(T0930-04-21) Role of Drug–Polymer Interactions and Polymer Concentration on Critical Cooling Rate during Hot-Melt Extrusion of Amorphous Solid Dispersions

Purpose: A large fraction of the new drug candidates in the drug development pipeline are characterized by poor aqueous solubility. If the oral absorption of these candidates is solubility-limited, they can potentially exhibit poor bioavailability.¹ Amorphous solid dispersions (ASDs) have drawn considerable attention due to their potential to enhance the aqueous solubility and therefore the bioavailability of poorly soluble drugs. In ASDs, the drug in the amorphous state, is entrapped and stabilized in a polymeric matrix. However, amorphous to crystalline transition can occur during product storage.² Once the solubility advantage of the amorphous form is lost, the product bioavailability can be seriously compromised. Generally, a high polymer concentration is used to delay the crystallization and improve the shelf-life of the product. However, this approach cannot be used for high-dose drugs. We aim to understand the impact of processing conditions on the ASD and mitigate risk of drug crystallization during product storage. Previously, Kumar and Suryanarayanan used the time-temperature-transition (T-T-T) diagrams to understand the crystallization behavior of amorphous APIs.^{3, 4} In four model drugs all with the same glass transition temperature (T_g), the thermodynamic activation barrier for nucleation was responsible for their difference in crystallization behavior.⁴ A T-T-T diagram can also serve as a tool to understand the crystallization behavior from melt and identify the potential for crystallization during cooling. With this as a basis, we aim to investigate the effectiveness of polymers to prepare ASDs that (i) are free from nuclei and (ii) can prevent growth of nuclei if at all they are formed. We hypothesize that the critical cooling rate derived from T-T-T diagram, which is required to prepare a stable ASD is a function of the strength of drug–polymer interactions and concentration of the polymer.

Methods: ASDs containing NIF and each of the polymers: PVP, HPMC-AS and PAA were prepared. The crystallization induction time was determined using a differential scanning calorimeter (Q2000, TA Instruments) and synchrotron radiation at a range of temperatures (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. T-T-T 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: The stronger drug–polymer interacting system exhibited longer crystallization induction times and lower critical cooling rates. At 90 °C, the crystallization induction time of amorphous NIF occurred at 4.8 ± 0.7 min. The addition of PVP (4% w/w) increased the crystallization induction time to 29.9 ± 3.6 min. On the other hand, PAA (4% w/w) did not have a pronounced effect on the onset. The critical cooling rate decreased from 17.6 ± 2.9 °C/min for amorphous NIF to 2.7 ± 0.3 °C/min for NIF–PVP ASD. When the PVP concentration was increased to 15 and 20% w/w, the crystallization induction time was increased to ~8 h and ~27 h as determined by the appearance of Debye-Scherrer rings in 2-dimensional X-ray diffraction pattern (Figure 1). The 2-dimensional diffraction patterns are converted into 1-dimensional patterns in Figure 2.

Conclusion: T-T-T diagrams were constructed using the isothermal crystallization method. We concluded that the critical cooling rate required to prepare an ASD is a function of the strength of drug–polymer interaction. The overall effect depended on both (i) the type of polymer, and (ii) the polymer concentration. High intensity synchrotron radiation helped us to detect the first evidence of crystallization in ASDs. A drug-polymer system with a stronger interaction, can be cooled at a slower rate and will exhibit higher physical stability. The practical usefulness of our work stems from the two-step approach to prepare a drug product by: (i) identifying conditions to avoid nucleation during the manufacture of ASDs and (ii) if this approach fails, then identifying the excipient to prevent growth of nuclei into larger crystals.

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) Angell, C. A. Glass-formers and viscous liquid slowdown since David Turnbull: Enduring puzzles and new twists. Mrs Bull 2008, 33 (5), 544-555.
(4) Kumar, N. S. K.; Suryanarayanan, R. Crystallization Propensity of Amorphous Pharmaceuticals: Kinetics and Thermodynamics. Mol. Pharmaceutics 2022, 19 (2), 472-483.

Acknowledgements: The project was partially supported by the William and Mildred Peters endowment fund. Parts of this work were carried out at the Characterization Facility, University of Minnesota, a member of the National Science Foundation-funded Materials Research Facilities Network (www.mrfn.org). This research used resources of the Advanced Photon Source; a U. S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DEAC02- 06CH11357. We thank Dr. Andrey Yakovenko for his help with the use of the 17-BM beamline.