Inclusion of methotrexate in alkyl-cyclodextrins: effects of host substitutents on the stability of complexes

The formation of complexes between an antineoplastic drug, methotrexate (MTX), and a series of native cyclodextrins (αCD, βCD, γCD) and synthetic or commercial β-derivatives (methylated, dimethylated and hydroxypropylated βCDs) was studied using the phase solubility and permeation methods, NMR and DSC. The apparent stability constants determined from the solubility diagram (Kcs)are in excellent agreement (P < 0.00001) with those calculated by the permeation method (Kcp). The degree of substitution (DS) and position of substituents on glucose residues significantly affect the complexing ability of β-inclusion agents. In particular, for dimethyl-derivatives, the presence of the alkyl-groups at the secondary face of CD (positions 2 and 3), sterically prevents host-guest interactions (Kcp = 0.0 M- 1 for 2,3DMβCD), while a methyl group in position 6 allows an easier association with MTX (Kcp = 932.3 M- 1 for 2,6DMβCD).