Michael H. Kress

Stereoselective [2,3]-wittig rearrangement of (1S,2R)-1-amino-indan-2-ol derived amide enolates

Abstract An efficient, diastereoselective [2,3]-Wittig rearrangement of α-allyloxy-amide enolates has been developed using (1S,2R)-1-amino-indan-2-ol as a chiral auxiliary. After auxiliary removal, the resultant optically active α-hydroxy acids have been transformed to functionalized amino acid derivatives.

Effect of Added Alkalizer and Surfactant on Dissolution and Absorption of the Potassium Salt of a Weakly Basic Poorly Water-Soluble Drug

Telcagepant potassium salt (MK-0974) is an oral calcitonin gene-related peptide receptor inhibitor investigated for the treatment of acute migraine. Under gastric pH conditions, the salt rapidly gels, then converts to an insoluble neutral form that creates an impervious shell on the tablet surface, resulting in a slow and variable release dissolution rate and poor bioavailability. Early attempts to develop a solid dosage form, including solid dispersion and nanosuspension formulations, resulted in low exposures in preclinical studies. Thus, a liquid-filled soft gelatin capsule (SGC) formulation (oblong 20) was used for clinical studies. However, a solid dosage form was desirable for commercialization. The slow dissolution of the tablet formulations was overcome by using a basifying agent, arginine, and inclusion of a nonionic surfactant, poloxamer 407. The combination of arginine and poloxamer in the formulation created a local transient basic microenvironment that promoted the dissolution of the salt and prevented rapid precipitation of the neutral form on the tablet surface to form the gel layer. The tablet formulation achieved fast absorption and comparable exposure to the SGC formulation. The final optimized 280 mg tablet formulation was successfully demonstrated to be bioequivalent to the 300 mg SGC formulation.

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.