Abstract
The naturally occurring compound α-lipoic acid (ALA) is implicated in manifold critical biological roles and its potent antioxidant properties and potential for treatment of various diseases have led to its widespread use as a dietary supplement. However, shortcomings of poor aqueous solubility and low thermal stability have hampered its development as a medicinal agent, prompting the use of cyclodextrins (CDs) to address these problems. The paucity of published structural data on the nature of the interactions between ALA and CDs motivated the present study, which describes the synthesis and X-ray structural elucidation of crystalline inclusion complexes between the biologically relevant R-(+)-α-lipoic acid (RALA) and the host molecules permethylated α-CD (TMA) and permethylated β-CD (TMB). Single crystal X-ray diffraction of TMA·RALA·6H2O and TMB·RALA revealed significantly different orientations of the RALA molecule within the TMA and TMB cavities, but in both cases the guest molecule is fully encapsulated by the respective parent host molecules and residues of CD molecules of neighboring complex units. While pure RALA melted at 46–48 °C, combined thermal analysis techniques indicated that on heating the respective complexes, the release of RALA occurred at significantly higher onset temperatures, in the range 150–170 °C.
Highlights
IntroductionThere is considerable current interest in enhancing the performance of compounds with proven medicinal benefits by incorporating them into multi-component systems
There is considerable current interest in enhancing the performance of compounds with proven medicinal benefits by incorporating them into multi-component systems. In this context, ‘performance’ relates to pharmaceutically relevant properties, primarily bioavailability and chemical stability [1], while the types of multi-component system that have been successfully exploited in enhancing performance include those in which the components are associated via non-covalent interactions. Examples of these constructs are co-crystals formed by linking bioactive molecules to water-soluble biocompatible co-formers via hydrogen bonds [2], and inclusion complexes between bioactive molecules and water-soluble macrocyclic carrier molecules based primarily on hydrophobic interactions [3]
Crystal data for the host molecules permethylated α-CD (TMA)·RALA·6H2 O 1, [C54 H96 O30 ·C8 H14 O2 S2 ·6H2 O] (M = 1539.71 g/mol): orthorhombic, space group P21 21 21, a = 15.1893(7) Å, b = 21.7433(11) Å, c = 23.4588(11) Å, V = 7747.6(6) Å3, Z = 4, T = 173(2) K, μ(MoKα) = 0.159 mm−1, Dcalc = 1.320 g/cm3, 72,052 reflections measured (3.2◦ ≤ 2Θ ≤ 50.5◦ ), 19,280 unique (Rint = 0.0423) which were used in all calculations
Summary
There is considerable current interest in enhancing the performance of compounds with proven medicinal benefits by incorporating them into multi-component systems. ‘performance’ relates to pharmaceutically relevant properties, primarily bioavailability and chemical stability [1], while the types of multi-component system that have been successfully exploited in enhancing performance include those in which the components are associated via non-covalent interactions Examples of these constructs are co-crystals formed by linking bioactive molecules to water-soluble biocompatible co-formers via hydrogen bonds [2], and inclusion complexes between bioactive molecules and water-soluble macrocyclic carrier molecules based primarily on hydrophobic interactions [3]. The present study relates to the well-established practice of using cyclodextrins (CDs) to improve the delivery of poorly soluble bioactive compounds [4] These molecules are cyclic oligosaccharides containing α-1,4-glucopyranose units that are linked by glycosidic bonds. As described in many articles, reviews and monographs, a CD molecule has the shape of a truncated cone with a hydrophilic exterior and a central hydrophobic
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