Dissolution Enhancement and Physicochemical Characterization of Valsartan in Solid Dispersions with β-CD, HP β-CD, and PVP K-30

Abstract

Solid dispersions (SDs) and physical mixtures (PMs) of valsartan in β-cyclodextrin (β-CD), hydroxypropyl β-cyclodextrin (HP β-CD), and polyvinyl pyrollidone (PVP K-30) were prepared to increase its solubility characteristics. The drug formulations were characterized in the solid state by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). By these physical determinations, drug–polymer interactions were found. Both the solubility and the dissolution rate of the drug in these formulations were increased. Drug contents were determined by UV spectrophotometry at a λmax of 249.5 nm. The phase solubility behavior of valsartan in various concentrations of β-CD, HP β-CD, and PVP K-30 (0.25–1.0% w/v) in distilled water was obtained at 37 ± 2 °C. The dissolution of valsartan is increased with increasing amounts of the hydrophilic carriers (i.e., β-CD, HP β-CD, and PVP K-30). Gibbs free energy (ΔGtr) values were all negative, indicating the spontaneous nature of valsartan solubilization. The SDs of valsartan with β-CD and HP β-CD were prepared at 1:1, 1:3, and 1:5 drug/carrier ratios by a kneading method, and PVP K-30 SDs were prepared at the same ratios (i.e., 1:1, 1:3 and 1:5 drug/carrier) by a lyophilization technique. The FTIR spectroscopic studies show the stability of valsartan and the absence of well-defined drug–polymer interaction. Compared with β-CD, HP β-CD showed better enhancement of dissolution rate; compared with HP β-CD, PVP K-30 showed better solubility and dissolution enhancement. INTRODUCTION From an economic point of view, low oral bioavailability results in the wasting of a large portion of an oral dose and adds to the cost of drug therapy, especially for expensive drugs (1). No matter how active or potentially active a new molecular entity (NME) is against a particular molecular target, if the NME is not available in solution at the site of action, it is not a viable candidate. As a result, the development of many exciting NMEs is stopped before their potentials are realized or confirmed because pharmaceutical companies cannot afford to conduct rigorous preclinical or clinical studies on molecules that do not have sufficient pharmacokinetic profiles due to poor water solubility (2). The rate of oral absorption of poorly soluble or BCS Class II drugs is often controlled by the dissolution rate in the gastrointestinal tract. Thus solubility and dissolution rate are the key determinants of oral bioavailability, which is the concluding point drawn for fate of oral bioavailability (3). Solubility is defined in quantitative terms as the concentration of solute in a saturated solution at a certain temperature, and in a qualitative way, it can be defined as the spontaneous interaction of two or more substances to form a homogeneous molecular dispersion (4). McBain (5) has stated, “Any material can be solubilized in any solvent by proper choice of solubilizing agent.” Final selection of solubilizing agent should be based on phase solubility studies. Among the various approaches to improve solubility, the solid dispersion technique has often proved to be the most successful in improving the dissolution and bioavailability of poorly soluble active pharmaceutical ingredients because it is simple, economic, and advantageous (6). The solid dispersion technique provides a means of reducing particle size to a nearly molecular level. As the soluble carrier dissolves, the insoluble drug is exposed to the dissolution medium as very fine particles for quick dissolution and absorption. In particular, polymers such as polyethylene glycols and polyvinylpyrrolidone have been used extensively as carriers for dispersions because of their low melting points and their hydrophilic environments (7). Cyclodextrins (CDs), with lipophilic inner cavities and hydrophilic outer surfaces, are capable of interacting with a large variety of guest molecules to form noncovalent inclusion complexes (8). CDs can have both stabilizing and destabilizing effects on chemically labile compounds, they *Corresponding author. diss-18-01-06.indd 39 2/24/2011 9:46:54 AM dx.doi.org/10.14227/DT180111P39