1,4-Benzodiazepines: Chemical stability and cyclodextrin solubilization

Benzodiazepines form a class of drugs that are used to treat wide variety of conditions such as anxiety, seizures, and insomnia. In general, benzodiazepines are lipophilic and poorly soluble in water at physiologic pH, and when solubilized undergo hydrolytic degradation. Thus, marketed products containing solubilized benzodiazepines most often consist of organic solvents or aqueous solutions containing relatively high concentrations of organic cosolvents and surfactants. There is however one exception. Midazolam injection is essentially pure aqueous solution of midazolam, unbuffered at pH of about 3 and shelf-life of over 2 years at room temperature. While most benzodiazepines form an unstable protonated ring-open form at acidic pH, the ring-open form of midazolam is both relatively stable and water-soluble. Still, for more concentrated midazolam solutions, such as nasal spray, organic solvents have been used. Benzodiazepines can be solubilized through formation of water-soluble cyclodextrin complexes but in spite of numerous successful clinical studies in humans, as well as in vivo studies in animals, no benzodiazepine/cyclodextrin formulations have reached the market. Here the chemistry of 1,4-benzodiazepines, their unusual degradation pathways and solubility in water is reviewed. [Display omitted]