1. health and fitness
2. disease
3. diabetes

Synthesis, Spectroscopic, X-ray diffraction, Thermal Characterization and
Biological Potential Study of Fe(II) and Co(II) Complexes of Pioglitazone: A
New Oral Antidiabetic Drug
Om Prakash*a and Bal Krishana
a
Department of Chemistry, Saifia Science College, Barkatullah University, Bhopal-462001
(India)
E- mail: [email protected]
Abstract
Metal complexes of pioglitazone hydrochloride (PLZ) drug are synthesized and characterized
using analytical data, molar conductance, IR, 1 H NMR, electronic, mass spectrometry, XRD and
thermal studies. From the analytical data, the complexes are proposed to have general formulae
[(C19 H19 N2 O3 S)+2 Fe(OH2 )2 ]SO4 2- and [(C19 H19 N2 O3 S)+2Co(OH2 )2 ]2Cl-.
The conductometric
titration using monovariation method reveals that complexes are L2 M type. The molar
conductance data indicates that all the metal chelates are ionic. IR spectra show that PLZ is
coordinated to the metal ions in which ligand molecules lie horizontally joining the central Fe(II)
and Co(II) atoms. The electronic spectra and magnetic moment reveal that these chelates have
octahedral geometry. Mass spectra are also used to confirm the proposed formulae and the
possible fragments resulted from fragmentation of PLZ and its Fe(II) and Co(II) complexes.
XRD data also used to calculate the various parameters like particle size, porosity, volume of
unit cell and density.
The thermal decomposition of complexes is studied
using
thermogravimetric (TGA) technique. The kinetic parameters such as Energy of activation (Ea),
enthalpy (ΔH), entropy (ΔS) and free energy change (ΔG) of the complexes are evaluated by
using the Freeman-Carroll and Sharp-Wentworth methods. The ligand (PLZ) and its Fe(II)
complex have been tested on wistar albino rats to assess their hypoglycemic activity.
Keywords : Transition metals, Antidiabetic drug, Spectroscopy, X-ray diffraction, TGA and
hypoglycemic activity.
1.
Introduction
The disease are as old as human race and since then in the early part of civilization man has been
trying to get relief from the various ailments by way of using various available material like plant
part such as fruits, seeds, leaves and roots as well as the various available metal salts. Diabetes is
a chronic disorder of carbohydrate, fat and protein metabolism characterized by increased fasting
and post prandial blood sugar levels. Researchers throughout the United States and the world are
working to better understand, prevent and treat this disease. Diabetes is an important human
illness afflicting many from various walks of life in different countries. The prevalence and
incidence of diabetes is increasing in most populations, being more prominent in de veloping
countries as follows, in USA more than 16 million, in Republic of China more than 14 million, in
Africa more than 20 million. India leads the world largest number diabetic subjects and is being
termed the “diabetes capital of the world” with 40.9 million people currently suffering from
diabetes and expected to rise 69.9 million by 2025 [1]. WHO has predicted that the major burden
will occur in developing countries. Diabetes mellitus is a complex metabolic disorder resulting
from either insulin deficiency or insulin dysfunction. Currently, the most commonly prescribed
medications for diabetes are metformin, second generation sulfonylureas like Gliclazide,
Glimeperide, Glibenclamide, Glipizide and thiazolidinediones which include pioglitazone and
rosiglitazone. Pioglitazone hydrochloride is an oral antidiabetic agent that has been shown to
affect abnormal glucose and lipid metabolism associated with insulin resistance by enhancing
insulin action on peripheral tissues in animals [2]. It is a white or almost white crystalline,
odourless powder, practically tasteless, insoluble in water and alcohols, but soluble in 0.1N
NaOH; it is freely soluble in dimethylformamide (DMF). Structure of pio glitazone hydrochloride
is given in Fig. 1. It exhibits slow gastrointestinal absorption rate and inter individual variation of
its bioavailability [3].
A survey of literature reveals that metal complexes of many drugs have been found to be more
effective than the drug alone [4] therefore, much attention is given to the use of thiazolidinedione
hydrochloride due to their high complexing nature with essential metals [5]. Recently, metals in
medicine have been recognized internationally as an important area for research. Transition
metal complexes are cationic, neutral or anionic species in which a transition metal is
coordinated by ligands [6]. Researches have shown significant progress in utilization of
transition metal complexes as drugs to treat numerous human diseases. Transition metals exhibit
different oxidation states and can interact with a number of negatively charged molecules. This
activity of transition metals has started the development of metal based drugs with promising
pharmacological application and may offer unique therapeutic opportunities [7]. The advances in
inorganic chemistry provide better opportunities to use metal complexes as therapeutic agents
[8]. The uses of transition metal complexes as therapeutic compounds have become more and
more prominent. These complexes offer a great diversity in their action [9]. Metal ions are
required for many critical functions in humans. Scarcity of some metal ions can lead to disease.
The role of iron in the human body is closely associated with haemo globin and the transport of
oxygen from the lungs to the tissue cell. Iron is an essential nutrient to cells for the functioning
of many biochemical processes, including electron transfer reactions, gene regulation, binding
and transport of oxygen and regulation of cell growth and differentiation. This homeostasis
involves the regulation of iron entry into the body [10]. Also cobalt is an essential element for all
animals, as the active centre of co-enzyme called cobalmines. These include vitamin B12 which is
vital to the formation of red blood cells essential for mammals.
Gupta et. al. [11] have reported a cobalt complex with quinoline, chinchoine etc. and it is
observed to be a powerful antimalarial up to some extent. For their biological importance Iqbal
et. al. [12] have synthesized and studied iron and cobalt complexes with many oral antidiabetic
agent [13-14]. Synthesis, spectral characterization, magnetic moment, mass, X-Ray diffraction,
and Kinetic studies of Cr(III) complex with metformin have been reported by Krishan et. al.
[15].
In this work we have prepared the chelates of Fe(II) and Co(II) with pioglitazone drug. The solid
chelates are characterized using different physico-chemical methods like elemental analyses (C,
H, N, S and metal content), IR,
1
H NMR, electronic spectra, magnetic moment, mass
spectrometry, X-ray diffraction and thermal analyses (TGA).
2.
Experime ntal
2.1
Ligand- Metal ratio
(a). To find out the ligand metal ratio, initially conductometric titration using monovariation
method are carried out at 27±1 ºC and 0.005 M solution of pioglitazone hydrochloride is
prepared in DMF. Similarly, solution of ferrous sulphate (FeSO 4 ) and cobalt chloride (CoCl2 ) are
prepared in the ethanol of 0.01M concentration. 20 ml of ligand is diluted to 200 ml with the
same solvent. The ligand is titrated conductometrically against metal salt solution taken in
burette using fraction of 1ml. Conductance was recorded after each addition with proper stirring.
Results were plotted in the form of graph between corrected conductance and volume of metal
salt added. From the equivalence point in the graph, ratio between ligand and metal are noted to
be 2:1 (L2 M).
(b). Formation of these complexes in 2:1 (L2 : M) ratio are also confirmed by Job’s method [16]
of continuous variation as modified by Turner and Anderson [17] Fig. 2(a)-(b) and Fig. 3(a)-(b)
(Table 1 to Table 4) using conductance as index property, from these values the stability constant
(log k) and free energy change (F), were also calculated by using formula [18-21];
.
2.2
Material and Method
All chemicals are used of analytical grade (A. R.). They include pure pioglitazone hydrochloride
with molecular formula (C 19 H20N 2O3 S.HCl), received from Morepen Laboratories, Distt. Solan
(H. P.) India. The metal salt of FeSO 4 and CoCl2 obtained from Hi media Laboratory, Mumbai,
India. Ethanol and DMF were used as a solvent.
2.3
Synthesis of Complexes
A weighed quantity of “Pioglitazone” (2 mole) is dissolved separately in minimum quantity of
DMF. The iron and cobalt solution are prepared by dissolving separately in the ethanol. Ligand
solution is added slowly with stirring into the solution of metallic salt at room temperature;
maintain the pH between 6.0 to 6.5 by adding dilute NaOH solution. On refluxing the mixture
for 3-4 h and on cooling, the precipitates of metal complexes are obtained, which are filtered off,
washed well with DMF and ethanol finally dried in vacuum and weighed.
2.4
Instrumentation
Molar conductances of complexes are measured by using Systronics Digital Conductivity meter.
Melting point was determined by Perkin Elmer Model melting point apparatus and is
uncorrected. The elemental analysis of the isolated complexes is carried out by using Coleman
Analyzer Model at the Departmental Micro Analytical Laboratory, CDRI, Lucknow, India. IR
spectra of ligand and complexes are recorded with Perkin Elmer Model 577 Spectrophotometer
in the range of 4000-450 cm-1 as KBr pellets CDRI, Lucknow, India. The electronic spectra of
the ligand and complexes are recorded with Perkin Elmer UV Winlab in the range of 200-800 nm
Punjab University, Chandigarh, India. The magnetic susceptibility measurement is carried out on
a vibration sample magnetometer (VSM) at the Indian Institute of Technology, Roorkee (India).
1
H NMR spectra of the ligand and isolated complexes are recorded on a Bruker DRX-300
Spectrophotometer and DMSO- d6 is used as solvent CDRI, Lucknow, India. The ESI-MS Mass
Spectra for pioglitazone- iron and cobalt complexes are performed on Waters UPLC-TQD Mass
Spectrometer. The given samples are subjected as such in front of DART source. Dry Helium
was used with 4LPM flow rate for ionization at 350 o C. The orifice1set at 28 V and spectra are
collected and print outs as averaged spectra of 6-8 scan at CDRI, Lucknow, India which provides
information about the complexes by examining the fragmentation pattern and total mass of the
complexes.
X–ray diffraction studies are carried out by X–ray Diffractometer model with 45kV rotating
anode and Cukα (1W=1.54060A°) radiation at Punjab University, Chandigarh, India. The
samples are scanned in the range 10.000 to 79. 9784 (2θ) powder data were indexes using
computer software (FPSUIT V2.0).
The thermogravimetric analysis (TGA) are carried out in dynamic nitrogen atmosphere (20
ml.min-1 ) with a heating rate of 10°Cmin-1 using shimatzu TGA-50H Thermal Analyzer at IIT
Bombay, India.
3.
Results and discussion
The formation of metal complexes with organic compounds has long been recognized. The
synthesized complexes are coloured and stable, being soluble in DMSO and insoluble in water,
ethanol etc. Analytical data and conductometric studies suggest 2:1 (L2 : M) ratio. Structures for
the complexes are shown in Fig. 4 (a, b).
3.1
Composition of metal complexes
The isolated solid complexes of Fe and Co metal ions with the PLZ ligand is subjected to
elemental analyses (C, H, N, S and metal content) and molar conductance. The results of
physical and analytical data are given in Table 5
3.2
Infra-red Spectral Studies
The IR spectra of ligand and isolated complexes are recorded within the range 4000-400 cm-1 . In
order to determine the coordination sites that may be involved in chelation, we compared the IR
spectra of the PLZ with their complexes as shown in Fig. 5(a, b, c). The tautomeric equilibrium
depends on the degree of conjugation, nature and position o f the substituent, polarity of the
solvent etc. This phenomenon has drawn considerable attention by several investigators and
characteristic spectral bands have been assigned to the individual tautomers.
The stretching vibration band in ligand at 3341 cm-1 can be ascribed to N-H group but in the
complexes this group is found at 3321 cm-1 and 3311 cm-1 respectively. The C=N stretching
frequency of the ligand (PLZ) appears at 1675cm-1 while in iron and cobalt complexes this
frequency is shifted at 1634 cm-1 and 1640 cm-1 . The shift of C=N group by changing frequency
in these complexes indicate that they are involved in the complexation. The IR band at 3691 cm-1
and 3634 cm-1 ν(H2 O) of coordinated water is an indication of binding of the water molecules to
the metal ions. New bands are found in the spectra of complexes in the region 507 cm-1 and 510
cm-1 which are assigned to M-O stretching vibrations. The proposed structure for the isolated
complexes is also supported by IR absorptions [22-25].
3.3
Electronic spectral and magnetic moment studies
Three bands in the regions of 11315 ± 20, 21420 ± 20 and 27710 ± 20 cm-1 are observed in the
electronic spectra of Fe(II) complex. These bands have been assigned to 6 A1 g→ 4 T1 g, 6 A1 g→
4
T2 g and 6 A1 g→ 4 Eg transitions respectively and suggested an octahedral geometry for the
complex [26]. The magnetic moment of Fe(II) complex is 5.92 B.M. which agree well with the
octahedral geometry of the iron complex [27]. In Co(II) complex two bands are observed at
11245 and 26490 cm-1 which are attributed to transitions
4
T1 g→
4
A2 g and
4
T2 g→
4
T1 g
respectively while another band at 29115 cm-1 region is seen which could be attributed to charge
transfer transition. These bands are consistent with the octahedral geometry of the complex [28].
The magnetic moment of Co(II) complex is 4.72 B.M. agree with the octahedral geometry of the
cobalt complex [29].
3.4
1
H NMR Studies
This technique gives information about the number and types of atoms in molecule and also gave
useful information regarding the environment of protons present in the complex. Fig. 6(a, b, c)
shows the NMR spectra for PLZ and its complexes.
Assignment
of
“Pioglitazone”-iron
complex,
molecular
formula
[(C 19 H19N 2O3 S)+2
Fe(OH2 )2 ]SO 42- (M. Wt.= 973.64), δ8.70 (s,1H,2-pyridine), δ8.39-8.40 (d,1H, 2-pyridine), δ7.947.96(d,1H, 2-pyridine), δ7.12-7.16(d,2H, 2-CH2 -Benzene), δ6.87-6.88(d, 2H, 2-CH2 -Benzene)
δ4.84-4.87(m,1H methine-CH), δ4.34-4.41(t, 2H methylene-CH2 ), δ3.46-3.93(t, 2H methyleneCH2 ), δ3.01-3.39(d, 2H methylene-CH2 ), δ2.50-2.80(s, Residual solvent DMSO-d6 ), δ1.25(t,3H
methyl-CH3 ) respectively.
Assignment of “Pioglitazone”- cobalt complex,
molecular
formula [(C 19 H19N 2O3 S)+2
Co(OH2 )2 ]2Cl- (M.Wt.= 951.73), δ8.71 (s,1H, 2-pyridine), δ8.37-8.41 (d,1H, 2-pyridine), δ7.957.97(d1H, 2-pyridine), δ7.10-7.15(d,2H, 2-CH2-Benzene), δ6.85-6.86(d, 2H, 2-CH2-Benzene)
δ4.84-4.87(m,1H methine-CH), δ4.36-4.41(t, 2H methylene-CH2 ), δ3.42-3.91(t, 2H methyleneCH2 ), δ3.00-3.37(d, 2H methylene-CH2 ), δ2.48-2.78(s, Residual solvent DMSO-d6 ), δ1.231.25(t,3H methyl-CH3 ) respectively. The structure for the complexes is also supported by various
authors [30-33].
3.5
Mass Spectral studies
Mass spectra represent the intensities of signals at various m/z values. It is highly characteristic
of the compound that no two compounds can have similar mass spectra. It provides information
regarding the molecular structure of organic and inorganic co mpounds. Mass spectrum of PLZ
and its Fe and Co complexes are presented in Fig.7(a, b, c).
Assignment of iron complex, molecular formula i.e. [(C 19 H19N2O3 S)+2 Fe(OH2 )2 ]SO42--,
(Mol.Wt.= 973.64), m/z 977.24 due to [(C 19 H19 N2 O3 S)+2 Fe(OH2 )2 ]SO 42- or (ML2 ∙)+. Molecular
ion peak (m+.); m/z 355.05 due to [C19 H20 N2 O3 S)]+ . base peak ion 100% relative abundance, m/z
224.01 due to [C 10 H9 NO3S]+. m/z 137.51 due to [C9 H12 N]+., m/z 120.14 due to [C 8 H10 N]+.
radical ion respectively.
Assignment of cobalt complex, molecular formula i.e. [(C 19 H19 N2 O3 S)+2 Co(OH2 )2 ]2Cl-, M.
Wt.= 951.73), m/z 950.35 due to [(C 19 H19 N2 O3 S)+2 Co(OH2 )2 ]2Cl- or (ML2 ∙)+. Molecular ion
peak (m+.); m/z 357.15 due to [C 19 H20 N2 O3 S)]+ . base peak ion 100% relative abundance, m/z
221.64 due to [C 10 H7 NO3S]+. m/z 133.52 due to [C 9 H12 N]+., m/z 121.18 due to [C 8 H10 N]+.
radical ion respectively.
3.6
X-Ray diffraction studies
The crystallographic data (scattering angles, d-spacing, and relative intensities) for PLZ with Fe
and Co are listed in Table 6 and Table 7 by using computer software (FPSUIT 2.0V). The X-ray
diffraction pattern for Fe and Co complexes is shown in Fig. 8(a, b). It can be seen from the
figures that the main characteristic scattering peaks for PLZ-Fe are at 11°, 19° and 34° while for
PLZ- Co these peaks are found to be at 0.5°, 19° and 22° positions.
From the crystallographic data, unit cell parameters are obtained for Fe(II) and Co(II) complexes
which attributed to monoclinic crystal system. The particle size of pioglitazone- iron and cobalt
complexes are 20.61 and 16.84 microns respectively, which is calculated from X-ray line
broadening using the Scherrer formula; t 

 cos
where t is the thickness of the sample, κ is a
coefficient and is equal to 0.89 here, β is the half- maximum line width, and λ is the wavelength
of X-rays. The porosity is 0.374% and 0.022% calculated by formula;
and
volume of the unit cell is 14074.31 and 14180.15 A° which is calculated by Volume (Å) = abc
where a, b and c are lattice parameters. Density =
is found 0.0623 g/cm3 and 0.0432 g/cm3
respectively. Space group for Fe(II) and Co(II) complexes are Pmmm and α = 90°, β = 90°, γ =
89.91°.
3.7
Thermal analyses (TGA) studies
Thermal analyses technique (TGA) is useful in both quantitative and qualitative analyses.
Samples can be identified and characterized by investigating their thermal behavior. TGA
measures weight changes. TGA curve study for the Fe(II) and Co(II) complexes is carried out
within the temperature range of 50-600°C Fig. 9(a, b). The dehydration step in Fe(II) complex is
found in the temperature range 150-170°C (Calcd Wt. loss: 3.69%, found, 3.72%) is
accompanied by the loss of water molecule. In case of Co(II) complex the dehydration takes
place in the temperature range 150-200°C(Calcd Wt. loss: 3.78%, found, 3.74) is also due to loss
of water molecule. The percent mass loss within the temperature range 200-510°C is 18.71 and
30.13 might be due to organic moiety in both the complexes. The organic part together with the
anions (Cl and SO 4 ) in the moiety of complexes may decompose in more than two steps with the
possibility of the formation of more than one intermediate which get decomposed to stable metal
oxides or chlorides over the temperature 500°C.
3.8
Kinetics studies
The Freeman-Carroll [34] and Sharp-Wentworth [35] methods have been employed for the
calculation of kinetic parameters of the newly synthesized complexes with help of dynamic TG
curve.
Freeman-Carroll method
In this method, activation energy and order of degradation are related to following equation as;
=
Where,
(1)
= rate of change of weight with time and Wr = Wc-W, Wc = Wt. loss at completion of
reaction, W = Total wt. loss up to time‘t’, Ea = Energy of activation, n = Order of reaction. The
plot of the term
Vs
is a straight line with a slope of (- Ea/2.303R) Fig. 10(a, b).
Energy of activation (Ea) is determined from the slope and order of reaction (n) obtained with
the help of intercept.
Sharp-Wentworth method
In this method Ea can be evaluated by the following expression;
=
Where,
Rate
(2)
= Rate of change of fraction of weight with change in temperature, β = Linear heating
. Fig.11(a, b) show a plot of the left-hand side of Eq. (2) against 1/T gives a slope from
which Ea was calculated. The entropy of activation (ΔS), enthalpy of activation (ΔH) and the free
energy change of activation (ΔG) were calculated using the following equations;
ΔS=
ΔH= Ea - RT
ΔG= ΔH - TΔS
The calculated values of kinetic parameters such as energy of activation (Ea), enthalpy (ΔH),
entropy (ΔS) and free energy change (ΔG) are given in Table 8. According to the kinetic data,
Fe(II) and Co(II) complexes have negative values of entropy, which indicate that complexes
have more ordered systems [36]. The values of ΔG is found to be positive for these complexes
which reveals that the free energy of the final residue is higher than that of the initial compound,
and all the decomposition steps are non-spontaneous processes. The positive value of ΔH means
that the decomposition processes are endothermic.
3.9
Hypoglycemic Study
We have tested the biological activity of PLZ drug and its Fe(II) complex by analyzing the
hypoglycemic activity on wistar albino rats by using Alloxan Induced Model. The anti-diabetic
activity is carried out on wistar albino rats of 4 months, of both sexes, weighing between 130 to
180 gm. They are provided from Sapience Bio-analytical Research Lab, Bhopal, (M. P.) India.
The animals are acclimatized to the standard laboratory conditions in cross ventilated animal
house at temperature 25±2°C relative humidity 44 –56% and light and dark cycles of 12:12
hours, fed with standard pallet diet and water ad libitum during experiment. The experiment is
approved by the Institutional Ethics Committee and as per CPCSEA guidelines (approval no.
1413/PO/a/11/CPCSEA).
The diabetes is induced by a single intraperitoenal injection of a freshly prepared solution of
Alloxan monohydrate (120 mg/kg b.w.) [37, 38]. Blood samples are collected after 5 days. Rats
with moderate diabetes having hyperglycemia (with blood glucose above 300 mg/dl) are taken
for the experiment.
Experimental Design
In the experiment, a total of 18 rats are used. The rats are divided into 3 groups, comprising of 6
animals in each group as follows;
Group A: Rats served as diabetic control.
Group B: Rats received Pioglitazone (PLZ) (10mg/kg, p.o.).
Group C: Rats received Pioglitazone- iron (PLZ- Fe) complex (10mg/kg, p.o.).
Blood samples are collected through tail vein and blood glucose levels were estimated using an
electronic glucometer (Gluco chek) and results are given in Table 9. An inspection of Table 5
shows that PLZ drug caused a marked decrease in blood sugar level to the extent while thier
Fe(II) complex reduces the blood sugar level than the parent drug pioglitazone. These facts
clearly indicate a better hypoglycemic activity of complex as compared to its parent drug which
is in agreement with the earlier findings of Iqbal and Co-workers [39, 40].
Conclusion
In the present paper, we have synthesized the complexes of pioglitazone drug with Fe(II) and
Co(II) metals. The structure of the complexes is confirmed by the spectroscopic techniques,
XRD and thermal analysis. Analytical data agrees with the molecular formulae of the complexes.
Molar conductance value supports the ionic nature of the complexes. IR and Mass spectra reveal
the presence of co-ordinated water molecules and symmetry of the complexes appears to be
octahedral. The tentative structures assigned to the complexes on the basis of analytical data
were further supported by modern spectroscopic methods like IR, 1 H NMR and Mass spectral
studies. In mass spectra of iron and cobalt complexes the base peak of the ligand appear on m/z
355.05 and 357.15 while short peak for Fe and Co complexes appear on m/z 974.24 and m/z
950.35 which is quite supportive. A detailed study of X-ray also supports the complex formation
and various parameters such as particle size, porosity, volume of unit cell and density of
synthesized complexes are evaluated. Kinetic parameters (Ea , ΔH, ΔS and ΔG) are also evaluated
by applying the Freeman-Carroll and Sharp –Wentworth methods. We have also carried out
hypoglycemic activity of drug with its Fe(II) complex on wistar albino rats and found that
complex reduced the blood sugar level more than the parent drug.
Acknowledge ment
The authors are thankful to the UGC New Delhi for financial assistance. Authors are also
thankful to CDRI Lucknow, P.U. Chandigarh and IIT Bombay for providing IR, NMR, Mass, XRay and TGA data.
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Figure captions:
Fig. 1
Structure of Pioglitazone hydrochloride ((±) ‐5‐{p‐[2‐(5‐ethyl‐2‐pyridyl)ethoxy]
benzyl}‐2, 4 ‐thiazolidinedione hydrochloride).
Fig. 2(a)-(b): Job’s curve and modified Job’s curve for PLZ – Fe complex.
Fig. 3(a)-(b): Job’s curve and modified Job’s curve for PLZ – Co complex.
Fig. 4(a)-(b): Structures of PLZ-Fe and PLZ-Co complexes.
Fig. 5(a)-(c): IR spectra of pioglitazone and its Fe and Co Complexes.
Fig. 6(a)-(c): NMR spectra of pioglitazone and its Fe and Co Complexes.
Fig. 7(a)-(c): Mass spectrum of pioglitazone and its Fe and Co Complexes.
Fig. 8(a)-(b): X-ray diffractogram of PLZ-Fe and PLZ-Co complexes.
Fig. 9(a)-(b): TGA curve of PLZ-Fe and PLZ-Co complexes.
Fig. 10(a)-(b): FC kinetic plot of PLZ-Fe and PLZ-Co complexes.
Fig. 11(a)-(b): SW kinetic plot of PLZ-Fe and PLZ-Co complexes.
Fig. 1
Fig. 2(a, b)
Fig. 3(a, b)
Fig. 4(a, b)
Fig. 5(a, b, c)
Fig. 6(a, b, c)
Fig. 7(a, b, c)
Fig. 8(a, b)
Fig. 9(a, b)
(b)
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
-0.0016 -0.0014 -0.0012 -0.0010 -0.0008 -0.0006 -0.0004 -0.0002
1/T
LogWr
Fig. 10(a, b)
Log(dw/dt)
LogWr
-2.8
(a)
-3.0
-3.2
-3.4
log(dc/dt)
1-c
-3.6
-3.8
-4.0
-4.2
-4.4
-4.6
-4.8
-5.0
1.2
1.4
1.6
1.8
2.0
2.2
2.4
2.6
2.8
3.0
3.2
3.4
1000
T
(b)
-2.6
-2.8
-3.0
log(dc/dt)
1-c
-3.2
-3.4
-3.6
-3.8
-4.0
-4.2
1.2
1.4
1.6
1.8
2.0
2.2
2.4
1000
T
Fig. 11(a, b)
2.6
2.8
3.0
3.2
3.4
Table 1 Job’s method of continuous variation.
PIOGLITAZONE WITH FERROUS SULPHATE
(Job’s Method)
Pioglitazone - 0.005M
FeSO 4.7H2 O - 0.005M
Solvent: 90 % Ethanol
Temperature - 27ºC
-3
Metal:Ligand
Conductance ×10 Mhos
Δ Conductance Corrected Δ
Ratio
×10-3 Mhos
Conductance
S:L
M:S
M:L
(C
+
C
C
)
×10-3 Mhos
C1
C2
C3
1
2
3
0:12
0.130
0.021
0.131
0.02
0
1:11
0.121
0.211
0.300
0.031
0.012
2:10
0.111
0.436
0491
0.055
0.035
3:9
0.102
0.654
0.685
0.071
0.049
4:8
0.092
0.888
0.899
0.081
0.058
5:7
0.078
1.075
1.083
0.070
0.047
6:6
0.063
1.270
1.269
0.064
0.04
7:5
0.054
1.425
1.422
0.057
0.031
8:4
0.045
1.602
1.596
0.051
0.026
9:3
0.036
1.863
1.854
0.045
0.02
10:2
0.024
1.983
1.969
0.038
0.014
11:1
0.017
2.014
1.998
0.033
0.007
12:0
0.006
2.021
2.000
0.027
0
Table 2 Job’s method of continuous variation modified by Turner and Anderson.
PIOGLITAZONE WITH FERROUS SULPHATE
(Modified Job’s Method)
Pioglitazone - 0.002M
FeSO 4.7H2 O - 0.002M
Solvent: 90 % Ethanol
Temperature - 27ºC
Metal:Ligand
Conductance ×10-3 Mhos
Δ Conductance Corrected Δ
Ratio
×10-3 Mhos
Conductance
S:L
M:S
M:L
C1
C2
C3
(C1 + C2 - C3 )
×10-3 Mhos
0:12
0.118
0.011
0.120
0.009
0
1:11
0.107
0.069
0.156
0.02
0.009
2:10
0.096
0.135
0.193
0.038
0.026
3:9
0.089
0.189
0.227
0.051
0.04
4:8
0.073
0.263
0.276
0.060
0.046
5:7
0.068
0.301
0.319
0.050
0.039
6:6
0.062
0.510
0.527
0.045
0.032
7:5
0.055
0.571
0.586
0.04
0.027
8:4
0.048
0.669
0.683
0.034
0.02
9:3
0.037
0.716
0.725
0.028
0.015
10:2
0.029
0.775
0.781
0.023
0.01
11:1
0.017
0.855
0.854
0.018
0.004
12:0
0.004
0.919
0.909
0.014
0
Table 3 Job’s method of continuous variation.
PIOGLITAZONE WITH COBALT CHLORIDE
(Job’s Method)
Pioglitazone - 0.005M
CoCl2 .6H2 O - 0.005M
Solvent: 90 % Ethanol
Temperature – 27°C
Metal:Ligand
Conductance ×10-3 Mhos Δ Conductance
Corrected Δ
-3
Ratio
S:L
M:S
M:L
×10 Mhos
Conductance
(C1 + C2 - C3 )
×10-3 Mhos
C1
C2
C3
0:12
0.131
0.007
0.130
0.008
0
1:11
0.121
0.049
0.152
0.018
0.01
2:10
0.112
0.074
0.158
0.028
0.02
3:9
0.100
0.100
0.164
0.046
0.037
4:8
0.093
0.138
0.176
0.055
0.045
5:7
0.085
0.147
0.182
0.05
0.041
6:6
0.077
0.156
0.191
0.042
0.032
7:5
0.063
0.175
0.202
0.036
0.027
8:4
0.055
0.187
0.212
0.03
0.02
9:3
0.043
0.204
0.223
0.024
0.016
10:2
0.032
0.219
0.231
0.02
0.011
11:1
0.021
0.236
0.240
0.017
0.007
12:0
0.011
0.248
0.248
0.011
0
Table 4 Job’s method of continuous variation modified by Turner and Anderson.
PIOGLITAZONE WITH COBALT CHLORIDE
(Modified Job’s Method)
Pioglitazone - 0.002M
CoCl2.6H2 O - 0.002M
Solvent: 90 % Ethanol
Temperature - 27ºC
Metal:Ligand
Conductance ×10-3 Mhos
Δ Conductance
Corrected Δ
-3
Ratio
S:L
M:S
M:L
×10 Mhos
Conductance
(C
+
C
C
)
×10-3 Mhos
C1
C2
C3
1
2
3
0:12
0.115
0.004
0.114
0.005
0
1:11
0.099
0.041
0.131
0.009
0.004
2:10
0.091
0.069
0.140
0.02
0.015
3:9
0.084
0.096
0.150
0.03
0.025
4:8
0.075
0.125
0.158
0.042
0.037
5:7
0.066
0.134
0.164
0.036
0.031
6:6
0.059
0.143
0.172
0.03
0.025
7:5
0.048
0.159
0.180
0.027
0.022
8:4
0.040
0.172
0.190
0.022
0.017
9:3
0.032
0.187
0.201
0.018
0.013
10:2
0.025
0.197
0.209
0.013
0.008
11:1
0.015
0.210
0.216
0.009
0.004
12:0
0.007
0.222
0.224
0.005
0
Table 5 Physical and analytical data of PLZ (C19 H20N2O3 S HCl) and its FeSO 4 and CoCl2
complexes.
Ligand /
Co mplex
Color
(Yield
%)
Elemental analysis calculated (found)
C
H
N
S
Metal
H2 O
SO4
Am
(Ω-1 mol-1 cm2 )
Log K
(L/ mole)
ΔF
(Kcal/ mole)
-
-
-
Cl
PLZ
white
58.03
(58.15)
5.09
(5.20)
7.12
(7.04)
8.14
(8.20)
-
-
-
PLZ-Fe
Light
brown
(51)
46.83
(46.72)
3.90
(4.03)
5.75
(5.62)
6.57
(6.46)
5.73
(5.65)
3.69
(3.12)
9.85
9.28
-
41
10.70
-14.74
PLZ-Co
Dark
green
(56)
47.91
(47.76)
3.99
(3.85)
5.88
(5.64)
6.72
(6.58)
6.19
(6.07)
3.78
(3.32)
-
7.46
7.30
44
11.13
-16.08
Table 6 X-ray diffraction data in terms of 2θ, lattice spacing and relative intensities for
pioglitazone –iron complex.
2θ
11.2888
12.8486
16.8848
17.8786
19.2164
22.4884
23.3370
24.4213
25.7956
27.5189
28.2792
28.7938
29.4040
32.0434
32.2955
34.0172
38.8308
48.9973
49.8849
I/I0
100.00
14.11
10.99
9.75
31.88
19.02
18.32
31.64
21.27
16.06
11.67
18.20
16.69
26.30
26.17
36.31
11.23
9.40
4.91
D obs
7.83836
6.89013
5.25106
4.96138
4.61889
3.95371
3.81182
3.64498
3.45382
3.24133
3.25589
3.10065
3.03768
2.79323
2.77200
2.63554
2.31920
1.85915
1.82662
Dcal
7.80903
6.90135
5.23328
4.95986
4.61936
3.95068
3.80644
3.64294
3.45068
3.23769
3.15422
3.09761
3.03725
2.79049
2.77024
2.63469
2.31691
1.85856
1.82663
h
0
0
1
3
0
1
1
2
0
3
1
6
1
0
2
4
6
10
7
k
3
0
4
3
5
4
6
6
0
4
6
3
0
8
8
7
7
5
2
l
0
4
2
2
1
5
1
1
8
6
5
3
9
3
2
4
4
5
12
Table 7 X-ray diffraction data in terms of 2θ, lattice spacing and relative intensities for
pioglitazone –cobalt complex.
2θ
10.5540
I/I0
69.89
D (Obs)
8.38237
D(Cal)
8.46731
h
1
k
0
l
3
16.3437
60.23
5.42369
5.42470
4
0
0
19.0109
99.40
4.66834
4.64949
2
3
4
19.8736
82.38
4.46760
4.46387
3
4
1
20.4293
53.81
4.34731
4.34770
1
4
4
22.0439
100.00
4.03241
4.02100
5
2
1
31.8513
52.99
2.80964
2.80664
7
1
4
39.3397
29.09
2.29037
2.28905
1
4
11
45.6199
37.40
1.98697
1.98754
9
3
7
Table 8 Kinetic parameters using the Freeman-Carroll and Sharp-Wentworth methods for
pioglitazone and their complexes.
Compound
[(C19 H19 N2 O3 S)+2 Fe.2H2O]SO4 2[(C19 H19 N 2O3 S)+2 Co.2H2O]2Cl-
Method
FC
SW
FC
SW
Parameter
Ea
(kJmole -1 )
18.23
16.61
21.72
14.14
ΔS
(JK-1 mole -1 )
-169.42
-208.55
-204.20
-240.73
ΔH
(kJmole -1 )
2.512
2.510
2.515
2.508
ΔG
(kJmole -1 )
61.43
65.07
63.77
72.24
n
0.8
1
0.9
3
Table 9 Hypoglycemic effect of pioglitazone and its Fe complex on alloxan induced diabetic
rats.
Group
Blood Glucose (ml/dl)
0 hrs
1hrs
2 hrs
3 hrs
4 hrs
(A) /control
484
±31.3
562
±20.0
475
±38.0
(-2%)
447
±36.9
(-8%)
436
±18.73
(-9%)
(B) PLZ
533
±22.3
554
±28.3
541
±36.3
(-9%)
460*
412**
±37.3
±29.3
(-16%) (-19%)
(C) PLZ-Fe
560
±18.5
548
±25.4
525
410** 376**
±35.2
±23.1
±27.2
(-14%) (-25%) (-22%)
5 hrs
6 hrs
7hrs
8hrs
452
±20.6
(-6%)
442
±46.7
(-8%)
431
±21.24
(-20%)
413
±18.5
(-1%)
354***
±28.7
(-15%)
372***
±24.5
(-11%)
388***
±32.7
(-7%)
350*** 341***
±18.8
±24.8
(-26%) (-31%)
335**
±32.2
(-29%)
365**
±44.6
(-33%)
385**
±21.3
(-17%)
values are ± SE of 6 rats.
% lowering from zero hour value is indicated within bracket.
*P ˂ 0.05, **P ˂ 0.01, ***P ˂ 0.001