A calorimetric investigation of thermodynamic and molecular mobility contributions to the physical stability of two pharmaceutical glasses

The purpose of this work was to investigate the contribution of thermodynamics and mobility to the physical stability of two pharmaceutical glasses with similar glass transition temperatures (Tg), by comparing configurational thermodynamic quantities and molecular relaxation time constants (tau) at temperatures below Tg. Ritonavir and nifedipine were chosen as model glasses because they show excellent and poor physical stability, respectively. Although ritonavir and nifedipine have similar Tg values (50 and 46 degrees C, respectively), amorphous ritonavir is quite stable while nifedipine has been reported to crystallize at temperatures as low as 40 degrees C below Tg. Modulated temperature differential scanning calorimetry (MTDSC) was used to characterize both crystalline phases and freshly prepared glasses. The glasses were then annealed at Tg-Ta = 25 degrees C while monitoring the extent of relaxation and heat capacity change as a function of time via MTDSC. Configurational thermodynamic quantities (Gc, Hc, and Sc) and molecular relaxation time constants, tau, were calculated from the calorimetric data. Interestingly, the Gibbs free energy driving force for crystallization was nearly identical for the two compounds. The largest differences were found in the configurational entropy (Sc) values for the fresh glasses and in the Sc values over time. Configurational entropy values were approximately 50% higher for ritonavir. The tau values of freshly prepared glasses indicated that both materials had similar initial mobility at the annealing temperatures and the temperature dependence of tau was approximately Arrhenius, regardless of age. Although initial tau values were similar, the tau values after 3 days annealing were approximately sixfold greater for ritonavir. The relatively poor physical stability of nifedipine compared to ritonavir is attributed to both the lower entropic barrier to crystallization for fresh and annealed glass, and higher molecular mobility in aged glasses of nifedipine. These observations below Tg are consistent with the previous work on physical stability of amorphous pharmaceuticals performed above Tg.