Release behavior of alkyl-p-aminobenzoate ester–PVP solid dispersions

Abstract

Solid polymer-drug dispersions are used to prepare and stabilize amorphous forms of poorly soluble drugs as a means of improving drug solubility, dissolution and bioavailability. Despite many reports on this subject, solid dispersion dissolution mechanisms have not been well understood. An early study was reported by Simonelli, Mehta and Higuchi (SMH) in 1969 and has served as a model for dispersion dissolution behavior. These authors proposed a dissolution model (SMH) which gave good agreement between their experimental results and model predictions for one drug and one type of PVP. Few researchers have applied this traditional approach (SMH) in a systematic fashion to solid dispersion systems. One difficulty is obtaining parameters needed for predictions such as polymer diffusion coefficient, diffusion layer thickness or other pertinent parameters. In this work, a general model has been developed based on the concepts in the traditional approach (SMH) and simulations with this model were performed to show how dispersion dissolution rates change with system variables. Such simulations showed underestimation of dissolution rates resulted when compounds had low solubility. In this work, solid dispersion dissolution behavior was studied systematically with a homologous compound series (alkyl-p-aminobenzoate esters, or PABA esters) and three polyvinylpyrrolidone (PVP) molecular weights (K15, K30 and K90). The PABA esters with varying solubility used in this study were methyl PABA (MePABA), ethyl PABA (EtPABA), propyl PABA (PrPABA) and butyl PABA (BuPABA). Six solid dispersions for each PABA ester and PVP (weight ratios of PVP:PABA ester 20:1, 10:1, 6:1, 3:1, 4:1 and 2:1) were prepared by a solvent evaporation method. Solid dispersions were obtained and their amorphous character confirmed by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC).