Disappearing and reappearing polymorphs. The benzocaine : picric acid system

The low-melting polymorphic modification of the 1:1 complex of benzocaine ( BC) and picric acid (PA) had earlier been reported to be an example of a '' disappearing polymorph". The BC:PA system has been reinvestigated by thermo microscopy, calorimetry, solid-state NMR, and X-ray crystallography. The ph ase diagram has been derived, and robust procedures for the crystallization of the two 1:1 complexes, a hydrate of the 1:1 complex, and a 2:1 complex have been devised. The structures of all four phases have been determined a nd compared using graph set analysis to characterize the hydrogen-bonding p atterns. It is shown that the thorough microscopic investigation of the the rmal behavior, combined with calorimetric methods, can lead to the developm ent of strategies to crystallize metastable polymorphic forms which may be difficult to obtain once their stable congeners have been obtained.