Solid-State NMR Analysis of Excipients and Drug-Excipient Interactions in the Amorphous State

Abstract

Solid-state NMR (SSNMR) experiments were used to investigate numerous aspects of pharmaceutically relevant amorphous materials, such as structure, molecular weight, water content, interactions with other molecules, and molecular mobility. This dissertation highlights the benefit of using SSNMR in conjunction with other techniques to gain a fuller understanding of the solid-state properties of amorphous pharmaceutical samples. The application of SSNMR to the analysis of polysaccharide-based excipients was demonstrated. Excipients that were studied included the following: alginic acid and sodium alginate, carrageenans, starch and derivatives, microcrystalline cellulose, and cellulose-based derivatives such as hydroxyethylcellulose, (HEC), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC). Results showed that although the peaks in the SSNMR spectra of these samples were broad, the resolution was sufficient for accurate form identification and differentiation. Relaxation measurements provided unique information on starch derivatives. A linear correlation between T1, the peak area of new signals, and the extent of hydrolysis of starch derivatives was observed. Experiments to explore the potential for SSNMR parameters to be correlated to functionally related characteristics of sodium alginate were performed. The ability to detect variations in monomer content among different grades was demonstrated. Hydration was found to increase the resolution of signals in the SSNMR spectra. Differences in intrinsic viscosity and molecular weight of samples with similar monomer content were correlated to SSNMR relaxation times. The hydrogen-bonding networks of the crystalline forms and the melt-quenched amorphous form of indomethacin were analyzed using SSNMR. Disruptions of this network when intimately mixed with PVP or HPMC were detected. SSNMR data supported the conclusion that indomethacin forms hydrogen bonds with PVP and HPMC at the expense of forming hydrogen bonds with other indomethacin molecules. The miscibility and mobility of indomethacin amorphous solid dispersions was probed using SSNMR relaxation measurements. Based on relaxation values, indomethacin appeared to form a miscible amorphous solid dispersion with HPMC at all conditions studied and with PVP in solvent-evaporated mixtures. Melt-quenched indomethacin:PVP mixtures appeared only partially miscible by SSNMR relaxation measurements, suggesting that better mixing was achieved using solvent evaporation. The mobility of amorphous indomethacin was significantly reduced in the presence of both PVP and HPMC.