Abstract
Two polymorphs (form I, form II) and amorphous form of candesartan cilexetil ((±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate; TCV-116) were characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (XRD), IR spectroscopy, and solid-state NMR. The molecular motion of TCV-116 in three forms was investigated by solid-state NMR, and signals due to the terminal cyclohexane ring of TCV-116 in form II were affected by temperature, whereas those in form I were scarcely affected. At lower (-89°C) and higher temperature (80°C), sharp signals due to the cyclohexane ring in form II were observed, whereas shallow signals were observed in the medium temperature range. These results indicated that the cyclohexane ring in form II presumably existed as the stable conformer : the chair form at lower temperature, and the chair form-chair form conformational change occurred at higher temperature. At the medium temperature, the broad and weak signals assigned to the cyclohexane ring in form II were presumably due to the flip-flop motion (correlation time being 10-4-10-5s) between the chair and boat forms. Results from the X-ray diffraction pattern and the crystal density also suggested that "free volume" for the flexible motion of the cyclohexane ring was present for form II.
