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http://www.revistadechimie.ro REV . CHIM. (Bucharest) ♦ 66 ♦ No. 2 ♦ 2015 240Analysis of Solid Binary Systems Containing Simvastatin
IONUT LEDETI1,2, GABRIELA VLASE2, IONEL CIUCANU2, TUDOR OLARIU1, ADRIANA FULIAS1*, LENUTA-MARIA SUTA1,
IONELA BELU3
1University of Medicine and Pharmacy “Victor Babeș”, Faculty of Pharmacy, Department of Pharmacy I, 2 Eftimie Murgu Sq.,
300041, Timisoara, Romania
2West University of Timisoara, Research Centre for Thermal Analysis in Environmental Problems, 16 Pestalozzi Str.., 300115,
Timisoara, Romania
3University of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Technology, 2-4 Petru Rares Str.,
200349, Craiova, Romania
This study belongs to a dedicated series of investigations regarding the compatibility in binary solid systems
of active pharmaceutical ingredients and different pharmaceutical excipients, aiming as a preliminary
formulation study. The compatibility/incompatibility of a currently used statin drug – simvastatin – with threepharmaceutical excipients – calcium lactate pentahydrate, mannitol and magnesium stearate was
investigated by employing three instrumental techniques – namely thermal analysis, Fourier-transform infrared
spectroscopy and powder X-Ray diffraction.
Keywords: simvastatin, excipient, lactate, mannitol, stearate, thermal analysis, FTIR, PXRD
The development of new pharmaceutical solid
formulations is, along with drug discovery, an importantmilestone in improving the quality of life for patients
suffering from different diseases. The cost of treatment is
mainly influenced by the cost of production of the activepharmaceutical ingredient (API), but as well by the
formulation cost, the last including the selection of
excipients (EXC). After patent expiring, development ofgeneric formulations can lead to a considerable lowering
of the price of drugs, making the treatment accessible to a
larger group of patients. By these means, preformulationstudies are necessary in the selection of adequate
excipients for a certain API. Monitoring the physico-
chemical properties of pharmaceutical substances andexcipients is a fundamental problem of the pharmaceutical
industry since the incompatibility can cause major
problems in obtaining of the pharmaceutical dosage formby changing the bioavailability and drug stability.
In order to evaluate the compatibility/incompatibility
state, several instrumental techniques can be employed,as long they assure the reproducibility and certainty of the
results. Along with thermal analysis (TG/DTG/HF), which
was reported as a fast and precise method for analyzingbinary mixtures of API+EXC [1-3], other instrumental tools
can be used; by far, the most convenient are spectroscopic
methods (FTIR) and PXRD studies [4,5].
Belonging to the class of HMG-CoA reductase inhibitors
[6], simvastatin (SIM) is used for the treatment of
dyslipidemia and the prevention of cardiovascular disease[7], and up to the date is considered an essential drug in
the 18th model list of World Health Organization published
in October 2013, as evidence for effectiveness and safety[8]. This list indicate that tablet formulations with a content
of 5 mg, 10 mg, 20 mg and 40 mg SIM should be
taken into account.
Excipients are compounds that must be generally
recognized as safe (GRAS) under the conditions of their
intended use. The use of excipients in pharmaceuticalformulations is an absolute need, since the amount of API
per tablet can go down as micrograms, making the
* email: afulias@umft.roadministration to patient inconvenient. As well, the final
formulation forms should be able to fulfill severalrequirements, such as therapeutic enhancement of the
API by facilitating drug absorption and/or in vivo solubility.
Excipients are used for enhancing several properties intablet, such as adhesion, binding and friction of
components, dissolution, colour and flavour and
preservation. Regarding the selected excipients for our
study, calcium lactate (CL) is used as a directly
compressible excipient as a filler-binder of tablets [9],mannitol (MAN) is used as tablet diluent and sweeting
agent, while magnesium stearate (MS) is used mainly as
anti-adherent and lubricant for tablets [6]. The structuralformulae of employed compounds used in this study are
presented in scheme 1.
This study aims towards evaluation of compatibility/
incompatibility of SIM in binary solid systems with
pharmaceutical excipients (calcium lactate pentahydrate,
mannitol and magnesium stearate) by employing threeinstrumental techniques – namely thermal analysis, Fourier-
transform infrared spectroscopy and powder X-Ray
diffraction.
Experimental part
Material and methods
Simvastatin (analytical standard) was obtained from
Fluka and used as received, without further purification.
As tested excipients, calcium lactate pentahydrate (FisherChemical), mannitol (Merk Germany) and magnesium
stearate (Union Derivan Spain) were used. All the samples
were kept in a sealed tubes before use, in order to avoidhumidity retention. The three samples (SIM+CL, SIM+MAN
and SIM+MS, respectively) consisted of equal masses of
active substance and each excipient. Physical mixtureswere prepared by simple mixing of the two substances in
an agate mortar with pestle for approximately 5 min . The
mass ratio (1:1) was chosen in order to maximize theprobability of observing any interaction.
The thermoanalytical TG curves were drawn up in a
dynamic air atmosphere under non-isothermal conditions

REV . CHIM. (Bucharest) ♦ 66 ♦ No. 2 ♦ 2015 http://www.revistadechimie.ro 241at a heating rate β…=…10 °C·min-1 using a Perkin-Elmer
DIAMOND equipment. Samples of mass in the range of 6-8 mg were put into aluminum crucibles and heated by
increasing temperature from ambient up to 500°C (TG
analysis). In order to evaluate the accuracy of themeasurements, two repetitions were realised with this
experimental protocol for the samples and the obtained
results were practically identical.
Attenuated Total Reflection Fourier Transform Infrared
Spectroscopy (ATR-FTIR) spectra of the samples were
obtained in attenuated total reflectance (ATR) mode on aBruker Vertex 70 spectrometer equipped with a Platinium
ATR, Bruker Diamond Type A225/Q. Spectra were collected
in the 4000-400 cm
-1 spectral range, with a resolution of 1
cm-1 and with 64 co-added scans.
The phase composition of the powders was established
by X-ray diffraction, using a Rigaku Ultima IV instrument
operating at 40 kV and 40 mA. The X-ray diffraction patterns
were recorded using the monochromated CuKα radiation
(λ =1.5406 Ao).
Results and discussions
Thermal analysis
Thermal characterization of the active substance used
in mixtures’ preparation is presented in figure 1. The thermalprofile is characterized by two main decomposition stages,
the first one consiststing in a one endothermic and one
exothermic step, respectively. The HF event with HF
max=
135 °C corresponds to the melting of SIM, the temperature
value being according to the one reported in literature [7].
On further heating (330-500°C), the thermoanalyticalcurves evidenced the occurrence of the degradation
process in a multistep evolution. This decomposition region
is characterized by a mass loss of 51.15% and by threemaxima observed on the HF curve (HF
max= 409; 459;
467°C).
Simultaneous thermoanalytical curves for magnesium
stearate (MS) obtained in air atmosphere (fig. 1) reveal
one endothermic step below 130°C, due to release of
structural water but also due to the melting of MS whichbegins theoretically at 110 °C. Actually, the melting appears
at high temperature, the HF presenting an endothermic
peak with a shoulder caused by the presence ofmagnesium palmitate [3].
In the case of pure mannitol (MAN), the TG/DTG/HF
curves are presented infigure 1. It was observed a higherthermal stability for this excipient. The first endothermic
event appears at 168°C and represents the melting. The
thermal degradation begins at temperature higher that 168°C, with a maximum situated on DTG curves at 345 °C,
accompanied by two events on HF curve: one endothermic
(HF
max= 343°C) and one exothermic (HFmax= 361°C). The
final mass of the residue at Tfinal= 500°C is ≈ 0 %, suggesting
the complete degradation of this excipient.
The third excipient used for obtaining the binary mixture
with SIM is calcium lactate pentahydrate (CL). The thermal
profile exhibits a single dehydration step in 38-140°C
temperature range, maxima on DTG and HF being 91°Cand 95°C, respectively. The experimental values ( Δm
found=
28.3 %) for the mass loss are in good agreement with the
total theoretical percentage of the water loss ( Δmcalculated=
29.2 %).
In the case of the binary mixtures which were analyzed,
we followed the allure of the thermoanalytical curveswhich must be, in the case of absence of any
incompatibilities, the peaks sum of the two pure
substances (SIM and excipient).
The TG-DTG-HF profile recorded for SIM+MS binary
mixture showed a good similarity with the superimposing
of thermoanalytical curves of the pure ingredients.According to HF curve, it can be identified the peaks which
corresponds to the melting of SIM at a HF
max=137 °C. The
main observation is the absence of a melting peak forexcipient which melts at ≈ 110°C. A possible explication
can be the endothermal effect for melting process which
is inferior than the other effects which appear in the caseof binary mixture. This explication is sustained by the mass
loss which occurs in 35-130°C temperature range and
which corresponds only to the dehydration of the excipientsince the active substance (SIM) has a constant mass until
183°C. The thermal degradation of the mixture (the main
process) begins at a temperature value close to the 183°C(TG
onset=189°C) with a DTG maximum at 264°C.
For the second mixture, namely SIM+MAN, the
thermoanalitycal results are more similar with the thermal
profile of pure components comparative with the precedent
case. The both melting processes are presented in the HFcurve at HF
max=133°C for SIM and HFmax=167 °C for MAN,
respectively. The TGonset of the decomposition step is
observed at 178 °C and is due to the thermal instability ofSIM.
In the case of SIM+CL binary mixture, it was observed
a modification of the maximum of dehydration processwhich appears at lower temperature (HF
max= 78°C,
DTGmax= 77 °C). The mass loss which corresponds for this
process has an experimental value ≈ 16.1 % and is in good
agreement with the loss of the hydration water contained
in the excipient structure taking into account the mixing
ratio 1:1 (0.5× Δmtheoret water loss excipient). The thermal behaviour
of mixture on temperature range 140-500°C is similar to
the superposition of thermal curves observed for SIM and
CL, respectively, suggesting, as in previous cases, the lackof incompatibility between these two analyzed
compounds.
Attenuated Total Reflection Fourier Transform Infrared
Spectroscopy
The FT-IR spectra of SIM+EXC mixtures (fig. 2) were
presented in comparison with those of the active substance
and pure excipients. Since the FTIR spectrum of MAN was
previously described [10] and the purpose of carrying FTIRand PXRD studies is to confirm the data suggested by
thermal analysis, the results are presented only for the
bands appearing for “reactive” functional groups of SIMthat can be involved in interactions. Following these
observations, the FTIR bands observed for SIM in spectral
region 3570-3490 cm
-1 (broad, νOH) is observed in all cases
Scheme 1. Structural formulas of simvastatin (SIM) and selected
excipients: calcium lactate pentahydrate (CL), mannitol (MAN)
and magnesium stearate (MS)

http://www.revistadechimie.ro REV . CHIM. (Bucharest) ♦ 66 ♦ No. 2 ♦ 2015 242of binary mixtures, as well the position of the band at 1694
cm-1 (νC=O). Also, the vibrations of C-O-C moieties from
lactone group (1265 cm-1, δC-O-C) and ester (1162 cm-1, δC-
O-C) appear at the same wavenumber in all binary mixtures,
suggesting that no alliteration of the molecular structure
of SIM occurs during preparation of binary mixtures.Following this observation, FTIR spectroscopy results are
in good agreement with the ones suggested by thermal
analysis, namely the lack of incompatibility underexperimental conditions between SIM and EXC.
Powder X-ray diffraction patter ns
The compatibility study by the use of PXRD diffraction is
carried out by a comparative analysis of diffraction patterns
observed for SIM, EXC and their binary mixture. The possibleinteraction occurring under ambient conditions is revealedby shifting and/or apparition/disappearance of peaks from
the pattern of binary mixture vs. the one recorded for purecompounds. Following this, figure 3 presents the recorded
spectra for the analyzed samples. As indicated by the PXRD
pattern of pure SIM, peaks were recorded at 2 θ as follows:
7.60; 9.15; 9.85; 10.70; 12.55; 14.75; 15.40; 16.30; 17.05;
17.50; 17.85; 18.55; 19.20; 21.75; 22.35; 23.40; 23.95;
24.80; 25.15; 25.60; 26.10; 27.55; 28.10; 28.75; 29.55 and31.65 °, these peaks being recognized as well in the patterns
of binary mixtures at exactly the same value or at a similar
one (±0.05 °). This fact is a confirmation that the structure
Fig. 1. TG/DTG/HF curves recorded for
samples (binary mixtures and pure
components) in dynamic air atmosphere
(β= 10 °C min-1)
Fig. 2. The ATR-FTIR spectra recorded for analyzed samples

REV . CHIM. (Bucharest) ♦ 66 ♦ No. 2 ♦ 2015 http://www.revistadechimie.ro 243of SIM is unaltered and no incompatibility is suggested by
this instrumental technique.
By their analysis, it can be stated that the patterns
recorded for binary mixtures is mainly the superposition of
the peaks recorded for pure components, while themodification of intensity is due to the decreasing of molar
fraction of the components in mixtures. The patterns
suggest that no modification of crystallinity for compoundsoccurs during sample preparation and storage.
Conclusions
This study described the employment of three fast and
reproducible techniques used for the evaluation of solid-
state compatibility study between active pharmaceuticalingredients and excipients, namely thermal analysis, FTIR
spectroscopy and PXRD. The analyzed active substance,
simvastatin, did not show any incompatibilities withselected excipients – mannitol, calcium lactate and
magnesium stearate under ambient conditions nor high
temperatures.
Acknowledgement: This work was performed at West University of
Timișoara and was supported by the strategic grant POSDRU/159/1.5/S/137750, Project “Doctoral and Postdoctoral programs support for
increased competitiveness in Exact Sciences research” cofinanced by
the European Social Fund within the Sectorial Operational ProgrammeHuman Resources Development 2007-2013” to Ionuț Ledeți.Fig. 3. PXRD patterns recorded for analyzed
samples
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Manuscript received: 5.05.2014