Onuki Yoshinori, Hasegawa Naoki, Kida Chihiro, Ikegami-Kawai Mayumi, Tsubuki Masayoshi, Shirozu Shunsuke, Obata Yasuko, Takayama Kozo
Department of Pharmaceutics, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501 Japan.
Central Research Laboratories, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501 Japan.
J Pharm Health Care Sci. 2015 Mar 9;1:9. doi: 10.1186/s40780-014-0009-9. eCollection 2015.
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.
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.
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.
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.
用输液稀释地西泮（DZP）注射液产生的大量沉淀是临床实践中非常关注的问题。本研究调查了不同条件下的沉淀行为。
对于样品制备，将DZP注射液（Horizon注射液和Cercine注射液）用各种输液（生理盐水、5%葡萄糖输液和Soldem 3A）以1×至40×（5mg/mL至0.125mg/mL）的指定稀释比例进行稀释。此外，为了测量DZP在样品中的溶解度，制备了DZP的饱和溶液。通过高效液相色谱法（HPLC）测量样品中的DZP浓度。本研究还使用各种分析方法研究了沉淀物：红外显微镜、（1）H-NMR、差示扫描量热法和粉末X射线衍射。
首先，研究了注射液与输液的相容性。在2×至20×的稀释比例下出现了大量沉淀。未观察到制剂和输液对相容性有显著影响。然后进一步研究了DZP的溶解度。溶解在混合液中的DZP浓度高于溶解度。这表明DZP在输液混合液中以过饱和状态存在。在本研究的下一阶段，使用各种分析方法研究了沉淀物。结果表明，输液混合液中的沉淀物主要由DZP组成，但也含有少量DZP注射液的成分，如苯甲酸和苯甲醇。
本研究阐明了用输液稀释DZP注射液后发生沉淀的细节。值得注意的是，输液混合液中的DZP以过饱和状态存在。这些发现为DZP注射液的临床实践提供了重要的见解。
