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abstracts
Owing to its potent antioxidant activity,α-lipoic acid (1,2-dithiolane-3-pentanoic acid) is widely used as a supplement and is recommended for treating a number of conditions including chronic liver disease and diabetes. The poor aqueous solubility of the acid (~0.003 M at 25 0C) has prompted studies of its interaction with cyclodextrins (CDs) as a possible route to improving its solubility. However, relatively few studies have focused on the isolation of solid CD inclusion complexes of the antioxidant, and in most cases the racemic form of the acid was employed. In the comprehensive study reported here, the bioactive (R)-(+)-enantiomeric form of the molecule was used exclusively, resulting in the isolation and structural characterization of its inclusion complexes with each of the native host CDs (α-, β- and γ-CD) as well as permethylated α-CD (TRIMEA), permethylated β-CD (TRIMEB) and 2,6-dimethylated-β-CD (DIMEB). The α-CD complex crystallizes in the trigonal system, space group R32, with three independent CD molecules in the asymmetric unit and is not isostructural with any known CD complex while the β-CD complex crystallizes in the monoclinic system (C2). With the host γ-CD, an orthorhombic (pseudo-tetragonal) inclusion complex was identified, an unusual result as γ-CD complexes generally crystallize in the tetragonal space group P4212. The complexes with TRIMEA and TRIMEB crystallize in the orthorhombic system (P212121), the modes of inclusion of the (R)-(+)-α-lipoic acid molecule in the respective hosts being reversed: the guest molecule is fully encapsulated by the former host with the dithiolane ring located at the secondary rim, while in the latter host, the dithiolane ring rests on the concave surface of the host cavity at the primary side. A significant level of guest disorder was detected in the inclusion complex with DIMEB (P21). Thermal and phase-solubility analyses complemented the X-ray structural studies.
abstracts
The hypolipidemic agent acipimox has various potential hydrogen bonding donor and acceptor sites. A series of multi-component crystals can be formed owing to these moieties. Acipimox forms such structures with benzamide, isonicotinamide and urea. Each of these systems has a unique hydrogen bonding arrangement leading to changes in the physicochemical properties of acipimox. X-ray analysis of a hydrated co-crystal, acipimox·benzamide·0.5H2O (space group C2/c) revealed layers of dimeric acipimox-benzamide units, the layers being linked by hydrogen bonding from a bridging water molecule. A salt with formula (acipimox)- (isonicotinamide)+ (space group P2(1)/c) results from proton transfer from the carboxyl group of acipimox to the pyridyl nitrogen of isonicotinamide. The carboxyl group engages in an electrostatic interaction with the protonated pyridyl nitrogen. In addition, a hydrogen bond is formed between the donor amide and the acceptor carboxyl group of a second acipimox anion. These form a macrocyclic structure composed of two pairs of acipimox-isonicotinamide counterions in a R44(22) H-bonded motif, giving rise to interlaced layers. Acipimox and urea form two distinct systems, both crystallising in the space group P(-1). The kinetic crystallisation product is a co-crystal with 1:1 acipimox:urea stoichiometry (R22(8) motif), a second distinct urea molecule self-assembles forming infinite chains within channels formed by the packing arrangement. The thermodynamic form is an acetonitrile solvate in which the solvent molecules are included in isolated sites. The different H-bonding systems in each of these multi-component crystals give rise to differing physicochemical properties. For example the melting and degradation temperatures for each of these systems is distinct: that of the acipimox·benzamide co-crystal is lower than that of acipimox while the crystals containing isonicotinamide and urea have higher melting and degradation temperatures.
