(W0930-12-80) Stabilizing Amorphous Solid Dispersions: Polymer Blend Approach with PVP of Differing Molecular Weights

Purpose: Amorphous solid dispersions (ASDs) are a promising way to improve the solubility and bioavailability of poorly water-soluble drugs¹. However, there is a risk that the amorphous drug will crystallize during storage, which would reduce its solubility and compromise its effectiveness². The amorphous-to-crystalline transformation typically occurs through two steps, nucleation, and crystal growth. In our previous work, we have demonstrated the use of time-temperature-transition (TTT) diagrams to determine the conditions to prepare nuclei-free ASDs^3,4. The time and temperature dependence of the amorphous to crystalline transformation is a combined effect of thermodynamics (activation barrier) and molecular mobility⁵. We previously reported that, with an increase in polymer molecular weight, the relaxation time, as well as the crystallization onset time of ASD, progressively decreased.⁶ However, the processing and manufacturing ASDs with high polymer molecular weight polymers can be challenging. This problem may be overcome by using polymer blends. Our goal was to prepare ASDs using a polymer blend (PVP of two different molecular weights) and study the drug crystallization behavior. Griseofulvin (GRF) ASDs (20% w/w polymer) were prepared with each (i) PVP K12 (20% w/w), (ii) PVP K30 (20% w/w), and (iii) a mixture of [PVP K12 (10% w/w) + PVP K30 (10% w/w)] and their crystallization behavior was evaluated.

Methods: The glass transition temperatures (T_g) of the ASDs were measured using a differential scanning calorimeter (DSC) equipped with a refrigerated cooling accessory. The maximum nucleation rate of GRF was observed to be around its Tg⁷. A two-step approach was used to determine the stability of ASDs. First, the dispersions were stored under conditions favoring nucleation (100 °C for 3 hours). The ASDs were then heated to a temperature favorable to crystallization (150 °C). Using modulated DSC, the specific heat capacity at 150 °C, was measured as a function of time. This enabled the determination of the crystallization induction time as well as the evaluation of the growth kinetics. The crystallization induction time of ASDs, when placed in contact with fasted state simulated intestinal fluid (FaSSIF), was determined, at 37 °C, by 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.

Results: While the isothermal crystallization was studied at 150 °C, the ASDs were previously nucleated at 100 °C for 3 hours. For the ASDs prepared with each PVP K12 and PVP K30, the crystallization onset times were 20 and 100 minutes respectively (Figure 1). Interestingly, a mixture of PVP K12 and K30 resulted in a longer onset time of ~ 130 minutes (Figure 1). Similar behavior was observed when the ASDs were placed in contact with FaSSIF. PVPK12 ASD crystallized immediately in the presence of FaSSIF, while the PVP K30 ASD revealed crystallization in 10 minutes (Figure 2). The ASD prepared with a mixture of PVP K12 and K30, resisted crystallization for 15 minutes. Thus, a polymer blend with different molecular weights provides an avenue to tailor the physical stability while overcoming the processing challenges associated with high molecular weight polymers.

Conclusion: For the same polymer concentration (20% w/w), a polymer blend (a mixture of PVP K12 and PVP K30) yielded ASDs, which were more stable than the dispersions prepared with the individual polymers. The resistance to crystallization was observed both at elevated temperatures and in contact with simulated intestinal fluid.

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) 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.
(4) 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).
(5) Kumar, N. S. K.; Suryanarayanan, R. Crystallization Propensity of Amorphous Pharmaceuticals: Kinetics and Thermodynamics. Mol. Pharmaceutics 2022, 19 (2), 472-483.
(6) Mohapatra, S.; Samanta, S.; Kothari, K.; Mistry, P.; Suryanarayanan, R. Effect of Polymer Molecular Weight on the Crystallization Behavior of Indomethacin Amorphous Solid Dispersions. Cryst Growth Des. 2017, 17, 3142-3150.
(7) Willaert, J. F.; Dudognon, E.; Mahieu, A.; Eddleston, M.; Jones, W; Descamps, M. The Role of Cracks in the Crystal Nucleation Process of Amorphous Griseofulvin. Phys. J. Special Topics 2017, 226, 837-847.

Figure 1. Plots of Cp/Cp_max as a function of time for GRF ASDs. The ASDs were held at 150 °C and the Cp was monitored as a function of time. Cp_max is the initial heat capacity value, and the crystallization onset times are shown.

Figure 2. The X-ray diffraction (synchrotron) patterns of ASDs placed in contact with FaSSIF for different periods.