In Vitro Solubility and Release Profile Correlation with pKa Value of Efavirenz Polymorphs

Abstract

Efavirenz (EFV) was approved by the United States Food and Drug Administration in 1998 with no polymorphic forms, but further research defined 23 different forms, including amorphous and solvated forms. This study aims to determine the ability of dissolved EFV polymorphs in in vitro media kinetic release models of pKa values. The polymorph types were obtained through various organic solvents such as acetonitrile, n-hexane, and methanol, i.e., form I, II, and III. The characteristics were distinguished by polarisation microscopy, differential scanning calorimetry (DSC), Fourier transform infrared (FTIR), and Raman spectroscopy. The solubility and dissolution of each polymorph were examined by adding 0.25% sodium lauryl sulphate (SLS) to the comparative dissolution media (water, HCl at pH 1.2, phosphate buffer at pH 4.6 and 6.8). The different microscopic shapes provided a unique fingerprint in the FTIR and the Raman spectra. The thermal behaviour examination provided a DSC thermogram with a specific melting point for each polymorph. The results of the solubility and dissolution tests reported that the highest peak was reached by form II, followed by forms III and I. These followed the pKa values of each polymorph, namely 10.12, 10.63, and 10.37 for form I, II, and III, respectively. The dissolution profile shows that pH conditions affect the release kinetics of form I compared to the metastable forms. The kinetic model of form I is pH-dependent; the acidic medium provided a slower release rate. Unlike the metastable forms, drug loading remained constant but still followed Higuchi’s kinetic release model, even in acidic medium.