Crystallization rate of amorphous nifedipine analogues unrelated to the glass transition temperature

To examine the relative contributions of molecular mobility and thermodynamic factor, the relationship between glass transition temperature (Tg) and the crystallization rate was examined using amorphous dihydropyridines (nifedipine (NFD), m-nifedipine (m-NFD), nitrendipine (NTR) and nilvadipine (NLV)) with differing Tg values. The time required for 10% crystallization, t90, was calculated from the time course of decreases in the heat capacity change at Tg. The t90 of NLV and NTR decreased with decreases in Tg associated with water sorption. The t90 versus Tg/T plots almost overlapped for samples of differing water contents, indicating that the crystallization rate is determined by molecular mobility as indicated by Tg. In contrast, differences in the crystallization rate between these four drugs cannot be explained only by molecular mobility, since the t90 values at a given Tg/T were in the order: NLV > NTR > NFD ≈ m-NFD. A lower rate was obtained for amorphous drugs with lower structural symmetry and more bulky functional groups, suggesting that these factors are also important. Furthermore, the crystallization rate of NTR in solid dispersions with poly(vinylpyrrolidone) (PVP) and hydroxypropyl methylcellulose (HPMC) decreased to a greater extent than expected from the increased Tg. This also suggests that factors other than molecular mobility affect the crystallization rate.