Didanosine Polymorphism in a Supercritical Antisolvent Process

Solid-state properties of active ingredients are crucial in pharmaceutical development owing to their significant clinical and economical implications. In the present work we investigated the solid-state properties and the solubility in water of didanosine, DDI, re-crystallized from a dimethylsulfoxide solution using supercritical CO2 as an antisolvent (SAS process) for comparison with the commercially available drug product. We also applied modern solid-state NMR (SS NMR) techniques, namely 2D H-1 DQ CRAMPS (Combined Rotation And Multiple Pulse Spectroscopy) and H-1-C-13 on- and off-resonance CP (cross polarization) FSLG-HETCOR experiments, known for providing reliable information about H-1-H-1 and H-1-C-13 intra- and intermolecular proximities, in order to address polymorphism issues arising from the crystallization of a new form in the supercritical process. A new polymorph of didanosine was obtained from the supercritical antisolvent process and characterized by means of 1D and 2D multinuclear (H-1, C-13, N-15) SS NMR. The particle size of the new crystal phase was reduced by varying the antisolvent density through a pressure increase. The structural differences between the commercial product and the SAS re-crystallized DDI are highlighted by X-ray diffractometry and well described by solid-state NMR. The carbon C6 C-13 chemical shift suggests that both commercial and re-crystallized didanosine samples are in the enol form. The analysis of homo- and heteronuclear proximities obtained by means of 2D NMR experiments shows that commercial and SAS re-crystallized DDI possess very similar molecular conformation and hydrogen bond network, but different packing. The new polymorph proved to be a metastable form at ambient conditions, showing higher solubility in water and lower stability to mechanical stress. (C) 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:1855-1870, 2010