The proposed method was developed for the determination of aluminum (Al) in large volume parenteral (LVP) drug products used in total parenteral nutrition (TPN) therapy. The determination of Al in LVP drug products was performed by an inductively coupled plasma mass spectrometer equipped with a dynamic reaction cell (DRC-ICP-MS). DRC-ICP-MS conditions for the analysis of Al were studied to obtain the best signal to background (S/N) ratios. The interfering polyatomic ions at mass 27 (Al) were reduced by using NH 3 as a reaction gas. The detection limit of Al in a 1% (v/v) HNO 3 aqueous solution was 2 ng/l. The Al contents in LVP drug products obtained by this method were in the range of 1.16-4.33 m mg/l and were less than 25 m mg/l, that is, the regulation value of Food and Drug Administration (FDA). In order to trace the origin of Al in LVP drug products, each part of the LVP drug product, which is composed of three chambers, was investigated. However, a clear difference of the Al contents in each chamber was not observed. Furthermore, the Al contents in injection bags were quantified. Although the Al contents in injection bags were relatively high (in the range of 27.5-33.6 m mg/g), dissolution of Al from the injection bags was not observed in the stability testing. From all of these results, it was concluded that the Al contents in the LVP drug products investigated originated in the amount of the Al in each raw material.Key words aluminum; large volume parenteral; total parenteral nutrition; inductively coupled plasma mass spectrometry; dynamic reaction cell Chem. Pharm. Bull. 56(4) 475-479 (2008) © 2008 Pharmaceutical Society of Japan * To whom correspondence should be addressed. e-mail: harigaya.koki@mc.mt-pharma.co.jp edge, this is the first report concerning the origin of the Al in LVP drug products. The results of the Al contents in LVP drug products obtained by the other methods such as ICP-AES and HPLC-FL are also described for the comparison. ExperimentalReagents Purified water (18.2 MW cm) from a Milli-Q water purification system (Millipore, Tokyo, Japan) associated to an Elix3 pre-system (Millipore, Tokyo, Japan) was used to prepare all solutions. Al standard solution (1000 mg/l) was purchased from Merck (Tokyo, Japan). Standard solution for the optimization for the DRC-ICP-MS instrument was purchased from PerkinElmer (Concord, Ontario, Canada). River water reference materials for trace elements purchased from The Japan Society for Analytical Chemistry (Tokyo, Japan) were used for the evaluation of three analytical methods. Nitric acid (HNO 3 ) of ultrapure analytical reagents grade was purchased from Tama Chemicals (Kanagawa, Japan). 2-Propanol of trace analysis grade was purchased from Kanto Chemical (Tokyo, Japan). Argon (Ar) gas (99.999% purity) and Oxygen (O 2 ) gas (99.999% purity) were purchased from Taiyo Nippon Sanso (Tokyo, Japan). NH 3 gas (99.999% purity) was purchased from Sumitomo Seika Chemicals (Osaka, Japan). Al labeling kit and Neo R3 Eluent purchased from Shino-Test (Tokyo, Jap...

An alkylating agent, 4-chloro-1-butanol, is a genotoxic impurity (GTI); it may be generated during the synthesis of active pharmaceutical ingredients (APIs). For the trace-level detection of GTIs in APIs, usually, gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LC-MS) is employed. In this study, a novel LC-inductively coupled plasma (ICP)-MS method was developed and validated. Linearity was observed over the 0.5 -50 ppm (μg/g API) range, with an R 2 value of 0.9994. The detection limit (DL) and quantitation limit (QL) were 0.2 and 0.5 ppm, respectively. The DL and QL values are well over the thresholds specified in the guidelines. The accuracy was 95.1 -114.7% for concentrations of 1 -50 ppm, and the relative standard deviation of the spiked recovery test's repeatability was 6.2%. In addition, six lots of an API were analyzed, and all results were lower than the reported threshold (1 ppm).

Phenylhydrazine is a genotoxic impurity commonly used as a raw material in active pharmaceutical ingredients. In this study, a novel method, using inductively coupled plasma-mass spectrometry combined with two-dimensional liquid chromatography (LC-ICP-MS), was employed for the quantitation of residual phenylhydrazine in antipyrine. The compound 2,3,5-triiodobenzoyl chloride, which contains three iodine atoms, was investigated as a derivatization reagent. The DL 0.06 ppm was obtained, and the method was applied to the quantitation of residual phenylhydrazine in antipyrine. No residual phenylhydrazine was detected in five lots of antipyrine obtained from the commercial source.

The analysis of genotoxic impurities (GTIs) in active pharmaceutical ingredients (APIs) is a challenging task. The target detection limit (DL) in an API is typically around 1 ppm (1 µg/g API). Therefore, a sensitive and selective analytical method is required for their analysis. 4-Chloro-1-butanol, an alkylating agent, is one of the GTIs. It is generated when tetrahydrofuran and hydrochloric acid are used during the synthesis of the APIs. In this study, a sensitive and robust gas chromatography-mass spectrometry (GC-MS) method was developed and validated for the identification of 4-chloro-1-butanol in APIs. In the GC-MS method, 3-chloro-1-butanol was employed as an internal standard to ensure accuracy and precision. Linearity was observed over the range 0. Key words 4-chloro-1-butanol; GC-MS; genotoxic impurity; active pharmaceutical ingredient; trace analysisThe analysis of genotoxic impurities (GTIs) in trace amounts is of increasing interest to pharmaceutical industries owing to its potential application in the detection of human carcinogenesis and in regulatory aspects. The assessment of GTIs during clinical development is a major liability.1-5) Since GTIs are expected to be present in active pharmaceutical ingredients (APIs), a method for the sensitive and selective analysis of GTIs is required. The allowable limits of GTIs in new commercial drugs are regulated by government agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), [6][7][8][9] although the toxicological assessment of GTIs is not addressed sufficiently in the International Conference on Harmonisation (ICH) guidelines. The present ICH Q3A and Q3B guidelines only describe the limits of conventional impurities and related substances, where typical levels are above 0.05%. Therefore, the ICH has been discussing about GTIs as part of the ICH M7 guideline. The allowable limits of GTIs are decided by the U.S. FDA and the EMA depending on the duration and the daily dose of exposure during the clinical development. A toxicological threshold of 1.5 µg/d is suggested. Typically, the target detection limit (DL) in an API is 1 ppm (1 µg/g API). Therefore, a sensitive and selective analytical method is required for their analysis.4-Chloro-1-butanol, an alkylating agent, is one of the GTIs, which is generated when tetrahydrofuran (THF) and hydrochloric acid (HCl) are used during the synthesis of APIs. The interaction of THF with HCl leads to the generation of 4-chloro-1-butanol (Fig. 1). THF and HCl are frequently used in the synthesis of APIs. Hence, it is necessary to confirm the fate of 4-chloro-1-butanol, to develop the process control for APIs and ensure their quality. The quantitation limit (QL), as per the analytical method, should be at low ppm levels, considering the protocols (the daily dose and the duration of exposure) of the clinical studies.As part of the analytical method, conventional analytical instrumentations such as the HPLC with UV detection (for nonvolatile GTIs) or the GC with flame ioniza...