Differential protonation and dynamic structure of doxylamine succinate in solution using ¹H and ¹³C NMR

Abstract

A protonation and dynamic structural study of doxylamine succinate, a 1:1 salt of succinic acid with dimethyl-[2-(1-phenyl-1-pyridin-2-yl-ethoxy)ethyl]amine, in solution using one- and two-dimensional 1H and 13C NMR experiments at variable temperature and concentration is presented. The two acidic protons of the salt doxylamine succinate are in 'intermediate' exchange at room temperature, as evidenced by the appearance of a broad signal. This signal evolves into two distinct signals below about -30 degrees C. A two-dimensional 1H-1H double quantum filtered correlation experiment carried out at -55 degrees C shows protonation of one of the acidic protons to the dimethylamine nitrogen. A two-dimensional rotating frame 1H-1H NOE experiment at the same temperature reveals that the other proton remains with the succinate moiety. Comparison of the 1H and 13C chemical shifts and the 13C T1 relaxation times of the salt with those of the free base further substantiate the findings.

Formation and Physicochemical Properties of Crystalline and Amorphous Salts with Different Stoichiometries Formed between Ciprofloxacin and Succinic Acid

“…Pharmaceutical examples of succinate salts comprising the singly ionized succinate moiety include: doxylamine succinate, sumatriptan succinate, strychnine succinate, desvenlafaxine succinate, and imiquimod succinate; in contrast metoprolol succinate has the counterion double ionized, that is, both of the carboxylic acid groups are deprotonated. Therefore it appears that monodissociated succinic acid prevails in pharmaceutical succinate salts and CS-I is a rare example of a salt comprising a fully dissociated succinic acid residue.…”

Effect of Encapsulating Arginine Containing Molecules on PLGA: A Solid-State NMR Study

“…In contrast to the pure arginine, two resonances are observed in the guanidine region (152–168 ppm). In general, carbons next to protonated amine groups are shifted to lower frequency;57–59 thus the high frequency resonance is ascribed to a deprotonated guanidine group ( 1 H– 15 N CP/MAS NMR spectrum, Fig. ESI‐6).…”