Molecular Salts of the Antidepressant Venlafaxine: An Effective Route to Solubility Properties Modifications

Abstract

The possibility of decreasing the solubility of the antidepressant drug venlafaxine hydrochloride by formation of molecular salts with organic acids accepted by the Pharmacopeia has been successfully investigated. Reacting venlafaxine with coumaric, ferulic, oxalic, salicylic, fumaric, and citric acids results in the protonation of the amino group and formation of the corresponding 1:1 molecular salts. All compounds have been characterized by a combination of solid state techniques, i.e., single crystal and powder X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, Fourier transform infrared spectroscopy and solid-state NMR (1H MAS, 13C and 15N CPMAS, 1H DQ MAS, two-dimensional (2D) 13C–1H HETCOR, and 2D 14N–1H J-HMQC) spectroscopy. Intrinsic dissolution tests were performed on the pure salts, and suitable candidates were selected for the preparation of solid formulations with excipients; dissolution profiles for the solid formulations were measured in water and sodium chloride solution, and compared with that of the commercial form of venlafaxine, showing that the coumarate salt might represent an improvement for extended release administrations.

NMR crystallography of molecular organics

“…Although the resolution of XPS spectra is relatively poor, the chemical shifts in N 1s binding energy are much less sensitive to changes in intermolecular interaction, and so do cleanly distinguish between protonation states. Changes to lower 15 N chemical shift of >10 ppm have similarly been observed protonating NH 2 [247], while consistent changes >10 ppm to higher frequency were observed on protonating tertiary amines [224] (consistent with the lidocaine example above). In the latter case, the protonation was confirmed using 14 N/ 1 H HMQC.…”

“…Most cases of using 13 C NMR to determine H positions have involved the different chemical shift of carboxylic vs. carboxylate carbon. Even so, the increase in 13 C isotropic chemical shift on deprotonation of CO 2 H is relatively small, up to 7 ppm stated [224], and has often been used to confirm a protonation state established by other means, e.g. using 15 N shifts [225].…”

“…using 15 N shifts [225]. In a set of salts / co-crystals of venlafaxine, the carboxylate resonance in one of the five salt forms was found be at lower, rather than higher, chemical shift than the neutral form [224]. Quantitative correlations between 13 C shifts and hydrogen bonding have often been elusive.…”

“…Other examples of using dipolar information to confirm predicted intermolecular contacts in structures solved by PXRD include Ref. [224]. In other cases, dipolar information has been more ambiguous.…”

Selective Synthesis of a Salt and a Cocrystal of the Ethionamide–Salicylic Acid System

“…29,30 Furthermore, SAL is a GRAS phenolic acid with analgesic and anti-inflammatory properties. 31,32 In order to fully identify and characterize the structural features of the two polymorphs, a complementary powder and single-crystal X-ray diffraction (PXRD and SC-XRD, respectively) and solid-state NMR (SSNMR) approach, supported by DFT calculations, was employed. From the SSNMR point of view, both common and advanced techniques ( 1 H MAS, 13 C and 15 N CPMAS, 1 H-{ 14 N} J-and D-HMQC, 1 H− 14 N PM-S-RESPDOR) were applied to discriminate between the neutral or ionic nature of the adducts.…”