The Impact of Isothermal Holds During Thermal Analysis Methods on the Categorization of
Amorphous Solid Dispersion Behavior
C. Zdaniewski, K. DeBoyace, P. L. Wildfong
Duquesne University
Purpose
Isothermal holds are used when characterizing amorphous solid dispersions by differential scanning calorimetry (DSC) in order to
remove moisture and erase thermal history. It was hypothesized that increasing isothermal hold times during characterization could
impact the apparent miscibility of drug in polymer. Miscibility changes that occur as a result of sample treatment could result in
erroneous categorization of dispersion behavior.
Methods
Tolbutamide and terfenadine were selected as model compounds as a result of previously observed differences in PVPva miscibility.
Co-solidified mixtures were prepared by melt quenching 75:25% w/w ratios of API to polymer. Crucibles containing molten
drug/polymer mixtures were quenched in ice water under nitrogen gas purge. Samples were stored overnight over P2O5 prior to
characterization. Co-solidified mixtures were analyzed using DSC, transmission PXRD (λ=1.5406° from 2-100°2θ), ambient polarized
light microscopy (PLM), and hot stage microscopy (HSM). DSC hold times (0 to 30 min) and ramp rates (0.5 to 20°C/min) were
independently varied to assess their impact in-situ. Samples were observed at elevated temperature using HSM for up to one hour to
aid interpretation of DSC results. The impact of elevated temperature on the bulk samples was also assessed by comparison of
characterization data for samples stored in an oven at 105°C for one hour with samples stored at room temperature.
Results
Tolbutamide/PVPva was miscible and did not phase separate as a result of isothermal holds during DSC characterization. A single
glass transition temperature was observed in DSC thermograms, no significant birefringence was observed via PLM, and no
characteristic Bragg peaks were present in PXRD diffraction patterns, indicating that the samples remained amorphous. After 3
months storage over P2O5 at room temperature, significant recrystallization was observed, and samples were examined using HSM.
Dissolution of the crystals into the polymer was observed at elevated temperature (Figure 1c/d), indicating the potential for
misclassification of the initial state of the system due to the solubilization of drug by the polymer.
Terfenadine/PVPva dispersions showed signs of re-crystallization as a result of rising hold times. This was informed by the presence
of melting endotherms and polymorphic forms by DSC. HSM showed the growth of crystals at elevated temperature (Figure 1a/b).
Samples stored in an oven for 1 hour at 105°C showed significant increase in crystallinity as informed by DSC, PXRD and PLM.
These results indicate that there is a potential for misclassification of the initial state of the system due to crystallization.
Conclusion
Miscibility changes that occur as a result of sample treatment could result in incorrect categorization of dispersion behavior. These
outcomes emphasize the importance of understanding how each step of a thermal method can impact characterization results. Due to
the complexity of amorphous solid dispersion systems, the use of a suite of characterization techniques is necessary to avoid incorrect
data interpretation. The duration of hold times in thermal methods should be carefully considered to avoid erroneous conclusions.