We investigated the influence of drug-polymer hydrogen bonding interactions on molecular mobility and the physical stability in solid dispersions of nifedipine with each of the polymers polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMCAS), and poly(acrylic acid) (PAA). The drug-polymer interactions were monitored by FT-IR spectroscopy, the molecular mobility was characterized using broadband dielectric spectroscopy, and the crystallization kinetics was evaluated by powder X-ray diffractometry. The strength of drug-polymer hydrogen bonding, the structural relaxation time, and the crystallization kinetics were rank ordered as PVP > HPMCAS > PAA. At a fixed polymer concentration, the fraction of the drug bonded to the polymer was the highest with PVP. Addition of 20% w/w polymer resulted in ∼65-fold increase in the relaxation time in the PVP dispersion and only ∼5-fold increase in HPMCAS dispersion. In the PAA dispersions, there was no evidence of drug-polymer interactions and the polymer addition did not influence the relaxation time. Thus, the strongest drug-polymer hydrogen bonding interactions in PVP solid dispersions translated to the longest structural relaxation times and the highest resistance to drug crystallization.

We investigated the correlation between molecular mobility and physical stability in three model systems, including griseofulvin, nifedipine, and nifedipine-polyvinylpyrrolidone dispersion, and identified the specific mobility mode responsible for instability. The molecular mobility in the glassy as well as the supercooled liquid states of the model systems were comprehensively characterized using dynamic dielectric spectroscopy. Crystallization kinetics was monitored by powder X-ray diffractometry using either a laboratory (in the supercooled state) or a synchrotron (glassy) X-ray source. Structural (α-) relaxation appeared to be the mobility responsible for the observed physical instability at temperatures above Tg. Although the direct measurement of the structural relaxation time below Tg was not experimentally feasible, dielectric measurements in the supercooled state were used to provide an estimate of the α-relaxation times as a function of temperature in glassy pharmaceuticals. Again, there was a strong correlation between the α-relaxation and physical instability (crystallization) in the glassy state but not with any secondary relaxations. These results suggest that structural relaxation is a major contributor to physical instability both above and below Tg in these model systems.

We investigated the influence of sorbed water concentration on the molecular mobility and crystallization behavior in a model amorphous drug and a solid dispersion. The temperature scaling (Tg/T) allowed us to simultaneously evaluate the effects of water content and temperature on the relaxation time. In the supercooled dispersions, once scaled, the relaxation times of the systems with different water content overlapped. Thus, the observed increase in mobility could be explained by the "plasticization" effect of water. This effect also explained the decrease in crystallization onset temperature brought about by water. That is, plasticization is the underlying mechanism governing the observed increase in mobility and physical instability in the supercooled state. Similar results were observed in the glassy drug substance. A single linear relationship was observed between crystallization time (time for 0.5% crystallization) and Tg/T in both dry and water containing systems. Since fragility is unaffected by modest amounts of water, much like crystallization time, the mobility in the glass is expected to scale with Tg.

We investigated the influence of polymer concentration (2.5-20% w/w) on the molecular mobility and the physical stability in solid dispersions of nifedipine (NIF) with polyvinylpyrrolidone (PVP). With an increase in polymer concentration, the α-relaxation times measured by broadband dielectric spectroscopy were longer, which reflects a decrease in molecular mobility. In the supercooled state, at a given temperature (between 55 and 75 °C), the relaxation time increased linearly as a function of polymer concentration (2.5-20% w/w). The temperature dependence of the relaxation time indicated that the fragility of the dispersion, and by extension the mechanism by which the polymer influences the relaxation time, was independent of polymer concentration. The time for NIF crystallization also increased as a function of polymer concentration. Therefore, by using molecular mobility as a predictor, a model was built to predict NIF crystallization from the dispersions in the supercooled state. The predicted crystallization times were in excellent agreement with the experimental data.

The influence of the molecular weight of polyvinylpyrrolidone (PVP) on the molecular mobility and physical stability of indomethacin (IMC)–PVP solid dispersions was investigated over a wide temperature range in the supercooled state. As the polymer molecular weight increased, there was a decrease in molecular mobility as evident from the longer α-relaxation times. Inhibition of IMC crystallization also increased as a function of polymer molecular weight. The extent of H-bonding interaction between drug and polymer, quantified by ssNMR, was independent of polymer molecular weight. Over a polymer concentration range of 5–20% w/w, the temperature dependence of mobility and viscosity was reasonably similar for different grades of PVP. It was concluded that the increase in effectiveness in crystallization inhibition as a function of polymer molecular weight is due to the increased viscosity, which slows down the mobility of these systems.