475301 Mechanistic and kinetic insight into cocrystallization of APIs in supercritical CO2

Tuesday, November 15, 2016
Grand Ballroom B (Hilton San Francisco Union Square)
Luis Padrela1, Barry Long1, Miguel A. Rodrigues2 and Kevin M. Ryan1, (1)University of Limerick, Limerick, Ireland, (2)Chemical Engineering, Instituto Superior Técnico TU Lisbon, Lisbon, Portugal

Pharmaceutical cocrystals are crystalline molecular complexes which have been driving much interest from both the academic and industrial environments because their physical and pharmacokinetic properties (e.g. solubility, stability) can be significantly improved as compared to the pure APIs1. Cocrystals can be prepared by several (classical) methods such as mechanochemical (e.g. neat and liquid-assisted grinding) or traditional solution crystallization approaches (e.g. solvent evaporation techniques and slurry techniques). However, using these techniques, cocrystals may become electrostatically charged (as may result from the stress applied in classical grinding methods) or suffer undesired interactions with organic solvents (when using classical evaporation or slurries-forming techniques) that may be incorporated into the crystal lattice with the possibility of solvate formation. Supercritical CO2 provides a novel medium for the cocrystallization between an API and a coformer2. This work explores the mechanisms and kinetics of cocrystallization of distinct APIs and coformers in supercritical CO2. Each API and coformer were placed in stoichiometric amounts inside a custom-built high-pressure vessel (internal volume = 10 cm3) and compressed with supercritical CO2 up to the desired pressure and temperature under magnetic stirring. In selected experimental runs, small amounts of distinct organic cosolvents (e.g. ethanol, methanol, acetone) were added to the raw materials inside the high pressure vessel before its pressurization with CO2. In-situ monitorization of the cocrystallization over time was performed using a Raman probe inserted into the high pressure vessel. The results show that it is possible to control the cocrystallization rate and the form of the API (e.g. cocrystal, polymorph) by tuning process variables such that the API and/or the coformer are more solubilized in the supercritical CO2.

Density Functional Theory (DFT) calculations have been applied to investigate API–coformer-solvent interactions and corresponding binding energies for each system in order to understand how distinct supercritical reaction media (pure CO2, CO2 with cosolvents) influence the final solid form outcome of APIs.

1. Fucke et al. N. J. Chem. 36 (2012) 1969-1977.

  1. Padrela et al. Cryst. Growth Des. 15 (2015) 3175-3181.

This work has been supported by Science Foundation Ireland, Grant number: 12/RC/2275.

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