(T1430-07-47) Probing Dynamics of Amorphous Solid Dispersions Using Carboxylic Acid Dimer Formation

Purpose: Amorphous solid dispersions (ASDs) are one of the advanced pharmaceutical strategies designed to improve the solubility and bioavailability of poorly soluble active pharmaceutical ingredients (APIs). Due to the growing number of new chemical entities with low solubility in drug pipelines, ASDs have gained considerable attention as a potential solution. However, the long-term physical and chemical instability, particularly the tendency of amorphous APIs to recrystallize, remains a significant challenge. The molecular mobility within ASDs, largely governed by the glass transition temperature (T_g) of both the drug and polymer components, plays a crucial role in the stability of these systems. While polymers with high T_gs are preferred to reduce molecular mobility, structural relaxation—a precursor to crystallization—persists even below the recommended storage temperature (T_g − 50 K). Current understanding of molecular mobility at these temperatures is limited, and thus it is necessary to use advanced characterization techniques like solid-state nuclear magnetic resonance (ssNMR) to probe relaxation behaviors and guide stable ASD design. We aim to study molecular mobility and structural relaxation as a function of API concentration, glass transition temperature, and API molecular structure, and polymer molecular weight, glass transition temperature, and structure, as well as annealing time.

Methods: ASDs were formulated using APIs (indomethacin (IMC) with T_g of -42°, ibuprofen (IBU) with T_g of 47°, salicylic acid (SA), benzoic acid (BA)) with varying T_g and HB capabilities, combined with non-hydrogen bonding (HB) polymers (e.g., polystyrene (PS) with varying size and T_g). Low drug loading (1%) enabled isolation of API dimerization behavior. ssNMR tracked dimer-to-monomer ratios via ¹³C-labeled carboxylic carbons. Temperature-dependent experiments (range: -40 to 160 °C) and time-dependent studies (0 °C, up to 20 days) were conducted. Data were analyzed using equilibrium constants (K_eq = [c_dimer]/[c_free]²) and Van’t Hoff equation (lnK_eq = -△H°/RT + △S°/R) to quantify enthalpy/entropy changes and structural relaxation.

Results: Using ¹³C ssNMR, distinct dimer (182.8 ppm) and monomer (173.9 ppm) peaks were identified in IBU:PS ASDs (Figure 1), as well as for other -COOH containing APIs in ASD systems. Figure 2 summarizes the percentages of IBU dimers out of total API molecules at different temperatures and the converted Van’t Hoff plot. Other ASD systems are omitted in the abstract, but in all ASDs, the percentage of dimers decreases with rising temperature. Although dimer percentage decreases similarly for all APIs, IBU and IMC exhibit plateaus before the decline begins. The plateau starts for IBU below 10°C and for IMC below 30°C. No plateau is observed for SA and BA above -40°C, though they may experience similar plateaus at even lower temperatures. Additionally, maximum dimer percentages vary: approximately 60% for IBU, 40% for IMC, 43% for SA, and 70% for BA (possibly higher for SA and BA below -40°C), likely due to the intrinsic hydrogen bonding abilities of the APIs. In the Van’t Hoff plots of all ASDs, a deviation from linearity is observed at ~40 °C despite their different T_gs and structures, indicating that the systems are under equilibrium at temperatures above 40 °C.Polymer T_g emerged as the primary determinant of structural relaxation thresholds. High-T_g polymers (e.g., PS MW 190,000, T_g = 97.1°C) delayed relaxation onset, with Van’t Hoff plot deviations occurring at ~40°C. In contrast, low-T_g polymers (PS MW 1,200, T_g = 40.9°C) showed deviations at ~10°C. The difference is also thought to be correlate with different molecular sizes of the polymers. Annealing studies at 0°C revealed persistent molecular mobility below T_g, as dimer percentages in IBU:PS increased from 52% to 56% over 20 days, approaching equilibrium predictions (Figure 3). This time-dependent relaxation emphasizes the necessity of long-term stability assessments, even under sub-T_g storage conditions.

Conclusion: This study has demonstrated the effect of API and polymer T_g, molecular structure, size, as well as annealing temperature and time on the dynamics of ASD systems. Monitoring dimer percentages in ASDs offers a novel approach to probing molecular dynamics at temperatures significantly below or above T_g, where conventional stability assessments are limited. This approach holds promise for characterizing dynamics in polymeric systems with weak HB, particularly relevant for ASD formulations designed to minimize strong API-polymer interactions, thereby optimizing drug release profiles without compromising stability. Such applications could guide the development of tailored ASD systems that balance enhanced dissolution rates with long-term physical stability.

References: [1] Hancock, B. C., Shamblin, S. L., & Zografi, G. (1995). Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures. Pharmaceutical research, 12, 799-806.
[2] Groёl, S., Menzen, T., & Winter, G. (2021). Calorimetric investigation of the relaxation phenomena in amorphous lyophilized solids. Pharmaceutics, 13(10), 1735.
[3] Yuan, X., Xiang, T. X., Anderson, B. D., & Munson, E. J. (2015). 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, 12(12), 4518-4528.


Figure 1. 13C NMR spectra of 13C labelled 1% IBU:99% PS ASD at different temperatures.


Figure 2. (a) Dimer percentage of IBU out the total IBU molecules in 1% IBU:99 % PS (Mw 35,000) at different temperatures, and (b) corresponding Van’t Hoff plots of Keq.


Figure 3. Dimer percentage of IBU out the total IBU molecules in 1% IBU:99 % PS (Mw 35,000) annealed at 0 °C with different annealing times.