(500f) When API Doesn't Crystallize: Enabling Commercialization of Amorphous Drug Substance through Particle Engineering and Material Science

Purpose: The ability to develop new small chemical entity (NCE) from the CMC perspective is highly dependent on its drugability and physicochemical properties. Increasing understanding of biological systems has led to more novel biological targets, which have produced NCEs that may not have perfect drug-like properties. When the molecule cannot be crystallized in its parent form and crystalline salts or cocrystals cannot be identified in traditional polymorph screens, the amorphous phase is the only option for development. The development of an amorphous drug substance can pose formidable technical challenges:

• How can the amorphous phase be isolated and stabilized as a solid, given its viscoelastic properties and propensity to form a gel?
• How can it be manufactured at multi-kg commercial scale with physical properties that are consistent and amenable for solid dosage formulation (tablet form)?
• What are the key physical quality attributes of the API that would enable manufacturability as a drug product?
• How can the decreased amorphous chemical and physical stability be overcome to enable product shelf life?
• What will a robust control strategy look like, given the structure-function-performance relationships between the drug substance and drug product?

In this presentation, we present the story behind the successful commercialization of an amorphous drug substance through innovative particle engineering approaches combining fundamental material science tetrahedron concepts. The drug substance is directly isolated as an amorphous solid with controlled physical properties that are amenable for roller compaction followed by compression into solid dosage form.

Method: In order to isolate the amorphous phase as a solid, an anti-solvent based precipitation process was developed, where the solvent combination was chosen to afford rapid precipitation of the solid. The physical properties of the amorphous drug substance was controlled by an innovative impinging jet precipitation process (IJP) for consistency during scale-up from pilot plant to commercial production. In order to control of physical properties post IJP, fundamental pharmaceutical material science principles were applied to the filtration/wash protocols to afford consistent removal of the precipitation solvent which is a strong plasticizer. Post filtration/wash, the wetcake was dried in an agitated filter dryer (AFD) to remove residual solvents to ICH limits. As the amorphous solids are prone to agglomeration, the impact of solvent level on the sticky (agglomeration) zone and shear distributions within the AFD were studied across scale to produce consistent dried API. At the DS/DP interface, the material science tetrahedron (MST) concept was applied to understand the role of API physical properties on the DP performance. Due to unique nature of the amorphous API, non-traditional API physical properties (other than particle size distribution) were identified as controls to ensure roller compaction and tablet process performance.

Results: Comprehensive solid form screens had not produced crystalline solid form. As a part of the overall in-silico solid form risk assessment, geometry optimization of API molecule was performed in Material Studio. The energy minimized structure revealed propensity for intramolecular H-bonding and lack of propensity for intermolecular H-bonding to form a stable crystal structure. The API has relatively high Tg (>100 °C), which affords its physical stability under dried environment. However, aside from water, the API has high affinity for various soluble solvents which are also strong plasticizers. The microstructure of the amorphous API (see Fig 1), hence the high specific surface area, is critical to ensure compressibility of the drug substance during tableting. The specific surface area was controlled via process parameters during the IJP and subsequent API isolation steps. Other bulk physical properties of the API, such as bulk density and flow, were also identified as critical attributes to ensure consistency in roller compaction. The API physical property control strategy was developed by leveraging understanding of drug substance unit operations on the material attributes and their impact on drug product manufacturability and critical quality attributes. To ensure product shelf-life, packaging configurations of the bulk drum substance and drug products were designed to prevent moisture ingress and ensure chemical stability.

Conclusion: When a developable crystalline state is not available, the development of such compound from a CMC perspective is a formidable and never-ending challenge. Here, we demonstrate that the development and commercialization of such compound is feasible, through the application of innovative particle engineering approaches and material science at the DS/DP interface.