“Intermolecular Interactions between Solids Amoxiciline and Omeprazole: a Solid state NMR Study

ALEXANDRE E SILVA, L. M.; RUSSO, M. G. ; NARDA, G. E. ; ELLENA, J. A; FERREIRA, A. G.; VENÂNCIO, T.

Angra dor Reis

Encuentro; 13th Nuclear Magnetic Resonance Users Meeting; 2011

AUREMN

INTERMOLECULAR INTERACTIONS BETWEEN SOLIDS AMOXICILINE AND OMEPRAZOLE: A SOLID STATE NMR STUDY   Lorena Mara Alexandre e Silva1, Marcos Guillermo Russo2, Griselda Edith Narda2, Javier Alcides Ellena3, Antonio Gilberto Ferreira1, Tiago Venâncio1 1 Departamento de Química – Universidade Federal de São Carlos, São Carlos, Brazil 2 Área de Química General e Inorgânica, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis, Argentina. 3 Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, Brazil venancio@ufscar.br   Keywords: amoxicillin, omeprazole, binary complex, solid state NMR.   Amoxicillin (AMX – fig.1a) is one of the most employed antibiotics to treat infections caused by different types of bacteria [1]. Omeprazole (OMZ – fig.1b) is the most used drug to treat gastric disorders (and also gastric ulcer) that can be one the side effects of several drugs [2]. This behavior leads to introduce the OMZ in the prescription.  (a)  (b) Fig.1. Chemical structure of amoxicillin (a) and omeprazole (b).   The association of these two drugs permitts the elimination Helicobater pylori, which is a bacterium that causes the majority of gastric ulcer, being a factor to develop stomach tumors [3]. Recently, binary systems have been widely studied [4] and the importance of these studies is to understand the mechanisms of the interactions drug-to-drug and drug-to-additives. It has been demonstrated that solid state NMR can be a very useful tool to elucidate these mechanisms [5]. Therefore, the aim of this work is to use the solid state NMR for studying the interactions between amoxiciline and omeprazole in a binary complex (AMX-OMZ), in order to have enough information to estimate the stability of the complex, taking into account their own activities. In this work we analyzed five different samples: OMZ, anhydrous AMX (AMXa), AMX.3H2O (AMXh), co-grinding AMXa-OMZ and AMXh-OMZ binary complexes. The isolated drugs were used as received and the AMX-OMZ binary complex was prepared by co-grinding. A Bruker Avance III NMR equipment was used by employing a 9.4T Oxford Magnet and a 4mm solid state probehead. For each sample it was performed a pool of solid state NMR techniques: CPTOSS (cross polarization with total sideband suppression), 1Hx13C-FSLG-HETCOR (frequency switched Lee-Goldburg heteronuclear correlation). For CPTOSS experiment we have used a 5KHz spinning speed, 2ms of contact time and 5s of recovering time. In fig. 2 it is shown the FSLG-HETCOR maps for all the samples. When we compare both fig.2c and 2a all the correlation signals from the acid protons (~10ppm) of the AMXa (fig.2a), disappear as the binary complex is formed (fig.2c). It can suggest that the AMXa-AMXa interactions can be broken when the complex with OMZ is formed. It can also be observed a weak correlation between the carbon in 159ppm with proton in 12ppm, which can be attributed to weak hydrogen bond between AMXa and OMZ. Any changes in the OMZ signals can be observed, also indicating that the interaction with AMX is weak. In the fig.2b is presented the FSLG-HETCOR obtained for the AMXh-OMZ binary complex. It is possible to observe that the number of correlation signals attributed to AMXh-AMXh interactions (fig.2d) has decreased. It suggests that the AMXh has a stronger interaction with OMZ molecules. However, it can be observed a correlation between a proton in ~12ppm and the C9 and C13 from OMZ, indicating a possible correlation with the N14 from aromatic ring. This same proton exhibits a correlation with C8 from OMZ. (a) (b) (c) (d) (d)   Fig.2. FSLG-HETCOR maps for: (a) AMXa-OMZ, (b) AMXh-OMZ, (c) AMXa, (d) AMOXh and (e) OMZ. Experimental parameters: contact time of 200ms, 10KHz of spinning speed. It can be concluded that according to results the AMXh-OMZ interaction is stronger than AMXa-OMZ. Some physical-chemical properties, such as solubility, can vary.   References 1.   A. Ghassempour, H. Rafati, A.L. Inasab; Y. Bashour, H. Ebrahimzadeh, M. Erfan AAPS Pharm. Sci. Tech., 2007, 8(4). 2.   R. M. Claramunt, C. López, J. Elguero ARKIVOC, 2006, 5. 3.   R.J. Adamek, M. Wegener, J. Labenz, M. Freitag, W. Opferkuch, G.H. Ruhl, Am. J. Gastroenterol, 1994, 89(1). 4.   A. Krupa, M. Majda, R. Jachowicz, W. Mozgawa, Thermochimica Acta, 2010, 509. 5.   H. W. Spiess,  Macromolecules, 2010, 43.   FAPESP (2009/13860-2), CNPq, CONICET