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

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.

Predictive Approach to Understand and Eliminate Tablet Breakage During Film Coating.

Pharmaceutical tablets can be susceptible to damage such as edge chipping or erosion of the core during the tablet coating process. The intersection of certain process parameters, equipment design, and tablet properties may induce more significant tablet damage such as complete tablet fracture. In this work, a hybrid predictive approach was developed using discrete element method (DEM) modeling and lab-based tablet impact experiments to identify conditions that may lead to tablet breakage events. The approach was extended to examine potential modifications to the coating equipment and process conditions in silico to mitigate the likelihood of tablet breakage during future batches. The approach is shown to enhance process understanding, identify optimal process conditions within development constraints, and de-risk the manufacture of future tablet coating batches.

Stream quality in a small urbanised catchment.

River-length patterns in the chemistry and biology of the Charlton Brook, an unclassified watercourse in Sheffield, England, have been examined. Five sampling sites for macroinvertebrates and pollutant analysis were used, in conjunction with Environment Agency's General Quality Assessment (GQA) methodologies and hydraulic analysis of the catchment. Sites were strategically located to account for the tributaries and the brook downstream of their confluence, to assess the potential impact from surface water outfalls (SWOs). Variations in GQA parameters indicate a significant drop in quality downstream of the SWOs that discharge to the study watercourse, with a marked drop in biological diversity noted at the onset of urbanisation. The decline in biological quality however is greater than that suggested by physicochemical analysis alone. There was a significant inverse relationship between impermeable area and biological diversity. Analysis of polycyclic aromatic hydrocarbons (PAHs) and trace metals in sediment from the watercourse showed significant yet irregular variations between sites. The potential toxicity of instream metal concentrations was determined using cumulative criterion unit (CCU) scores, which highlighted cadmium, copper and lead as the major sources of potential chronic instream toxicity. The threshold for likely harm to aquatic life is exceeded at all sites. In the absence of different physical characteristics, comparisons of the chemical and biological data indicate that the benthic macroinvertebrate population of such watercourses are adversely affected by the stormwater inputs.