A Solid-State NMR Study of Phase Structure, Molecular Interactions, and Mobility in Blends of Citric Acid and Paracetamol

Citric acid anhydrate (CAA) and paracetamol (PARA), prepared as crystalline physical mixtures and as amorphous blends, were studied using 13C solid-state cross polarization magic angle spinning (CPMAS) NMR. Amorphous blends showed significant line broadening from the conformational distribution as compared to the crystalline samples. Also, chemical shift variations were observed between crystalline and amorphous blends, which were attributed to differences in intermolecular interactions. Averaging of proton rotating-frame spin-lattice relaxation times (T1ρ) probed via different 13C sites in the amorphous blends confirmed molecular level mixing. For some, initially amorphous, sample compositions the onset of crystallization was evident directly from spectra and from the significantly longer T1ρ relaxations. Thus, crystallization caused phase separation with properties of the two phases resembling those of pure CAA and PARA, respectively. 13C spectra of amorphous 50/50 (w/w, %) CAA/PARA recorded from above the glass transition temperature broadened as the temperature increased to a maximum at T ≈ Tg + 33 K. This was the result of a dynamic interference between the line narrowing techniques being applied and the time scale of molecular reorientation in the miscible melt. The derived average correlation time was found to correspond well with previous results from melt rheology. We conclude that the underlying reasons for physical instability (i.e., crystallization from the miscible melt, including molecular interactions and dynamics) of this class of amorphous binary mixtures can be effectively evaluated using NMR spectroscopy. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1862-1870, 2009