Physicochemical Characterization of Efavirenz–Cyclodextrin Inclusion Complexes

Abstract

Efavirenz (EFV) is an oral antihuman immunodeficiency virus type 1 drug with extremely poor aqueous solubility. Thus, its gastrointestinal absorption is limited by the dissolution rate of the drug. The objective of this study was to characterize the inclusion complexes of EFV with beta-cyclodextrin (beta-CD), hydroxypropyl beta-CD (HPbetaCD), and randomly methylated beta-CD (RMbetaCD) to improve the solubility and dissolution of EFV. The inclusion complexation of EFV with cyclodextrins in the liquid state was characterized by phase solubility studies. The solid-state characterization of various EFV and CD systems was performed by X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy analyses. Dissolution studies were carried out in distilled water using US Pharmacopeia dissolution rate testing equipment. Phase solubility studies provided an A(L)-type solubility diagram for beta-CD and A(P)-type solubility diagram for HPbetaCD and RMbetaCD. The phase solubility data enabled calculating stability constants (K (s)) for EFV-betaCD, EFV-HPbetaCD, and EFV-RMbetaCD systems which were 288, 469, and 1,073 M(-1), respectively. The physical and kneaded mixtures of EFV with CDs generally provided higher dissolution of EFV as expected. The dissolution of EFV was substantially higher with HPbetaCD and RMbetaCD inclusion complexes prepared by the freeze drying method. Thus, complexation with HPbetaCD and RMbetaCD could possibly improve the dissolution rate-limited absorption of EFV.