Dana E. Moseson

Amorphous solid dispersion (ASD) manufacturability is constrained by active pharmaceutical ingredient physicochemical properties; high melting point (Tm) and high glass transition temperature (Tg) limit hot-melt extrusion (HME), and low organic solubility limits spray-drying (SD) throughput. We evaluated lipophilic counterion choice as a solid-state design lever to enable ASD manufacturability by SD or HME. Nine lipophilic salts of atazanavir (ATZ) and mebendazole (MBZ) were prepared with sulfate and sulfonate counterions spanning a range of chain lengths and steric bulk, and characterized by 1H nuclear magnetic resonance spectroscopy, powder X-ray diffraction, differential scanning calorimetry, and polarized light microscopy. Lipophilic salts showed Tm and Tg reductions relative to their free base, with Tg reductions of up to approximately 30 °C. Organic solubility in ethanol, acetone, and tetrahydrofuran improved 2–15× or greater across most salt-solvent combinations. Vacuum compression molding confirmed that a representative lipophilic salt (ATZ-pTSA) enables thermal amorphization at HME-relevant processing temperatures, where the ATZ free base does not fully melt or dissolve into the model polymer. Counterion choice functions as a solid-state design lever for ASD manufacturability through a proposed lattice-packing disruption mechanism that simultaneously reduces Tm and Tg and improves organic solubility.

Does the performance of an amorphous solid dispersion rely on having 100% amorphous content? What specifications are appropriate for crystalline content within an amorphous solid dispersion (ASD) drug product? In this Perspective, the origin and significance of crystallinity within amorphous solid dispersions will be considered. Crystallinity can be found within an ASD from one of two pathways: (1) incomplete amorphization, or (2) crystal creation (nucleation and crystal growth). While nucleation and crystal growth is the more commonly considered pathway, where crystals originate as a physical stability failure upon accelerated or prolonged storage, manufacturing-based origins of crystallinity are possible as well. Detecting trace levels of crystallinity is a significant analytical challenge, and orthogonal methods should be employed to develop a holistic assessment of sample properties. Probing the impact of crystallinity on release performance which may translate to meaningful clinical significance is inherently challenging, requiring optimization of dissolution test variables to address the complexity of ASD formulations, in terms of drug physicochemical properties (e.g., crystallization tendency), level of crystallinity, crystal reference material selection, and formulation characteristics. The complexity of risk presented by crystallinity to product performance will be illuminated through several case studies, highlighting that a one-size-fits-all approach cannot be used to set specification limits, as the risk of crystallinity can vary widely based on a multitude of factors. Risk assessment considerations surrounding drug physicochemical properties, formulation fundamentals, physical stability, dissolution, and crystal micromeritic properties will be discussed.