Quality-by-Design Approach for Chromatographic Analysis of Metformin, Empagliflozin and Linagliptin

Abstract

New analytical quality by design-oriented HPLC method with multiple response optimization (Derringer’s desirability function) was demonstrated for simultaneous analysis of three antidiabetic drugs (metformin hydrochloride/empagliflozin/linagliptin) in a fixed-dose combination. Central composite design was employed for systematic optimization of critical method parameters, namely, % organic phase (X1), aqueous phase pH (X2) and flow rate (X3) while resolution, capacity factor and theoretical plate number as critical analytical attributes. Effective chromatographic separation of title analytes was accomplished on Std. Discovery C18 column at 30°C with mobile phase comprising acetonitrile: phosphate buffer pH 5 (38:62% v/v), pumped at a flow rate of 1 mL/min by isocratic elution pattern and UV detection at 222 nm. The model is rectilinear in the range of 1.0–200, 0.2–40 and 0.1–20 μg/mL at retention times of 3.04, 3.93 and 5.99 min for metformin, empagliflozin and linagliptin, respectively. The method obeyed all validation parameters of ICH Q2(R1) guidelines. The proposed HPLC method was highly robust for method transfer, regulatory flexibility within design space and can be used for assay of pharmaceutical dosage forms comprising these analytes. The proposed method was applied for stability studies of drugs under various stress conditions.

New Validated Stability-Indicating Rp-HPLC Method for the Simultaneous Determination of Metformin Hydrochloride, Linagliptin and Empagliflozin in Bulk and Pharmaceutical Dosage Forms

“…The % of degradation was shown within the range of 12.9-2. 9 % at various stresses conditions and the % of degradation from a previous study was found within 7.76-0.13 % [29]. The proposed method was stability indicating as it is evidenced by clear separation of degradation peaks from analyte peaks in the chromatograms of forced degradation studies (fig.…”

“…about 10%-150% of the working concentration ranges of each drug, whereas in previously reported methods, the linearity of the calibration curve was ranged in 10%-100% [28][29][30] The very low measures of LOD and LOQ indicate better sensitivity of the proposed method for the analysis of metformin HCl, linagliptin, and empagliflozin [30][31]. The proposed method showed a remarkable outcome compared to a previous report with respect to low LOD and LOQ, particularly for metformin HCl [29]. The %RSD values of both method and intermediate precision were less than 2, which implies that the proposed method is precise.…”

“…As compared to previous literature reports; fast, sensitive, and costeffective stability-indicating analytical method was developed for the simultaneous estimation of metformin HCl, linagliptin, and empagliflozin [28,29]. The analytical method was developed and optimized to determine suitable chromatographic conditions for obtaining sharp and well-resolved peaks of metformin HCl, linagliptin, and empagliflozin with minimal tailing.…”

“…An extensive literature search revealed that several analytical methods were reported for the analysis of metformin HCl, linagliptin, empagliflozin, a combination of metformin and linagliptin, a combination of metformin and empagliflozin, and a combination of linagliptin and empagliflozin using Ultraviolet spectroscopy [13][14][15][16], reverse phase high-performance liquid chromatography (RP-HPLC) [17][18][19][20][21][22][23][24][25], and ultra-performance liquid chromatography (UPLC) [26,27]. However, only a few RP_HPLC methods were reported for the simultaneous determination of metformin HCl, linagliptin, and empagliflozin in their recently approved fixed dosage combinations [28][29][30] and thus, there is a need to develop rapid, sensitive, and cost-effective stability indicating RP-HPLC method for the simultaneous estimation of metformin HCl, linagliptin and empagliflozin in fixed dosage combinations. Hence, the present study was aimed to develop a simple, sensitive, rapid, accurate, and precise stability-indicating RP-HPLC method for the simultaneous determination of metformin HCl, linagliptin, and empagliflozin in their bulk and combined dosage forms.…”

Analytical quality by design based on design space in reversed-phase-high performance liquid chromatography analysis for simultaneous estimation of metformin, linagliptin and empagliflozin

“…Two analytical methods were reported to simultaneously determine the triple therapy MET, LIN and EMP using ultra high performance liquid chromatography (UPLC) [22] and thin-layer chromatography densitometric methods [23]. Another method was recently proposed by S. Gurrala et al ., where the study used the analytical Quality by Design (AQbD) paradigm and method operable design region (MODR) in optimization of a high performance liquid chromatography (HPLC) method for the simultaneous determination of the MET, LIN and EMP [24]. However, the article included many downsides that may have affected the validity and integrity of the applied AQbD and MODR procedures, e.g.…”