| Abstract: | Short‐chain aliphatic amines are a class of hazardous impurities in drug substances. A simple method, involving derivatization followed by high‐performance liquid chromatography with diode array detection, has been developed for residue determination of eight aliphatic amines simultaneously in drug substances. Different halonitrobenzenes derivatization reagents were systematically compared. As a result, 1‐fluoro‐2‐nitro‐4‐(trifluoromethyl)benzene was selected since the derivatization effectively shifted the absorption wavelength to the visible region (400–450 nm), where most drug substances, impurities and even the derivatization reagent absorb very weakly. Due to the redshift effect, interference was minimized and adequately low limits of quantitation were reached (0.24–0.80 nmol/mL). Moreover, the derivatization reaction was readily carried out in dimethyl sulfoxide at room temperature for 1 h using N ,N‐diisopropylethylamine as catalyst to achieve the highest yield. Without any pre‐treatment, the derivatives were analyzed by high‐performance liquid chromatography with diode array detection. The high stability of the derivatives within 24 h at room temperature (RSD<1.04%) further facilitated the simultaneous preparation and consecutive analysis of quantities of samples. Finally, the proposed method was successfully applied for residue determination of eight aliphatic amines simultaneously in eight drug substance samples. This study could be helpful for the routine analysis and residue control of aliphatic amines in drug substances. |
