Drug Solubilization by Mixtures of Cyclodextrins: Additive and Synergistic Effects

Abstract

Cyclodextrins are popular drug solubilizers, but the use of the natural cyclodextrins is hampered by their tendency to co-precipitate with the drug. To understand and overcome such problems, we have studied the solubility of dexamethasone in the presence of natural β-cyclodextrin and γcyclodextrin, individually and in various combinations. Equilibrium models of the phase-solubility diagrams with individual cyclodextrins revealed that dexamethasone was solubilized as 1:1 complexes, but formation of insoluble higher-order complexes set an upper limit to the concentration of solubilized dexamethasone. This limit could be raised from 8 mM to 17 mM by using combinations of the two cyclodextrins, as their solubilizing properties were additive in some regions of the phase-solubility diagram and synergistic in other regions. The additive effects arise from the additivity of solubilities-same phenomenon contributes to the good solubilizing properties of many modified cyclodextrins. The synergistic effects, however, could not be explained. The results open up for an increased use of the natural cyclodextrins as an improved alternative to modified cyclodextrins.

Investigation of Praziquantel/Cyclodextrin Inclusion Complexation by NMR and LC-HRMS/MS: Mechanism, Solubility, Chemical Stability, and Degradation Products

“…The total concentration of PZQ was determined using validated methods (Table S1). Based on Higuchi and Connors, , all observed phase diagrams were classified as A L type (Figures S1–S3). The stability constants determined for 1:1 complexes correlate fairly well, although some discrepancies between UV–vis and other methods were observed.…”

“…Solubility measurements were carried out according to Higuchi and Connors. , An excess amount of PZQ was weighed, followed by an addition of 5 mL of water. Selected cyclodextrins were added into each sample to achieve a final concentration of cyclodextrin in the range of 0–40 mM (for β-CD, 0–12.5 mM).…”

Exploring the Origins of Enthalpy–Entropy Compensation by Calorimetric Studies of Cyclodextrin Complexes

“…34 In the global fit ΔCp is assumed to be temperature independent. This assumption is based on personal experience with CD complexes, 15,18,[34][35][36] and there is no indication in the literature that ΔCp for CD complexes should exhibit any significant temperature dependence within the currently investigated temperature range. [37][38][39] Assuming a temperature independent ΔCp the binding constant can be expressed as:…”

Complexation with Random Methyl-β-Cyclodextrin and (2-Hydroxypropyl)-β-Cyclodextrin Promotes Chrysin Effect and Potential for Liver Fibrosis Therapy

“…Such a result could be obtained by complexation with cyclodextrins (CDs) [16,17]. CDs are cyclic oligosaccharides derived from starch degradation and frequently used as drug solubilizers [18,19]. Random methyl-β-cyclodextrin (RAMEB) and (2-hydroxypropyl)-β-cyclodextrin (HPBCD) are two types of CDs that induce low toxicity, and original complexes with CHR were developed and characterized in a previous study of our group [20].…”