Abstract
Objective: Sitagliptin phosphate and metformin hydrochloride tablet is an FDA approved combination product for the treatment of diabetes mellitus type 2. There are no reported evidence for estimation of undesired (S)-sitagliptin in a combination product. The objective of this study was to develop a high sensitive liquid chromatography method for the determination of (S)-enantiomer of sitagliptin phosphate in a fixed dose combination formula of metformin and sitagliptin.
 Methods: The proposed novel high-performance liquid chromatography (HPLC) method uses programmed gradient elution of a mixture of ethanol-diethylamine(DEA) 100:0.1 (v/v) as mobile phase-A and a mixture of methanol-water 60:40 (v/v) as mobile phase-B. The chromatographic conditions were designed to nullify the metformin interference and in which sitagliptin enantiomers elute first and followed by metformin. A satisfactory resolution (≥2.5) between (S)-sitagliptin and active form (R)-sitagliptin was achieved with gradient elution on Chiralpak IA column (5μm, 4 × 250 mm) at a flow rate of 0.5 ml/min and the detector wavelength set at 265 nm. The injection volume set as 10 µl. The developed method has been validated as per the International Conference on Harmonisation (ICH) guidelines.
 Results: The proposed HPLC method for determination of (S)-sitagliptin, showed good linearity in the concentration range of 0.5 µg/ml to 13.6 µg/ml and capable to quantify accurately up to the lowest level (LOQ) of 0.017%. The validated method was successfully applied to quantify the (S)-sitagliptin for different marketed formulations of sitagliptin with metformin and sitagliptin alone, and the corresponding recovery values were found to be in the range of 95.1% to 98.4%.
 Conclusion: The proposed validated HPLC method was found to be suitable for the quantitative determination of (S)-sitagliptin in the formulations of sitagliptin with metformin and sitagliptin alone.
Highlights
Sitagliptin phosphate (SIT) is chemically 7-[(3R)-3-amino-1-oxo-4(2,4,5 trifluorophenyl) butyl]-5,6,7,8-tetrahydo-3-(trifluoromethyl)1,2,4-Triazolo [4,3-a] pyrazine phosphate (1:1) monohydrate
It should be confirmed that the eutomer is present in the required dose while the distomer level should be analyzed as an impurity, as prescribed in the guidelines imposed by the International Conference on Harmonization (ICH), more precisely in guideline Q6A [5]
The system used for method development and validation study was Agilent high-performance liquid chromatography (HPLC) 1200 series (Agilent technologies, Germany) with Ezchrom elite software equipped with G1322A degasser, G1311A quaternary pump, G1315C auto-injector, G16A column oven and G1315C DAD detector
Summary
Sitagliptin phosphate (SIT) is chemically 7-[(3R)-3-amino-1-oxo-4(2,4,5 trifluorophenyl) butyl]-5,6,7,8-tetrahydo-3-(trifluoromethyl)1,2,4-Triazolo [4,3-a] pyrazine phosphate (1:1) monohydrate (fig. 1). Literature survey reveals that there are analytical methods available for determination of (S)-enantiomer of sitagliptin in bulk drug and formulation samples of sitagliptin phosphate using chiral stationary phases by HPLC [6,7]. The reported chiral chromatographic methods were not suitable for estimation of (S)enantiomer of sitagliptin in combination drug product of sitagliptin and metformin. The aim of the present article describes the quantitative determination of (S)-enantiomer of sitagliptin phosphate in a combination dosage of SIT and MET by using reverse phase chromatography. In continuation of our research work for determination of impurities in pharmaceutical dosage forms [22,23], the present communication forms the first report of a simple, sensitive and reproducible method for determination of (S)-enantiomer of sitagliptin phosphate in combination product of SIT and MET
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