Correlation of solid-state NMR relaxation times to functional properties such as chemical stability and particle size

Abstract

The purpose of the work presented in this dissertation was to investigate the correlation between the particle size of crystalline active pharmaceutical ingredients (APIs) and their solid-state NMR (SSNMR) proton spin-lattice relaxation times (1H T1) using model compounds. Dicumarol and salicylic acid were selected as model compounds for this study. Crystalline samples of the model compounds containing particles with sizes ranging from 1 &um- 800 &um were prepared by sieving, spray-drying, and anti-solvent precipitation. The physical state and the particle size of the materials prepared were characterized. A model that describes the correlation observed between the 1H T1 time of the dicumarol and the salicylic acid materials and their particle size was proposed. The model was based on the assumption that spin diffusion is the main spin-lattice relaxation mechanism. The way that SSNMR relaxation time measurements could be used to characterize the polydispersity of crystalline powders using physical mixtures of dicumarol was also investigated. A short investigation of the effect of different compaction forces on the homogeneity of formulated tablets of salicylic acid was also conducted. Different 1H T1 times were obtained for salicylic acid at all compaction forces, and heavier compaction forces lead to a larger decrease in 1H T1 time. Finally, the effect of grinding on the chemical stability of a crystalline API gabapentin was investigated. Changes in 1H T1 times of ground crystalline gabapentin Form II were correlated with the chemical stability of the material: samples with shorter 1H T1 times were the least chemical stable. The physical meaning for the reduction in 1H T1 time observed was believed to be both the presence of crystal defects and the decrease in particle size of the material. This research provided evidence that SSNMR can be used to characterize bulk properties as well as molecular level characteristics of pharmaceutical solids. This could improve the characterization of formulated drug products during drug development.