Relationship Between the Crystallization Rates of Amorphous Nifedipine, Phenobarbital, and Flopropione, and Their Molecular Mobility as Measured by Their Enthalpy Relaxation and 1H NMR Relaxation Times

Abstract

Isothermal crystallization of amorphous nifedipine, phenobarbital, and flopropione was studied at temperatures above and below their glass transition temperatures (Tg). A sharp decrease in the crystallization rate with decreasing temperature was observed for phenobarbital and flopropione, such that no crystallization was observed at temperatures 20–30°C lower than their Tg within ordinary experimental time periods. In contrast, the crystallization rate of nifedipine decreased moderately with decreasing temperature, and considerable crystallization was observed at 40°C below its Tg within 4 months. The molecular mobility of these amorphous drugs was assessed by enthalpy relaxation and 1H‐NMR relaxation measurements. The enthalpy relaxation time of nifedipine was smaller than that of phenobarbital or flopropinone at the same T − Tg values, suggesting higher molecular mobility of nifedipine. The spin–lattice relaxation time in the rotating frame (T1ρ) decreased markedly at temperature above Tg. The slope of the Arrhenius type plot of the T1ρ for nifedipine protons changed at about 10°C below the Tg, whereas the slope for phenobarbital protons became discontinuous at about 10°C above the Tg. Even at temperatures below its Tg, the spin–spin relaxation process of nifedipine could be described by the sum of its Gaussian relaxation, which is characteristic of solid protons, and its Lorentzian relaxation, which is characteristic of protons with higher mobility. In contrast, no Lorentzian relaxation was observed for phenobarbital or flopropione at temperatures below their Tg. These results also suggest that nifedipine has higher molecular mobility than phenobarbital and flopropione at temperatures below Tg. The faster crystallization of nifedipine than that of phenobarbital or flopropione observed at temperatures below its Tg may be partly ascribed to its higher molecular mobility at these temperatures. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 408–416, 2000