Drug substances impurities

FIGURE 7 (a) Impurity profile of Intermediate produced by the new process. Peaks after 8 min were impurities that were not previously observed when the Intermediate was produced via the old process, (b) Chromatogram of the drug substance made from intermediate of poor quality. Peak at 22 min retention time is the drug substance Impurity at 36 min retention time was a new impurity and failed specifications. 

Eckers et al. used on-line coupled reversed-phase LC to a Q-TOF mass spectrometer, and have successfully identified trace imparities in cimetidine. In an earlier paper published by Haskins et al., they successfully identified four chromatographically unresolved reaction by-products in cimetidine, using LC-FTMS. Another example nsing fast LC coupled with a Q-TOF mass spectrometer was the identification of cimetidine-related drug substance impurities reported by Lee et al. The exact masses for six impurities were determined with an experimental error of less than 3.1 ppm. 

During the course of the manufacture of a pure drug substance, impurities may arise as follows ... 

Nicolas, E. C. Scholz,T. H. 1998. Active drug substance impurity profiling part II. LC/MS/MS fingerprinting. J. Pharm. Biomed. Anal., 16, 825-836. 

However, these titration methods can be used in early development when a reference standard is not available. Also, the spectrometric-based assay methods such as ultraviolet (UV) may be nonspecific because most of the drug substance impurities contain a similar chromophore as the parent molecule. If UV is used, UV absorption is measured at one or more wavelengths and the absorbance value is recorded for a particular concentration. Sandor Gorog has critically evaluated the difference between specific and nonspecific assay methods in the European and US Pharmacopoeias [23]. The difference between the mean and the accepted true value with a defined confidence interval should be reported in the acceptance criteria. 

E. C. Nicolas and T. H. Scholz, Active drug substance impurity profiling. Part I. LC/UV diode array spectral matching,/. Pharm. Biomed.Anal. 16 (1998),813-824. 

Many of the most important chemical questions in the pharmaceutical industry involve the analysis of complex mixtures. Identification of low-level metabolites and drug substance impurities usually requires high-performance liquid chromatography for the separation of these mixtures or isolation of a compound of interest from a sample matrix. In these analyses, the structural information obtainable for the low-level compounds is limited by the type of detection used. The coupling of HPLC and mass spectrometry has become routine and provides useful molecular weight and fragmentation information, but this is often not enough for complete structure elucidation. 

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