Particle engineering at the drug substance, drug product interface: a comprehensive platform approach to enabling continuous drug substance to drug product processing with differentiated material properties

Abstract

Direct compression offers a simple route to generate pharmaceutical dosage units and is core to the growing arena of continuous manufacturing. However, direct compression can be untenable for some active materials. This paper will outline three specific challenges API’s can present to direct (active pharmaceutical ingredients) compression. The first involves API’s having exceedingly high aspect ratio (“needles”) or small particle size resulting in low bulk density and poor flow properties. Two additional cases are relatively newer challenges to direct compression driven by the growing need for solubility enhancing formulations, and involve nano-crystalline materials and spray dried amorphous dispersions. Multiple approaches for managing high aspect ratio or micronized API’s have been implemented during the crystallization process or via particle coating downstream from API isolation. Fewer options have been reported for the successful conversion of nano-crystalline materials or spray dried amorphous dispersions into materials amenable to direct compression as these materials offer another specific set of challenges. One route that has not been explored that stands to allow continuous drug product processing across a broader product portfolio involves evaluating opportunities at the drug substance/drug product interface. Here, the options achieved through targeted introduction of excipients to the drug substance processing steps during product precipitation and/or isolation from a product slurry are discussed. This approach introduces new opportunities for designing multicomponent particles through productive and inherently continuous processes. This also offers a longer-term potential route to integrate across continuous drug substance processing to continuous drug product processing.

Keywords:

• Particle engineering
• continuous processing
• hierarchical particles
• drug substance/drug product interface

Acknowledgments

The authors would like to thank fellow researchers and engineers at Merck who have been involved in designing the equipment and generating the materials discussed in this manuscript: Rob O’Connor, Fransicso Guzman, Tiffany Chiang, Mike Toth, Al D’Alessandro, John Roosa and Joe Kukura (who took a week of vacation dedicated to complete critical early stage, proof of concept, pilot scale runs).

Disclosure statement

No potential conflict of interest was reported by the authors.