Nuclear magnetic resonance investigation of the interaction of water vapor with sildenafil citrate in the solid state

Solid-state carbon-13 (C-13) and nitrogen-15 (N-15) nuclear magnetic resonance (NMR) have been used to investigate how water interacts with sildenafil citrate. When the humidity is altered, the water concentration in the solid compound changes in a reversible manner. The proportion of occupied sites depends on the humidity, but the water concentration never reaches a rational (e.g., 1: 1) stoichiometric ratio to form a true hydrate. The NMR spectra were obtained under several humidity-controlled conditions to determine what changes occur as the water content is varied and where the water is located in the crystal structure. Only one set of N-15 and C-13 signals is observed for each humidity level. This shows that water incorporated into the crystal lattice of sildenafil citrate is very mobile and exchanges rapidly on the NMR time scale between various sites. The C-13 data are consistent with formation of a hydrogen bond between a water molecule and one carbonyl of the citrate anion. The spectra also show that the water content affects the environment (perhaps influencing the average conformation) of the propyl group. Additionally, N-15 dipolar dephasing experiments show that the sildenafil molecule is only protonated in the piperazine ring. The work is supported by solution-state NMR. (C) 2004 Wiley-Liss, Inc.