Preparation and evaluation of metastable solid-state forms of lopinavir.

Abstract

In this work, we present the preparation and evaluation of previously unreported metastable forms of the antiretroviral drug, lopinavir. By maintaining the chemical structure, physicochemical properties like the glass transition temperature (T(g)), dissolution and solubility can be readily attributed to the stability of the system. Commercially-available lopinavir was used to prepare partially amorphous crystals, semicrystalline needles, resins and glasses. The physicochemical properties of each were investigated using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and powder X-ray diffraction (PXRD). Each sample's thermal and spectroscopic analyses, as well as dissolution and solubility studies were performed one month after sample preparation, for better comparability. Glass transition temperature, activation energy for global molecular mobility (deltaE(Tg)), and activation energy for local molecular mobility (deltaE(beta)) were assessed as primary indicators for structural stability of the systems. Relating these properties to aqueous solubility revealed that each metastable form possessed its own unique equilibrium solubility. Cumulative dissolved fractions (alpha) were fitted against deceleratory kinetics models, and from the data hereby obtained the dissolution process was determined to followed first-order kinetics (R2 = 0.998). From the rate constants, the activation energy for dissolution (deltaE(Diss)) of each sample was calculated. The results suggest that multiple metastable solid-state forms of lopinavir can exist under similar conditions, depending on the preparation conditions.