Controlling pharmaceutical polymorphism in crystallization processes represents a major challenge
in pharmaceutical science and engineering. For instance, CO2-antisolvent crystallization typically
favors the formation of metastable forms of carbamazepine (CBZ), a highly polymorphic drug, with
impurities of other forms. This work demonstrates for the first time that a supercritical CO2-
antisolvent crystallization process in combination with certain molecular additives allows control of
the polymorphic outcome of carbamazepine. We show herein that in the presence of sodium stearate
and Eudragit L-100, needle-shaped crystals of CBZ form II are obtained, while blocky-shaped
crystals of CBZ form III are obtained in the presence of Kollidon VA64, sodium dodecyl sulfate,
ethyl cellulose and maltitol. This selectivity for pure forms in this supercritical set up contrasts to
the results when the same set of additives where used in a solvent evaporation method that yielded
mixtures of form I, II and III. The type of additive used in the CO2-antisolvent crystallization
process impacted both the product crystals polymorphic form and size. A detailed molecular-level
analysis along with DFT calculations allowed us to give a mechanistic insight into the role of
sodium stearate and Eudragit L-100 in facilitating nucleation of the metastable form II.