TUGAS RESUME JURNAL INTERNASIONAL

“Solid-state Preformulation Studies of Amiodarone Hydrochloride”

(Journal of Thermal Analysis and Calorimetry)

Diajukan Untuk Memenuhi Tugas Mata Kuliah Teknologi Sediaan Solida

Disusun Oleh
Kelompok 7 Kelas A:
1. Naura Bathari Winarto (172210101062)
2. Ardyakinanti Fitrymahareni (172210101070)
3. Dinar Mutia Rani K. (172210101128)

Dosen:
Eka Deddy I, M.Sc.,Apt.

FAKULTAS FARMASI
UNIVERSITAS
JEMBER 2019
 “Solid-state Preformulation Studies of Amiodarone Hydrochloride”

1. Pendahuluan
Berdasarkan strukturnya, AM mempunyai pengaruh terhadap hormon tiroid karena
dapat berinteraksi dengan reseptor inti hormon tiroid. AM merupakan obat yang umumnya
digunakan dalam pengobatan aritmia yang sulit diobati dengan obat lainnya. Saat ini
karakterisasi AM pada sediaan padat, sediaan murni dan campuran preformulasi masih
dilaporkan sangat buruk dalam literatur, beberapa hanya menggambarkan kondisi termal dan
kinetika dekomposisi AM dalam kondisi isotermal pada nitrogen, sementara efek eksipien
terhadap sifat in vivo hanya diselidiki dan dilaporkan oleh Masi et al. Sampai saat ini, Drug
Bank menunjukkan bahwa AM dapat digunakan sebagai larutan dan tablet yang
diformulasikan serta disuntikkan dengan dosis antara 100-400 mg AM per tablet.
Penelitian untuk karakterisasi AM dalam sediaan padat sebagai bahan aktif murni, serta
dalam campuran biner padat yang terdiri dari AM dan eksipien yang umum digunakan seperti
polyvinylpyrrolidone (PVP) mikrokristalin selulosa (MC), pati, talkum, dan laktosa anhidrat.
Sebagai alat instumental, digunakan teknik temoanalitik dan spektroskopi.

2. Material dan metode

Amiodarone hidroklorida (AM) diperoleh dari sigma dengan kemurnian >98% dan
digunakan tanpa pemurnian lebih lanjut. Bahan eksipien yang digunakan dan diterima adalah
pati (GPA USA), mikrokristalin selulosa (ParChem Trading Ltd,USA), laktosa (Meggle,
Jerman), polyvinylpyrrolidone (BASF, Jerman), dan talkum (Luzenac Pharma, Italia).
Campuran biner dari AM dan eksipien disiapkan dengan mencampur kedua bahan
tersebut dengan jumlah yang sama, kemudian campuran di triturasi pada mortar sekitar 5
menit. Rasio 1:1 (m/m) dipilih untuk memaksimalkan probabilitas dalam pengamatan
interaksi.
Data DSC dikumpulkan dalam PerkinElmer Pyris Diamond DSC untuk sampel yang
mengalami tekanan termal sedang selaam 48 jam dalam botol bersegel pada suhu 40°C.
Sampel yang dianalisis disegel dalan cawan lebur alumunim. Program suhu diatur untuk
meningkat sekitar 300°C dengan tingkat pemanasan 10°C min -1, dibawah aliran nitrogen
(50mL min-1). Data di proses dengan software PerkinElmer Pyris.

3. Hasil dan Diskusi

Analisis UATR-FTIR : Analisis UATR-FTIR dari AM murni

Solid-state Preformulation Studies of Amiodarone Hydrochloride

Kelompok 7 Kelas A
 Spektroskopi UATR-FTIR menunjukkan bahwa preparasi sampel dengan menggiling
AM dengan eksipien yang dipilih tidak mengarah pada interaksi, karena semua pita yang
berhubungan dengan kelompok fungsional “reaktif” dari AM ditemukan tidak berubah dalam
spektrum FTIR campuran biner.
Analisis TG / DTG / HF
AM didekomposisi dalam satu tahap antara temperatur 1 0 dan 400 dengan
kehilangan massa ∆m = 87,51%. Dengan menganalisis kurva Heat Flow, dua puncak
yang terdefinisi dengan baik memiliki panas yang berbeda: satu endotermik dengan
maksimum pada 162,3 C yang sesuai dengan proses peleburan dan yang lainnya
merupakan efek eksotermik (HFmax = 17 7 ˚ ) yang menjadi ciri awal dari
termooksidasi. Dekomposisi AM dimulai pada temperatur 173 ˚ dan maksimum pada
kurva DTG masing-masing pada 2 2 ˚ dan 270 ˚ .
Data DSC
AM diberi perlakuan sebelumnya pada 40 ˚ selama 48 jam dalam vial tertutup
kemudian diselidiki oleh DSC di bawah atmosfer nitrogen inert. Puncak endotermik
diidentifikasi dengan daya pikat tajam pada 1 3 9 ˚ sesuai dengan titik leleh AM; entalpi
fusi yang terkait dengan proses ini adalah D fusH = 86,6 Jg-1. Teknik DSC mengungkapkan
bahwa AM tidak mengalami modifikasi di bawah perlakuan termal yang dikenakan.

4. KESIMPULAN
Tiga teknik instrumental digunakan untuk menilai kompatibilitas/ inkompatibilitas AM
dengan polyvinylpyrrolidone (PVP), microcrystalline cellulose (MC), starch (St), talc (T) dan
anhidrous lactose (L), yaitu teknik termoanalitik (TG/DTG/HF), Spektroskopi DSC dan
UATR-FTIR. Untuk menganalisis pengaruh tekanan termal moderat terhadap sampel biner
versus AM murni (40 ˚ / 48 jam) teknik DS digunakan. AM ditemukan stabil secara
termal, sementara campuran biner memberikan perbedaan penting pada posisi puncak dan
entalpi fusi. Kecuali talc, yang kompatibel dengan AM dalam semua kondisi, empat eksipien
lainnya ditemukan tidak sesuai dengan AM.
Studi kami mengungkapkan kegunaan analisis termal sebagai metode skrining calon
eksipien untuk amiodaron yang cepat dan mudah digunakan selama studi preformulasi.
Namun, dalam pengembangan formulasi padatan generik yang mengandung amiodarone,
eksipien yang disebutkan di atas harus dihindari.

Solid-state Preformulation Studies of Amiodarone Hydrochloride

Kelompok 7 Kelas A
 J Therm Anal Calorim
DOI 10.1007/s10973-016-5256-6
Solid-state preformulation studies of amiodarone hydrochloride
Adriana Ledet¸i1 • Gabriela Vlase2 • Titus Vlase2 • Vasile Bercean3 •
Marius Sorin Murariu4 • Ionut¸ Ledet¸i1 • Lenut¸a-Maria S¸ uta1
Received: 15 October 2015 / Accepted: 14 January 2016
© Akade´miai Kiado´, Budapest, Hungary 2016
Abstract This paper deals with the application of fast
screening tools such as FTIR, thermal analysis and DSC in
the evaluation of compatibility between the active phar-
maceutical ingredient amiodarone hydrochloride and dif-
ferent pharmaceutical excipients used in tablet
formulations, such as polyvinylpyrrolidone, microcrys-
talline cellulose, starch, talc and anhydrous lactose. Sam-
ples were investigated initially immediately after
preparation by FTIR analysis and later by TG/DTG/HF
technique. It was found that under ambient condition,
amiodarone hydrochloride was compatible with all
selected excipients. During the non-isothermal thermal
treatment in oxidative atmosphere, amiodarone showed
incompatibility with lactose. The final investigations
consisted of main- taining the samples under moderate
thermal stress (48 h at 40 °C), when DSC investigations
revealed that thermal- induced interactions occurred with
all selected excipients except talc.
& Ionu¸t Lede¸ti
ionut.ledeti@umft.ro
1
Faculty of Pharmacy, University of Medicine and Pharmacy
‘‘Victor Babes¸’’, Eftimie Murgu Square 2, 300041
Timisoara, Romania
2
Research Center for Thermal Analysis in Environmental
Problems, West University of Timisoara, Pestalozzi Street
16, 300115 Timisoara, Romania
3
Faculty of Industrial Chemistry and Environmental
Engineering, Politehnica University Timis¸oara, 6 Carol
Telbisz, 300001 Timisoara, Romania
4
Faculty of Medicine, Department of Surgery II, First Surgical
Clinic, University of Medicine and Pharmacy ‘‘Victor
Babes¸’’, Eftimie Murgu Square 2, 300041 Timisoara,
Romania
Keywords Amiodarone · Preformulation studies ·
Excipients · Thermal analysis · Compatibility
Introduction
Cardiovascular diseases are nowadays the leading cause of
mortality at the global level [1]. In the class of antiar-
rhythmic agents, amiodarone is classified as class III agent
(according to Singh–Vaughan Williams classification) [2],
mainly affecting potassium ion efflux. However, amio-
darone also has class I, II and IV activity [3].
Amiodarone (AM, (2-{4-[(2-butyl-1-benzofuran-3-yl)-
carbonyl]-2,6-diiodophenoxy}ethyl)diethylamine)) is used
in the treatment of a wide range of cardiac tachyarrhyth-
mias, including both ventricular and supraventricular
(atrial) ones [4]. The structure of amiodarone hydrochlo-
ride is presented in Fig. 1.
By the structural point of view, AM is related to the
thyroid hormone, and some of the antiarrhythmic actions as
well as the toxicity can be associated with the interaction
with nuclear thyroid hormone receptor. AM is mainly used
in arrhythmias that are otherwise difficult to treat with
other medications [5, 6].
Amiodarone was intensely studied in the last year, and
there are numerous papers dealing mainly with its in vivo
activity and side effects caused by intravenous adminis-
tration [7], acute renal failure [8], risk of heart block [9],
thyroid dysfunction [10, 11], acute body pain after
administration [12], hair loss [13] and pulmonary toxicity
[14]. However, contributions to the solid-state characteri-
zation of AM as pure ingredient and in preformulation
mixtures were poorly reported in the literature. To our
knowledge, only the paper of Yoshida et al. [15] described
the thermal behaviour and decomposition kinetics of AM
13

O Sigma (C25H29I2NO3 HCl, purity [98 %, m.p. provided by
I
O Lot#061M1422 V) and used as received, without further
NH+
O Cl–
I Corporation, USA), microcrystalline cellulose (ParChem
Fig. 1 Structure of amiodarone hydrochloride
under isothermal conditions, in nitrogen atmosphere, while
the excipient effect over the in vivo properties was solely
investigated and reported by Masi et al. [16]. To date,
DrugBank [17] indicates that AM can be used as formu-
lated as well as injectable solutions and tablets, with
strength between 100 and 400 mg AM per tablet. As
excipients, most of the solid formulations contain lactose
monohydrate, povidone, colloidal anhydrous silica, mag-
nesium stearate and pregelatinized maize starch [18].
Pharmaceutical excipients play different roles in phar-
maceutical technology. Their main role is to assure both
mechanical and chemical stability of the API and of the
tablet, in order to facilitate the administration to the
patient. Since numerous solid pharmaceutical formulations
contain low quantities of API (including the order of
micrograms), the direct administration to the patient is
impossible due to several reasons, the most important
being the imprecise dosage. According to these
observations, the necessity of analysing the behaviour of
mixtures between APIs and excipients is clearly revealed
[19–27], since the final for- mulation administered to the
patient is the tablet. We have previously reported in
several papers [28, 29] data regarding the evaluation of
compatibility/incompatibility of APIs with excipients, by
using thermoanalytical tools [30, 31], FTIR spectroscopy
[32], DSC [33, 34] and XRD studies [30–32]. However,
these tools can be used in the study of newly designed
compounds, tested for in vitro and in vivo biolog- ical
activities [33, 34], which can be correlated with the
results suggested by kinetic analysis of pure APIs or com-
mercialized solid forms such as tablets and capsules [35,
36]. Following these considerations, we set our goal as
investigating the solid-state characterization of AM as pure
API (active pharmaceutical ingredient), as well as in solid
binary mixtures consisting in AM and commonly used
excipients, such as polyvinylpyrrolidone (PVP), micro-
crystalline cellulose (MC), starch (St), talc (T) and anhy-
drous lactose (L). As instrumental tools, thermoanalytical
techniques (TG/DTG/HF/DSC) and spectroscopy (UATR-
FTIR) were used.
A. Lede¸ti et al.
Materials and methods
Amiodarone hydrochloride (AM) was obtained from
MSDS 158–163 · °C, MW 681.77 g mol-1, CAS
19774-82-4,
purification. The excipients (pharmaceutical grade) were
used as received as follows: starch (Grain Processing
Trading Ltd., USA), lactose (Meggle, Germany),
polyvinylpyrrolidone (BASF, Germany) and talc (Luzenac
Pharma, Italy).
The binary mixtures of AM ? excipient were
prepared by mixing equal quantities (mass) of AM and
each excip-
ient. Physical mixtures were prepared by trituration of the
two substances in an agate mortar for approximately 5 min.
The 1:1 (m/m) ratio was chosen in order to maximize the
probability of observing the interaction(s).
Universal attenuated total reflection Fourier transform
infrared spectroscopy (UATR-FTIR) spectra of the
samples were collected on a PerkinElmer SPECTRUM 100
device. The samples were analysed in solid-state, without
any a priori preparation of the sample. Spectra were
collected after 64 co-added scans, with a resolution of 4
cm-1, on the spectral domain 4000–600 cm-1.
The thermoanalytical TG/DTG/HF curves were deter-
mined in dynamic air atmosphere under non-isothermal
conditions at a heating rate b = 10 °C min-1 using a
PerkinElmer DIAMOND equipment. Samples of masses of
approximately 5 mg were put into aluminium crucibles and
heated by increasing temperature from ambient up to
400 °C. For determining the thermal effects, the DTA data
(lV) were converted in HF (heat flow) data (mW). In order
to evaluate the accuracy of the measurements, two repeti-
tions were done with this experimental protocol for the
samples, and the obtained results were practically identical.
DSC data were collected on a PerkinElmer Pyris Diamond
DSC for the samples that were subjected to moderate thermal
stress for 48 h in sealed vials at 40 °C. The analysed samples
were sealed in pierced aluminium crucibles. The temperature
program was set to increase from ambient to 300 °C with a
heating rate of 10 °C min-1, under nitrogen flow (50 mL
min-1). All the data
were processed by PerkinElmer Pyris software.
Results and discussion
UATR-FTIR analysis
UATR-FTIR analysis of pure AM
The UATR-FTIR spectrum of pure AM is presented in
Fig. 2. AM shows C–H stretching vibration bands from
13
Solid-state preformulation studies of amiodarone hydrochloride

methyl groups at 2977, 2963 and 2858 cm-1, respectively,

Generally, the search of interaction between the com-
from methylene groups at 2933, 2918 and 2880 cm-1. C–H
ponents using UATR-FTIR spectroscopy is carried out by
deformation vibrations from C–CH3 bonds appear at 1477
analysing the shifting to lower/higher wavenumbers of the
cm-1 (asym) and 1381 cm-1 (sym), while for the ones
bands corresponding to ‘‘reactive’’ functional groups, as
from methylene group, they appear at 1454 and 1432 cm-1.
well as the disappearance of some bands. In a previous
The aromatic structure presents the =C–H stretching
paper [37], we stated that the modification of the APIs
around 3040 cm-1, while the in-plane defor- mation for
structure generally occurs on reactive functional bands
the 1,2,3,5-tetrasubstituted ring occurs in 900–860 spectral
with a higher probability versus the modification of alkyl
range. The characteristic ketone band for diaryl ketone is
or aryl chains. Following this consideration, in Table 1, the
represented by an intense and sharp band at 1629 cm-1,
bands corresponding to vibration of reactive functional
while the aryl–alkyl ether band and the one from
groups from AM in binary mixtures are presented in
benzofuran ring appear at 1285 and 1246 cm-1,
comparison with the results described for pure AM.
respectively. Also, the NH? vibrations are represented by
UATR-FTIR spectroscopy suggests that sample prepa-
the sharp bands at 1790 and 1560 cm-1. These bands are in
ration by grinding of AM with the selected excipients does
good agreement with the chemical structure of the com-
not lead to interactions, since all the bands corresponding
pound and confirm the structure and the purity of the API.
to ‘‘reactive’’ functional groups from AM are found unal-
tered in the FTIR spectra of the binary mixture. The
observed shifting at ±3 cm-1 is due to processing of FTIR
data by the spectrometer, not due to interaction between
(a) AM and excipients.
AM
For further analysis of compatibility/incompatibility of
AM+L
AM with excipients under thermal stress, two other similar
instrumental techniques were used, but in different condi-
Transmittance/a.u.

AM+MC AM+St
tions: TG/DTG/HF analysis in open crucible and in
AM+PVP oxidative condition and DSC analysis in closed crucible in
inert medium.

TG/DTG/HF analysis

AM+T
Thermal behaviour of pure AM

Since no data were reported for the thermal stability of

4000 3750 3500 3250 3000 2750 2500 2250 pure AM in dynamic air atmosphere, and following the
Wavenumber/cm–1 con- sideration that the interpretation of the
thermoanalytical curves of the binary mixtures requires the
(b)
AM analysis of thermal stability of the pure API, we firstly
analysed AM by this technique.
AM+L AM+MC AM+St The thermoanalytical curves (TG/DTG/HF) determined
Transmittance/a.u.

AM+ PVP for AM in dynamic air atmosphere at a heating rate b = 10

°C min-1 are presented in Fig. 3a–c.
AM shows an increased stability, being thermally
stable up to 156 °C under dynamic air atmosphere. AM is
decomposed in a single stage between 160 and 400 °C,
with a mass loss Dm = 87.51 %. By analysing the HF
curve, two well-defined peaks which have a different
AM+T
thermal were observed: one endothermic with a maximum
at 162.3 °C corresponding to the melting process and the
other an exothermic effect (HFmax = 176.7 °C), which
1750 1500 1250 1000 750 characterizes the beginning of the thermooxidation. The
Wavenumber/cm–1 decomposition of AM starts at 173 °C and presents maxi-
mum on the DTG curve which appears at 262 and 270 °C,
Fig. 2 UATR-FTIR spectra of AM and binary mixtures AM ? respectively, and is correlated with the decomposition
ex- cipients: a 4000–2250 cm-1 and b 1875–600 cm-1 spectral
regions process of AM.

13
 A. Lede¸ti et al.

Table 1 UATR-FTIR data collected from spectra of pure AM and AM in binary systems
Sample UATR-FTIR characteristic bands/cm-1
mC–H mC=O mC–O ether/furane m?
NH

AM 2977; 2963; 2858; 2933; 2918; 2880 1629 1285; 1246 1560
AM ? L 2977; 2964; 2859; 2934; 2917; 2881 1630 1285; 1246 1560
AM ? MC 2976; 2962; 2858; 2932; 2917; 2879 1630 1285; 1247 1559
AM ? St 2976; 2961; 2858; 2932; 2917; 2881 1631 1285; 1246 1558
AM ? PVP 2978; 2962; 2857; 2932; 2918; 2881 1630 1285; 1246 1559
AM ? T 2977; 2963; 2859; 2934; 2918; 2881 1630 1285; 1247 1557

(a) (b)
Mass/a.u.

DTG/a.u.
AM AM+L AM+MC AM+St AM+PVP AM+T AM AM+L AM+MC AM+St AM+PVP AM+T

0 100 200 300 400 0 100 200 300 400

Temperature/°C Temperature/°C

(c)
Heat flow/a.u.

AM
AM+L
AM+MC
AM+St
AM+PVP
AM+T
0 100 200 300 400
Temperature/°C

Fig. 3 Thermoanalytical profile of AM in dynamic air atmosphere at b = 10 °C min-1

Thermal behaviour of binary mixtures AM ? temperatures of the processes occurring with mass loss.
excipients The differences were expected to be noticed, since the
thermal stability of excipients was different. However,
Binary mixtures of AM with excipient were analysed in investigations on the DTGmax revealed that the processes
same experimental conditions as pure AM. The obtained attributed to the degradation of AM are on the same tem-
thermoanalytical curves are presented in Fig. 3a–c, and the perature range in binary mixtures, suggesting the compat-
results are presented in Table 2. ibility between API and excipients. One exception was
The thermoanalytical profile of AM versus binary mix- noticed, i.e. lactose, where the corresponding peaks to the
tures revealed some differences, especially in the onset

13
Solid-state preformulation studies of amiodarone hydrochloride

Table 2 Comparative thermal behaviour of AM versus binary mixtures by TG/DTG/HF analysis

Samples TG DTGmax/°C HF Dm/% Dfus H/J g-1
Tonset/°C Tonset/°C Tpeak/°C

AM 157 163; 258; 270 149 162; 177; 230 87.5 65.4
AM ? L 92 122; 206; 216; 240 145 156; 172; 235 1.5; 66.3 28.4
AM ? MC 41 169; 239 149 162; 172; 222 2.5; 8.9; 63.6 29.7
AM ? St 41 167; 210; 239 147 161; 173; 208; 233 5.5; 7; 56.5 30.3
AM ? PVP 47 167; 308; 462 146 160; 178 3.5; 4; 66 26.8
AM ? T 152 168; 233 145 162; 172; 234 7.6; 28.7 35.9

degradation of AM are shifted to lower temperatures. In

Table 3 Comparative thermal behaviour of AM versus binary mix-
this case, an incompatibility was noticed. tures by DSC analysis

DSC data Samples DSC DSCmax/°C Dfus H/J g-1

Tonset/°C

Since no interactions occur between AM and excipients AM 157 164; 175 80.6
(except lactose) at temperatures below melting under rapid AM ? L 135 144; 184; 197 44.3
increase in temperature, the samples were subjected to AM ? MC 143 156 50.3
moderate thermal stress in isothermal conditions (40 °C) AM ? St 133 154; 192 47.7
for 48 h. AM ? PVP 90 121 100.7
The pretreated AM at 40 °C for 48 h in sealed vials was AM ? T 154 162; 172 39.3
investigated by DSC under inert nitrogen atmosphere
(Fig. 4). The endothermic peak was identified with a sharp
allure at 163.9 °C, corresponding to the melting of AM; the excipients showed interactions with AM after subjected to
fusion enthalpy associated with this process was D fus- H = 40 °C for 48 h, except talc. In all cases, modifications of
86.6 J g-1. The DSC technique revealed that AM did not the melting peak were observed, as well as modification
suffer modifications under the subjected thermal treatment. of the degradation process of AM molecule. The values
In comparison, DSC data for binary mixtures subjected obtained for enthalpy of fusion varied as well on a large
to isothermal stress revealed some modification of the domain, suggesting the overlapping of thermal processes
thermoanalytical curves, as follows (Table 3): all of AM and excipient. In the case of binary mixture of
AM ? T, the DSC curve suggested that no interaction
occurred, since the peaks were observed at temperature
closer to the ones determined for pure AM. Also, the
value for DfusH decreased to half in comparison with the
pure AM.

Conclusions
DSC/a.u.

Thermal stability of AM in dynamic air atmosphere versus

AM AM+L AM+MC AM+St AM+PVP
AM+T
0 100
Temperature/°C
Fig. 4 DSC curves of AM and AM ? excipients in nitrogen
atmosphere at b = 10 °C min-1
inert medium was studied by employment of TG/DTG/HF
technique, as well as DSC study. It was shown that AM is
thermally stable up to considerably high temperature in
both inert and oxidative medium. However, the degrada-
tion process is different, being represented in air by intense
200 300 thermooxidations, while in nitrogen, these processes are
negligible.
Three instrumental techniques were used for assessing
the compatibility/incompatibility of AM with
polyvinylpyrrolidone (PVP), microcrystalline cellulose
(MC), starch (St), talc (T) and anhydrous lactose (L),

13

namely thermoanalytical techniques (TG/DTG/HF), DSC
and UATR-FTIR spectroscopy.
Since under ambient temperature, FTIR analysis did not
reveal any incompatibility, TG analysis was used. In this
case, under rapid heating of the samples, an interaction was
induced between AM and lactose, which was evidenced by
a considerable shifting of DTG peaks to lower
temperatures.
In order to analyse the influence of the moderate
thermal stress over the binary samples versus pure AM
(40 °C/ 48 h), DSC technique was employed. AM was
found to be thermally stable, while binary mixtures
presented impor- tant differences in both peak positions
and in the fusion enthalpies. Except talc, which was
compatible with AM in all conditions, the other four
excipients were found to be incompatible with AM.
Our study revealed the utility of thermal analysis as a
rapid and convenient method of screening of candidate
excipients for amiodarone during preformulation studies.
However, in the development of generic solid formulations
containing amiodarone, the above-mentioned excipients
should be avoided.
Acknowledgements This work was partly supported by the strate-
gic grant POSDRU/159/1.5/S/137750, Project ‘‘Doctoral and Post-
doctoral programs support for increased competitiveness in Exact
Sciences research’’ cofinanced by the European Social Fund within
the Sectoral Operational Programme Human Resources Development
2007–2013 to Ionu¸t Lede¸ti.
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