Anomalous Properties of Cyclodextrins and Their Complexes in Aqueous Solutions

Abstract

Cyclodextrins (CDs) are cyclic oligosaccharides that emerged as industrial excipients in the early 1970s and are currently found in at least 130 marketed pharmaceutical products, in addition to numerous other consumer products. Although CDs have been the subject of close to 100,000 publications since their discovery, and although their structure and properties appear to be trivial, CDs are constantly surprising investigators by their unique physicochemical properties. In aqueous solutions, CDs are solubilizing complexing agents of poorly soluble drugs while they can also act as organic cosolvents like ethanol. CDs and their complexes self-assemble in aqueous solutions to form both nano- and microparticles. The nanoparticles have diameters that are well below the wavelength of visible light; thus, the solutions appear to be clear. However, the nanoparticles can result in erroneous conclusions and misinterpretations of experimental results. CDs can act as penetration enhancers, increasing drug permeation through lipophilic membranes, but they do so without affecting the membrane barrier. This review is an account of some of the unexpected results the authors have encountered during their studies of CDs as pharmaceutical excipients.

Keywords: aggregation; cyclodextrins; microparticles; nanoparticles; properties; supersaturated solutions.

Figure 1

Phase-solubility profiles and classification of drug/CD complexes according to Higuchi and Connors [21].

Figure 2

In general, one drug molecule (D) forms a complex with one CD molecule in pure water, and, if the complex is water-soluble, an A_L-type phase-solubility diagram is observed (Table 1). (A) Classical A_L-type phase-solubility profile of a 1:1 drug/CD complex (D/CD) according to Higuchi and Connors [21]. [D]_T is the total concentration of dissolved drug, and [CD]_T is the total concentration of CD in solution. In this case, S₀ is equal to the intercept (S_int). (B) Aggregation of drug molecules in water where only the monomeric drug can form a 1:1 complex with CD. (C) Drug aggregation, where S₀ is the concentration of not only dissolved monomeric drug but also dissolved nanosized drug aggregates (S₀ > S_int). Here, the stability constant (K_1:1) of the complex cannot be determined from the slope and intercept, and the complexation efficiency (CE) is used to evaluate the CD solubilization [61].

Figure 3

The effect of polyvinylpyrrolidone with a molecular weight of 40,000 (PVP) on the solubility of βCD and carbamazepine in water at room temperature (23 °C). Solubility of βCD when no carbamazepine is present (●). Solubility of βCD (○) and carbamazepine (□) when the complexation medium contains both excess βCD and excess carbamazepine. Unpublished results based on experiments described in [81].

Figure 4

Phase-solubility diagram of hydrocortisone in aqueous βCD medium with (○) and without (●) 1% (w/v) sodium acetate at room temperature (22–23 °C) and pH 6.9. Based on data with permission from [84].

Figure 5

Passive permeation of a lipophilic drug from an aqueous exterior through mucus (a viscous unstirred water layer) to the mucosal surface where the drug partitions into the mucosa (a lipophilic membrane barrier) and then permeates the mucosa. The concentration gradient within the mucus layer (C_A − C_M) is the driving force for drug permeation through the mucus layer (i.e., diffusion barrier), and the concentration gradient within the mucosa (C₁ − C₂) is the driving force for drug permeation through the mucosa (i.e., membrane barrier). J_Mucus, J_Mucosa, P_Mucus and P_Mucosa are the drug fluxes and permeation coefficients through the aqueous mucus layer and the mucosa, respectively.

Figure 6

Effect of sulfobutylether β-cyclodextrin (SBEβCD), α-tocopheryl succinate esterified to polyethylene glycol 1000 (TPGS), 2-hydroxypropyl-β-cyclodextrin (HPβCD), Cremophor RH40 (Crem RH40), and polysorbate 20 (Tween 20) in aqueous 0.01 M HCl solution on the solubility of itraconazole. An excess amount of dissolve itraconazole (50 mg/mL) in dimethylformamide (DMF) was added to a medium containing no or 2.5% (w/v) of the excipients, and the itraconazole concentration was monitored for 120 min. The equilibrium solubility (S₀) of itraconazole was determined to be 21 µg/mL in the HPβCD medium and 206 µg/mL in the SBEβCD medium. Adapted from Brewster et al. with permission [107].