Stability and compatibility study on enalapril maleate using thermoanalytical techniques

Article abstract of DOI:10.1007/s10973-007-8187-4

This paper demonstrates the application of thermal analysis in compatibility and stability studies between an ACE inhibitor (enalapril maleate) and excipients. The results have helped to elucidate the reason of a stability problem observed during the storage of enalapril maleate tablets. Incompatibility between enalapril maleate and colloidal silicon dioxide was detected. Besides, it was confirmed that the reaction between enalapril maleate and NaHCO₃increases the thermal stability of the drug. This study supports the importance of using thermoanalytical methods in the development of pharmaceuticals.

Full text of DOI:10.1007/s10973-007-8187-4

Journal of Thermal Analysis and Calorimetry, Vol. 93 (2008) 3, 881–886
STABILITY AND COMPATIBILITY STUDY ON ENALAPRIL MALEATE
USING THERMOANALYTICAL TECHNIQUES
1
R. L. O. Rezende , M. I. R. M. Santoro and J. R. Matos
1
2*
1Department of Pharmacy, College of Pharmaceutical Sciences, University of S±o Paulo, SP, Brazil
2Department of Fundamental Chemistry, Chemistry Institute, University of S±o Paulo, SP, Brazil
This paper demonstrates the application of thermal analysis in compatibility and stability studies between an ACE inhibitor
(enalapril maleate) and excipients. The results have helped to elucidate the reason of a stability problem observed during the storage
of enalapril maleate tablets. Incompatibility between enalapril maleate and colloidal silicon dioxide was detected. Besides, it was
confirmed that the reaction between enalapril maleate and NaHCO3 increases the thermal stability of the drug. This study supports
the importance of using thermoanalytical methods in the development of pharmaceuticals.
Keywords: compatibility, DSC, enalapril maleate, stability, TG, thermal stabilization
Introduction
patibility studies, but the data provided by DSC can be
more easily interpreted when they are supported by
thermogravimetry (TG). The application of both DSC
and TG in the same study is very common [3–8].
Incompatibilities between drug and excipient(s)
can change the stability and bioavailability of drug
products and can also affect their stability as well as
the efficiency during their administration. Loss of bi-
ological activity, formation of complexes or eutectics
and acid-base interactions may occur due to these
incompatibilities [1].
Thermoanalytical methods are among the frequently
used techniques for problems solving in pharmaceuti-
cal technology areas. Amongst others, one of their
frequent applications is the compatibility study be-
tween drugs and excipients, mainly in preformulation
studies. Drug-excipient compatibility studies are es-
sential steps of the development of different drug for-
mulations, helping in the selection of the proper ex-
cipients which increase the probability to obtain a
stable solid dosage form.
Enalapril maleate (EM) is an angiotensin-con-
verting enzyme (ACE) inhibitor and it is used in the
treatment of cardiovascular diseases, which are known
to be the principal cause of mortality in modern societ-
ies. Cardiovascular diseases for which EM is pre-
scribed include hypertension, left ventricular systolic
dysfunction and myocardial infarct, and it is also
known to significantly retard renal function loss asso-
ciated with diabetic nephropathy, which is caused by a
combination of diabetes mellitus and hypertension [9].
EM alone is temperature stable either under dry or
different humidity conditions. However, it becomes un-
stable when it is mixed with the matrix, during tablet
making and exposed to the same conditions [10]. Since
EM is incompatible with most of the commonly used ex-
cipients, it is very difficult to formulate a stable solid oral
dosage form for it [11]. Ungboriboonpisal et al. [12] ex-
pressed the necessity of the analysis of EM formulations
and the importance of searching for suitable storage con-
ditions. In their study, from a total of 54 samples with a
declared expiration date of 3 years, 48.1% were found to
contain degradation products exceeding the adopted
The use of thermoanalytical methods in drug-
excipient compatibility studies offers many advan-
tages over the classical methods of incompatibility
detection between the active compound and the ex-
cipients. In the conventional methods, drug is added
to the excipients and they are subjected to high tem-
peratures and high percentages of relative humidity
for a considerable time. Then, they are analyzed using
different techniques, e.g. high-performance liquid
chromatography (HPLC), thin-layer chromatogra-
phy (TLC), etc. This procedure often takes several
weeks or even months to generate sufficient data sup-
porting or denying the compatibility. On the contrary,
one of the major advantages of the thermoanalytical
techniques is the rapid analysis, and besides, the pos-
sibility of detecting physical interactions such as the
formation of eutectic mixture or adsorption between
drug and excipients [1, 2].
Among the various existing thermoanalytical
methods, differential scanning calorimetry (DSC) is the
most important one employed in drug-excipient com-
*
Author for correspondence: jdrmatos@usp.br
1388–6150/$20.00
© 2008 Akadémiai Kiadó, Budapest
Akadémiai Kiadó, Budapest, Hungary
Springer, Dordrecht, The Netherlands

REZENDE et al.
5.0% limit. In order to better interpret the results, the
for the pure EM and for its mixture with colloidal sili-
con dioxide (SiO2) was also investigated in order to
determine the activation energy (Ea) in the degrada-
tion reaction in each case.
54 samples were divided in three sub-groups according to
their date of manufacturing. Those manufactured until a
year before the study comprised 26 samples, those manu-
factured between one to two years before the study com-
prised 17 samples and those manufactured between two
to three years before the study comprised 8 samples. It
was found that 26.9, 70.6 and 87.5% of the samples from
each sub-group, respectively, were substandard medi-
cines as defined by the World Health Organization [13].
Moreover, most of the approved samples were less than
7 months old.
Experimental
Materials
EM and excipients were of pharmaceutical grade, ex-
cept for the colorants, which were of food grade. They
were all kindly donated by a Brazilian company. The
excipients were spray-dried lactose (Super-Tab®), mic-
rocrystalline cellulose (Microcel®), magnesium stearate,
colloidal silicon dioxide (Cab-O-Sil® M5-P), NaHCO3
and the colorants Red n° 40 and Yellow n° 6, both alu-
minum lake pigments. Compatibility studies were car-
ried out using 1:1 mass/mass binary mixtures of drug
and excipient. Each excipient was mixed with the drug
by grinding them together in a mortar with a pestle.
Pharmaceutical grade NaHCO3 and analytical
grade MgO were used to evaluate the thermal stabili-
zation methods. The two products were reacted sepa-
rately with EM after solubilizing all the reactants in
water. Stoichiometrically, one mole of EM reacts
with 3 moles of NaHCO3 and with 1.5 mole of MgO.
Once the reactions were completed, the resulted prod-
ucts were dried overnight in an Edwards do Brasil®
model L4KR lyophilizer.
In addition, EM exhibits two polymorphic
forms, which – according to their melting behavior –
are very similar [14]. Nevertheless, Eyjolfsson [15]
found evidence suggesting that Form II is much less
stable than Form I when it is in a tablet formulation
matrix containing sodium hydrogen carbonate
(NaHCO3) as stabilizer.
In the present work, the compatibility of EM
with excipients of a specific tablet formulation was
investigated by DSC and TG. The selected formula-
tion seemed to show a stability problem, character-
ized by the apparent formation of gas or the release of
some volatile substance during the storage of the drug
product. The problem was observed even under nor-
mal storage conditions but became even more evident
when the product was stored under controlled, drastic
conditions (accelerated stability studies). The packag-
ing material became distended because of gas release
by the product, allowing the tablets to move around
inside the packaging (Fig. 1). At the time, this behav-
ior was attributed to an incompatibility between some
of the components used in the formulation.
The thermal degradation kinetics were studied
by the standard isothermal isoconversional method,
where the Ea can be calculated from the slope of the
lnt vs. 1/T plot (for a given conversion fraction and
without assuming any decomposition model).
In fact, the aim of this study was to explain the
reason of the above problem and to find a solution for
it. Besides, two methods of thermal stabilization of
EM already reported in the literature were also evalu-
ated by TG. One of these consists in reacting EM with
sodium hydrogen carbonate (NaHCO3) [16] and the
other one consists in reacting EM with magnesium
oxide (MgO) [17]. The thermal degradation kinetics
Methods
DSC curves were obtained using a Shimadzu®
DSC-50 cell. About 1 mg of pure drug and about 2 mg
of drug-excipient mixture was weighted to aluminum
pans in order to keep the amount of drug approxi-
mately constant. Dynamic purging (nitrogen, flow
rate: 100 mL min–1) and a heating rate of 10°C min–1
from room temperature up to 300°C was applied. In-
dium (m.p.=156.6°C; DHfus=28.54 J g–1) and zinc
(m.p.=419.5°C) standards were used to calibrate the
DSC cell previously.
TG/DTG curves were obtained with
a
Shimadzu® TGA-50 thermobalance using platinum
crucibles containing about 5 mg of samples, under dy-
namic nitrogen atmosphere (50 mL min–1) and at a
heating rate of 10°C min–1 from room temperature up
to 300°C for the drug-excipient compatibility studies,
and from room temperature up to 600°C for the evalu-
ation of the thermal stabilization methods.
Fig. 1 Distension of the packaging material and release of
tablets from PVC blisters
882
J. Therm. Anal. Cal., 93, 2008

STABILITY AND COMPATIBILITY STUDIES ON ENALAPRIL MALEATE
For the kinetic studies the same experimental
as heat, moisture and light on two different EM tablet
formulations: one with an acidic matrix and the other
with a basic matrix containing NaHCO3. It was demon-
strated that the latter was almost resistant to photolysis.
This was considered an important observation by the
manufacturer because its EM tablets were packed in
PVC-aluminum blisters, while presumably all the other
manufacturers use aluminum–aluminum blisters to
pack their EM tablets. Although the cost of packing the
tablets in PVC–aluminum blisters is lower, this kind of
blister does not provide complete protection against
light as the aluminum–aluminum blister does (since
that PVC does not act as a barrier to light transmis-
sion). This was the reason which led the manufacturer
to use NaHCO3 in the formulation in order to ensure a
basic matrix and, therefore, to minimize the suscepti-
bility of the drug to photolysis.
conditions were applied. Five different kinetic curves
were obtained in each study, with temperatures rang-
ing from 125 to 145°C (for EM alone) and from 105
to 125°C (for 1:1 mass/mass binary mixture of EM
and SiO2), with 5°C increments for each curve. Calcu-
lations were performed from the curves at the same
degree of conversion, which was made equal to 5% of
mass loss under isothermal conditions.
In fact, NaHCO3 reacts with EM according to the
following equation:
C20H28N2O5·C4H4O4 + 3NaHCO3 ®
C20H27N2NaO5 + C4H2Na2O4 + 3CO2 + 3H2O
Fig. 2 TG/DTG and DSC curves of enalapril maleate
The TG curve of the 1:1 mass/mass binary mix-
ture between EM and NaHCO3, shown in Fig. 3, when
compared to the TG curve of the pure EM and to the
TG curve of the pure NaHCO3 (both also shown in
Fig. 3), confirms the reaction between the drug and
the excipient, evidenced by the premature mass loss.
The same TG curve (magnified in its initial part) also
demonstrates that this reaction may occur even at
temperatures below 30°C. This finding suggests that,
if the chemical reaction does not complete before the
packaging process, it may certainly continue further,
since it does not require temperatures higher than
room temperature to take place. The reaction can be
easily predicted since EM contains three carboxyl
groups, which lends acidic character to the molecule
(structural formula in Fig. 4), while NaHCO3 is a ba-
sic salt. Nevertheless, one cannot consider this an in-
compatibility attributed to an acid-base interaction.
Results and discussion
The thermoanalytical curves of enalapril maleate are
presented in Fig. 2.
The TG/DTG curves show that EM is thermally
stable up to 140°C and presents a noteworthy mass
loss step between 140–235°C (Dml=26.2% and
TpeakDTG=182.9°C). The endothermic DSC peak is
related to the melting of the substance (Ton -
set=150.2°C) followed by another partially overlapped
endothermic event due to thermal decomposition. The
apparent heat of fusion was 59.1 kJ mol–1. These re-
sults are in reasonable agreement with the ones
reported in [2, 14, 18–21]. The thermal decomposi-
tion of EM starts with the loss of one molecule of
maleic acid together with one molecule of water,
which is eliminated in an intramolecular cyclization
reaction of the enalapril molecule that leads to the for-
mation of enalapril diketopiperazine [18–21]. The
degradation pathway of EM was found to be pH de-
pendent. While enalapril diketopiperazine is the main
degradation product formed when EM is not mixed
with any excipient or when EM is in an acidic matrix,
enalaprilate is the major degradant formed when EM
is in a basic matrix [10].
Consequently, the first result of the present study
was the observation that the manufacturer was making
incorrect use of NaHCO3 in the formulation. The man-
ufacturer added NaHCO3 to the formulation in order to
maintain a basic pH for the drug product matrix, based
on the work of Al-Omari et al. [10]. In this work, the
authors investigated the influence of parameters such
Fig. 3 TG curves of enalapril maleate, of NaHCO3 and of their
1:1 physical mixture
J. Therm. Anal. Cal., 93, 2008
883

REZENDE et al.
Fig. 4 Structural formula of EM showing its 3 carboxyl groups
The reaction is, in fact, a thermal stabilization method
for EM already described in the literature [16]. Be-
sides, there is a release of CO2 during the reaction,
which was indeed the responsible for the packaging
swelling. A single tablet containing 20 mg of EM is
able to release approximately 2.7 cm3 of CO2 (STP)
assuming a complete reaction between the NaHCO3
and the total amount of EM in the tablet.
Fig. 5 TG and DTG curves of enalapril maleate and its 1:1
physical mixture with SiO2
In spite of the fact that the reaction takes place
by the simple physical contact among the species in
the solid state and at room temperature, for solid oral
dosage forms of EM where NaHCO3 is present, the
correct manufacturing process must ensure that the
reaction between the two components has finished be-
fore the packaging step. It can be done by the addition
of NaHCO3 previously dissolved in water, followed
by an oven drying at 50°C, according to [16]. The pre-
vious dissolution of NaHCO3 facilitates its contact
with the drug, while heating during drying accelerates
the reaction. The end-point of the reaction must be
monitored by weighing with the aid of stoichiometric
calculations (here one has to consider the mass of CO2
lost to the atmosphere and the total amount of water
lost during the drying stage which includes the added
water and the water formed during the reaction).
Although the interaction between EM and
NaHCO3 is rather an expected reaction than an in-
compatibility, at least one of the other excipients
studied here interacts with the drug, probably de-
creasing the stability of the formulation. The
TG/DTG and DSC curves of the binary mixtures of
EM and SiO2 (Figs 5 and 6, respectively) indicate that
SiO2 results in a decrease of more than 20°C in the on-
set temperature of degradation for the drug.
Fig. 6 DSC curves of enalapril maleate and its 1:1 physical
mixture with SiO2
The superimposed isothermal TG curves ob-
tained for the EM degradation kinetic study are col-
lected in Fig. 7 (the ones related to the degradation ki-
netic study of the 1:1 mass/mass binary mixture of
EM and SiO2 were obtained as described above, but
will not be shown herein). These curves indicate the
dependence of the mass loss rate on the isothermal
temperature, i.e., the higher the temperature the less
time is needed to reach the same mass loss. These
curves were used to plot the graph of lnt vs. the recip-
rocal of temperature, 1/T (K–1) (Fig. 8). The data
shown in Table 1 were obtained from this graph using
a linear regression. The value of Ea was calculated by
multiplying the slope of the appropriate linear equa-
Fig. 7 Isothermal TG curves of EM obtained between
125–145°C, with increments of 5°C
tion by the molar gas constant (R=8.314 J K–1 mol–1).
A 40% decrease in the Ea value can be observed for
the thermal degradation reaction of EM when it is
mixed with SiO2 keeping 1:1 mass/mass ratio. There-
fore, the use of SiO2 as excipient should be avoided in
formulations containing EM, since it may act as a cat-
alyst in the thermal decomposition of this drug even
though SiO2 is usually employed at low concentra-
884
J. Therm. Anal. Cal., 93, 2008

STABILITY AND COMPATIBILITY STUDIES ON ENALAPRIL MALEATE
Table 1 Representative kinetic parameters calculated from data presented in Fig. 8
2
Regression coefficient, (r )
Linear regression equation
Activation energy/kJ mol–1
EM
lnt=24226 1/T–55.78
lnt=14615 1/T–33.95
0.992
0.995
201
122
EM:SiO2 binary mixture
of EM in the melted excipient, what makes the re-
search on incompatibilities impossible, as far as solid-
state interactions are concerned. However, based on
data from classical accelerated stability studies [11], it
was found that MgE as well as MC, calcium phos-
phates and also many of the common disintegrants
(starch, sodium starch glycolate, crospovidone and
croscarmellose sodium) contribute to the EM decom-
position. No interactions were observed between EM
and the other excipients studied in the present work.
There are two described thermal stabilization
methods for EM in which the drug is made to react with
a basic compound to form a new enalapril salt. One
method consists in reacting EM with an alkaline sodium
compound, such as NaOH, Na2CO3 or NaHCO3 to yield
enalapril sodium and disodium maleate [16]. The other
consists of reacting EM with MgO, which, in its turn,
yields the magnesium salts of enalapril and maleic
acid [17]. The latter is claimed to be a method of thermal
stabilization for various ACE inhibitors, including EM,
but is preferably applied to quinapril. To evaluate and
compare these two methods, TG/DTG curves were re-
corded for the products of the reaction between EM and
MgO (P1) and between EM and NaHCO3 (P2). These
TG/DTG curves are depicted in Fig. 9.
Fig. 8 lnt vs. 1/T plot for EM and its 1:1 mass/mass mixture
with SiO2
tions (as it is the case for the studied formulation, in
which SiO2 is employed at 1% mass/mass).
In 1987, Cotton et al. [2] reported an interaction in
which the degradation rate of EM was accelerated by sev-
eral orders of magnitude in the presence of micro-
crystalline cellulose (MC). It was noticed that this ex-
cipient seemed to reduce the apparent heat of fusion of the
drug. As mentioned earlier, at a heating rate of 10°C min–1,
the DSC curve of EM shows two partially superimposed
endothermic events. The first is due to melting and the sec-
ond one is due to thermal decomposition. This indicates
that decomposition takes place during the melting in some
extent. Moreover, in the DSC curve of the EM:MC binary
mixture there is an increase in the degree of overlapping of
the two events. For this reason, the accurate determination
of the heat of fusion is unrealistic. Consequently, the de-
crease of the heat of fusion in the presence of MC could
not be confirmed. No attempts were made in order to sepa-
rate the thermal events by decreasing the heating rate.
More recently, Devi and Babu [22] also demonstrated the
increase in the degradation rate of EM in presence of MC
by performing DTA studies and accelerated stability test.
The interaction between EM and dibasic calcium phos-
phate was also reported. Therefore, we believe there is suf-
ficient evidence in the literature to avoid the use of MC in
EM formulations.
Only the first step of the whole thermal degrada-
tion process of a substance gives information with re-
gard to its stability, since the subsequent steps are no
longer directly related to the original molecule. The
TG/DTG curves show that while the first mass loss
step for EM reaches its maximum rate at 182.9°C
(TpeakDTG), for P2 it shifts to 297.9°C. On the other
hand, for P1 the first stage of thermal degradation ap-
pears in the same temperature range as that observed
for EM. However, this could be attributed to an incom-
The magnesium stearate (MgE), in its turn, is a
mixture of magnesium salts of different fatty acids,
consisting mainly of stearic acid and palmitic acid
and, in minor proportions, other fatty acids. Commer-
cial MgE samples melt in the range of 117–150°C,
while high purity MgE melts at 128±2°C [23]. Since
EM melts only at 150.2°C (Tonset) the earlier melting
of MgE can lead to partial or complete solubilization
Fig. 9 TG/DTG curves of enalapril maleate and of the reaction
products, P1 and P2
J. Therm. Anal. Cal., 93, 2008
885

REZENDE et al.
4 A. Marini, V. Berbenni, S. Moioli, G. Bruni,
plete reaction between EM and MgO. If the reaction
between EM and MgO has not reached the theoretical
yield (100%) for the expected products, the TG/DTG
curves of P1 could have been affected by the remaining
EM (the nonreacted fraction). This fraction would be
present as contaminant, mixed with the reaction prod-
uct. Moreover, if this hypothesis is true, then it would
indicate that, according to the yield of the stabilization
reactions, the stabilization of EM by the reaction with
NaHCO3 is more easily achieved than by the reaction
with MgO. On the other hand, the second mass loss
step for P1 starts almost at the same temperature where
the thermal degradation of P2 begins. Once again, if
the first mass loss step for P1 could be attributed to
non-reacted EM, this would indicate that the second
mass loss step is indeed the product of the reaction be-
tween EM and MgO. Consequently, both products
(P1 and P2) would have similar thermal stabilities.
P. Cofrancesco, C. Margheritis and M. Villa, J. Therm.
Anal. Cal., 73 (2003) 529.
5 A. Marini, V. Berbenni, M. Pegoretti, G. Bruni,
P. Cofrancesco, C. Sinistri and M. Villa, J. Therm. Anal.
Cal., 73 (2003) 547.
6 G. G. G. Oliveira, H. G. Ferraz and J. S. R. Matos,
J. Therm. Anal. Cal., 79 (2005) 267.
7 L. C. S. Cides, A. A. S. Araújo, M. Santos-Filho and
J. R. Matos, J. Therm. Anal. Cal., 84 (2006) 441.
8 D. Kiss, R. Zelkó, Cs. Novák and Zs. Éhen, J. Therm.
Anal. Cal., 84 (2006) 447.
9 J. G. Hardman, L. E. Limbird, P. B. Molinoff,
R. W. Ruddon and A. G. Gilman, As Bases
Farmacológicas da TerapÃutica, McGraw-Hill
Interamericana Editores, México-DF 1996, p. 544.
10 M. M. Al-Omari, M. K. Abdelah, A. A. Badwan and
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11 B. C. Sherman, Stable Solid Pharmaceutical Compositions
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12 S. Ungboriboonpisal and C. Wongpinairat, Mahidol Univ.
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Conclusions
13 World Health Organization. Fact Sheet N° 275. 2003.
Aviable in:
http://www.who.int/mediacentre/factsheets/2003/fs275/en/.
Last access: 02/22/2008.
Although thermoanalytical methods are not able to
completely replace the classical methods for incompat-
ibility detection, they are valuable tools in the analysis
of formulation problems. TG/DTG and DSC experi-
ments made it possible to recognize the reason of the
blisters’ distension, which was attributed to the inap-
propriate use of NaHCO3 in the formulation. More-
over, incompatibility was found between EM and
SiO2, since the excipient noticeably decreased the ther-
mal stability of the drug. However, since SiO2 is used
at low concentrations in tablet making, the impact of
this interaction must be carefully evaluated. Also, the
reaction product between NaHCO3 and EM was found
to be unambiguously more stable than EM itself. How-
ever, further studies are necessary to reach a conclu-
sion regarding the stabilization of EM using MgO.
14 D. P. Ip, G. S. Brenner, J. M. Stevenson, S. Lindenbaum,
A. W. Douglas, S. D. Klein and J. A. McCauley, Int. J.
Pharm., 28 (1986) 183.
15 R. Eyjolfsson, Pharmazie, 57 (2002) 347.
16 B. C. Sherman, Stable Solid Formulation of Enalapril Salt
and Process for Preparation Thereof, WO Pat. 97/05881,
20 fev. 1997, p. 17.
17 J. E. Daniel, M. R. Harris, G. C. Hokanson and J. Weiss,
Stabilization of Formulations Containing ACE Inhibitors
by Magnesium Oxide, WO Pat. 9962560,
09 dez. 1999, p. 27.
18 D. P. Ip, G. S. Brenner, J. M. Stevenson, S. Lindenbaum,
A. W. Douglas, S. D. Klein and J. A. McCauley,
Int. J. Pharm., 28 (1986) 183.
19 S.-L. Wang, S.-Y. Lin and T.-F. Chen, Chem. Pharm.
Bull., 49 (2001) 402.
20 S.-Y. Lin, S.-L. Wang, T.-F. Chen and T.-C. Hu,
Eur. J. Pharm. Biopharm., 54 (2002) 249.
21 B. Stanisz, J. Pharm. Biomed. Anal., 31 (2003) 375.
22 E. A. G. Pineda, A. D. M. Ferrarezi, J. G. Ferrarezi and
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Acknowledgements
The authors acknowledge the Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq) and the
Funda¸±o de Amparo ´ Pesquisa do Estado de São Paulo
(FAPESP) for their financial support.
23 M. V. Devi and P. S. S. K. Babu, Int. J. Pharm. Excipients,
2 (2000) 153.
24 R. C. Rowe, P. J. Sheskey and P. J. Weller,
Pharmaceutical Excipients 2003, Single-User Version,
For Windows, Pharmaceutical Press, London 2003,
CD-ROM.
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