Effects of aging on crystallization, dissolution and absorption characteristics of amorphous tolbutamide-2-hydroxypropyl-beta-cyclodextrin complex

The effects of storage on the crystallization, dissolution and absorption o f tolbutamide from amorphous tolbutamide-2-hydroxypropyl-beta-cyclodextrin (HP-beta CyD) complex were investigated. in comparison with those of polyvi nylpyrrolidone (PVP) solid dispersion. The amorphous solid complex of tolbu tamide with HP-beta CyD and the solid dispersion of tolbutamide with PVP we re prepared by a spray-drying method, During storage, a stable form of tolb utamide (form I) was crystallized from the amorphous PVP dispersion, wherea s a metastable form of tolbutamide (form II) was crystallized from the HP-b eta-CyD complex, The dissolution rate of tolbutamide from both HP-beta-CyD complex and PVP dispersion was significantly faster than that of tolbutamid e alone. However, the dissolution rate from the PVP dispersion markedly dec reased with storage, because of the formation of slow dissolving form I cry stals. On the other hand, the dissolution rate from the HP-beta-CyD complex was only slightly decreased due to the formation of fast dissolving formII crystals. These in vitro dissolution characteristics were clearly reflecte d in the in vivo absorption of tolbutamide and the glucose plasma level aft er oral administration in dogs. The results suggested that HP-beta-CyD is u seful not only for converting crystalline tolbutamide to an amorphous subst ance, but also for maintaining the fast dissolution rate of the drug over a long period. Furthermore, the crystallization of drugs from CyD complexes, with storage, seemed to be different from that involving polymer excipient s such as PVP.