Formation of Composite Crystals by Precipitation in Supercritical CO2

Acetaminophen (A) and p -acetoxyacetanilide (PAA) were used as model drug substances to study purification and coformulation of structurally similar molecules by crystallization from supercritical CO 2 . Incorporation of PAA into the crystal structure of A was defined by the mutual solubility of crystals of both molecules according to their different solvent−solute interactions, by the thermodynamics of the A-PAA solid solution phase, and by the kinetics of crystallization reflected by the specific surface interactions. The interaction between PAA and A resulted in significant changes to the crystal bulk and surface free energy, particle size, and morphology. Accurate determination of the lattice constants revealed the formation of a secondary A-PAA phase with a deformed crystal lattice. The observed changes in the thermal behavior of the resulting solid solutions are explained mainly by changes of the entropy of the solid phase with smaller changes in enthalpy and even smaller elastic energy contributions.