The Solid Dispersion of Benzodiazepins with Phosphatidylcholine. The Effect of Substituents of Benzodiazepins on the Formation of Solid Dispersions.

Abstract

Solid dispersions of four benzodiazepins, nitrazepam (NZP), nimetazepam (NMP), diazepam (DZP) and medazepam (MZP), with phosphatidylcholine (PC) were prepared to investigate the effect of functional groups of benzodiazepins. These benzodiazepins were present in an amorphous state immediately after preparation of the solid dispersion. The limit mole fractions for the amorphous state were 0.50 (NZP), 0.25 (NMP), 0.25-0.40 (DZP) and 0.25 (MZP). Infrared spectra and thermal analysis suggested an interaction, probably a hydrogen bond, between PC and NZP. In contrast, no interaction was suggested between PC and NMP, DZP or MZP, because they have no functional donor groups for the hydrogen bond. NZP solid dispersion showed no change after 1 year, but NMP, DZP and MZP solid dispersion showed recrystallization of drugs after 1 year. Thus, it was considered that some interaction between PC and the drug was needed to prevent the recrystallization. Dissolution of NZP in pH 7.0 phosphate buffer solution was much faster from NZP solid dispersion than from NZP crystals, and there was no aging effect of the solid dispersion. Dissolution of DZP also improved with the formation of a solid dispersion, but the dissolution rate became slower with time.