Dissolution-Enhancing Mechanism of Alkalizers in Poloxamer-Based Solid Dispersions and Physical Mixtures Containing Poorly Water-Soluble Valsartan

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The purpose of this study was to investigate the effects of alkalizers in dissolution rate and crystal structure of valsartan (VAL) in Poloxamer 407 (POX)-based solid dispersions (SD). VAL, a poorly-water soluble drug was selected as a model drug because of its low solubility at low pH. The POX-based SDs containing alkalizers (Na2CO3, MgO, meglumine and arginine) were prepared by melting method. The dissolution tests were performed using the United States Pharmacopeia (USP) paddle II method in enzyme-free simulated gastric fluid (pH 1.2) for 2 h. Microenvironmental pH (pHM) was examined potentiometrically by using a surface pH electrode. Dissolution rate of SD incorporating Na2CO3 was drastically increased. The differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) data indicated that crystalline structure of VAL in SD was transformed to amorphous form by the addition of alkalizers but could not explain the differences in the dissolution rates. The molecular interaction between VAL and Na2CO3 was observed in the Fourier transform infrared spectroscopy (FT-IR) spectra by the shift of C=O band from 1732 to 1719 cm−1 and the disappearance of carbonyl group at 1598 cm−1. Furthermore, Na2CO3 efficiently modulated pHM by providing a favorable microenvironment for drug dissolution. A combination of SD method and use of alkalizer is a promising approach to modulate release rate of poorly water-soluble and ionizable drug with an aid of changes of drug crystallinity, molecular interaction and pHM.
公益社団法人　日本薬学会の論文

Dissolution-Enhancing Mechanism of Alkalizers in Poloxamer-Based Solid Dispersions and Physical Mixtures Containing Poorly Water-Soluble Valsartan

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