Inclusion complexes and self-assembled cyclodextrin aggregates for increasing the solubility of benzimidazoles

Abstract

Albendazole and fenbendazole are imidazole derivatives that exhibit broad spectrum activity against parasites, but the low solubility of these drugs considerably reduces their effectiveness. Complexation of albendazole and fenbendazole with cyclodextrins (β-cyclodextrin and hydroxypropyl-β-cyclodextrin) in both water and an aqueous solution of polyvinylpyrrolidone (PVP-k30) was studied to determine if it could increase the solubility and dissolution rate of the drugs. In an aqueous solution, β-cyclodextrin increased the solubility of albendazole from 0.4188 to ∼93.47 µg mL-1 (223×), and of fenbendazole from 0.1054 to 45.56 µg mL-1 (432×); hydroxypropyl-β-cyclodextrin, on the other hand, increased solubility to ∼443.06 µg mL-1 (1058×) for albendazole and ∼159.36 μg mL-1 (1512×) for fenbendazole. The combination of hydroxypropyl-β-cyclodextrin and polyvinylpyrrolidone enabled a solubility increase of 1412× (∼591.22 µg mL-1) for albendazole and 1373× (∼144.66 µg mL-1) for fenbendazole. The dissolution rate of the drugs was significantly increased in binary and ternary systems, with hydroxypropyl-β-cyclodextrin proving to be more effective. The presence of the water-soluble PVP-k30 increased the dissolution rate and amorphization of the complexes. Analysis of the changes in displacement and the profile of the cyclodextrin bands in the 1 H NMR spectra revealed a molecular interaction and pointed to an effective complexation in the drug/cyclodextrin systems. Monomeric forms and nanoclusters of cyclodextrins were observed in the drug/cyclodextrin systems, suggesting that the increase in solubility of the drugs in the presence of cyclodextrins should not be attributed only to the formation of inclusion complexes, but also to the formation of cyclodextrin aggregates.

Pharmaceutical Salts of Fenbendazole with Organic Counterions: Structural Analysis and Solubility Performance

“…Although potassium and sodium salts of the drug have been recently patented by Cirilli et al, no evidence of multicomponent crystalline forms with organic coformers or counterions has been reported. Instead, alternative strategies based on solid dispersions, , cyclodextrins, polymeric micelles, and nanocrystals have been adopted to modify the physicochemical profile of fenbendazole.…”

Cyclodextrins: Structural, Chemical, and Physical Properties, and Applications

“…For example, the aqueous solubility of β-CD increases to >1200 mg/mL (>80-fold increase from 18.5 mg/mL) when the 2-hydroxy group is replaced with a 2-hydroxypropyl group to become 2-hydroxypropyl β-CD (HP-βCD) [47]. Albendazole and fenbendazole, two imidazole based drugs used to treat alveolar echinococcosi [109], had tremendously different aqueous solubilities upon complexation with β-CD and HPβ-CD [110] (See Table 5). From Table 5, it is clearly seen that introducing chemical modifications can tremendously affect drug solubility in water.…”

“…Comparsion of Albendazole and Fenbendazole Aqueous Solubtility when complexed with β-CD and HPβ-CD. Datak taken from[110].…”

Cyclodextrin-Modified Nanomaterials for Drug Delivery: Classification and Advances in Controlled Release and Bioavailability

“…According to the biopharmaceutical classification system, drugs can be divided into four categories based on their solubility and membrane permeability [18]. In this sense, CDs have been widely used to improve the solubility of class II and IV drugs (which have low aqueous solubility), for cancer treatments and parasitic diseases, among many other pathologies [19][20][21][22]. However, there are also reports of a complex formation for class I and III drugs, since CDs have been used to increase stability and mask flavors and odors, among other factors [23][24][25][26][27][28].…”