Effect of Cyclodextrin Types and Co-Solvent on Solubility of a Poorly Water Soluble Drug

The aim of the study was to investigate the solubility of piroxicam (Prx) depending on the inclusion complexation with various cyclodextrins (CDs) and on ethanol as a co-solvent. The phase-solubility method was applied to determine drug solubility in binary and ternary systems. The results showed that in systems consisting of the drug dissolved in ethanol–water mixtures, the drug solubility increased exponentially with a rising concentration of ethanol. The phase solubility measurements of the drug in aqueous solutions of CDs, β-CD and γ-CD exhibited diagrams of AL-type, whereas 2,6-dimethyl-β-CD revealed AP-type. The destabilizing effect of ethanol as a co-solvent was observed for all complexes regardless of the CD type, as a consequence of it the lowering of the complex formation constants. In systems with a higher concentration of ethanol, the drug solubility was increased in opposition to the decreasing complex formation constants. According to this study, the type of CDs played a more important role on the solubility of Prx, and the use of ethanol as a co-solvent exhibited no synergistic effect on the improvement of Prx solubility. The Prx solubility was increased again due to the better solubility in ethanol.© 2016 by the author

Theoretical and Experimental Studies on Inclusion Complexes of Pinostrobin and β-Cyclodextrins

Pinostrobin (PNS) belongs to the flavanone subclass of flavonoids which shows several biological activities such as anti-inflammatory, anti-cancerogenic, anti-viral and anti-oxidative effects. Similar to other flavonoids, PNS has a quite low water solubility. The purpose of this work is to improve the solubility and the biological activities of PNS by forming inclusion complexes with β-cyclodextrin (βCD) and its derivatives, heptakis-(2,6-di-O-methyl)-β-cyclodextrin (2,6-DMβCD) and (2-hydroxypropyl)-β-cyclodextrin (HPβCD). The AL-type diagram of the phase solubility studies of PNS exhibited the formed inclusion complexes with the 1:1 molar ratio. Inclusion complexes were prepared by the freeze-drying method and were characterized by differential scanning calorimetry (DSC). Two-dimensional nuclear magnetic resonance (2D-NMR) and steered molecular dynamics (SMD) simulation revealed two different binding modes of PNS, i.e., its phenyl- (P-PNS) and chromone- (C-PNS) rings preferably inserted into the cavity of βCD derivatives whilst only one orientation of PNS, where the C-PNS ring is inside the cavity, was detected in the case of the parental βCD. All PNS/βCDs complexes had a higher dissolution rate than free PNS. Both PNS and its complexes significantly exerted a lowering effect on the IL-6 secretion in LPS-stimulated macrophages and showed a moderate cytotoxic effect against MCF-7 and HeLa cancer cell lines in vitro.© 2018 by the author

Metadynamics supports molecular dynamics simulation-based binding affinities of eucalyptol and beta-cyclodextrin inclusion complexes

The development of various molecular dynamics methods enables the detailed investigation of association processes, like host–guest complexes, including their dynamics and, additionally, the release of the guest compound. As an example of the application of such methods, the inclusion complexation of cyclodextrins with eucalyptol is described. Eucalyptol is the major constituent of eucalyptus oil, which exhibits anti-inflammatory properties. This compound has many applications including flavors, fragrances and medical therapies. However, its pharmaceutical applications are limited due to volatility and low water solubility. Cyclodextrins (CDs) are compounds that are capable of forming inclusion complexes with eucalyptol to enhance solubility and stability. In the present work, molecular dynamics (MD) simulations and free energy calculations were performed to determine the molecular structure, dynamical behaviour and binding affinities of the host–guest inclusion complexes of eucalyptol with native beta-cyclodextrin (βCD) and its derivatives, 2,6-dimethyl-βCD (2,6-DMβCD) and the three hydroxypropyl-βCDs (2-HPβCD, 6-HPβCD and 2,6-DHPβCD). In the inclusion complex, eucalyptol preferentially locates within the hydrophobic cavity with all βCDs studied here. The binding affinities were calculated by MM/PBSA and QM/PBSA with the M06-2X/6-31G(d,p) level of theory and are in relatively good agreement with the experimental stability constants in the order of 2,6-DMβCD > βCD > 2-HPβCD. In addition, recently developed metadynamics simulations were applied to investigate the eucalyptol's release pathways from the cavity of the CDs. The results from this study show that MD simulations, metadynamics and related free energy calculations provide an excellent support for experimental studies, and they give additional information about the structural and dynamical behaviour of inclusion complexes as well as the energetic details about host–guest interactions. Moreover, the releasing direction and possible dissociation rates of the inclusion complexes were also predicted