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

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