(M1530-11-73) Impact of Structural Relaxation in Amorphous Solid Dispersions

Purpose: Structural relaxation is the process of an amorphous material undergoing energy reduction towards equilibrium. Amorphous solid dispersions (ASDs) are drug/polymer mixtures that are commonly to improve the solubility of drugs. However, the potential for drug crystallization in ASDs remains a significant problem. When structural relaxation occurs in ASDs, it helps stabilize the glassy matrix. Although structural relaxation has been studied extensively, the study of structural relaxation at temperatures significantly below the glass transition has not been fully explored. The purpose of this study is to use solid-state NMR spectroscopy to explore the relationship between the glass transition temperature (T_g) and structural relaxation at temperatures significantly below T_g.

Methods: Drug-polymer amorphous solid dispersions were prepared by cryomilling followed by melt-quench. 0.5% to 2% of drug loading with ¹³C isotopically enriched drugs were used. Samples were packed in 7.5 mm zirconia rotors, and sealed with Kel-F end-caps. ¹³C spectra were acquired using cross-polarization magic angle spinning (CP/MAS) at 4.8 kHz, using total sideband suppression (TOSS) and SPINAL64 decoupling. Single pulse experiments were used at temperatures above 90 ^oC. Lead nitrate was used to calibrate the temperature. Spectra were obtained from -40 ^oC to 160 ^oC at every 10 ^oC. Samples were equilibrated at each temperature for at least 10 minutes before spectra acquisition.

Results: In this study, we are using the equilibrium between hydrogen bonded dimers and free species in ASDs to study structural relaxation. When equilibrium is achieved, the amount of free molecules and dimers can be quantified to give us an equilibrium constant. By changing temperature and measuring the corresponding equilibrium constant, we can generate a Van’t Hoff plot. The natural log of the equilibrium constant and inverse temperature should have a linear relationship, but beyond a certain temperature, there is a deviation from linearity. This difference is related to the free energy difference. Three systems with 99% of polystyrene and 1% of indomethacin, ibuprofen, and salicylic acid, respectively, have been studied, and it has been found the dimer/free ratio of the drug changes as the temperature changes. For example, in Figure 1, the dimer/free ratio of ibuprofen stays the same from -40 to 10 ^oC, but starts to decrease linearly above 10 ^oC. In 1% salicylic acid-99% polystyrene, dimer/free ratio shows a linear decrease from -40 to 160 ^oC. In 1% indomethacin-99% polystyrene, dimer/free ratio shows a non-linear decrease from 20 to 70 ^oC, followed by a linear decrease from 100 to 160 ^oC.¹ After applying Van’t Hoff equation, in Figure 2, ln(K_eq) has a linear relationship with 1/T until a deviation from theory starts at around 20 ^oC below the T_g of polystyrene. All three systems with indomethacin, ibuprofen, and salicylic acid show similar trends in Van’t Hoff plots.

Conclusion: The three systems that have been studied so far share the same temperature where the free energy difference starts to show (20 ^oC below the T_g of polystyrene), but exhibit different trends of dimer/free ratio at low temperatures (below T_g of polystyrene) even with 1% of drug in 99% of polymer. It suggests that the T_gs of the drug and polymer both play a role in the structural relaxation behavior in the glassy system. Further studies with drugs and polymers with different T_gs and hydrogen bonding abilities are needed to determine the exact relationship between T_g and structural relaxation.

References: [1] Yuan, X.; Xiang, T.-X.; Anderson, B. D.; Munson, E. J. Hydrogen Bonding Interactions in Amorphous Indomethacin and Its Amorphous Solid Dispersions with Poly(Vinylpyrrolidone) and Poly(Vinylpyrrolidone-Co-Vinyl Acetate) Studied Using 13C Solid-State NMR. Molecular Pharmaceutics 2015, 12 (12), 4518–4528.

Figure 1. 1% ibuprofen – 99% polystyrene dimer/free ratio as a function of temperature

Figure 2. Van’t Hoff plot of Keq for 1% ibuprofen carboxylic acid dimerization in 99% polystyrene