RESUMO
Inadequate aqueous solubilities of bioactive compounds hinder their ability to be developed for medicinal applications. The potent antioxidant pterostilbene (PTB) is a case in point. The aim of this study was to use a series of modified water-soluble cyclodextrins (CDs), namely, hydroxypropyl ß-CD (HPßCD), dimethylated ß-CD (DIMEB), randomly methylated ß-CD (RAMEB), and sulfobutyl ether ß-CD sodium salt (SBECD) to prepare inclusion complexes of PTB via various solid, semi-solid, and solution-based treatments. Putative CD-PTB products generated by solid-state co-grinding, kneading, irradiation with microwaves, and the evaporative treatment of CD-PTB solutions were considered to have potential for future applications. Primary analytical methods for examining CD-PTB products included differential scanning calorimetry and Fourier transform infrared spectroscopy to detect the occurrence of binary complex formation. Phase solubility analysis was used to probe CD-PTB complexation in an aqueous solution. Complexation was evident in both the solid-state and in solution. Complex association constants (K1:1) in an aqueous solution spanned the approximate range of 15,000 to 55,000 M-1; the values increased with the CDs in the order HPßCD < DIMEB < RAMEB < SBECD. Significant PTB solubility enhancement factors were recorded at 100 mM CD concentrations, the most accurately determined values being in the range 700-fold to 1250-fold.
RESUMO
Overcoming the challenges of poor aqueous solubility of active pharmaceutical ingredients (APIs) is necessary to render them bioavailable. This study addresses the poor solubility of two potent steroid hormones, 17ß-estradiol (BES) and progesterone (PRO), via their complexation with two water-soluble native cyclodextrins (CDs) namely ß-CD and γ-CD. The hydrated inclusion complexes ß-CD·BES, ß-CD·PRO, γ-CD·BES and γ-CD·PRO were prepared via kneading and co-precipitation, and 1H NMR spectroscopic analysis of solutions of their pure complex crystals yielded the host-guest stoichiometries 2:1, 2:1, 1:1 and 3:2, respectively. Both powder X-ray diffraction (PXRD) and single-crystal X-ray diffraction (SCXRD) were employed for focused studies of the isostructurality of the CD complexes with known complexes and structural elucidation of the new complexes, respectively. SCXRD analyses of ß-CD·BES, ß-CD·PRO and γ-CD·PRO at 100(2) K yielded the first crystal structures of CD complexes containing the hormones BES and PRO, while the complex γ-CD·BES was readily shown to be isostructural with γ-CD·PRO by PXRD. Severe disorder of the encapsulated steroid molecules in the respective channels of the CD molecular assemblies was evident, however, preventing their modelling, but combination of the host-guest stoichiometries and water contents of the four hydrated inclusion complexes enabled accurate assignment of the chemical formulae of these ternary systems. Predicted electron counts for the complexed molecules BES and PRO correlated reasonably well with the complex compositions indicated by 1H NMR spectroscopy. Subsequent measurements of the aqueous solubilities of the four complexes confirmed significant solubility improvements effected by encapsulation of the steroids within the CDs, yielding solubility enhancement factors for BES and PRO in the approximate range 5-20.
RESUMO
Pterostilbene (3,5-dimethoxy-4'-hydroxystilbene, PTB) is a natural dietary stilbene, occurring primarily in blueberries and Pterocarpus marsupium heartwood. The interest in this compound is related to its different biological and pharmacological properties, such as its antioxidant, anti-inflammatory, and anticarcinogenic activities and its capacity to reduce and regulate cholesterol and blood sugar levels. Nevertheless, its use in therapy is hindered by its low aqueous solubility; to overcome this limitation we studied the feasibility of the use of cyclodextrins (CDs) as solubility-enhancing agents. CDs are natural macrocyclic oligomers composed of α-d-glucose units linked by α-1,4 glycosidic bonds to form torus-shaped molecules, responsible for inclusion complex formation with organic molecules. In particular, the aim of this study was to evaluate the feasibility of complexation between PTB and native CDs using various preparative methods. The isolated solid products were characterized using differential scanning calorimetry (DSC), simultaneous thermogravimetric/DSC analysis (TGA/DSC), Fourier transform infrared (FT-IR) spectroscopy, and X-ray diffraction (XRD) on powder and single crystals. The results indicated little or no evidence of the affinity of PTB to complex with α-CD using the kneading method. However, with ß-CD and γ-CD thermal analysis revealed an interaction which was also corroborated by FT-IR and 1H-NMR spectroscopy. With ß-CD, a hydrated complex of PTB was isolated and its characterization by single-crystal XRD revealed, for the first time, the mode of inclusion of the PTB molecule in the cavity of a CD. To complement the solid-state data, liquid-phase studies were carried out to establish the effect of CDs on the aqueous solubility of PTB and to determine the complex stoichiometries and the association constants for complex formation. Phase-solubility studies showed AL-type profiles for α- and ß-CD and a BS profile for γ-CD, with K1:1 values of 1144, 4950, and 133 M-1 for α-CD·PTB, ß-CD·PTB, and γ-CD·PTB, respectively. The stoichiometry of CD·PTB complexes, determined by Job's method, revealed for each system a 1:1 molar ratio. The dissolution rate of PTB was approximately doubled just by employing simple physical mixtures, but the best performance was achieved by products obtained via kneading and co-precipitation, which effected the complete dissolution of PTB in 40 and 20 min for ß-CD and γ-CD, respectively.
