The use of variable temperature ¹³C solid‐state MAS NMR and GIPAW DFT calculations to explore the dynamics of diethylcarbamazine citrate

Abstract

Experimental 13 C solid-state magic-angle spinning (MAS) Nuclear Magnetic Resonance (NMR) as well as Density-Functional Theory (DFT) gauge-including projector augmented wave (GIPAW) calculations were used to probe disorder and local mobility in diethylcarbamazine citrate, (DEC) + (citrate) − . Thiscompound has been used as the first option drug for the treatment of filariasis, a disease endemic in tropical countries and caused by adult worms of Wuchereria bancrofti, which is transmitted by mosquitoes. We firstly present 2D 13 C-1 H dipolar-coupling-mediated heteronuclear correlation spectra recorded at moderate spinning frequency, to explore the intermolecular interaction between DEC and citrate molecules. Secondly, we investigate the dynamic behavior of (DEC) + (citrate) − by varying the temperature and correlating the experimental MAS NMR results with DFT GIPAW calculations that consider two (DEC) + conformers (in a 70:30 ratio) for crystal structures determined at 293 and 235 K. Solid-state NMR provides insights on slow exchange dynamics revealing conformational changes involving particularly the DEC ethyl groups.

A theoretical NMR study of polymorphism in crystal structures of azoles and benzazoles

“…This work shows the limitations of the combined use of solid-state NMR (SSNMR) and GIPAW calculations to clarify problems related to tautomerism, polymorphism, and desmotropy. [7][8][9][52][53][54][55] When the molecule bears a heavy-atom substituent, either an empirical model using a dummy variable or ZORA-SO calculations are necessary to account for the experimental chemical shifts, especially for atoms directly bonded to an heavy atom, such as bromine and iodine.…”

“…The application of SSNMR as a tool for polymorphism investigation was highlighted on a seminal paper published by Robin K. Harris entitled “Applications of solid‐state NMR to pharmaceutical polymorphism and related matters.” We have used this approach recently and so have done several authors, for instance, to explore the dynamics of diethylcarbamazine citrate …”

“…[7] We have used this approach recently [8] and so have done several authors, for instance, to explore the dynamics of diethylcarbamazine citrate. [9] Recently, we have reported a theoretical NMR study of a set of benzazole crystal structures by using GIPAW calculations. [10] We concluded that this method reproduces with high accuracy the experimental 13 C-NMR and 15 N-NMR measurements in the solid state.…”

Periodic DFT Calculations—Review of Applications in the Pharmaceutical Sciences

“…However, in this topic of imposed outer parameters, periodic calculations are also implemented inversely: not as an achieving but verifying tool for new structures. This is how eventually the existence of the obtained during the direct compression, high-stability ethenzamide-aliphatic dicarboxylic acids co-crystals have been proven [152] or structural differences in the diethylcarbamazine citrate at 293 K and 235 K have been described [153].…”

A curious case of dynamic disorder in pyrrolidine rings elucidated by NMR crystallography

“…Solid-state NMR spectroscopy is a powerful tool for investigating crystallographic disorder, with the potential to exploit several pharmaceutically-relevant nuclei ( 1 H, 13 C, 15 N) and the ability to probe specific sites in the structure. 5,6 NMR crystallography is capable of distinguishing static from dynamic structural disorder, has been used for investigating dynamics in pharmaceuticals, [7][8][9][10] and can be used to improve structural models. [11][12][13][14][15][16][17] Conversely, the presence of dynamics may not be immediately apparent from X-ray data, especially for data acquired at low temperatures due to a ''freezing'' of the motion.…”