A novel Raman spectroscopic approach to identify polymorphism in leflunomide: a combined experimental and theoretical study

Abstract

Polymorphism is an important characteristic which affects the activity, solubility and other physical properties of a compound and can be induced by varying temperature, pressure and solvent. The presence and conversion of α to β polymorphic forms of an anti‐rheumatic drug leflunomide have been studied by temperature‐dependent and in situ Raman observations. Both α and β polymorphs were found to co‐exist in the temperature interval 367–372 K. The α form alone exists below 367 K and the β form alone above 373 K. The CO stretching band clearly demonstrates the α → β conversion because of breaking of N–H···O bond and formation of N–H···N bond. On cooling the Raman spectra suggest the irreversibility of this conversion. Thermodynamic stability, crystal parameters and surface morphology of both forms in the leflunomide powder used for the present study have been verified by differential scanning calorimetry, X‐ray powder diffraction and scanning electron microscopy. Copyright © 2015 John Wiley & Sons, Ltd.

Recent advances in linear and non‐linear Raman spectroscopy. Part XI

“…Sharma described a novel Raman spectroscopic approach to identify polymorphism in leflunomide through a combined experimental and theoretical study. The presence and conversion of α to β polymorphic forms of an antirheumatic drug leflunomide was studied by temperature‐dependent and in situ Raman observations …”

Surface enhanced Raman scattering based reaction monitoring of in vitro decyclization of creatinine → creatine

“…8 Density functional theory is an extensively used technique for the optimization of molecular structures and for obtaining meaningful structurespectra correlation. [33][34][35][36] The density functional theoretical (DFT) method, having Becke's non local three-parameter exchange along with the Lee-Yang-Parr correctional functional (B3LYP), 37,38 was employed for the calculations. We used two different basis sets: LanL2DZ, which is a double z quality basis set that takes into consideration the Los Alamos effective core potential for Ag, 39 and a 6-311++G(d,p) basis set for the carbon, nitrogen, oxygen and hydrogen atoms.…”

Detection of in Vitro Metabolite Formation of Leflunomide: A Fluorescence Dynamics and Electronic Structure Study

“…It is reported that the E isomer of teriflunomide interacts more strongly with DHODH than the Z isomer does. − In silico studies based on density functional theory (DFT) were recently performed to study the adsorption of leflunomide on carbon nanotubes . DFT-optimized structures of leflunomide, teriflunomide, and the analogues of teriflunomide were reported by Panek et al Temperature-dependent Raman and X-ray diffraction (XRD) studies have revealed that leflunomide exists in two polymorphic forms α and β, the former being predominantly present at room temperature and the latter occurring at temperatures higher than 373 K. The α and β forms have different hydrogen bonding patterns between monomers. , …”

“…18 DFT-optimized structures of leflunomide, teriflunomide, and the analogues of teriflunomide were reported by Panek et al 19 Temperature-dependent Raman and X-ray diffraction (XRD) studies have revealed that leflunomide exists in two polymorphic forms α and β, the former being predominantly present at room temperature and the latter occurring at temperatures higher than 373 K. The α and β forms have different hydrogen bonding patterns between monomers. 20,21 The action of leflunomide as a drug starts after formation of its metabolite. Therefore, the metabolic reaction plays a key role in pharmacological applications of leflunomide, and it is important to understand thoroughly the underlying process of drug action after its intake.…”