(M0930-11-75) Predicting the Stability of Amorphous Formulations Mixtures with Terahertz Spectroscopy

Purpose: Crystalline drug formulations have limited drug solubility. The drug particle size can be reduced, or the crystalline drug can be converted into an amorphous form to increase drug solubility. However, amorphous drugs are highly unstable as they will revert to their crystalline form over time. Polymers are widely used in the pharmaceutical industry as excipients and stabilisers for amorphous formulations. Adding polymers into pharmaceutical formulations will allow polymers to create drug-polymer interaction. This prevents the drug particles from coming into proximity and rearranging the molecules to form a crystalline structure. One of the parameters conventionally used to describe the stability of an amorphous formulation is the glass transition temperature (T_g). Higher T_g usually correlates to higher physical stability. However, some drugs have the same T_g but have different physical stability. This suggests that using T_g alone to predict the physical stability may not be the most accurate. One recent method proposed to predict physical stability is by studying the slope between the onset of local and global mobility, which can be detected by using neutron scattering. However, as neutron scattering is costly, terahertz time-domain spectroscopy (THz-TDS) is a more attractive method to detect the slope.

Methods: THz-TDS is a technique that probes molecular mobility, and mobility is related to the stability of the formulation. In this study, THz-TDS was used to predict the concentration of indomethacin (IMC) and PVP/VA copolymer, which results in the highest physical stability. First, different concentrations of IMC-PVP/VA mixture were milled at room temperature for homogeneity, and then the mixture was melted and quench-cooled into a clear amorphous pellet. The samples were measured with a TeraPulse 4000 spectrometer over a range of temperatures between 80 to 420 K.

Results: Pure PVP/VA shows the highest absorption coefficient, which indicates the highest molecular mobility. There is a gradual increase in molecular mobility for all concentrations from 80 K to T_g and a more drastic change in molecular mobility from T_g to 420 K. Higher concentrations of indomethacin result in a greater change in molecular mobility at T_g. After normalising all concentrations to the molecular mobility at 80 K, the slopes between the onset of local and global mobility for each concentration can be observed. The concentration of 30% IMC shows the lowest slope, which suggests that this is the concentration for IMC-PVP/VA mixture with the highest physical stability.

Conclusion: The use of terahertz spectroscopy allows the investigation of molecular mobility of different drug concentrations over a range of temperatures. Increasing the drug concentration results in lower T_g but does not correlate to a lower slope between the onset of local and global mobility. The concentration with the lowest slope is predicted to have the highest physical stability.

References: Knopp, M. M., Olesen, N. E., Holm, P., Langguth, P., Holm, R., & Rades, T. (2015). Influence of polymer molecular weight on drug–polymer solubility: a comparison between experimentally determined solubility in PVP and prediction derived from solubility in monomer. Journal of pharmaceutical sciences, 104(9), 2905-2912.

Mobility of different concentrations of indomethacin in PVP/VA mixtures at 1 THz. The starred point indicates the glass transition temperature of each concentration.

Mobility of different concentrations of indomethacin in PVP/VA mixtures at 1 THz that is normalised to the mobility at 80 K.

The calculated slope between the onset of local and global mobility for each concentration of indomethacin in PVP/VA mixtures.