187A - ABRATEC

IX Congresso Brasileiro de Análise Térmica e Calorimetria
09 a 12 de novembro de 2014 – Serra Negra – SP - Brasil
Abstract
In the present study were evaluated the compatibility of ciprofibrate (CIP) with pharmaceutical
excipients usually used in the solid forms by analytical techniques. Binary mixtures with pharmaceutical
excipients were examined by Differential Screening Calorimetry (DSC) initially used to assess
compatibility of mixtures of CIP and each selected excipients in a 1:1 (w/w) physical mixtures. The
Fourier Transform Infrared (FTIR) spectroscopy and X-ray Powder Diffractometry were used to provide
a complete investigation of the binary mixtures. The CIP:hydroxypropylmethylcellulose mixture
displayed some physical interaction based on the DSC results, but the FTIR study ruled out any
chemical change. The binary mixture with microcrystalline cellulose showed changes in the XRDP.
Keywords: Ciprofibrate. Drug-excipient interaction. Thermal analysis. FTIR. XRPD.
Introduction
The study of drug-excipient mixture compatibility is an important stage in the preformulation studies
during the development of pharmaceutical forms [1]. Thermoanalytical methods are frequently used to
investigate and predict physicochemical incompatibilities between drugs and pharmaceutical excipients
[2,3]. Techniques like X-ray powder diffractometry and FTIR are valuable tools for getting accurate
conclusions [4-6].
This study aimed to evaluate the thermal stability of CIP and the impact that the excipients used in the
development of solid dosage forms can bring when combined in binary mixtures (BMs) 1:1 (w/w).
Experimental
Materials
The CIP and the following excipients were used in pharmaceutical grade purity: starch, microcrystalline
cellulose (MC), hydroxypropylmethylcellulose (HPMC), monohydrate lactose (ML) and sodium lauryl
sulfate (SLS).
Physical mixtures of CIP with each selected excipient were prepared in a 1:1 (w:w) ratio in a vortex for
approximately 3 min. The 1:1 (w/w) ration was chosen in order to maximize the probability of observing
any possible interaction.
IX Congresso Brasileiro de Análise Térmica e Calorimetria
09 a 12 de novembro de 2014 – Serra Negra – SP - Brasil
Methods
Thermal Analysis
DSC curves were obtained in Shimadzu Calorimeter, model DSC-60, cell using aluminum-sealed
crucibles containing approximately 2 mg of sample under dynamic N2 atmosphere (flow rate of 100 mL
min-1) and heating rate of 10 °C min-1 in the temperature range from 30 up to 400 °C. DSC was
calibrated with indium and lead metal standart.
TG curves were obtained in a Shimadzu thermobalance, model DTG-60, under dynamic N2 atmosphere
(flow rate 50 mL min-1) and heating rate of 10 °C min-1 in the temperature range from 30 up to 400 °C.
Samples were weighted in platinum crucibles about 2 mg. The TG instrument was calibrated using
indium and aluminum metal standart.
Fourier Transform Infrared Spectroscopy and X-Ray Powder Diffraction
Infrared spectra were recorded at room temperature using a Spectrum 1000 - PerkinElmer using KBr
compressed discs. Each spectrum was obtained by averaging 32 scans from 4000 down to 600 cm-1 with
1 cm-1 of spectral resolution.
Powder X-ray Powder Diffraction (XRPD) data were collected in a Shimadzu XRD-7000 diffractometer
under 40kV, 30mA, using Cu K (= 1.54056 Å) equipped with a polycapillary focusing optics under
parallel geometry coupled with a graphite monochromator, scanned over an angular range of 4-70° (2)
with a step size of 0.01° (2) and a time constant of 5 s step-1. The sample holder was submitted to a
spinning of 30 cycles per minute to minimize rugosity effects and to reduce any eventual preferred
orientation. The lattice parameters were determined by Rietveld fitting analysis.
Results and discussion
Thermal Behavior of CIP
The TG/DTG and DSC curves obtained for CIP are presented in Figure 1. The DSC curve of CIP
presents a sharp endothermic event at 115.9 °C (Tonset = 114.7 °C; Hfus = 109.9 J g−1) indicating the
melting at approximately 115 °C as indicated in literature [7]. At this temperature range, the TG/DTG
curves did not show any mass loss. The TG/DTG curves shows that CIP is thermally stable up to 135
°C.
IX Congresso Brasileiro de Análise Térmica e Calorimetria
09 a 12 de novembro de 2014 – Serra Negra – SP - Brasil
Figure 1 - TG/DTG and DSC curves of pure CIP.
Drug-excipient compatibility studies
The thermoanalytical data of CIP and tested excipients, obtained from the thermal curves (Figure 2), are
collected in Table 1.
Figure 2 - DSC curve of pure CIP and excipients.
Table 1- Thermoanalytical data of CIP and excipients.
Substance
Ciprofibrate
Starch
MC
HPMC
LM
SLS
DSC curves
Tonset (°C)
114.3
34.8
31.6
34.8
142.4; 167.7; 197.6
90.4; 184.8
Nature of process
Tpeak DSC (°C)
115.9
53.7
51.4
44.2
145.5; 171.9; 207.7
97.7; 188.1
Melting [7]
Gelatinization [8]
Dehydratation
Dehydratation
Dehydratation; crystalline transition; melting [9,10]
Dehydration; melting [11,12]
The thermal curves of binary mixtures (Figure 3) can be considered as a superposition of the curves of
CIP and all studied excipients, evidencing the absence of any incompatibility between CIP and starch,
MC, ML and SLS. Meaningful change in the melting event of CIP was found out only for the binary
IX Congresso Brasileiro de Análise Térmica e Calorimetria
09 a 12 de novembro de 2014 – Serra Negra – SP - Brasil
mixture of CIP with HPMC indicating possible interaction. Besides, the enthalpy heat involved in the
melting event of the CIP was reduced to half except for the HMPC mixture, as showed in the Table 2.
Figure 3 - DSC curves of CIP and its 1:1 physical mixtures.
Table 2 - Thermoanalytical data of CIP and drug-excipient physical mixtures.
Sample
CIP
Starch: CIP
MC: CIP
HPMC: CIP
LM: CIP
SLS:CIP
DSC curves
Tonset (°C)
114.3
114.5
114.6
98.9
114.7
111.8
Hfusion (J g−1)
Tpeak DSC (°C)
115.9
116.2
116.5
110.4
116.3
114.2
201.87
97.93
107.60
75.53
99.65
102.34
The FTIR spectroscopy was used as a supplementary technique in order to investigate possibles
chemical interactions. The Figure 4 presents the IR spectra of CIP and its binary mixtures.
Figure 4 - IR spectra of CIP and its binary mixtures.
IX Congresso Brasileiro de Análise Térmica e Calorimetria
09 a 12 de novembro de 2014 – Serra Negra – SP - Brasil
The FTIR spectra of the binary mixtures exhibit all the main absorption bands of CIP. Therefore, no
chemical interactions were detected. In addition, it can be concluded that the interaction between CIP
and HPMC shown by DSC is a solid state interaction.
The X-ray diffraction patterns of the CIP and binary mixtures are showed in the Figure 5. The
diffractogram of CIP mixtures with starch, HPMC, ML and SLS presents the main lines of the pure CIP.
Despite observing the appearance of new peaks in these mixtures, they can be related to each excipient
mixture. However, the diffraction pattern of CIP:MC changed so that the material began to show
amorphous phase. This change may have an impact on its bioavailability, processability, and chemical
and physical stability the formulation [13].
Figure 5 - X-ray diffractogram of CIP and its binary mixtures.
Conclusions
The compatibilities of CIP with selected pharmaceutical excipients were studied by DSC, XRPD and
FTIR. The data from DSC and FTIR indicated solid state interaction of the CIP with HPMC. The XRPD
analysis showed the change from crystalline to amorphous form in the CIP:MC mixture.
Acknowledgements
The authors are grateful to CNPq, CAPES and FAPEMIG for financial support.
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IX Congresso Brasileiro de Análise Térmica e Calorimetria
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