Solid‐State Nuclear Magnetic Resonance of Pharmaceutical Formulations

Abstract

Analysis of pharmaceutical solids using solid‐state nuclear magnetic resonance ( NMR ) spectroscopy is finally coming of age. The wealth of information that solid‐state NMR can provide is unmatched by any other single technique used to characterize pharmaceutical solids. Perhaps the area where NMR can provide the most benefit to pharmaceutical scientists is in the analysis of formulated drug products, where the active pharmaceutical ingredient ( API ) is diluted in the presence of one or more inactive ingredients, or excipients. Unlike most other techniques, NMR has the ability to selectively characterize the physical states of the API as well as excipients, as they exist together within the formulation, without separation or sample destruction. Critical issues such as crystal form, crystallinity, amorphous content, ionization states, hydration states, molecular mobility, and drug–excipient interactions may all be studied using modern solid‐state NMR . Here we examine some of the presently available literature, provide relevant references, and demonstrate examples of how to best utilize the technique and interpret the results.

DNP‐enhanced solid‐state NMR spectroscopy of active pharmaceutical ingredients

“…Relaxation and spin diffusion solid‐state NMR experiments have been broadly applied to probe the macroscopic structure and ordering or mixing within solid materials such as polymers . In the context of pharmaceutical formulations, analysis of T 1 relaxation time constants, rotating‐frame longitudinal relaxation times ( T 1ρ ), and spin diffusion rates are commonly used to assess the degree of mixing between excipients, polymers, coformers, and APIs . Here, we describe how experimental measurements of relayed DNP enhancements and signal buildup rates can be fit to numerical models of spin diffusion (described above) to determine the particle or domain size of APIs within formulations.…”

“…Solid‐state NMR spectroscopy is now an established method for the characterization of pure, multicomponent (i.e., cocrystals and ASDs), and formulated APIs. Many excellent reviews and books describe the established applications of solid‐state NMR spectroscopy to APIs . One key application of solid‐state NMR spectroscopy to APIs is the identification and differentiation of polymorphs.…”

Fast 19F Magic-Angle Spinning Nuclear Magnetic Resonance for the Structural Characterization of Active Pharmaceutical Ingredients in Blockbuster Drugs

“…In drug formulations, the active pharmaceutical ingredient (API) typically only comprises a fraction of the overall mixture. Therefore, characterization of drug formulations by nuclear magnetic resonance (NMR) with commonly used 13 C- or 1 H-detected experiments presents a challenge, since the spectrum invariably reports predominantly on the excipients. − …”

Probing the Distribution of Water in a Multi-Component System by Solid-State NMR Spectroscopy

“…A process called proton spin diffusion, enabled by 1 H-1 H dipolar coupling, serves to average out the observed 1 H T 1 for a given sample. For further treatment of relaxation processes in NMR spectroscopy, interested readers are encouraged to refer to references (14)(15)(16)(17)(18).…”