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

Abstract

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.

Highlights

Amorphous Elagolix Sodium, a first-in-class GnRH antagonist.

MD simulations reveal a prevalence of intramolecular hydrogen bonds, repulsive API-API and API-solvent interactions, hence difficulty of crystallization.

Amorphous API, enabled by high specific surface area, functions as a drug product binder.

A novel impinging jet mixer developed for precipitation, followed by solvent removal steps to prevent sintering due to glass transition.

CFD modeling applied to optimize mixing and maintain material high porosity, a key factor in its tablet compressibility.

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 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.

Are you looking for excipients in commercial quantities?

Order your commercial quantities of excipients with Pharma Excipients

excipients formulation