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 1H DQ CRAMPS (Combined Rotation And Multiple Pulse Spectroscopy) and 1H-13C on‐ and off‐resonance CP (cross polarization) FSLG‐HETCOR experiments, known for providing reliable information about 1H-1H and 1H-13C 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 (1H, 13C, 15N) 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 13C 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. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1855-1870, 2010