Advanced technologies
1(1) (2012), 07-15
Agneš J. Kapor1, Ljubiša B. Nikolić2, Vesna D. Nikolić2*, Mihajlo Z. Stanković2,
Milorad D.Cakić2, Dušica P. Ilić2, Ivana I. Mladenović-Ranisavljević2, Ivan S. Ristić3
1 Faculty of Sciences, Department of Physics, University of Novi Sad, Novi Sad, Serbia
2 Faculty of Technology, University of Niš, Leskovac, Serbia
3 Faculty of Technology, University of Novi Sad, Serbia
This paper presents a synthesis of iron(II) fumarate based on the conversion of
fumaric acid into disodium fumarate in molar ratio of 1:2 by the neutralization
process. Disodium fumarate, as intermediate, in a nitrogen atmosphere it reacts with iron(II)-sulfate in molar ratio of 1:1. The obtained iron(II) fumarate is a
reddish precipitate with the purity of 98 %. In order to improve the poor solubility of the synthesized iron(II) fumarate, inclusion complexes with β-cyclodextrin
(β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) were prepared by using
a co-precipitation method in molar ratio of 1:1. The characterization of inclusion complexes, iron(II) fumarate and cyclodextrin was done out by using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry
(DSC) and X-Ray Diffraction (XRD) methods. The solubility of iron(II) fumarate
in the pure state and in the complexes was determined by UV/VIS method.
The best solubility was obtained for the 2-hydroxypropyl-β-cyclodextrin: iron(II)
fumarate complex.
UDC 577.164.1
Keywords: antianemic, iron(II) fumarate, inclusion
complexes, β-cyclodextrin, 2-hydroxypropyl-βcyclodextrin, solubility
Many products based on organic and inorganic com- salts and organic acids labeled with the 59Fe isotope sugpounds of iron(II) and iron(III) are used for the treatment gest that the addition of promoters does not lead to imof sideropenic anemia. Depending on the type of anemia provements in products performances but has only a comand its etiology, the treatment is carried out by giving oral mercial effect [7]. Iron compounds which have been used
or parenteral iron preparations. Oral therapy, as more suit- for therapy nowadays can be classified into several groups
able in medical practice, is applied only in terms of good of iron salts, iron chelates, polynuclear iron(III) complexes
iron absorption from the gastrointestinal tract and if no and carbohydrates.
side effects such as nausea, pain or vomiting common for
Iron(II) fumarate is the iron(II) salt of fumaric acid. It is a
oral iron preparations appear [1-3].
fine reddish orange to reddish-brown granular powder, hardly
Iron(II) compounds have better absorption and they soluble in water, with the solubility of 0.14 g/100 cm3 and of
are mainly used in oral therapy [4]. However, and almost very low solubility in alcohol, less than 0.01 g/100 cm3. It
without exception, all oral preparations in use cause more is stable even at temperatures of above 200 oC. A precuror less side effects. The pharmaceutical industry strives sor for the synthesis of iron(II) fumarate is a fumaric acid,
to different formulations of final products (micro-encapsu- trans-1,2-ethylenedicarboxylic acid, the structural formula
lation, the use of plastic matrix, additives, etc..) to reduce of which is given in Figure 1a. The solubility of this acid
side effects, but overall, the currently achieved results in water at room temperature is very small, it is relatively
have not been satisfactory [5, 6]. The presence of addi- nonvolatile, does not yield anhydride and is weaker than a
tives in formulations for improving the iron absorption is cis-isomer maleic acid. The structure of iron(II) fumarate is
being particularly criticized. The tests conducted with iron shown in Figure 1 b.
*Author address: Vesna Nikolić, Faculty of Technology,
16000 Leskovac, Bulevar oslobođenja 124, Serbia
e-mail: [email protected]
The manucsript received: March, 05, 2012.
Paper accepted: Jun, 18, 2012.
1(1) (2012), 07-15
Advanced technologies
The literature offers data on the complexes of Cu(II) with
fumarate anion [8]. In the compound crystal structure the
copper centers are interlocked by fumarate ligands, giving
a novel [Cu(í-C4H2O4)(NH3)2]n(H2O)n infinite chain as shown
in Figure 2.
Figure 1. The structure of a) trans-1,2-ethylenedicarboxylic acid (fumaric acid), b) iron(II) fumarate
Figure 2. ORTEP diagram of [Cu(í-C4H2O4)(NH3)2]n(H2O)n with labeling scheme
showing 50 % probability thermal ellipsoids for all nonhydrogen atoms
Each copper ion is placed in a distorted square pyramidal environment. Two nitrogen atoms of the coordinated
ammonia and two oxygen atoms of two different fumarate
units define the equatorial plane of the pyramid. The axial
position is occupied by an oxygen atom of the third fumarate anion. Thus, each Cu(II) center is linked to three different fumarate anions. The bond lengths in the equatorial
plane are: Cu-N, 1.975(5) Å; Cu-O(1), 1.973(5) Å; Cu-O3,
1.994(5) Å. The axial bond length is 2.458(6) Å [8]. Two
carboxylic groups of the fumarate ligand have two different coordination modes. In the first mode, the carboxylic
group acts as a bridge linked to two Cu(II) ions [8]. For
iron(II) fumarate, the results of magnetic measurements
(magnetic susceptibility) indicate that iron(II) ion within the
studied complex appears in the low spin state with the two
unpaired electrons, pointing towards the coordination polyhedron in the shape of elongated octahedron [9]. Iron(II)
fumarate in the crystalline state mostly builds a macromolecular chain [9]. The results are suggesting that these
structures are different and that the structure of iron(II)
fumarate is more suitable for the presented tests [8] related to the complex of copper(II) fumarate. Complexes of
08 iron(II) ions with other compounds have also been studied.
Thus, complexes of iron (II) with antipyrine and pyridine Noxide were investigated [10].
Preparations based on iron(II) fumarate are now widely
used because of its good properties such as good adsorption affinity in the body and low toxicity. Good adsorption in
the body and minimal side effects are considered to originate from the ligand, fumarate ion, which is an intermediate in the Krebs cycle and is present in living organisms
In most research papers the content of iron in iron(II)
fumarate was examined by Mössbauer spectroscopy [12,
13]. The iron content in dietary supplements was also examined by the same method [14-16].
Cyclodextrins are non-reducing oligosaccharides, cylindrical in shape, resembling a truncated cup. Depending on the number of glucopyranose units linked with α-(1 →
4) bond they can be classified as cyclomaltohexose (six
glucopyranose units, α-cyclodextrin), cyclomaltoheptose
(seven glucopyranose units, β-cyclodextrin) and cyclomaltooctose (eight glucopyranose units, γ-cyclodextrin)
Advanced technologies
1(1) (2012), 07-15
They are increasingly used in the formulations of pharX-ray diffraction was performed on a Phillips Xpert
maceutical products to ensure their safer application. In- powder diffractometer. The samples were exposed to
clusion complexes with different medicinal substances monochromatic CuKα radiation and analyzed under the
are increasingly used in order to improve physical and angle of 2θ between 8 and 44° with 0.05° increments and
chemical characteristics (solubility, evaporation, stabil- recording time, t=5 s. The voltage and the strength of the
ity increase, etc.) of pharmacologically active substances electric current were 40 kV and 20 mA, respectively.
[18-21]. They can be used in formulations that are being
The solubility of iron(II) fumarate in a pure and complex
applied orally, parenterally, or locally. Cyclodextrins are form was determined with UV/VIS spectrophotometric
also used as extenders or carriers of drugs [18, 22, 23].
method by measuring UV absorbance at 218 nm on a Varian Cary UV-VIS-100 Conc. Spectrophotometer. Distilled
water was used as a reference for all spectrophotometric mesurements. For the purpose of the concentration
The synthesis of iron(II) fumarate. The synthesis of measurement, calibration curves are established for pure
iron(II) fumarate is based on the fumaric acid conversion iron(II) fumarate (A=-0.079+0.0554.C, r=0.99, the conceninto disodium fumarate by neutralization in the molar ratio tration up to 35 μg/cm3), the complex with β-cyclodextrin
of 1:2. Disodium fumarate, as intermediate mater, reacts (A=0.0568+0.0281.C, r=0.98, the concentration up to
with iron(II) sulfate in the molar ratio of 1:1, yielding iron(II) 120 μg/cm3) and the complex with 2-hydroxypropyl-βfumarate, brick-red precipitate with over 98 % purity. The cyclodextrin (A=0.0317+0.0215.C, r=0.97, the concentrareaction was performed in nitrogen atmosphere at tion up to 120 μg/cm3).
90 °C during 30 minutes providing an inert atmosphere
required to prevent oxidation of ferrous ions to ferric. The
Results and discussion
resulting precipitate was separated from the solution by
filtration in vacuum. In order to remove impurities that
Many drugs used in clinical practice have reduced a
originate mainly from unreacted salts (Na2SO4, FeSO4 therapeutic effect because of their poor physico-chemical
and disodium fumarate), the residue was rinsed several characteristics. Poor solubility, especially of the drugs
times with distilled water, then dried at 105 °C for one used in the long-term treatment, leads to increased side
hour. Iron(II) fumarate was further used to prepare effects. Therefore, pharmaceutical formulations of active
inclusion complexes.
components with cyclodextrines are prepared. The literature offers a number of papers related to the preparation
Preparation of inclusion complexes. Molecular inclu- and characterization of cyclodextrin inclusion complexes
sion complexes of iron(II) fumarate with β-cyclodextrin or with different drugs in order to increase their solubility. For
with 2-hydroxypropyl-β-cyclodextrin were prepared by the instance, there are studies on the drugs belonging to the
co-precipitation method. Iron(II) fumarate (169.9 mg) was group of 1,4 dihydropyridine, felodipine [24], nicardipine
mixed with β-cyclodextrin (1135 mg) or 2-hydroxypropyl- [25], nifedipine [26,27], amlodipine [21], atenolol [19] and
β-cyclodextrin (1540 mg) and dissolved in 250 cm³ of others incorporated in the cavity of cyclodextrin. Thus
distilled water. The obtained mixtures were mixed for formed inclusion complexes increase solubility of drugs,
72 h at room temperature, evaporated at 50 °C to the vol- which provides better bioavailability and a safer applicaume of about 20 cm³ and then dried in a desiccator over tion.
concentrated sulfuric acid at the temperature of 25 °C.
Antianemics, including iron(II) fumarate, have poor solubility too and therefore exhibit increased side effects
Preparation of physical mixture. Physical mixtures while used in a longer period of time. The aim of this work
were prepared by simple mixing of iron(II) fumarate with was to prepare inclusion complexes of cyclodextrin with
complexing agents, β-cyclodextrin and 2-hydroxypropyl-β- iron(II) fumarate and to determine the solubility of these
cyclodextrin in molar ratio of 1:1 (host:guest).
formulations. For the characterization of the prepared inclusion complexes with β-cyclodextrin and 2-hydroxypropylCharacterization methods
β-cyclodextrin various methods (FTIR, DSC, XRD) were
FTIR spectra of iron(II) fumarate, inclusion complexes
with cyclodextrins, complexing agents and corresponding
FTIR spectra of pure iron(II) fumarate, complex agents
physical mixtures were recorded as KBr pellets (0.3 mg of β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin
samples, 150 mg of KBr) on Bomem Hartmann & Braun together with molecular inclusion complexes, β-cyclodextrin:
MB-series spectrophotometer.
iron(II) fumarate and 2-hydroxypropyl-β-cyclodextrin:
DSC curves of the samples were recorded on Univer- iron(II) fumarate are shown in Figures 3 and 4.
sal V4. 4A TA Instruments DSC with the scanning rate
of 10 °C/min, within the temperature range of 50-350 °C.
Thermal properties were studied by heating of about 3 mg
of the sample in closed aluminum containers, in nitrogen
1(1) (2012), 07-15
Advanced technologies
Figure 3. FTIR spectra of A) iron(II) fumarate, B) β-cyclodextrin, C) β-cyclodextrin: iron(II)
fumarate complex, D) physical mixture of β-cyclodextrin with iron(II) fumarate
The analysis of FTIR spectra of complexes shows that
the spectra are basically similar but there are differences
in some of the band positions for complexes as compared
to the pure iron(II) fumarate. Centroid band in the spectra
of complexes is more intense in the area of stretching (OH)
vibrations and shifted a few units towards lower or higher
frequencies compared to the position of a similar band in
the cyclodextrin spectra.This indicates that an interaction
between iron(II) fumarate and cyclodextrin occurred in a
10 complex. Also, there is a shift in spectra of both complexes
for the band occurring in cyclodextrin at about 1370 cm-1
towards a higher frequency registered at 1395 cm-1.
In 2-hydroxypropyl-β-cyclodextrin complex the band
that appeared at 757 cm-1 shifted to 792 cm-1. For the
complexes in the range of 600-700 cm-1 new bands (at 675
and 643 cm-1) appeared. Some bands which are present
in the iron(II) fumarate spectrum are absent from the spectra of the complexes. It was noticed that the stretching vi-
1(1) (2012), 07-15
Advanced technologies
bration (COOˉ) band at 1385 cm-1 is shifted to the higher
frequency side in the spectrum of iron(II) fumarate, while
in the complexes it occurs at 1395 cm-1. Based on the
changes observed in FTIR spectra, it can be concluded
that complexes do not represent a simple physical mixture.
On the contrary, iron(II) fumarate was included into cyclo-
dextrin cavities and supra molecular structures - inclusion
complexes were built. Bands typical for C1 conformation
of glucopyranose units at 950, 860 and 756 cm-1 have almost the same intensity, shape and position as with cyclodextrin, suggesting that C1 conformation of glucopyranose
units did not change during the synthesis of the complex.
Figure 4. FTIR spectra of A) iron(II) fumarate, B) 2-hydroxypropyl-β-cyclodextrin,
C) 2-hydroxypropyl-β-cyclodextrin:iron(II) fumarate complex, D) physical mixture
of 2-hydroxypropyl-β-cyclodextrin with iron(II) fumarate
1(1) (2012), 07-15
Advanced technologies
The results of DSC analisys are presented in Figure 5 a-g.
Figure 5. DSC diagrams a) iron(II) fumarate, b) β-cyclodextrin c) physical mixture of β-cyclodextrin with iron(II) fumarate,
d) β-cyclodextrin: iron(II) fumarate complex, e) 2-hydroxypropyl-β-cyclodextrin, f) physical mixture
of 2-hydroxypropyl-β-cyclodextrin and iron(II) fumarate g) 2-hydroxypropyl-β-cyclodextrin: iron(II) fumarate complex.
12 Advanced technologies
1(1) (2012), 07-15
Figure 7. XR diffraction patterns: a) 2-hydroxypropyl-β-cyclodextrin b) iron(II) fumarate, c) 2-hydroxypropyl-βcyclodextrin:iron(II) fumarate complex, d) physical mixture of 2-hydroxypropyl-β-cyclodextrin with iron(II) fumarate
Figure 6. XR diffraction patterns: a) β-cyclodextrin, b) iron(II) fumarate, c) β-cyclodextrin:
iron(II) fumarate complex, d) physical mixture of β-cyclodextrin with iron(II) fumarate
1(1) (2012), 07-15
Advanced technologies
Exothermic peak of pure iron(II) fumarate, which occurs By complexation of iron(II) fumarate with cyclodextrin a suat about 277 °C, represents a destruction temperature of pramolecular structure is obtained, which can increase the
iron(II) fumarate. DSC curves, reflecting physical changes bioavailability and, therefore, show better performance in
of the host and guest molecules in the complexes, are dif- therapy due to the increased solubility of the active subferent for the destruction regime of individual components. stance, iron (II) fumarate.
These results also support the finding that iron(II) fumarate
is included in the cavity of the host.
Diffraction patterns of iron(II) fumarate inclusion complexes with the corresponding cyclodextrins, physi- This work is a part of the research done within the project
cal mixtures and pure components of iron(II) fumarate, TP 34012. The authors would like to thank the Ministry of
β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin are Education and Science, Republic of Serbia.
shown in Figures 6 and 7, respectively. XRD spectra of
physical mixtures contain peaks arising from iron(II) fumarate
and host molecules, while the peaks originating from the
structure of iron(II) fumarate are not present. The absence [1] D. M. Cvetković, V. D. Nikolić, L. B. Nikolić, Ispitivanje
of pronounced peaks obtained with 2-hydroxypropyl-βprimarnih fizičko-hemijskih i farmako-bioloških karakteristika
cyclodextrin and its complex indicates increased the amorpolinuklearnih kompleksa gvožđa(III) sa dekstranom i
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Figure 8. Solubility profiles of iron(II) fumarate in pure and
complex form
The best solubility of iron(II) fumarate is achieved within 2-hydroxypropyl-β-cyclodextrin: iron(II) fumarate complex
(2.71 mg/cm3). Lower solubility of 2.05 mg/cm3 is achieved
within β-cyclodextrin: iron(II) fumarate complex, while the lowest solubility of 1.37 mg/cm3 was obtained for the pure
iron(II) fumarate. These results are consistent with the
research studies on solubility of different drugs with inclusion complexes found in literature [19-21, 24, 28]. For instance, in inclusion complexes with usnic acid there was
a 70-fold solubility increase in usnic acid in hydroxypropylβ-cyclodextrin while in the presence of β-cyclodextrin the
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Agneš J. Kapor1, Ljubiša B. Nikolić2, Vesna D. Nikolić2*, Mihajlo Z. Stanković2,
Milorad D.Cakić2, Dušica P. Ilić2, Ivana I. Mladenović-Ranisavljević2, Ivan S. Ristić3
1 Prirodno-matematički fakultet, Departman za fiziku, Univerzitet u Novom Sadu, Novi Sad, Srbija
2 Tehnološki fakultet u Leskovcu, Univerzitet u Nišu, Leskovac, Srbija
3 Tehnološki fakultet, Univerzitet u Novom Sadu, Novi Sad, Srbija
U ovom radu sintetisan je gvožđe(II)-fumarat polazeći od fumarne kiseline koja
je postupkom neutralizacije prevedena u natrijum fumarat pri molskom odnosu 1:2. Intermedijer natrijum fumarat reakcijom sa gvožđe(II)-sulfatom u molskom odnosu 1:1 u atmosferi azota daje gvožđe(II)-fumarat, mrko crveni talog,
čistoće 98 %. Da bi se korigovala slaba rastvorljivost sintetisanog gvožđe(II)fumarata pripremljeni su inkluzioni kompleksi sa β-ciklodekstrinom (β-CD) i
2-hidroksipropil-β-ciklodekstrinom (HP-βCD) koprecipitacionom metodom,
sa molskim odnosom 1:1. Karakterizacija inkluzionih kompleksa, gvožđe(II)fumarata i ciklodekstrina izvršena je primenom FT-IR, DSC i XRD metoda.
Primenom UV/VIS metode određena je rastvorljivost gvožđe(II)-fumarata u
čistom i kompleksiranom stanju. Pokazano je da je najveća rastvorljivost u
obliku kompleksa 2-hidroksipropil-β-cikoldekstrin:gvožđe(II)-fumarat.
UDK 577.164.1
Ključne reči: antianemik, gvožđe(II)-fumarat, inkluzioni kompleksi, β-ciklodekstrin, 2-hidroksipropil-βciklodekstrin, rastvorljivost.
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