Formation and Characterization of Crystals Containing a Pleuromutilin Derivative, Succinic Acid and Water

An unusual pharmaceutical solid containing a pleuromutilin derivative, succinic acid and water is studied with a combination of physiochemical methods. The parent pleuromutilin derivative creates a host structure that contains large channels, which are occupied by variable amounts of both succinic acid and water. The inherent disorder of the system does not lend itself to detailed single-crystal X-ray diffraction studies; hence a combination of powder X-ray diffraction (PXRD) and solid-state NMR (SSNMR) techniques were used to characterize this system and understand its behavior. A variety of one and two-dimensional SSNMR experiments were used to understand the proton transfer and the hydrogen bonding network, including 1H−13C heteronuclear correlation experiments and measurements of the principal components of 13C chemical shift tensors. This crystal system can exist as two distinct phases; a hemisuccinate phase containing a doubly ionized succinate molecule with two cations of the pleuromutilin derivative, and a succinic acid rich phase which contains a singly ionized succinate molecule hydrogen bonded to another fully protonated succinic acid for every mole of the pleuromutilin derivative. Individual particles can contain mixtures of these two phases, leading to a range of apparent stoichiometries between the succinic acid and pleuromutilin derivative. Both phases are variable hydrates and were characterized by gravimetric vapor sorption and variable humidity 13C SSNMR techniques.