Synthesis and characterization of metal complexes of acebutolol, atenolol, and propranolol antihypertension drugs

Article abstract of DOI:10.1081/SIM-120039270

The complexation of two transition metal ions with the β-blocker drugs acebutolol (HL¹), atenolol (HL²), and propranolol (HL³) was studied in methanol and acetonitrile media at M:L (metal:ligand) molar ratio from 1:1 to 1:

Full text of DOI:10.1081/SIM-120039270

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Synthesis and Characterization of Metal Complexes
of Acebutolol, Atenolol, and Propranolol
Antihypertension Drugs
Ayşegül Gölcü a , Cem Yücesoy b & Selahattin Serin c
a Department of Chemistry, Faculty of Science and Arts, University of Kahramanmaras
Sütçü İmam, Ferhuş, Kahramanmaraş, Turkey
b Department of Analytical Chemistry, Faculty of Pharmacy, University of Ankara,
Tandogˇan, Ankara, Turkey
c Department of Chemistry, Faculty of Science and Arts, Çukurova University, 01100,
Balcalı, Adana, Turkey
Published online: 16 Nov 2010.
To cite this article: Ayşegül Gölcü , Cem Yücesoy & Selahattin Serin (2004) Synthesis and Characterization of Metal
Complexes of Acebutolol, Atenolol, and Propranolol Antihypertension Drugs, Synthesis and Reactivity in Inorganic and
Metal-Organic Chemistry, 34:7, 1259-1275, DOI: 10.1081/SIM-120039270
To link to this article: http://dx.doi.org/10.1081/SIM-120039270
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SYNTHESIS AND REACTIVITY IN INORGANIC AND METAL-ORGANIC CHEMISTRY
Vol. 34, No. 7, pp. 1259–1275, 2004
Synthesis and Characterization of
Metal Complexes of Acebutolol,
Atenolol, and Propranolol
Antihypertension Drugs
1
Ays¸egu¨l Golcu, Cem Yucesoy, and
2
¨
¨
¨
Selahattin Serin3,
*
1Department of Chemistry, Faculty of Science and Arts,
˙
University of Kahramanmaras Su¨tc¸u¨ Imam, Ferhus¸,
Kahramanmaras¸, Turkey
2Department of Analytical Chemistry, Faculty of Pharmacy,
ˇ
University of Ankara, Tandogan, Ankara, Turkey
3Department of Chemistry, Faculty of Science and Arts,
C¸ ukurova University, Balcalı, Adana, Turkey
ABSTRACT
The complexation of two transition metal ions with the b-blocker drugs
acebutolol (HL1), atenolol (HL2), and propranolol (HL3) was studied in
*
Correspondence: Selahattin Serin, Department of Chemistry, Faculty of Science and
Arts, C¸ ukurova University, 01100, Balcalı, Adana, Turkey; E-mail: serin@ksu.edu.tr.
1259
DOI: 10.1081/SIM-120039270
0094-5714 (Print); 1532-2440 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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¨
¨ ¨
Golcu, Yucesoy, and Serin
1260
methanol and acetonitrile media at M : L (metal : ligand) molar ratio
from 1 : 1 to 1 : 10. Cu(II) complexes with ligands having the stoichio-
metric ratio 1 : 4 (mononuclear copper(II) complexes) and 1 : 1 (binuclear
copper(II) complexes) were prepared. The analytical data show that
the metal to ligand ratio in the mononuclear Co(II) complexes was
1 : 2. The complexes were characterized on the basis of analytical
data, magnetic moments, atomic absorption, infrared and electronic
spectral data. Molar conductivities of the complexes at room temperature
were measured. The conductivity values of the mononuclear Cu(II)
complexes indicate weak electrolyte behavior, whereas the binuclear
Cu(II) and mononuclear Co(II) complexes are non-electrolytes. The
thermal properties of all complexes have been studied by the DTA
and TG.
Key Words: Metal complexes; Molar conductivity; Transition
metal ion.
INTRODUCTION
Acebutolol (HL1) (N-[3-acetyl-4-[2-hydroxy-3-[(1-methylethyl)amino]
propoxy]-phenyl]butanamide), atenolol (HL2) (2-[4(2-hydroxy-3-izopropyl-
aminopropoxy)phenyl]acetamide), and propranolol (HL3) (1-[(1-methylethyl)
amino]-3-(1-naphtaleneo-xy)-2-propanol)[1] are drugs widely used in the
treatment of hypertension, angina and thyrotoxicosis and are almost comple-
tely metabolized in man.[2] The major metabolites identified in plasma and
urine include conjugates of these drugs.[3]
Recently, complexation has often been used to influence biological
processes that are metal-dependent.[4,5] Recent studies proved that when
bioorganic molecules are introduced as transition metal chelates they have
increased activities and more therapeutic importance.[5,6] Since most of
the labile copper in human plasma is loosely bound to albumin, this
metal can bind to amino acids and other chelating ligands.[7–9] It is of inter-
est, therefore, to determine the copper binding properties of b-blocker drugs
and their hydrochloride salts.[10–12] The other example among transition
metals, iron, is being considered the most important one with a functional
role in living systems, e.g., proteins containing iron participate in oxygen
transport and electron transfer processes.[13] In addition, it is known that
some Zn(II)–drug complexes are extremely effective in treatment of
AIDS.[14]
Thus, this paper represents a further step in these investigations
and is concerned with complex formation of Cu(II) and Co(II) with
2
acebutolol hydrochloride (HL1 HCl), atenolol (HL ), and propranolol
.

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Metal Complexes of Antihypertension Drugs
1261
hydrochloride (HL3 HCl). They have the following structural formulae
(Fig. 1).
.
EXPERIMENTAL
Materials
Acebutolol hydrochloride was obtained from Bayer Turkish Chemical
Industries, Istanbul, Turkey, and atenolol and propranolol hydrochloride
ˇ
were courtesy of Sanofi Dogu Drug Co., Istanbul, Turkey, respectively. All
chemicals and solvents were obtained from E. Merck or Carlo Erba. Deionized
water was used in order to eliminate undesirable ions.
Figure 1. The structures of ligands.

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Golcu, Yucesoy, and Serin
1262
Physical Measurements
The carbon, hydrogen, and nitrogen analyses were obtained using a Leco
932 CHNS elemental analyzer. The infrared spectra were obtained on a
Shimadzu 8300 FTIR spectrophotometer using KBr discs (4000–400 cm21).
The electronic spectra were recorded on a Shimadzu 160 A spectrophotometer
in DMSO. Magnetic susceptibilities were measured by the Gouy method at
room temperature using Hg[Co(SCN)4] as calibrant. Molar conductances of
all complexes were determined in DMSO (ꢀ1023 M) at room temperature
using a Jenway Model 4070 conductivity meter. The metal contents of the
complexes were determined by an Ati Unicam 929 Model AA spectrometer
in solutions prepared by decomposing the compounds in aqua regia and
then subsequently digesting in concentrated HNO3/H2O2 (1/1). The thermal
analysis studies were performed on a model DT-40 Shimadzu thermal analy-
zer using 40 mg samples. The DTA and TG curves were obtained at a heating
rate of 10 8C min21. In all cases, the 20–800 8C temperature range was studied
in dry nitrogen atmosphere.
Preparation of the Complexes
3
Mononuclear Cu(II) Complexes of HL1 HCl and HL HCl
.
.
NaOH (0.200 g, 5 mmol) was dissolved in water (5 mL) and was added
3
drop-wise to a solution of HL1 HCl (1.865 g, 5.0 mmol) or HL HCl
.
.
(1.293 g, 5.0 mmol) in methanol (15 mL). The metal salts, 0.5 mmol
1
.
.
(0.0855 g) CuCl2 2H2O (for HL ), and 0.5 mmol (0.090 g) Cu(AcO)2 H2O
(for HL3), were employed as starting materials for the preparation of the com-
plexes. The following general preparative method was used. To a solution of
the ligand (5 mmol) in methanol (15 mL) an equimolar amount of aqueous
standard 1 ꢀ 1023N NaOH solution (5 mL) was added drop-wise with stir-
ring. To the resulting clear solution, (pH 5–7) a methanolic solution
(20 mL) of the required metal chloride or metal acetate was added until the
final metal ion : ligand : NaOH molar ratio was 1 : 10 : 10. The reaction
mixtures were stirred for 2 and 24 hr at room temperature, respectively. The
resulting violet precipitates were filtered, washed with methanol/water (1 : 1
v/v), and dried in vacuo over P4O10 for several days.
Mononuclear Cu(II) Complex of HL2
.
The 0.5 mmol (0.090 g) methanolic Cu(AcO)2 H2O solution (20 mL) was
added drop-wise to a methanolic solution (15 mL) of HL2 (1.331 g, 5.0 mmol).

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Metal Complexes of Antihypertension Drugs
1263
The reaction mixture was stirred for 48 hr at 4 8C. The resulting violet precipi-
tate was filtered, washed with methanol/water (1 : 1 v/v), and dried in vacuo
over P4O10 for several days.
3
Binuclear Cu(II) Complexes of HL1 HCl and HL HCl
.
.
Binuclear Cu(II) complexes of the ligands HL1 and HL3, were prepared
by a procedure analogous to the mononuclear Cu(II) complexes, using
metal ion : ligand : NaOH in the molar ratio 1 : 2 : 2. The reaction mixtures
were stirred for 20 and 120 min at room temperature and 40 8C, respectively.
The green precipitates were filtered, washed with methanol/water (1 : 1, v/v),
and dried in vacuo over P4O10.
Binuclear Cu(II) Complex for HL2
.
A 2.5 mmol (0.4537 g) methanolic Cu(AcO)2 H2O solution (20 mL) was
added drop-wise to a methanolic solution (15 mL) of HL2 (1.331 g, 5.0 mmol).
The reaction mixture was stirred for 20 min at room temperature. The resulting
green precipitate was filtered, washed with methanol/water (1 : 1 v/v), and
dried in vacuo over P4O10 for several days.
3
Mononuclear Cobalt Complexes of HL1 HCl and HL HCl
.
.
A 5 mL of NaOH solution (0.2000 g, 5 mmol) was added drop-wise to a
water/acetonitrile (1/5, v/v) solution of HL1 HCl (1.865 g, 5.0 mmol) or
.
HL3 HCl (1.293 g, 5.0 mmol) (15 mL). To this, a solution (15 mL) of
.
.
2.5 mmol (0.415 g) CoCl2 2H2O in acetonitrile/water (5/1, v/v) was
added. The reaction mixture was stirred for 30 and 60 min at room tempera-
ture, respectively. Precipitates of varying colors (HL1 gray and HL3 green-
ish-blue) were obtained. The complexes were separated by filtration,
washed with acetonitrile/water (1 : 1), and dried in vacuo over P4O10.
Mononuclear Co(II) Complex for HL2
.
A solution of 2.5 mmol (0.415 g) CoCl2 2H2O in acetonitrile/water (5/1,
v/v) solution (15 mL) was added drop-wise to a water/acetonitrile (1/5, v/v)
solution of HL2 (1.331 g, 5.0 mmol) (15 mL). The reaction mixture was stirred
for 30 min at room temperature. A blue precipitate was obtained. The complex
was separated by filtration, washed with acetonitrile/water (1 : 1), and dried
in vacuo over P4O10.
Chloride ions in the complexes [Cu(HL1)4]Cl2 and [Cu2(L1)2Cl2] were
determined by titration with AgNO3.

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Golcu, Yucesoy, and Serin
1264
RESULTS AND DISCUSSION
The goal of this study was to synthesize Cu(II) and Co(II) complexes of
the antihypertensive drugs acebutolol, atenolol, and propranolol, which are
aryloxypropanolamine derivatives. The [M] : [L] ratios were varied from
1 : 10 to 10 : 10, to find out the optimal ratio for complex formation. The effect
of heat on the complex formation was investigated changing the reaction
temperature from þ48C to the boiling point of the solvents used. The effect of
pH on the complex formation was investigated; pH 6–7 was found to be the
optimal interval.[15] The complex formation reactions were carried out with
acetate and chloride salts of Cu(II) and Co(II). The highest yield for the
acebutolol metal complexes was obtained with the chloride salts of Cu(II)
and Co(II) as atenolol and propranolol react with acetate salts of Cu(II) and
Co(II) preferably. This situation maybe due to the role of the substitute groups
attached to the benzene ring. Yields of all complexes were investigated in
different solvents such as water, methanol, and acetonitrile. The best yield
for the Cu(II) and Co(II) complexes were obtained from methanol and aceto-
nitrile, respectively. The effect of the reaction time was also investigated.
Reaction mixtures were stirred in time intervals from 10 min to 48 hr.
The molecular formulae of the complexes have been assigned on the basis of
theiranalyticaldatagiveninTable1.Accordingly,[M(HL)4]Xn, [M2(L)2Xn],and
.
[M(L)2 (H2O)y] are suggested as general formulas for the mononuclear Cu(II)
(Fig. 1), binuclear Cu(II) (Fig. 2), and mononuclear Co(II) (Fig. 3) complexes
reported herein, respectively, where HL1, HL2, and HL3 are ligands, X is an
anion (chloride or acetate), n is the number of anions attached (n ¼ 2) and y is
the number of coordinated water molecules (y ¼ 2); y is zero in the mononuclear
and binuclear Cu(II) complexes. All of the complexes are soluble in DMSO.
The molar conductance (LM) values (given in parentheses) in DMSO for
[Cu(HL1)4]Cl2 (22.65), [Cu(HL2)4](OAc)2 (21.80), and [Cu(HL3)4](OAc)2
(22.93) suggest a 1 : 4 electrolytic nature of these complexes. The binuclear
Cu(II) and mononuclear Co(II) complexes were found to be non-electrolyte
in DMSO.[16]
Infrared Spectra
The important infrared bands are given in Table 2. In determining the
mode of binding of the ligand to the metal ion in the complexes. The following
four regions of the infrared spectrum have been studied.
1. The region 3271–3463 cm21 associated with the n(OH) vibra-
tional mode.

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Metal Complexes of Antihypertension Drugs
1265

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¨
¨ ¨
Golcu, Yucesoy, and Serin
1266
Figure 2. Suggested structure of the mononuclear complexes [Cu(HL)4]X2,
(HL ¼ HL1, HL2, and HL3; L ¼ L1, L2, and L3; X ¼ Cl for HL1, X ¼ OAc for HL2
and HL3).
2. The 2931–3350 cm21 region associated with the n(NH2) and n(NH)
modes.
3. The 1579–1689 cm21 region associated with the n(C55O) and d(NH)
modes.
4. The region 400–600 cm21 due to n(M–N) and n(M–O) vibrations.
Figure 3. Suggested structure of the binuclear complexes [Cu2(L)2X2] (R is defined
as in Fig. 2).

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Metal Complexes of Antihypertension Drugs
1267
d

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Golcu, Yucesoy, and Serin
1268
The spectra of the free ligands (HL1, HL2, and HL3) showed absorption
bands at 3288, 3355–3174 and 3280 cm21corresponding to the n(OH),
n(NH2), and n(NH) stretching frequencies, respectively, participating in the
formation of intra- and/or intermolecular H-bonds. The bands in the 1620–
1664 cm21 range are assigned to d(NH) and n(C55O).
The mononuclear Cu(II) complexes exhibited bands at 3340–3107,
3420–3190, and 3271–3190 cm21 for n(OH), n(NH2), n(NH) and at 1664,
1639 and 1620 cm21 for d(NH) and n(C55O),[17,18] respectively. These
suggest coordination of the oxygen and nitrogen atoms of the aminoalcohol
fragment of the ligands (Fig. 2).
The binuclear Cu(II) complexes of the ligands HL1, HL2, and HL3 show
bands at 3446–3350, 3192–3174, and 3213 cm21, respectively, for n(NH2)
and d(NH). n(OH) bands were not observed here because of the deprotonation
of the alcohol oxygen. Sharp bands attributable to n(C55O) and n(NH2) motions
maybe described as the asymmetric (1660–1610 cm21) N–H stretches,
suggesting coordination with the NH group of the ligands (Fig. 3).[19,20]
We observed that the presence of coordinated water in the infrared spectra
of Co(L1)2(H2O)2, Co(L2)2(H2O)2, and Co(L3)2(H2O)2 is indicated by broad
bands at 3463, 3458, and 3450 cm21, respectively[21] (Fig. 4).
The bands for all complexes between 530 and 439 cm21 are assigned to
vibrations that are probably coupled M–N and M–O modes, in accordance
with literature data.[17,19,21]
Electronic Absorption Spectra
The wave lengths of the absorption maxima, as well as the corres-
ponding molar absorptivities (1), are given in Table 3. The electronic
Figure 4. Suggested structure of the mononuclear complexes [Co(L)2(H2O)2] (R is
defined as in Fig. 2).

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Metal Complexes of Antihypertension Drugs
1269
Table 3. Electronic spectra and magnetic moments of all complexes in DMSO.
Complex
lmax (1, M21 cm21
)
m
eff (B.M.)a
[Cu(HL1)4]Cl2
750b (176), 521 (1.6 ꢀ 103),
330 (1.2 ꢀ 103)
1.89
[Cu2(L1)2Cl2]
[Co(L1)2(H2O)2]
709 (189), 372b (1.1 ꢀ 103)
680b (162), 633 (148), 613 (141),
364 (1.2 ꢀ 103)
1.80
4.17
[Cu(HL2)4](OAc)2
[Cu2(L2)2(OAc)2]
[Co(L2)2(H2O)2]
694 (358), 527 (495), 302 (2.6 ꢀ 103)
707 (129), 385 (3.6 ꢀ 103)
741b (174), 630 (167), 610 (144),
270 (2.5 ꢀ 103)
1.90
1.85
4.11
[Cu(HL3)4](OAc)2
[Cu2(L3)2(OAc)2]
[Co(L3)2(H2O)2]
711 (184), 521 (389), 290 (3.7 ꢀ 103)
703 (191), 547 (481), 392 (1.7 ꢀ 103)
682 (166), 648 (171), 613 (154),
394 (1.6 ꢀ 103)
1.93
1.81
4.23
aMagnetic moment per metal atom.
bShoulder.
spectra of the complexes were taken in DMSO in order to obviate the
effect of the solvent. The spectra of all complexes contain some absorption
bands in the 750–521 nm range (relatively weak, low-energy bands),
which maybe assigned to the d–d transitions in a distorted octahedral or
tetrahedral configuration. These data are in accord with the assumption
for the formation of M–N and M–O bonds.[16,23–25] The electronic spec-
tra of all complexes, except the binuclear Cu(II) complexes, contain bands
with higher molar absorptivity in the 364–290 nm range, and these bands are
assigned to primarily ligand-centered transitions. The bands at higher energies
are associated with benzene p–pꢁ transitions. The more intense bands at
392–372 nm in the binuclear Cu(II) complexes maybe due to the coincidence
of charge transfer d–pꢁ, L ! M or M ! L, and intraligand n–pꢁ tran-
sitions.[26–28] In addition, the presence of Cu–O bands were indicated also
by the second, higher-energy band, typical for ligand to metal charge transfer
in polynuclear Cu(II) complexes with oxygen bridges.[29,30]
In order to study the stoichiometry of the colored products, the molar ratio
between metal ions and each drug was determined using the continuous vari-
ation method.[31,32] Unfortunately, the method could be applied only to the
1
2
four complexes ([Co(L1)2 (H2O)2], [Cu2(L )2Cl2], [Cu2(L )2(OAc)2], and
[Co(L3)2(H2O)2]) because they have a specific wave length in the UV-Vis
region. It was found that the ratios between copper and the drugs or cobalt
and the drugs are 1 : 1 or 1 : 2, respectively.[33–35] Application of Job’s method
.

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Golcu, Yucesoy, and Serin
1270
of continuous variation indicates a molar ratio of donor to acceptor of 1 : 1 for
HL2, HL3 and 1 : 2 for HL1, HL3, with respect to the drug salt.
Atomic Absorption Spectra
The ratios of the metal present in all complexes were determined by
atomic absorption spectroscopy. The complexes were decomposed in
HNO3/H2O2 (1/1) and then dissolved in 1.5 N HNO3. The amounts of Cu
and Co were determined (Table 1). They support the structures given in
Figs. 2–4.[36–38]
Magnetic Measurements
The magnetic moments (B.M.) of the complexes were measured at room
temperature and support the structures for the mononuclear and binuclear
complexes[39] (Table 3). The magnetic moment of the mononuclear Cu(II)
complexes, ([Cu(HL1)4]Cl2, [Cu(HL2)4](OAc)2, and [Cu(HL3)4](OAc)2) and
binuclear Cu(II) complexes ([Cu2(L1)2Cl2], [Cu2(L2)2(OAc)2], and [Cu2
(L3)2(OAc)2]), are rather lower (1.80–1.93) than those of the octahedral
mononuclear Co(II) complexes ([Co(L1)2(H2O)2], [Co(L2)2(H2O)2], and
[Co(L3)2(H2O)2]). The magnetic susceptibility of these complexes obey the
Curie–Weiss law, indicating an antiferromagnetic interaction between the
pair of copper ions. The magnetic moments of the mononuclear Cu(II) com-
plexes lie in the 1.89–1.93 B.M. range. Due to steric interactions of the larger
size of the ligands, the lower coordination number six has been assigned to
these complexes.[40] The mononuclear Cu(II) complexes may have the usual
octahedral structure. In these complexes, two ligands act as bidentates (OH,
NH) neutral ligand. The other two ligands act as monodentate. These ligands
are coordinate as neutral molecules. The magnetic moments of the binuclear
Cu(II) complexes (1.80–1.85 B.M.) lie in the range expected for the
copper(II) chelates. These values suggest that the copper atom is in a tetra-
hedral environment. The cobalt complexes have an effective magnetic
moment of 4.11–4.23 B.M. per cobalt atom at room temperature and these
complexes are octahedral around the cobalt(II) ion.[41]
Thermal Studies
Thermal analyses of the prepared complexes were made in air in
the temperature range of 70–750 8C to establish their compositional

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Metal Complexes of Antihypertension Drugs
Table 4. Thermal degradation of the complexes.
1271
Loss of
Loss of
ligands mass
found
coordinated
water found
(calcd.) (%)
T
T
Final
product
Complex
(8C)
(calcd.) (%)
(8C)
[Cu(HL1)4]Cl2
—
—
—
87.0 (87.3)
91.0 (90.5)
86.0 (86.1)
89.5 (90.0)
87.0 (87.6)
88.0 (87.9)
87.6 (87.5)
84.6 (84.8)
91.0 (89.7)
193.8
199.5
257.0
201.7
193.8
257.3
207.1
210.3
268.0
CuO
CuO
CoO
CuO
CuO
CoO
CuO
CuO
CoO
[Cu2(L1)2Cl2]
—
4.60 (4.70)
—
[Co(L1)2(H2O)2]
[Cu(HL2)4](OAc)2
[Cu2(L2)2(OAc)2]
[Co(L2)2(H2O)2]
[Cu(HL3)4](OAc)2
[Cu2(L3)2(OAc)2]
[Co(L3)2(H2O)2]
161
—
—
—
5.40 (5.48)
—
—
145
—
—
149
5.80 (5.89)
differences as well as to ascertain the nature of associated water.[20] The
hydrated drug complexes of Co(II) are stable up to 144–160 8C. Above
this temperatures, the cobalt complexes dissociated two molecules of coor-
dinated water, as demonstrated by the TG curve and the DTA endothermal
effect.[13] The thermogravimetric measurements for the cobalt complexes
have shown a reduction of the sample weights by about 5.80–5.40% in
the same temperature range. The thermal decomposition of the anhydrous
Co(II) complexes starts in the 220–370 8C range and is completed at
550–750 8C. The final decomposition products are metal oxides. In
addition, the amount of mass loss observed at ꢀ125–370 8C in the TG
curves of the mononuclear and binuclear Cu(II) complexes show that
these complexes do not have any molecules of water coordinated to the
metal ion. The DTA curve of the Cu(II) complexes of the ligands HL1,
HL2, and HL3 exhibit an exothermic peak at ꢀ350 8C associated with
the thermal dissociation of halogen or acetate, respectively.[17,19] All
Cu(II) complexes undergo complete decomposition to the metal oxide as
residue (see Table 4).
The TG curves of all complexes show that the thermal decomposition of
the compounds occur in several steps. It is possible to suggest that the different
groups in the ligands and complexes effect the stability of the complexes.
Furthermore, it is known that the electronegativity and atomic radius of the
central metal ion also effect the thermal stability.
As a result of the dehydration and decomposition, the observed
weight losses for all complexes are in good-agreement with the calculated
values.

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Golcu, Yucesoy, and Serin
ACKNOWLEDGMENTS
The authors gratefully acknowledge the funding of this work by the
˙
Research Fund (Project No: 2001/2-1) of Kahramanmaras¸ Su¨tc¸u¨ Imam
University, Kahramanmaras¸, Turkey. They also greatly thank Prof. Dr. Nevzat
Ku¨lcu¨ and his assistants (University of Mersin, Faculty of Science and Arts,
Department of Chemistry, Mersin, Turkey) for DTA-TG analyses.
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3. Lo, M.; Riegelman, S. Determination of propranolol and its major meta-
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Received February 7, 2002
Accepted March 23, 2004
Referee I: D. A. Krogstad
Referee II: S. L. Phillips

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