Thermodynamic Principles for the Design of Polymers for Drug Formulations.

Polymers play an essential role in drug formulation and production of medical devices, implants, and diagnostics. Following drug discovery, an appropriate formulation is selected to enable drug delivery. This task can be exceedingly challenging owing to the large number of potential delivery methods and formulation and process variables that can interact in complex ways. This evolving solubility challenge has inspired an increasing emphasis on the developability of drug candidates in early discovery as well as various advanced drug solubilization strategies. Among the latter, formulation approaches that lead to prolonged drug supersaturation to maximize the driving force for sustained intestinal absorption of an oral product, or to allow sufficient time for injection after reconstitution of a parenteral lyophile formulation, have attracted increasing interest. Although several kinetic and thermodynamic components are involved in stabilizing amorphous dispersions, it is generally assumed that maximum physical stability, defined in terms of inhibition of drug crystallization, requires that the drug and excipient remain intimately mixed. Phase separation of the drug from its excipient may be the first step that ultimately leads to crystallization. We discuss the role of advanced thermodynamics using two examples: ASD and vitamin E-stabilized ultrahigh-molecular weight polyethylene implants.