title: Supersaturated state of diazepam injection following dilution with infusion fluid.
abstract: BACKGROUND
  Significant precipitation produced by the dilution of diazepam (DZP) injection with an infusion fluid is a great concern for the clinical practice. In this study, the precipitation behavior under different conditions was investigated.
  
  
  METHODS
  For the sample preparation, DZP injections (Horizon injection and Cercine injection) were diluted with various infusion fluids (Saline, 5% glucose infusion fluid and Soldem 3A) at designated dilution ratios ranging from 1× to 40× (5 mg/mL to 0.125 mg/mL). In addition, to measure the solubility of DZP in the samples, the saturated solutions of DZP were prepared. The DZP concentrations in the samples were measured by high-performance liquid chromatography (HPLC). This study also investigated the precipitate using various analytical methods: infrared microscopy, (1)H-NMR, differential scanning calorimetry, and powder X-ray deflection.
  
  
  RESULTS
  First, the compatibility of injection with infusion fluids was investigated. Significant precipitation occurred at dilution ratios ranging from 2× to 20×. No significant effects of formulations and infusion fluids on the compatibility were observed. The solubility of DZP was then further investigated. The concentration of DZP dissolved in the admixtures was higher than the solubility. This indicated that DZP existed in a supersaturated state in the infusion fluid admixtures. In the next phase of this study, the precipitate was investigated using various analytical methods. Results showed that the precipitate in infusion fluid admixtures was mostly composed of DZP, but also contained small amounts of the ingredients of DZP injection, such as benzoic acid and benzyl alcohol.
  
  
  CONCLUSIONS
  This study clarified details of the precipitation occurring after dilution of DZP injection with infusion fluids. It is worth noting that DZP in an infusion admixture existed in a supersaturated state. These findings offer important insight into the clinical practice of DZP injection.
authors.affiliation: Department of Pharmaceutics, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501 Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Onuki
authors.affiliation: Department of Pharmaceutics, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501 Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Hasegawa
authors.affiliation: Department of Pharmaceutics, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501 Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Kida
authors.affiliation: Central Research Laboratories, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501 Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ikegami-Kawai
authors.affiliation: Central Research Laboratories, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501 Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Tsubuki
authors.affiliation: Division of Applied Pharmaceutical Education and Research, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501 Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Shirozu
authors.affiliation: Department of Pharmaceutics, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501 Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Obata
authors.affiliation: Department of Pharmaceutics, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501 Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Takayama
keywords: 1H-NMR; Diazepam injection; IR microscopy; Infusion fluids; Precipitation; Supersaturated state
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