Anisotropic Crystal Growth Inhibition by Polymeric Additives: Impact on Modulation of Naproxen Crystal Shape and Size

This study investigated the effects of polymeric additives such as hydroxypropyl methyl cellulose (HPMC) and polyvinylpyrrolidone (PVP) on the growth kinetics of naproxen crystal, a model poorly water-soluble active pharmaceutical ingredient. These additives are commonly used in pharmaceutical formulations to stabilize fine crystalline suspensions and amorphous solid dispersions. Measurement of seed crystal growth rate in ethanol–water solution as a function of supersaturation suggested a spiral growth mechanism, with the b (needle) axis growth rate five times faster than the c-axis growth rate at 40% relative supersaturation. At nearly equivalent supersaturations, growth along the b-axis was completely inhibited at one end of the seed crystal in the presence of either of the two polymeric additives. In contrast, growth at the other end of the b-axis was significantly accelerated in the presence of PVP. Molecular modeling revealed preferential interaction of the additives with the {011} faces of naproxen crystal, consequently leading to selective growth inhibition along the +b axis. This simulation result is consistent with the asymmetrical crystal growth observed experimentally. Growth promotion in the −b direction of naproxen crystal (in the presence of PVP alone) was explained based on hydrophobic–hydrophilic intermolecular interactions occurring at the crystal–solution interface. In the light of these findings, the use of polymeric additives, either singly or in combination, to modulate naproxen crystal shape and size was further explored.