Preclinical formulations for discovery and toxicology: physicochemical challenges

Abstract

Formulations play a key role in assessing the biological properties of a molecule during drug discovery. Maximising exposure is the primary objective in early animal experimentation, so that the pharmacokinetics, pharmacodynamics and toxicological signals can be put into context with the biological response to specific targets. Consistency in the exposure is also a key aspect, and effective formulation and drug delivery strategies are important to achieve this. Diversity in the physiology between various animal species, routes of administration and limitations posed by specific pharmacological models make formulation development that much more challenging. Poor physicochemical properties of compounds in the early stages need to be kept under consideration while screening for formulation vehicles. This review captures the various challenges posed at different stages of drug discovery for formulation of a compound to dose in animals. Approaches to formulations for various routes of administration are discussed. Limitations posed by the goals for various animal studies such as early efficacy studies, pharmacokinetic studies and toxicology studies are identified and some strategies are proposed. Physicochemical characterisations that are needed to select formulation vehicles as well as to identify potential issues are suggested.

Keywords::

• drug discovery
• formulation
• pharmacology
• physicochemical
• preclinical
• solubility
• toxicology
• vehicle

Acknowledegment

The author gratefully acknowledges A Rohner, S Kaufman and M Veniant-Ellison for providing data on vehicle effects in various pharmacology models. The author also thanks A Koparkar, D Ostovic and S Rabel Riley for reviewing this manuscript and providing valuable comments, as well as J Jona for input on vehicle dose volume information.

Notes

IV: Intravenous; PO: Oral.