Abstract
Abstract Background Impurity profiling is now receiving critical attention from regulatoryauthorities. For trace level quantification of potential genotoxic impurities(PGIs), conventional analytical techniques like high-performance liquidchromatography (HPLC) and gas chromatography (GC) are inadequate; consequently,there is a great need to apply hyphenated analytical techniques to developsensitive analytical methods for the analysis of pharmaceuticals. Methods A selective and sensitive liquid chromatography-tandem mass spectrometry(LC-MS/MS) method was developed for the simultaneous determination of(4-sulfamoylphenyl)hydrazine hydrochloride (SHH) and(4-methyl-acetophenone)para-sulfonamide phenylhydrazine hydrochloride(MAP) PGIs in celecoxib active pharmaceutical ingredient (API). The LC-MS/MSanalysis of SHH and MAP PGIs was done on Symmetry C18 (150 mm ×4.6 mm, 3.5 μm) analytical column, and the mobile phase used was5.0 mM ammonium acetate-acetonitrile in the ratio of 30:70(v/v). The flow rate used was 0.7 mL/min. Triplequadrupole mass detector coupled to positive electrospray ionization operated inmultiple reaction monitoring (MRM) mode was used for the quantification of SHH andMAP PGIs. The method was validated as per International Conference onHarmonization (ICH) guidelines and was able to quantitate both SHH and MAP PGIs at1.0 ppm with respect to 10 mg/mL of celecoxib. Results The proposed method was specific, linear, accurate, precise, and robust. Thecalibration curves show good linearity between the concentration range of 0.06 and7.5 ppm for both SHH and MAP PGIs. The correlation coefficient obtained was>0.9998 in each case. The method has very low limit of detection (LOD) andlimit of quantification (LOQ). The obtained LOD and LOQ values were 0.02 and0.06 ppm, respectively, for both SHH and MAP PGIs. For both the PGIs,excellent recoveries of 95.0% to 104.0% were obtained at a concentration range of0.06 to 3.0 ppm. The developed method was also applied to determine the SHHand MAP PGIs in three formulation batches of celecoxib. Conclusions The proposed method is simple and accurate and is a good quality control tool forthe simultaneous quantitative determination of SHH and MAP PGIs at very low levelsin celecoxib during its manufacturing.
Highlights
Impurity profiling is receiving critical attention from regulatory authorities
Celecoxib reduces the number of colon and rectum polyps in patients with familial adenomatous polyposis (Clemett and Goa 2000; Silverstein et al 2000). It is chemically named as 4-[5-(4-methylphenyl)-3-(trifluoromethyl) pyrazol-1-yl]benzene sulfonamide, and the chemical structure of celecoxib is shown in Figure 1. (4-Sulfamoylphenyl) hydrazine hydrochloride (SHH) and (4-methyl-acetophenone)para-sulfonamide phenylhydrazine hydrochloride (MAP) are the two important key intermediates used in the synthesis of celecoxib, which are identified as potential genotoxic impurities (PGIs) in finished pharmaceutical substances due to their electrophilic functional groups (Ashby and Tennant 1988; Muller et al 2006)
Several analytical methods have been used to determine celecoxib concentrations in human plasma with various analytical techniques such as highperformance liquid chromatography-UV (HPLC-UV), liquid chromatography-mass spectrometry (LC-MS), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) (Jalalizadeh et al 2004; Zarghi et al 2006; Emami et al 2006; Chow et al 2004; Stormer et al 2003; Abdel-Hamid et al 2001; Werner et al 2002; Bräutigam et al 2001), and few methods have been reported for the determination of impurities in celecoxib using high-performance liquid chromatography (HPLC) and LC-MS/MS (Satyanarayana et al 2004; Rao et al 2006; Jadhav and Shinqare 2005)
Summary
For trace level quantification of potential genotoxic impurities (PGIs), conventional analytical techniques like high-performance liquid chromatography (HPLC) and gas chromatography (GC) are inadequate; there is a great need to apply hyphenated analytical techniques to develop sensitive analytical methods for the analysis of pharmaceuticals. Impurity profiling is receiving critical attention from regulatory authorities. For accurate determination of PGIs at trace levels, the abovementioned techniques are inadequate; there is a great need to develop better analytical methods for the analysis of such PGIs in pharmaceutical industries. Various kinds of hyphenated chromatographic techniques and methodologies have been explored as useful approaches
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