Controlling the Polymorphism of Indomethacin with Poloxamer 407 in a Gas Antisolvent Crystallization Process

Abstract

The polymorphic control of active pharmaceutical ingredients (APIs) is a major challenge in the manufacture of medicines. Crystallization methods that use supercritical carbon dioxide as an antisolvent can create unique solid forms of APIs, with a particular tendency to generate metastable polymorphic forms. In this work, the effects of processing conditions within a gas antisolvent (GAS) crystallization method, such as pressure, stirring rate, and temperature, as well as the type of solvent used and the presence of an additive, on the polymorphism of indomethacin were studied. Consistent formation of the X-ray powder diffraction-pure α polymorphic form of indomethacin by GAS was only achieved when a polymer, poloxamer 407, was used as an additive. Using the GAS method in combination with poloxamer 407 as a molecular additive enabled full control over the polymorphic form of indomethacin, regardless of the processing conditions employed, such as pressure, temperature, stirring rate, and type of solvent. A detailed molecular modeling study provided insight into the role of poloxamer 407 in the polymorphic outcome of indomethacin and concluded that it favored the formation of the α polymorph.

Recent Progress in Antisolvent Crystallization of Pharmaceuticals with a Focus on the Membrane‐Based Technologies

“…2(d) shows the mixing behavior of a flow of 218 L of liquid at two different speeds of the impeller, which plays a crucial role on the antisolvent crystallization kinetics. In another study, Canellas et al [49] used carbon dioxide as the gas antisolvent (GAS) to control the polymorphism of indomethacin (IMC) using poloxamer 407 polymer. Fig.…”

“…IndAc: Acetone used as the solvent, IndAcP: Acetone used as the solvent and poloxamer 407 as the additive, IndEt: Ethyl acetate used as the solvent, and IndEtP: Ethyl acetate used as the solvent and poloxamer 407 as the additive. Reproduced with permission from reference [49].…”

“…In another study, Canellas et al. [49] used carbon dioxide as the gas antisolvent (GAS) to control the polymorphism of indomethacin (IMC) using poloxamer 407 polymer. Fig.…”