Characterization, Purity Determination and Decomposition Kinetics of Ezetimibe Under Non-Isothermal Conditions

Author(s): Guilherme A. G. Martins, Fabio S. Murakami, Maximiliano S. Sangoi, Vitor Todeschini, Larissa S. Bernardi, Paulo R. Oliveira*

Journal Name: Current Pharmaceutical Analysis

Volume 15 , Issue 4 , 2019

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Graphical Abstract:


Background: Ezetimibe is a lipid-lowering agent used therapeutically alone or in combination of other drugs. The properties of the solid-state of drugs are critical factors in the pharmaceutical formulation development. Several instrumental techniques can be employed in the analysis of new formulations, but the thermoanalytical techniques, provide a fast and careful evaluation of physicochemical properties of a compound.

Objective: To carry out the physicochemical characterization, purity evaluation and non-isothermal kinetic studies of ezetimibe raw material.

Methods: A combination of the following different analytical technics was employed: Differential Scanning Calorimetry, Thermogravimetric, Scanning Electron Microscopy, X-ray powder diffraction.

Results: The results evidenced the crystalline characteristic of ezetimibe. The sample purity was 99.06 % ± 0.02 and the thermal decomposition followed a zero order kinetic, with activation energy of 96.56 kJ mol–1 and Arrhenius frequency factor of 3,442 x 109 min-1.

Conclusion: The characterization of ezetimibe together with the non-isothermal kinetic degradation represents important studies for the pharmaceutical area, since it provides crucial information for the pharmacotechnical/quality control/production areas that should establish the specifications necessary to standardize the requirements of the raw material acquire to ensure the batch-to-batch reproducibility.

Keywords: Ezetimibe, thermal analysis, purity evaluation, decomposition kinetic, non-isothermal, solid-state, drugs.

Roumeli, E.; Tsiapranta, A.; Pavlidou, E.; Vourlias, G.; Kachrimanis, K.; Bikiaris, D.; Chrissafis, K. Compatibility study between trandolapril and natural excipients used in solid dosage forms. J. Therm. Anal. Calorim., 2013, 111(3), 2109-2115.
Fuliaş, A.; Ledeţi, I.; Vlase, G.; Vlase, T. Physico-chemical solid-state characterization of pharmaceutical pyrazolones: an unexpected thermal behaviour. J. Pharm. Biomed. Anal., 2013, 81-82, 44-49.
Veiga, A.; Oliveira, P.R.; Bernardi, L.S.; Mendes, C.; Silva, M.A.S.; Sangoi, M.S.; Janissek, P.R.; Murakami, F.S. Solid-state compatibility studies of a drug without melting point. J. Therm. Anal. Calorim., 2018, 131(3), 3201-3209.
Monajjemzadeh, F. LC-mass as a complementary method in detecting drug-excipient incompatibility of pharmaceutical products. J. Mol. Pharm. Org. Process Res., 2014, 2(1), 1-2.
Monajjemzadeh, F.; Hassanzadeh, D.; Valizadeh, H.; Siahi-Shadbad, M.R.; Mojarrad, J.S.; Robertson, T.A.; Roberts, M.S. Compatibility studies of acyclovir and lactose in physical mixtures and commercial tablets. Eur. J. Pharm. Biopharm., 2009, 73(3), 404-413.
De Barros Lima, Í.P.; Lima, N.G.P.B.; Barros, D.M.C.; Oliveira, T.S.; Mendonca, C.M.S.; Barbosa, E.G.; Raffin, F.N.; De Lima, E. Moura, T.F.A.; Gomes, A.P.B.; Ferrari, M.; Aragão, C.F.S. Com-patibility study between hydroquinone and the excipients used in semi-solid pharmaceutical forms by thermal and non-thermal techniques. J. Therm. Anal. Calorim., 2015, 120(1), 719-732.
de Mendonça, C.M.S.; de Barros, L.I.P.; Aragão, C.F.S.; Gomes, A.P.B. Thermal compatibility between hydroquinone and retinoic acid in pharmaceutical formulations. J. Therm. Anal. Calorim., 2014, 115(3), 2277-2285.
Murphy, C.B. Differential thermal analysis. Anal. Chem., 1958, 30(4), 867-872.
Höhne, G.W.H.; Hemminger, W.F.; Flammersheim, H-J. Differential Scanning Calorimetry, 2nd ed; Springer Berlin Heidelberg: Berlin, Heidelberg, 2003.
Alothman, Z.; Rahman, N.; Siddiqui, M.R. Review on pharma-ceutical impurities, stability studies and degradation products: an analytical approach. Rev. Adv. Sci. Eng., 2013, 2(2), 155-166.
Siddiqui, M.R.; AlOthman, Z.A.; Rahman, N. Analytical techniques in pharmaceutical analysis: a review. Arab. J. Chem., 2017, 10, S1409-S1421.
Rahman, N.; Azmi, S.N.H.; Wu, H-F. The importance of impurity analysis in pharmaceutical products: an integrated approach. Accredit. Qual. Assur., 2006, 11(1-2), 69-74.
S.R., Byrn; R.R., Pfeiffer J.G.S. Solid-State Chemistry of Drugs, 2nd ed; Ssci Inc: West Lafayette, Indiana, USA, 1999.
Bernardi, L.S.; Ferreira, F.F.; Cuffini, S.L.; Campos, C.E.M.; Monti, G.A.; Kuminek, G.; Oliveira, P.R.; Cardoso, S.G. Solid-state evaluation and polymorphic quantification of venlafaxine hydrochloride raw materials using the rietveld method. Talanta, 2013, 117, 189-195.
Teleginski, L.K.; Maciel, A.B.; Mendes, C.; Silva, M.A.S.; Bernardi, L.S.; de Oliveira, P.R. Fluconazole-excipient compatibility studies as the first step in the development of a formulation candidate for biowaiver. J. Therm. Anal. Calorim., 2015, 120(1), 771-781.
Ghaderi, F.; Nemati, M.; Siahi-Shadbad, M.R.; Valizadeh, H.; Monajjemzadeh, F. Physicochemical evaluation and non-isothermal kinetic study of the drug-excipient interaction between doxepin and lactose. Powder Technol., 2015, 286, 845-855.
Fulias, A.; Vlase, T.; Vlase, G.; Szabadai, Z.; Rusu, G.; Bandur, G. Thermoanalytical study of cefadroxil and its mixtures with different excipients. Rev. Chim., 2010, 1(12), 3-7.
Ghaderi, F.; Nemati, M.; Siahi-Shadbad, M.R.; Valizadeh, H.; Monajjemzadeh, F. DSC kinetic study of the incompatibility of doxepin with dextrose: application to pharmaceutical preformulation studies. J. Therm. Anal. Calorim., 2016, 123(3), 2081-2090.
Pani, N.; Nath, L.; Acharya, S. Compatibility studies of nateglinide with excipients in immediate release tablets. Acta Pharm., 2011, 61(2), 237-247.
Jahangiri, A.; Barzegar-Jalali, M.; Garjani, A.; Javadzadeh, Y.; Hamishehkar, H.; Rameshrad, M.; Adibkia, K. Physicochemical characterization and pharmacological evaluation of ezetimibe-PVP K30 solid dispersions in hyperlipidemic rats. Colloids Surf. B Biointerfaces, 2015, 134, 423-430.
Toth, P. Phan; Dayspring, T. Ezetimibe therapy: mechanism of action and clinical update. Vasc. Health Risk Manag., 2012, 8(1), 415.
Rosenblum, S.B.; Huynh, T.; Afonso, A.; Davis, H.R.; Yumibe, N.; Clader, J.W.; Burnett, D.A. Discovery of 1-(4-fluorophenyl)-(3 R)-[3-(4-fluorophenyl)-(3 S)- hydroxypropyl]-(4 S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of cholesterol absorption. J. Med. Chem., 1998, 41(6), 973-980.
Mulye, S.P.; Jamadar, S.A.; Karekar, P.S.; Pore, Y.V.; Dhawale, S.C. Improvement in physicochemical properties of ezetimibe using a crystal engineering technique. Powder Technol., 2012, 222, 131-138.
Löbenberg, R.; Amidon, G.L. Modern bioavailability, bioequivalence and biopharmaceutics classification system. new scientific approaches to international regulatory standards. Eur. J. Pharm. Biopharm., 2000, 50(1), 3-12.
Sugandha, K.; Kaity, S.; Mukherjee, S.; Isaac, J.; Ghosh, A. Solubility enhancement of ezetimibe by a cocrystal engineering technique. Cryst. Growth Des, 2014, 14 9), 4475-4486.
Patil, A.; Pore, Y.; Gavhane, Y.; Patil, S.; Patil, S. Spherical crystallization of ezetimibe for improvement in physicochemical and micromeritic properties. J. Pharm. Investig., 2014, 44(3), 213-224.
Bali, V.; Ali, M.; Ali, J. Study of surfactant combinations and development of a novel nanoemulsion for minimising variations in bioavailability of ezetimibe. Colloids Surf. B Biointerfaces, 2010, 76(2), 410-420.
Ozawa, T. A new method of analyzing thermogravimetric data. Bull. Chem. Soc. Jpn., 1965, 38(11), 1881-1886.
Oliveira, P.R.; Barth, T.; Todeschini, V.; Dalmora, S.L. Simultaneous liquid chromatographic determination of ezetimibe and simvastatin in pharmaceutical products. J. AOAC Int., 2007, 90(6), 1566-1572.
Zhang, D.; Su, J. Investigation of reduction process and related impurities in ezetimibe. J. Pharm. Biomed. Anal., 2015, 107, 355-363.
Sancheti, P.P.; Karekar, P.; Vyas, V.M.; Shah, M.; Pore, Y.V. Preparation and physicochemical characterization of surfactant based solid dispersions of ezetimibe. Pharmazie, 2009, 64(4), 227-231.
Mura, P.; Gratteri, P.; Faucci, M.T. Compatibility studies of multicomponent tablet formulations: DSC and experimental mixture design. J. Therm. Anal. Calorim., 2002, 68(2), 541-551.
Giron, D. Contribution of thermal methods and related techniques to the rational development of pharmaceuticals-Part 2. Pharm. Sci. Technol. Today, 1998, 1(6), 262-268.
Huang, Y.; Cheng, Y.; Alexander, K.; Dollimore, D. The thermal analysis study of the drug captopril. Thermochim. Acta, 2001, 367-368, 43-58.

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Article Details

Year: 2019
Published on: 19 March, 2019
Page: [327 - 332]
Pages: 6
DOI: 10.2174/1573412914666180213131010
Price: $65

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