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IX Congresso Brasileiro de Anlise Trmica e Calorimetria

09 a 12 de novembro de 2014 Serra Negra SP - Brasil

Compatibility study between atorvastatin and excipients using DSC and FTIR

Edilamar Pereira da Silva, aMaxciara Agda Vicente Pereira, aIgor Prado de Barros Lima, aNaiana

Gondim Pereira de Barros Lima, a Euzbio Guimares Barbosa, aCcero Flvio Soares Arago, aAna Paula
Barreto Gomes
a

Laboratory Quality Control (LCQMed), Pharmaceutical Sciences Department Federal University of

Rio Grande do Norte UFRN, Av, General Cordeiro de Faria s/n, Petrpolis, Zip. 59000-000, Natal
Rio Grande do Norte - Brazil

Abstract: The objective of this study was to characterize the atorvastatin and evaluate possible
interactions between atorvastatin and various excipients by DSC and FT -IR. The DSC curves were
obtained using a Shimadzu calorimeter, Model DSC -60 in the aluminum crucible under heating rate of
20 C/min at a temperature of 25-400C. The spectra of the samples were obtained on a FTIR - ATR -21
model IRprestige Shimadzu spectrophotometer at a wavelength of 700-4000 cm-1 on average of 20 scans.
The theoretical spectrum was obtained using an ad hoc algorithm. From the analysis of DSC and
evaluation of Pearson correlations, we observed physical interactions with excipients, starch glycolate,
pre gelatinized starch, croscarmellose, sodium lauryl sulfate, magnesium stearate and mannitol. There is
no interaction with lactose.
Keywords: Atorvastatin, preformulation study, DSC, FT-IR.

Introduction
The atorvastatin is an antilipemic agent by the group of statins and is normally used as
atorvastatin calcium. Its molecular formula is: C66H68CaF2N4O10 3H2O. Atorvastatin calcium is a white
crystalline powder, of molecular weight of 1,209.4 g/mol and melting point between the following
temperatures 159.2 C and 160.7 C [1].
There are many medicines based on statins on the market and, although there are methods
pharmacopoeial assays in compendiums foreigners, there are no methods described for atorvastatin in
Brazilian Pharmacopoeia fifth edition, but have few work in this direction [2].
Preformulation study consists in the characterization of chemical and physical interactions of
drugs through binary mixtures drug+excipients. Thus, the thermal techniques are defined as a set of
techniques that allow measuring the physicochemical properties of a substance as a function of
temperature [3]. The thermal technique used most in the pharmaceutical area is the Differential Scanning
Calorimetry. Many other works were also developed using the differential scanning calorimetry for the
characterization of drugs and preformulation studies, as well as other authors [4-9].

IX Congresso Brasileiro de Anlise Trmica e Calorimetria


09 a 12 de novembro de 2014 Serra Negra SP - Brasil
Jin and Ulrich (2010) presented the characterization of atorvastatin that may be present in
multiple polymorphic forms depending on the type of solvent used [6]. Thus, it is necessary to conduct
further studies of preformulation for atorvastatin, by the need for characterization and determination of
stability to ensure quality of product that is of such importance for the treatment of dyslipidemias. The
aim of this study was to characterize the atorvastatin and to evaluate possible interactions atorvastatin +
excipients by DSC and FTIR.

Materials and Methods


Materials
Atorvastatin calcium, provided by Gemini. The excipients were: lubricant (magnesium stearate),
diluent (mannitol); disintegrants (starch glycolate and croscarmellose); wetting agent (sodium lauryl
sulfate), obtained of Henrifarma; diluent and agglutinant (lactose monohydrate, starch pre gelatinized)
obtained of Galena and Henrifarma, respectively; diluent and disintegrant (microcrystalline cellulose 101,
microcrystalline cellulose 102) obtained of Galena and Henrifarma, respectively. The binary mixtures
atorvastatin : excipient (2 mg) were prepared by simple mixing with a spatula at proportion of 1:1 (w / w)
and analyzed by DSC and FTIR.

Thermal Analysis
DSC curves were recorded with a Differential Scanning Calorimeter (Shimadzu, model DSC-50)
using a closed aluminum crucible. The apparatus was calibrated using indium as the standard. A rising
temperature experiment was conducted in the temperature range 25400 C at heating a rate of 10 and 20
C min-1 in nitrogen flow 50 mL min-1. The mass was 2.0 0.5 mg range. TG curves of the sample were
obtained in a thermobalance Shimadzu model DTG-60, with nitrogen flow 50 mL / min, at a heating rate
of 20 C min-1 from 25 C to 900 C. The mass was 5mg using alumina crucible. The verification of the
thermobalance was taken through the standard calcium oxalate. The curves were analyzed using the
software from Shimadzu.

Spectroscopy Fourier Transform Infrared (FTIR)


The spectra of individual samples and binary mixtures were obtained on a spectrophotometer
FTIR-ATR model IRprestige-21 from Shimadzu at a wavelength of 700-4000 cm-1 on average of 20 scans
per sample. We evaluated the spectral constancy of atorvastatin and binary mixtures by making a linear
correlation between the theoretical spectrum and the real spectrum of the sample obtained at room
temperature (25 C). The theoretical spectrum was obtained using an ad hoc algorithm that normalizes all
spectra and combines the spectrum based on the molar physical mixture composition. The next
correlation (r = 1) was indicative of the absence of physicochemical interaction.

Results and Discussion

Thermal characterization of Atorvastatin

IX Congresso Brasileiro de Anlise Trmica e Calorimetria


09 a 12 de novembro de 2014 Serra Negra SP - Brasil
DSC and TG/DTG curves of atorvastatin are shown in Figure 1. DSC curve of atorvastatin ( 20 C min-1) shows an endothermic event whose melting Tonset was 151 C and Tpeak was 161 C (H - 42
J g-1). Then another endothermic event is observed which can be attributed to a phase transition
characteristic of this polymorph with the following decomposition there of around 250 C.

FIGURE 1. Curves DSC (continuous line); TG (dashed) and first derivative TG (dotted) of atorvastatin in heating
rate 20 C min-1.

DSC data corroborate with TG data showing no weight loss observed in the range of melting in
addition to the decomposition starts at 190 C. TG curve presented four steps as can be seen in DTG. The
first step corresponds to the moisture loss equivalent to 3%, which is not observed in the DSC. According
to Zhang et al (2009), DSC curve shows three endothermic events. The first event between 75-125 C
(enthalpy of 24.29 J g-1) is attributed to loss of three molecules of water, consistent with the TG data. The
melting peak of atorvastatin according Zhang (2009) happened to 158.8C and enthalpy of 86.85 J g-1[7].
Carvalho et al (2012) evaluated four batches of atorvastatin calcium by thermal analysis, X-ray diffraction
and infrared. This study revealed that two batches of atorvastatin calcium crystals are two lots are
amorphous and therefore exhibit the same polymorph structure as reported in the literature [8].
The atorvastatin was analyzed by FTIR for different temperatures: 130,150,170,190 and 205 C
(Figure 2). It showed only the region of the fingerprint. The bands at 1650.3 corresponds to the C = O
stretch; at 1469.3 corresponding to C = C stretching; at 1381.6 and 1159.6 corresponding the C-C stretch.
These assignments were characteristics of atorvastatin. Already at 130 C is possible to notice changes in
the spectrum as bands and extending formation of new vibration, getting more obvious each increase in
temperature.

IX Congresso Brasileiro de Anlise Trmica e Calorimetria

190 C

250 C

09 a 12 de novembro de 2014 Serra Negra SP - Brasil


500
101
100
99
98
97
100
96

1000

1500

2000

1000

1500

2000

98
96

170 C

94
100
98

Atorvastatin

130 C

150 C

96
105
100
95
90
100
98
96
94
100
90
80
500

Wave number

FIGURE 2. FTIR spectra of atorvastatin at different temperatures (130,150,170,190 and 205 C).

Preformulation study
The atorvastatin produces melting peak small at heating rate of 10 C min-1 and consequently a
little enthalpy. Then, the preformulation study was realized at heating rate of 20 C min-1 (Figure 3). DSC
has been proposed for evaluating physico-chemical interactions between active pharmaceutical
ingredients and excipients quickly. When there are displacements in the onset temperature of melting or
decrease of melting enthalpy can be indicating interactions.

Figure 3. DSC curves of atorvastatin (1) + excipients: (2) sodium lauryl sulfate, (3) croscarmellose, (4) pregelatinized starch, (5) Microcrystalline cellulose 101 (MC 101) (6) lactose, (7) mannitol, (8) microcrystalline
cellulose 102 (MC 102) and (9) and magnesium stearate (10) sodium starch glycolate.

IX Congresso Brasileiro de Anlise Trmica e Calorimetria


09 a 12 de novembro de 2014 Serra Negra SP - Brasil
The atorvastatin studied there is a limited thermal behavior due to low intensity of melting peak.
When in binary mixtures the melting peak of atorvastatin disappear, or decrease of intensity, or
displacement indicate physical interaction. So, we suggest that occurs physical interactions with
following excipients: croscarmellose, pre-gelatinized starch, microcrystalline cellulose 101 (MC 101),
microcrystalline cellulose 102 (MC 102), magnesium stearate, sodium starch glycolate and sodium lauryl
sulfate. DSC curve of atorvastatin + lactose shows only the characteristic endothermic peaks of lactose.
According to the literature [9], lactose melting at 144 C prior to the melting of atorvastatin which
promotes the solubility of atorvastatin into the lactose and subsequent disappearance of the peak
temperature of atorvastatin. Therefore, there is no interaction with lactose. This is confirmed with
Pearsons correlation (data no showed). DSC curve of atorvastatin+mannitol cause the disappearance of
the melting peak characteristic of atorvastatin or appearance of only peak of the excipient. Thus, we
suggest interactions which may be physical or chemical. This confirmation will be evaluated with
additional tests of FTIR.

Spectroscopy Fourier Transform Infrared (FTIR)


Figure 4 shows a comparison of the theoretical and experimental spectra for mixtures with
sodium lauryl sulfate and mannitol excipient. Pearson's correlation was done to others excipients but there
are no interaction (data no shown).

1600

1200

1000

800

1600
1.0

0.8

0.8

0.6

Pearson Correlation

0.6

1.0

0.5

0.0

1200

1000

800

1000

800

Pearson Correlation

Theoretical expectro

0.5

0.0

1.0

1.0

0.5

0.5

0.0

1400

1.0

Mannitol

Sodium lauryl sulfate

1400

1.0

0.0

Experimental expectro
1600

1400

1200

1000
-1

Wave number (cm )

800

Theoretical expectro

Experimental expectro
1600

1400

1200

-1

Wave number (cm )

Figure 4 - Comparison of the theoretical and experimental spectra for the mixtures: atorvastatin + sodium lauryl
sulfate and atorvastatin + mannitol. It was shown only in the fingerprint region.

Then, in the figure 4 can be possible to see the Pearson's correlation for sodium lauryl sulfate and
there is no interactions, because the r is close to 0.8 showing a good correlation. However, the Pearson's
correlation for binary mixture of atorvastatin + mannitol showed changes in the intensity of spectrum in
1650.3 cm-1 (r = 0.65) and 1381 cm-1 (r = 0.69), indicating a moderate correlation between the theoretical

IX Congresso Brasileiro de Anlise Trmica e Calorimetria


09 a 12 de novembro de 2014 Serra Negra SP - Brasil
and experimental spectrum in this region. Therefore, we can be suggest at environment temperature a
chemical interaction of atorvastatin and mannitol excipient probably linked by hydrogen bonds. This
hypotesis can be confirmed using others techniques with HPLC or DRX.
Conclusions
The results confirm that DSC may be useful to be applied in the characterization of active
pharmaceutical ingredients and preformulation study as technique rapid "screening" for selecting between
multiple carriers, optimizing the choice of the components of a formulation. Thus, physical interactions
observed with the following excipients: sodium starch glycolate, pre-gelatinized starch, sodium lauryl
sulfate, croscarmellose and magnesium stearate. There is no interaction with lactose. There are possible
chemical interactions with mannitol.

References
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Stress Conditions and Chemical Analysis by HPLC. Molecules. 2013; 18: 1447-1456.
[2] Zerbini APN. Desenvolvimento e avaliao de minicomprimidos contendo atorvastatina clcica.
Universidade de So Paulo, 2010.
[3] FARMACOPEIA BRASILEIRA, VOLUME 1, 5 edio, 2010.
[4] Mendona CMS, Lima IPB, Arago CFS, Gomes APB. Thermal compatibility between hydroquinone
and retinoic acid in pharmaceutical formulations. J. Therm Anal Calorim. 2013; DOI 10.1007//s10973013-2941-6.
[5] Freire FD, Arago CF, LIMA TFA, Raffim FN. Compatibility study between chlorpropamide and
excipients in their physical mixtures. J Therm Anal Calorim. 2009; 97: 355357.
[6] Jin YS & Ulrich J. New Crystalline Solvates of Atorvastatin Calcium. Chem. Eng. Technol. 2010; 33,
5: 839844.
[7] Zhang HX, Wang JX, Zhang ZB, LE Y, SHEN ZG, CHEN JF. Micronization of atorvastatin calcium
by antisolvent precipitation process. International Journal of Pharmaceutics. 2009; 374: 106113.
[8] Carvalho KP, Rocha TC and Leles MIG. Characterization of atorvastatin by TG and DSC. Brazilian
Journal of Thermal Analysis 2012; 1: 79-83.
[9] Yoshida MI, Oliveira MA, Lacerda CD, Bonella AF, Valotto RS. Caracterizao Trmica da
Atorvastatina e Estudos de Compatibilidade de Formulaes Farmacuticas. Brazilian Journal of Thermal
Analysis. 2012; 1: 73-78.