Morphology of Porous Hosts Directs Preferred Polymorph Formation and Influences Kinetics of Solid/Solid Transitions of Confined Pharmaceuticals

Abstract

The pore morphology of a porous host may determine which polymorph a crystallizable guest preferentially forms and may influence the kinetics of solid/solid transitions. Slow cooling of the drug acetaminophen (ACE) inside the straight cylindrical pores of anodic aluminum oxide (AAO, tortuosity = 1) in contact with a bulk ACE surface film preferentially yields uniformly oriented form II and/or form III crystals. The occurring orientations of form II and form III crystals are characterized by high structural registry along the AAO pores. The uniformly oriented form III crystals inside the AAO pores were readily converted into likewise uniformly oriented form II crystals by a solid/solid transition. Thus, we obtained uniformly oriented form II crystals in AAO at high yields. We suggest that sporadic heterogeneous nucleation at bulk crystals formed in the bulk surface film on top of the AAO coupled with kinetic selection of crystal orientations results in fast growth of properly oriented crystals along the 100 pm deep AAO pores. This mechanism is suppressed in controlled porous glass (CPG) having isotropic spongelike pores (tortuosity > 1.5) with free growth paths on the order of 100 nm, where form I formed instead. Moreover, the transition from form III to form II is suppressed in CPG. Possible reasons may include impingement of the propagation front of the solid/solid transition on the CPG pore walls after short propagation paths and inevitable formation of form II grains with different orientations separated by energetically disadvantageous grain boundaries. The results reported here are relevant to mesoscopic crystal engineering aimed at controlled drug release from nanoscale delivery systems. Polymorphs not accessible otherwise in nanoscale containers may be produced at high yields. The principles reported here may be transferred to areas such as nanowire-based organic electronics.