Investigating Albendazole Desmotropes by Solid-State NMR Spectroscopy

Abstract

Characterization of the molecular structure and physicochemical solid-state properties of the solid forms of pharmaceutical compounds is a key requirement for successful commercialization as potential active ingredients in drug products. These properties can ultimately have a critical effect on the solubility and bioavailability of the final drug product. Here, the desmotropy of Albendazole forms I and II was investigated at the atomic level. Ultrafast magic angle spinning (MAS) solid-state nuclear magnetic resonance (NMR) spectroscopy, together with powder X-ray diffraction, thermal analysis, and Fourier transform infrared spectroscopy, were performed on polycrystalline samples of the two solids in order to fully characterize and distinguish the two forms. High-resolution one-dimensional (1)H, (13)C, and (15)N together with two-dimensional (1)H/(1)H single quantum-single quantum, (1)H/(1)H single quantum-double quantum, and (1)H/(13)C chemical shift correlation solid-state NMR experiments under MAS conditions were extensively used to decipher the intramolecular and intermolecular hydrogen bonding interactions present in both solid forms. These experiments enabled the unequivocal identification of the tautomers of each desmotrope. Our results also revealed that both solid forms may be described as dimeric structures, with different intermolecular hydrogen bonds connecting the tautomers in each dimer.

Hybridizing cross-polarization with NOE or refocused-INEPT enhances the sensitivity of MAS NMR spectroscopy

“…Particularly, one-dimensional proton-enhanced 13 C (or 15 N) CPMAS NMR spectroscopy has become an indispensable and essential tool for the study of physical and chemical properties of various non-soluble and non-crystalline solids such as bone [5,6], membrane proteins [7–9], amyloid fibrils [10,11], polymers [12–14], pharmaceutical compounds [15,16], etc. Despite that CP leads to a substantial gain in signal sensitivity with an enhancement factor of γ H /γ X , the polarization transfer efficiency can be severely limited by weak heteronuclear dipolar couplings, as in the case of dynamic systems or semi-solids where molecular motions suppress dipolar couplings [17].…”

Selective excitation enables assignment of proton resonances and 1H-1H distance measurement in ultrafast magic angle spinning solid state NMR spectroscopy

“…[19][20][21] As a result, an increasing number of studies utilizing protondetection NMR under ultrafast MAS have been reported in the recent years. [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] Novel pulse sequences under ultrafast MAS conditions have been demonstrated for the measurement of heteronuclear dipolar coupling and chemical shift aniosotropy. 26,[38][39][40][41] The unique combination of 1 H-1 H dipolar recoupling and ultrafast MAS has made proton-detected solidstate NMR methods to be quite attractive and enabled the possibility of using 1 H-1 H dipolar coupling for potential structural studies.…”

Enhancing NMR Sensitivity of Natural‐Abundance Low‐γ Nuclei by Ultrafast Magic‐Angle‐Spinning Solid‐State NMR Spectroscopy

“…Solid‐state NMR spectroscopy has been playing very important roles by rendering substantial insights into the atomic‐resolution molecular structures and dynamics of various types of solids including polymers, protein assemblies, bone, amyloid aggregates, and pharmaceutical compounds, However, its poor sensitivity has severely limited the application of this mighty technique. In fact, many exciting applications cannot utilize the benefits of sophisticated multidimensional solid‐state NMR techniques.…”