Melt Crystallization of Indomethacin Polymorphs in the Presence of Poly(ethylene oxide): Selective Enrichment of the Polymer at the Crystal-Liquid Interface.

Additives have been known to influence the crystallization behavior of amorphous pharmaceuticals. In this study, the semicrystalline polymer, poly(ethylene oxide) (PEO), exhibited a different impact on the crystal growth kinetics of indomethacin (IMC) polymorphs grown from the melt. Polarized light microscopy and Raman microscopy were employed to reveal the differences in phase separation occurring at the crystal-liquid interface of IMC polymorphs in the presence of PEO. It was found that at the same condition of melt crystallization PEO could be significantly enriched at the crystal growth front of IMC γ and α forms but not at that of the δ form. The local content of PEO at the growth front was proposed to correlate with the solubility of IMC polymorphs in the molten PEO. The distinct drug-polymer distribution at the crystal-liquid interface of IMC polymorphs could have different impacts on the thermodynamic and kinetic factors in the process of crystallization, resulting in different enhancements of crystal growth rates for the polymorphs. This study is beneficial to understanding the crystallization behavior of polymorphic drugs in the presence of polymeric additives, and more attention needs to be focused on the interfacial phenomena during crystal growth.