Dissolution Behavior and Thermodynamic Stability of Fused-Sugar Dispersions of a Poorly Water-Soluble Drug

The current research was undertaken to develop and evaluate dissolution profiles of thermodynamically stabilized sugar dispersions of the poorly water-soluble, model drug etoricoxib (ETX). Fused-sugar dispersions were formulated using sorbitol, xylitol, and maltose separately, and the binary systems were stabilized by incorporation of the antiplasticizing agents poloxamer 407 and PVP K30 to obtain ternary and quaternary systems. The sugar dispersions (F1–F12) were subjected to in vitro dissolution studies, and based on model-independent dissolution parameters, ETX–sorbitol binary/ ternary/composite systems were selected for thermodynamic stability study. The aged ETX–sorbitol composite dispersion (SF8) displayed the highest percent dissolution efficiency (%DE80min of 78.48), the minimum t50% of 4.45 min, and the least tendency to recrystallize (Dcryst of 0.68), confirming maximum amorphization and thermodynamic stability among all the composite dispersions. The SEM photomicrographs reveal complete miscibility of drug in the aged quaternary dispersion SF8, and its diffuse reflectance (DR) spectrum confirms the absence of any chemical change. Conclusively, sorbitol binary systems can be effectively stabilized by incorporation of PVP K30–poloxamer 407 and retain the dissolution characteristics of sugar dispersions upon aging. INTRODUCTION Drug release is a crucial and rate-limiting step for oral bioavailability, particularly for drugs with low gastrointestinal solubility and high permeability (1). Many researchers have concluded that an improvement in the release profiles of these drugs by suitable formulation can enhance their bioavailability and reduce side effects (2, 3). Class II drugs are considered the best candidates for intervention by formulation, and several methods have been developed to overcome their low aqueous solubility. Salt formation, pH adjustment, and complexation are wellknown strategies for solubility enhancement, though their use is restricted to a considerably small group of molecules (4, 5). Stupak and Bates (6) have reported other ways to improve drug dissolution in aqueous media that include particle size reduction and the addition of solubilizing agents that can promote wettability and increase drug saturation solubility locally. The latter strategies are combined in the formulation of solid dispersions. Literature is also available on improvement in solubility of BCS Class II drugs by solid dispersion techniques. Reports (7–11) on solid dispersions have conclded that the dissolution properties and hence the bioavailability of slightly water-soluble drug compounds are improved by dispersing them into inert hydrophilic carriers in the solid state. In a solid dispersion, either the drug is dissolved in a matrix or it can be dispersed homogeneously as fine particles in amorphous or crystalline hydrophilic carriers. Various carriers have been used to prepare solid dispersions, and sugars are one such carrier. The sugars investigated for the preparation of solid dispersions include lactose for nitrazepam (12) and sucrose, trehalose, and two oligofructoses (inulin DP11 and inulin DP23 having number-average degrees of polymerization of 11 and 23, respectively) for diazepam (13). Similarly, mannitol, lactose, and galactose have been investigated for carbamazepine (12). D-mannitol and sucroester have also been reported for improvement in the oral absorption of triamterene (14) and canrenone (15), respectively. The sugar solid dispersions in each case resulted in an increase in the dissolution rate of the drug, but the single-sugar systems were not thermodynamically stable. The use of sugar combinations overcame some difficulties previously reported with single-sugar systems. Lloyd et al. (16) reported enhancement in the dissolution rates of hydrocortisone and prednisone utilizing ternary sugar solid dispersion systems in tablet form. The dispersion systems were prepared by the fusion method using 50:50 sucrose/mannitol and 50:50 sorbitol/mannitol. Both the dissolution profiles and the stability of the ternary systems were better than those of the binary systems. In sugar dispersions, the drug–sugar ratio markedly affects the dissolution rate and thermodynamic stability of the system. When the drug load is low, the sugar does not dissolve too fast, and the dissolution rate of the drug is high. However, when the drug load is high, the sugar dissolves faster, and the dissolution rate of drug is slow and incomplete. This occurs because a high concentration of drug results in uncontrolled formation of large drug crystals upon aging, and consequently, due to the crystalline nature and low specific surface area, the drug crystals *Corresponding author. diss-18-03-08.indd 62 8/31/2011 1:42:55 PM dx.doi.org/10.14227/DT180311P62