Complex Formation of Nitrazepam in Coprecipitating and in Co-grinding with Methylated fl-Cyclodextrins

Complex formation of nitrazepam with heptakis-(2,6-di-0-methyl)-β-cyclodextrin (DM-β-CyD) and heptakis-(2,3,6-tri-0-methyl)-/J-cyclodextrin (TM-/J-CyD) together with a-, β-, and y-cyclodextrins (CyDs) in aqueous solution was confirmed by the solubility method. AL type phase solubility diagrams were obtained in all cases. The highest stability constant and the highest solubilized amount of nitrazepam was obtained with DM-/J-CyD, in the order DM-β-CyD > /J-CyD > TM-0-CyD > y-CyD > oc-CyD. Complex formation of nitrazepam with DM-β-CyD and TM-/f-CyD in the solid state was assessed by differential scanning calorimetry (DSC), infrared (IR) spectroscopy and X-ray diffractometry. Crystalline inclusion complex of nitrazepam with DM-/f-CyD in 1:2 molar ratio was obtained by the coprecipitation method. X-Ray diffraction analyses explained that nitrazepam was transformed from the crystalline to non-crystalline (amorphous) state by grinding with methylated β-CyDs. DSC analyses revealed that the heat of fusion due to nitrazepam disappeared in the ground mixture and coprecipitate of nitrazepam with DM-β-CyD in 1:2 molar ratio, which demonstrated the optimum content of dispersal nitrazepam with DM-/J-CyD in the solid state. IR spectra showed that there were higher frequency shifts for the carbonyl stretching band of nitrazepam in the ground mixtures and coprecipitates of DM-/S-CyD and TM-/f-CyD similar to the case of nitrazepam in CHCl3 solution, which were considered due to the monomolecular dispersion of nitrazepam in a hydrophobic environment. © 1990, The Pharmaceutical Society of Japan. All rights reserved.