Diastereomeric Salt Formation by the γ-Amino Acid RS-Baclofen and L-Malic Acid: Stabilization by Strong Heterosynthons Based on Hydrogen Bonds between RNH₃⁺ and COOH/COO^– Groups

Abstract

Baclofen (BAC) is an important chiral active pharmaceutical ingredient for the treatment of specific neurological disorders that is commercially available only as RS-BAC (racemate). Using the liquid-assisted grinding technique, combination of RS-BAC with DL-MA in 1:1 stoichiometric ratio yielded a crystalline solid phase mixture of the enantiomeric salts R-BAC:L-MA and S-BAC:D-MA. Single-crystals suitable for SCXRD analysis of R-BAC:L-MA were obtained by fractional crystallization from a solution of RS-BAC and L-MA in a solvent mixture of ethyl acetate and water. Analysis of the supramolecular interaction patterns revealed that the crystal structure is stabilized by strong N+–H···–O, N+–H···O and O–H···–O hydrogen-bonding interactions. A comparative study with structurally related compounds enabled to identify common homo- and heterosynthons involving RNH3 +, OH, and COOH/COO– groups. The spectroscopic, structural and thermogravimetric studies of the enantiomeric solid phase mixture of R-BAC:L-MA and S-BAC:D-MA was accomplished by examination of some basic pharmaceutically relevant physicochemical properties. Phase stability studies in aqueous media simulating the gastrointestinal tract physiological conditions (pH 1.2 and 4.5) showed that R-BAC:L-MA/S-BAC:D-MA transforms into BAC within a few minutes. However, upon exposure to standard thermal/humidity stress conditions, the phases were stable. The decomposition changes the kinetics of the dissolution process under sink conditions, but the calculated intrinsic dissolution rates of RS-BAC and R-BAC:L-MA/S-BAC:L-MA resulted to be quite similar.

Chiral Resolution of RS-Baclofen via a Novel Chiral Cocrystal of R-Baclofen and L-Mandelic Acid

“…Baclofen, a drug used to treat muscle spasticity, for instance from spinal cord injuries, is one of the chiral drugs still sold in a racemic form. Previous research has shown that the two baclofen enantiomers have different bioactivities. , Accordingly, many processes have been developed to produce enantiopure baclofen or to separate the enantiomers of baclofen: asymmetric synthesis, chiral chromatography, , preferential crystallization, and resolution by diastereomeric salt formation. , The latter method is widely applied in industry since it is easy to scale up economically. The resolution occurs by forming diastereomeric salts from the racemate and a chiral resolving agent where the diastereomers formed have different physical and chemical properties since they are not mirror images to each other.…”

Tailoring Chlorthalidone Aqueous Solubility by Cocrystallization: Stability and Dissolution Behavior of a Novel Chlorthalidone-Caffeine Cocrystal

“…Comparison of the solid-state IR spectra of the starting materials and products of cocrystallization experiments allows establishing the formation of a new solid phase since changes in the vibrations of functional groups occur due to changes in the interaction patterns, particularly when hydrogen bonding motifs are varying [62][63][64]. The IR spectra of CTD (polymorph I), CAF, and CTD-CAF are shown in Figure 7, with the IR spectra of CTD and CAF matching with previously reported data [10,65].…”

(R)-Baclofen [(R)-4-amino-3-(4-chlorophenyl)butanoic acid]

“…In addition, baclofen has been recently approved in France as an alternative medication to treat alcohol dependence (Reade, 2021). Considering those new developments, the establishment of synthetic routes towards enantiopure (R)-baclofen were discussed recently (Co ´rdova-Villanueva et al, 2018;Gendron et al, 2019).…”