Unraveling the complexity of amorphous solid as direct ingredient for conventional oral solid dosage form: The story of Elagolix Sodium.

Autor: Ho R; Small Molecule CMC Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, IL 60064, USA. Electronic address: raimundo.ho@abbvie.com., Hong RS; Small Molecule CMC Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, IL 60064, USA., Kalkowski J; Small Molecule CMC Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, IL 60064, USA., Spence KC; Operations Product Development Science & Technology, AbbVie Inc., 1 N Waukegan Road, North Chicago, IL 60064, USA., Kruger AW; Operations Product Development Science & Technology, AbbVie Inc., 1 N Waukegan Road, North Chicago, IL 60064, USA., Jayanth J; CMC Strategy & Portfolio Leadership, AbbVie Inc., 1 N Waukegan Road, North Chicago, IL 60064, USA., Nere NK; Small Molecule CMC Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, IL 60064, USA., Mukherjee S; Operations Product Development Science & Technology, AbbVie Inc., 1 N Waukegan Road, North Chicago, IL 60064, USA., Sheikh AY; Small Molecule CMC Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, IL 60064, USA., Bordawekar SV; Small Molecule CMC Development, AbbVie Inc., 1 N Waukegan Road, North Chicago, IL 60064, USA.
Jazyk: angličtina
Zdroj: International journal of pharmaceutics [Int J Pharm] 2024 Nov 15; Vol. 665, pp. 124656. Date of Electronic Publication: 2024 Sep 06.
DOI: 10.1016/j.ijpharm.2024.124656
Abstrakt: Conventional solid oral dosage form development is not typically challenged by reliance on an amorphous drug substance as a direct ingredient in the drug product, as this may result in product development hurdles arising from process design and scale-up, control of physical quality attributes, drug product processability and stability. Here, we present the Chemistry, Manufacturing and Controls development journey behind the successful commercialization of an amorphous drug substance, Elagolix Sodium, a first-in-class, orally active gonadotropin-releasing hormone antagonist. The reason behind the lack of crystalline state was assessed via Molecular Dynamics (MD) at the molecular and inter-molecular level, revealing barriers for nucleation due to prevalence of intra-molecular hydrogen bond, repulsive interactions between active pharmaceutical ingredient (API) molecules and strong solvation effects. To provide a foundational basis for the design of the API manufacturing process, we modeled the solvent-induced plasticization behavior experimentally and computationally via MD for insights into molecular mobility. In addition, we applied material science tetrahedron concepts to link API porosity to drug product tablet compressibility. Finally, we designed the API isolation process, incorporating computational fluid dynamics modeling in the design of an impinging jet mixer for precipitation and solvent-dependent glass transition relationships in the cake wash, blow-down and drying process, to enable the consistent manufacture of a porous, non-sintered amorphous API powder that is suitable for robust drug product manufacturing.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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