Elucidating polymorphic behaviour of curcumin during antisolvent crystallization: insights from Raman spectroscopy and molecular modeling

Abstract

The focus of this work was to understand the polymorphic behavior of curcumin crystallized from two different organic solvents by Liquid Antisolvent (LAS) precipitation. LAS precipitation of curcumin from ethanol yielded the metastable (orthorhombic) Form 3, while acetonitrile led to the precipitation of stable (monoclinic) Form 1. The in-situ Raman spectroscopy revealed the difference in clustering of curcumin molecules in the respective organic solutions. Results from molecular dynamics (MD) simulations and density functional theory (DFT) calculations when combined with Raman spectroscopy observations indicated that the weak interactions between curcumin and acetonitrile molecules and strong CH���O interactions between curcumin molecules at the phenolic ends resulted in nucleation of Form 1 in acetonitrile. On the other hand, stronger interactions between ethanol and curcumin molecules at the polar end groups led to parallel stacking of curcumin molecules and thereby favored nucleation of Form 3 in ethanol. Furthermore, the solvatochromic effect observed in organic solutions of curcumin in ethanol and acetonitrile was found to be related to solvent-induced conformations and, in turn, to be an initial indicator of nucleation of curcumin polymorphs from those organic solutions.