Zhu Koudi, Kerry Michael, Serr Barbara, Mintert Markus
Pharma Solutions, IFF, Midland, MI 48640, USA.
Pharma Solutions, IFF, Midland, MI 48640, USA.
J Pharm Biomed Anal. 2023 Oct 25;235:115648. doi: 10.1016/j.jpba.2023.115648. Epub 2023 Aug 15.
Regulatory authorities like the U.S. Food and Drug Administration (FDA) have set strict specification levels for N-nitrosamines in finished drug products. Nitrite is a potential precursor for the formation of probable carcinogenic N-nitrosamines when secondary or tertiary amines are also present in the active pharmaceutical ingredient (API) synthesis or drug formulation process. An accurate and sensitive determination of nitrite will be useful when a drug product manufacturer chooses to investigate the reaction kinetics between nitrite and amines or to select appropriate excipients for its drug formulation. Pharmaceutical excipient manufacturers may also need an accurate nitrite measurement to investigate the nitrite content in their excipients. This study details the development and validation of an ion chromatography mass spectrometry (IC-MS) method for trace nitrite determination in microcrystalline cellulose materials, one of the important pharmaceutical excipients used in many drug formulations. MS operated under selected ion monitoring mode was used to solve the commonly encountered interference issue with conductivity detection, and nitrite isotope internal standard was employed to address the ion suppression issue with MS detection. The installation of an after-column "jumper" to flush water with an auxiliary pump through the MS when it is not used for data collection avoided sensitivity loss due to trace salt accumulation in the ion source. Validation of the optimized method was satisfactory, with linearity of nitrite in the concentration range of 0.02-7.50 ppm (µg/g) having a regression coefficient of > 0.999, precision of RSD < 9.5% at 0.03 ppm and RSD < 3.4% at 0.4 ppm and recovery of 92.0-103.0%. The limit of detection and limit of quantitation were 0.005 and 0.016 ppm, respectively.
美国食品药品监督管理局（FDA）等监管机构已为成品药品中的N-亚硝胺设定了严格的规格标准。当活性药物成分（API）合成或药物制剂过程中同时存在仲胺或叔胺时，亚硝酸盐是形成可能致癌的N-亚硝胺的潜在前体。当药品制造商选择研究亚硝酸盐与胺之间的反应动力学或为其药物制剂选择合适的辅料时，准确、灵敏地测定亚硝酸盐将很有帮助。药用辅料制造商也可能需要准确测量亚硝酸盐，以研究其辅料中的亚硝酸盐含量。本研究详细介绍了一种离子色谱-质谱联用（IC-MS）方法的开发与验证，该方法用于测定微晶纤维素材料中的痕量亚硝酸盐，微晶纤维素是许多药物制剂中使用的重要药用辅料之一。采用在选择离子监测模式下运行的质谱来解决电导率检测中常见的干扰问题，并采用亚硝酸盐同位素内标来解决质谱检测中的离子抑制问题。安装柱后“跳线”，以便在不用于数据采集时用辅助泵通过质谱冲洗水，避免了由于离子源中痕量盐积累而导致的灵敏度损失。优化方法的验证结果令人满意，亚硝酸盐在0.02 - 7.50 ppm（μg/g）浓度范围内的线性回归系数> 0.999，在0.03 ppm时的精密度RSD < 9.5%，在0.4 ppm时的精密度RSD < 3.4%，回收率为92.0 - 103.0%。检测限和定量限分别为0.005和0.016 ppm。
