A Perspective on Synthetic and Solid-Form Enablement of Inhalation Candidates

Abstract

The administration of compounds by a dry-powder inhaler presents significant challenges to the development and discovery chemist, owing to the stringent requirements placed upon the physical characteristics of the active pharmaceutical ingredient and the high complexity of the molecules concerned. The current state of synthetic chemistry technology is such that commercial syntheses of these compounds are demanding but achievable. While synthetic chemistry will remain a major component of the development of inhaled therapies, the main challenge facing practitioners in this area is the early identification of a suitable solid form. Further advances in the prediction of solid-form properties would significantly enable this field and may allow triage of molecules to be carried out at the design stage of projects.

Formulation Design of Dry Powders for Inhalation

“…As such, inclusion of functional groups to facilitate rapid metabolism (e.g., a soft‐drug approach) is desirable. “Inhaled by design” concepts result in drugs with molecular properties that are markedly different from those of current marketed respiratory drugs . This is illustrated for new classes of asthma and COPD therapeutics in Table .…”

“…These results have implications for the developability of inhaled‐by‐design molecules. Selby et al mainly view this as a liability, pointing out that the major issues with these molecules are overall synthetic complexity and identification of a suitable solid‐state form. Increasingly, solid‐state challenges are resolved through the formation of salts with exotic counterions that may pose regulatory risk and will likely require additional toxicology studies to gain market approval.…”