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Abstract

ABSTRACT:Midazolam is used as short-acting pre-anesthetic benzodiazepine with solubility of <0.1mg/mL at neutral-pH, which increases considerably in acidic media. Midazolam commercial acidic aqueous parenteral formulation (pH~3.3) causes pain and inflammation at administration site, which induces low patientcompliance. According to the absence of non-parenteral formulation, available parenteral dosage-form administered orally that showed bitter-taste with low bioavailability. Alternatively, intranasally administration was rapidly absorbed, with improved bioavailability. However, not only causes nasal mucosa irritation due to acidic media, but also needs large solution amount because of midazolam low solubility. On contrary of previous studies, which focused on solubility improvement in acidic pH, the aim of this study is to compare solubility enhancement techniques at nasal physiological pH (6). Different techniques evaluated including buffer solutions (Britton-Robinson, citrate and phosphate), inclusion-complexation (β-CD), polymeric-micellar-solubilization(HPMC) and co-solvency (PEG400 and P.G) separately in mentioned buffers. Ternary-diagram with the best-selected system examined in different ratios. As a result, phosphate buffer in combination with applied techniques indicated solubility enhancement ratio of 17.9, 22