Investigation of the Effects of Pharmaceutical Processing Upon Solid-State NMR Relaxation Times and Implications to Solid-State Formulation Stability

Crystalline lactose was subjected to various forms of pharmaceutical processing including compaction, lyophilization, spray drying, and cryogrinding. 13C cross polarization and magic-angle spinning (CPMAS) NMR spectra were acquired for bulk crystalline lactose as well as the processed samples. Saturation recovery experiments to determine proton spin-lattice relaxation times (1H T1) showed that the α-monohydrate form had a 1H T1 of 243 s, while compaction resulted in a threefold reduction in T1 (79 s), with little change in the spectrum. Lyophilization and spray drying both produced amorphous lactose, with relaxation times around 4 s. Cryogrinding for various times produced mixtures of crystalline and amorphous material, with the amount of amorphous material increasing with grinding time. Sixty minutes of grinding time produced mostly amorphous material, with some crystalline material remaining. The 1H T1 of this sample was 2.0 s. Reducing particle size, introducing crystal defect sites, and producing amorphous material all serve to reduce the T1 by creating sites of high mobility. Spin diffusion to the high-energy sites creates a uniform 1H T1 across the sample. The result is shorter relaxation times for the high-energy mixtures. Relaxation measurements performed on dosage forms could potentially be used to predict stability of pharmaceutical formulations.