Thermal behavior of the β-blocker propranolol

Article abstract of DOI:10.1007/s10973-015-5118-7

The thermal behavior of the β-blocker anti-hypertensive drug propranolol was investigated using thermoanalytical techniques TG-DTA, DSC and the evolved gas analysis by TG-FTIR, providing information regarding thermal stability, decomposition steps, melting point and heat of fusion of the compound. The results pointed for the decomposition in a single mass loss step, after melting. DSC data revealed that cold crystallization occurred in heat-cool-heat cycles, around 165 °C. TG-FTIR presented 1-naphthol, isopropylamine and HCl as principal decomposition products. A tentative mechanism for the thermal behavior of propranolol is presented.

Full text of DOI:10.1007/s10973-015-5118-7

J Therm Anal Calorim (2016) 123:1013–1017
DOI 10.1007/s10973-015-5118-7
Thermal behavior of the b-blocker propranolol
1
1
1
Beatriz Ambrozini
•
Priscila Cervini
•
´
Eder Tadeu Gomes Cavalheiro
Received: 9 January 2015 / Accepted: 19 October 2015 / Published online: 18 November 2015
Ó Akad e´ miai Kiad o´ , Budapest, Hungary 2015
Abstract The thermal behavior of the b-blocker anti-
hypertensive drug propranolol was investigated using
thermoanalytical techniques TG–DTA, DSC and the
evolved gas analysis by TG–FTIR, providing information
regarding thermal stability, decomposition steps, melting
point and heat of fusion of the compound. The results
pointed for the decomposition in a single mass loss step,
after melting. DSC data revealed that cold crystallization
occurred in heat–cool–heat cycles, around 165 °C. TG–
FTIR presented 1-naphthol, isopropylamine and HCl as
principal decomposition products. A tentative mechanism
for the thermal behavior of propranolol is presented.
The anti-hypertensive drugs are classified into different
classes according to their therapeutic effect and action
mechanism.
Thus, the drugs of b-blocker class block the b-adren-
ergic receptors in the central nervous system, causing
vasodilatation. They are indicated for the treatment and
prevention of the myocardial infarction, angina pectoris
and cardiac arrhythmias. Sometimes, their use is limited by
the occurrence of side effects, such as muscle fatigue in the
lower extremities, general tiredness and impaired physical
performance. Probably, many factors contribute to these
symptoms.
Propranolol (Fig. 1) was the first successfully developed
b-blocker [3] and can be used alone or in association with
others drugs for the treatment of the hypertension, and it is
available in the generic form of propranolol hydrochloride.
The commercially available preparations of this active
ingredient are tablets and injectable solutions.
Keywords Propranolol Á TG–DTA Á Thermal behavior Á
Evolved gas analysis
Introduction
Because of the numerous issues involved in drug for-
mulation, usage, storage and final disposal, it is important
to understand thermal properties of pharmaceutical mate-
rials [4, 5].
The main objective of hypertension treatment is controlling
the blood pressure in order to reduce cardiovascular mor-
bidity and mortality. Thus, the anti-hypertensive drugs
should not only control blood pressure within safe levels,
but also avoid the risk of cardiovascular events [1, 2].
A recent literature survey showed that there are few
studies regarding the thermal analysis of propranolol.
Using microcalorimetry, Fagher and Monti [6] demon-
strated that propranolol oral administration caused a
decrease in thermogenesis in human skeletal muscle sam-
ples. Macedo et al. [7] studied the thermal behavior of
some anti-hypertensive drugs, including propranolol. Their
purities were determined by DSC, and the thermogravi-
metric data allowed determination of the kinetic parame-
ters. In other paper, Macedo et al. [8] demonstrated that
DSC of propranolol binary mixtures presented similar
phase transition to propranolol drug. DSC-photovisual
assay revealed an interaction similar to the Maillard
&
Priscila Cervini
pcervini@iqsc.usp.br
Beatriz Ambrozini
biaambro@gmail.com
´
Eder Tadeu Gomes Cavalheiro
cavalheiro@iqsc.usp.br
1
Departamento de Qu ´ı mica e F ´ı sica Molecular, Instituto de
Qu ´ı mica de S a˜ o Carlos, USP, Av. Trabalhador S a˜ o-Carlense,
4
00, Caixa Postal 780, S a˜ o Carlos,
S a˜ o Paulo CEP 13560-970, Brazil
123

1
014
B. Ambrozini et al.
-
1
CH3
10 °C min
under N2 dynamic atmosphere flowing at
-
1
5
0 mL min , in a temperature interval of -50 to 200 °C
N
H
CH3
O
using covered aluminum pans with a central pinhole (/
= 0.7 mm) in the lid. Curves were obtained in the heat–
cool–heat successive cycles. A TA DSC-Q10 unit con-
trolled by the Thermal Advantage for Q-Series (version
OH
HCl
5.4.0 software, both from TA instruments) coupled to the
Fig. 1 Chemical formulae of propranolol
RCS cooling accessory was used. Calibrations of the
equipment for temperature and enthalpy were performed
using the indium metal standard (99.99 % purity),
according to the manufacturer’s recommendations.
reaction, and TG isothermal study showed a difference in
the profile between the drug and tablets due excipients
quality and problems in manufacture process. M oˆ nica et al.
[
9] revealed that propranolol plasma presented reduction in
3
0.0
TG
phase transition enthalpy comparable to the plasma dena-
tured by perchloric acid in the last DSC cycles of freezing.
Gerber and L o¨ tter [10] studied the compatibility between
propranolol hydrochloride and tablet excipients using dif-
ferential scanning calorimetry (DSC). They verified that
propranolol interacts with a number of commonly used
tablet excipients.
100
80
DTA
DTG
–
–
0.1
2
1
0
0.2
6
4
2
0
0
0
0
–0.3
Bartolomei et al. [11] investigated the polymorphism of
(
R,S) propranolol hydrochloride by DSC, TG and others
–0.4
techniques. The authors showed that propranolol
hydrochloride existed in three different crystalline habits
called forms I, II and III, according to their decreasing
melting temperatures.
–
1
–0.5
600
0
200
400
Temperature/°C
In the literature, reports regarding the analysis of the
volatile products evolved during the propranolol decom-
position were not found. Thus, this paper aims to investi-
gate the gases evolved during heating of propranolol by
TG–FTIR and together with DSC curves, proposing a
mechanism for propranolol decomposition.
Fig. 2 TG/DTG-DTA curves of the propranolol (m = 10.40 mg) in
atmosphere
N
2
cycle 1
–1
2
W g
Materials and methods
Propranolol hydrochloride (Natural Pharma, Brazil) was
stored in a refrigerator before analysis and used without
further purification.
cycle 2
Simultaneous TG/DTG and DTA analysis were carried
out in open a-alumina sample holders (90 lL) in a simul-
taneous SDT-Q600 modulus controlled by the Thermal
Advantage Q-Series (version 5.4.0 software, both from TA
Instruments). Experimental parameters for TG curves
were: sample mass of 10 ± 1 mg (mass precision 0.1 lg)
cycle 3
cycle 4
-
1
and heating rate of 10 °C min under dynamic N atmo-
2
-
sphere flowing at 50 mL min from room temperature to
1
6
00 °C. The apparatus was calibrated for temperature with
–50
0
50
100
150
200
a zinc standard as recommended by the manufacturer
instructions.
Temperature/°C
DSC curves were obtained using sample mass of c.a.
Fig. 3 Heat–cool–heat DSC curves of the propranolol
(m = 5.90 mg)
6
.0 ± 0.5 mg (mass precision 0.1 mg), heating rate of
1
23

Thermal behavior of the b-blocker propranolol
1015
The analyses of the evolved gaseous products was car-
ried out by connecting the exhaust of the TG–DTA
equipment to a Nicolet iS10 spectrophotometer (Thermo
Scientific), with a gas cell operating at 250 °C and a DTGS
KBr detector. The coupling was performed using a stain-
less steel line transfer (length 1200 mm; diameter 3 mm)
heated at 225 °C and purged with nitrogen. FTIR spectra
were recorded with 32 scans per spectrum at a resolution of
-
4 cm . The interferometer and the gas cell compartments
1
were purged with highly purified N for 20 min previously
2
to the TG run. The TG curve was taken using a heating rate
-
1
of 10 °C min and samples weighing about 12 mg in a-
alumina crucibles, and the same purified N for the furnace
1
2
-
atmosphere control flowing at 50 mL min
.
0.10
0.05
Results and discussion
0
.00
Propranolol TG/DTG-DTA curves are presented in Fig. 2.
In TG curve, it can be observed that there is any mass loss
until approximately 200 °C. However, at 160.6 °C an
endothermic peak appeared in the DTA curve, corre-
sponding to the melting of the drug with initial temperature
at 151.8 °C.
8
0.0
50.0
3
000
2
000
1
000
10.0
Fig. 4 3D-FTIR spectra of gaseous products evolved during the
decomposition of propranolol, along the analysis time
According to TG/DTG curves, the propranolol presented
a single mass loss step between 199.6 and 369.9 °C in
Fig. 5 Experimental and
database [13] FTIR gas-phase
spectra for the three compounds
suggested as evolved gases
during propranolol
decomposition
Spectrum at 7 min
0.1
Spectrum at 31 min
Spectrum at 67 min
Experimental
spectra
CO2
0.2
HCl
Databases
library spectra
C H O
1
0
8
C H N
3
9
4000
3500
3000
2500
2000
1500
1000
500
Wavenumber/cm–1
123

1
016
B. Ambrozini et al.
which 99.80 % of the initial sample mass is lost corre-
sponding to decomposition of the drug. In the same tem-
perature range, there is an endothermic peak at 312.0 °C in
the DTA curve.
In agreement with the TG curve, one can observe an
intense gas release in the 27.5 to 40.0 min interval, cor-
responding to 290–420 °C. According to the database
records, in this temperature range there are the character-
istic peaks in the FTIR spectra of 1-naphthol at 3647, 1525,
Figure 3 presents propranolol heat–cool–heat DSC
curves. In the first heating, an endothermic peak at
-
1
1412, 1286, 1240, 1205, 1046, 1008 cm ; isopropylamine
-1
-
1
1
66.7 °C (Tonset = 163.9 °C, DHfus = 16.31 kJ mol
)
at 3055, 2967, 2914, 2872 cm
and HCl in the
-
1
relative to the melting process was observed in agreement
with previously reported results [12]. In the first cooling,
crystallization was not observed, instead of that a glass
transition, typical of amorphous compounds, was detected
c.a. 30 °C.
2840–2660 cm range. A comparison of the experimental
and data base peaks for the three compounds suggested
here is presented in Fig. 5. A tentative attribution of such
peaks is presented in Table 1.
Thus, one can conclude that propranolol decomposed in
the 199.6–369.9 °C range releasing 1-naphthol, isopropy-
lamine and HCl. It should be expected the release of iso-
propanol once it is also part of the molecule. However, a
secure detection of this alcohol could not be performed
once the isopropanol IR spectra peaks are similar to those
of the other constituents, but we can suggest the evolution
of such alcohol during decomposition as well, but not
confirmed. A tentative mechanism for such decomposition
is presented in Fig. 6.
In the second heating, one can observe the reversion on
the glass transition, represented by baseline deviation c.a.
3
0 °C, an exothermic event centered at 125.3 °C
-1
(
DHcryst = 13.10 kJ mol ), probably associated with a
cold crystallization event, followed by melting
endothermic process with peak at 165.7 °C (T
a
=
onset
-
1
1
61.7 °C, DHfus = 15.42 kJ mol ) [12]. During the sec-
ond cooling, the same characteristics of the first cooling
were observed.
The investigation of gases evolved during the propra-
nolol thermal decomposition revealed peaks of gas evolu-
tion at 7, 31 and 67 min (respectively at 90, 330 and
It is interesting to note that in other b-blockers atenolol,
nadolol [15] and carvedilol [16] already investigated it was
found that the molecules start decomposition from the
aliphatic branch including the isopropylamine. However, in
the present case the structure of the molecule seems to
provide conditions for the entire decomposition followed
by volatilization of the 1-naphthol, a volatile compound not
present in the other b-blockers.
6
90 °C), as presented in Fig. 4. The identification of the
species was made according to Nicolet TGA Vapor Phase
and EPA Vapor Phase database library contained in the
Omnic 8.0 software (Thermo Scientific) [13].
In the first peak, CO and traces of H O were detected,
2
2
and in the last one, only CO appeared although this gas
2
could be detected all along the experiment. The first
detection could be related to carbon dioxide from the
residues on the line/furnace and at higher temperature the
gas was released from the decomposition of the residues of
the sample.
CH3
N
H
CH3
O
(s)
(l)
OH
HCl
Table 1 Tentative FTIR peak attribution for the evolved gases from
propranolol decomposition
CH3
CH3
-
1
a
Compound
-Naphthol
Wave number/cm
Attribution
N
O
H
OH
1
3647
O–H stretch
C=C ring stretch
O–H bend
HCl
1
1
1
1
525, 1412
286
205
C–O stretch
C–H
008
Isopropylamine
3055
N–H stretch
C–H stretch
C–N stretch
H–Cl stretch
OH
?
CH
HCl
H C
CH3
2
1
914, 2872
092
3
3
+
+
+
HN
CH3
OH
Hydrochloric acid
2840–2660
a
According to Silverstein et al. [14]
Fig. 6 Tentative mechanism for the thermal behavior of propranolol
1
23

Thermal behavior of the b-blocker propranolol
1017
6
. Fagher B, Monti M. Thermogenic effect of two b-adrenoceptor
blocking drugs, propranolol and carvedilol, on skeletal muscle in
rats. A microcalorimetric study. Thermochim Acta. 1995;251:
Conclusions
TG, DTG, DTA and DSC curves and FTIR spectra provide
information on the thermal behavior of the propranolol
hydrochloride, such as melting and stability of the drug.
The evolved gas analysis during the thermal decompo-
sition of the drug using TG–FTIR presented as principal
decomposition products 1-naphthol, isopropylamine and
HCl, being the rest of the molecule represented by iso-
propanol, not detected in the evolved gas analysis by TG–
FTIR. A tentative mechanism for the thermal behavior of
propranolol was proposed.
1
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Acknowledgements The authors are grateful to agencies FAPESP
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