Abstract

During forced degradation, the intrinsic stability of active pharmaceutical ingredients (APIs) could be determined and possible impurities that would occur during the shelf life of the drug substance or the drug product could be estimated. Vildagliptin belongs to relatively new oral antidiabetic drugs named gliptins, inhibiting dipeptidyl peptidase 4 (DPP-4) and prolonging the activities of the endogenous incretin hormones. At the same time, some gliptins were shown as prone to degradation under specific pH and temperature conditions, as well as in the presence of some reactive excipients. Thus, forced degradation of vildagliptin was performed at high temperature in extreme pH and oxidative conditions. Then, selective LC-UV was used for quantitative determination of non-degraded vildagliptin in the presence of its degradation products and for degradation kinetics. Finally, identification of degradation products of vildagliptin was performed using an UHPLC-DAD-MS with positive ESI. Stability of vildagliptin was also examined in the presence of pharmaceutical excipients, using mid-IR and NIR with principal component analysis (PCA). At 70 °C almost complete disintegration of vildagliptin occurred in acidic, basic, and oxidative media. What is more, high degradation of vildagliptin following the pseudo first-order kinetics was observed at room temperature with calculated k values 4.76 × 10−4 s−1, 3.11 × 10−4 s−1, and 1.73 × 10−4 s−1 for oxidative, basic and acidic conditions, respectively. Next, new degradation products of vildagliptin were detected using UHPLC-DAD-MS and their molecular structures were proposed. Three degradants were formed under basic and acidic conditions, and were identified as [(3-hydroxytricyclo- [3.3.1.13,7]decan-1-yl)amino]acetic acid, 1-{[(3-hydroxytricyclo[3.3.1.13,7]decan-1-yl)amino]acetyl}-pyrrolidine-2-carboxylic acid and its O-methyl ester. The fourth degradant was formed in basic, acidic, and oxidative conditions, and was identified as 1-{[(3-hydroxytricyclo[3.3.1.13,7]-decan-1-yl)amino]acetyl}pyrrolidine-2-carboxamide. When stability of vildagliptin was examined in the presence of four excipients under high temperature and humidity, a visible impact of lactose, mannitol, magnesium stearate, and polyvinylpirrolidone was observed, affecting-NH- and CO groups of the drug. The obtained results (kinetic parameters, interactions with excipients) may serve pharmaceutical industry to prevent chemical changes in final pharmaceutical products containing vildagliptin. Other results (e.g., identification of new degradation products) may serve as a starting point for qualifying new degradants of vildagliptin as it is related to substances in pharmacopoeias.

Highlights

  • Gliptins constitute a class of drugs increasingly used for the treatment of type 2 diabetes mellitus, inhibiting dipeptidyl peptidase 4 (DPP4), the enzyme that inactivates the incretin hormones such as glucagon-like peptide 1 (GLP1) and glucose dependent insulinotropic polypeptide (GIP)

  • The chromatograms showed that the peaks of vildagliptin were free from interferences of these from degradation products

  • The results presented here complemented the current knowledge about chemical stability of important antidiabetic drug vildagliptin

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Summary

Introduction

Gliptins constitute a class of drugs increasingly used for the treatment of type 2 diabetes mellitus, inhibiting dipeptidyl peptidase 4 (DPP4), the enzyme that inactivates the incretin hormones such as glucagon-like peptide 1 (GLP1) and glucose dependent insulinotropic polypeptide (GIP). GLP1 and GIP serve as important prandial stimulators of insulin secretion and regulators of blood glucose concentration. Inhibition of DPP4 by gliptins prolongs the activities of endogenous GLP1 and GIP, decreasing the elevated blood glucose in diabetic patients [1]. Vildagliptin is a substratemimicking inhibitor containing cyanopyrrolidine motif [2]. It is rapidly absorbed and quickly cleared from plasma, and required to be administered twice daily as compared to once daily dosing for some other gliptins [3].

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