非晶質固体医薬品原料としてのエラゴリクスナトリウムの経口固形製剤開発における複雑性の解明
Developing oral solid dosage forms that rely on an amorphous active pharmaceutical ingredient (API) presents significant challenges in process design, physical quality control, and stability management. This work describes the chemistry, manufacturing, and controls development for Elagolix Sodium, a first-in-class oral gonadotropin-releasing hormone antagonist that exists exclusively in an amorphous state. Molecular dynamics (MD) simulations at both molecular and intermolecular levels revealed that intramolecular hydrogen bonding, repulsive API–API interactions, and strong solvation effects collectively impede crystalline nucleation. Solvent-induced plasticization was characterized experimentally and computationally to understand molecular mobility. Material science tetrahedron principles were applied to correlate API porosity with tablet compressibility. An impinging jet mixer was designed using computational fluid dynamics for precipitation, and glass transition relationships guided cake wash, blow-down, and drying steps. Together, these approaches enabled consistent production of a porous, non-sintered amorphous powder suitable for robust downstream tablet manufacturing.
Molecular dynamics simulations identified that intramolecular hydrogen bonding, repulsive intermolecular interactions, and strong solvation effects collectively prevent crystalline nucleation in Elagolix Sodium, stabilizing its amorphous form.
The delivery route is not clearly identifiable from this paper. For hydrogen intake, inhalation is the most efficient route; inhalation, however, carries explosion risk (empirical LFL of 10%; high-concentration devices are not recommended).
See also:
https://h2-papers.org/en/papers/39245087