*3.1. Selection of the Solvents*

The proper selection of the best solvent for the development of a liquisolid system, mainly based on its solubilizing power towards the drug, is of critical importance to reduce the amount of solid adsorbent excipient, and, consequently, the final total weight of the dosage form. Then, as the first step of this study, the solubilizing effect towards GLY of a wide variety of non-volatile, water-miscible solvents (Labrasol®, Transcutol®, Solketal®, Kolliphor®HS15, 2-PYR, PEG 400, glycofurol, DMA, benzyl benzoate and 1,3-butandiole), was evaluated. With this purpose, the minimal amount of each solvent necessary to solubilize 5 mg GLY (therapeutic drug dosage) was determined. As shown in Figure 1, DMA and 2-PYR emerged as the most effective solvents, requiring, respectively, only 0.025 or 0.050 mL to solubilize 5 mg drug, and then were chosen as the liquid vehicles for GLY liquisolid systems preparation. The safe and effective use of 2-PYR as a solvent for drug solubilization has been reported, in virtue of its lack of mutagenic or genotoxic activity [51], and its low developmental toxicity, and high oral LD50 (5g/kg body weight in rats) (www.epa.gov/chemical-under-tsca). On the other hand, DMA is approved by FDA as an excipient in parenteral and nasal spray products (www.accessdata.fda.gov) and its safe use as a solubilizer, included also in intravenous pediatric formulations, has been proved [52–54].

**Figure 1.** Solubility of glyburide (GLY) in the different solvent examined, expressed as mL of solvent necessary to solubilize 5 mg drug (therapeutic single dose).

GLY stability in the selected solvents was verified, by checking its concentration at interval times up to six months by spectrophotometric assay. No variations of drug concentration, and no modifications of its UV curve were observed, indicative of drug stability and absence of degradation phenomena.
