Leveraging Solid State Form and Physiochemical Properties for Early Clinical Formulation Efforts: Opportunities and Challenges During Telcagepant Liquid Capsule Development

Lipid-based formulations (LBF) have emerged as an attractive formulation strategy to deliver poorly water-soluble drug molecules. The final dosage form, which can be either a liquid or a semisolid, is typically filled into hard-shell or soft gelatin capsules. Due to the relatively straightforward formulation development steps required, LBFs are especially suitable to support early phase clinical studies for a new chemical entity. However, line-of-sight to late stage clinical studies and commercialization requires a thorough understanding of the physical and chemical properties of the API, as well as potential interactions with excipients and the capsule shell materials used. This report describes the formulation development efforts of telcagepant, a novel candidate for the treatment of acute migraine. The key challenges associated with the formulation are discussed, including low API solubility in the excipient matrix, capsule cross-linking, as well as physical and chemical instability. Initially, telcagepant was formulated as a liquid LBF using the crystalline neutral form of the molecule, aided by in situ salt formation, and filled into hard-shell gelatin capsules. Following an extensive search and evaluation of potential options, a liquid formulation using the potassium ethanolate form of the molecule, filled into soft gelatin capsules, was selected for late stage clinical studies and commercialization. However, disproportionation of the salt form, which was further exacerbated by hydrolysis of the excipients, eventually led to the loss of API solubilization within the vehicle matrix. The development challenges encountered with stability requirements, pharmacokinetic targets, and commercial market demands are discussed in details, as well as the risk assessment and mitigation strategies employed in delivering this molecule to patients.