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    Self-Association of Rafoxanide in Aqueous Media and Its Application in Preparing Amorphous Solid Dispersions

    Year: 2017

    Journal: Mol. Pharm., Volume 14, MAY, page 1790–1799

    Authors: Meng, Fan; Liu, Tongzhou; Schneider, Elizabeth; Alzobaidi, Shehab; Gil, Marco; Zhang, Feng

    Organizations: Hovione LLC

    Keywords: rafoxanide; self-association; surface active; amorphous solid dispersion; solubilization; spray drying

    Our primary objective is to characterize the self-association of rafoxanide in alkaline media. The second objective is to illustrate the feasibility of-using rafoxanide micellar solution as the feed solution to prepare amorphous solid dispersion via spray drying. Rafoxanide is a poorly water-soluble drug. It is a weak acid, and its poor aqueous solubility is due to its hydrophobicity. The surface-active property of rafoxanide has not been previously reported. It was discovered that the addition of a small percentage of organic solvents is required to elevate the solubility of rafoxanide above the critical micelle concentration to allow for the formation of micelles. Our fluorescence decay study confirms the self-association of rafoxanide in a cosolvent consisting of 70%, v/v, NaOH solution and 30%, v/v, acetone. The position of each functional group in the micellar structures using the H-1 NMR technique was identified. The critical micelle concentration of rafoxanide in the cosolvent is determined to be 302 mu g/mL using a surface tension method. The solubility of rafoxanide in 0.1 N NaOH solution is less than 11 mu g/mL. Interestingly, the apparent solubility increased to 38,400 mu g/mL in the presence of 30% acetone as the result of micelle formation. This unique solubility characteristic makes it feasible to prepare rafoxanide amorphous solid dispersions by spray drying a predominantly aqueous (70% 0.1 N NaOH solution and 30% acetone) based feed solution. Povidone and copovidone were both used as polymeric carriers. Based on solid-state characterization, including differential scanning calorimetry, X-ray powder diffraction, and hot-stage polarized light microscopy, our results indicate that rafoxanide solid dispersions prepared using this novel process are amorphous. Approximately 750-fold increase in the-concentration of rafoxanide in aqueous media at pH 6.8 was achieved with the amorphous solid dispersions.
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