The 3′-Keto–Diol Equilibrium of Trospectomycin Sulfate Bulk Drug and Freeze-Dried Formulation: Solid-State Carbon-13 Cross-Polarization Magic Angle Spinning (CP/MAS) and High-Resolution Carbon-13 Nuclear Magnetic Resonance (NMR) Spectroscopy Studies

Understanding how moisture interacts with a drug or formulation is a critical component of product development. This study demonstrates how water affects the 3'-gem-diol ? 3'-keto equilibrium in trospectomycin sulfate bulk drug and freeze-dried formulation, as probed by solid-state carbon-13 cross-polarization magic angle spinning (CP/MAS) and high-resolution nuclear magnetic resonance (NMR) spectroscopy. Drying the bulk drug or formulation to low water levels dehydrates trospectomycin sulfate from the diol to the keto form. Carbon-13 CP/MAS NMR spectroscopy measures the keto drug concentration in solid samples directly. The bulk drug, which contains approximately 16% water, is more than 90% in the 3'-diol form. Oven drying to 95%) of the drug is in the 3'-diol form. After equilibration at 60°C, however, the 3'-keto content increases to 7%, and in d6-DMSO solvent at 25°C the drug is mostly (60%) in the 3'-keto form.