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

Abstract

Herein is presented a rare example of salt/ cocrystal polymorphism involving the adduct between ethionamide (ETH) and salicylic acid (SAL). Both the salt and cocrystal forms have the same stoichiometry and composition and are both stable at room temperature. The synthetic procedure was successfully optimized in order to selectively obtain both polymorphs. The two adducts' structures were thoroughly investigated by means of singlecrystal X-ray diffraction, solid-state NMR spectroscopy, and density functional theory (DFT) calculations. From the solidstate NMR point of view, the combination of mono-and multinuclear experiments ( 1 H MAS, 13 C and 15 N CPMAS, 1 H-{ 14 N} D-HMQC, 1 H− 14 N PM-S-RESPDOR) provided undoubted spectroscopic evidence about the different positions of the hydrogen atom along the main N•••H•••O interaction. In particular, the 1 H− 14 N PM-S-RESPDOR allowed N−H distance measurements through the 1 H detected signal at a very high spinning speed (70 kHz), which remarkably agree with those derived by DFT optimized X-ray diffraction, even on a natural abundance real system. The thermodynamic relationship between the salt and the cocrystal was inquired from the experimental and computational points of view, enabling the characterization of the two polymorphs as enantiotropically related. The performances of the two forms in terms of dissolution rate are comparable to each other but significantly higher with respect to the pure ETH.

Molecular Crystal Forms of Antitubercular Ethionamide with Dicarboxylic Acids: Solid-State Properties and a Combined Structural and Spectroscopic Study

“…In all cases, endothermic DSC peaks, corresponding to lower melting points than for pure ETN, are observed. This behavior is recurrent for ETN as all the adducts reported in literature are characterized by lower melting points [ 16 , 25 , 26 , 27 ].…”

“…The latter, in particular, are more and more commonly pursued as an alternative to salts in the quest for performance enhancement of APIs, because cocrystallization offers greater opportunities than salification: (i) it is viable for molecules that do not display any ionizable moiety; (ii) the possible coformers (i.e., molecules selected to cocrystallize with the API) are more numerous than the possible counterions; (iii) cocrystallization can significantly improve the solubility of the APIs without altering their permeability. As of today, many pharmaceutical cocrystals have been successfully prepared and reported in the literature [ 7 , 16 , 17 , 18 , 19 , 20 ].…”

“…Notably, in all salts reported in the literature, N5 of ETN appears to be protonated, while in all cocrystal structures of ETN with carboxylic acids, the COOH group is involved in hydrogen bond (HB) contacts with both N5 (COOH···N) and N10 (C=O···HN). Most recently, some of us managed to selectively obtain both a salt and a cocrystal for the ETN−salicylic acid system, which display remarkable in vitro bioavailability properties [ 16 ]. This further proves ETN to be a very feasible molecule to undergo the crystal engineering approach.…”

Fast Acquisition of Proton‐Detected HETCOR Solid‐State NMR Spectra of Quadrupolar Nuclei and Rapid Measurement of NH Bond Lengths by Frequency Selective HMQC and RESPDOR Pulse Sequences

“…The accuracy of the NH bond length measurements can be improved by using a phase modulated saturation pulse to more reliably saturate the 14 N spins. [24][25] 1 H{ 14 N} FS RESPDOR was also performed on the ammonium 1 H signal of hist at 17.2 ppm to confirm the accuracy of the NH distance measurements (Figure S11). Using 1 H{ 14 N} FS RESPDOR rNH = 1.10 Å was determined, in good agreement with the value of rNH = 1.09 Å measured by Levitt and co-workers with 15 N{ 1 H} symmetry-based recoupling, separated local field (SLF) experiments on 15 N-enriched hist.…”

“…[24] However, experiment times on the order of 6-10 hours have been reported to record 1 H{ 14 N} RESPDOR dipolar dephasing curves of amino acids [24] and multicomponent APIs. [25] 1 H{ 14 N} FS RESPDOR allowed complete dipolar dephasing curves to be obtained in only 20 minutes each for 1 and 2 (Figure 4D, Figures S9 and S10). 1 H{ 14 N} RESPDOR curves for 1 and 2 were calculated with the SIMPSON simulation program for a 1 H-14 N-14 N spin system.…”