Insight into the Role of Additives in Controlling Polymorphic Outcome: A CO₂‑Antisolvent Crystallization Process of Carbamazepine

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 CBZ. 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 crystal polymorphic form and size. A detailed molecular-level analysis along with density functional theory 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.