传统的固体口服剂型开发通常不会受到依赖无定形药物作为药物产品中的直接成分的挑战。因为这可能会导致工艺设计和放大带来的产品开发障碍,物理质量属性的控制,药品的加工性能和稳定性。这里,我们介绍化学,无定形药物成功商业化背后的制造和控制发展历程,Elagolix钠,一流的,口服活性促性腺激素释放激素拮抗剂。通过分子动力学(MD)在分子和分子间水平上评估了缺乏结晶状态的原因,揭示了由于分子内氢键普遍存在而导致的成核障碍,API分子之间的排斥相互作用和强溶剂化效应。为API制造工艺的设计提供基础依据,我们通过MD对溶剂诱导的塑化行为进行了实验和计算建模,以了解分子迁移率。此外,我们应用材料科学四面体概念将API孔隙率与药物产品片剂可压缩性联系起来。最后,我们设计了API隔离流程,将计算流体动力学模型纳入撞击射流混合器的设计中,用于滤饼洗涤中的沉淀和溶剂依赖性玻璃化转变关系,排放和干燥过程,为了实现多孔材料的一致制造,非烧结无定形API粉末,适用于强大的药物产品制造。
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 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.