Anion Effect on the Binary and Ternary Phase Diagrams of Chiral Medetomidine Salts and Conglomerate Crystal Formation

Abstract

The binary phase diagrams of hydrogen halides salts of medetomidine (Med.HX, X:Br,I) and hydrogen oxalate salt of medetomidine (Med.Ox) were determined based on thermogravimetric/differential thermal analysis (TGA/DTA) and their crystal structure behavior was confirmed by comparison of the X-ray diffractometry and FT-IR spectroscopy of the racemate and pure enantiomer. All hydrogen halide salts presented racemic compound behavior. Heat of fusion of halides salt of (rac)-medetomidine decreased with ionic radius increase. Eutectic points for Med.HCl (previously reported), Med.HBr, and Med.HI rest were unchanged approximately. The solubility of different enantiomeric mixtures of Med.HBr and Med.HI were measured at 10, 20, and 30°C in 2-propanol showing a solubility increase with ionic radius. A binary phase diagram of Med.Ox shows a racemic conglomerate behavior. The solubility of enantiomeric mixtures of Med.Ox were measured at 10, 20, 30, and 40°C. The ternary phase diagram of Med.Ox in ethanol conforms to a conglomerate crystal forming system, favoring its enantiomeric purification by preferential crystallization.

Stereoselective Crystallization as a Basis for Single‐Enantiomer Drug Production

“…Pure enantiomers of atenolol 27 were obtained via preferential crystallization in the form of salts with p ‐toluic acid . Racemic medetomidine 28 is used in medical practice as a hydrochloride but it becomes a conglomerate in the form of oxalic acid salt . The registered racemic forms of omeprazole 29 , free acid and its magnesium salt, are not prone to spontaneous resolution.…”

Physicochemical characterization and decomposition kinetics of (S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole HCl/S-enantiomer of medetomidineHCl

“…The structural and thermal properties of the racemate drug and its hydrated form are well studied [11]. The racemic species of the halide salts, as well as the oxalate salts of medetomidine, were studied by melting point, infrared spectroscopy and thermal analysis [12]. The binary and ternary phase diagrams of medetomidine hydrochloride are also known [13].…”

Development and validation of a chiral LC‐MS method for the enantiomeric resolution of (+) and (−)‐medetomidine in equine plasma by using polysaccharide‐based chiral stationary phases

“…A significant number of research works have been published related to the chiral resolution of racemates on a large scale using kinetic resolution by crystallization and enzymatic resolution methods [26][27][28][29] . Liquid chromatography (LC) evolved as a key technique for chiral separations due to the availability of large number of chiral stationary phases and lesser time to establish a method [30][31][32][33][34][35][36][37][38][39] .…”