187A - ABRATEC
Transcrição
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. References [1] Chaves LL, Rolim LA, Gonçalves MLCM, Vieira ACC, Alves LDS, Soares MFR, Soares-Sobrinho JL, Lima MCA, Rolim-Neto PJ. Study of stability and drug-excipient compatibility of diethylcarbamazine citrate. J Therm Anal Calorim. 2013;111( 3):2179-86. [2] Pinto MF, de Moura EA, de Souza FS, Macêdo RO. Thermal compatibility studies of nitroimidazoles and excipients. J Therm Anal Calorim. 2010;102:323-9. IX Congresso Brasileiro de Análise Térmica e Calorimetria 09 a 12 de novembro de 2014 – Serra Negra – SP - Brasil [3] Mendonça CMS, Lima IPB, Aragão CFS, Gomes APB. Thermal compatibility between hydroquinone and retinoic acid in pharmaceutical formulations. J Therm Anal Calorim. 2014;115(3): 2277-85. [4] Oliveira PR, Stulzer HK, Bernardi LS, Borgmann SHM, Cardoso SG, Silva MAS. Sibutramine hydrochloride monohydrate, thermal behavior, decomposition kinetics and compatibility studies. J Therm Anal Calorim. 2010;100:277-82. [5] Roumeli E, Tsiapranta A, Pavlidou E, Vourlias G, Kachrimanis K, Bikiaris D, et al. Compatibility study between trandolapril and natural excipients used in solid dosage forms. J Therm Anal Calorim. 2012;111:2109-15. [6] Pani N, Nath L, Acharya S, Bhuniya B. Application of DSC, IST, and FTIR study in the compatibility testing of nateglinide with different pharmaceutical excipients. J Therm Anal Calorim. 2012;108(1):219-26. [7] BRITISH Pharmacopoeia. London: Her Majesty's Stationary Office, 2004. [8] Leliévre J, Liu H. A review of thermal studies of starch gelatinization. Thermochimica Acta.1994;246(2):309-15. [9] Araújo AA, Storpirtis S, Mercuri LP, Carvalho FM, dos Santos Filho M, Matos JR. Thermal analysis of the antiretroviral zidovudine (AZT) and excipients used in solid dosage forms. Int J Pharm.2003; 260(2): 303-14. [10] Bertol CD, Cruz AP, Stulzer HK, Murakami FS, Silva MAS. Thermal decomposition kinetics and compatibility studies of primaquine under isothermal and non-isothermal conditions. J Therm Anal Calorim.2010;102:187-92. [11] Pereira MAV, Fonseca GD, Silva-Júnior AA, Fernandes-Pedrosa MF, de Moura M de FV, Barbosa EG, Gomes APB, dos Santos KSCR. Compatibility study between chitosan and pharmaceutical excipients used in solid dosage forms. J Therm Anal Calorim.2014;116(2):1091-1100 [12] Park YJ, Ryu DS, Li DX, Quan QZ, Oh DH, Kim JO, Seo YG, Lee YI, Yong CS, Woo JS, Choi HG. Physicochemical Characterization of Tacrolimus-loaded Solid Dispersion with Sodium Carboxylmethyl Cellulose and Sodium Lauryl Sulfate. Arch Pharm Res. 2009;32( 6):893-8. [13] Heinz A, Savolainen M, Rades T, Strachan CJ. Quantifying ternary mixtures of different solid-state forms of indomethacin by Raman and near-infrared spectroscopy.2007;32:182-92.