Thermally Induced Solid-State Transformation of Cimetidine. A Multi-spectroscopic/Chemometrics Determination of the Kinetics of the Process and Structural Elucidation of one of the Products as a Stable N3-Enamino Tautomer

CALVO, NATALIA L; SIMONETTI, S. O.; MAGGIO, R. M.; KAUFMAN, T. S.

ANALYTICA CHIMICA ACTA

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2015 vol. 875 p. 22 - 32

0003-2670

Exposure of cimetidine (CIM) to dry heat (160-180ºC) afforded, upon cooling, a glassy solid containing new and hitherto unknown products. The kinetics of this process was studied by a second order chemometrics-assisted multi-spectroscopic approach. Proton and carbon-13 nuclear magnetic resonance (NMR), as well as ultraviolet and infrared spectroscopic data were jointly used, whereas multivariate curve resolution with alternating least squares (MCR-ALS) was employed as the chemometrics method to extract process information. It was established that drug degradation follows a first order kinetics. One of the products was structurally characterized by mono- and bi-dimensional NMR experiments. It was found to be the N3-enamino tautomer (TAU) of CIM, resulting from the thermal isomerization of the double bond of the cyanoguanidine moiety of the drug, from the imine form to its N3-enamine state. The thus generated tautomer demonstrated to be stable for months in the glassy solid and in methanolic solutions. A theoretical study of CIM and TAU revealed that the latter is less stable; however, the energy barrier for tautomer interconversion is high enough, precluding the process to proceed rapidly at room temperature.