Formulation Possibilities of a Weak Base with a Narrow Solubility Range

The target of this article is to summarize the chemical and pharmaceutical (formulation) approaches that were found to be suitable for increasing the bioavailability of a model weak base (SAR1) with a very narrow good solubility range at physiologically relevant pH. (1) As part of the preformulation and formulation development to support toxicological and first in man studies of a free base (SAR1), several formulation approaches, including particle size reduction, emulsions, permeability enhancers, amorphous dispersions, salt formation, and co-crystal formation, were screened by in vitro dissolution methods and in vivo pharmacokinetic (PK) studies to evaluate and rank formulation performance. From the PK studies, it was observed that a suspension formulation containing a SAR1 fumaric acid (1:1) co-crystal provided the best oral exposure. Sensitivity of the co-crystal to physical disintegration into base and fumaric acid was solved by including Cremophor ELP as a solubility enhancer, surfactant, and co-crystal protector. This formulation was well-tolerated in rat. A flow-through dissolution method was more discriminating than the paddle type dissolution equipment for evaluation of co-crystal containing solid formulations.