SPL Set ID: 793416e3-25c6-4637-a025-b6c1465665c7

Midazolam Injection, USP is a water-soluble benzodiazepine available as a sterile, nonpyrogenic parenteral dosage form for intravenous or intramuscular injection. Each mL contains midazolam hydrochloride,USP equivalent to 1 mg or 5 mg midazolam compounded with 0.8% sodium chloride; the pH is adjusted to approximately 3 (2.5 to 3.5) and is adjusted with sodium hydroxide and, if necessary, hydrochloric acid. Midazolam is a white to light yellow crystalline compound, insoluble in water. The hydrochloride salt of midazolam, which is formed in situ , is soluble in aqueous solutions. Chemically, midazolam HCl,USP is 8-chloro-6-(2-fluorophenyl)-1-methyl- 4H -imidazo[1,5-a][1,4]benzodiazepine hydrochloride. Midazolam hydrochloride,USP has the empirical formula C 18 H 13 ClFN 3 •HCl, a calculated molecular weight of 362.25 and the following structural formula: Under the acidic conditions required to solubilize midazolam in the product, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring. The amount of open-ring form is dependent upon the pH of the solution. At the specified pH of the product, the solution may contain up to about 25% of the open-ring compound. At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such. The following chart plots the percentage of midazolam present as the open-ring form as a function of pH in aqueous solutions. As indicated in the graph, the amount of open-ring compound present in solution is sensitive to changes in pH over the pH range specified for the product: 3.0 to 4.0 for the 1 mg/mL concentration and 3.0 to 3.6 for the 5 mg/mL concentration. Above pH 5, at least 99% of the mixture is present in the closed-ring form. structural formula midazolam pH Dependence