrinho JL, Lima MCA, Ro-
lim-Neto PJ. Study of stability and drug-excipient compatibility
of diethylcarbamazine citrate. J Therm Anal Calorim. 2013;111:
2179–86.
9. Pinto MF, de Moura EA, de Souza FS, Macêdo RO. Thermal
compatibility studies of nitroimidazoles and excipients. J Therm
Anal Calorim. 2010;102:323–9.
10. Mendonça CMS, Lima IPB, Aragão CFS, Gomes APB. Thermal
compatibility between hydroquinone and retinoic acid in phar-
maceutical formulations. J Therm Anal Calorim. 2013;. doi:
10.1007/s10973-013-2941-6.
11. de Oliveira MA, Yoshida MI, Gomes ECL, Mussel WN, Vianna-
Soares CD, Pianetti GA. Análise térmica aplicada à caracter-
ização da sinvastatina em formulações farmacêuticas. Quim
Nova. 2010;33(8):1653–7.
12. Nep EI, Conway BR. Preformulation studies on grewia gum as a
formulation excipient. J Therm Anal Calorim. 2012;108:197–205.
13. Monajjemzadeh F, Hassanzadeh D, Valizadeh H, Siahi-Shadbad
MR, Mojarrad JS, Robertson TA, Roberts MS. Compatibility
studies of acyclovir and lactose in physical mixtures and com-
mercial tablets. Eur J Pharm Biopharm. 2009;73:404–13.
123
2318
14. Roumeli E, Tsiapranta A, Pavlidou E, Vourlias G, Kachrimanis
K, Bikiaris D, Chrissafis K. Compatibility study between
trandolapril and natural excipients used in solid dosage forms.
J Therm Anal Calorim. 2013;111:2109–15.
15. Yoshida MI, Gomes ECL, Soares CDV, Cunha AF, Oliveira MA.
Thermal analysis applied to verapamil hydrochloride. Charac-
terization in pharmaceutical formulations. Molecules. 2010;15:
2439–52.
16. Salama NN, El Ries MA, Toubar S, El Hamid MA, Walash MI.
Thermoanalytical investigation of some sulfone-containing drugs.
J Anal Methods Chem. 2012;. doi:10.1155/2012/439082.
17. Bragagni M, Beneitez C, Martı́n C, Ossa Dhpdl, Mura Pa, Gil-
Alegre ME. Selection of PLA polymers for the development of
injectable prilocaine controlled release microparticles: usefulness
of thermal analysis. Int J Pharm. 2013;441:468–75.
18. Klancnik G, Medved J, Mrvar P. Differential thermal analysis
(DTA) and differential scanning calorimetry (DSC) as a method
of material investigation. RMZ-M&G. 2010;57:127–42.
19. Gopinath R, Naidu RAS. Pharmaceutical preformulation stud-
ies—Current Review. IJPBA. 2011;2(5):1391–400.
20. Swamivelmanickam M, Valliappan K, Reddy PG, Madhukar A,
Manavalan R. Preformulation studies for amoxicillin trihydrate
and dicloxacillin sodium as mouth dissolve tablets. Int J Chem-
Tech Res. 2009;1(4):1032–5.
21. Silva JPS, Lobo JMS. Compatibility studies between nebicapone,
a novel COMT inhibitor, and excipients using stepwise isother-
mal high sensitivity DSC method. J Therm Anal Calorim.
2010;102:317–21.
22. Aigner Z, Heinrich R, Sipos E, Farkas G, Ciurba A, Berkesi O,
Szabó-Révész P. Compatibility studies of aceclofenac with retard
tablet excipients by means of thermal and FT-IR spectroscopic
methods. J Therm Anal Calorim. 2011;104:265–71.
23. Tita D, Jurca T, Fulias A, Tita EMB. Compatibility study of the
acetylsalicylic acid with different solid dosage forms excipients.
J Therm Anal Calorim. 2013;112:407–19.
24. Thumma S, Repka MA. Compatibility studies of promethazine
hydrochloride with tablet excipients by means of thermal and
non-thermal methods. Pharmazie. 2009;64(3):183–9.
25. Cides LCS, Araújo 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;84:441–5.
26. 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;102:187–92.
27. Rowe RC, Sheskey PJ, Owen SC. Handbook of pharmaceutical
Excipient. 5th ed. London: Pharmaceutical Press; 2006.
28. Patel Badalkumar R, Jatav Rajesh K, Jatav Rakesh K, Sheorey
Rajendra V. Formulation development & evaluation of cefpo-
doxime proxetil dispersible tablets. Int J Drug Dev Res. 2012;
4(2):124–31.
29. Júlio TA, Zâmara IF, Garcia JS, Trevisan MG. Compatibility of
sildenafil citrate and pharmaceutical excipients by thermal anal-
ysis and LC–UV. J Therm Anal Calorim. 2013;111:2037–44.
123
View publication stats
N. G. P. B. Lima et al.
30. Freire FD, Aragão CFS, de Lima e Moura FA, Raffin FN.
Compatibility study between chlorpropamide and excipients in
their physical mixtures. J Therm Anal Calorim. 2009;97:355–7.
31. Collier JW, Shah RB, Gupta A, Sayeed V, Habib MJ, Khan MA.
Influence of formulation and processing factors on stability of
levothyroxine sodium pentahydrate. AAPS PharmSciTech. 2010;
11:18–25.
32. Bacon Ke. Differential thermal analysis of high polymers. II.
Effects of diluents on melting behavior of polyethylenes. J Polym
Sci. 1961;50:79–86.
33. Soares-Sobrinho JL, Soares MFLR, Lopes PQ, Correia LP, Souza
FS, Macêdo RO, Rolim-Neto PJ. A preformulation study of a new
medicine for Chagas disease treatment: physicochemical char-
acterization, thermal stability, and compatibility of benznidazole.
AAPS PharmSciTech. 2010;11(3):1391–6.
34. Costa SPM, Silva KER, Medeiros GCR, Rolim LA, Oliveira JF,
Lima MCA, Galdino SL, Pitta IR, Neto PJR. Thermal behavior
and compatibility analysis of the new chemical entity LPSF/FZ4.
Thermoch Acta. 2013;. doi:10.1016/j.tca.2013.03.003.
35. Soares MFLR, Soares-Sobrinho JL, da Silva KER, Alves LDS,
Lopes PQ, Correia LP, Souza FS, Macêdo RO, Rolim-Neto PJ.
Thermal characterization of antimicrobial drug ornidazole and its
compatibility in a solid pharmaceutical product. J Therm Anal
Calorim. 2011;104:307–13.
36. Lavor EP, Freire FD, Aragão CFS, Raffin FN, Moura TFAL.
Application of thermal analysis to the study of anti-tuberculosis drug
compatibility. Part 1. J Therm Anal Calorim. 2012;108:207–12.
37. Haines PJ, Reading M, Wilburn FW. Differential thermal anal-
ysis and differential scanning calorimetry. In: Brown ME, editor.
Handbook of thermal analysis and calorimetry. Chap. 5. v.1
Principles and practice. Amsterdam: Elsevier Science; 1998.
p. 279–361.
38. Peres-Filho MJ, Gaeti MPN, de Oliveira SR, Marreto RN, Lima
EM. Thermoanalytical investigation of olanzapine compatibility
with excipients used in solid oral dosage forms. J Therm Anal
Calorim. 2011;104:255–60.
39. Tita B, Bandur AFG, Marian E, Tita D. Compatibility study
between ketoprofen and pharmaceutical excipients used in solid
dosage forms. J Pharm Biomed Anal. 2011;56:221–7.
40. Lavor EP, Navarro MVM, Freire FD, Aragão CFS, Raffin FN,
Barbosa EG, Moura TFAL. Application of thermal analysis to the
study of antituberculosis drugs–excipient compatibility. J Therm
Anal Calorim. 2013;. doi:10.1007/s10973-013-3050-2.
41. Bernardi LS, Oliveira PR, Murakami FS, Silva MAS, Borgmann
SHM, Cardoso SG. Characterization of venlafaxine hydrochlo-
ride and compatibility studies with pharmaceutical excipients.
J Therm Anal Calorim. 2009;97:729–33.
42. 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;108:219–26.
43. Maximiano FP, Novack KM, Bahia MT, Sá-Barreto LL, Cunha-
Filho MSS. Polymorphic screen and drug–excipient compatibility
studies of the antichagasic benznidazole. J Therm Anal Calorim.
2011;106:819–24.