Relationship between the crystallization rates of amorphous nifedipine, phenobarbital, and flopropione, and their molecular mobility as measured by their enthalpy relaxation and H-1 NMR relaxation times

Isothermal crystallization of amorphous nifedipine, phenobarbital, and flop ropione was studied at temperatures above and below their glass transition temperatures (T-g). A sharp decrease in the crystallization rate with decre asing temperature was observed for phenobarbital and flopropione, such that no crystallization was observed at temperatures 20-30 degrees C lower than their T-g within ordinary experimental time periods. In contrast, the crys tallization rate of nifedipine decreased moderately with decreasing tempera ture, and considerable crystallization was observed at 40 degrees C below i ts T-g within 4 months. The molecular mobility of these amorphous drugs was assessed by enthalpy relaxation and H-1-NMR relaxation measurements. The e nthalpy relaxation time of nifedipine was smaller than that of phenobarbita l or flopropinone at the same T - T-g values, suggesting higher molecular m obility of nifedipine. The spin-lattice relaxation time in the rotating fra me (T-1 rho) decreased markedly at temperature above T-g. The slope of the Arrhenius type plot of the T-1 rho for nifedipine protons changed at about 10 degrees C below the T-g, whereas the slope for phenobarbital protons bec ame discontinuous at about 10 degrees C above the T-g. Even at temperatures below its T-g, the spin-spin relaxation process of nifedipine could be des cribed by the sum of its Gaussian relaxation, which is characteristic of so lid protons, and its Lorentzian relaxation, which is characteristic of prot ons with higher mobility. In contrast, no Lorentzian relaxation was observe d for phenobarbital or flopropione at temperatures below their T-g. These r esults also suggest that nifedipine has higher molecular mobility than phen obarbital and flopropione at temperatures below T-g. The faster crystalliza tion of nifedipine than that of phenobarbital or flopropione observed at te mperatures below its T-g may be partly ascribed to its higher molecular mob ility at these temperatures. (C) 2000 Wiley-Liss, Inc. and the American Pha rmaceutical Association J Pharm Sci 89: 408-416, 2000.