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.
Exposure of cimetidine (CIM) to dry heat (160-180°C) 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.
Pharmaceutical Analysis, Department of Organic Chemistry, School of Pharmaceutical and Biochemical Sciences, National University of Rosario and Institute of Chemistry of Rosario (IQUIR, CONICET-UNR), Suipacha 531, Rosario (S2002LRK), Argentina.
Natalia L
NL
Calvo
Pharmaceutical Analysis, Department of Organic Chemistry, School of Pharmaceutical and Biochemical Sciences, National University of Rosario and Institute of Chemistry of Rosario (IQUIR, CONICET-UNR), Suipacha 531, Rosario (S2002LRK), Argentina.
Sebastian O
SO
Simonetti
Pharmaceutical Analysis, Department of Organic Chemistry, School of Pharmaceutical and Biochemical Sciences, National University of Rosario and Institute of Chemistry of Rosario (IQUIR, CONICET-UNR), Suipacha 531, Rosario (S2002LRK), Argentina.
Rubén M
RM
Maggio
Pharmaceutical Analysis, Department of Organic Chemistry, School of Pharmaceutical and Biochemical Sciences, National University of Rosario and Institute of Chemistry of Rosario (IQUIR, CONICET-UNR), Suipacha 531, Rosario (S2002LRK), Argentina. Electronic address: kaufman@iquir-conicet.gov.ar.
Teodoro S
TS
Kaufman
D002927:Cimetidine / Q000737:chemistry*; D006635:Histamine H2 Antagonists / Q000737:chemistry*; D006358:Hot Temperature; D007536:Isomerism; D007700:Kinetics; D016018:Least-Squares Analysis; D009682:Magnetic Resonance Spectroscopy; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared
D006635:Histamine H2 Antagonists; D002927:Cimetidine
Cimetidine; Multi-spectroscopic/chemometric approach; Multivariate curve resolution with alternating least squares determination; Nuclear magnetic resonance spectroscopy; Spectroscopic characterization; Stable tautomeric form