Effect of polymers and cyclodextrins on solubility, permeability and distribution of enzalutamide and apalutamide antiandrogens

Solubility, lipophilicity and permeability are crucial issues determining the bioavailability of drugs. Antiandrogens enzalutamide and apalutamide with high antitumoral activity demonstrate poor solubility in aqueous media in a whole range of pH. In this study in order to enhance the solubility, the overall investigation of enzalutamide (ENZ) and apalutamide (APL) behavior in polyethylene glycol 6000 (PEG), pluronic F127 (F127), beta-cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin (TM-beta-CD) solutions was carried out. The phase solubility experiments showed that all the excipients increase the solubility of the compounds. The following order of the excipients action on the solubility was estimated: PEG < TM-beta-CD < beta-CD < HP-beta-CD < F127 for both investigated substances. Hanson solubility parameter was applied to explain the role of the solubilizer's nature on the solubility. The permeability through the cellulose membrane (MWCO 12-14 kDa) was assessed and demonstrated a decrease in the presence of all excipients. Since F127 and HP-beta-CD revealed the best solubilizing ability, the permeability at several concentrations of these excipients was studied and discussed. In addition, the distribution coefficients in octanol/water system were evaluated for both compounds in the presence of HP-beta-CD in aqueous phase. Both the permeability and distribution coefficients demonstrated a drastic decrease upon the excipient concentration growth. Interrelations of the above parameters with the solubility were revealed, graphically illustrated and discussed. (C) 2020 Published by Elsevier B.V.

Automated summary

Solubility, permeability, and distribution coefficients of drugs such as enzalutamide and apalutamide can be affected by excipients like PEG, F127, beta-CD, HP-beta-CD, and TM-beta-CD. While all excipients increase solubility, F127 and HP-beta-CD demonstrate the best solubilizing ability. However, the increase in excipient concentration also leads to a decrease in permeability and distribution coefficients.