Abstract
A stability-indicating LC method was developed for quantification of linagliptin (LGT) and three synthetic impurities. The method utilizes a Thermo Scientific® RP-8 column (100 mm × 4.6 mm; 5 μm) with the PDA detector for quantitation of impurities. A mixture of 0.1% formic acid with pH 3.5 (A) and acetonitrile (B) was used as the mobile phase at a flow rate of 0.6 mL·min−1 with gradient elution. The percentage of mobile phase B increases from 30% to 70% over 5 min and decreases from 70% to 30% between 5 and 8 min. The method was validated according to International Council for Harmonization (ICH) guidelines. The LOD values obtained were 0.0171 μg·mL−1 and 0.015 μg·mL−1 for LGT and impurities, respectively. The LOQ values were 0.06 μg·mL−1 for LGT and impurities. In all cases, the correlation coefficients of LGT and impurities were >0.999, showing the linearity of the method. The % recovery of the LGT and added impurity were in the range of 92.92–99.79%. The precision of the method showed values less than 1.47% for LGT and less than 4.63% for impurities. The robustness was also demonstrated by small modifications in the chromatographic conditions. The selectivity was evidenced because the degradation products formed in stress conditions did not interfere in the determination of LGT and impurities. Toxicity prediction studies suggested toxicity potential of the impurities, which was confirmed using biological safety studies in vitro.
Highlights
Diabetes mellitus is a chronic, nontransmissible metabolic disease that affects approximately 422 million individuals worldwide, with a projected doubling over the 20 years according to the World Health Organization [1]
The type 2 mellitus diabetes is more common and is more likely to increase in the population. is disease is characterized by insulin secretion disorder, insulin resistance in target tissues, or receptor desensitization of insulin [2]
Linagliptin (LGT) is an orally active and competitive DPP-4 enzyme inhibitor used to treat type 2 diabetics which failed to achieve glycemic control with metformin alone [3]. e drug is administered as a single drug once daily as a 5 mg dose in adults and/or in combination with metformin or empagliflozin [4, 5]. e drug is approved in the US, Europe, Japan, Brazil, and other countries [6]
Summary
Diabetes mellitus is a chronic, nontransmissible metabolic disease that affects approximately 422 million individuals worldwide, with a projected doubling over the 20 years according to the World Health Organization [1]. E literature reviewed presents a series of studies for quantification of the drug LGT in biological fluids [7,8,9] and in pharmaceutical forms [10,11,12,13,14] and characterization of synthetic impurities [15, 16]; no studies have been described to quantify the drug in the presence of its main synthetic impurities. The toxicity of LGT and its impurities was evaluated against different software in order to predict whether these molecules present some risk of causing a mutagenic effect to biological cells. The toxicity of LGT and its impurities was evaluated against different software in order to predict whether these molecules present some risk of causing a mutagenic effect to biological cells. ese results may assist in understanding the mechanisms of possible toxic effects caused by these molecules
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