(T1030-12-80) Use of the Time–Temperature–Transformation Diagram to Evaluate the Role of Molecular Mobility on the Drug Stability in Amorphous Solid Dispersions

Purpose: Amorphous solid dispersions (ASDs) have emerged as a promising strategy to enhance the solubility and bioavailability of poorly water-soluble drugs¹. However, the amorphous drug can crystallize during storage, losing its solubility advantage and compromising bioavailability.² Drawing from previous work on time-temperature-transition (TTT) diagrams, which elucidate the crystallization behavior of amorphous APIs, we studied how polymers can be effectively used to prepare nuclei-free ASDs and prevent the growth of any formed nuclei.^{3, 4} Our previous work demonstrated a correlation between the strength of drug-polymer interactions and critical cooling rates to avoid both nucleation and crystallization in ASDs.⁵ In the current work, we evaluated the role of molecular mobility (measured as α-relaxation time) on the stabilization of the drug in the ASD using the TTT diagram. Drug crystallization was also evaluated in the presence of dissolution medium. Our overall goal was to identify the factors governing the drug stabilization in ASDs using a broad group of polymers including hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVPVA64) and poly(ethylene glycol)–poly(vinyl acetate)–poly(vinyl caprolactam) graft copolymer (Soluplus®).

Methods: ASDs containing nifedipine (NIF) and each of the polymers were prepared. Glass transition temperatures (T_g) were measured using a differential scanning calorimeter (DSC) equipped with a refrigerated cooling accessory. A two-step approach was used to determine the critical cooling rate to avoid nucleation and crystallization. First, the dispersions were stored under conditions favoring nucleation. The ASDs were then heated to a temperature favorable to crystallization. The crystallization induction time was determined, at a range of temperatures, using modulated DSC and synchrotron X-ray diffractometry (17-BM-B beamline at Argonne National Laboratory, IL, USA). A monochromatic X-ray beam (wavelength 0.4485 Å; diameter 300 μm) and a 2D detector were used. The α-relaxation times were determined by dielectric spectroscopy. TTT diagrams were generated using the crystallization induction time, which provided the critical cooling rate to prevent (i) nucleation and (ii) crystallization of the drug during the ASD preparation.

Results: As the polymer concentration was increased, there was pronounced rise in the T_g of the PVP and PVPVA64 dispersions, whereas the change was much smaller in the HPMCAS and Soluplus® ASDs. At 90 °C, the crystallization induction time of amorphous NIF occurred at < 5 min. The addition of PVPVA64 and Soluplus® (4% w/w) increased the crystallization induction time to ~72 and 43 min respectively (Figure 1). On the other hand, the effect was smaller in the case of PVP and HPMCAS at the same concentration. Based on the TTT diagrams plotted using crystallization onset times, the critical cooling rates (CR_crit) were calculated. CR_crit decreased from ~17.6 °C/min for amorphous NIF to ~1.1 °C/min for NIF–PVPVA64 ASD. The dielectric loss spectra of amorphous NIF and ASDs with 10% polymer (w/w) were obtained. As the strength of drug-polymer interaction increased, the dielectric loss peak shifted towards lower frequencies, indicating a decrease in molecular mobility and increase in relaxation times. The resistance to crystallization was a function of the T_g of the ASD, except in the Soluplus® system. This is also reflected in the molecular mobility (α-relaxation time) in that the Soluplus® dispersion, in spite of the highest mobility demonstrated the second longest crystallization onset time (Figure 2). At 70 °C, the PVPVA64 ASD has t_α of ~4.4 x 10^-3s, which is more than an order of magnitude higher than that of amorphous NIF 2.1 x 10^-4s.

Conclusion: The time-temperature-transformation (TTT) diagrams were an effective tool to study the effect of different polymers on the critical cooling rate (CR_crit) required to prevent drug nucleation and crystallization during the preparation of ASDs. We further extended the application of TTT diagrams to understand the relationship between molecular mobility and critical cooling rate. In general, stronger interactions between the drug and polymer led to longer α-relaxation times. These results offer valuable insights into the influence of molecular mobility and drug-polymer interactions on the stability of ASDs. Our ongoing studies are aimed at developing a mechanistic understanding of this observation.

References: (1) Babu, N. J.; Nangia, A. Solubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals. Cryst. Growth Des. 2011, 11 (7), 2662-2679.
(2) Yu, L. Amorphous Pharmaceutical Solids: Preparation, Characterization and Stabilization. Advanced Drug Delivery Reviews 2001, 48 (1), 27-42.
(3) Kumar, N. S. K.; Suryanarayanan, R. Crystallization Propensity of Amorphous Pharmaceuticals: Kinetics and Thermodynamics. Mol. Pharmaceutics 2022, 19 (2), 472-483.
(4) Lalge, R.; Kumar, N. S. K.; Suryanarayanan, R. Implications of Drug–Polymer Interactions on Time–Temperature–Transformation: A Tool to Assess the Crystallization Propensity in Amorphous Solid Dispersions. Mol. Pharmaceutics 2023, 20 (3), 1806-1817.
(5) Lalge, R., Kumar, N. S. K., & Suryanarayanan, R.. Understanding the Effect of Nucleation in Amorphous Solid Dispersions through Time–Temperature Transformation. Mol. Pharmaceutics 2023 (in press).