Polymorphic Phase Transformation Pathways under Nanoconfinement: Flufenamic Acid

Flufenamic acid (FFA) is a highly polymorphic compound, with nine forms to date. When melt crystallization was performed under nanoscale confinement in controlled pore glass (CPG), the formation of the extremely unstable FFA form VIII was favored. Under confinement, form VIII was sufficiently stable to allow the measurement of its melting point, which decreased with decreasing pore size in accord with the Gibbs–Thomson relationship, enabling determination of the otherwise elusive melting point of the bulk form. Moreover, the transformation pathways among the various polymorphs depended on pore size, proceeding as form VIII → form II → form I for nanocrystals embedded in 30–50-nm diameter pores, and form VIII → form IV → form III in 100–200 nm pores. In contrast, form VIII converts directly to form III in the bulk. Whereas previous reports have demonstrated that nanoconfinement can alter (thermodynamic) polymorph stability rankings, these results illustrate that nanoscale confinement can arrest and alter phase transformations kinetics such that otherwise hidden pathways can be observed.